Corneal Ulcer

Corneal Ulcer

Synonyms and Related Keywords

Bacterial keratitis, Fungal keratitis, Acanthamoeba keratitis, Herpes simplex keratitis, corneal infection, open sore on the cornea, contact lenses, contact lens wearers, ulcerative keratitis




What is corneal ulcer ?

A corneal ulcer is an erosion or open sore in the outer layer of the cornea the clear structure overlying the iris (which is the colored part of your eye). It is common associated with infection by a bacterium, virus, fungus, or parasite.The corneal ulcer, or ulcerative keratitis, is an inflammatory or more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans particularly in the tropics and the agrarian societies. In developing countries, corneal ulcer is frequently the cause of great morbidity as well as economic loss to the person and family. Children afflicted by Vitamin A deficiency are at high risk for corneal ulcer and may become blind in both eyes, which may persist lifelong, causing tremendous & avoidable loss to the person and the society.



Corneal anatomy of the human

The cornea is a transparent structure that is part of the outer layer of the eye. It refracts light and protects the contents of the eye. The corneal thickness ranges from 450 to 610 micrometres and on an average 550 µm. thick in caucasian eyes. In Indian eyes, the average thickness is slightly less at 510 µm. The trigeminal nerve supplies the cornea via the long ciliary nerves. There are pain receptors in the outer layers and pressure receptors are deeper.
Transparency is achieved through a lack of blood vessels, pigmentation, and keratin, and through tight layered organization of the collagen fibers. The collagen fibers cross the full diameter of the cornea in a strictly parallel fashion and allow 99 percent of the light to pass through without scattering.
There are five layers in the human cornea, from outer to inner:
Epithelium
Bowman's layer
Stroma
Descemet's membrane
Endothelium
The outer layer is the epithelium, which is 25 to 40 µm micrometers and five to seven cell layers thick. The epithelium holds the tear film in place and also prevents water from invading the cornea and disrupting the collagen fibers. This prevents corneal edema, which gives it a cloudy appearance. It is also a barrier to infectious agents. The epithelium sticks to the basement membrane, which also separates the epithelium from the stroma. The corneal stroma comprises 90 percent of the thickness of the cornea. It contains the collagen fibers organized into lamellae. The lamellae are in sheets which separate easily. Posterior to the stroma is Descemet's membrane, which is a basement membrane for the corneal endothelium. The endothelium is a single cell layer that separates the cornea from the aqueous humor.

Most Commmon cause of corneal ulcers are caused by infections.

Corneal ulcers are most commonly caused by an infection with bacteria, viruses, fungi or amoebae. Other causes are abrasions (scratches) or foreign bodies, inadequate eyelid closure, severely dry eyes, severe allergic eye disease, and various inflammatory disorders.
Contact lens wear, especially soft contact lenses worn overnight, may cause a corneal ulcer. Herpes simplex keratitis is a serious viral infection. It may cause repeated attacks that are triggered by stress, exposure to sunlight, or any condition that impairs the immune system. Bacterial infections cause corneal ulcers and are common in people who wear contact lenses. Fungal keratitis can occur after a corneal injury involving plant material, or in immunosuppressed people. Acanthamoeba keratitis occurs in contact lens users, especially those who attempt to make their own homemade cleaning solutions.Fungal infections can cause corneal ulcers and may develop with improper care of contact lenses or the overuse of eyedrops that contain steroids.
Viral infections are also possible causes of corneal ulcers. Such viruses include the herpes simplex virus (the virus that causes cold sores) or the varicella virus (the virus that causes chickenpox and shingles).
Tiny tears to the corneal surface may become infected and lead to corneal ulcers. These tears can come from direct trauma by scratches or metallic or glass particles striking the cornea. Such injuries damage the corneal surface and make it easier for bacteria to invade and cause a corneal ulcer.
Disorders that cause dry eyes can leave your eye without the germ-fighting protection of tears and cause ulcers.
Disorders that affect the eyelid and prevent your eye from closing completely, such as Bell's palsy, can dry your cornea and make it more vulnerable to ulcers.
Any condition which causes loss of sensation of the corneal surface may increase the risk of corneal ulceration.
Chemical burns or other caustic (damaging) solution splashes can injure the cornea and lead to corneal ulceration.
People who wear contact lenses are at an increased risk of corneal ulcers. The risk of corneal ulcerations increases tenfold when using extended-wear soft contact lenses. Extended-wear contact lenses refer to those contact lenses that are worn for several days without removing them at night. Contact lenses may damage your cornea in many ways:
Scratches on the edge of your contact lens can scrape the cornea's surface and make it more vulnerable to bacterial infections.
Similarly, tiny particles of dirt trapped underneath the contact lens can scratch the cornea.
Bacteria may be on the improperly cleaned lens and get trapped on the undersurface of the lens. If your lenses are left in your eyes for long periods of time, these bacteria can multiply and cause damage to the cornea.
Wearing lenses for extended periods of time can also block oxygen to the cornea, making it more susceptible to infections.
Risk factors are dry eyes, severe allergies, history of inflammatory disorders, contact lens wear, immunosuppression, trauma, and generalized infection.

Corneal Ulcer Symptoms

Eye pain
Impaired vision, Blurry vision
Eye redness( red eye)
White patch on the cornea
Sensitivity to light (photophobia)
Watery eyes, Tearing
Eye burning, itching and discharge
Feeling that something is in your eye
Pus or thick discharge draining from your eye
Pain when looking at bright lights
Swollen eyelids
A white or gray round spot on the cornea that is visible with the naked eye if the ulcer is large

Diagnosis of Corneal ulcer

Because corneal ulcers are a serious problem, you should see your ophthalmologist (a medical doctor who specializes in eye care and surgery).
Your ophthalmologist will be able to detect if you have an ulcer by using a special eye microscope, known as a slit lamp. To make the ulcer easier to see, he or she will put a drop containing the dye fluorescein into your eye.
If your ophthalmologist thinks that an infection is responsible for the ulcer, he or she may then get samples of the ulcer to send to the laboratory for identification.
Visual acuity
Tear test
Slit-lamp examination
Pupillary reflex response
Keratometry (measurement of the cornea)
Scraping the ulcer for analysis or culture
Fluorescein stain of the cornea
Blood tests to check for inflammatory disorders may also be needed.
Diagnosis is done by direct observation under magnified view of slit lamp revealing the ulcer on the cornea. The use of fluorescein stain, which is taken up by exposed corneal stroma and appears green, helps in defining the margins of the corneal ulcer, and can reveal additional details of the surrounding epithelium. Herpes simplex ulcers show a typical dendritic pattern of staining. Rose-Bengal dye is also used for supra-vital staining purposes, but it may be very irritating to the eyes. In descemetoceles, the Descemet's membrane will bulge forward and after staining will appear as a dark circle with a green boundary, because it does not absorb the stain. Doing a corneal scraping and examining under the microscope with stains like Gram's and KOH preparation may reveal the bacteria and fungi respectively. Microbiological culture tests may be necessary to isolate the causative organisms for some cases. Other tests that may be necessary include a Schirmer's test for keratoconjunctivitis sicca and an analysis of facial nerve function for facial nerve paralysis.

Treatment

Proper diagnosis is essential for optimal treatment. Bacterial corneal ulcer require intensive fortified antibiotic therapy to treat the infection. Fungal corneal ulcers require intensive application of topical anti-fungal agents. Viral corneal ulceration caused by herpes virus may antivirals like topical acyclovir oint instilled at least five times a day. Alongside, supportive therapy like pain medications are given, including topical cycloplegics like atropine or homatropine to dilate the pupil and thereby stop spasms of the ciliary muscle. Superficial ulcers may heal in less than a week. Deep ulcers and descemetoceles may require conjunctival grafts or conjunctival flaps, soft contact lenses, or corneal transplant. Proper nutrition, including protein intake and Vitamin C are usually advised. In cases of Keratomalacia, where the corneal ulceration is due to a deficiency of Vitamin A, supplementation of the Vitamin A by oral or intramuscular route is given. Drugs that are usually contraindicated in corneal ulcer are topical corticosteroids and anesthetics - these should not be used on any type of corneal ulcer because they prevent healing, may lead to superinfection with fungi and other bacteria and will often make the condition much worse.
So can conclude that how to treatment corneal ulcer
Self-Care at Home

If you wear contact lenses, remove them immediately.
Apply cool compresses to the affected eye.
Do not touch or rub your eye with your fingers.
Limit spread of infection by washing your hands often and drying them with a clean towel.
Take over-the-counter pain medications, such as acetaminophen or ibuprofen.

Medical Treatment
Your ophthalmologist will remove your contact lenses if you are wearing them.
Your ophthalmologist will generally not place a patch over your eye if he or she suspects that you have a bacterial infection. Patching creates a warm dark environment that allows bacterial growth.
Hospitalization may be required if the ulcer is severe

Prognosis of corneal ulcer

Untreated, a corneal ulcer or infection can permanently damage the cornea. Untreated corneal ulcers may also perforate the eye (cause holes), resulting in spread of the infection inside, increasing the risk of permanent visual problems.

Possible Complications of corneal ulcer

Corneal scarring
Severe vision loss
Loss of the eye

Prevention of corneal ulcer

Prompt, early attention by an ophthalmologist for an eye infection may prevent the condition from worsening to the point of ulceration. Wash hands and pay rigorous attention to cleanliness while handling contact lenses, and avoid wearing contact lenses overnight.

Hormones

Hypothalamic and Hypophyseal Hormones

The endocrine system is controlled by the brain. Nerve cells of the hypothalamus
synthesize and release messenger substances that regulate adenohypophyseal
(AH) hormone release or are themselves secreted into the body as
hormones. The latter comprise the socalled neurohypophyseal (NH) hormones.
The axonal processes of hypothalamic neurons project to the neurohypophysis,
where they store the nonapeptides vasopressin (= antidiuretic hormone,
ADH) and oxytocin and release them on demand into the blood. Therapeutically
(ADH, oxytocin), these peptide hormones are given parenterally
or via the nasal mucosa. The hypothalamic releasing hormones
are peptides. They reach their target cells in the AH lobe by way of a
portal vascular route consisting of two serially connected capillary beds. The
first of these lies in the hypophyseal stalk, the second corresponds to the
capillary bed of the AH lobe. Here, the hypothalamic hormones diffuse from
the blood to their target cells, whose activity they control. Hormones released
from the AH cells enter the blood, in which they are distributed to peripheral
organs.
Nomenclature of releasing hormones:
RH–releasing hormone; RIH—release inhibiting hormone.
GnRH: gonadotropin-RH = gonadorelin stimulates the release of FSH
(follicle-stimulating hormone) and LH (luteinizing hormone).
TRH: thyrotropin-RH (protirelin) stimulates the release of TSH (thyroid
stimulating hormone = thyrotropin). CRH: corticotropin-RH stimulates
the release of ACTH (adrenocorticotropic hormone = corticotropin).
GRH: growth hormone-RH (somatocrinin) stimulates the release of GH
(growth hormone = STH, somatotropic hormone). GRIH somatostatin inhibits
release of STH (and also other peptide hormones including insulin, glucagon,
and gastrin). PRH: prolactin-RH remains to be
characterized or established. Both TRH and vasoactive intestinal peptide (VIP)
are implicated. PRIH inhibits the release of prolactin
and could be identical with dopamine. Hypothalamic releasing hormones
are mostly administered (parenterally) for diagnostic reasons to test AH function.
Therapeutic control of AH cells. GnRH is used in hypothalamic infertility
in women to stimulate FSH and LH secretion and to induce ovulation. For this
purpose, it is necessary to mimic the physiologic intermittent “pulsatile” release
(approx. every 90 min) by means of a programmed infusion pump.
Gonadorelin superagonists are GnRH analogues that bind with very
high avidity to GnRH receptors of AH cells. As a result of the nonphysiologic
uninterrupted receptor stimulation, initial augmentation of FSH and LH output
is followed by a prolonged decrease. Buserelin, leuprorelin, goserelin, and triptorelin
are used in patients with prostatic carcinoma to reduce production of
testosterone, which promotes tumor growth. Testosterone levels fall as much
as after extirpation of the testes. The dopamine D2 agonists bromocriptine
and cabergoline inhibit prolactin-releasing AH cells (indications:
suppression of lactation, prolactin-producing tumors). Excessive,
but not normal, growth hormone release can also be inhibited (indication:
acromegaly).
Octreotide is a somatostatin analogue; it is used in the treatment of
somatostatin-secreting pituitary tumors.

Thyroid Hormone Therapy
Thyroid hormones accelerate metabolism.Their release is regulated by
the hypophyseal glycoprotein TSH,whose release, in turn, is controlled by
the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of
thyroid hormones rises; by means of this negative feedback mechanism, hormone
production is “automatically” adjusted to demand.
The thyroid releases predominantly thyroxine (T4). However, the active form
appears to be triiodothyronine (T3); T4 is converted in part to T3, receptor affinity
in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly
and has a shorter duration than does that of T4. Plasma elimination t1/2 for T4
is about 7 d; that for T3, however, is only 1.5 d. Conversion of T4 to T3 releases iodide;
150 μg T4 contains 100 μg of iodine. For therapeutic purposes, T4 is chosen,
although T3 is the active form and better absorbed from the gut. However,
with T4 administration, more constant blood levels can be achieved because
degradation of T4 is so slow. Since absorption of T4 is maximal from an empty
stomach, T4 is taken about 1/2 h before breakfast.
Replacement therapy of hypothyroidism. Whether primary, i.e., caused
by thyroid disease, or secondary, i.e., resulting from TSH deficiency, hypothyroidism
is treated by oral administration of T4. Since too rapid activation of
metabolism entails the hazard of cardiac overload (angina pectoris, myocardial
infarction), therapy is usually started with low doses and gradually increased.
The final maintenance dose required to restore a euthyroid state depends
on individual needs (approx.150 μg/d).

Thyroid suppression therapy of euthyroid goiter. The cause of goiter
(struma) is usually a dietary deficiencyof iodine. Due to an increased
TSH action, the thyroid is activated to raise utilization of the little iodine available
to a level at which hypothyroidism is averted. Therefore, the thyroid increases
in size. In addition, intrathyroid depletion of iodine stimulates growth.
Because of the negative feedback regulation of thyroid function, thyroid
activation can be inhibited by administration of T4 doses equivalent to the endogenous
daily output (approx. 150 μg/d). Deprived of stimulation, the
inactive thyroid regresses in size.If a euthyroid goiter has not persisted
for too long, increasing iodine supply (potassium iodide tablets) can also be
effective in reversing overgrowth of the gland.
In older patients with goiter due to iodine deficiency there is a risk of provoking
hyperthyroidism by increasing iodine intake : During chronic
maximal stimulation, thyroid follicles can become independent of TSH stimulation
(“autonomic tissue”). If the iodine supply is increased, thyroid hormone
production increases while TSH secretion decreases due to feedback inhibition.
The activity of autonomic tissue, however, persists at a high level; thyroxine
is released in excess, resulting in iodine-induced hyperthyroidism.
Iodized salt prophylaxis. Goiter is endemic in regions where soils are deficient
in iodine. Use of iodized table salt allows iodine requirements (150–
300 μg/d) to be met and effectively prevents goiter.
is treated by oral administration of T4. Since too rapid activation of
metabolism entails the hazard of cardiac overload (angina pectoris, myocardial
infarction), therapy is usually started with low doses and gradually increased.
The final maintenance dose required to restore a euthyroid state depends
on individual needs (approx. 150 μg/d).

Hyperthyroidism and Antithyroid Drugs
Thyroid overactivity in Graves’ disease results from formation of IgG antibodies
that bind to and activate TSH receptors. Consequently, there is overproduction
of hormone with cessation of TSH secretion. Graves’ disease can abate
spontaneously after 1–2 y. Therefore,initial therapy consists of reversible
suppression of thyroid activity by means of antithyroid drugs. In other
forms of hyperthyroidism, such as hormone-producing (morphologically benign)
thyroid adenoma, the preferred therapeutic method is removal of tissue,
either by surgery or administration of 131iodine in sufficient dosage. Radioiodine
is taken up into thyroid cells and destroys tissue within a sphere of a few
millimeters by emitting !-(electron) particles during its radioactive decay.
Concerning iodine-induced hyperthyroidism. Antithyroid drugs inhibit thyroid
function. Release of thyroid hormone is preceded by a chain of events. A
membrane transporter actively accumulates iodide in thyroid cells; this is
followed by oxidation to iodine, iodination of tyrosine residues in thyroglobulin,
conjugation of two diiodotyrosine groups, and formation of T4 and T3
moieties. These reactions are catalyzed by thyroid peroxidase, which is localized
in the apical border of the follicular cell membrane. T4-containing thyroglobulin
is stored inside the thyroid follicles in the form of thyrocolloid. Upon
endocytotic uptake, colloid undergoes lysosomal enzymatic hydrolysis, enabling
thyroid hormone to be released as required. A “thyrostatic” effect can result
from inhibition of synthesis or release. When synthesis is arrested, the
antithyroid effect develops after a delay, as stored colloid continues to be utilized.
Antithyroid drugs for long-term therapy. Thiourea derivatives
(thioureylenes, thioamides) inhibit peroxidase and, hence, hormone synthesis.
In order to restore a euthyroid state, two therapeutic principles can be
applied in Graves’ disease: a) monotherapy with a thioamide with gradual dose
reduction as the disease abates) administration of high doses of a thioamide
with concurrent administration of thyroxine to offset diminished hormone
synthesis. Adverse effects of thioamides are rare; however, the possibility
of agranulocytosis has to be kept in mind.
Perchlorate, given orally as the sodium salt, inhibits the iodide pump. Adverse
reactions include aplastic anemia. Compared with thioamides, its therapeutic
importance is low but it is used as an adjunct in scintigraphic imaging of
bone by means of technetate when accumulation in the thyroid gland has
to be blocked.

Short-term thyroid suppression.
Iodine in high dosage (>6000 μg/d) exerts a transient “thyrostatic” effect in
hyperthyroid, but usually not in euthyroid, individuals. Since release is also
blocked, the effect develops more rapidly than does that of thioamides.
Clinical applications include: preoperative suppression of thyroid secretion
according to Plummer with Lugol’s solution (5% iodine + 10% potassium iodide,
50–100 mg iodine/d for a maximum of 10 d). In thyrotoxic crisis, Lugol’s solution
is given together with thioamides and !-blockers. Adverse effects: allergies;
contraindications: iodine-induced thyrotoxicosis.
Lithium ions inhibit thyroxine release. Lithium salts can be used instead
of iodine for rapid thyroid suppression in iodine-induced thyrotoxicosis. Regarding
administration of lithium in manic-depressive illness.

Glucocorticoid Therapy
I. Replacement therapy. The adrenal cortex (AC) produces the glucocorticoid
cortisol (hydrocortisone) and the mineralocorticoid aldosterone. Both steroid
hormones are vitally important in adaptation responses to stress situations,
such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal
ACTH, aldosterone secretion by angiotensin II in particular. In
AC failure (primary AC insuffiency: Addison’s disease), both cortisol and aldosterone
must be replaced; when ACTH production is deficient (secondary AC insufficiency),
cortisol alone needs to be replaced. Cortisol is effective when given
orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by
5- to 10-fold. Aldosterone is poorly effective via the oral route; instead,
the mineralocorticoid fludrocortisone (0.1 mg/d) is given.
II. Pharmacodynamic therapy
with glucocorticoids . In unphysiologically high concentrations, cortisol or
other glucocorticoids suppress all phases(exudation, proliferation, scar formation)
of the inflammatory reaction, i.e.,the organism’s defensive measures
against foreign or noxious matter. This effect is mediated by multiple components,
all of which involve alterations in gene transcription. Glucocorticoids
inhibit the expression of genes encoding for proinflammatory proteins
(phospholipase-A2, cyclooxygenase 2,IL-2-receptor). The expression of these
genes is stimulated by the transcription factor NF!B. Binding to the glucocorticoid
receptor complex prevents translocation af NF!B to the nucleus. Conversely,
glucocorticoids augment the expression of some anti-inflammatory proteins,
e.g., lipocortin, which in turn inhibits phospholipase A2. Consequently,
release of arachidonic acid is diminished, as is the formation of inflammatory
mediators of the prostaglandin and leukotriene series . At very high
dosage, nongenomic effects may also contribute.
Desired effects. As anti-allergics, immunosuppressants, or anti-inflammatory
drugs, glucocorticoids display excellent efficacy against “undesired” inflammatory
reactions. Unwanted effects. With short-term
use, glucocorticoids are practically free of adverse effects, even at the highest
dosage. Long-term use is likely to cause changes mimicking the signs of
Cushing’s syndrome (endogenous overproduction of cortisol). Sequelae of
the anti-inflammatory action: lowered resistance to infection, delayed wound
healing, impaired healing of peptic ulcers. Sequelae of exaggerated glucocorticoid
action: a) increased gluconeogenesis and release of glucose; insulin-dependent
conversion of glucose to triglycerides(adiposity mainly noticeable in
the face, neck, and trunk); “steroid-diabetes” if insulin release is insufficient;
b) increased protein catabolism with atrophy of skeletal musculature (thin
extremities), osteoporosis, growth retardation in infants, skin atrophy. Sequelae
of the intrinsically weak, but now manifest, mineralocorticoid action
of cortisol: salt and fluid retention, hypertension, edema; KCl loss with danger
of hypokalemia. Measures for Attenuating or Preventing
Drug-Induced Cushing’s Syndrome a) Use of cortisol derivatives with less
(e.g., prednisolone) or negligible mineralocorticoid activity (e.g., triamcinolone,
dexamethasone). Glucocorticoid activity of these congeners is more pronounced.
Glucorticoid, anti-inflammatory and feedback inhibitory actions
on the hypophysis are correlated. An exclusively anti-inflammatory congener
does not exist. The “glucocorticoid” related Cushingoid symptoms
cannot be avoided. The table lists relative activity (potency) with reference to
cortisol, whose mineralo- and glucocorticoid activities are assigned a value of
1.0. All listed glucocorticoids are effective orally.

b) Local application. Typical adverse effects, however, also occur locally, e.g.,
skin atrophy or mucosal colonization with candidal fungi. To minimize
systemic absorption after inhalation, derivatives should be used that have a
high rate of presystemic elimination, such as beclomethasone dipropionate,
flunisolide, budesonide, or fluticasone propionate .
b) Lowest dosage possible. For longterm medication, a just sufficient dose
should be given. However, in attempting to lower the dose to the minimal effective
level, it is necessary to take into account that administration of exogenous
glucocorticoids will suppress production of endogenous cortisol due to
activation of an inhibitory feedback mechanism. In this manner, a very low
dose could be “buffered,” so that unphysiologically high glucocorticoid activity
and the anti-inflammatory effect are both prevented.
Effect of glucocorticoid administration on adrenocortical cortisol production
(A). Release of cortisol depends on stimulation by hypophyseal ACTH,
which in turn is controlled by hypothalamic corticotropin-releasing hormone
(CRH). In both the hypophysis and hypothalamus there are cortisol receptors
through which cortisol can exert a feedback inhibition of ACTH or CRH release.
By means of these cortisol “sensors,” the regulatory centers can monitor whether
the actual blood level of the hormone corresponds to the “set-point.” If the
blood level exceeds the set-point, ACTH output is decreased and, thus, also the
cortisol production. In this way cortisol level is maintained within the required
range. The regulatory centers respond to synthetic glucocorticoids as they do
to cortisol. Administration of exogenous cortisol or any other glucocorticoid reduces
the amount of endogenous cortisol needed to maintain homeostasis. Release
of CRH and ACTH declines ("inhibition of higher centers by exogenous
glucocorticoid”) and, thus, cortisol secretion (“adrenocortical suppression”).
After weeks of exposure to unphysiologically high glucocorticoid doses, the
cortisol-producing portions of the adrenal cortex shrink (“adrenocortical
atrophy”). Aldosterone-synthesizing capacity, however, remains unaffected.
When glucocorticoid medication is suddenly withheld, the atrophic cortex is
unable to produce sufficient cortisol and a potentially life-threatening cortisol
deficiency may develop. Therefore, glucocorticoid therapy should always be
tapered off by gradual reduction of the dosage.
Regimens for prevention of adrenocortical atrophy. Cortisol secretion
is high in the early morning and low in the late evening (circadian
rhythm). This fact implies that the regulatory centers continue to release CRH
or ACTH in the face of high morning blood levels of cortisol; accordingly,
sensitivity to feedback inhibition must be low in the morning, whereas the opposite
holds true in the late evening. a) Circadian administration: The
daily dose of glucocorticoid is given in the morning. Endogenous cortisol production
will have already begun, the regulatory centers being relatively insensitive
to inhibition. In the early morning hours of the next day, CRF/-
ACTH release and adrenocortical stimulation will resume.

b) Alternate-day therapy: Twice the daily dose is given on alternate mornings.
On the “off” day, endogenous cortisol production is allowed to occur.
The disadvantage of either regimen is a recrudescence of disease symptoms
during the glucocorticoid-free interval.

Androgens, Anabolic Steroids, Antiandrogens

Androgens are masculinizing substances. The endogenous male gonadal hormone
is the steroid testosterone from the interstitial Leydig cells of the testis.
Testosterone secretion is stimulated by hypophyseal luteinizing hormone (LH),
whose release is controlled by hypothalamic GnRH (gonadorelin). Release
of both hormones is subject to feedback inhibition by circulating testosterone.
Reduction of testosterone to dihydrotestosterone occurs in most target
organs; the latter possesses higher affinity for androgen receptors. Rapid
intrahepatic degradation (plasma t1/2 ~ 15 min) yields androsterone among
other metabolites (17-ketosteroids) that are eliminated as conjugates in the
urine. Because of rapid hepatic metabolism, testosterone is unsuitable for oral
use. Although it is well absorbed, it undergoes virtually complete presystemic
elimination. Testosterone (T.) derivatives for
clinical use. T. esters for i.m. depot injection are T. propionate and T. heptanoate
(or enanthate). These are given in oily solution by deep intramuscular injection.
Upon diffusion of the ester from the depot, esterases quickly split off the
acyl residue, to yield free T. With increasing lipophilicity, esters will tend to
remain in the depot, and the duration of action therefore lengthens. A T. ester for
oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this
ester is absorbed into the lymph, enabling it to bypass the liver and enter, via
the thoracic duct, the general circulation. 17-a Methyltestosterone is effective
by the oral route due to its increased metabolic stability, but because of the
hepatotoxicity of C17-alkylated androgens (cholestasis, tumors) its use should
be avoided. Orally active mesterolone is 1!-methyl-dihydrotestosterone. Transdermal
delivery systems for T. are also available.
Indications. For hormone replacement in deficiency of endogenous T.
production and palliative treatment of breast cancer, T. esters for depot injection
are optimally suited. Secondary sex characteristics and libido are maintained;
however, fertility is not promoted. On the contrary, spermatogenesis
may be suppressed because of feedback inhibition of hypothalamohypophyseal
gonadotropin secretion. Stimulation of spermatogenesis
in gonadotropin (FSH, LH) deficiency can be achieved by injection of HMG
and HCG. HMG or human menopausal gonadotropin is obtained from the urine
of postmenopausal women and is rich in FSH activity. HCG, human chorionic
gonadotropin, from the urine of pregnant women, acts like LH.
Anabolics are testosterone derivatives (e.g., clostebol, metenolone, nandrolone,
stanozolol) that are used in debilitated patients, and misused by athletes,
because of their protein anabolic effect. They act via stimulation of androgen
receptors and, thus, also display androgenic actions (e.g., virilization in females,
suppression of spermatogenesis). The antiandrogen cyproterone
acts as a competitive antagonist of T. In addition, it has progestin activity
whereby it inhibits gonadotropin secretion. Indications: in men, inhibition
of sex drive in hypersexuality; prostatic cancer. In women: treatment
of virilization, with potential utilization of the gestagenic contraceptive effect.
Flutamide, an androgen receptor antagonist possessing a different chemical
structure, lacks progestin activity. Finasteride inhibits 5!-reductase,
the enzyme converting T. into dihydrotestosterone (DHT). Thus, the androgenic
stimulus is reduced in those tissues in which DHT is the active species (e.g.,
prostate). T.-dependent tissues or functions are not or hardly affected (e.g.,
skeletal muscle, negative feedback inhibition of gonadotropin secretion, and libido).
Finasteride can be used in benign prostate hyperplasia to shrink the gland
and, possibly, to improve micturition.

Follicular Growth and Ovulation, Estrogen and Progestin Production

Follicular maturation and ovulation, as well as the associated production of female
gonadal hormones, are controlled by the hypophyseal gonadotropins FSH
(follicle-stimulating hormone) and LH (luteinizing hormone). In the first half of
the menstrual cycle, FSH promotes growth and maturation of ovarian follicles
that respond with accelerating synthesis of estradiol. Estradiol stimulates
endometrial growth and increases the permeability of cervical mucus for
sperm cells. When the estradiol blood level approaches a predetermined setpoint,
FSH release is inhibited due to feedback action on the anterior hypophysis.
Since follicle growth and estrogen production are correlated, hypophysis
and hypothalamus can “monitor” the follicular phase of the ovarian cycle
through their estrogen receptors. Within hours after ovulation, the tertiary follicle
develops into the corpus luteum, which then also releases progesterone
in response to LH. The former initiates the secretory phase of the endometrial
cycle and lowers the permeability of cervical mucus. Nonruptured follicles
continue to release estradiol under the influence of FSH. After 2 wk, production
of progesterone and estradiol subsides, causing the secretory endometrial layer
to be shed (menstruation).The natural hormones are unsuitable
for oral application because they are subject to presystemic hepatic elimination.
Estradiol is converted via estrone to estriol; by conjugation, all three
can be rendered water soluble and amenable to renal excretion. The major
metabolite of progesterone is pregnandiol, which is also conjugated and eliminated
renally. Estrogen preparations. Depot preparations for i.m. injection are oily
solutions of esters of estradiol (3- or 17- OH group). The hydrophobicity of the
acyl moiety determines the rate of absorption, hence the duration of effect.
Released ester is hydrolyzed to yield free estradiol.
Orally used preparations. Ethinylestradiol (EE) is more stable metabolically,
passes largely unchanged through the liver after oral intake and mimics estradiol
at estrogen receptors. Mestranol itself is inactive; however, cleavage of
the C-3 methoxy group again yields EE. In oral contraceptives, one of the two
agents forms the estrogen component. (Sulfate-)conjugated estrogens
can be extracted from equine urine and are used for the prevention of postmenopausal
osteoporosis and in the therapy of climacteric complaints. Because
of their high polarity (sulfate, glucuronide), they would hardly appear
suitable for this route of administration. For transdermal delivery, an adhesive
patch is available that releases estradiol transcutaneously into the body.
Progestin preparations. Depot formulations for i.m. injection are 17-
!-hydroxyprogesterone caproate and medroxyprogesterone acetate. Preparations
for oral use are derivatives of 17!- ethinyltestosterone = ethisterone (e.g.,
norethisterone, dimethisterone, lynestrenol,desogestrel, gestoden), or of
17!-hydroxyprogesterone acetate (e.g.,chlormadinone acetate or cyproterone
acetate). These agents are mainly used as the progestin component in oral contraceptives.
Indications for estrogens and progestins include: hormonal contraception
, hormone replacement, as in postmenopausal women for prophylaxis
of osteoporosis; bleeding anomalies, menstrual complaints. Concerning
adverse effects, see p.

Estrogens with partial agonist activity (raloxifene, tamoxifene) are being
investigated as agents used to replace estrogen in postmenopausal osteoporosis
treatment, to lower plasma lipids, and as estrogen antagonists in
the prevention of breast cancer. Raloxifen—in contrast to tamoxifen—is an antagonist
at uterine estrogen receptors.

Oral Contraceptives

Inhibitors of ovulation. Negative feedback control of gonadotropin release
can be utilized to inhibit the ovarian cycle. Administration of exogenous estrogens
(ethinylestradiol or mestranol) during the first half of the cycle permits
FSH production to be suppressed (as it is by administration of progestins
alone). Due to the reduced FSH stimulation of tertiary follicles, maturation of
follicles and, hence, ovulation are prevented. In effect, the regulatory brain
centers are deceived, as it were, by the elevated estrogen blood level, which
signals normal follicular growth and a decreased requirement for FSH stimulation.
If estrogens alone are given during the first half of the cycle, endometrial
and cervical responses, as well as other functional changes, would occur in the
normal fashion. By adding a progestin during the second half of the cycle,
the secretory phase of the endometrium and associated effects can be elicited.
Discontinuance of hormone administration would be followed by
menstruation. The physiological time course of estrogen-
progesterone release is simulated in the so-called biphasic (sequential)
preparations. In monophasic preparations, estrogen and progestin
are taken concurrently. Early administration of progestin reinforces the inhibition
of CNS regulatory mechanisms, prevents both normal endometrial
growth and conditions for ovum implantation, and decreases penetrability
of cervical mucus for sperm cells. The two latter effects also act to prevent
conception. According to the staging of progestin administration, one distinguishes
(A): one-, two-, and three-stage preparations. In all cases, “withdrawalbleeding”
occurs when hormone intake is discontinued (if necessary, by substituting
dummy tablets). Unwanted effects: An increased incidence
of thrombosis and embolism is attributed to the estrogen component in
particular. Hypertension, fluid retention, cholestasis, benign liver tumors,
nausea, chest pain, etc. may occur. Apparently there is no increased overall
risk of malignant tumors. Minipill. Continuous low-dose administration
of progestin alone can prevent conception. Ovulations are not
suppressed regularly; the effect is then due to progestin-induced alterations in
cervical and endometrial function. Because of the need for constant intake at
the same time of day, a lower success rate, and relatively frequent bleeding
anomalies, these preparations are now rarely employed.
“Morning-after” pill. This refers to administration of a high dose of estrogen
and progestin, preferably within 12 to 24 h, but no later than 72 h after coitus.
Menstrual bleeding ensues, which prevents implantation of the fertilized
ovum (normally on the 7th day after fertilization). Similarly, implantation
can be inhibited by mifepristone, which is an antagonist at both progesterone
and glucocorticoid receptors and which also offers a noninvasive means of inducing
therapeutic abortion in early pregnancy.
Stimulation of ovulation. Gonadotropin secretion can be increased by
pulsatile delivery of GnRH. The estrogen antagonists clomiphene and cyclofenil
block receptors mediating feedback inhibition of central neuroendocrine
circuits and thereby disinhibit gonadotropin release. Gonadotropins
can be given in the form of HMG and HCG .

Insulin Therapy

Insulin is synthesized in the B- (or !-) cells of the pancreatic islets of Langerhans.
It is a protein (MW 5800) consisting of two peptide chains linked by two
disulfide bridges; the A chain has 21 and the B chain 30 amino acids. Insulin is the
“blood-sugar lowering” hormone. Upon ingestion of dietary carbohydrates, it is
released into the blood and acts to prevent a significant rise in blood glucose
concentration by promoting uptake of glucose in specific organs, viz., the
heart, adipose tissue, and skeletal muscle, or its conversion to glycogen in the
liver. It also increases lipogenesis and protein synthesis, while inhibiting lipolysis
and release of free fatty acids. Insulin is used in the replacement
therapy of diabetes mellitus to supplement a deficient secretion of endogenous
hormone.
Sources of therapeutic insulin preparations (A). Insulin can be obtained
from pancreatic tissue of slaughtered animals. Porcine insulin differs
from human insulin merely by one B chain amino acid, bovine insulin by two
amino acids in the A chain and one in the B chain. With these slight differences,
animal and human hormone display similar biological activity. Compared
with human hormone, porcine insulin is barely antigenic and bovine insulin has
a little higher antigenicity. Human insulin is produced by two methods: biosynthetically,
by substituting threonine for the C-terminal alanine in the B chain of
porcine insulin; or by gene technology involving insertion of the appropriate
human DNA into E. coli bacteria. Types of preparations . As a
peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal
proteases) and thus needs to be given parenterally. Usually, insulin
preparations are injected subcutaneously. The duration of action depends
on the rate of absorption from the injection site.
Short-acting insulin is dispensed as a clear neutral solution known as
regular insulin. In emergencies, such as hyperglycemic coma, it can be given
intravenously (mostly by infusion because i.v. injections have too brief an action;
plasma t1/2 ~ 9 min). With the usual subcutaneous application, the effect
is evident within 15 to 20 min, reaches a peak after approx. 3 h, and lasts for approx.
6 h. Lispro insulin has a faster onset and slightly shorter duration of action.
Insulin suspensions. When the hormone is injected as a suspension of
insulin-containing particles, its dissolution and release in subcutaneous tissue
are retarded (rapid, intermediate, and slow insulins). Suitable particles can be
obtained by precipitation of apolar, poorly water-soluble complexes consisting
of anionic insulin and cationic partners, e.g., the polycationic protein
protamine or the compound aminoquinuride (Surfen). In the presence of zinc
and acetate ions, insulin crystallizes; crystal size determines the rate of dissolution.
Intermediate insulin preparations (NPH or isophane, lente or zinc insulin)
act for 18 to 26 h, slow preparations (protamine zinc insulin, ultralente
or extended zinc insulin) for up to 36 h. Combination preparations contain
insulin mixtures in solution and in suspension (e.g., ultralente); the plasma
concentration-time curve represents the sum of the two components.
Unwanted effects. Hypoglycemia results from absolute or relative overdosage
. Allergic reactions are rare—locally: redness at injection site,
atrophy of adipose tissue (lipodystrophy); systemically: urticaria, skin rash,
anaphylaxis. Insulin resistance can result from binding to inactivating antibodies.
A possible local lipohypertrophy can be avoided by alternating injection
sites.

Treatment of Insulin-Dependent Diabetes Mellitus

“Juvenile onset” (type I) diabetes mellitus is caused by the destruction of insulin-
producing B cells in the pancreas, necessitating replacement of insulin
(daily dose approx. 40 U, equivalent to approx. 1.6 mg).
Therapeutic objectives are: (1) prevention of life-threatening hyperglycemic
(diabetic) coma; (2) prevention of diabetic sequelae (angiopathy with
blindness, myocardial infarction, renal failure), with precise “titration” of the
patient being essential to avoid even short-term spells of pathological hyperglycemia;
(3) prevention of insulin overdosage leading to life-threatening
hypoglycemic shock (CNS disturbance due to lack of glucose).
Therapeutic principles. In healthy subjects, the amount of insulin is “automatically”
matched to carbohydrate intake, hence to blood glucose concentration.
The critical secretory stimulus is the rise in plasma glucose level. Food intake
and physical activity (increased glucose uptake into musculature, decreased
insulin demand) are accompanied by corresponding changes in insulin
secretion (A, left track). In the diabetic, insulin could be administered
as it is normally secreted; that is, injection of short-acting insulin
before each main meal plus bedtime administration of a Lente preparation to
avoid a nocturnal shortfall of insulin. This regimen requires a well-educated,
cooperative, and competent patient. In other cases, a fixed-dosage schedule
will be needed, e.g., morning and evening injections of a combination insulin
in constant respective dosage (A). To avoid hypo- or hyperglycemias with
this regimen, dietary carbohydrate (CH) intake must be synchronized with the
time course of insulin absorption from the s.c. depot. Caloric intake is to be distributed
(50% CH, 30% fat, 20% protein) in small meals over the day so as to
achieve a steady CH supply—snacks, late night meal. Rapidly absorbable CH
(sweets, cakes) must be avoided (hyperglycemic—peaks) and replaced with
slowly digestible ones. Acarbose (an !-glucosidase inhibitor)
delays intestinal formation of glucose from disaccharides.
Any change in eating and living habits can upset control of blood sugar:
skipping a meal or unusual physical stress leads to hypoglycemia; increased
CH intake provokes hyperglycemia.Hypoglycemia is heralded by
warning signs: tachycardia, unrest,tremor, pallor, profuse sweating. Some
of these are due to the release of glucose-mobilizing epinephrine. Countermeasures:
glucose administration, rapidly absorbed CH orally or 10–20 g glucose
i.v. in case of unconsciousness; if necessary, injection of glucagon, the
pancreatic hyperglycemic hormone. Even with optimal control of blood
sugar, s.c. administration of insulin cannot fully replicate the physiological situation.
In healthy subjects, absorbed glucose and insulin released from the
pancreas simultaneously reach the liver in high concentration, whereby effective
presystemic elimination of both substances is achieved. In the diabetic,
s.c. injected insulin is uniformly distributed in the body. Since insulin concentration
in blood supplying the liver cannot rise, less glucose is extracted from
portal blood. A significant amount of glucose enters extrahepatic tissues,
where it has to be utilized.

Treatment of Maturity-Onset (Type II) Diabetes Mellitus

In overweight adults, a diabetic metabolic condition may develop (type II or
non-insulin-dependent diabetes) when there is a relative insulin deficiency—
enhanced demand cannot be met by a diminishing insulin secretion. The
cause of increased insulin requirement is a loss of insulin receptors or an
impairment of the signal cascade activated by the insulin receptor. Accordingly,
insulin sensitivity of cells declines. This can be illustrated by comparing
concentration-binding curves in cells from normal and obese individuals
(A). In the obese, the maximum binding possible (plateau of curve) is displaced
downward, indicative of the reduction in receptor numbers. Also, at low insulin
concentrations, there is less binding of insulin, compared with the control condition.
For a given metabolic effect a certain number of receptors must be occupied.
As shown by the binding curves (dashed lines), this can still be achieved
with a reduced receptor number, although only at a higher concentration of
insulin. Development of adult diabetes
(B). Compared with a normal subject, the obese subject requires a continually
elevated output of insulin (orange curves) to avoid an excessive rise of
blood glucose levels (green curves) during a glucose load. When the secretory
capacity of the pancreas decreases, this is first noted as a rise in blood glucose
during glucose loading (latent diabetes). Subsequently, not even the fasting
blood level can be maintained (manifest, overt diabetes). A diabetic condition
has developed, although insulin release is not lower than that in a healthy
person (relative insulin deficiency).Treatment. Caloric restriction to
restore body weight to normal is associated with an increase in insulin receptor
number or cellular responsiveness. The releasable amount of insulin is
again adequate to maintain a normal metabolic rate.
Therapy of first choice is weight reduction, not administration of
drugs! Should the diabetic condition fail to resolve, consideration should first be
given to insulin replacement .

Oral antidiabetics of the sulfonylurea type increase the sensitivity of B-cells
towards glucose, enabling them to increase release of insulin. These drugs
probably promote depolarization of the !-cell membrane by closing off ATP-gated
K+ channels. Normally, these channels are closed when intracellular levels
of glucose, hence of ATP, increase. This drug class includes tolbutamide (500–
2000 mg/d) and glyburide (glibenclamide) (1.75–10.5 mg/d). In some patients,
it is not possible to stimulate insulin secretion from the outset; in others,
therapy fails later on. Matching dosage of the oral antidiabetic and caloric
intake follows the same principles as apply to insulin. Hypoglycemia is the
most important unwanted effect. Enhancement of the hypoglycemic effect
can result from drug interactions: displacement of antidiabetic drug from
plasma protein-binding sites by sulfonamides or acetylsalicylic acid.

Metformin, a biguanide derivative,
can lower excessive blood glucose levels, provided that insulin is present.
Metformin does not stimulate insulin release. Glucose release from the liver is
decreased, while peripheral uptake is enhanced. The danger of hypoglycemia
apparently is not increased. Frequent adverse effects include: anorexia, nausea,
and diarrhea. Overproduction of lactic acid (lactate acidosis, lethality 50%) is
a rare, potentially fatal reaction. Metformin is used in combination with sulfonylureas
or by itself. It is contraindicated in renal insufficiency and should therefore
be avoided in elderly patients. Thiazolidinediones (Glitazones: rosiglitazone,
pioglitazone) are insulinsensitizing agents that augment tissue
responsiveness by promoting the synthesis or the availability of plasmalemmal
glucose transporters via activation of a transcription factor (peroxisome
proliferator-activated receptor-").

Drugs for Maintaining Calcium
Homeostasis At rest, the intracellular concentration
of free calcium ions (Ca2+) is kept at 0.1 μM (see p. 128 for mechanisms involved).
During excitation, a transient rise of up to 10 μM elicits contraction in
muscle cells (electromechanical coupling) and secretion in glandular cells
(electrosecretory coupling). The cellular content of Ca2+ is in equilibrium with
the extracellular Ca2+ concentration (approx. 1000 μM), as is the plasma protein-
bound fraction of calcium in blood. Ca2+ may crystallize with phosphate to
form hydroxyapatite, the mineral of bone. Osteoclasts are phagocytes that
mobilize Ca2+ by resorption of bone. Slight changes in extracellular Ca2+ concentration
can alter organ function: thus, excitability of skeletal muscle increases
markedly as Ca2+ is lowered (e.g., in hyperventilation tetany). Three
hormones are available to the body for maintaining a constant extracellular
Ca2+ concentration. Vitamin D hormone is derived
from vitamin D (cholecalciferol). Vitamin D can also be produced in the body; it is
formed in the skin from dehydrocholesterol during irradiation with UV light.
When there is lack of solar radiation, dietary intake becomes essential, cod
liver oil being a rich source. Metabolically active vitamin D hormone results
from two successive hydroxylations: in the liver at position 25 (! calcifediol)
and in the kidney at position 1 (!calcitriol = vit. D hormone). 1-Hydroxylation
depends on the level of calcium homeostasis and is stimulated by parathormone
and a fall in plasma levels of Ca2+ or phosphate. Vit. D hormone promotes
enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of
the increased Ca2+ and phosphate concentration in blood, there is an increased
tendency for these ions to be deposited in bone in the form of hydroxyapatite
crystals. In vit. D deficiency, bone mineralization is inadequate
(rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vit. D is
given; in liver disease calcifediol may be indicated, in renal disease calcitriol. Effectiveness,
as well as rate of onset and cessation of action, increase in the order vit. D. <>

Antibacterial Drugs

Antibacterial Drugs
Drugs for Treating Bacterial Infections
When bacteria overcome the cutaneous
or mucosal barriers and penetrate body
tissues, a bacterial infection is present.
Frequently the body succeeds in removing
the invaders, without outward signs
of disease, by mounting an immune response.
If bacteria multiply faster than
the body’s defenses can destroy them,
infectious disease develops with inflammatory
signs, e.g., purulent wound infection
or urinary tract infection. Appropriate
treatment employs substances
that injure bacteria and thereby prevent
their further multiplication, without
harming cells of the host organism (1).
Apropos nomenclature: antibiotics
are produced by microorganisms (fungi,
bacteria) and are directed “against life”
at any phylogenetic level (prokaryotes,
eukaryotes). Chemotherapeutic agents
originate from chemical synthesis. This
distinction has been lost in current usage.
Specific damage to bacteria is particularly
practicable when a substance
interferes with a metabolic process that
occurs in bacterial but not in host cells.
Clearly this applies to inhibitors of cell
wall synthesis, because human and animal
cells lack a cell wall. The points of
attack of antibacterial agents are schematically
illustrated in a grossly simplified
bacterial cell, as depicted in (2).
In the following sections, polymyxins
and tyrothricin are not considered
further. These polypeptide antibiotics
enhance cell membrane permeability.
Due to their poor tolerability, they are
prescribed in humans only for topical
use.
The effect of antibacterial drugs can
be observed in vitro (3). Bacteria multiply
in a growth medium under control
conditions. If the medium contains an
antibacterial drug, two results can be
discerned: 1. bacteria are killed—bactericidal
effect; 2. bacteria survive, but do
not multiply—bacteriostatic effect. Although
variations may occur under
therapeutic conditions, different drugs
can be classified according to their respective
primary mode of action (color
tone in 2 and 3).
When bacterial growth remains unaffected
by an antibacterial drug, bacterial
resistance is present. This may occur
because of certain metabolic characteristics
that confer a natural insensitivity
to the drug on a particular strain of
bacteria (natural resistance). Depending
on whether a drug affects only a few or
numerous types of bacteria, the terms
narrow-spectrum (e.g., penicillin G) or
broad-spectrum (e.g., tetracyclines)
antibiotic are applied. Naturally susceptible
bacterial strains can be transformed
under the influence of antibacterial
drugs into resistant ones (acquired
resistance), when a random genetic alteration
(mutation) gives rise to a resistant
bacterium. Under the influence of
the drug, the susceptible bacteria die
off, whereas the mutant multiplies unimpeded.
The more frequently a given
drug is applied, the more probable the
emergence of resistant strains (e.g., hospital
strains with multiple resistance)!
Resistance can also be acquired
when DNA responsible for nonsusceptibility
(so-called resistance plasmid) is
passed on from other resistant bacteria
by conjugation or transduction.

Inhibitors of Cell Wall Synthesis
In most bacteria, a cell wall surrounds
the cell like a rigid shell that protects
against noxious outside influences and
prevents rupture of the plasma membrane
from a high internal osmotic
pressure. The structural stability of the
cell wall is due mainly to the murein
(peptidoglycan) lattice. This consists of
basic building blocks linked together to
form a large macromolecule. Each basic
unit contains the two linked aminosugars
N-acetylglucosamine and N-acetylmuramyl
acid; the latter bears a peptide
chain. The building blocks are synthesized
in the bacterium, transported outward
through the cell membrane, and
assembled as illustrated schematically.
The enzyme transpeptidase cross-links
the peptide chains of adjacent aminosugar
chains.
Inhibitors of cell wall synthesis
are suitable antibacterial agents, because
animal and human cells lack a cell
wall. They exert a bactericidal action on
growing or multiplying germs. Members
of this class include !-lactam antibiotics
such as the penicillins and cephalosporins,
in addition to bacitracin and
vancomycin.
Penicillins (A). The parent substance
of this group is penicillin G (benzylpenicillin).
It is obtained from cultures
of mold fungi, originally from Penicillium
notatum. Penicillin G contains
the basic structure common to all penicillins,
6-amino-penicillanic acid (p.
271, 6-APA), comprised of a thiazolidine
and a 4-membered !-lactam ring. 6-
APA itself lacks antibacterial activity.
Penicillins disrupt cell wall synthesis by
inhibiting transpeptidase. When bacteria
are in their growth and replication
phase, penicillins are bactericidal; due
to cell wall defects, the bacteria swell
and burst.
Penicillins are generally well tolerated;
with penicillin G, the daily dose
can range from approx. 0.6 g i.m. (= 106
international units, 1 Mega I.U.) to 60 g
by infusion. The most important adverse
effects are due to hypersensitivity
(incidence up to 5%), with manifestations
ranging from skin eruptions to
anaphylactic shock (in less than 0.05% of
patients). Known penicillin allergy is a
contraindication for these drugs. Because
of an increased risk of sensitization,
penicillins must not be used locally.
Neurotoxic effects, mostly convulsions
due to GABA antagonism, may occur
if the brain is exposed to extremely
high concentrations, e.g., after rapid i.v.
injection of a large dose or intrathecal
injection.
Penicillin G undergoes rapid renal
elimination mainly in unchanged form
(plasma t1/2 ~ 0.5 h). The duration of
the effect can be prolonged by:
1. Use of higher doses, enabling plasma
levels to remain above the minimally
effective antibacterial concentration;
2. Combination with probenecid. Renal
elimination of penicillin occurs
chiefly via the anion (acid)-secretory
system of the proximal tubule (-COOH
of 6-APA). The acid probenecid (p. 316)
competes for this route and thus retards
penicillin elimination;
3. Intramuscular administration in
depot form. In its anionic form (-COO-)
penicillin G forms poorly water-soluble
salts with substances containing a positively
charged amino group (procaine,
p. 208; clemizole, an antihistamine;
benzathine, dicationic). Depending on
the substance, release of penicillin from
the depot occurs over a variable interval.


Although very well tolerated, penicillin
G has disadvantages (A) that limit
its therapeutic usefulness: (1) It is inactivated
by gastric acid, which cleaves
the !-lactam ring, necessitating parenteral
administration. (2) The !-lactam
ring can also be opened by bacterial enzymes
(!-lactamases); in particular,
penicillinase, which can be produced by
staphylococcal strains, renders them resistant
to penicillin G. (3) The antibacterial
spectrum is narrow; although it encompasses
many gram-positive bacteria,
gram-negative cocci, and spirochetes,
many gram-negative pathogens
are unaffected.
Derivatives with a different substituent
on 6-APA possess advantages
(B): (1) Acid resistance permits oral administration,
provided that enteral absorption
is possible. All derivatives
shown in (B) can be given orally. Penicillin
V (phenoxymethylpenicillin) exhibits
antibacterial properties similar to
those of penicillin G. (2) Due to their
penicillinase resistance, isoxazolylpenicillins
(oxacillin dicloxacillin, flucloxacillin)
are suitable for the (oral) treatment
of infections caused by penicillinaseproducing
staphylococci. (3) Extended
activity spectrum: The aminopenicillin
amoxicillin is active against many gramnegative
organisms, e.g., coli bacteria or
Salmonella typhi. It can be protected
from destruction by penicillinase by
combination with inhibitors of penicillinase
(clavulanic acid, sulbactam, tazobactam).
The structurally close congener ampicillin
(no 4-hydroxy group) has a similar
activity spectrum. However, because
it is poorly absorbed (<50%) and therefore
causes more extensive damage to
the gut microbial flora (side effect: diarrhea),
it should be given only by injection.
A still broader spectrum (including
Pseudomonas bacteria) is shown by carboxypenicillins
(carbenicillin, ticarcillin)
and acylaminopenicillins (mezclocillin,
azlocillin, piperacillin). These substances
are neither acid stable nor penicillinase
resistant.
Cephalosporins (C). These !-lactam
antibiotics are also fungal products
and have bactericidal activity due to inhibition
of transpeptidase. Their
shared basic structure is 7-aminocephalosporanic
acid, as exemplified by
cephalexin (gray rectangle). Cephalosporins
are acid stable, but many are
poorly absorbed. Because they must be
given parenterally, most—including
those with high activity—are used only
in clinical settings. A few, e.g., cephalexin,
are suitable for oral use. Cephalosporins
are penicillinase-resistant, but
cephalosporinase-forming organisms
do exist. Some derivatives are, however,
also resistant to this !-lactamase.
Cephalosporins are broad-spectrum
antibacterials. Newer derivatives (e.g.,
cefotaxime, cefmenoxin, cefoperazone,
ceftriaxone, ceftazidime, moxalactam)
are also effective against pathogens resistant
to various other antibacterials.
Cephalosporins are mostly well tolerated.
All can cause allergic reactions, some
also renal injury, alcohol intolerance,
and bleeding (vitamin K antagonism).
Other inhibitors of cell wall synthesis.
Bacitracin and vancomycin
interfere with the transport of peptidoglycans
through the cytoplasmic
membrane and are active only against
gram-positive bacteria. Bacitracin is a
polypeptide mixture, markedly nephrotoxic
and used only topically. Vancomycin
is a glycopeptide and the drug of
choice for the (oral) treatment of bowel
inflammations occurring as a complication
of antibiotic therapy (pseudomembranous
enterocolitis caused by Clostridium
difficile). It is not absorbed.


Inhibitors of Tetrahydrofolate Synthesis
Tetrahydrofolic acid (THF) is a co-enzyme
in the synthesis of purine bases
and thymidine. These are constituents
of DNA and RNA and required for cell
growth and replication. Lack of THF
leads to inhibition of cell proliferation.
Formation of THF from dihydrofolate
(DHF) is catalyzed by the enzyme dihydrofolate
reductase. DHF is made from
folic acid, a vitamin that cannot be synthesized
in the body, but must be taken
up from exogenous sources. Most bacteria
do not have a requirement for folate,
because they are capable of synthesizing
folate, more precisely DHF, from
precursors. Selective interference with
bacterial biosynthesis of THF can be
achieved with sulfonamides and trimethoprim.
Sulfonamides structurally resemble
p-aminobenzoic acid (PABA), a precursor
in bacterial DHF synthesis. As
false substrates, sulfonamides competitively
inhibit utilization of PABA, hence
DHF synthesis. Because most bacteria
cannot take up exogenous folate, they
are depleted of DHF. Sulfonamides thus
possess bacteriostatic activity against a
broad spectrum of pathogens. Sulfonamides
are produced by chemical synthesis.
The basic structure is shown in
(A). Residue R determines the pharmacokinetic
properties of a given sulfonamide.
Most sulfonamides are well absorbed
via the enteral route. They are
metabolized to varying degrees and
eliminated through the kidney. Rates of
elimination, hence duration of effect,
may vary widely. Some members are
poorly absorbed from the gut and are
thus suitable for the treatment of bacterial
bowel infections. Adverse effects
may include, among others, allergic reactions,
sometimes with severe skin
damage, displacement of other plasma
protein-bound drugs or bilirubin in neonates
(danger of kernicterus, hence contraindication
for the last weeks of gestation
and in the neonate). Because of the
frequent emergence of resistant bacteria,
sulfonamides are now rarely used.
Introduced in 1935, they were the first
broad-spectrum chemotherapeutics.
Trimethoprim inhibits bacterial
DHF reductase, the human enzyme being
significantly less sensitive than the
bacterial one (rarely bone marrow depression).
A 2,4-diaminopyrimidine, trimethoprim,
has bacteriostatic activity
against a broad spectrum of pathogens.
It is used mostly as a component of cotrimoxazole.
Co-trimoxazole is a combination of
trimethoprim and the sulfonamide sulfamethoxazole.
Since THF synthesis is
inhibited at two successive steps, the
antibacterial effect of co-trimoxazole is
better than that of the individual components.
Resistant pathogens are infrequent;
a bactericidal effect may occur.
Adverse effects correspond to those of
the components.
Although initially developed as an
antirheumatic agent (p. 320), sulfasalazine
(salazosulfapyridine) is used mainly
in the treatment of inflammatory
bowel disease (ulcerative colitis and
terminal ileitis or Crohn’s disease). Gut
bacteria split this compound into the
sulfonamide sulfapyridine and mesalamine
(5-aminosalicylic acid). The latter
is probably the anti-inflammatory agent
(inhibition of synthesis of chemotactic
signals for granulocytes, and of H2O2
formation in mucosa), but must be
present on the gut mucosa in high concentrations.
Coupling to the sulfonamide
prevents premature absorption
in upper small bowel segments. The
cleaved-off sulfonamide can be absorbed
and may produce typical adverse
effects (see above).
Dapsone (p. 280) has several therapeutic
uses: besides treatment of leprosy,
it is used for prevention/prophylaxis
of malaria, toxoplasmosis, and actinomycosis.



Inhibitors of DNA Function
Deoxyribonucleic acid (DNA) serves as a
template for the synthesis of nucleic acids.
Ribonucleic acid (RNA) executes
protein synthesis and thus permits cell
growth. Synthesis of new DNA is a prerequisite
for cell division. Substances
that inhibit reading of genetic information
at the DNA template damage the
regulatory center of cell metabolism.
The substances listed below are useful
as antibacterial drugs because they do
not affect human cells.
Gyrase inhibitors. The enzyme gyrase
(topoisomerase II) permits the orderly
accommodation of a ~1000 μmlong
bacterial chromosome in a bacterial
cell of ~1 μm. Within the chromosomal
strand, double-stranded DNA has a
double helical configuration. The former,
in turn, is arranged in loops that
are shortened by supercoiling. The gyrase
catalyzes this operation, as illustrated,
by opening, underwinding, and
closing the DNA double strand such that
the full loop need not be rotated.
Derivatives of 4-quinolone-3-carboxylic
acid (green portion of ofloxacin
formula) are inhibitors of bacterial gyrases.
They appear to prevent specifically
the resealing of opened strands and
thereby act bactericidally. These agents
are absorbed after oral ingestion. The
older drug, nalidixic acid, affects exclusively
gram-negative bacteria and attains
effective concentrations only in
urine; it is used as a urinary tract antiseptic.
Norfloxacin has a broader spectrum.
Ofloxacin, ciprofloxacin, and
enoxacin, and others, also yield systemically
effective concentrations and are
used for infections of internal organs.
Besides gastrointestinal problems
and allergy, adverse effects particularly
involve the CNS (confusion, hallucinations,
seizures). Since they can damage
epiphyseal chondrocytes and joint cartilages
in laboratory animals, gyrase inhibitors
should not be used during pregnancy,
lactation, and periods of growth.
Azomycin (nitroimidazole) derivatives,
such as metronidazole, damage
DNA by complex formation or strand
breakage. This occurs in obligate anaerobes,
i.e., bacteria growing under O2
exclusion. Under these conditions, conversion
to reactive metabolites that attack
DNA takes place (e.g., the hydroxylamine
shown). The effect is bactericidal.
A similar mechanism is involved in the
antiprotozoal action on Trichomonas vaginalis
(causative agent of vaginitis and
urethritis) and Entamoeba histolytica
(causative agent of large bowel inflammation,
amebic dysentery, and hepatic
abscesses). Metronidazole is well absorbed
via the enteral route; it is also
given i.v. or topically (vaginal insert).
Because metronidazole is considered
potentially mutagenic, carcinogenic,
and teratogenic in the human, it should
not be used longer than 10 d, if possible,
and be avoided during pregnancy and
lactation. Timidazole may be considered
equivalent to metronidazole.
Rifampin inhibits the bacterial enzyme
that catalyzes DNA template-directed
RNA transcription, i.e., DNA-dependent
RNA polymerase. Rifampin acts
bactericidally against mycobacteria (M.
tuberculosis, M. leprae), as well as many
gram-positive and gram-negative bacteria.
It is well absorbed after oral ingestion.
Because resistance may develop
with frequent usage, it is restricted to
the treatment of tuberculosis and leprosy
(p. 280).
Rifampin is contraindicated in the
first trimester of gestation and during
lactation.
Rifabutin resembles rifampin but
may be effective in infections resistant
to the latter.

Inhibitors of Protein Synthesis
Protein synthesis means translation
into a peptide chain of a genetic message
first copied (transcribed) into m-
RNA (p. 274). Amino acid (AA) assembly
occurs at the ribosome. Delivery of amino
acids to m-RNA involves different
transfer RNA molecules (t-RNA), each of
which binds a specific AA. Each t-RNA
bears an “anticodon” nucleobase triplet
that is complementary to a particular
m-RNA coding unit (codon, consisting of
3 nucleobases.
Incorporation of an AA normally involves
the following steps (A):
1. The ribosome “focuses” two codons
on m-RNA; one (at the left) has
bound its t-RNA-AA complex, the AA
having already been added to the peptide
chain; the other (at the right) is
ready to receive the next t-RNA-AA
complex.
2. After the latter attaches, the AAs
of the two adjacent complexes are
linked by the action of the enzyme peptide
synthetase (peptidyltransferase).
Concurrently, AA and t-RNA of the left
complex disengage.
3. The left t-RNA dissociates from
m-RNA. The ribosome can advance
along the m-RNA strand and focus on
the next codon.
4. Consequently, the right t-RNAAA
complex shifts to the left, allowing
the next complex to be bound at the
right.
These individual steps are susceptible
to inhibition by antibiotics of different
groups. The examples shown originate
primarily from Streptomyces bacteria,
some of the aminoglycosides also
being derived from Micromonospora
bacteria.
1a. Tetracyclines inhibit the binding
of t-RNA-AA complexes. Their action
is bacteriostatic and affects a broad
spectrum of pathogens.
1b. Aminoglycosides induce the
binding of “wrong” t-RNA-AA complexes,
resulting in synthesis of false proteins.
Aminoglycosides are bactericidal.
Their activity spectrum encompasses
mainly gram-negative organisms.
Streptomycin and kanamycin are used
predominantly in the treatment of tuberculosis.
Note on spelling: -mycin designates
origin from Streptomyces species; -micin
(e.g., gentamicin) from Micromonospora
species.
2. Chloramphenicol inhibits peptide
synthetase. It has bacteriostatic activity
against a broad spectrum of
pathogens. The chemically simple molecule
is now produced synthetically.
3. Erythromycin suppresses advancement
of the ribosome. Its action is
predominantly bacteriostatic and directed
against gram-positve organisms.
For oral administration, the acid-labile
base (E) is dispensed as a salt (E. stearate)
or an ester (e.g., E. succinate).
Erythromycin is well tolerated. It is a
suitable substitute in penicillin allergy
or resistance. Azithromycin, clarithromycin,
and roxithromycin are derivatives
with greater acid stability and better
bioavailability. The compounds mentioned
are the most important members
of the macrolide antibiotic group, which
includes josamycin and spiramycin. An
unrelated action of erythromycin is its
mimicry of the gastrointestinal hormone
motiline (! interprandial bowel
motility).
Clindamycin has antibacterial activity
similar to that of erythromycin. It
exerts a bacteriostatic effect mainly on
gram-positive aerobic, as well as on anaerobic
pathogens. Clindamycin is a
semisynthetic chloro analogue of lincomycin,
which derives from a Streptomyces
species. Taken orally, clindamycin
is better absorbed than lincomycin,
has greater antibacterial efficacy and is
thus preferred. Both penetrate well into
bone tissue.



Tetracyclines are absorbed from
the gastrointestinal tract to differing degrees,
depending on the substance, absorption
being nearly complete for
doxycycline and minocycline. Intravenous
injection is rarely needed (rolitetracycline
is available only for i.v. administration).
The most common unwanted
effect is gastrointestinal upset
(nausea, vomiting, diarrhea, etc.) due to
(1) a direct mucosal irritant action of
these substances and (2) damage to the
natural bacterial gut flora (broad-spectrum
antibiotics) allowing colonization
by pathogenic organisms, including
Candida fungi. Concurrent ingestion of
antacids or milk would, however, be inappropriate
because tetracyclines form
insoluble complexes with plurivalent
cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) resulting
in their inactivation; that is, absorbability,
antibacterial activity, and
local irritant action are abolished. The
ability to chelate Ca2+ accounts for the
propensity of tetracyclines to accumulate
in growing teeth and bones. As a result,
there occurs an irreversible yellowbrown
discoloration of teeth and a reversible
inhibition of bone growth. Because
of these adverse effects, tetracycline
should not be given after the second
month of pregnancy and not prescribed
to children aged 8 y and under. Other
adverse effects are increased photosensitivity
of the skin and hepatic damage,
mainly after i.v. administration.
The broad-spectrum antibiotic
chloramphenicol is completely absorbed
after oral ingestion. It undergoes
even distribution in the body and readily
crosses diffusion barriers such as the
blood-brain barrier. Despite these advantageous
properties, use of chloramphenicol
is rarely indicated (e.g., in CNS
infections) because of the danger of
bone marrow damage. Two types of bone
marrow depression can occur: (1) a
dose-dependent, toxic, reversible form
manifested during therapy and, (2) a
frequently fatal form that may occur after
a latency of weeks and is not dose
dependent. Due to high tissue penetrability,
the danger of bone marrow depression
must also be taken into account
after local use (e.g., eye drops).
Aminoglycoside antibiotics consist
of glycoside-linked amino-sugars
(cf. gentamicin C1α, a constituent of the
gentamicin mixture). They contain numerous
hydroxyl groups and amino
groups that can bind protons. Hence,
these compounds are highly polar,
poorly membrane permeable, and not
absorbed enterally. Neomycin and paromomycin
are given orally to eradicate
intestinal bacteria (prior to bowel surgery
or for reducing NH3 formation by
gut bacteria in hepatic coma). Aminoglycosides
for the treatment of serious
infections must be injected (e.g., gentamicin,
tobramycin, amikacin, netilmicin,
sisomycin). In addition, local inlays
of a gentamicin-releasing carrier can be
used in infections of bone or soft tissues.
Aminoglycosides gain access to the bacterial
interior by the use of bacterial
transport systems. In the kidney, they
enter the cells of the proximal tubules
via an uptake system for oligopeptides.
Tubular cells are susceptible to damage
(nephrotoxicity, mostly reversible). In
the inner ear, sensory cells of the vestibular
apparatus and Corti’s organ may be
injured (ototoxicity, in part irreversible).


Drugs for Treating Mycobacterial
Infections
Mycobacteria are responsible for two
diseases: tuberculosis, mostly caused by
M. tuberculosis, and leprosy due to M. leprae.
The therapeutic principle applicable
to both is combined treatment
with two or more drugs. Combination
therapy prevents the emergence of resistant
mycobacteria. Because the antibacterial
effects of the individual substances
are additive, correspondingly
smaller doses are sufficient. Therefore,
the risk of individual adverse effects is
lowered. Most drugs are active against
only one of the two diseases.
Antitubercular Drugs (1)
Drugs of choice are: isoniazid, rifampin,
ethambutol, along with streptomycin
and pyrazinamide. Less well tolerated,
second-line agents include: p-aminosalicylic
acid, cycloserine, viomycin, kanamycin,
amikacin, capreomycin, ethionamide.
Isoniazid is bactericidal against
growing M. tuberculosis. Its mechanism
of action remains unclear. (In the bacterium
it is converted to isonicotinic acid,
which is membrane impermeable,
hence likely to accumulate intracellularly.)
Isoniazid is rapidly absorbed after
oral administration. In the liver, it is inactivated
by acetylation, the rate of
which is genetically controlled and
shows a characteristic distribution in
different ethnic groups (fast vs. slow
acetylators). Notable adverse effects
are: peripheral neuropathy, optic neuritis
preventable by administration of
vitamin B6 (pyridoxine); hepatitis, jaundice.
Rifampin. Source, antibacterial activity,
and routes of administration are
described on p. 274. Albeit mostly well
tolerated, this drug may cause several
adverse effects including hepatic damage,
hypersensitivity with flu-like
symptoms, disconcerting but harmless
red/orange discoloration of body fluids,
and enzyme induction (failure of oral
contraceptives). Concerning rifabutin
see p. 274.
Ethambutol. The cause of its specific
antitubercular action is unknown.
Ethambutol is given orally. It is generally
well tolerated, but may cause dosedependent
damage to the optic nerve
with disturbances of vision (red/green
blindness, visual field defects).
Pyrazinamide exerts a bactericidal
action by an unknown mechanism. It is
given orally. Pyrazinamide may impair
liver function; hyperuricemia results
from inhibition of renal urate elimination.
Streptomycin must be given i.v. (pp.
278ff) like other aminoglycoside antibiotics.
It damages the inner ear and the
labyrinth. Its nephrotoxicity is comparatively
minor.
Antileprotic Drugs (2)
Rifampin is frequently given in combination
with one or both of the following
agents:
Dapsone is a sulfone that, like sulfonamides,
inhibits dihydrofolate synthesis
(p. 272). It is bactericidal against
susceptible strains of M. leprae. Dapsone
is given orally. The most frequent adverse
effect is methemoglobinemia with
accelerated erythrocyte degradation
(hemolysis).
Clofazimine is a dye with bactericidal
activity against M. leprae and antiinflammatory
properties. It is given
orally, but is incompletely absorbed. Because
of its high lipophilicity, it accumulates
in adipose and other tissues
and leaves the body only rather slowly
(t1/2 ~ 70 d). Red-brown skin pigmentation
is an unwanted effect, particularly
in fair-skinned patients.

Antifungal Drugs

Drugs Used in the Treatment of
Fungal Infections
Infections due to fungi are usually confined
to the skin or mucous membranes:
local or superficial mycosis. However, in
immune deficiency states, internal organs
may also be affected: systemic or
deep mycosis.
Mycoses are most commonly due to
dermatophytes, which affect the skin,
hair, and nails following external infection.
Candida albicans, a yeast organism
normally found on body surfaces, may
cause infections of mucous membranes,
less frequently of the skin or internal organs
when natural defenses are impaired
(immunosuppression, or damage
of microflora by broad-spectrum antibiotics).
Imidazole derivatives inhibit ergosterol
synthesis. This steroid forms an
integral constituent of cytoplasmic
membranes of fungal cells, analogous to
cholesterol in animal plasma membranes.
Fungi exposed to imidazole derivatives
stop growing (fungistatic effect)
or die (fungicidal effect). The spectrum
of affected fungi is very broad. Because
they are poorly absorbed and
poorly tolerated systemically, most
imidazoles are suitable only for topical
use (clotrimazole, econazole oxiconazole,
isoconazole, bifonazole, etc.). Rarely, this
use may result in contact dermatitis. Miconazole
is given locally, or systemically
by short-term infusion (despite its poor
tolerability). Because it is well absorbed,
ketoconazole is available for oral administration.
Adverse effects are rare; however,
the possibility of fatal liver damage
should be noted. Remarkably, ketoconazole
may inhibit steroidogenesis
(gonadal and adrenocortical hormones).
Fluconazole and itraconazole are newer,
orally effective triazole derivatives. The
topically active allylamine naftidine
and the morpholine amorolfine also inhibit
ergosterol synthesis, albeit at another
step.
The polyene antibiotics, amphotericin
B and nystatin, are of bacterial
origin. They insert themselves into fungal
cell membranes (probably next to
ergosterol molecules) and cause formation
of hydrophilic channels. The resultant
increase in membrane permeability,
e.g., to K+ ions, accounts for the fungicidal
effect. Amphotericin B is active
against most organisms responsible for
systemic mycoses. Because of its poor
absorbability, it must be given by infusion,
which is, however, poorly tolerated
(chills, fever, CNS disturbances, impaired
renal function, phlebitis at the
infusion site). Applied topically to skin
or mucous membranes, amphotericin B
is useful in the treatment of candidal
mycosis. Because of the low rate of enteral
absorption, oral administration in
intestinal candidiasis can be considered
a topical treatment. Nystatin is used only
for topical therapy.
Flucytosine is converted in candida
fungi to 5-fluorouracil by the action of a
specific cytosine deaminase. As an antimetabolite,
this compound disrupts
DNA and RNA synthesis (p. 298), resulting
in a fungicidal effect. Given orally,
flucytosine is rapidly absorbed. It is well
tolerated and often combined with amphotericin
B to allow dose reduction of
the latter.
Griseofulvin originates from molds
and has activity only against dermatophytes.
Presumably, it acts as a spindle
poison to inhibit fungal mitosis. Although
targeted against local mycoses,
griseofulvin must be used systemically.
It is incorporated into newly formed
keratin. “Impregnated” in this manner,
keratin becomes unsuitable as a fungal
nutrient. The time required for the eradication
of dermatophytes corresponds
to the renewal period of skin, hair, or
nails. Griseofulvin may cause uncharacteristic
adverse effects. The need for
prolonged administration (several
months), the incidence of side effects,
and the availability of effective and safe
alternatives have rendered griseofulvin
therapeutically obsolete.

Antiviral Drugs

Chemotherapy of Viral Infections
Viruses essentially consist of genetic
material (nucleic acids, green strands in
(A) and a capsular envelope made up of
proteins (blue hexagons), often with a
coat (gray ring) of a phospholipid (PL)
bilayer with embedded proteins (small
blue bars). They lack a metabolic system
but depend on the infected cell for their
growth and replication. Targeted therapeutic
suppression of viral replication
requires selective inhibition of those
metabolic processes that specifically
serve viral replication in infected cells.
To date, this can be achieved only to a
limited extent.
Viral replication as exemplified
by Herpes simplex viruses (A): (1) The
viral particle attaches to the host cell
membrane (adsorption) by linking its
capsular glycoproteins to specific structures
of the cell membrane. (2) The viral
coat fuses with the plasmalemma of the
host cell and the nucleocapsid (nucleic
acid plus capsule) enters the cell interior
(penetration). (3) The capsule opens
(“uncoating”) near the nuclear pores
and viral DNA moves into the cell nucleus.
The genetic material of the virus can
now direct the cell’s metabolic system.
(4a) Nucleic acid synthesis: The genetic
material (DNA in this instance) is replicated
and RNA is produced for the purpose
of protein synthesis. (4b) The proteins
are used as “viral enzymes” catalyzing
viral multiplication (e.g., DNA
polymerase and thymidine kinase), as
capsomers, or as coat components, or
are incorporated into the host cell
membrane. (5) Individual components
are assembled into new virus particles
(maturation). (6) Release of daughter viruses
results in spread of virus inside
and outside the organism. With herpes
viruses, replication entails host cell destruction
and development of disease
symptoms.
Antiviral mechanisms (A). The organism
can disrupt viral replication
with the aid of cytotoxic T-lymphocytes
that recognize and destroy virus-producing
cells (viral surface proteins) or
by means of antibodies that bind to and
inactivate extracellular virus particles.
Vaccinations are designed to activate
specific immune defenses.
Interferons (IFN) are glycoproteins
that, among other products, are released
from virus-infected cells. In
neighboring cells, interferon stimulates
the production of “antiviral proteins.”
These inhibit the synthesis of viral proteins
by (preferential) destruction of viral
DNA or by suppressing its translation.
Interferons are not directed against
a specific virus, but have a broad spectrum
of antiviral action that is, however,
species-specific. Thus, interferon for use
in humans must be obtained from cells
of human origin, such as leukocytes
(IFN-α), fibroblasts (IFN-β), or lymphocytes
(IFN-γ). Interferons are also used
to treat certain malignancies and autoimmune
disorders (e.g., IFN-α for chronic
hepatitis C and hairy cell leukemia;
IFN-β for severe herpes virus infections
and multiple sclerosis).
Virustatic antimetabolites are
“false” DNA building blocks (B) or nucleosides.
A nucleoside (e.g., thymidine)
consists of a nucleobase (e.g., thymine)
and the sugar deoxyribose. In antimetabolites,
one of the components is defective.
In the body, the abnormal nucleosides
undergo bioactivation by attachment
of three phosphate residues
(p. 287).
Idoxuridine and congeners are incorporated
into DNA with deleterious
results. This also applies to the synthesis
of human DNA. Therefore, idoxuridine
and analogues are suitable only for topical
use (e.g., in herpes simplex keratitis).
Vidarabine inhibits virally induced
DNA polymerase more strongly than it
does the endogenous enzyme. Its use is
now limited to topical treatment of severe
herpes simplex infection. Before
the introduction of the better tolerated
acyclovir, vidarabine played a major
part in the treatment of herpes simplex
encephalitis.
Among virustatic antimetabolites,
acyclovir (A) has both specificity of the
highest degree and optimal tolerability,


because it undergoes bioactivation only
in infected cells, where it preferentially
inhibits viral DNA synthesis. (1) A virally
coded thymidine kinase (specific to H.
simplex and varicella-zoster virus) performs
the initial phosphorylation step;
the remaining two phosphate residues
are attached by cellular kinases. (2) The
polar phosphate residues render acyclovir
triphosphate membrane impermeable
and cause it to accumulate in infected
cells. (3) Acyclovir triphosphate
is a preferred substrate of viral DNA
polymerase; it inhibits enzyme activity
and, following its incorporation into viral
DNA, induces strand breakage because
it lacks the 3’-OH group of deoxyribose
that is required for the attachment
of additional nucleotides. The high
therapeutic value of acyclovir is evident
in severe infections with H. simplex viruses
(e.g., encephalitis, generalized infection)
and varicella-zoster viruses
(e.g., severe herpes zoster). In these cases,
it can be given by i.v. infusion. Acyclovir
may also be given orally despite
its incomplete (15%–30%) enteral absorption.
In addition, it has topical uses.
Because host DNA synthesis remains
unaffected, adverse effects do not include
bone marrow depression. Acyclovir
is eliminated unchanged in urine
(t1/2 ~ 2.5 h).
Valacyclovir, the L-valyl ester of
acyclovir, is a prodrug that can be administered
orally in herpes zoster infections.
Its absorption rate is approx.
twice that of acyclovir. During passage
through the intestinal wall and liver, the
valine residue is cleaved by esterases,
generating acyclovir.
Famcyclovir is an antiherpetic prodrug
with good bioavailability when
given orally. It is used in genital herpes
and herpes zoster. Cleavage of two acetate
groups from the “false sugar” and
oxidation of the purine ring to guanine
yields penciclovir, the active form. The
latter differs from acyclovir with respect
to its “false sugar” moiety, but mimics it
pharmacologically. Bioactivation of
penciclovir, like that of acyclovir, involves
formation of the triphosphorylated
antimetabolite via virally induced
thymidine kinase.
Ganciclovir (structure on p. 285) is
given by infusion in the treatment of severe
infections with cytomegaloviruses
(also belonging to the herpes group);
these do not induce thymidine kinase,
phosphorylation being initiated by a
different viral enzyme. Ganciclovir is
less well tolerated and, not infrequently,
produces leukopenia and thrombopenia.
Foscarnet represents a diphosphate
analogue.
As shown in (A), incorporation of
nucleotide into a DNA strand entails
cleavage of a diphosphate residue. Foscarnet
(B) inhibits DNA polymerase by
interacting with its binding site for the
diphosphate group. Indications: systemic
therapy of severe cytomegaly infection
in AIDS patients; local therapy of
herpes simplex infections.
Amantadine (C) specifically affects
the replication of influenza A (RNA) viruses,
the causative agent of true influenza.
These viruses are endocytosed
into the cell. Release of viral DNA requires
protons from the acidic content
of endosomes to penetrate the virus.
Presumably, amantadine blocks a channel
protein in the viral coat that permits
influx of protons; thus, “uncoating” is
prevented. Moreover, amantadine inhibits
viral maturation. The drug is also
used prophylactically and, if possible,
must be taken before the outbreak of
symptoms. It also is an antiparkinsonian



Drugs for the Treatment of AIDS
Replication of the human immunodeficiency
virus (HIV), the causative
agent of AIDS, is susceptible to targeted
interventions, because several virusspecific
metabolic steps occur in infected
cells (A). Viral RNA must first be transcribed
into DNA, a step catalyzed by viral
“reverse transcriptase.” Doublestranded
DNA is incorporated into the
host genome with the help of viral integrase.
Under control by viral DNA, viral
replication can then be initiated, with
synthesis of viral RNA and proteins (including
enzymes such as reverse transcriptase
and integrase, and structural
proteins such as the matrix protein lining
the inside of the viral envelope).
These proteins are assembled not individually
but in the form of polyproteins.
These precursor proteins carry an N-terminal
fatty acid (myristoyl) residue that
promotes their attachment to the interior
face of the plasmalemma. As the virus
particle buds off the host cell, it carries
with it the affected membrane area
as its envelope. During this process, a
protease contained within the polyprotein
cleaves the latter into individual,
functionally active proteins.
I. Inhibitors of Reverse Transcriptase
IA. Nucleoside agents
These substances are analogues of thymine
(azidothymidine, stavudine),
adenine (didanosine), cytosine (lamivudine,
zalcitabine), and guanine (carbovir,
a metabolite of abacavir). They
have in common an abnormal sugar
moiety. Like the natural nucleosides,
they undergo triphosphorylation, giving
rise to nucleotides that both inhibit reverse
transcriptase and cause strand
breakage following incorporation into
viral DNA.
The nucleoside inhibitors differ in
terms of l) their ability to decrease circulating
HIV load; 2) their pharmacokinetic
properties (half life ! dosing
interval ! compliance; organ distribution
!passage through blood-brainbarrier);
3) the type of resistance-inducing
mutations of the viral genome and the
rate at which resistance develops; and
4) their adverse effects (bone marrow
depression, neuropathy, pancreatitis).
IB. Non-nucleoside inhibitors
The non-nucleoside inhibitors of reverse
transcriptase (nevirapine, delavirdine,
efavirenz) are not phosphorylated.
They bind to the enzyme with
high selectivity and thus prevent it from
adopting the active conformation. Inhibition
is noncompetitive.
II. HIV protease inhibitors
Viral protease cleaves precursor proteins
into proteins required for viral
replication. The inhibitors of this protease
(saquinavir, ritonavir, indinavir,
and nelfinavir) represent abnormal
proteins that possess high antiviral efficacy
and are generally well tolerated in
the short term. However, prolonged administration
is associated with occasionally
severe disturbances of lipid and
carbohydrate metabolism. Biotransformation
of these drugs involves cytochrome
P450 (CYP 3A4) and is therefore
subject to interaction with various other
drugs inactivated via this route.
For the dual purpose of increasing
the effectiveness of antiviral therapy
and preventing the development of a
therapy-limiting viral resistance, inhibitors
of reverse transcriptase are combined
with each other and/or with protease
inhibitors.
Combination regimens are designed
in accordance with substancespecific
development of resistance and
pharmacokinetic parameters (CNS
penetrability, “neuroprotection,” dosing
frequency).

Disinfectants

Disinfectants and Antiseptics
Disinfection denotes the inactivation or
killing of pathogens (protozoa, bacteria,
fungi, viruses) in the human environment.
This can be achieved by chemical
or physical means; the latter will not be
discussed here. Sterilization refers to
the killing of all germs, whether pathogenic,
dormant, or nonpathogenic. Antisepsis
refers to the reduction by chemical
agents of germ numbers on skin and
mucosal surfaces.
Agents for chemical disinfection
ideally should cause rapid, complete,
and persistent inactivation of all germs,
but at the same time exhibit low toxicity
(systemic toxicity, tissue irritancy,
antigenicity) and be non-deleterious to
inanimate materials. These requirements
call for chemical properties that
may exclude each other; therefore,
compromises guided by the intended
use have to be made.
Disinfectants come from various
chemical classes, including oxidants,
halogens or halogen-releasing agents,
alcohols, aldehydes, organic acids, phenols,
cationic surfactants (detergents)
and formerly also heavy metals. The basic
mechanisms of action involve denaturation
of proteins, inhibition of enzymes,
or a dehydration. Effects are dependent
on concentration and contact
time.
Activity spectrum. Disinfectants
inactivate bacteria (gram-positive >
gram-negative > mycobacteria), less effectively
their sporal forms, and a few
(e.g., formaldehyde) are virucidal.
Applications
Skin “disinfection.” Reduction of germ
counts prior to punctures or surgical
procedures is desirable if the risk of
wound infection is to be minimized.
Useful agents include: alcohols (1- and
2-propanol; ethanol 60–90%; iodine-releasing
agents like polyvinylpyrrolidone
[povidone, PVP]-iodine as a depot form
of the active principle iodine, instead of
iodine tincture), cationic surfactants,
and mixtures of these. Minimal contact
times should be at least 15 s on skin areas
with few sebaceous glands and at
least 10 min on sebaceous gland-rich
ones.
Mucosal disinfection: Germ counts
can be reduced by PVP iodine or chlorhexidine
(contact time 2 min), although
not as effectively as on skin.
Wound disinfection can be achieved
with hydrogen peroxide (0.3%–1% solution;
short, foaming action on contact
with blood and thus wound cleansing)
or with potassium permanganate
(0.0015% solution, slightly astringent),
as well as PVP iodine, chlorhexidine,
and biguanidines.
Hygienic and surgical hand disinfection:
The former is required after a suspected
contamination, the latter before
surgical procedures. Alcohols, mixtures
of alcohols and phenols, cationic surfactants,
or acids are available for this purpose.
Admixture of other agents prolongs
duration of action and reduces
flammability.
Disinfection of instruments: Instruments
that cannot be heat- or steamsterilized
can be precleaned and then
disinfected with aldehydes and detergents.
Surface (floor) disinfection employs
aldehydes combined with cationic surfactants
and oxidants or, more rarely,
acidic or alkalizing agents.
Room disinfection: room air and
surfaces can be disinfected by spraying
or vaporizing of aldehydes, provided
that germs are freely accessible.

Antiparasitic Agents

Drugs for Treating Endo- and
Ectoparasitic Infestations
Adverse hygienic conditions favor human
infestation with multicellular organisms
(referred to here as parasites).
Skin and hair are colonization sites for
arthropod ectoparasites, such as insects
(lice, fleas) and arachnids (mites).
Against these, insecticidal or arachnicidal
agents, respectively, can be used.
Endoparasites invade the intestines or
even internal organs, and are mostly
members of the phyla of flatworms and
roundworms. They are combated with
anthelmintics.
Anthelmintics. As shown in the table,
the newer agents praziquantel and
mebendazole are adequate for the treatment
of diverse worm diseases. They
are generally well tolerated, as are the
other agents listed.
Insecticides. Whereas fleas can be
effectively dealt with by disinfection of
clothes and living quarters, lice and
mites require the topical application of
insecticides to the infested subject.
Chlorphenothane (DDT) kills insects
after absorption of a very small
amount, e.g., via foot contact with
sprayed surfaces (contact insecticide).
The cause of death is nervous system
damage and seizures. In humans DDT
causes acute neurotoxicity only after
absorption of very large amounts. DDT
is chemically stable and degraded in the
environment and body at extremely
slow rates. As a highly lipophilic substance,
it accumulates in fat tissues.
Widespread use of DDT in pest control
has led to its accumulation in food
chains to alarming levels. For this reason
its use has now been banned in
many countries.
Lindane is the active γ-isomer of
hexachlorocyclohexane. It also exerts a
neurotoxic action on insects (as well as
humans). Irritation of skin or mucous
membranes may occur after topical use.
Lindane is active also against intradermal
mites (Sarcoptes scabiei, causative
agent of scabies), besides lice and fleas.
It is more readily degraded than DDT.
Permethrin, a synthetic pyrethroid,
exhibits similar anti-ectoparasitic
activity and may be the drug of choice
due to its slower cutaneous absorption,
fast hydrolytic inactivation, and rapid
renal elimination.


Antimalarials
The causative agents of malaria are plasmodia,
unicellular organisms belonging
to the order hemosporidia (class protozoa).
The infective form, the sporozoite,
is inoculated into skin capillaries when
infected female Anopheles mosquitoes
(A) suck blood from humans. The sporozoites
invade liver parenchymal cells
where they develop into primary tissue
schizonts. After multiple fission, these
schizonts produce numerous merozoites
that enter the blood. The preerythrocytic
stage is symptom free. In
blood, the parasite enters erythrocytes
(erythrocytic stage) where it again multiplies
by schizogony, resulting in the
formation of more merozoites. Rupture
of the infected erythrocytes releases the
merozoites and pyrogens. A fever attack
ensues and more erythrocytes are infected.
The generation period for the
next crop of merozoites determines the
interval between fever attacks. With
Plasmodium vivax and P. ovale, there can
be a parallel multiplication in the liver
(paraerythrocytic stage). Moreover,
some sporozoites may become dormant
in the liver as “hypnozoites” before entering
schizogony. When the sexual
forms (gametocytes) are ingested by a
feeding mosquito, they can initiate the
sexual reproductive stage of the cycle
that results in a new generation of
transmittable sporozoites.
Different antimalarials selectively
kill the parasite’s different developmental
forms. The mechanism of action is
known for some of them: pyrimethamine
and dapsone inhibit dihydrofolate
reductase (p. 273), as does chlorguanide
(proguanil) via its active metabolite. The
sulfonamide sulfadoxine inhibits synthesis
of dihydrofolic acid (p. 272). Chloroquine
and quinine accumulate within
the acidic vacuoles of blood schizonts
and inhibit polymerization of heme, the
latter substance being toxic for the
schizonts.
Antimalarial drug choice takes into
account tolerability and plasmodial resistance.
Tolerability. The first available
antimalarial, quinine, has the smallest
therapeutic margin. All newer agents
are rather well tolerated.
Plasmodium (P.) falciparum, responsible
for the most dangerous form
of malaria, is particularly prone to develop
drug resistance. The incidence of
resistant strains rises with increasing
frequency of drug use. Resistance has
been reported for chloroquine and also
for the combination pyrimethamine/
sulfadoxine.
Drug choice for antimalarial
chemoprophylaxis. In areas with a risk
of malaria, continuous intake of antimalarials
affords the best protection
against the disease, although not
against infection. The drug of choice is
chloroquine. Because of its slow excretion
(plasma t1/2 = 3d and longer), a single
weekly dose is sufficient. In areas
with resistant P. falciparum, alternative
regimens are chloroquine plus pyrimethamine/
sulfadoxine (or proguanil,
or doxycycline), the chloroquine analogue
amodiaquine, as well as quinine
or the better tolerated derivative mefloquine
(blood-schizonticidal). Agents active
against blood schizonts do not prevent
the (symptom-free) hepatic infection,
only the disease-causing infection
of erythrocytes (“suppression therapy”).
On return from an endemic malaria region,
a 2 wk course of primaquine is adequate
for eradication of the late hepatic
stages (P. vivax and P. ovale).
Protection from mosquito bites
(net, skin-covering clothes, etc.) is a
very important prophylactic measure.
Antimalarial therapy employs the
same agents and is based on the same
principles. The blood-schizonticidal
halofantrine is reserved for therapy only.
The pyrimethamine-sulfadoxine
combination may be used for initial selftreatment.
Drug resistance is accelerating in
many endemic areas; malaria vaccines
may hold the greatest hope for control
of infection.

Anticancer Drugs

Chemotherapy of Malignant Tumors
A tumor (neoplasm) consists of cells
that proliferate independently of the
body’s inherent “building plan.” A malignant
tumor (cancer) is present when
the tumor tissue destructively invades
healthy surrounding tissue or when dislodged
tumor cells form secondary tumors
(metastases) in other organs. A
cure requires the elimination of all malignant
cells (curative therapy). When
this is not possible, attempts can be
made to slow tumor growth and thereby
prolong the patient’s life or improve
quality of life (palliative therapy).
Chemotherapy is faced with the problem
that the malignant cells are endogenous
and are not endowed with special
metabolic properties.
Cytostatics (A) are cytotoxic substances
that particularly affect proliferating
or dividing cells. Rapidly dividing
malignant cells are preferentially injured.
Damage to mitotic processes not
only retards tumor growth but may also
initiate apoptosis (programmed cell
death). Tissues with a low mitotic rate
are largely unaffected; likewise, most
healthy tissues. This, however, also applies
to malignant tumors consisting of
slowly dividing differentiated cells. Tissues
that have a physiologically high
mitotic rate are bound to be affected by
cytostatic therapy. Thus, typical adverse
effects occur:
Loss of hair results from injury to
hair follicles; gastrointestinal disturbances,
such as diarrhea, from inadequate
replacement of enterocytes
whose life span is limited to a few days;
nausea and vomiting from stimulation of
area postrema chemoreceptors ;
and lowered resistance to infection from
weakening of the immune system .
In addition, cytostatics cause bone
marrow depression. Resupply of blood
cells depends on the mitotic activity of
bone marrow stem and daughter cells.
When myeloid proliferation is arrested,
the short-lived granulocytes are the first
to be affected (neutropenia), then blood
platelets (thrombopenia) and, finally,
the more long-lived erythrocytes (anemia).
Infertility is caused by suppression
of spermatogenesis or follicle maturation.
Most cytostatics disrupt DNA metabolism.
This entails the risk of a potential
genomic alteration in healthy
cells (mutagenic effect). Conceivably,
the latter accounts for the occurrence of
leukemias several years after cytostatic
therapy (carcinogenic effect). Furthermore,
congenital malformations are to
be expected when cytostatics must be
used during pregnancy (teratogenic effect).
Cytostatics possess different mechanisms
of action.
Damage to the mitotic spindle.
The contractile proteins of the spindle
apparatus must draw apart the replicated
chromosomes before the cell can divide.
This process is prevented by the
so-called spindle poisons (see also colchicine)
that arrest mitosis at
metaphase by disrupting the assembly
of microtubules into spindle threads.
The vinca alkaloids, vincristine and vinblastine
(from the periwinkle plant, Vinca
rosea) exert such a cell-cycle-specific
effect. Damage to the nervous system is
a predicted adverse effect arising from
injury to microtubule-operated axonal
transport mechanisms.
Paclitaxel, from the bark of the pacific
yew (Taxus brevifolia), inhibits disassembly
of microtubules and induces
atypical ones. Docetaxel is a semisynthetic
derivative.


Inhibition of DNA and RNA synthesis
(A). Mitosis is preceded by replication
of chromosomes (DNA synthesis)
and increased protein synthesis (RNA
synthesis). Existing DNA (gray) serves as
a template for the synthesis of new
(blue) DNA or RNA. De novo synthesis
may be inhibited by:
Damage to the template (1). Alkylating
cytostatics are reactive compounds
that transfer alkyl residues into
a covalent bond with DNA. For instance,
mechlorethamine (nitrogen mustard) is
able to cross-link double-stranded DNA
on giving off its chlorine atoms. Correct
reading of genetic information is thereby
rendered impossible. Other alkylating
agents are chlorambucil, melphalan,
thio-TEPA, cyclophosphamide (p. 300,
320), ifosfamide, lomustine, and busulfan.
Specific adverse reactions include
irreversible pulmonary fibrosis due to
busulfan and hemorrhagic cystitis
caused by the cyclophosphamide metabolite
acrolein (preventable by the
uroprotectant mesna). Cisplatin binds to
(but does not alkylate) DNA strands.
Cystostatic antibiotics insert themselves
into the DNA double strand; this
may lead to strand breakage (e.g., with
bleomycin). The anthracycline antibiotics
daunorubicin and adriamycin (doxorubicin)
may induce cardiomyopathy. Bleomycin
can also cause pulmonary fibrosis.
The epipodophyllotoxins, etoposide
and teniposide, interact with topoisomerase
II, which functions to split,
transpose, and reseal DNA strands
(p. 274); these agents cause strand
breakage by inhibiting resealing.
Inhibition of nucleobase synthesis
(2). Tetrahydrofolic acid (THF) is required
for the synthesis of both purine
bases and thymidine. Formation of THF
from folic acid involves dihydrofolate
reductase (p. 272). The folate analogues
aminopterin and methotrexate (amethopterin)
inhibit enzyme activity as
false substrates. As cellular stores of THF
are depleted, synthesis of DNA and RNA
building blocks ceases. The effect of
these antimetabolites can be reversed
by administration of folinic acid (5-formyl-
THF, leucovorin, citrovorum factor).
Incorporation of false building
blocks (3). Unnatural nucleobases (6-
mercaptopurine; 5-fluorouracil) or nucleosides
with incorrect sugars (cytarabine)
act as antimetabolites. They inhibit
DNA/RNA synthesis or lead to synthesis
of missense nucleic acids.
6-Mercaptopurine results from biotransformation
of the inactive precursor
azathioprine (p. 37). The uricostatic allopurinol
inhibits the degradation of 6-
mercaptopurine such that co-administration
of the two drugs permits dose
reduction of the latter.
Frequently, the combination of cytostatics
permits an improved therapeutic
effect with fewer adverse reactions.
Initial success can be followed by
loss of effect because of the emergence
of resistant tumor cells. Mechanisms of
resistance are multifactorial:
Diminished cellular uptake may result
from reduced synthesis of a transport
protein that may be needed for
membrane penetration (e.g., methotrexate).
Augmented drug extrusion: increased
synthesis of the P-glycoprotein
that extrudes drugs from the cell (e.g.,
anthracyclines, vinca alkaloids, epipodophyllotoxins,
and paclitaxel) is reponsible
for multi-drug resistance
(mdr-1 gene amplification).
Diminished bioactivation of a prodrug,
e.g., cytarabine, which requires
intracellular phosphorylation to become
cytotoxic.
Change in site of action: e.g., increased
synthesis of dihydrofolate reductase
may occur as a compensatory
response to methotrexate.
Damage repair: DNA repair enzymes
may become more efficient in repairing
defects caused by cisplatin.

Immune Modulatiors

Inhibition of Immune Responses
Both the prevention of transplant rejection
and the treatment of autoimmune
disorders call for a suppression of immune
responses. However, immune
suppression also entails weakened defenses
against infectious pathogens and
a long-term increase in the risk of neoplasms.
A specific immune response begins
with the binding of antigen by lymphocytes
carrying specific receptors
with the appropriate antigen-binding
site. B-lymphocytes “recognize” antigen
surface structures by means of membrane
receptors that resemble the antibodies
formed subsequently. T-lymphocytes
(and naive B-cells) require the
antigen to be presented on the surface
of macrophages or other cells in conjunction
with the major histocompatibility
complex (MHC); the latter permits
recognition of antigenic structures
by means of the T-cell receptor. T-helper
cells carry adjacent CD-3 and CD-4
complexes, cytotoxic T-cells a CD-8
complex. The CD proteins assist in docking
to the MHC. In addition to recognition
of antigen, activation of lymphocytes
requires stimulation by cytokines.
Interleukin-1 is formed by macrophages,
and various interleukins (IL), including
IL-2, are made by T-helper cells. As
antigen-specific lymphocytes proliferate,
immune defenses are set into motion.
I. Interference with antigen recognition.
Muromonab CD3 is a monoclonal
antibody directed against mouse
CD-3 that blocks antigen recognition by
T-lymphocytes (use in graft rejection).
II. Inhibition of cytokine production
or action. Glucocorticoids modulate
the expression of numerous
genes; thus, the production of IL-1 and
IL-2 is inhibited, which explains the
suppression of T-cell-dependent immune
responses. Glucocorticoids are
used in organ transplantations, autoimmune
diseases, and allergic disorders.
Systemic use carries the risk of iatrogenic
Cushing’s syndrome .
Cyclosporin A is an antibiotic polypeptide
from fungi and consists of 11, in
part atypical, amino acids. Given orally,
it is absorbed, albeit incompletely. In
lymphocytes, it is bound by cyclophilin,
a cytosolic receptor that inhibits the
phosphatase calcineurin. The latter
plays a key role in T-cell signal transduction.
It contributes to the induction
of cytokine production, including that of
IL-2. The breakthroughs of modern
transplantation medicine are largely attributable
to the introduction of cyclosporin
A. Prominent among its adverse
effects are renal damage, hypertension,
and hyperkalemia.
Tacrolimus, a macrolide, derives
from a streptomyces species; pharmacologically
it resembles cyclosporin A,
but is more potent and efficacious.
The monoclonal antibodies daclizumab
and basiliximab bind to the α-
chain of the II-2 receptor of T-lymphocytes
and thus prevent their activation,
e.g., during transplant rejection.
III. Disruption of cell metabolism
with inhibition of proliferation. At
dosages below those needed to treat
malignancies, some cytostatics are also
employed for immunosuppression, e.g.,
azathioprine, methotrexate, and cyclophosphamide.
The antiproliferative
effect is not specific for lymphocytes
and involves both T- and Bcells.
Mycophenolate mofetil has a more
specific effect on lymphocytes than on
other cells. It inhibits inosine monophosphate
dehydrogenase, which catalyzes
purine synthesis in lymphocytes.
It is used in acute tissue rejection responses.
IV. Anti-T-cell immune serum is
obtained from animals immunized with
human T-lymphocytes. The antibodies
bind to and damage T-cells and can thus
be used to attenuate tissue rejection.

Antidotes

Antidotes and treatment of poisonings
Drugs used to counteract drug overdosage
are considered under the appropriate
headings, e.g., physostigmine with
atropine; naloxone with opioids; flumazenil
with benzodiazepines; antibody
(Fab fragments) with digitalis; and
N-acetyl-cysteine with acetaminophen
intoxication.
Chelating agents serve as antidotes
in poisoning with heavy metals.
They act to complex and, thus, “inactivate”
heavy metal ions. Chelates (from
Greek: chele = claw [of crayfish]) represent
complexes between a metal ion
and molecules that carry several binding
sites for the metal ion. Because of
their high affinity, chelating agents “attract”
metal ions present in the organism.
The chelates are non-toxic, are excreted
predominantly via the kidney,
maintain a tight organometallic bond
also in the concentrated, usually acidic,
milieu of tubular urine and thus promote
the elimination of metal ions.
Na2Ca-EDTA is used to treat lead
poisoning. This antidote cannot penetrate
cell membranes and must be given
parenterally. Because of its high binding
affinity, the lead ion displaces Ca2+ from
its bond. The lead-containing chelate is
eliminated renally. Nephrotoxicity predominates
among the unwanted effects.
Na3Ca-Pentetate is a complex of diethylenetriaminopentaacetic
acid (DPTA)
and serves as antidote in lead and other
metal intoxications.
Dimercaprol (BAL, British Anti-Lewisite)
was developed in World War II
as an antidote against vesicant organic
arsenicals . It is able to chelate various
metal ions. Dimercaprol forms a liquid,
rapidly decomposing substance
that is given intramuscularly in an oily
vehicle. A related compound, both in
terms of structure and activity, is dimercaptopropanesulfonic
acid, whose
sodium salt is suitable for oral administration.
Shivering, fever, and skin reactions
are potential adverse effects.
Deferoxamine derives from the
bacterium Streptomyces pilosus. The
substance possesses a very high ironbinding
capacity, but does not withdraw
iron from hemoglobin or cytochromes.
It is poorly absorbed enterally and must
be given parenterally to cause increased
excretion of iron. Oral administration is
indicated only if enteral absorption of
iron is to be curtailed. Unwanted effects
include allergic reactions. It should be
noted that blood letting is the most effective
means of removing iron from the
body; however, this method is unsuitable
for treating conditions of iron overload
associated with anemia.
D-penicillamine can promote the
elimination of copper (e.g., in Wilson’s
disease) and of lead ions. It can be given
orally. Two additional uses are cystinuria
and rheumatoid arthritis. In the former,
formation of cystine stones in the
urinary tract is prevented because the
drug can form a disulfide with cysteine
that is readily soluble. In the latter, penicillamine
can be used as a basal regimen
. The therapeutic effect
may result in part from a reaction with
aldehydes, whereby polymerization of
collagen molecules into fibrils is inhibited.
Unwanted effects are: cutaneous
damage (diminished resistance to mechanical
stress with a tendency to form
blisters), nephrotoxicity, bone marrow
depression, and taste disturbances.


Antidotes for cyanide poisoning
(A). Cyanide ions (CN-) enter the organism
in the form of hydrocyanic acid
(HCN); the latter can be inhaled, released
from cyanide salts in the acidic
stomach juice, or enzymatically liberated
from bitter almonds in the gastrointestinal
tract. The lethal dose of HCN can
be as low as 50 mg. CN- binds with high
affinity to trivalent iron and thereby arrests
utilization of oxygen via mitochondrial
cytochrome oxidases of the
respiratory chain. An internal asphyxiation
(histotoxic hypoxia) ensues while
erythrocytes remain charged with O2
(venous blood colored bright red).
In small amounts, cyanide can be
converted to the relatively nontoxic
thiocyanate (SCN-) by hepatic “rhodanese”
or sulfur transferase. As a therapeutic
measure, thiosulfate can be given
i.v. to promote formation of thiocyanate,
which is eliminated in urine. However,
this reaction is slow in onset. A
more effective emergency treatment is
the i.v. administration of the methemoglobin-
forming agent 4-dimethylaminophenol,
which rapidly generates
trivalent from divalent iron in hemoglobin.
Competition between methemoglobin
and cytochrome oxidase for CN- ions
favors the formation of cyanmethemoglobin.
Hydroxocobalamin is an alternative,
very effective antidote because its
central cobalt atom binds CN- with high
affinity to generate cyanocobalamin.
Tolonium chloride (Toluidin
Blue). Brown-colored methemoglobin,
containing tri- instead of divalent iron,
is incapable of carrying O2. Under normal
conditions, methemoglobin is produced
continuously, but reduced again
with the help of glucose-6-phosphate
dehydrogenase. Substances that promote
formation of methemoglobin (B)
may cause a lethal deficiency of O2. Tolonium
chloride is a redox dye that can
be given i.v. to reduce methemoglobin.
Obidoxime is an antidote used to
treat poisoning with insecticides of the
organophosphate type (p. 102). Phosphorylation
of acetylcholinesterase
causes an irreversible inhibition of acetylcholine
breakdown and hence flooding
of the organism with the transmitter.
Possible sequelae are exaggerated
parasympathomimetic activity, blockade
of ganglionic and neuromuscular
transmission, and respiratory paralysis.
Therapeutic measures include: 1.
administration of atropine in high dosage
to shield muscarinic acetylcholine
receptors; and 2. reactivation of acetylcholinesterase
by obidoxime, which
successively binds to the enzyme, captures
the phosphate residue by a nucleophilic
attack, and then dissociates
from the active center to release the enzyme
from inhibition.
Ferric Ferrocyanide (“Berlin
Blue,” B) is used to treat poisoning with
thallium salts (e.g., in rat poison), the
initial symptoms of which are gastrointestinal
disturbances, followed by nerve
and brain damage, as well as hair loss.
Thallium ions present in the organism
are secreted into the gut but undergo
reabsorption. The insoluble, nonabsorbable
colloidal Berlin Blue binds thallium
ions. It is given orally to prevent absorption
of acutely ingested thallium or to
promote clearance from the organism
by intercepting thallium that is secreted
into the intestines.

Psychopharmacologicals

Benzodiazepines
Benzodiazepines modify affective responses
to sensory perceptions; specifically,
they render a subject indifferent
towards anxiogenic stimuli, i.e., anxiolytic
action. Furthermore, benzodiazepines
exert sedating, anticonvulsant,
and muscle-relaxant (myotonolytic, p.
182) effects. All these actions result
from augmenting the activity of inhibitory
neurons and are mediated by specific
benzodiazepine receptors that
form an integral part of the GABAA receptor-
chloride channel complex. The
inhibitory transmitter GABA acts to
open the membrane chloride channels.
Increased chloride conductance of the
neuronal membrane effectively shortcircuits
responses to depolarizing inputs.
Benzodiazepine receptor agonists
increase the affinity of GABA to its receptor.
At a given concentration of
GABA, binding to the receptors will,
therefore, be increased, resulting in an
augmented response. Excitability of the
neurons is diminished.
Therapeutic indications for benzodiazepines
include anxiety states associated
with neurotic, phobic, and depressive
disorders, or myocardial infarction
(decrease in cardiac stimulation
due to anxiety); insomnia; preanesthetic
(preoperative) medication;
epileptic seizures; and hypertonia of
skeletal musculature (spasticity, rigidity).
Since GABA-ergic synapses are confined
to neural tissues, specific inhibition
of central nervous functions can be
achieved; for instance, there is little
change in blood pressure, heart rate,
and body temperature. The therapeutic
index of benzodiazepines, calculated
with reference to the toxic dose producing
respiratory depression, is greater
than 100 and thus exceeds that of barbiturates
and other sedative-hypnotics
by more than tenfold. Benzodiazepine
intoxication can be treated with a specific
antidote (see below).
Since benzodiazepines depress responsivity
to external stimuli, automotive
driving skills and other tasks requiring
precise sensorimotor coordination
will be impaired.
Triazolam (t1/2 of elimination
~1.5–5.5 h) is especially likely to impair
memory (anterograde amnesia) and to
cause rebound anxiety or insomnia and
daytime confusion. The severity of these
and other adverse reactions (e.g., rage,
violent hostility, hallucinations), and
their increased frequency in the elderly,
has led to curtailed or suspended use of
triazolam in some countries (UK).
Although benzodiazepines are well
tolerated, the possibility of personality
changes (nonchalance, paradoxical excitement)
and the risk of physical dependence
with chronic use must not be
overlooked. Conceivably, benzodiazepine
dependence results from a kind of
habituation, the functional counterparts
of which become manifest during abstinence
as restlessness and anxiety; even
seizures may occur. These symptoms
reinforce chronic ingestion of benzodiazepines.
Benzodiazepine antagonists, such
as flumazenil, possess affinity for benzodiazepine
receptors, but they lack intrinsic
activity. Flumazenil is an effective
antidote in the treatment of benzodiazepine
overdosage or can be used
postoperatively to arouse patients sedated
with a benzodiazepine.
Whereas benzodiazepines possessing
agonist activity indirectly augment
chloride permeability, inverse agonists
exert an opposite action. These substances
give rise to pronounced restlessness,
excitement, anxiety, and convulsive
seizures. There is, as yet, no
therapeutic indication for their use.


Pharmacokinetics of Benzodiazepines
All benzodiazepines exert their actions
at specific receptors (p. 226). The choice
between different agents is dictated by
their speed, intensity, and duration of
action. These, in turn, reflect physicochemical
and pharmacokinetic properties.
Individual benzodiazepines remain
in the body for very different lengths of
time and are chiefly eliminated through
biotransformation. Inactivation may entail
a single chemical reaction or several
steps (e.g., diazepam) before an inactive
metabolite suitable for renal elimination
is formed. Since the intermediary
products may, in part, be pharmacologically
active and, in part, be excreted
more slowly than the parent substance,
metabolites will accumulate with continued
regular dosing and contribute
significantly to the final effect.
Biotransformation begins either at
substituents on the diazepine ring (diazepam:
N-dealkylation at position 1;
midazolam: hydroxylation of the methyl
group on the imidazole ring) or at the
diazepine ring itself. Hydroxylated midazolam
is quickly eliminated following
glucuronidation (t1/2 ~ 2 h). N-demethyldiazepam
(nordazepam) is biologically
active and undergoes hydroxylation
at position 3 on the diazepine
ring. The hydroxylated product (oxazepam)
again is pharmacologically active.
By virtue of their long half-lives, diazepam
(t1/2 ~ 32 h) and, still more so, its
metabolite, nordazepam (t1/2 50–90 h),
are eliminated slowly and accumulate
during repeated intake. Oxazepam
undergoes conjugation to glucuronic acid
via its hydroxyl group (t1/2 = 8 h) and
renal excretion (A).
The range of elimination half-lives
for different benzodiazepines or their
active metabolites is represented by the
shaded areas (B). Substances with a
short half-life that are not converted to
active metabolites can be used for induction
or maintenance of sleep (light
blue area in B). Substances with a long
half-life are preferable for long-term
anxiolytic treatment (light green area)
because they permit maintenance of
steady plasma levels with single daily
dosing. Midazolam enjoys use by the i.v.
route in preanesthetic medication and
anesthetic combination regimens.
Benzodiazepine Dependence
Prolonged regular use of benzodiazepines
can lead to physical dependence.
With the long-acting substances marketed
initially, this problem was less obvious
in comparison with other dependence-
producing drugs because of the
delayed appearance of withdrawal
symptoms. The severity of the abstinence
syndrome is inversely related to
the elimination t1/2, ranging from mild
to moderate (restlessness, irritability,
sensitivity to sound and light, insomnia,
and tremulousness) to dramatic (depression,
panic, delirium, grand mal seizures).
Some of these symptoms pose
diagnostic difficulties, being indistinguishable
from the ones originally treated.
Administration of a benzodiazepine
antagonist would abruptly provoke abstinence
signs. There are indications
that substances with intermediate elimination
half-lives are most frequently
abused (violet area in B).

Therapy of Manic-Depressive Illness
Manic-depressive illness connotes a
psychotic disorder of affect that occurs
episodically without external cause. In
endogenous depression (melancholia),
mood is persistently low. Mania refers
to the opposite condition (p. 234). Patients
may oscillate between these two
extremes with interludes of normal
mood. Depending on the type of disorder,
mood swings may alternate
between the two directions (bipolar depression,
cyclothymia) or occur in only
one direction (unipolar depression).
I. Endogenous Depression
In this condition, the patient experiences
profound misery (beyond the
observer’s empathy) and feelings of severe
guilt because of imaginary misconduct.
The drive to act or move is inhibited.
In addition, there are disturbances
mostly of a somatic nature (insomnia,
loss of appetite, constipation, palpitations,
loss of libido, impotence, etc.). Although
the patient may have suicidal
thoughts, psychomotor retardation prevents
suicidal impulses from being carried
out. In A, endogenous depression is
illustrated by the layers of somber colors;
psychomotor drive, symbolized by
a sine oscillation, is strongly reduced.
Therapeutic agents fall into two
groups:
! Thymoleptics, possessing a pronounced
ability to re-elevate depressed
mood e.g., the tricyclic antidepressants;
! Thymeretics, having a predominant
activating effect on psychomotor
drive, e g., monoamine oxidase inhibitors.
It would be wrong to administer
drive-enhancing drugs, such as amphetamines,
to a patient with endogenous
depression. Because this therapy fails to
elevate mood but removes psychomotor
inhibition (A), the danger of suicide
increases.
Tricyclic antidepressants (TCA;
prototype: imipramine) have had the
longest and most extensive therapeutic
use; however, in the past decade, they
have been increasingly superseded by
the serotonin-selective reuptake inhibitors
(SSRI; prototype: fluoxetine).
The central seven-membered ring
of the TCAs imposes a 120° angle
between the two flanking aromatic
rings, in contradistinction to the flat
ring system present in phenothiazine
type neuroleptics (p. 237). The side
chain nitrogen is predominantly protonated
at physiological pH.
The TCAs have affinity for both receptors
and transporters of monoamine
transmitters and behave as antagonists
in both respects. Thus, the neuronal reuptake
of norepinephrine (p. 82) and serotonin
(p. 116) is inhibited, with a resultant
increase in activity. Muscarinic
acetylcholine receptors, !-adrenoceptors,
and certain 5-HT and histamine(
H1) receptors are blocked. Interference
with the dopamine system is
relatively minor.
How interference with these transmitter/
modulator substances translates
into an antidepressant effect is still hypothetical.
The clinical effect emerges
only after prolonged intake, i.e., 2–3 wk,
as evidenced by an elevation of mood
and drive. However, the alteration in
monoamine metabolism occurs as soon
as therapy is started. Conceivably, adaptive
processes (such as downregulation
of cortical serotonin and "-adrenoceptors)
are ultimately responsible. In
healthy subjects, the TCAs do not improve
mood (no euphoria).
Apart from the antidepressant effect,
acute effects occur that are evident
also in healthy individuals. These vary
in degree among individual substances
and thus provide a rationale for differentiated
clinical use (p. 233), based
upon the divergent patterns of interference
with amine transmitters/modulators.
Amitriptyline exerts anxiolytic,
sedative and psychomotor dampening
effects. These are useful in depressive
patients who are anxious and agitated.
In contrast, desipramine produces
psychomotor activation. Imipramine



occupies an intermediate position. It
should be noted that, in the organism,
biotransformation of imipramine leads
to desipramine (N-desmethylimipramine).
Likewise, the desmethyl derivative
of amitriptyline (nortriptyline) is
less dampening.
In nondepressive patients whose
complaints are of predominantly psychogenic
origin, the anxiolytic-sedative
effect may be useful in efforts to bring
about a temporary “psychosomatic uncoupling.”
In this connection, clinical
use as “co-analgesics” (p. 194) may be
noted.
The side effects of tricyclic antidepressants
are largely attributable to the
ability of these compounds to bind to
and block receptors for endogenous
transmitter substances. These effects
develop acutely. Antagonism at muscarinic
cholinoceptors leads to atropinelike
effects such as tachycardia, inhibition
of exocrine glands, constipation,
impaired micturition, and blurred vision.
Changes in adrenergic function are
complex. Inhibition of neuronal catecholamine
reuptake gives rise to superimposed
indirect sympathomimetic
stimulation. Patients are supersensitive
to catecholamines (e.g., epinephrine in
local anesthetic injections must be
avoided). On the other hand, blockade
of !1-receptors may lead to orthostatic
hypotension.
Due to their cationic amphiphilic
nature, the TCA exert membrane-stabilizing
effects that can lead to disturbances
of cardiac impulse conduction
with arrhythmias as well as decreases in
myocardial contractility. All TCA lower
the seizure threshold. Weight gain may
result from a stimulant effect on appetite.
Maprotiline, a tetracyclic compound,
largely resembles tricyclic
agents in terms of its pharmacological
and clinical actions. Mianserine also
possesses a tetracyclic structure, but
differs insofar as it increases intrasynaptic
concentrations of norepinephrine
by blocking presynaptic !2-receptors,
rather than reuptake. Moreover, it has
less pronounced atropine-like activity.
Fluoxetine, along with sertraline,
fluvoxamine, and paroxetine, belongs to
the more recently developed group of
SSRI. The clinical efficacy of SSRI is considered
comparable to that of established
antidepressants. Added advantages
include: absence of cardiotoxicity,
fewer autonomic nervous side effects,
and relative safety with overdosage.
Fluoxetine causes loss of appetite and
weight reduction. Its main adverse effects
include: overarousal, insomnia,
tremor, akathisia, anxiety, and disturbances
of sexual function.
Moclobemide is a new representative
of the group of MAO inhibitors. Inhibition
of intraneuronal degradation of
serotonin and norepinephrine causes an
increase in extracellular amine levels. A
psychomotor stimulant thymeretic action
is the predominant feature of MAO
inhibitors. An older member of this
group, tranylcypromine, causes irreversible
inhibition of the two isozymes
MAOA and MAOB. Therefore, presystemic
elimination in the liver of biogenic
amines, such as tyramine, which are ingested
in food (e.g., aged cheese and
Chianti), will be impaired. To avoid the
danger of a hypertensive crisis, therapy
with tranylcypromine or other nonselective
MAO inhibitors calls for stringent
dietary rules. With moclobemide,
this hazard is much reduced because it
inactivates only MAOA and does so in a
reversible manner.


II. Mania
The manic phase is characterized by exaggerated
elation, flight of ideas, and a
pathologically increased psychomotor
drive. This is symbolically illustrated in
A by a disjointed structure and aggressive
color tones. The patients are overconfident,
continuously active, show
progressive incoherence of thought and
loosening of associations, and act irresponsibly
(financially, sexually etc.).
Lithium ions. Lithium salts (e.g.,
acetate, carbonate) are effective in controlling
the manic phase. The effect becomes
evident approx. 10 d after the
start of therapy. The small therapeutic
index necessitates frequent monitoring
of Li+ serum levels. Therapeutic levels
should be kept between 0.8–1.0 mM in
fasting morning blood samples. At higher
values there is a risk of adverse effects.
CNS symptoms include fine tremor,
ataxia or seizures. Inhibition of the renal
actions of vasopressin (p. 164) leads to
polyuria and thirst. Thyroid function is
impaired (p. 244), with compensatory
development of (euthyroid) goiter.
The mechanism of action of Li ions
remains to be fully elucidated. Chemically,
lithium is the lightest of the alkali
metals, which include such biologically
important elements as sodium and potassium.
Apart from interference with
transmembrane cation fluxes (via ion
channels and pumps), a lithium effect of
major significance appears to be membrane
depletion of phosphatidylinositol
bisphosphates, the principal lipid substrate
used by various receptors in
transmembrane signalling (p. 66).
Blockade of this important signal transduction
pathway leads to impaired ability
of neurons to respond to activation
of membrane receptors for transmitters
or other chemical signals. Another site
of action of lithium may be GTP-binding
proteins responsible for signal transduction
initiated by formation of the agonist-
receptor complex.
Rapid control of an acute attack of
mania may require the use of a neuroleptic
(see below).
Alternate treatments. Mood-stabilization
and control of manic or hypomanic
episodes in some subtypes of
bipolar illness may also be achieved
with the anticonvulsants valproate and
carbamazepine, as well as with calcium
channel blockers (e.g., verapamil, nifedipine,
nimodipine). Effects are delayed
and apparently unrelated to the mechanisms
responsible for anticonvulsant
and cardiovascular actions, respectively.
III. Prophylaxis
With continued treatment for 6 to 12
months, lithium salts prevent the recurrence
of either manic or depressive
states, effectively stabilizing mood at a
normal level.

Therapy of Schizophrenia
Schizophrenia is an endogenous psychosis
of episodic character. Its chief
symptoms reflect a thought disorder
(i.e., distracted, incoherent, illogical
thinking; impoverished intellectual
content; blockage of ideation; abrupt
breaking of a train of thought: claims of
being subject to outside agencies that
control the patient’s thoughts), and a
disturbance of affect (mood inappropriate
to the situation) and of psychomotor
drive. In addition, patients exhibit delusional
paranoia (persecution mania) or
hallucinations (fearfulness hearing of
voices). Contrasting these “positive”
symptoms, the so-called “negative”
symptoms, viz., poverty of thought, social
withdrawal, and anhedonia, assume
added importance in determining the
severity of the disease. The disruption
and incoherence of ideation is symbolically
represented at the top left (A) and
the normal psychic state is illustrated as
on p. 237 (bottom left).
Neuroleptics
After administration of a neuroleptic,
there is at first only psychomotor dampening.
Tormenting paranoid ideas and
hallucinations lose their subjective importance
(A, dimming of flashy colors);
however, the psychotic processes still
persist. In the course of weeks, psychic
processes gradually normalize (A); the
psychotic episode wanes, although
complete normalization often cannot be
achieved because of the persistence of
negative symptoms. Nonetheless, these
changes are significant because the patient
experiences relief from the torment
of psychotic personality changes;
care of the patient is made easier and
return to a familiar community environment
is accelerated.
The conventional (or classical) neuroleptics
comprise two classes of compounds
with distinctive chemical structures:
1. the phenothiazines derived
from the antihistamine promethazine
(prototype: chlorpromazine), including
their analogues (e.g., thioxanthenes);
and 2. the butyrophenones (prototype:
haloperidol). According to the chemical
structure of the side chain, phenothiazines
and thioxanthenes can be subdivided
into aliphatic (chlorpromazine,
triflupromazine, p. 239 and piperazine
congeners (trifluperazine, fluphenazine,
flupentixol, p. 239).
The antipsychotic effect is probably
due to an antagonistic action at dopamine
receptors. Aside from their main
antipsychotic action, neuroleptics display
additional actions owing to their
antagonism at
– muscarinic acetylcholine receptors !
atropine-like effects;
– !-adrenoceptors for norepinephrine
! disturbances of blood pressure
regulation;
– dopamine receptors in the nigrostriatal
system ! extrapyramidal motor
disturbances; in the area postrema !
antiemetic action (p. 330), and in the
pituitary gland !increased secretion
of prolactin (p. 242);
– histamine receptors in the cerebral
cortex ! possible cause of sedation.
These ancillary effects are also elicited
in healthy subjects and vary in intensity
among individual substances.
Other indications. Acutely, there is
sedation with anxiolysis after neuroleptization
has been started. This effect can
be utilized for: “psychosomatic uncoupling”
in disorders with a prominent
psychogenic component; neuroleptanalgesia
(p. 216) by means of the butyrophenone
droperidol in combination
with an opioid; tranquilization of overexcited,
agitated patients; treatment of
delirium tremens with haloperidol; as
well as the control of mania (see p. 234).
It should be pointed out that neuroleptics
do not exert an anticonvulsant
action, on the contrary, they may lower
seizure thershold.


Because they inhibit the thermoregulatory
center, neuroleptics can be employed
for controlled hypothermia
(p. 202).
Adverse Effects. Clinically most
important and therapy-limiting are extrapyramidal
disturbances; these result
from dopamine receptor blockade.
Acute dystonias occur immediately after
neuroleptization and are manifested
by motor impairments, particularly in
the head, neck, and shoulder region. After
several days to months, a parkinsonian
syndrome (pseudoparkinsonism)
or akathisia (motor restlessness) may
develop. All these disturbances can be
treated by administration of antiparkinson
drugs of the anticholinergic type,
such as biperiden (i.e., in acute dystonia).
As a rule, these disturbances disappear
after withdrawal of neuroleptic
medication. Tardive dyskinesia may become
evident after chronic neuroleptization
for several years, particularly
when the drug is discontinued. It is due
to hypersensitivity of the dopamine receptor
system and can be exacerbated
by administration of anticholinergics.
Chronic use of neuroleptics can, on
occasion, give rise to hepatic damage associated
with cholestasis. A very rare,
but dramatic, adverse effect is the malignant
neuroleptic syndrome (skeletal
muscle rigidity, hyperthermia, stupor)
that can end fatally in the absence of intensive
countermeasures (including
treatment with dantrolene, p. 182).
Neuroleptic activity profiles. The
marked differences in action spectra of
the phenothiazines, their derivatives
and analogues, which may partially resemble
those of butyrophenones, are
important in determining therapeutic
uses of neuroleptics. Relevant parameters
include: antipsychotic efficacy
(symbolized by the arrow); the extent
of sedation; and the ability to induce extrapyramidal
adverse effects. The latter
depends on relative differences in antagonism
towards dopamine and acetylcholine,
respectively (p. 188). Thus,
the butyrophenones carry an increased
risk of adverse motor reactions because
they lack anticholinergic activity and,
hence, are prone to upset the balance
between striatal cholinergic and dopaminergic
activity.
Derivatives bearing a piperazine
moiety (e.g., trifluperazine, fluphenazine)
have greater antipsychotic potency
than do drugs containing an aliphatic
side chain (e.g., chlorpromazine, triflupromazine).
However, their antipsychotic
effects are qualitatively indistinguishable.
As structural analogues of the
phenothiazines, thioxanthenes (e.g.,
chlorprothixene, flupentixol) possess a
central nucleus in which the N atom is
replaced by a carbon linked via a double
bond to the side chain. Unlike the phenothiazines,
they display an added thymoleptic
activity.
Clozapine is the prototype of the
so-called atypical neuroleptics, a group
that combines a relative lack of extrapyramidal
adverse effects with superior
efficacy in alleviating negative symptoms.
Newer members of this class include
risperidone, olanzapine, and sertindole.
Two distinguishing features of
these atypical agents are a higher affinity
for 5-HT2 (or 5-HT6) receptors than
for dopamine D2 receptors and relative
selectivity for mesolimbic, as opposed
to nigrostriatal, dopamine neurons.
Clozapine also exhibits high affinity for
dopamine receptors of the D4 subtype,
in addition to H1 histamine and muscarinic
acetylcholine receptors. Clozapine
may cause dose–dependent seizures
and agranulocytosis, necessitating close
hematological monitoring. It is strongly
sedating.
When esterified with a fatty acid,
both fluphenazine and haloperidol can
be applied intramuscularly as depot
preparations.


Psychotomimetics
(Psychedelics, Hallucinogens)
Psychotomimetics are able to elicit psychic
changes like those manifested in
the course of a psychosis, such as illusionary
distortion of perception and
hallucinations. This experience may be
of dreamlike character; its emotional or
intellectual transposition appears inadequate
to the outsider.
A psychotomimetic effect is pictorially
recorded in the series of portraits
drawn by an artist under the influence
of lysergic acid diethylamide (LSD). As
the intoxicated state waxes and wanes
like waves, he reports seeing the face of
the portrayed subject turn into a grimace,
phosphoresce bluish-purple, and
fluctuate in size as if viewed through a
moving zoom lens, creating the illusion
of abstruse changes in proportion and
grotesque motion sequences. The diabolic
caricature is perceived as threatening.
Illusions also affect the senses of
hearing and smell; sounds (tones) are
“experienced” as floating beams and
visual impressions as odors (“synesthesia”).
Intoxicated individuals see themselves
temporarily from the outside and
pass judgement on themselves and
their condition. The boundary between
self and the environment becomes
blurred. An elating sense of being one
with the other and the cosmos sets in.
The sense of time is suspended; there is
neither present nor past. Objects are
seen that do not exist, and experiences
felt that transcend explanation, hence
the term “psychedelic” (Greek delosis =
revelation) implying expansion of consciousness.
The contents of such illusions and
hallucinations can occasionally become
extremely threatening (“bad” or “bum
trip”); the individual may feel provoked
to turn violent or to commit suicide. Intoxication
is followed by a phase of intense
fatigue, feelings of shame, and humiliating
emptiness.
The mechanism of the psychotogenic
effect remains unclear. Some hallucinogens
such as LSD, psilocin, psilocybin
(from fungi), bufotenin (the cutaneous
gland secretion of a toad), mescaline
(from the Mexican cactuses Lophophora
williamsii and L. diffusa; peyote) bear a
structural resemblance to 5-HT (p. 116),
and chemically synthesized amphetamine-
derived hallucinogens (4-methyl-
2,5-dimethoxyamphetamine; 3,4-dimethoxyamphetamine;
2,5-dimethoxy-
4-ethyl amphetamine) are thought to
interact with the agonist recognition
site of the 5-HT2A receptor. Conversely,
most of the psychotomimetic effects are
annulled by neuroleptics having 5-HT2A
antagonist activity (e.g. clozapine, risperidone).
The structures of other
agents such as tetrahydrocannabinol
(from the hemp plant, Cannabis sativa—
hashish, marihuana), muscimol (from
the fly agaric, Amanita muscaria), or
phencyclidine (formerly used as an injectable
general anesthetic) do not reveal
a similar connection. Hallucinations
may also occur as adverse effects
after intake of other substances, e.g.,
scopolamine and other centrally active
parasympatholytics.
The popular psychostimulant, methylenedioxy-
methamphetamine (MDMA,
“ecstasy”) acutely increases neuronal
dopamine and norepinephrine release
and causes a delayed and selective
degeneration of forebrain 5-HT nerve
terminals.
Although development of psychological
dependence and permanent psychic
damage cannot be considered established
sequelae of chronic use of psychotomimetics,
the manufacture and
commercial distribution of these drugs
are prohibited (Schedule I, Controlled
Drugs).

Hypnotics

Soporifics, Hypnotics
During sleep, the brain generates a patterned
rhythmic activity that can be
monitored by means of the electroencephalogram
(EEG). Internal sleep cycles
recur 4 to 5 times per night, each
cycle being interrupted by a Rapid Eye
Movement (REM) sleep phase . The
REM stage is characterized by EEG activity
similar to that seen in the waking
state, rapid eye movements, vivid
dreams, and occasional twitches of individual
muscle groups against a background
of generalized atonia of skeletal
musculature. Normally, the REM stage is
entered only after a preceding non-REM
cycle. Frequent interruption of sleep
will, therefore, decrease the REM portion.
Shortening of REM sleep (normally
approx. 25% of total sleep duration) results
in increased irritability and restlessness
during the daytime. With undisturbed
night rest, REM deficits are
compensated by increased REM sleep
on subsequent nights .
Hypnotics fall into different categories,
including the benzodiazepines
(e.g., triazolam, temazepam, clotiazepam,
nitrazepam), barbiturates (e.g.,
hexobarbital, pentobarbital), chloral hydrate,
and H1-antihistamines with sedative
activity (p. 114). Benzodiazepines
act at specific receptors (p. 226). The
site and mechanism of action of barbiturates,
antihistamines, and chloral hydrate
are incompletely understood.
All hypnotics shorten the time
spent in the REM stages . With repeated
ingestion of a hypnotic on several
successive days, the proportion of
time spent in REM vs. non-REM sleep
returns to normal despite continued
drug intake. Withdrawal of the hypnotic
drug results in REM rebound, which tapers
off only over many days . Since
REM stages are associated with vivid
dreaming, sleep with excessively long
REM episodes is experienced as unrefreshing.
Thus, the attempt to discontinue
use of hypnotics may result in the
impression that refreshing sleep calls
for a hypnotic, probably promoting
hypnotic drug dependence.
Depending on their blood levels,
both benzodiazepines and barbiturates
produce calming and sedative effects,
the former group also being anxiolytic.
At higher dosage, both groups promote
the onset of sleep or induce it .
Unlike barbiturates, benzodiazepine
derivatives administered orally
lack a general anesthetic action; cerebral
activity is not globally inhibited
(respiratory paralysis is virtually impossible)
and autonomic functions, such as
blood pressure, heart rate, or body temperature,
are unimpaired. Thus, benzodiazepines
possess a therapeutic margin
considerably wider than that of barbiturates.
Zolpidem (an imidazopyridine)
and zopiclone (a cyclopyrrolone) are
hypnotics that, despite their different
chemical structure, possess agonist activity
at the benzodiazepine receptor.
Due to their narrower margin of
safety (risk of misuse for suicide) and
their potential to produce physical dependence,
barbiturates are no longer or
only rarely used as hypnotics. Dependence
on them has all the characteristics
of an addiction.
Because of rapidly developing tolerance,
choral hydrate is suitable only
for short-term use.
Antihistamines are popular as
nonprescription (over-the-counter)
sleep remedies (e.g., diphenhydramine,
doxylamine), in which case their
sedative side effect is used as the principal
effect.
Sleep–Wake Cycle and Hypnotics
The physiological mechanisms regulating
the sleep-wake rhythm are not completely
known. There is evidence that
histaminergic, cholinergic, glutamatergic,
and adrenergic neurons are more
active during waking than during the
NREM sleep stage. Via their ascending
thalamopetal projections, these neurons
excite thalamocortical pathways
and inhibit GABA-ergic neurons. During
sleep, input from the brain stem decreases,
giving rise to diminished thalamocortical
activity and disinhibition
of the GABA neurons. The shift in
balance between excitatory (red) and
inhibitory (green) neuron groups
underlies a circadian change in sleep
propensity, causing it to remain low in
the morning, to increase towards early
afternoon (midday siesta), then to decline
again, and finally to reach its peak
before midnight (B1).
Treatment of sleep disturbances.
Pharmacotherapeutic measures are indicated
only when causal therapy has
failed. Causes of insomnia include emotional
problems (grief, anxiety, “stress”),
physical complaints (cough, pain), or
the ingestion of stimulant substances
(caffeine-containing beverages, sympathomimetics,
theophylline, or certain
antidepressants). As illustrated for emotional
stress (B2), these factors cause an
imbalance in favor of excitatory influences.
As a result, the interval between
going to bed and falling asleep becomes
longer, total sleep duration decreases,
and sleep may be interrupted by several
waking periods.
Depending on the type of insomnia,
benzodiazepine with short or
intermediate duration of action are indicated,
e.g., triazolam and brotizolam
(t1/2 ~ 4–6 h); lormetazepam or temazepam
(t1/2 ~ 10–15 h). These drugs shorten
the latency of falling asleep, lengthen
total sleep duration, and reduce the frequency
of nocturnal awakenings. They
act by augmenting inhibitory activity.
Even with the longer-acting benzodiazepines,
the patient awakes after about
6–8 h of sleep, because in the morning
excitatory activity exceeds the sum of
physiological and pharmacological inhibition
(B3). The drug effect may, however,
become unmasked at daytime when
other sedating substances (e.g., ethanol)
are ingested and the patient shows an
unusually pronounced response due to
a synergistic interaction (impaired ability
to concentrate or react).
As the margin between excitatory
and inhibitory activity decreases with
age, there is an increasing tendency towards
shortened daytime sleep periods
and more frequent interruption of nocturnal
sleep .
Use of a hypnotic drug should not
be extended beyond 4 wk, because tolerance
may develop. The risk of a rebound
decrease in sleep propensity after
drug withdrawal may be avoided by
tapering off the dose over 2 to 3 wk.
With any hypnotic, the risk of suicidal
overdosage cannot be ignored.
Since benzodiazepine intoxication may
become life-threatening only when
other central nervous depressants (ethanol)
are taken simultaneously and can,
moreover, be treated with specific benzodiazepine
antagonists, the benzodiazepines
should be given preference
as sleep remedies over the all but obsolete
barbiturates.

General Anesthetic Drugs

General Anesthesia and General
Anesthetic Drugs
General anesthesia is a state of drug-induced
reversible inhibition of central
nervous function, during which surgical
procedures can be carried out in the absence
of consciousness, responsiveness
to pain, defensive or involuntary movements,
and significant autonomic reflex
responses .
The required level of anesthesia depends
on the intensity of the pain-producing
stimuli, i.e., the degree of nociceptive
stimulation. The skilful anesthetist,
therefore, dynamically adapts the
plane of anesthesia to the demands of
the surgical situation. Originally, anesthetization
was achieved with a single
anesthetic agent (e.g., diethylether—
first successfully demonstrated in 1846
by W. T. G. Morton, Boston). To suppress
defensive reflexes, such a “mono-anesthesia”
necessitates a dosage in excess
of that needed to cause unconsciousness,
thereby increasing the risk of paralyzing
vital functions, such as cardiovascular
homeostasis . Modern anesthesia
employs a combination of different
drugs to achieve the goals of surgical
anesthesia (balanced anesthesia). This
approach reduces the hazards of anesthesia.
In C are listed examples of drugs
that are used concurrently or sequentially
as anesthesia adjuncts. In the case
of the inhalational anesthetics, the
choice of adjuncts relates to the specific
property to be exploited (see below).
Muscle relaxants, opioid analgesics such
as fentanyl, and the parasympatholytic
atropine are discussed elsewhere in
more detail.
Neuroleptanalgesia can be considered
a special form of combination anesthesia,
in which the short-acting opioid
analgesics fentanyl, alfentanil, remifentanil
is combined with the strongly
sedating and affect-blunting neuroleptic
droperidol. This procedure is used in
high-risk patients (e.g., advanced age,
liver damage).
Neuroleptanesthesia refers to the
combined use of a short-acting analgesic,
an injectable anesthetic, a short-acting
muscle relaxant, and a low dose of a
neuroleptic.
In regional anesthesia (spinal anesthesia)
with a local anesthetic,
nociception is eliminated, while
consciousness is preserved. This procedure,
therefore, does not fall under the
definition of general anesthesia.
According to their mode of application,
general anesthetics in the restricted
sense are divided into inhalational
(gaseous, volatile) and injectable agents.
Inhalational anesthetics are administered
in and, for the most part, eliminated
via respired air. They serve to
maintain anesthesia. Pertinent substances
are considered on.
Injectable anesthetics are
frequently employed for induction.
Intravenous injection and rapid onset of
action are clearly more agreeable to the
patient than is breathing a stupefying
gas. The effect of most injectable anesthetics
is limited to a few minutes. This
allows brief procedures to be carried out
or to prepare the patient for inhalational
anesthesia (intubation). Administration
of the volatile anesthetic must then
be titrated in such a manner as to counterbalance
the waning effect of the injectable
agent.
Increasing use is now being made
of injectable, instead of inhalational, anesthetics
during prolonged combined
anesthesia (total intravenous anesthesia—
TIVA).
“TIVA” has become feasible thanks
to the introduction of agents with a suitably
short duration of action, including
the injectable anesthetics propofol and
etomidate, the analgesics alfentanil und
remifentanil, and the muscle relaxant
mivacurium. These drugs are eliminated
within minutes after being adminstered,
irrespective of the duration of
anesthesia.
Inhalational Anesthetics
The mechanism of action of inhalational
anesthetics is unknown. The diversity
of chemical structures (inert gas
xenon; hydrocarbons; halogenated hydrocarbons)
possessing anesthetic activity
appears to rule out involvement of
specific receptors. According to one hypothesis,
uptake into the hydrophobic
interior of the plasmalemma of neurons
results in inhibition of electrical excitability
and impulse propagation in the
brain. This concept would explain the
correlation between anesthetic potency
and lipophilicity of anesthetic drugs (A).
However, an interaction with lipophilic
domains of membrane proteins is also
conceivable. Anesthetic potency can be
expressed in terms of the minimal alveolar
concentration (MAC) at which
50% of patients remain immobile following
a defined painful stimulus (skin
incision). Whereas the poorly lipophilic
N2O must be inhaled in high concentrations
(>70% of inspired air has to be replaced),
much smaller concentrations
(< 5%) are required in the case of the
more lipophilic halothane.
The rates of onset and cessation of
action vary widely between different inhalational
anesthetics and also depend
on the degree of lipophilicity. In the case
of N2O, there is rapid elimination from
the body when the patient is ventilated
with normal air. Due to the high partial
pressure in blood, the driving force for
transfer of the drug into expired air is
large and, since tissue uptake is minor,
the body can be quickly cleared of N2O.
In contrast, with halothane, partial pressure
in blood is low and tissue uptake is
high, resulting in a much slower elimination.
Given alone, N2O (nitrous oxide,
“laughing gas”) is incapable of producing
anesthesia of sufficient depth for
surgery. It has good analgesic efficacy
that can be exploited when it is used in
conjunction with other anesthetics. As a
gas, N2O can be administered directly.
Although it irreversibly oxidizes vitamin
B12, N2O is not metabolized appreciably
and is cleared entirely by exhalation.
Halothane (boiling point [BP]
50 °C), enflurane (BP 56 °C), isoflurane
(BP 48 °C), and the obsolete methoxyflurane
(BP 104 °C) have to be vaporized by
special devices. Part of the administered
halothane is converted into hepatotoxic
metabolites . Liver damage may result
from halothane anesthesia. With a
single exposure, the risk involved is unpredictable;
however, there is a correlation
with the frequency of exposure and
the shortness of the interval between
successive exposures.
Up to 70% of inhaled methoxyflurane
is converted to metabolites that
may cause nephrotoxicity, a problem
that has led to the withdrawal of the
drug.
Degradation products of enflurane
or isoflurane (fraction biotransformed
<2%) are of no concern.
Halothane exerts a pronounced hypotensive
effect, to which a negative inotropic
effect contributes. Enflurane
and isoflurane cause less circulatory depression.
Halothane sensitizes the myocardium
to catecholamines (caution: serious
tachyarrhythmias or ventricular
fibrillation may accompany use of catecholamines
as antihypotensives or tocolytics).
This effect is much less pronounced
with enflurane and isoflurane.
Unlike halothane, enflurane and isoflurane
have a muscle-relaxant effect that
is additive with that of nondepolarizing
neuromuscular blockers.
Desflurane is a close structural relative
of isoflurane, but has low lipophilicity
that permits rapid induction and recovery
as well as good control of anesthetic
depth.
Injectable Anesthetics
Substances from different chemical
classes suspend consciousness when
given intravenously and can be used as
injectable anesthetics . Unlike inhalational
agents, most of these drugs affect
consciousness only and are devoid
of analgesic activity (exception: ketamine).
The effect cannot be ascribed to
nonselective binding to neuronal cell
membranes, although this may hold for
propofol.
Most injectable anesthetics are
characterized by a short duration of action.
The rapid cessation of action is
largely due to redistribution: after
intravenous injection, brain concentration
climbs rapidly to anesthetic levels
because of the high cerebral blood flow;
the drug then distributes evenly in the
body, i.e., concentration rises in the periphery,
but falls in the brain—redistribution
and cessation of anesthesia .
Thus, the effect subsides before the drug
has left the body. A second injection of
the same dose, given immediately after
recovery from the preceding dose, can
therefore produce a more intense and
longer effect. Usually, a single injection
is administered. However, etomidate
and propofol may be given by infusion
over a longer time period to maintain
unconsciousness.
Thiopental and methohexital belong
to the barbiturates which, depending on
dose, produce sedation, sleepiness, or
anesthesia. Barbiturates lower the pain
threshold and thereby facilitate defensive
reflex movements; they also depress
the respiratory center. Barbiturates
are frequently used for induction
of anesthesia.
Ketamine has analgesic activity that
persists beyond the period of unconsciousness
up to 1 h after injection. On
regaining consciousness, the patient
may experience a disconnection
between outside reality and inner mental
state (dissociative anesthesia). Frequently
there is memory loss for the duration
of the recovery period; however,
adults in particular complain about distressing
dream-like experiences. These
can be counteracted by administration
of a benzodiazepine (e.g., midazolam).
The CNS effects of ketamine arise, in
part, from an interference with excitatory
glutamatergic transmission via ligand-
gated cation channels of the
NMDA subtype, at which ketamine acts
as a channel blocker. The non-natural
excitatory amino acid N-methyl-Daspartate
is a selective agonist at this receptor.
Release of catecholamines with
a resultant increase in heart rate and
blood pressure is another unrelated action
of ketamine.
Propofol has a remarkably simple
structure. Its effect has a rapid onset and
decays quickly, being experienced by
the patient as fairly pleasant. The intensity
of the effect can be well controlled
during prolonged administration.
Etomidate hardly affects the autonomic
nervous system. Since it inhibits
cortisol synthesis, it can be used in the
treatment of adrenocortical overactivity
(Cushing’s disease).
Midazolam is a rapidly metabolized
benzodiazepine that is used for
induction of anesthesia. The longer-acting
lorazepam is preferred as adjunct
anesthetic in prolonged cardiac surgery
with cardiopulmonary bypass; its amnesiogenic
effect is pronounced.

Opioids

Opioid Analgesics—Morphine Type
Source of opioids. Morphine is an opium
alkaloid . Besides morphine,
opium contains alkaloids devoid of analgesic
activity, e.g., the spasmolytic papaverine,
that are also classified as opium
alkaloids. All semisynthetic derivatives
(hydromorphone) and fully synthetic
derivatives (pentazocine, pethidine
= meperidine, l-methadone, and
fentanyl) are collectively referred to as
opioids. The high analgesic effectiveness
of xenobiotic opioids derives from their
affinity for receptors normally acted
upon by endogenous opioids (enkephalins,
!-endorphin, dynorphins). Opioid
receptors occur in nerve cells. They
are found in various brain regions and
the spinal medulla, as well as in intramural
nerve plexuses that regulate the
motility of the alimentary and urogenital
tracts. There are several types of opioid
receptors, designated μ, ", #, that
mediate the various opioid effects; all
belong to the superfamily of G-proteincoupled
receptors.
Endogenous opioids are peptides
that are cleaved from the precursors
proenkephalin, pro-opiomelanocortin,
and prodynorphin. All contain the amino
acid sequence of the pentapeptides
[Met]- or [Leu]-enkephalin. The effects
of the opioids can be abolished by
antagonists (e.g., naloxone), with the
exception of buprenorphine.
Mode of action of opioids. Most
neurons react to opioids with hyperpolarization,
reflecting an increase in K+
conductance. Ca2+ influx into nerve terminals
during excitation is decreased,
leading to a decreased release of excitatory
transmitters and decreased synaptic
activity. Depending on the cell
population affected, this synaptic inhibition
translates into a depressant or excitant
effect.
Effects of opioids. The analgesic
effect results from actions at the level
of the spinal cord (inhibition of nociceptive
impulse transmission) and the
brain (attenuation of impulse spread,
inhibition of pain perception). Attention
and ability to concentrate are impaired.
There is a mood change, the direction
of which depends on the initial condition.
Aside from the relief associated
with the abatement of strong pain,
there is a feeling of detachment (floating
sensation) and sense of well-being
(euphoria), particularly after intravenous
injection and, hence, rapid buildup
of drug levels in the brain. The desire
to re-experience this state by renewed
administration of drug may become
overpowering: development of psychological
dependence. The atttempt to quit
repeated use of the drug results in withdrawal
signs of both a physical (cardiovascular
disturbances) and psychological
(restlessness, anxiety, depression)
nature. Opioids meet the criteria of “addictive”
agents, namely, psychological
and physiological dependence as well as
a compulsion to increase the dose. For
these reasons, prescription of opioids is
subject to special rules (Controlled Substances
Act, USA; Narcotic Control Act,
Canada; etc). Regulations specify,
among other things, maximum dosage
(permissible single dose, daily maximal
dose, maximal amount per single prescription).
Prescriptions need to be issued
on special forms the completion of
which is rigorously monitored. Certain
opioid analgesics, such as codeine and
tramadol, may be prescribed in the usual
manner, because of their lesser potential
for abuse and development of
dependence.

Differences between opioids regarding
efficacy and potential for dependence
probably reflect differing affinity
and intrinsic activity profiles for
the individual receptor subtypes. A given
sustance does not necessarily behave
as an agonist or antagonist at all receptor
subtypes, but may act as an agonist
at one subtype and as a partial agonist/
antagonist or as a pure antagonist
(p. 214) at another. The abuse potential
is also determined by kinetic properties,
because development of dependence is
favored by rapid build-up of brain concentrations.
With any of the high-efficacy
opioid analgesics, overdosage is likely
to result in respiratory paralysis (impaired
sensitivity of medullary chemoreceptors
to CO2). The maximally possible
extent of respiratory depression is
thought to be less in partial agonist/
antagonists at opioid receptors (pentazocine,
nalbuphine).
The cough-suppressant (antitussive)
effect produced by inhibition of the
cough reflex is independent of the effects
on nociception or respiration
(antitussives: codeine. noscapine).
Stimulation of chemoreceptors in
the area postrema results in
vomiting, particularly after first-time administration
or in the ambulant patient.
The emetic effect disappears with repeated
use because a direct inhibition of
the emetic center then predominates,
which overrides the stimulation of area
postrema chemoreceptors.
Opioids elicit pupillary narrowing
(miosis) by stimulating the parasympathetic
portion (Edinger-Westphal nucleus)
of the oculomotor nucleus.
Peripheral effects concern the motility
and tonus of gastrointestinal
smooth muscle; segmentation is enhanced,
but propulsive peristalsis is inhibited.
The tonus of sphincter muscles
is raised markedly. In this fashion, morphine
elicits the picture of spastic constipation.
The antidiarrheic effect is
used therapeutically (loperamide, p.
178). Gastric emptying is delayed (pyloric
spasm) and drainage of bile and
pancreatic juice is impeded, because the
sphincter of Oddi contracts. Likewise,
bladder function is affected; specifically
bladder emptying is impaired due to increased
tone of the vesicular sphincter.
Uses: The endogenous opioids
(metenkephalin, leuenkephalin, !-endorphin)
cannot be used therapeutically
because, due to their peptide nature,
they are either rapidly degraded or excluded
from passage through the bloodbrain
barrier, thus preventing access to
their sites of action even after parenteral
administration .
Morphine can be given orally or
parenterally, as well as epidurally or
intrathecally in the spinal cord. The opioids
heroin and fentanyl are highly lipophilic,
allowing rapid entry into the
CNS. Because of its high potency, fentanyl
is suitable for transdermal delivery.
In opiate abuse, “smack” (“junk,”
“jazz,” “stuff,” “China white;” mostly
heroin) is self administered by injection
(“mainlining”) so as to avoid first-pass
metabolism and to achieve a faster rise
in brain concentration. Evidently, psychic
effects (“kick,” “buzz,” “rush”) are
especially intense with this route of administration.
The user may also resort to
other more unusual routes: opium can
be smoked, and heroin can be taken as
snuff .
Metabolism . Like other opioids
bearing a hydroxyl group, morphine is
conjugated to glucuronic acid and eliminated
renally. Glucuronidation of the
OH-group at position 6, unlike that at
position 3, does not affect affinity. The
extent to which the 6-glucuronide contributes
to the analgesic action remains
uncertain at present. At any rate, the activity
of this polar metabolite needs to
be taken into account in renal insufficiency
(lower dosage or longer dosing
interval).
Tolerance. With repeated administration
of opioids, their CNS effects can
lose intensity (increased tolerance). In
the course of therapy, progressively
larger doses are needed to achieve the
same degree of pain relief. Development
of tolerance does not involve the peripheral
effects, so that persistent constipation
during prolonged use may
force a discontinuation of analgesic
therapy however urgently needed.
Therefore, dietetic and pharmacological
measures should be taken prophylactically
to prevent constipation, whenever
prolonged administration of opioid
drugs is indicated.
Morphine antagonists and partial
agonists. The effects of opioids can be
abolished by the antagonists naloxone
or naltrexone, irrespective of the receptor
type involved. Given by itself,
neither has any effect in normal subjects;
however, in opioid-dependent
subjects, both precipitate acute withdrawal
signs. Because of its rapid presystemic
elimination, naloxone is only
suitable for parenteral use. Naltrexone
is metabolically more stable and is given
orally. Naloxone is effective as antidote
in the treatment of opioid-induced
respiratory paralysis. Since it is more
rapidly eliminated than most opioids,
repeated doses may be needed. Naltrexone
may be used as an adjunct in withdrawal
therapy.
Buprenorphine behaves like a partial
agonist/antagonist at μ-receptors.
Pentazocine is an antagonist at μ-receptors
and an agonist at #-receptors.
Both are classified as “low-ceiling” opioids,
because neither is capable of
eliciting the maximal analgesic effect
obtained with morphine or meperidine.
The antagonist action of partial agonists
may result in an initial decrease in effect
of a full agonist during changeover to
the latter. Intoxication with buprenorphine
cannot be reversed with antagonists,
because the drug dissociates only
very slowly from the opioid receptors
and competitive occupancy of the receptors
cannot be achieved as fast as the
clinical situation demands.
Opioids in chronic pain: In the
management of chronic pain, opioid
plasma concentration must be kept continuously
in the effective range, because
a fall below the critical level would
cause the patient to experience pain.
Fear of this situation would prompt intake
of higher doses than necessary.
Strictly speaking, the aim is a prophylactic
analgesia.
Like other opioids (hydromorphone,
meperidine, pentazocine, codeine),
morphine is rapidly eliminated,
limiting its duration of action to approx.
4 h. To maintain a steady analgesic effect,
these drugs need to be given every
4 h. Frequent dosing, including at nighttime,
is a major inconvenience for
chronic pain patients. Raising the individual
dose would permit the dosing
interval to be lengthened; however, it
would also lead to transient peaks
above the therapeutically required plasma
level with the attending risk of unwanted
toxic effects and tolerance development.
Preferred alternatives include
the use of controlled-release
preparations of morphine, a fentanyl
adhesive patch, or a longer-acting opioid
such as l-methadone. The kinetic
properties of the latter, however, necessitate
adjustment of dosage in the
course of treatment, because low dosage
during the first days of treatment
fails to provide pain relief, whereas high
dosage of the drug, if continued, will
lead to accumulation into a toxic concentration
range.
When the oral route is unavailable
opioids may be administered by continuous
infusion (pump) and when appropriate
under control by the patient – advantage:
constant therapeutic plasma
level; disadvantage: indwelling catheter.
When constipation becomes intolerable
morphin can be applied near the
spinal cord permitting strong analgesic
effect at much lower total dosage.

Local Anesthetics

Local Anesthetics
Local anesthetics reversibly inhibit impulse
generation and propagation in
nerves. In sensory nerves, such an effect
is desired when painful procedures
must be performed, e.g., surgical or dental
operations.
Mechanism of action. Nerve impulse
conduction occurs in the form of
an action potential, a sudden reversal in
resting transmembrane potential lasting
less than 1 ms. The change in potential
is triggered by an appropriate stimulus
and involves a rapid influx of Na+
into the interior of the nerve axon.
This inward flow proceeds through a
channel, a membrane pore protein, that,
upon being opened (activated), permits
rapid movement of Na+ down a chemical
gradient ([Na+]ext ~ 150 mM, [Na+]int
~ 7 mM). Local anesthetics are capable
of inhibiting this rapid inward flux of
Na+; initiation and propagation of excitation
are therefore blocked .
Most local anesthetics exist in part
in the cationic amphiphilic form (cf).
This physicochemical property favors
incorporation into membrane
interphases, boundary regions between
polar and apolar domains. These are
found in phospholipid membranes and
also in ion-channel proteins. Some evidence
suggests that Na+-channel blockade
results from binding of local anesthetics
to the channel protein. It appears
certain that the site of action is reached
from the cytosol, implying that the drug
must first penetrate the cell membrane.

Local anesthetic activity is also
shown by uncharged substances, suggesting
a binding site in apolar regions
of the channel protein or the surrounding
lipid membrane.
Mechanism-specific adverse effects.
Since local anesthetics block Na+
influx not only in sensory nerves but also
in other excitable tissues, they are
applied locally and measures are taken
to impede their distribution
into the body. Too rapid entry into the
circulation would lead to unwanted
systemic reactions such as:
! blockade of inhibitory CNS neurons,
manifested by restlessness and seizures
(countermeasure: injection of a
Benzodiazepine ); general paralysis
with respiratory arrest after
higher concentrations.
! blockade of cardiac impulse conduction,
as evidenced by impaired AV
conduction or cardiac arrest (countermeasure:
injection of epinephrine).
Depression of excitatory processes
in the heart, while undesired
during local anesthesia, can be put to
therapeutic use in cardiac arrhythmias.

Forms of local anesthesia. Local
anesthetics are applied via different
routes, including infiltration of the tissue
(infiltration anesthesia) or injection
next to the nerve branch carrying
fibers from the region to be anesthetized
(conduction anesthesia of the
nerve, spinal anesthesia of segmental
dorsal roots), or by application to the
surface of the skin or mucosa (surface
anesthesia). In each case, the local anesthetic
drug is required to diffuse to
the nerves concerned from a depot
placed in the tissue or on the skin.
High sensitivity of sensory nerves,
low sensitivity of motor nerves. Impulse
conduction in sensory nerves is
inhibited at a concentration lower than
that needed for motor fibers. This difference
may be due to the higher impulse
frequency and longer action potential
duration in nociceptive, as opposed to
motor, fibers.
Alternatively, it may be related to
the thickness of sensory and motor
nerves, as well as to the distance
between nodes of Ranvier. In saltatory
impulse conduction, only the nodal
membrane is depolarized. Because depolarization
can still occur after blockade
of three or four nodal rings, the area
exposed to a drug concentration sufficient
to cause blockade must be larger
for motor fibers (p. 205B).
This relationship explains why sen sory
stimuli that are conducted via
myelinated A"-fibers are affected later
and to a lesser degree than are stimuli
conducted via unmyelinated C-fibers.
Since autonomic postganglionic fibers
lack a myelin sheath, they are particularly
susceptible to blockade by local
anesthetics. As a result, vasodilation ensues
in the anesthetized region, because
sympathetically driven vasomotor tone
decreases. This local vasodilation is undesirable.

Diffusion and Effect
During diffusion from the injection site
(i.e., the interstitial space of connective
tissue) to the axon of a sensory nerve,
the local anesthetic must traverse the
perineurium. The multilayered perineurium
is formed by connective tissue
cells linked by zonulae occludentes
and therefore constitutes a
closed lipophilic barrier.
Local anesthetics in clinical use are
usually tertiary amines; at the pH of
interstitial fluid, these exist partly as the
neutral lipophilic base (symbolized by
particles marked with two red dots) and
partly as the protonated form, i.e., amphiphilic
cation (symbolized by particles
marked with one blue and one red
dot). The uncharged form can penetrate
the perineurium and enters the endoneural
space, where a fraction of the
drug molecules regains a positive
charge in keeping with the local pH. The
same process is repeated when the drug
penetrates the axonal membrane (axolemma)
into the axoplasm, from which
it exerts its action on the sodium channel,
and again when it diffuses out of the
endoneural space through the unfenestrated
endothelium of capillaries into
the blood.
The concentration of local anesthetic
at the site of action is, therefore,
determined by the speed of penetration
into the endoneurium and the speed of
diffusion into the capillary blood. In order
to ensure a sufficiently fast build-up
of drug concentration at the site of action,
there must be a correspondingly
large concentration gradient between
drug depot in the connective tissue and
the endoneural space. Injection of solutions
of low concentration will fail to
produce an effect; however, too high
concentrations must also be avoided because
of the danger of intoxication resulting
from too rapid systemic absorption
into the blood.
To ensure a reasonably long-lasting
local effect with minimal systemic action,
a vasoconstrictor (epinephrine,
less frequently norepinephrine (p. 84)
or a vasopressin derivative; p. 164) is often
co-administered in an attempt to
confine the drug to its site of action. As
blood flow is diminished, diffusion from
the endoneural space into the capillary
blood decreases because the critical
concentration gradient between endoneural
space and blood quickly becomes
small when inflow of drug-free blood is
reduced. Addition of a vasoconstrictor,
moreover, helps to create a relative
ischemia in the surgical field. Potential
disadvantages of catecholamine-type
vasoconstrictors include reactive hyperemia
following washout of the constrictor
agent and cardiostimulation
when epinephrine enters the systemic
circulation. In lieu of epinephrine,
the vasopressin analogue felypressin
can be used as an adjunctive
vasoconstrictor (less pronounced
reactive hyperemia, no arrhythmogenic
action, but danger of coronary constriction).
Vasoconstrictors must not be applied
in local anesthesia involving the
appendages (e.g., fingers, toes).
Characteristics of chemical structure.
Local anesthetics possess a uniform
structure. Generally they are secondary
or tertiary amines. The nitrogen
is linked through an intermediary chain
to a lipophilic moiety—most often an
aromatic ring system.
The amine function means that local
anesthetics exist either as the neutral
amine or positively charged ammonium
cation, depending upon their dissociation
constant (pKa value) and the
actual pH value. The pKa of typical local
anesthetics lies between 7.5 and 9.0.
The pka indicates the pH value at which
50% of molecules carry a proton. In its
protonated form, the molecule possesses
both a polar hydrophilic moiety (protonated
nitrogen) and an apolar lipophilic
moiety (ring system)—it is amphiphilic.
Graphic images of the procaine
molecule reveal that the positive charge
does not have a punctate localization at
the N atom; rather it is distributed, as
shown by the potential on the van der
Waals’ surface. The non-protonated
form (right) possesses a negative partial
charge in the region of the ester bond
and at the amino group at the aromatic
ring and is neutral to slightly positively
charged (blue) elsewhere. In the protonated
form (left), the positive charge is
prominent and concentrated at the amino
group of the side chain (dark blue).
Depending on the pKa, 50 to 5% of
the drug may be present at physiological
pH in the uncharged lipophilic form.
This fraction is important because it
represents the lipid membrane-permeable
form of the local anesthetic,
which must take on its cationic amphiphilic
form in order to exert its action.
Clinically used local anesthetics are
either esters or amides. This structural
element is unimportant for efficacy;
even drugs containing a methylene
bridge, such as chlorpromazine
or imipramine, would exert a
local anesthetic effect with appropriate
application. Ester-type local anesthetics
are subject to inactivation by tissue esterases.
This is advantageous because of
the diminished danger of systemic intoxication.
On the other hand, the high
rate of bioinactivation and, therefore,
shortened duration of action is a disadvantage.
Procaine cannot be used as a surface
anesthetic because it is inactivated faster
than it can penetrate the dermis or
mucosa.
The amide type local anesthetic
lidocaine is broken down primarily in
the liver by oxidative N-dealkylation.
This step can occur only to a restricted
extent in prilocaine and articaine because
both carry a substituent on the Catom
adjacent to the nitrogen group. Articaine
possesses a carboxymethyl
group on its thiophen ring. At this position,
ester cleavage can occur, resulting
in the formation of a polar -COO– group,
loss of the amphiphilic character, and
conversion to an inactive metabolite.
Benzocaine (ethoform) is a member
of the group of local anesthetics lacking
a nitrogen that can be protonated at
physiological pH. It is used exclusively
as a surface anesthetic.
Other agents employed for surface
anesthesia include the uncharged polidocanol
and the catamphiphilic cocaine,
tetracaine, and lidocaine.

Antipyretic Analgesics and Antiinflammatory Drugs

Antipyretic Analgesics
Acetaminophen, the amphiphilic acids
acetylsalicylic acid (ASA), ibuprofen,
and others, as well as some pyrazolone
derivatives, such as aminopyrine and
dipyrone, are grouped under the label
antipyretic analgesics to distinguish
them from opioid analgesics, because
they share the ability to reduce fever.
Acetaminophen (paracetamol) has
good analgesic efficacy in toothaches
and headaches, but is of little use in inflammatory
and visceral pain. Its mechanism
of action remains unclear. It can
be administered orally or in the form of
rectal suppositories (single dose,
0.5–1.0 g). The effect develops after
about 30 min and lasts for approx. 3 h.
Acetaminophen undergoes conjugation
to glucuronic acid or sulfate at the phenolic
hydroxyl group, with subsequent
renal elimination of the conjugate. At
therapeutic dosage, a small fraction is
oxidized to the highly reactive N-acetylp-
benzoquinonimine, which is detoxified
by coupling to glutathione. After ingestion
of high doses (approx. 10 g), the
glutathione reserves of the liver are depleted
and the quinonimine reacts with
constituents of liver cells. As a result,
the cells are destroyed: liver necrosis.
Liver damage can be avoided if the thiol
group donor, N-acetylcysteine, is given
intravenously within 6–8 h after ingestion
of an excessive dose of acetaminophen.
Whether chronic regular intake of
acetaminophen leads to impaired renal
function remains a matter of debate.
Acetylsalicylic acid (ASA) exerts an
antiinflammatory effect, in addition to
its analgesic and antipyretic actions.
These can be attributed to inhibition of
cyclooxygenase. ASA can be given
in tablet form, as effervescent powder,
or injected systemically as lysinate
(analgesic or antipyretic single dose,
O.5–1.0 g). ASA undergoes rapid ester
hydrolysis, first in the gut and subsequently
in the blood. The effect outlasts
the presence of ASA in plasma (t1/2 ~
20 min), because cyclooxygenases are
irreversibly inhibited due to covalent
binding of the acetyl residue. Hence, the
duration of the effect depends on the
rate of enzyme resynthesis. Furthermore,
salicylate may contribute to the
effect. ASA irritates the gastric mucosa
(direct acid effect and inhibition of cytoprotective
PG synthesis) and
can precipitate bronchoconstriction
(“aspirin asthma,” pseudoallergy) due
to inhibition of PGE2 synthesis and overproduction
of leukotrienes. Because ASA
inhibits platelet aggregation and prolongs
bleeding time, it should
not be used in patients with impaired
blood coagulability. Caution is also
needed in children and juveniles because
of Reye’s syndrome. The latter has
been observed in association with febrile
viral infections and ingestion of
ASA; its prognosis is poor (liver and
brain damage). Administration of ASA at
the end of pregnancy may result in prolonged
labor, bleeding tendency in
mother and infant, and premature closure
of the ductus arteriosus. Acidic
nonsteroidal antiinflammatory drugs
(NSAIDS) are derived from ASA.
Among antipyretic analgesics, dipyrone
(metamizole) displays the highest
efficacy. It is also effective in visceral
pain. Its mode of action is unclear, but
probably differs from that of acetaminophen
and ASA. It is rapidly absorbed
when given via the oral or rectal route.
Because of its water solubility, it is also
available for injection. Its active metabolite,
4-aminophenazone, is eliminated
from plasma with a t1/2 of approx. 5 h.
Dipyrone is associated with a low incidence
of fatal agranulocytosis. In sensitized
subjects, cardiovascular collapse
can occur, especially after intravenous
injection. Therefore, the drug should be
restricted to the management of pain
refractory to other analgesics. Propyphenazone
presumably acts like metamizole
both pharmacologically and toxicologically.

Antipyretic Analgesics

Eicosanoids
Origin and metabolism. The eicosanoids,
prostaglandins, thromboxane,
prostacyclin, and leukotrienes, are
formed in the organism from arachidonic
acid, a C20 fatty acid with four
double bonds (eicosatetraenoic acid).
Arachidonic acid is a regular constituent
of cell membrane phospholipids; it is
released by phospholipase A2 and forms
the substrate of cyclooxygenases and
lipoxygenases.
Synthesis of prostaglandins (PG),
prostacyclin, and thromboxane proceeds
via intermediary cyclic endoperoxides.
In the case of PG, a cyclopentane
ring forms in the acyl chain. The letters
following PG (D, E, F, G, H, or I) indicate
differences in substitution with hydroxyl
or keto groups; the number subscripts
refer to the number of double
bonds, and the Greek letter designates
the position of the hydroxyl group at C9
(the substance shown is PGF2!). PG are
primarily inactivated by the enzyme 15-
hydroxyprostaglandindehydrogenase.
Inactivation in plasma is very rapid;
during one passage through the lung,
90% of PG circulating in plasma are degraded.
PG are local mediators that attain
biologically effective concentrations
only at their site of formation.
Biological effects. The individual
PG (PGE, PGF, PGI = prostacyclin) possess
different biological effects.
Nociceptors. PG increase sensitivity
of sensory nerve fibers towards ordinary
pain stimuli (p. 194), i.e., at a given
stimulus strength there is an increased
rate of evoked action potentials.
Thermoregulation. PG raise the set
point of hypothalamic (preoptic) thermoregulatory
neurons; body temperature
increases (fever).
Vascular smooth muscle. PGE2
and PGI2 produce arteriolar vasodilation;
PGF2, venoconstriction.
Gastric secretion. PG promote the
production of gastric mucus and reduce
the formation of gastric acid .
Menstruation. PGF2! is believed to
be responsible for the ischemic necrosis

of the endometrium preceding menstruation.
The relative proportions of individual
PG are said to be altered in dysmenorrhea
and excessive menstrual
bleeding.
Uterine muscle. PG stimulate labor
contractions.
Bronchial muscle. PGE2 and PGI2
induce bronchodilation; PGF2! causes
constriction.
Renal blood flow. When renal
blood flow is lowered, vasodilating PG
are released that act to restore blood
flow.
Thromboxane A2 and prostacyclin
play a role in regulating the aggregability
of platelets and vascular diameter.

Leukotrienes increase capillary
permeability and serve as chemotactic
factors for neutrophil granulocytes. As
“slow-reacting substances of anaphylaxis,”
they are involved in allergic reactions
; together with PG, they
evoke the spectrum of characteristic inflammatory
symptoms: redness, heat,
swelling, and pain.
Therapeutic applications. PG derivatives
are used to induce labor or to
interrupt gestation; in the therapy
of peptic ulcer, and in peripheral
arterial disease.
PG are poorly tolerated if given
systemically; in that case their effects
cannot be confined to the intended site
of action.

Nonsteroidal Antiinflammatory
(Antirheumatic) Agents
At relatively high dosage (> 4 g/d), ASA
may exert antiinflammatory effects
in rheumatic diseases (e.g., rheumatoid
arthritis). In this dose range,
central nervous signs of overdosage
may occur, such as tinnitus, vertigo,
drowsiness, etc. The search for better
tolerated drugs led to the family of nonsteroidal
antiinflammatory drugs
(NSAIDs). Today, more than 30 substances
are available, all of them sharing
the organic acid nature of ASA. Structurally,
they can be grouped into carbonic
acids (e.g., diclofenac, ibuprofen, naproxene,
indomethacin) or
enolic acids (e.g., azapropazone, piroxicam,
as well as the long-known but
poorly tolerated phenylbutazone). Like
ASA, these substances have analgesic,
antipyretic, and antiinflammatory activity.
In contrast to ASA, they inhibit cyclooxygenase
in a reversible manner.
Moreover, they are not suitable as inhibitors
of platelet aggregation. Since
their desired effects are similar, the
choice between NSAIDs is dictated by
their pharmacokinetic behavior and
their adverse effects.
Salicylates additionally inhibit the
transcription factor NFKB, hence the expression
of proinflammatory proteins.
This effect is shared with glucocorticoids
and ibuprofen, but not
with some other NSAIDs.
Pharmacokinetics. NSAIDs are
well absorbed enterally. They are highly
bound to plasma proteins (A). They are
eliminated at different speeds: diclofenac
(t1/2 = 1–2 h) and piroxicam (t1/2 ~ 50
h); thus, dosing intervals and risk of accumulation
will vary. The elimination of
salicylate, the rapidly formed metabolite
of ASA, is notable for its dose dependence.
Salicylate is effectively reabsorbed
in the kidney, except at high urinary
pH. A prerequisite for rapid renal
elimination is a hepatic conjugation reaction
, mainly with glycine (salicyluric acid)
and glucuronic acid. At
high dosage, the conjugation may become
rate limiting. Elimination now increasingly
depends on unchanged salicylate,
which is excreted only slowly.
Group-specific adverse effects can
be attributed to inhibition of cyclooxygenase.
The most frequent problem,
gastric mucosal injury with risk of peptic
ulceration, results from reduced synthesis
of protective prostaglandins (PG),
apart from a direct irritant effect. Gastropathy
may be prevented by co-administration
of the PG derivative, misoprostol.
In the intestinal tract,
inhibition of PG synthesis would similarly
be expected to lead to damage of
the blood mucosa barrier and enteropathy.
In predisposed patients, asthma attacks
may occur, probably because of a
lack of bronchodilating PG and increased
production of leukotrienes. Because
this response is not immune mediated,
such “pseudoallergic” reactions
are a potential hazard with all NSAIDs.
PG also regulate renal blood flow as
functional antagonists of angiotensin II
and norepinephrine. If release of the latter
two is increased (e.g., in hypovolemia),
inhibition of PG production may
result in reduced renal blood flow and renal
impairment. Other unwanted effects
are edema and a rise in blood pressure.
Moreover, drug-specific side effects
deserve attention. These concern the
CNS (e.g., indomethacin: drowsiness,
headache, disorientation), the skin (piroxicam:
photosensitization), or the
blood (phenylbutazone: agranulocytosis).
Outlook: Cyclooxygenase (COX)
has two isozymes: COX-1, a constitutive
form present in stomach and kidney;
and COX-2, which is induced in inflammatory
cells in response to appropriate
stimuli. Presently available NSAIDs inhibit
both isozymes. The search for
COX-2-selective agents (Celecoxib, Rofecoxib)
is intensifying because, in theory,
these ought to be tolerated better.

Thermoregulation and Antipyretics
Body core temperature in the human is
about 37 °C and fluctuates within ± 1 °C
during the 24 h cycle. In the resting
state, the metabolic activity of vital organs
contributes 60% (liver 25%, brain
20%, heart 8%, kidneys 7%) to total heat
production. The absolute contribution
to heat production from these organs
changes little during physical activity,
whereas muscle work, which contributes
approx. 25% at rest, can generate
up to 90% of heat production during
strenuous exercise. The set point of the
body temperature is programmed in the
hypothalamic thermoregulatory center.
The actual value is adjusted to the set
point by means of various thermoregulatory
mechanisms. Blood vessels supplying
the skin penetrate the heat-insulating
layer of subcutaneous adipose tissue
and therefore permit controlled
heat exchange with the environment as
a function of vascular caliber and rate of
blood flow. Cutaneous blood flow can
range from ~ 0 to 30% of cardiac output,
depending on requirements. Heat conduction
via the blood from interior sites
of production to the body surface provides
a controllable mechanism for heat
loss.
Heat dissipation can also be
achieved by increased production of
sweat, because evaporation of sweat on
the skin surface consumes heat (evaporative
heat loss). Shivering is a mechanism
to generate heat. Autonomic neural
regulation of cutaneous blood flow
and sweat production permit homeostatic
control of body temperature.
The sympathetic system can either reduce
heat loss via vasoconstriction or
promote it by enhancing sweat production.
When sweating is inhibited due to
poisoning with anticholinergics (e.g.,
atropine), cutaneous blood flow increases.
If insufficient heat is dissipated
through this route, overheating occurs
(hyperthermia).
Thyroid hyperfunction poses a
particular challenge to the thermoregulatory
system, because the excessive secretion
of thyroid hormones causes
metabolic heat production to increase.
In order to maintain body temperature
at its physiological level, excess heat
must be dissipated—the patients have a
hot skin and are sweating.
The hypothalamic temperature
controller (B1) can be inactivated by
neuroleptics, without impairment
of other centers. Thus, it is possible
to lower a patient’s body temperature
without activating counter-regulatory
mechanisms (thermogenic shivering).
This can be exploited in the treatment
of severe febrile states (hyperpyrexia)
or in open-chest surgery with
cardiac by-pass, during which blood
temperature is lowered to 10 °C by
means of a heart-lung machine.
In higher doses, ethanol and barbiturates
also depress the thermoregulatory
center, thereby permitting
cooling of the body to the point of death,
given a sufficiently low ambient temperature
(freezing to death in drunkenness).
Pyrogens (e.g., bacterial matter) elevate—
probably through mediation by
prostaglandins and interleukin-
1—the set point of the hypothalamic
temperature controller. The body
responds by restricting heat loss (cutaneous
vasoconstriction ! chills) and by
elevating heat production (shivering), in
order to adjust to the new set point (fever).
Antipyretics such as acetaminophen
and ASAreturn the set
point to its normal level (B2) and thus
bring about a defervescence.

Drugs for the Suppression of Pain, Analgesics

Pain Mechanisms and Pathways
Pain is a designation for a spectrum of
sensations of highly divergent character
and intensity ranging from unpleasant
to intolerable. Pain stimuli are detected
by physiological receptors (sensors,
nociceptors) least differentiated morphologically,
viz., free nerve endings.
The body of the bipolar afferent first-order
neuron lies in a dorsal root ganglion.
Nociceptive impulses are conducted via
unmyelinated (C-fibers, conduction velocity
0.2–2.0 m/s) and myelinated axons
(A!-fibers, 5–30 m/s). The free endings
of A! fibers respond to intense
pressure or heat, those of C-fibers respond
to chemical stimuli (H+, K+, histamine,
bradykinin, etc.) arising from tissue
trauma. Irrespective of whether
chemical, mechanical, or thermal stimuli
are involved, they become significantly
more effective in the presence of
prostaglandins.
Chemical stimuli also underlie pain
secondary to inflammation or ischemia
(angina pectoris, myocardial infarction),
or the intense pain that occurs during
overdistention or spasmodic contraction
of smooth muscle abdominal organs,
and that may be maintained by local
anoxemia developing in the area of
spasm (visceral pain).
A! and C-fibers enter the spinal
cord via the dorsal root, ascend in the
dorsolateral funiculus, and then synapse
on second-order neurons in the
dorsal horn. The axons of the second-order
neurons cross the midline and ascend
to the brain as the anterolateral
pathway or spinothalamic tract. Based
on phylogenetic age, neo- and paleospinothalamic
tracts are distinguished.
Thalamic nuclei receiving neospinothalamic
input project to circumscribed areas
of the postcentral gyrus. Stimuli
conveyed via this path are experienced
as sharp, clearly localizable pain. The
nuclear regions receiving paleospinothalamic
input project to the postcentral
gyrus as well as the frontal, limbic
cortex and most likely represent the
pathway subserving pain of a dull, aching,
or burning character, i.e., pain that
can be localized only poorly.
Impulse traffic in the neo- and paleospinothalamic
pathways is subject to
modulation by descending projections
that originate from the reticular formation
and terminate at second-order neurons,
at their synapses with first-order
neurons, or at spinal segmental interneurons
(descending antinociceptive
system). This system can inhibit impulse
transmission from first- to second-
order neurons via release of opiopeptides
(enkephalins) or monoamines
(norepinephrine, serotonin).
Pain sensation can be influenced
or modified as follows:
elimination of the cause of pain
lowering of the sensitivity of nociceptors
(antipyretic analgesics, local
anesthetics)
interrupting nociceptive conduction
in sensory nerves (local anesthetics)
suppression of transmission of nociceptive
impulses in the spinal medulla
(opioids)
inhibition of pain perception (opioids,
general anesthetics)
! altering emotional responses to
pain, i.e., pain behavior (antidepressants
as “co-analgesics,”).

Drugs Acting on Motor Systems

Drugs Affecting Motor Function

The smallest structural unit of skeletal
musculature is the striated muscle fiber.
It contracts in response to an impulse of
its motor nerve. In executing motor programs,
the brain sends impulses to the
spinal cord. These converge on !-motoneurons
in the anterior horn of the spinal
medulla. Efferent axons course, bundled
in motor nerves, to skeletal muscles.
Simple reflex contractions to sensory
stimuli, conveyed via the dorsal
roots to the motoneurons, occur without
participation of the brain. Neural
circuits that propagate afferent impulses
into the spinal cord contain inhibitory
interneurons. These serve to prevent
a possible overexcitation of motoneurons
(or excessive muscle contractions)
due to the constant barrage of
sensory stimuli.
Neuromuscular transmission of
motor nerve impulses to the striated
muscle fiber takes place at the motor
endplate. The nerve impulse liberates
acetylcholine (ACh) from the axon terminal.
ACh binds to nicotinic cholinoceptors
at the motor endplate. Activation of
these receptors causes depolarization of
the endplate, from which a propagated
action potential (AP) is elicited in the
surrounding sarcolemma. The AP triggers
a release of Ca2+ from its storage organelles,
the sarcoplasmic reticulum
(SR), within the muscle fiber; the rise in
Ca2+ concentration induces a contraction
of the myofilaments (electromechanical
coupling). Meanwhile, ACh is
hydrolyzed by acetylcholinesterase
(p. 100); excitation of the endplate subsides.
If no AP follows, Ca2+ is taken up
again by the SR and the myofilaments
relax.
Clinically important drugs (with
the exception of dantrolene) all interfere
with neural control of the muscle
cell Centrally acting muscle relaxants
lower muscle tone by augmenting
the activity of intraspinal inhibitory
interneurons. They are used in the treatment
of painful muscle spasms, e.g., in
spinal disorders. Benzodiazepines enhance
the effectiveness of the inhibitory
transmitter GABA at GABAA receptors.
Baclofen stimulates GABAB receptors.
2-Adrenoceptor agonists such
as clonidine and tizanidine probably act
presynaptically to inhibit release of excitatory
amino acid transmitters.
The convulsant toxins, tetanus toxin
(cause of wound tetanus) and strychnine
diminish the efficacy of interneuronal
synaptic inhibition mediated by
the amino acid glycine. As a consequence
of an unrestrained spread of
nerve impulses in the spinal cord, motor
convulsions develop. The involvement
of respiratory muscle groups endangers
life.
Botulinum toxin from Clostridium
botulinum is the most potent poison
known. The lethal dose in an adult is approx.
10–6 mg. The toxin blocks exocytosis
of ACh in motor (and also parasympathetic)
nerve endings. Death is
caused by paralysis of respiratory muscles.
Injected intramuscularly at minuscule
dosage, botulinum toxin type A is
used to treat blepharospasm, strabismus,
achalasia of the lower esophageal
sphincter, and spastic aphonia.
A pathological rise in serum Mg2+
levels also causes inhibition of ACh release,
hence inhibition of neuromuscular
transmission.
Dantrolene interferes with electromechanical
coupling in the muscle cell
by inhibiting Ca2+ release from the SR. It
is used to treat painful muscle spasms
attending spinal diseases and skeletal
muscle disorders involving excessive
release of Ca2+ (malignant hyperthermia).


Muscle Relaxants

Muscle relaxants cause a flaccid paralysis
of skeletal musculature by binding to
motor endplate cholinoceptors, thus
blocking neuromuscular transmission.
According to whether receptor occupancy
leads to a blockade or an excitation
of the endplate, one distinguishes
nondepolarizing from depolarizing
muscle relaxants. As adjuncts to
general anesthetics, muscle relaxants
help to ensure that surgical procedures
are not disturbed by muscle contractions
of the patient.
Nondepolarizing muscle relaxants
Curare is the term for plant-derived arrow
poisons of South American natives.
When struck by a curare-tipped arrow,
an animal suffers paralysis of skeletal
musculature within a short time after
the poison spreads through the body;
death follows because respiratory muscles
fail (respiratory paralysis). Killed
game can be eaten without risk because
absorption of the poison from the gastrointestinal
tract is virtually nil. The curare
ingredient of greatest medicinal
importance is d-tubocurarine. This
compound contains a quaternary nitrogen
atom (N) and, at the opposite end of
the molecule, a tertiary N that is protonated
at physiological pH. These two
positively charged N atoms are common
to all other muscle relaxants. The fixed
positive charge of the quaternary N accounts
for the poor enteral absorbability.
d-Tubocurarine is given by i.v. injection
(average dose approx. 10 mg). It
binds to the endplate nicotinic cholinoceptors
without exciting them, acting as
a competitive antagonist towards ACh.
By preventing the binding of released
ACh, it blocks neuromuscular transmission.
Muscular paralysis develops within
about 4 min. d-Tubocurarine does not
penetrate into the CNS. The patient
would thus experience motor paralysis
and inability to breathe, while remaining
fully conscious but incapable of expressing
anything. For this reason, care
must be taken to eliminate consciousness
by administration of an appropriate
drug (general anesthesia) before using
a muscle relaxant. The effect of a single
dose lasts about 30 min.
The duration of the effect of d-tubocurarine
can be shortened by administering
an acetylcholinesterase inhibitor,
such as neostigmine. Inhibition
of ACh breakdown causes the concentration
of ACh released at the endplate
to rise. Competitive “displacement” by
ACh of d-tubocurarine from the receptor
allows transmission to be restored.
Unwanted effects produced by d-tubocurarine
result from a nonimmunemediated
release of histamine from
mast cells, leading to bronchospasm, urticaria,
and hypotension. More commonly,
a fall in blood pressure can be attributed
to ganglionic blockade by d-tubocurarine.
Pancuronium is a synthetic compound
now frequently used and not
likely to cause histamine release or ganglionic
blockade. It is approx. 5-fold
more potent than d-tubocurarine, with
a somewhat longer duration of action.
Increased heart rate and blood pressure
are attributed to blockade of cardiac M2-
cholinoceptors, an effect not shared by
newer pancuronium congeners such as
vecuronium and pipecuronium.
Other nondepolarizing muscle relaxants
include: alcuronium, derived
from the alkaloid toxiferin; rocuronium,
gallamine, mivacurium, and atracurium.
The latter undergoes spontaneous
cleavage and does not depend on
hepatic or renal elimination.

Depolarizing Muscle Relaxants

In this drug class, only succinylcholine
(succinyldicholine, suxamethonium)
is of clinical importance. Structurally, it
can be described as a double ACh molecule.
Like ACh, succinylcholine acts as
agonist at endplate nicotinic cholinoceptors,
yet it produces muscle relaxation.
Unlike ACh, it is not hydrolyzed by
acetylcholinesterase. However, it is a
substrate of nonspecific plasma cholinesterase
(serum cholinesterase).
Succinylcholine is degraded more slowly
than is ACh and therefore remains in
the synaptic cleft for several minutes,
causing an endplate depolarization of
corresponding duration. This depolarization
initially triggers a propagated
action potential (AP) in the surrounding
muscle cell membrane, leading to contraction
of the muscle fiber. After its i.v.
injection, fine muscle twitches (fasciculations)
can be observed. A new AP can
be elicited near the endplate only if the
membrane has been allowed to repolarize.
The AP is due to opening of voltagegated
Na-channel proteins, allowing
Na+ ions to flow through the sarcolemma
and to cause depolarization. After a
few milliseconds, the Na channels close
automatically (“inactivation”), the
membrane potential returns to resting
levels, and the AP is terminated. As long
as the membrane potential remains incompletely
repolarized, renewed opening
of Na channels, hence a new AP, is
impossible. In the case of released ACh,
rapid breakdown by ACh esterase allows
repolarization of the endplate and
hence a return of Na channel excitability
in the adjacent sarcolemma. With
succinylcholine, however, there is a persistent
depolarization of the endplate
and adjoining membrane regions. Because
the Na channels remain inactivated,
an AP cannot be triggered in the adjacent
membrane.
Because most skeletal muscle fibers
are innervated only by a single endplate,
activation of such fibers, with lengths
up to 30 cm, entails propagation of the
AP through the entire cell. If the AP fails,
the muscle fiber remains in a relaxed
state.
The effect of a standard dose of succinylcholine
lasts only about 10 min. It
is often given at the start of anesthesia
to facilitate intubation of the patient. As
expected, cholinesterase inhibitors are
unable to counteract the effect of succinylcholine.
In the few patients with a
genetic deficiency in pseudocholinesterase
(= nonspecific cholinesterase), the
succinylcholine effect is significantly
prolonged.
Since persistent depolarization of
endplates is associated with an efflux of
K+ ions, hyperkalemia can result (risk of
cardiac arrhythmias).
Only in a few muscle types (e.g.,
extraocular muscle) are muscle fibers
supplied with multiple endplates. Here
succinylcholine causes depolarization
distributed over the entire fiber, which
responds with a contracture. Intraocular
pressure rises, which must be taken into
account during eye surgery.
In skeletal muscle fibers whose motor
nerve has been severed, ACh receptors
spread in a few days over the entire
cell membrane. In this case, succinylcholine
would evoke a persistent depolarization
with contracture and hyperkalemia.
These effects are likely to occur
in polytraumatized patients undergoing
follow-up surgery.


Antiparkinsonian Drugs

Parkinson’s disease (shaking palsy) and
its syndromal forms are caused by a degeneration
of nigrostriatal dopamine
neurons. The resulting striatal dopamine
deficiency leads to overactivity of
cholinergic interneurons and imbalance
of striopallidal output pathways, manifested
by poverty of movement (akinesia),
muscle stiffness (rigidity), tremor
at rest, postural instability, and gait disturbance.
Pharmacotherapeutic measures are
aimed at restoring dopaminergic function
or suppressing cholinergic hyperactivity.
L-Dopa. Dopamine itself cannot
penetrate the blood-brain barrier; however,
its natural precursor, L-dihydroxyphenylalanine
(levodopa), is effective in
replenishing striatal dopamine levels,
because it is transported across the
blood-brain barrier via an amino acid
carrier and is subsequently decarboxylated
by DOPA-decarboxylase, present
in striatal tissue. Decarboxylation also
takes place in peripheral organs where
dopamine is not needed, likely causing
undesirable effects (tachycardia, arrhythmias
resulting from activation of
!1-adrenoceptors, hypotension,
and vomiting). Extracerebral production
of dopamine can be prevented by
inhibitors of DOPA-decarboxylase (carbidopa,
benserazide) that do not penetrate
the blood-brain barrier, leaving
intracerebral decarboxylation unaffected.
Excessive elevation of brain dopamine
levels may lead to undesirable reactions,
such as involuntary movements
(dyskinesias) and mental disturbances.
Dopamine receptor agonists. Deficient
dopaminergic transmission in the
striatum can be compensated by ergot
derivatives (bromocriptine, lisuride,
cabergoline, and pergolide) and
nonergot compounds (ropinirole, pramipexole).
These agonists stimulate dopamine
receptors (D2, D3, and D1 subtypes),
have lower clinical efficacy than
levodopa, and share its main adverse effects.
Inhibitors of monoamine oxidase-
B (MAOB). This isoenzyme breaks
down dopamine in the corpus striatum
and can be selectively inhibited by selegiline.
Inactivation of norepinephrine,
epinephrine, and 5-HT via MAOA is unaffected.
The antiparkinsonian effects of
selegiline may result from decreased
dopamine inactivation (enhanced levodopa
response) or from neuroprotective
mechanisms (decreased oxyradical formation
or blocked bioactivation of an
unknown neurotoxin).
Inhibitors of catechol-O-methyltransferase
(COMT). L-Dopa and dopamine
become inactivated by methylation.
The responsible enzyme can be
blocked by entacapone, allowing higher
levels of L-dopa and dopamine to be
achieved in corpus striatum.
Anticholinergics. Antagonists at
muscarinic cholinoceptors, such as
benzatropine and biperiden,
suppress striatal cholinergic overactivity
and thereby relieve rigidity and
tremor; however, akinesia is not reversed
or is even exacerbated. Atropinelike
peripheral side effects and impairment
of cognitive function limit the tolerable
dosage.
Amantadine. Early or mild parkinsonian
manifestations may be temporarily
relieved by amantadine. The
underlying mechanism of action may
involve, inter alia, blockade of ligandgated
ion channels of the glutamate/
NMDA subtype, ultimately leading to a
diminished release of acetylcholine.
Administration of levodopa plus
carbidopa (or benserazide) remains the
most effective treatment, but does not
provide benefit beyond 3–5 y and is followed
by gradual loss of symptom control,
on-off fluctuations, and development
of orobuccofacial and limb dyskinesias.
These long-term drawbacks of
levodopa therapy may be delayed by
early monotherapy with dopamine receptor
agonists. Treatment of advanced
disease requires the combined administration
of antiparkinsonian agents.



Antiepileptics

Epilepsy is a chronic brain disease of diverse
etiology; it is characterized by recurrent
paroxysmal episodes of uncontrolled
excitation of brain neurons. Involving
larger or smaller parts of the
brain, the electrical discharge is evident
in the electroencephalogram (EEG) as
synchronized rhythmic activity and
manifests itself in motor, sensory, psychic,
and vegetative (visceral) phenomena.
Because both the affected brain region
and the cause of abnormal excitability
may differ, epileptic seizures can
take many forms. From a pharmacotherapeutic
viewpoint, these may be
classified as:
– general vs. focal seizures;
– seizures with or without loss of consciousness;
– seizures with or without specific
modes of precipitation.
The brief duration of a single epileptic
fit makes acute drug treatment
unfeasible. Instead, antiepileptics are
used to prevent seizures and therefore
need to be given chronically. Only in the
case of status epilepticus (a succession of
several tonic-clonic seizures) is acute
anticonvulsant therapy indicated —
usually with benzodiazepines given i.v.
or, if needed, rectally.
The initiation of an epileptic attack
involves “pacemaker” cells; these differ
from other nerve cells in their unstable
resting membrane potential, i.e., a depolarizing
membrane current persists
after the action potential terminates.
Therapeutic interventions aim to
stabilize neuronal resting potential and,
hence, to lower excitability. In specific
forms of epilepsy, initially a single drug
is tried to achieve control of seizures,
valproate usually being the drug of first
choice in generalized seizures, and carbamazepine
being preferred for partial
(focal), especially partial complex, seizures.
Dosage is increased until seizures
are no longer present or adverse effects
become unacceptable. Only when
monotherapy with different agents
proves inadequate can changeover to a
second-line drug or combined use (“add
on”) be recommended, provided
that the possible risk of pharmacokinetic
interactions is taken into account (see
below). The precise mode of action of
antiepileptic drugs remains unknown.
Some agents appear to lower neuronal
excitability by several mechanisms of
action. In principle, responsivity can be
decreased by inhibiting excitatory or activating
inhibitory neurons. Most excitatory
nerve cells utilize glutamate and
most inhibitory neurons utilize !-aminobutyric
acid (GABA) as their transmitter
. Various drugs can lower
seizure threshold, notably certain neuroleptics,
the tuberculostatic isoniazid,
and "-lactam antibiotics in high doses;
they are, therefore, contraindicated in
seizure disorders.
Glutamate receptors comprise
three subtypes, of which the NMDA
subtype has the greatest therapeutic
importance. (N-methyl-D-aspartate is a
synthetic selective agonist.) This receptor
is a ligand-gated ion channel that,
upon stimulation with glutamate, permits
entry of both Na+ and Ca2+ ions into
the cell. The antiepileptics lamotrigine,
phenytoin, and phenobarbital inhibit,
among other things, the release of glutamate.
Felbamate is a glutamate antagonist.
Benzodiazepines and phenobarbital
augment activation of the GABAA receptor
by physiologically released amounts
of GABA . Chloride influx
is increased, counteracting depolarization.
Progabide is a direct GABA-mimetic.
Tiagabin blocks removal of GABA
from the synaptic cleft by decreasing its
re-uptake. Vigabatrin inhibits GABA catabolism.
Gabapentin may augment the
availability of glutamate as a precursor
in GABA synthesis and can also act as
a K+-channel opener.


Carbamazepine, valproate, and
phenytoin enhance inactivation of voltage-
gated sodium and calcium channels
and limit the spread of electrical excitation
by inhibiting sustained high-frequency
firing of neurons.
Ethosuximide blocks a neuronal Ttype
Ca2+ channel and represents a
special class because it is effective only
in absence seizures.
All antiepileptics are likely, albeit to
different degrees, to produce adverse
effects. Sedation, difficulty in concentrating,
and slowing of psychomotor drive
encumber practically all antiepileptic
therapy. Moreover, cutaneous, hematological,
and hepatic changes may necessitate
a change in medication. Phenobarbital,
primidone, and phenytoin may
lead to osteomalacia (vitamin D prophylaxis)
or megaloblastic anemia (folate
prophylaxis). During treatment with
phenytoin, gingival hyperplasia may develop
in ca. 20% of patients.
Valproic acid (VPA) is gaining increasing
acceptance as a first-line drug;
it is less sedating than other anticonvulsants.
Tremor, gastrointestinal upset,
and weight gain are frequently observed;
reversible hair loss is a rarer occurrence.
Hepatotoxicity may be due to
a toxic catabolite (4-en VPA).
Adverse reactions to carbamazepine
include: nystagmus, ataxia, diplopia,
particularly if the dosage is raised
too fast. Gastrointestinal problems and
skin rashes are frequent. It exerts an
antidiuretic effect (sensitization of collecting
ducts to vasopressin !water intoxication).
Carbamazepine is also used to treat
trigeminal neuralgia and neuropathic
pain.
Valproate, carbamazepine, and other
anticonvulsants pose teratogenic
risks. Despite this, treatment should
continue during pregnancy, as the potential
threat to the fetus by a seizure is
greater. However, it is mandatory to administer
the lowest dose affording safe
and effective prophylaxis. Concurrent
high-dose administration of folate may
prevent neural tube developmental defects.
Carbamazepine, phenytoin, phenobarbital,
and other anticonvulsants (except
for gabapentin) induce hepatic enzymes
responsible for drug biotransformation.
Combinations between anticonvulsants
or with other drugs may result
in clinically important interactions
(plasma level monitoring!).
For the often intractable childhood
epilepsies, various other agents are
used, including ACTH and the glucocorticoid,
dexamethasone. Multiple
(mixed) seizures associated with the
slow spike-wave (Lennox–Gastaut) syndrome
may respond to valproate, lamotrigine,
and felbamate, the latter being
restricted to drug-resistant seizures
owing to its potentially fatal liver and
bone marrow toxicity.
Benzodiazepines are the drugs of
choice for status epilepticus (see
above); however, development of tolerance
renders them less suitable for
long-term therapy. Clonazepam is used
for myoclonic and atonic seizures.
Clobazam, a 1,5-benzodiazepine exhibiting
an increased anticonvulsant/sedative
activity ratio, has a similar range of
clinical uses. Personality changes and
paradoxical excitement are potential
side effects.
Clomethiazole can also be effective
for controlling status epilepticus, but is
used mainly to treat agitated states, especially
alcoholic delirium tremens and
associated seizures.
Topiramate, derived from D-fructose,
has complex, long-lasting anticonvulsant
actions that cooperate to limit
the spread of seizure activity; it is effective
in partial seizures and as an add-on
in Lennox–Gastaut syndrome.

Gastrointestinal Drugs

Drugs for Dissolving Gallstones (A)
Following its secretion from liver into
bile, water-insoluble cholesterol is held
in solution in the form of micellar complexes
with bile acids and phospholipids.
When more cholesterol is secreted
than can be emulsified, it precipitates
and forms gallstones (cholelithiasis).
Precipitated cholesterol can be reincorporated
into micelles, provided the cholesterol
concentration in bile is below
saturation. Thus, cholesterol-containing
stones can be dissolved slowly. This
effect can be achieved by long-term oral
administration of chenodeoxycholic
acid (CDCA) or ursodeoxycholic acid
(UDCA). Both are physiologically occurring,
stereoisomeric bile acids (position
of the 7-hydroxy group being ! in UCDA
and " in CDCA). Normally, they represent
a small proportion of the total
amount of bile acid present in the body
(circle diagram in A); however, this increases
considerably with chronic administration
because of enterohepatic
cycling, p. 38). Bile acids undergo almost
complete reabsorption in the ileum.
Small losses via the feces are made up
by de novo synthesis in the liver, keeping
the total amount of bile acids constant
(3–5 g). Exogenous supply removes
the need for de novo synthesis of
bile acids. The particular acid being supplied
gains an increasingly larger share
of the total store.
The altered composition of bile increases
the capacity for cholesterol uptake.
Thus, gallstones can be dissolved
in the course of a 1- to 2 y treatment,
provided that cholesterol stones are
pure and not too large (<15 mm), gall
bladder function is normal, liver disease
is absent, and patients are of normal
body weight. UCDA is more effective
(daily dose, 8–10 mg) and better tolerated
than is CDCA (15 mg/d; frequent
diarrhea, elevation of liver enzymes in
plasma). Stone formation may recur after
cessation of successful therapy.
Compared with surgical treatment,
drug therapy plays a subordinate role.
UCDA may also be useful in primary biliary
cirrhosis.
Choleretics are supposed to stimulate
production and secretion of dilute
bile fluid. This principle has little therapeutic
significance.
Cholekinetics stimulate the gallbladder
to contract and empty, e.g., egg
yolk, the osmotic laxative MgSO4, the
cholecystokinin-related ceruletide (given
parenterally). Cholekinetics are employed
to test gallbladder function for
diagnostic purposes.
Pancreatic enzymes (B) from
slaughtered animals are used to relieve
excretory insufficiency of the pancreas
(! disrupted digestion of fats; steatorrhea,
inter alia). Normally, secretion of
pancreatic enzymes is activated by
cholecystokinin/pancreozymin, the enterohormone
that is released into blood
from the duodenal mucosa upon contact
with chyme. With oral administration
of pancreatic enzymes, allowance
must be made for their partial inactivation
by gastric acid (the lipases, particularly).
Therefore, they are administered
in acid-resistant dosage forms.
Antiflatulents (carminatives) serve
to alleviate meteorism (excessive accumulation
of gas in the gastrointestinal
tract). Aborad propulsion of intestinal
contents is impeded when the latter are
mixed with gas bubbles. Defoaming
agents, such as dimethicone (dimethylpolysiloxane)
and simethicone, in combination
with charcoal, are given orally
to promote separation of gaseous and
semisolid contents.

Antidiarrheals

Antidiarrheal Agents

Causes of diarrhea : Many bacteria
(e.g., Vibrio cholerae) secrete toxins
that inhibit the ability of mucosal enterocytes
to absorb NaCl and water and, at
the same time, stimulate mucosal secretory
activity. Bacteria or viruses that invade
the gut wall cause inflammation
characterized by increased fluid secretion
into the lumen. The enteric musculature
reacts with increased peristalsis.
The aims of antidiarrheal therapy
are to prevent: (1) dehydration and
electrolyte depletion; and (2) excessively
high stool frequency. Different therapeutic
approaches (in green) listed
are variously suited for these purposes.
Adsorbent powders are nonabsorbable
materials with a large surface
area. These bind diverse substances, including
toxins, permitting them to be
inactivated and eliminated. Medicinal
charcoal possesses a particularly large
surface because of the preserved cell
structures. The recommended effective
antidiarrheal dose is in the range of
4–8 g. Other adsorbents are kaolin (hydrated
aluminum silicate) and chalk.
Oral rehydration solution (g/L of
boiled water: NaCl 3.5, glucose 20,
NaHCO3 2.5, KCl 1.5). Oral administration
of glucose-containing salt solutions
enables fluids to be absorbed because
toxins do not impair the cotransport of
Na+ and glucose (as well as of H2O)
through the mucosal epithelium. In this
manner, although frequent discharge of
stool is not prevented, dehydration is
successfully corrected.
Opioids. Activation of opioid receptors
in the enteric nerve plexus results
in inhibition of propulsive motor activity
and enhancement of segmentation
activity. This antidiarrheal effect was
formerly induced by application of opium
tincture (paregoric) containing morphine.
Because of the CNS effects (sedation,
respiratory depression, physical
dependence), derivatives with peripheral
actions have been developed.
Whereas diphenoxylate can still produce
clear CNS effects, loperamide does not
affect brain functions at normal dosage.
Loperamide is, therefore, the opioid
antidiarrheal of first choice. The prolonged
contact time of intestinal contents
and mucosa may also improve absorption
of fluid. With overdosage,
there is a hazard of ileus. It is contraindicated
in infants below age 2 y.
Antibacterial drugs. Use of these
agents (e.g., cotrimoxazole,) is
only rational when bacteria are the
cause of diarrhea. This is rarely the case.
It should be kept in mind that antibiotics
also damage the intestinal flora
which, in turn, can give rise to diarrhea.
Astringents such as tannic acid
(home remedy: black tea) or metal salts
precipitate surface proteins and are
thought to help seal the mucosal epithelium.
Protein denaturation must not include
cellular proteins, for this would
mean cell death. Although astringents
induce constipation (cf. Al3+ salts,),
a therapeutic effect in diarrhea
is doubtful.
Demulcents, e.g., pectin (home
remedy: grated apples) are carbohydrates
that expand on absorbing water.
They improve the consistency of bowel
contents; beyond that they are devoid
of any favorable effect.

Laxatives

Laxatives

Laxatives promote and facilitate bowel
evacuation by acting locally to stimulate
intestinal peristalsis, to soften bowel
contents, or both.
1. Bulk laxatives. Distention of the
intestinal wall by bowel contents stimulates
propulsive movements of the gut
musculature (peristalsis). Activation of
intramural mechanoreceptors induces a
neurally mediated ascending reflex contraction
and descending relaxation
whereby the intraluminal
bolus is moved in the anal direction.
Hydrophilic colloids or bulk gels
comprise insoluble and nonabsorbable
carbohydrate substances that expand
on taking up water in the bowel.
Vegetable fibers in the diet act in this
manner. They consist of the indigestible
plant cell walls containing homoglycans
that are resistant to digestive enzymes,
e.g., cellulose.
Bran, a grain milling waste product,
and linseed (flaxseed) are both rich in
cellulose. Other hydrophilic colloids derive
from the seeds of Plantago species
or karaya gum. Ingestion of hydrophilic
gels for the prophylaxis of constipation
usually entails a low risk of side effects.
However, with low fluid intake in combination
with a pathological bowel
stenosis, mucilaginous viscous material
could cause bowel occlusion (ileus).
Osmotically active laxatives
are soluble but nonabsorbable particles
that retain water in the bowel by virtue
of their osmotic action. The osmotic
pressure (particle concentration) of
bowel contents always corresponds to
that of the extracellular space. The intestinal
mucosa is unable to maintain a
higher or lower osmotic pressure of the
luminal contents. Therefore, absorption
of molecules (e.g., glucose, NaCl) occurs
isoosmotically, i.e., solute molecules are
followed by a corresponding amount of
water. Conversely, water remains in the
bowel when molecules cannot be absorbed.
With Epsom and Glauber’s salts
(MgSO4 and Na2SO4, respectively), the
SO4
2– anion is nonabsorbable and retains
cations to maintain electroneutrality.
Mg2+ ions are also believed to
promote release from the duodenal mucosa
of cholecystokinin/pancreozymin,
a polypeptide that also stimulates peristalsis.
These so-called saline cathartics
elicit a watery bowel discharge 1–3 h after
administration (preferably in isotonic
solution). They are used to purge the
bowel (e.g., before bowel surgery) or to
hasten the elimination of ingested poisons.
Glauber’s salt (high Na+ content) is
contraindicated in hypertension, congestive
heart failure, and edema. Epsom
salt is contraindicated in renal failure
(risk of Mg2+ intoxication).
Osmotic laxative effects are also
produced by the polyhydric alcohols,
mannitol and sorbitol, which unlike glucose
cannot be transported through the
intestinal mucosa, as well as by the nonhydrolyzable
disaccharide, lactulose.
Fermentation of lactulose by colon bacteria
results in acidification of bowel
contents and microfloral damage. Lactulose
is used in hepatic failure in order
to prevent bacterial production of ammonia
and its subsequent absorption
(absorbable NH3 ! nonabsorbable
NH4
+), so as to forestall hepatic coma.
2. Irritant laxatives—purgatives
cathartics. Laxatives in this group exert
an irritant action on the enteric mucosa.
Consequently, less fluid is absorbed
than is secreted. The increased filling of
the bowel promotes peristalsis; excitation
of sensory nerve endings elicits enteral
hypermotility. According to the
site of irritation, one distinguishes the
small bowel irritant castor oil from the
large bowel irritants anthraquinone and
diphenolmethane derivatives.
Misuse of laxatives. It is a widely
held belief that at least one bowel
movement per day is essential for
health; yet three bowel evacuations per
week are quite normal. The desire for
frequent bowel emptying probably
stems from the time-honored, albeit


mistaken, notion that absorption of colon
contents is harmful. Thus, purging
has long been part of standard therapeutic
practice. Nowadays, it is known
that intoxication from intestinal substances
is impossible as long as the liver
functions normally. Nonetheless, purgatives
continue to be sold as remedies to
“cleanse the blood” or to rid the body of
“corrupt humors.”
There can be no objection to the ingestion
of bulk substances for the purpose
of supplementing low-residue
“modern diets.” However, use of irritant
purgatives or cathartics is not without
hazards. Specifically, there is a risk of
laxative dependence, i.e., the inability to
do without them. Chronic intake of irritant
purgatives disrupts the water and
electrolyte balance of the body and can
thus cause symptoms of illness (e.g.,
cardiac arrhythmias secondary to hypokalemia).
Causes of purgative dependence
(B). The defecation reflex is triggered
when the sigmoid colon and rectum are
filled. A natural defecation empties the
large bowel up to and including the descending
colon. The interval between
natural stool evacuations depends on
the speed with which these colon segments
are refilled. A large bowel irritant
purgative clears out the entire colon.
Accordingly, a longer period is needed
until the next natural defecation can occur.
Fearing constipation, the user becomes
impatient and again resorts to
the laxative, which then produces the
desired effect as a result of emptying
out the upper colonic segments. Therefore,
a “compensatory pause” following
cessation of laxative use must not give
cause for concern (1).
In the colon, semifluid material entering
from the small bowel is thickened
by absorption of water and salts
(from about 1000 to 150 mL/d). If, due
to the action of an irritant purgative, the
colon empties prematurely, an enteral
loss of NaCl, KCl and water will be incurred.
To forestall depletion of NaCl
and water, the body responds with an
increased release of aldosterone (p.
124), which stimulates their reabsorption
in the kidney. The action of aldosterone
is, however, associated with increased
renal excretion of KCl. The enteral
and renal K+ loss add up to a K+ depletion
of the body, evidenced by a fall
in serum K+ concentration (hypokalemia).
This condition is accompanied by
a reduction in intestinal peristalsis
(bowel atonia). The affected individual
infers “constipation,” again partakes of
the purgative, and the vicious circle is
closed (2).
Chologenic diarrhea results when
bile acids fail to be absorbed in the ileum
(e.g., after ileal resection) and enter
the colon, where they cause enhanced
secretion of electrolytes and water,
leading to the discharge of fluid stools.


2.a Small Bowel Irritant Purgative,
Ricinoleic Acid
Castor oil comes from Ricinus communis
(castor plants; Fig: sprig, panicle,
seed); it is obtained from the first coldpressing
of the seed (shown in natural
size). Oral administration of 10–30 mL
of castor oil is followed within 0.5 to 3 h
by discharge of a watery stool. Ricinoleic
acid, but not the oil itself, is active. It
arises as a result of the regular processes
involved in fat digestion: the duodenal
mucosa releases the enterohormone
cholecystokinin/pancreozymin into the
blood. The hormone elicits contraction
of the gallbladder and discharge of bile
acids via the bile duct, as well as release
of lipase from the pancreas (intestinal
peristalsis is also stimulated). Because
of its massive effect, castor oil is hardly
suitable for the treatment of ordinary
constipation. It can be employed after
oral ingestion of a toxin in order to hasten
elimination and to reduce absorption
of toxin from the gut. Castor oil is
not indicated after the ingestion of lipophilic
toxins likely to depend on bile acids
for their absorption.
2.b Large Bowel Irritant Purgatives
(p. 177 ff)
Anthraquinone derivatives (p. 176) are
of plant origin. They occur in the leaves
(folia sennae) or fruits (fructus sennae)
of the senna plant, the bark of Rhamnus
frangulae and Rh. purshiana, (cortex
frangulae, cascara sagrada), the roots of
rhubarb (rhizoma rhei), or the leaf extract
from Aloe species (p. 176). The
structural features of anthraquinone derivatives
are illustrated by the prototype
structure depicted on p. 177.
Among other substituents, the anthraquinone
nucleus contains hydroxyl
groups, one of which is bound to a sugar
(glucose, rhamnose). Following ingestion
of galenical preparations or of the
anthraquinone glycosides, discharge of
soft stool occurs after a latency of 6 to 8
h. The anthraquinone glycosides themselves
are inactive but are converted by
colon bacteria to the active free aglycones.
Diphenolmethane derivatives (p. 177)
were developed from phenolphthalein,
an accidentally discovered laxative, use
of which had been noted to result in
rare but severe allergic reactions. Bisacodyl
and sodium picosulfate are converted
by gut bacteria into the active colonirritant
principle. Given by the enteral
route, bisacodyl is subject to hydrolysis
of acetyl residues, absorption, conjugation
in liver to glucuronic acid (or also to
sulfate, p. 38), and biliary secretion into
the duodenum. Oral administration is
followed after approx. 6 to 8 h by discharge
of soft formed stool. When given
by suppository, bisacodyl produces its
effect within 1 h.
Indications for colon-irritant purgatives
are the prevention of straining at
stool following surgery, myocardial infarction,
or stroke; and provision of relief
in painful diseases of the anus, e.g.,
fissure, hemorrhoids.
Purgatives must not be given in abdominal
complaints of unclear origin.
3. Lubricant laxatives. Liquid paraffin
(paraffinum subliquidum) is almost nonabsorbable
and makes feces softer and
more easily passed. It interferes with
the absorption of fat-soluble vitamins
by trapping them. The few absorbed
paraffin particles may induce formation
of foreign-body granulomas in enteric
lymph nodes (paraffinomas). Aspiration
into the bronchial tract can result in lipoid
pneumonia. Because of these adverse
effects, its use is not advisable.

Drugs for the Treatment of Peptic Ulcers

Drugs for Gastric and Duodenal Ulcers

In the area of a gastric or duodenal peptic
ulcer, the mucosa has been attacked
by digestive juices to such an extent as
to expose the subjacent connective tissue
layer (submucosa). This self-digestion
occurs when the equilibrium
between the corrosive hydrochloric acid
and acid-neutralizing mucus, which
forms a protective cover on the mucosal
surface, is shifted in favor of hydrochloric
acid. Mucosal damage can be
promoted by Helicobacter pylori bacteria
that colonize the gastric mucus.
Drugs are employed with the following
therapeutic aims: (1) to relieve
pain; (2) to accelerate healing; and (3)
to prevent ulcer recurrence. Therapeutic
approaches are threefold: (a) to reduce
aggressive forces by lowering H+
output; (b) to increase protective forces
by means of mucoprotectants; and (c) to
eradicate Helicobacter pylori.
I. Drugs for Lowering Acid
Concentration
Ia. Acid neutralization. H+-binding
groups such as CO3
2–, HCO3
– or OH–, together
with their counter ions, are contained
in antacid drugs. Neutralization
reactions occurring after intake of
CaCO3 and NaHCO3, respectively, are
shown in (A) at left. With nonabsorbable
antacids, the counter ion is dissolved
in the acidic gastric juice in the
process of neutralization. Upon mixture
with the alkaline pancreatic secretion in
the duodenum, it is largely precipitated
again by basic groups, e.g., as CaCO3 or
AlPO4, and excreted in feces. Therefore,
systemic absorption of counter ions or
basic residues is minor. In the presence
of renal insufficiency, however, absorption
of even small amounts may cause
an increase in plasma levels of counter
ions (e.g., magnesium intoxication with
paralysis and cardiac disturbances). Precipitation
in the gut lumen is responsible
for other side effects, such as reduced
absorption of other drugs due to
their adsorption to the surface of precipitated
antacid or, phosphate depletion
of the body with excessive intake of
Al(OH)3.
Na+ ions remain in solution even in
the presence of HCO3
–-rich pancreatic
secretions and are subject to absorption,
like HCO3
–. Because of the uptake of Na+,
use of NaHCO3 must be avoided in conditions
requiring restriction of NaCl intake,
such as hypertension, cardiac failure,
and edema.
Since food has a buffering effect,
antacids are taken between meals (e.g.,
1 and 3 h after meals and at bedtime).
Nonabsorbable antacids are preferred.
Because Mg(OH)2 produces a laxative
effect (cause: osmotic action, p. 170, release
of cholecystokinin by Mg2+, or
both) and Al(OH)3 produces constipation
(cause: astringent action of Al3+),
these two antacids are frequently
used in combination.
Ib. Inhibitors of acid production.
Acting on their respective receptors, the
transmitter acetylcholine, the hormone
gastrin, and histamine released intramucosally
stimulate the parietal cells of
the gastric mucosa to increase output of
HCl. Histamine comes from enterochromaffin-
like (ECL) cells; its release is
stimulated by the vagus nerve (via M1
receptors) and hormonally by gastrin.
The effects of acetylcholine and histamine
can be abolished by orally applied
antagonists that reach parietal cells via
the blood.
The cholinoceptor antagonist pirenzepine,
unlike atropine, prefers cholinoceptors
of the M1 type, does not
penetrate into the CNS, and thus produces
fewer atropine-like side effects.
The cholinoceptors on parietal
cells probably belong to the M3 subtype.
Hence, pirenzepine may act by blocking
M1 receptors on ECL cells or submucosal
neurons.
Histamine receptors on parietal
cells belong to the H2 type and
are blocked by H2-antihistamines. Because
histamine plays a pivotal role in
the activation of parietal cells, H2-antihistamines
also diminish responsivity
to other stimulants, e.g., gastrin (in gas-
trin-producing pancreatic tumors, Zollinger-
Ellison syndrome). Cimetidine,
the first H2-antihistamine used therapeutically,
only rarely produces side effects
(CNS disturbances such as confusion;
endocrine effects in the male, such
as gynecomastia, decreased libido, impotence).
Unlike cimetidine, its newer
and more potent congeners, ranitidine,
nizatidine, and famotidine, do not interfere
with the hepatic biotransformation
of other drugs.
Omeprazole can cause maximal
inhibition of HCl secretion. Given
orally in gastric juice-resistant capsules,
it reaches parietal cells via the blood. In
the acidic milieu of the mucosa, an active
metabolite is formed and binds covalently
to the ATP-driven proton pump
(H+/K+ ATPase) that transports H+ in exchange
for K+ into the gastric juice. Lansoprazole
and pantoprazole produce
analogous effects. The proton pump inhibitors
are first-line drugs for the treatment
of gastroesophageal reflux disease.
II. Protective Drugs
Sucralfate contains numerous aluminum
hydroxide residues. However, it
is not an antacid because it fails to lower
the overall acidity of gastric juice. After
oral intake, sucralfate molecules undergo
cross-linking in gastric juice, forming
a paste that adheres to mucosal defects
and exposed deeper layers. Here sucralfate
intercepts H+. Protected from acid,
and also from pepsin, trypsin, and bile
acids, the mucosal defect can heal more
rapidly. Sucralfate is taken on an empty
stomach (1 h before meals and at bedtime).
It is well tolerated; however, released
Al3+ ions can cause constipation.
Misoprostol is a semisynthetic
prostaglandin derivative with greater
stability than natural prostaglandin,
permitting absorption after oral administration.
Like locally released prostaglandins,
it promotes mucus production
and inhibits acid secretion. Additional
systemic effects (frequent diarrhea; risk
of precipitating contractions of the
gravid uterus) significantly restrict its
therapeutic utility.
Carbenoxolone is a derivative
of glycyrrhetinic acid, which occurs in
the sap of licorice root (succus liquiritiae).
Carbenoxolone stimulates mucus
production. At the same time, it has a
mineralocorticoid-like action (due to inhibition
of 11-!-hydroxysteroid dehydrogenase)
that promotes renal reabsorption
of NaCl and water. It may,
therefore, exacerbate hypertension,
congestive heart failure, or edemas. It is
obsolete.
III. Eradication of Helicobacter pylori
C. This microorganism plays an important
role in the pathogenesis of
chronic gastritis and peptic ulcer disease.
The combination of antibacterial
drugs and omeprazole has proven effective.
In case of intolerance to amoxicillin
or clarithromycin, metronidazole
can be used as a substitute.
Colloidal bismuth compounds
are also effective; however, the problem
of heavy-metal exposure compromises
their long-term use.

Diuretics

Diuretics

An Overview
Diuretics (saluretics) elicit increased
production of urine (diuresis). In the
strict sense, the term is applied to drugs
with a direct renal action. The predominant
action of such agents is to augment
urine excretion by inhibiting the reabsorption
of NaCl and water.
The most important indications for
diuretics are:
Mobilization of edemas: In edema
there is swelling of tissues due to accumulation
of fluid, chiefly in the extracellular
(interstitial) space. When a diuretic
is given, increased renal excretion
of Na+ and H2O causes a reduction in
plasma volume with hemoconcentration.
As a result, plasma protein concentration
rises along with oncotic pressure.
As the latter operates to attract
water, fluid will shift from interstitium
into the capillary bed. The fluid content
of tissues thus falls and the edemas recede.
The decrease in plasma volume
and interstitial volume means a diminution
of the extracellular fluid volume
(EFV). Depending on the condition, use
is made of: thiazides, loop diuretics, aldosterone
antagonists, and osmotic diuretics.
Antihypertensive therapy. Diuretics
have long been used as drugs of first
choice for lowering elevated blood pressure
. Even at low dosage, they
decrease peripheral resistance (without
significantly reducing EFV) and thereby
normalize blood pressure.
Therapy of congestive heart failure.
By lowering peripheral resistance, diuretics
aid the heart in ejecting blood (reduction
in afterload); cardiac
output and exercise tolerance are
increased. Due to the increased excretion
of fluid, EFV and venous return decrease
(reduction in preload).
Symptoms of venous congestion, such
as ankle edema and hepatic enlargement,
subside. The drugs principally
used are thiazides (possibly combined
with K+-sparing diuretics) and loop diuretics.
Prophylaxis of renal failure. In circulatory
failure (shock), e.g., secondary to
massive hemorrhage, renal production
of urine may cease (anuria). By means of
diuretics an attempt is made to maintain
urinary flow. Use of either osmotic
or loop diuretics is indicated.
Massive use of diuretics entails a
hazard of adverse effects : (1) the
decrease in blood volume can lead to
hypotension and collapse; (2) blood viscosity
rises due to the increase in erythro-
and thrombocyte concentration,
bringing an increased risk of intravascular
coagulation or thrombosis.
When depletion of NaCl and water
(EFV reduction) occurs as a result of diuretic
therapy, the body can initiate
counter-regulatory responses,
namely, activation of the renin-angiotensin-
aldosterone system. Because
of the diminished blood volume,
renal blood flow is jeopardized. This
leads to release from the kidneys of the
hormone, renin, which enzymatically
catalyzes the formation of angiotensin I.
Angiotensin I is converted to angiotensin
II by the action of angiotensin-converting
enzyme (ACE). Angiotensin II
stimulates release of aldosterone. The
mineralocorticoid promotes renal reabsorption
of NaCl and water and thus
counteracts the effect of diuretics. ACE
inhibitors augment the effectiveness
of diuretics by preventing this
counter-regulatory response.

NaCl Reabsorption in the Kidney
The smallest functional unit of the kidney
is the nephron. In the glomerular
capillary loops, ultrafiltration of plasma
fluid into Bowman’s capsule (BC) yields
primary urine. In the proximal tubules
(pT), approx. 70% of the ultrafiltrate is
retrieved by isoosmotic reabsorption of
NaCl and water. In the thick portion of
the ascending limb of Henle’s loop (HL),
NaCl is absorbed unaccompanied by
water. This is the prerequisite for the
hairpin countercurrent mechanism that
allows build-up of a very high NaCl concentration
in the renal medulla. In the
distal tubules (dT), NaCl and water are
again jointly reabsorbed. At the end of
the nephron, this process involves an aldosterone-
controlled exchange of Na+
against K+ or H+. In the collecting tubule,
vasopressin (antidiuretic hormone,
ADH) increases the epithelial permeability
for water, which is drawn into
the hyperosmolar milieu of the renal
medulla and thus retained in the body.
As a result, a concentrated urine enters
the renal pelvis.
Na+ transport through the tubular
cells basically occurs in similar fashion
in all segments of the nephron. The
intracellular concentration of Na+ is significantly
below that in primary urine.
This concentration gradient is the driving
force for entry of Na+ into the cytosol
of tubular cells. A carrier mechanism
moves Na+ across the membrane. Energy
liberated during this influx can be
utilized for the coupled outward transport
of another particle against a gradient.
From the cell interior, Na+ is moved
with expenditure of energy (ATP hydrolysis)
by Na+/K+-ATPase into the extracellular
space. The enzyme molecules
are confined to the basolateral parts of
the cell membrane, facing the interstitium;
Na+ can, therefore, not escape back
into tubular fluid.
All diuretics inhibit Na+ reabsorption.
Basically, either the inward or the
outward transport of Na+ can be affected.

Osmotic Diuretics
Agents: mannitol, sorbitol. Site of action:
mainly the proximal tubules. Mode of
action: Since NaCl and H2O are reabsorbed
together in the proximal tubules,
Na+ concentration in the tubular fluid
does not change despite the extensive
reabsorption of Na+ and H2O. Body cells
lack transport mechanisms for polyhydric
alcohols such as mannitol
and sorbitol, which are
thus prevented from penetrating cell
membranes. Therefore, they need to be
given by intravenous infusion. They also
cannot be reabsorbed from the tubular
fluid after glomerular filtration. These
agents bind water osmotically and retain
it in the tubular lumen. When Na
ions are taken up into the tubule cell,
water cannot follow in the usual
amount. The fall in urine Na+ concentration
reduces Na+ reabsorption, in part
because the reduced concentration gradient
towards the interior of tubule cells
means a reduced driving force for Na+
influx. The result of osmotic diuresis is a
large volume of dilute urine.
Indications: prophylaxis of renal
hypovolemic failure, mobilization of
brain edema, and acute glaucoma.

Diuretics of the Sulfonamide Type
These drugs contain the sulfonamide
group -SO2NH2. They are suitable for
oral administration. In addition to being
filtered at the glomerulus, they are subject
to tubular secretion. Their concentration
in urine is higher than in blood.
They act on the luminal membrane of
the tubule cells. Loop diuretics have the
highest efficacy. Thiazides are most frequently
used. Their forerunners, the
carbonic anhydrase inhibitors, are now
restricted to special indications.
Carbonic anhydrase (CAH) inhibitors,
such as acetazolamide and sulthiame,
act predominantly in the proximal
tubules. CAH catalyzes CO2 hydration/
dehydration reactions:
H+ + HCO3
–H2CO3!H20 + CO2.
The enzyme is used in tubule cells
to generate H+, which is secreted into
the tubular fluid in exchange for Na+.
There, H+ captures HCO3
–, leading to formation
of CO2 via the unstable carbonic
acid. Membrane-permeable CO2 is taken
up into the tubule cell and used to regenerate
H+ and HCO3
–. When the enzyme
is inhibited, these reactions are
slowed, so that less Na+, HCO3
– and water
are reabsorbed from the fast-flowing
tubular fluid. Loss of HCO3
– leads to acidosis.
The diuretic effectiveness of CAH
inhibitors decreases with prolonged
use. CAH is also involved in the production
of ocular aqueous humor. Present
indications for drugs in this class include:
acute glaucoma, acute mountain
sickness, and epilepsy. Dorzolamide can
be applied topically to the eye to lower
intraocular pressure in glaucoma.
Loop diuretics include furosemide
(frusemide), piretanide, and bumetanide.
With oral administration, a strong
diuresis occurs within 1 h but persists
for only about 4 h. The effect is rapid, intense,
and brief (high-ceiling diuresis).
The site of action of these agents is the
thick portion of the ascending limb of
Henle’s loop, where they inhibit
Na+/K+/2Cl– cotransport. As a result,
these electrolytes, together with water,
are excreted in larger amounts. Excretion
of Ca2+ and Mg2+ also increases.
Special toxic effects include: (reversible)
hearing loss, enhanced sensitivity to
renotoxic agents. Indications: pulmonary
edema (added advantage of i.v. injection
in left ventricular failure: immediate
dilation of venous capacitance
vessels ! preload reduction); refractoriness
to thiazide diuretics, e.g., in renal
hypovolemic failure with creatinine
clearance reduction (<30 mL/min); prophylaxis
of acute renal hypovolemic
failure; hypercalcemia. Ethacrynic acid
is classed in this group although it is not
a sulfonamide.
Thiazide diuretics (benzothiadiazines)
include hydrochlorothiazide,
benzthiazide, trichlormethiazide, and
cyclothiazide. A long-acting analogue is
chlorthalidone. These drugs affect the
intermediate segment of the distal tubules,
where they inhibit a Na+/Cl– cotransport.
Thus, reabsorption of NaCl
and water is inhibited. Renal excretion
of Ca2+ decreases, that of Mg2+ increases.
Indications are hypertension, cardiac
failure, and mobilization of edema.
Unwanted effects of sulfonamidetype
diuretics: hypokalemia is a consequence
of excessive K+ loss in the terminal
segments of the distal tubules
where increased amounts of Na+ are
available for exchange with K+; hyperglycemia
and glycosuria; hyperuricemia—
increase in serum urate levels
may precipitate gout in predisposed
patients. Sulfonamide diuretics compete
with urate for the tubular organic
anion secretory system.

Potassium-Sparing Diuretics

These agents act in the distal portion of
the distal tubule and the proximal part
of the collecting ducts where Na+ is reabsorbed
in exchange for K+ or H+. Their
diuretic effectiveness is relatively minor.
In contrast to sulfonamide diuretics,
there is no increase in K+ secretion;
rather, there is a risk of hyperkalemia.
These drugs are suitable for oral
administration.
a) Triamterene and amiloride, in addition
to glomerular filtration, undergo
secretion in the proximal tubule. They
act on the luminal membrane of tubule
cells. Both inhibit the entry of Na+,
hence its exchange for K+ and H+. They
are mostly used in combination with
thiazide diuretics, e.g., hydrochlorothiazide,
because the opposing effects on K+
excretion cancel each other, while the
effects on secretion of NaCl complement
each other.
b) Aldosterone antagonists. The
mineralocorticoid aldosterone promotes
the reabsorption of Na+ (Cl– and
H2O follow) in exchange for K+. Its hormonal
effect on protein synthesis leads
to augmentation of the reabsorptive capacity
of tubule cells. Spironolactone, as
well as its metabolite canrenone, are antagonists
at the aldosterone receptor
and attenuate the effect of the hormone.
The diuretic effect of spironolactone develops
fully only with continuous administration
for several days. Two possible
explanations are: (1) the conversion
of spironolactone into and accumulation
of the more slowly eliminated
metabolite canrenone; (2) an inhibition
of aldosterone-stimulated protein synthesis
would become noticeable only if
existing proteins had become nonfunctional
and needed to be replaced by de
novo synthesis. A particular adverse effect
results from interference with gonadal
hormones, as evidenced by the development
of gynecomastia (enlargement
of male breast). Clinical uses include
conditions of increased aldosterone
secretion, e.g., liver cirrhosis with
ascites.
Antidiuretic Hormone (ADH) and
Derivatives (B)
ADH, a nonapeptide, released from the
posterior pituitary gland promotes reabsorption
of water in the kidney. This
response is mediated by vasopressin receptors
of the V2 subtype. ADH enhances
the permeability of collecting duct
epithelium for water (but not for electrolytes).
As a result, water is drawn
from urine into the hyperosmolar interstitium
of the medulla. Nicotine augments
and ethanol decreases
ADH release. At concentrations above
those required for antidiuresis, ADH
stimulates smooth musculature, including
that of blood vessels (“vasopressin”).
The latter response is mediated by
receptors of the V1 subtype. Blood pressure
rises; coronary vasoconstriction
can precipitate angina pectoris. Lypressin
(8-L-lysine vasopressin) acts like
ADH. Other derivatives may display only
one of the two actions.
Desmopressin is used for the therapy
of diabetes insipidus (ADH deficiency),
nocturnal enuresis, thrombasthemia
, and chronic hypotension;
it is given by injection or via
the nasal mucosa (as “snuff”).
Felypressin and ornipressin serve as
adjunctive vasoconstrictors in infiltration
local anesthesia.

Drugs used in Hyperlipoproteinemias

Lipid-Lowering Agents

Triglycerides and cholesterol are essential
constituents of the organism.
Among other things, triglycerides represent
a form of energy store and cholesterol
is a basic building block of biological
membranes. Both lipids are water
insoluble and require appropriate transport
vehicles in the aqueous media of
lymph and blood. To this end, small
amounts of lipid are coated with a layer
of phospholipids, embedded in which
are additional proteins—the apolipoproteins
(A). According to the amount and
the composition of stored lipids, as well
as the type of apolipoprotein, one distinguishes
4 transport forms:

Lipoprotein metabolism. Enterocytes
release absorbed lipids in the form
of triglyceride-rich chylomicrons. Bypassing
the liver, these enter the circulation
mainly via the lymph and are hydrolyzed
by extrahepatic endothelial
lipoprotein lipases to liberate fatty acids.
The remnant particles move on into
liver cells and supply these with cholesterol
of dietary origin.
The liver meets the larger part
(60%) of its requirement for cholesterol
by de novo synthesis from acetylcoenzyme-
A. Synthesis rate is regulated at
the step leading from hydroxymethylglutaryl
CoA (HMG CoA) to mevalonic
acid, with HMG CoA reductase
as the rate-limiting enzyme.
The liver requires cholesterol for
synthesizing VLDL particles and bile acids.
Triglyceride-rich VLDL particles are
released into the blood and, like the
chylomicrons, supply other tissues with
fatty acids. Left behind are LDL particles
that either return into the liver or supply
extrahepatic tissues with cholesterol.
LDL particles carry apolipoprotein B
100, by which they are bound to receptors
that mediate uptake of LDL into the
cells, including the hepatocytes (receptor-
mediated endocytosis).
HDL particles are able to transfer
cholesterol from tissue cells to LDL particles.
In this way, cholesterol is transported
from tissues to the liver.
Hyperlipoproteinemias can be
caused genetically (primary h.) or can
occur in obesity and metabolic disorders
(secondary h). Elevated LDL-cholesterol
serum concentrations are associated
with an increased risk of atherosclerosis,
especially when there is a concomitant
decline in HDL concentration
(increase in LDL:HDL quotient).
Treatment. Various drugs are available
that have different mechanisms of
action and effects on LDL (cholesterol)
and VLDL (triglycerides). Their use is
indicated in the therapy of primary hyperlipoproteinemias.
In secondary hyperlipoproteinemias,
the immediate
goal should be to lower lipoprotein levels
by dietary restriction, treatment of
the primary disease, or both.
Drugs. Colestyramine and colestipol
are nonabsorbable anion-exchange
resins. By virtue of binding bile acids,
they promote consumption of cholesterol
for the synthesis of bile acids; the

liver meets its increased cholesterol demand
by enhancing the expression of
HMG CoA reductase and LDL receptors
(negative feedback).
At the required dosage, the resins
cause diverse gastrointestinal disturbances.
In addition, they interfere with
the absorption of fats and fat-soluble vitamins
(A, D, E, K). They also adsorb and
decrease the absorption of such drugs as
digitoxin, vitamin K antagonists, and
diuretics. Their gritty texture and bulk
make ingestion an unpleasant experience.
The statins, lovastati= L , simvastatin = s,
pravastatin =p , fluvastatin = F,
cerivastatin, and atorvastatin, inhibit
HMG CoA reductase. The active group of
L, S, P, and F (or their metabolites) resembles
that of the physiological substrate
of the enzyme. L and S are lactones
that are rapidly absorbed by the
enteral route, subjected to extensive
first-pass extraction in the liver, and
there hydrolyzed into active metabolites.
P and F represent the active form
and, as acids, are actively transported by
a specific anion carrier that moves bile
acids from blood into liver and also mediates
the selective hepatic uptake of
the mycotoxin, amanitin (A). Atorvastatin
has the longest duration of action.
Normally viewed as presystemic elimination,
efficient hepatic extraction
serves to confine the action of the statins
to the liver. Despite the inhibition of
HMG CoA reductase, hepatic cholesterol
content does not fall, because hepatocytes
compensate any drop in cholesterol
levels by increasing the synthesis of
LDL receptor protein (along with the reductase).
Because the newly formed reductase
is inhibited, too, the hepatocyte
must meet its cholesterol demand by
uptake of LDL from the blood (B). Accordingly,
the concentration of circulating
LDL decreases, while its hepatic
clearance from plasma increases. There
is also a decreased likelihood of LDL being
oxidized into its proatheroslerotic
degradation product. The combination
of a statin with an ion-exchange resin
intensifies the decrease in LDL levels. A
rare, but dangerous, side effect of the
statins is damage to skeletal musculature.
This risk is increased by combined
use of fibric acid agents (see below).
Nicotinic acid and its derivatives
(pyridylcarbinol, xanthinol nicotinate,
acipimox) activate endothelial lipoprotein
lipase and thereby lower triglyceride
levels. At the start of therapy, a
prostaglandin-mediated vasodilation
occurs (flushing and hypotension) that
can be prevented by low doses of acetylsalicylic
acid.
Clofibrate and derivatives (bezafibrate,
etofibrate, gemfibrozil) lower plasma
lipids by an unknown mechanism.
They may damage the liver and skeletal
muscle (myalgia, myopathy, rhabdomyolysis).
Probucol lowers HDL more than
LDL; nonetheless, it appears effective in
reducing atherogenesis, possibly by reducing
LDL oxidation.
3-Polyunsaturated fatty acids (eicosapentaenoate,
docosahexaenoate)
are abundant in fish oils. Dietary supplementation
results in lowered levels
of triglycerides, decreased synthesis of
VLDL and apolipoprotein B, and improved
clearance of remnant particles,
although total and LDL cholesterol are
not decreased or are even increased.
High dietary intake may correlate with a
reduced incidence of coronary heart
disease.

Plasma Volume Expanders

Plasma Volume Expanders

Major blood loss entails the danger of
life-threatening circulatory failure, i.e.,
hypovolemic shock. The immediate
threat results not so much from the loss
of erythrocytes, i.e., oxygen carriers, as
from the reduction in volume of circulating
blood.
To eliminate the threat of shock, replenishment
of the circulation is essential.
With moderate loss of blood, administration
of a plasma volume expander
may be sufficient. Blood plasma
consists basically of water, electrolytes,
and plasma proteins. However, a plasma
substitute need not contain plasma
proteins. These can be suitably replaced
with macromolecules (“colloids”)
that, like plasma proteins, (1) do
not readily leave the circulation and are
poorly filtrable in the renal glomerulus;
and (2) bind water along with its solutes
due to their colloid osmotic properties. In
this manner, they will maintain circulatory
filling pressure for many hours. On
the other hand, volume substitution is
only transiently needed and therefore
complete elimination of these colloids
from the body is clearly desirable.
Compared with whole blood or
plasma, plasma substitutes offer several
advantages: they can be produced more
easily and at lower cost, have a longer
shelf life, and are free of pathogens such
as hepatitis B or C or AIDS viruses.
Three colloids are currently employed
as plasma volume expanders—
the two polysaccharides, dextran and
hydroxyethyl starch, as well as the polypeptide,
gelatin.
Dextran is a glucose polymer
formed by bacteria and linked by a 1!6
instead of the typical 1!4 bond. Commercial
solutions contain dextran of a
mean molecular weight of 70 kDa (dextran
70) or 40 kDa (lower-molecularweight
dextran, dextran 40). The chain
length of single molecules, however,
varies widely. Smaller dextran molecules
can be filtered at the glomerulus
and slowly excreted in urine; the larger
ones are eventually taken up and degraded
by cells of the reticuloendothelial
system. Apart from restoring blood
volume, dextran solutions are used for
hemodilution in the management of
blood flow disorders.
As for microcirculatory improvement,
it is occasionally emphasized that
low-molecular-weight dextran, unlike
dextran 70, may directly reduce the aggregability
of erythrocytes by altering
their surface properties. With prolonged
use, larger molecules will accumulate
due to the more rapid renal excretion
of the smaller ones. Consequently,
the molecular weight of dextran circulating
in blood will tend towards a
higher mean molecular weight with the
passage of time.
The most important adverse effect
results from the antigenicity of dextrans,
which may lead to an anaphylactic
reaction.
Hydroxyethyl starch (hetastarch) is
produced from starch. By virtue of its
hydroxyethyl groups, it is metabolized
more slowly and retained significantly
longer in blood than would be the case
with infused starch. Hydroxyethyl
starch resembles dextrans in terms of
its pharmacological properties and
therapeutic applications.
Gelatin colloids consist of crosslinked
peptide chains obtained from
collagen. They are employed for blood
replacement, but not for hemodilution,
in circulatory disturbances.

Antithrombotics

Prophylaxis and Therapy of Thromboses

Upon vascular injury, the coagulation
system is activated: thrombocytes and
fibrin molecules coalesce into a “plug”
that seals the defect and halts
bleeding (hemostasis). Unnecessary
formation of an intravascular clot – a
thrombosis – can be life-threatening. If
the clot forms on an atheromatous
plaque in a coronary artery, myocardial
infarction is imminent; a thrombus in a
deep leg vein can be dislodged, carried
into a lung artery, and cause complete
or partial interruption of pulmonary
blood flow (pulmonary embolism).
Drugs that decrease the coagulability
of blood, such as coumarins and heparin
(A), are employed for the prophylaxis
of thromboses. In addition, attempts
are directed at inhibiting the aggregation
of blood platelets, which are
prominently involved in intra-arterial
thrombogenesis. For the therapy
of thrombosis, drugs are used that
dissolve the fibrin meshwork!fibrinolytics.
An overview of the coagulation
cascade and sites of action for coumarins
and heparin is shown in A. There are
two ways to initiate the cascade (B): 1)
conversion of factor XII into its active
form (XIIa, intrinsic system) at intravascular
sites denuded of endothelium; 2)
conversion of factor VII into VIIa (extrinsic
system) under the influence of a tissue-
derived lipoprotein (tissue thromboplastin).
Both mechanisms converge
via factor X into a common final pathway.
The clotting factors are protein
molecules. “Activation” mostly means
proteolysis (cleavage of protein fragments)
and, with the exception of fibrin,
conversion into protein-hydrolyzing
enzymes (proteases). Some activated
factors require the presence of phospholipids
(PL) and Ca2+ for their proteolytic
activity. Conceivably, Ca2+ ions
cause the adhesion of factor to a phospholipid
surface, as depicted in C. Phospholipids
are contained in platelet factor
3 (PF3), which is released from aggregated
platelets, and in tissue thromboplastin
(B). The sequential activation
of several enzymes allows the aforementioned
reactions to “snowball”, culminating
in massive production of fibrin.
Progression of the coagulation cascade
can be inhibited as follows:
1) coumarin derivatives decrease
the blood concentrations of inactive factors
II, VII, IX, and X, by inhibiting their
synthesis; 2) the complex consisting of
heparin and antithrombin III neutralizes
the protease activity of activated factors;
3) Ca2+ chelators prevent the enzymatic
activity of Ca2+-dependent factors;
they contain COO-groups that bind
Ca2+ ions (C): citrate and EDTA (ethylenediaminetetraacetic
acid) form soluble
complexes with Ca2+; oxalate precipitates
Ca2+ as insoluble calcium oxalate.
Chelation of Ca2+ cannot be used
for therapeutic purposes because Ca2+
concentrations would have to be lowered
to a level incompatible with life
(hypocalcemic tetany). These compounds
(sodium salts) are, therefore,
used only for rendering blood incoagulable
outside the body.

Coumarin Derivatives (A)
Vitamin K promotes the hepatic !-carboxylation
of glutamate residues on the
precursors of factors II, VII, IX, and X, as
well as that of other proteins, e.g., protein
C, protein S, or osteocalcin. Carboxyl
groups are required for Ca2+-mediated
binding to phospholipid surfaces.
There are several vitamin K derivatives
of different origins: K1 (phytomenadione)
from chlorophyllous
plants; K2 from gut bacteria; and K3
(menadione) synthesized chemically.
All are hydrophobic and require bile acids
for absorption.
Oral anticoagulants. Structurally
related to vitamin K, 4-hydroxycoumarins
act as “false” vitamin K and prevent
regeneration of reduced (active) vitamin
K from vitamin K epoxide, hence
the synthesis of vitamin K-dependent
clotting factors.
Coumarins are well absorbed after
oral administration. Their duration of
action varies considerably. Synthesis of
clotting factors depends on the intrahepatocytic
concentration ratio of coumarins
to vitamin K. The dose required
for an adequate anticoagulant effect
must be determined individually for
each patient (one-stage prothrombin
time). Subsequently, the patient must
avoid changing dietary consumption of
green vegetables (alteration in vitamin
K levels), refrain from taking additional
drugs likely to affect absorption or elimination
of coumarins (alteration in coumarin
levels), and not risk inhibiting
platelet function by ingesting acetylsalicylic
acid.
The most important adverse effect
is bleeding. With coumarins, this
can be counteracted by giving vitamin
K1. Coagulability of blood returns to
normal only after hours or days, when
the liver has resumed synthesis and restored
sufficient blood levels of clotting
factors. In urgent cases, deficient factors
must be replenished directly (e.g., by
transfusion of whole blood or of prothrombin
concentrate).
Heparin (B)
A clotting factor is activated when the
factor that precedes it in the clotting
cascade splits off a protein fragment and
thereby exposes an enzymatic center.
The latter can again be inactivated physiologically
by complexing with antithrombin
III (AT III), a circulating glycoprotein.
Heparin acts to inhibit clotting
by accelerating formation of this
complex more than 1000-fold. Heparin
is present (together with histamine) in
the vesicles of mast cells; its physiological
role is unclear. Therapeutically used
heparin is obtained from porcine gut or
bovine lung. Heparin molecules are
chains of amino sugars bearing -COO–
and -SO4 groups; they contain approx.
10 to 20 of the units depicted in (B);
mean molecular weight, 20,000. Anticoagulant
efficacy varies with chain
length. The potency of a preparation is
standardized in international units of
activity (IU) by bioassay and comparison
with a reference preparation.
The numerous negative charges are
significant in several respects: (1) they
contribute to the poor membrane penetrability—
heparin is ineffective when
applied by the oral route or topically onto
the skin and must be injected; (2) attraction
to positively charged lysine residues
is involved in complex formation
with ATIII; (3) they permit binding of
heparin to its antidote, protamine
(polycationic protein from salmon
sperm).
If protamine is given in heparin-induced
bleeding, the effect of heparin is
immediately reversed.
For effective thromboprophylaxis, a
low dose of 5000 IU is injected s.c. two
to three times daily. With low dosage of
heparin, the risk of bleeding is sufficiently
small to allow the first injection
to be given as early as 2 h prior to surgery.
Higher daily i.v. doses are required
to prevent growth of clots. Besides
bleeding, other potential adverse effects
are: allergic reactions (e.g., thrombocytopenia)
and with chronic administration,
reversible hair loss and osteoporosis.

Low-molecular-weight heparin (average
MW ~5000) has a longer duration
of action and needs to be given only
once daily (e.g., certoparin, dalteparin,
enoxaparin, reviparin, tinzaparin).
Frequent control of coagulability is
not necessary with low molecular
weight heparin and incidence of side effects
(bleeding, heparin-induced thrombocytopenia)
is less frequent than with
unfractionated heparin.
Fibrinolytic Therapy (A)
Fibrin is formed from fibrinogen
through thrombin (factor IIa)-catalyzed
proteolytic removal of two oligopeptide
fragments. Individual fibrin molecules
polymerize into a fibrin mesh that can
be split into fragments and dissolved by
plasmin. Plasmin derives by proteolysis
from an inactive precursor, plasminogen.
Plasminogen activators can be infused
for the purpose of dissolving clots
(e.g., in myocardial infarction). Thrombolysis
is not likely to be successful unless
the activators can be given very soon
after thrombus formation. Urokinase
is an endogenous plasminogen activator
obtained from cultured human kidney
cells. Urokinase is better tolerated than
is streptokinase. By itself, the latter is
enzymatically inactive; only after binding
to a plasminogen molecule does
the complex become effective in converting
plasminogen to plasmin. Streptokinase
is produced by streptococcal
bacteria, which probably accounts for
the frequent adverse reactions. Streptokinase
antibodies may be present as a
result of prior streptococcal infections.
Binding to such antibodies would neutralize
streptokinase molecules.
With alteplase, another endogenous
plasminogen activator (tissue
plasminogen activator, tPA) is available.
With physiological concentrations this
activator preferentially acts on plasminogen
bound to fibrin. In concentrations
needed for therapeutic fibrinolysis this
preference is lost and the risk of bleeding
does not differ with alteplase and
streptokinase. Alteplase is rather shortlived
(inactivation by complexing with
plasminogen activator inhibitor, PAI)
and has to be applied by infusion. Reteplase,
however, containing only the
proteolytic active part of the alteplase
molecule, allows more stabile plasma
levels and can be applied in form of two
injections at an interval of 30 min.
Inactivation of the fibrinolytic
system can be achieved by “plasmin inhibitors,”
such as !-aminocaproic acid,
p-aminomethylbenzoic acid (PAMBA),
tranexamic acid, and aprotinin, which
also inhibits other proteases.
Lowering of blood fibrinogen
concentration. Ancrod is a constituent
of the venom from a Malaysian pit viper.
It enzymatically cleaves a fragment
from fibrinogen, resulting in the formation
of a degradation product that cannot
undergo polymerization. Reduction
in blood fibrinogen level decreases the
coagulability of the blood. Since fibrinogen
(MW ~340 000) contributes to the
viscosity of blood, an improved “fluidity”
of the blood would be expected.
Both effects are felt to be of benefit in
the treatment of certain disorders of
blood flow.


Intra-arterial Thrombus Formation (A)
Activation of platelets, e.g., upon contact
with collagen of the extracellular
matrix after injury to the vascular wall,
constitutes the immediate and decisive
step in initiating the process of primary
hemostasis, i.e., cessation of bleeding.
However, in the absence of vascular injury,
platelets can be activated as a result
of damage to the endothelial cell
lining of blood vessels. Among the multiple
functions of the endothelium, the
production of NO˙ and prostacyclin plays
an important role. Both substances inhibit
the tendency of platelets to adhere
to the endothelial surface (platelet adhesiveness).
Impairment of endothelial
function, e.g., due to chronic hypertension,
cigarette smoking, chronic elevation
of plasma LDL levels or of blood
glucose, increases the probability of
contact between platelets and endothelium.
The adhesion process involves
GPIB/IX, a glycoprotein present in the
platelet cell membrane and von Willebrandt’s
factor, an endothelial membrane
protein. Upon endothelial contact,
the platelet is activated with a resultant
change in shape and affinity to
fibrinogen. Platelets are linked to each
other via fibrinogen bridges: they
undergo aggregation.
Platelet aggregation increases like
an avalanche because, once activated,
platelets can activate other platelets. On
the injured endothelial cell, a platelet
thrombus is formed, which obstructs
blood flow. Ultimately, the vascular lumen
is occluded by the thrombus as the
latter is solidified by a vasoconstriction
produced by the release of serotonin
and thromboxane A2 from the aggregated
platelets. When these events occur in
a larger coronary artery, the consequence
is a myocardial infarction; involvement
of a cerebral artery leads to
stroke.
The von Willebrandt’s factor plays a
key role in thrombogenesis. Lack of this
factor causes thrombasthenia, a pathologically
decreased platelet aggregation.
Relative deficiency of the von Willebrandt’s
factor can be temporarily overcome
by the vasopressin anlogue desmopressin
(p. 164), which increases the
release of available factor from storage
sites.
Formation, Activation, and Aggregation
of Platelets (B)
Platelets originate by budding off from
multinucleate precursor cells, the megakaryocytes.
As the smallest formed
element of blood (dia. 1–4 μm), they can
be activated by various stimuli. Activation
entails an alteration in shape and
secretion of a series of highly active substances,
including serotonin, platelet activating
factor (PAF), ADP, and thromboxane
A2. In turn, all of these can activate
other platelets, which explains the
explosive nature of the process.
The primary consequence of activation
is a conformational change of an integrin
present in the platelet membrane,
namely, GPIIB/IIIA. In its active
conformation, GPIIB/IIIA shows high affinity
for fibrinogen; each platelet contains
up to 50,000 copies. The high plasma
concentration of fibrinogen and the
high density of integrins in the platelet
membrane permit rapid cross-linking of
platelets and formation of a platelet
plug.


Inhibitors of Platelet Aggregation
Platelets can be activated by mechanical
and diverse chemical stimuli, some of
which, e.g., thromboxane A2, thrombin,
serotonin, and PAF, act via receptors on
the platelet membrane. These receptors
are coupled to Gq proteins that mediate
activation of phospholipase C and hence
a rise in cytosolic Ca2+ concentration.
Among other responses, this rise in Ca2+
triggers a conformational change in
GPIIB/IIIA, which is thereby converted
to its fbrinogen-binding form. In contrast,
ADP activates platelets by inhibiting
adenylyl cyclase, thus causing internal
cAMP levels to decrease. High cAMP
levels would stabilize the platelet in its
inactive state. Formally, the two messenger
substances, Ca2+ and cAMP, can
be considered functional antagonists.
Platelet aggregation can be inhibited
by acetylsalicylic acid (ASA), which
blocks thromboxane synthase, or by recombinant
hirudin (originally harvested
from leech salivary gland), which
binds and inactivates thrombin. As yet,
no drugs are available for blocking aggregation
induced by serotonin or PAF.
ADP-induced aggregation can be prevented
by ticlopidine and clopidogrel;
these agents are not classic receptor antagonists.
ADP-induced aggregation is
inhibited only in vivo but not in vitro in
stored blood; moreover, once induced,
inhibition is irreversible. A possible explanation
is that both agents already
interfere with elements of ADP receptor
signal transduction at the megakaryocytic
stage. The ensuing functional defect
would then be transmitted to newly
formed platelets, which would be incapable
of reversing it.
The intra-platelet levels of cAMP
can be stabilized by prostacyclin or its
analogues (e.g., iloprost) or by dipyridamole.
The former activates adenyl cyclase
via a G-protein-coupled receptor;
the latter inhibits a phosphodiesterase
that breaks down cAMP.
The integrin (GPIIB/IIIA)-antagonists
prevent cross-linking of platelets.
Their action is independent of the aggregation-
inducing stimulus. Abciximab
is a chimeric human-murine monoclonal
antibody directed against GPIIb/IIIa
that blocks the fibrinogen-binding site
and thus prevents attachment of fibrinogen.
The peptide derivatives, eptifibatide
and tirofiban block GPIIB/IIIA
competitively, more selectively and have
a shorter effect than does abciximab.
Presystemic Effect of Acetylsalicylic Acid

Inhibition of platelet aggregation by
ASA is due to a selective blockade of
platelet cyclooxygenase (B). Selectivity
of this action results from acetylation of
this enzyme during the initial passage of
the platelets through splanchnic blood
vessels. Acetylation of the enzyme is irreversible.
ASA present in the systemic
circulation does not play a role in platelet
inhibition. Since ASA undergoes extensive
presystemic elimination, cyclooxygenases
outside platelets, e.g., in endothelial
cells, remain largely unaffected.
With regular intake, selectivity is enhanced
further because the anuclear
platelets are unable to resynthesize new
enzyme and the inhibitory effects of
consecutive doses are added to each
other. However, in the endothelial cells,
de novo synthesis of the enzyme permits
restoration of prostacyclin production.
Adverse Effects of Antiplatelet Drugs
All antiplatelet drugs increase the risk of
bleeding. Even at the low ASA doses
used to inhibit platelet function (100
mg/d), ulcerogenic and bronchoconstrictor
(aspirin asthma) effects may occur.
Ticlopidine frequently causes diarrhea
and, more rarely, leukopenia, necessitating
cessation of treatment. Clopidogrel
reportedly does not cause hematological
problems.
As peptides, hirudin and abciximab
need to be injected; therefore their use
is restricted to intensive-care settings.

Antianemics

Drugs for the Treatment of Anemias
Anemia denotes a reduction in red
blood cell count, hemoglobin content,
or both. Oxygen (O2) transport capacity
is decreased.
Erythropoiesis (A). Blood corpuscles
develop from stem cells through
several cell divisions. Hemoglobin is
then synthesized and the cell nucleus is
extruded. Erythropoiesis is stimulated
by the hormone erythropoietin (a glycoprotein),
which is released from the
kidneys when renal O2 tension declines.
Given an adequate production of
erythropoietin, a disturbance of erythropoiesis
is due to two principal causes:
1. Cell multiplication is inhibited because
DNA synthesis is insufficient. This
occurs in deficiencies of vitamin B12 or
folic acid (macrocytic hyperchromic
anemia). 2. Hemoglobin synthesis is
impaired. This situation arises in iron
deficiency, since Fe2+ is a constituent of
hemoglobin (microcytic hypochromic
anemia).
Vitamin B12 (B)
Vitamin B12 (cyanocobalamin) is produced
by bacteria; B12 generated in the
colon, however, is unavailable for absorption
(see below). Liver, meat, fish,
and milk products are rich sources of
the vitamin. The minimal requirement
is about 1 μg/d. Enteral absorption of vitamin
B12 requires so-called “intrinsic
factor” from parietal cells of the stomach.
The complex formed with this glycoprotein
undergoes endocytosis in the
ileum. Bound to its transport protein,
transcobalamin, vitamin B12 is destined
for storage in the liver or uptake into tissues.
A frequent cause of vitamin B12 deficiency
is atrophic gastritis leading to a
lack of intrinsic factor. Besides megaloblastic
anemia, damage to mucosal linings
and degeneration of myelin
sheaths with neurological sequelae will
occur (pernicious anemia).
Optimal therapy consists in parenteral
administration of cyanocobalamin
or hydroxycobalamin (Vitamin
B12a; exchange of -CN for -OH group).
Adverse effects, in the form of hypersensitivity
reactions, are very rare.
Folic Acid (B). Leafy vegetables and
liver are rich in folic acid (FA). The minimal
requirement is approx. 50 μg/d.
Polyglutamine-FA in food is hydrolyzed
to monoglutamine-FA prior to being absorbed.
FA is heat labile. Causes of deficiency
include: insufficient intake, malabsorption
in gastrointestinal diseases,
increased requirements during pregnancy.
Antiepileptic drugs (phenytoin,
primidone, phenobarbital) may decrease
FA absorption, presumably by inhibiting
the formation of monoglutamine-
FA. Inhibition of dihydro-FA reductase
(e.g., by methotrexate, p. 298)
depresses the formation of the active
species, tetrahydro-FA. Symptoms of deficiency
are megaloblastic anemia and
mucosal damage. Therapy consists in
oral administration of FA or in folinic
acid when deficiency is caused
by inhibitors of dihydro—FA—reductase.
Administration of FA can mask a
vitamin B12 deficiency. Vitamin B12 is required
for the conversion of methyltetrahydro-
FA to tetrahydro-FA, which is
important for DNA synthesis (B). Inhibition
of this reaction due to B12 deficiency
can be compensated by increased FA
intake. The anemia is readily corrected;
however, nerve degeneration progresses
unchecked and its cause is made
more difficult to diagnose by the absence
of hematological changes. Indiscriminate
use of FA-containing multivitamin
preparations can, therefore, be
harmful.


Iron Compounds
Not all iron ingested in food is equally
absorbable. Trivalent Fe3+ is virtually
not taken up from the neutral milieu of
the small bowel, where the divalent Fe2+
is markedly better absorbed. Uptake is
particularly efficient in the form of
heme (present in hemo- and myoglobin).
Within the mucosal cells of the gut,
iron is oxidized and either deposited as
ferritin (see below) or passed on to the
transport protein, transferrin, a !1-glycoprotein.
The amount absorbed does
not exceed that needed to balance losses
due to epithelial shedding from skin
and mucosae or hemorrhage (so-called
“mucosal block”). In men, this amount
is approx. 1 mg/d; in women, it is approx.
2 mg/d (menstrual blood loss),
corresponding to about 10% of the dietary
intake. The transferrin-iron complex
undergoes endocytotic uptake
mainly into erythroblasts to be utilized
for hemoglobin synthesis.
About 70% of the total body store of
iron (~5 g) is contained within erythrocytes.
When these are degraded by macrophages
of the reticuloendothelial
(mononuclear phagocyte) system, iron
is liberated from hemoglobin. Fe3+ can
be stored as ferritin (= protein apoferritin
+ Fe3+) or returned to erythropoiesis
sites via transferrin.
A frequent cause of iron deficiency
is chronic blood loss due to gastric/intestinal
ulcers or tumors. One liter of
blood contains 500 mg of iron. Despite a
significant increase in absorption rate
(up to 50%), absorption is unable to keep
up with losses and the body store of iron
falls. Iron deficiency results in impaired
synthesis of hemoglobin and anemia.
The treatment of choice (after the
cause of bleeding has been found and
eliminated) consists of the oral administration
of Fe2+ compounds, e.g., ferrous
sulfate (daily dose 100 mg of iron
equivalent to 300 mg of FeSO4, divided
into multiple doses). Replenishing of
iron stores may take several months.
Oral administration, however, is advantageous
in that it is impossible to overload
the body with iron through an intact
mucosa because of its demand-regulated
absorption (mucosal block).
Adverse effects. The frequent gastrointestinal
complaints (epigastric
pain, diarrhea, constipation) necessitate
intake of iron preparations with or after
meals, although absorption is higher
from the empty stomach.
Interactions. Antacids inhibit iron
absorption. Combination with ascorbic
acid (Vitamin C), for protecting Fe2+
from oxidation to Fe3+, is theoretically
sound, but practically is not needed.
Parenteral administration of Fe3+
salts is indicated only when adequate
oral replacement is not possible. There
is a risk of overdosage with iron deposition
in tissues (hemosiderosis). The
binding capacity of transferrin is limited
and free Fe3+ is toxic. Therefore, Fe3+
complexes are employed that can donate
Fe3+ directly to transferrin or can
be phagocytosed by macrophages, enabling
iron to be incorporated into ferritin
stores. Possible adverse effects are,
with i.m. injection: persistent pain at
the injection site and skin discoloration;
with i.v. injection: flushing, hypotension,
anaphylactic shock.

Drugs Acting on Smooth Muscle

Drugs Used to Influence Smooth MuscleOrgans

Bronchodilators. Narrowing of bronchioles
raises airway resistance, e.g., in
bronchial or bronchitic asthma. Several
substances that are employed as bronchodilators
are described elsewhere in
more detail: 2-sympathomimetics
( given by pulmonary, parenteral, or
oral route), the methylxanthine theophylline
( given parenterally ororally),
as well as the parasympatholytic
ipratropium ( given by inhalation).
Spasmolytics. N-Butylscopolamine
is used for the relief of painful
spasms of the biliary or ureteral ducts.
Its poor absorption (N.B. quaternary N;
absorption rate <10%) necessitates parenteral
administration. Because the
therapeutic effect is usually weak, a potent
analgesic is given concurrently, e.g.,
the opioid meperidine. Note that some
spasms of intestinal musculature can be
effectively relieved by organic nitrates
(in biliary colic) or by nifedipine (esophageal
hypertension and achalasia).
Myometrial relaxants (Tocolytics).
2-Sympathomimetics such as fenoterol
or ritodrine, given orally or parenterally,
can prevent premature labor
or interrupt labor in progress when dangerous
complications necessitate cesarean
section. Tachycardia is a side effect
produced reflexly because of !2-mediated
vasodilation or direct stimulation of
cardiac !1-receptors. Magnesium sulfate,
given i.v., is a useful alternative
when -mimetics are contraindicated,
but must be carefully titrated because
its nonspecific calcium antagonism
leads to blockade of cardiac impulse
conduction and of neuromuscular
transmission.
Myometrial stimulants. The neurohypophyseal
hormone oxytocin is given parenterally
(or by the nasal or buccal route) before, during, or after
labor in order to prompt uterine contractions
or to enhance them. Certain
prostaglandins or analogues of them
(F2": dinoprost; E2: dinoprostone,
misoprostol, sulprostone) are capable of
inducing rhythmic uterine contractions
and cervical relaxation at any time. They
are mostly employed as abortifacients
(oral or vaginal application of misoprostol
in combination with mifepristone.
Ergot alkaloids are obtained from
Secale cornutum (ergot), the sclerotium
of a fungus (Claviceps purpurea) parasitizing
rye. Consumption of flour from
contaminated grain was once the cause
of epidemic poisonings (ergotism) characterized
by gangrene of the extremities
(St. Anthony’s fire) and CNS disturbances
(hallucinations).
Ergot alkaloids contain lysergic acid
(formula in A shows an amide). They act
on uterine and vascular muscle. Ergometrine
particularly stimulates the uterus.
It readily induces a tonic contraction
of the myometrium (tetanus uteri). This
jeopardizes placental blood flow and fetal
O2 supply. The semisynthetic derivative
methylergometrine is therefore
used only after delivery for uterine contractions
that are too weak.
Ergotamine, as well as the ergotoxine
alkaloids (ergocristine, ergocryptine,
ergocornine), have a predominantly
vascular action. Depending on the initial
caliber, constriction or dilation may
be elicited. The mechanism of action is
unclear; a mixed antagonism at "-
adrenoceptors and agonism at 5-HT-receptors
may be important. Ergotamine
is used in the treatment of migraine.
Its congener, dihydroergotamine,
is furthermore employed in orthostatic
complaints .
Other lysergic acid derivatives are
the 5-HT antagonist methysergide, the
dopamine agonists bromocriptine, pergolide,
and cabergolide ,
and the hallucinogen lysergic acid diethylamide
(LSD).

Inhibitors of the RAA System

Inhibitors of the RAA System
Angiotensin-converting enzyme (ACE)
is a component of the antihypotensive
renin-angiotensin-aldosterone (RAA)
system. Renin is produced by specialized
cells in the wall of the afferent arteriole
of the renal glomerulus. These
cells belong to the juxtaglomerular apparatus
of the nephron, the site of contact
between afferent arteriole and distal
tubule, and play an important part in
controlling nephron function. Stimuli
eliciting release of renin are: a drop in
renal perfusion pressure, decreased rate
of delivery of Na+ or Cl– to the distal tubules,
as well as -adrenoceptor-mediated
sympathoactivation. The glycoprotein
renin enzymatically cleaves the
decapeptide angiotensin I from its circulating
precursor substrate angiotensinogen.
ACE, in turn, produces biologically
active angiotensin II (ANG II) from
angiotensin I (ANG I).
ACE is a rather nonspecific peptidase
that can cleave C-terminal dipeptides
from various peptides (dipeptidyl
carboxypeptidase). As “kininase II,” it
contributes to the inactivation of kinins,
such as bradykinin. ACE is also present in
blood plasma; however, enzyme localized
in the luminal side of vascular endothelium
is primarily responsible for the
formation of angiotensin II. The lung is
rich in ACE, but kidneys, heart, and other
organs also contain the enzyme.
Angiotensin II can raise blood pressure
in different ways, including (1)
vasoconstriction in both the arterial and
venous limbs of the circulation; (2)
stimulation of aldosterone secretion,
leading to increased renal reabsorption
of NaCl and water, hence an increased
blood volume; (3) a central increase in
sympathotonus and, peripherally, enhancement
of the release and effects of
norepinephrine.
ACE inhibitors, such as captopril
and enalaprilat, the active metabolite of
enalapril, occupy the enzyme as false
substrates. Affinity significantly influences
efficacy and rate of elimination.
Enalaprilat has a stronger and longerlasting
effect than does captopril. Indications
are hypertension and cardiac
failure.
Lowering of an elevated blood pressure
is predominantly brought about by
diminished production of angiotensin II.
Impaired degradation of kinins that exert
vasodilating actions may contribute
to the effect.
In heart failure, cardiac output rises
again because ventricular afterload diminishes
due to a fall in peripheral resistance.
Venous congestion abates as a
result of (1) increased cardiac output
and (2) reduction in venous return (decreased
aldosterone secretion, decreased
tonus of venous capacitance
vessels).
Undesired effects. The magnitude
of the antihypertensive effect of ACE inhibitors
depends on the functional state
of the RAA system. When the latter has
been activated by loss of electrolytes
and water (resulting from treatment
with diuretic drugs), cardiac failure, or
renal arterial stenosis, administration of
ACE inhibitors may initially cause an excessive
fall in blood pressure. In renal
arterial stenosis, the RAA system may be
needed for maintaining renal function
and ACE inhibitors may precipitate renal
failure. Dry cough is a fairly frequent
side effect, possibly caused by reduced
inactivation of kinins in the bronchial
mucosa. Rarely, disturbances of taste
sensation, exanthema, neutropenia,
proteinuria, and angioneurotic edema
may occur. In most cases, ACE inhibitors
are well tolerated and effective. Newer
analogues include lisinopril, perindopril,
ramipril, quinapril, fosinopril, benazepril,
cilazapril, and trandolapril.
Antagonists at angiotensin II receptors.
Two receptor subtypes can be
distinguished: AT1, which mediates the
above actions of AT II; and AT2, whose
physiological role is still unclear. The
sartans (candesartan, eprosartan, irbesartan,
losartan, and valsartan) are AT1
antagonists that reliably lower high
blood pressure. They do not inhibit
degradation of kinins and cough is not a
frequent side-effect.

Vasodilators

Vasodilators–Overview
The distribution of blood within the circulation
is a function of vascular caliber.
Venous tone regulates the volume of
blood returned to the heart, hence,
stroke volume and cardiac output. The
luminal diameter of the arterial vasculature
determines peripheral resistance.
Cardiac output and peripheral resistance
are prime determinants of arterial
blood pressure.
In A, the clinically most important
vasodilators are presented in the order
of approximate frequency of therapeutic
use. Some of these agents possess
different efficacy in affecting the venous
and arterial limbs of the circulation
(width of beam).
Possible uses. Arteriolar vasodilators
are given to lower blood pressure in
hypertension, to reduce cardiac
work in angina pectoris, and to
reduce ventricular afterload (pressure
load) in cardiac failure. Venous
vasodilators are used to reduce venous
filling pressure (preload) in angina pectoris
or cardiac failure.
Practical uses are indicated for each
drug group.
Counter-regulation in acute hypotension
due to vasodilators (B). Increased
sympathetic drive raises heart
rate (reflex tachycardia) and cardiac
output and thus helps to elevate blood
pressure. Patients experience palpitations.
Activation of the renin-angiotensin-
aldosterone (RAA) system serves to
increase blood volume, hence cardiac
output. Fluid retention leads to an increase
in body weight and, possibly,
edemas. These counter-regulatory processes
are susceptible to pharmacological
inhibition (!-blockers, ACE inhibitors,
AT1-antagonists, diuretics).
Mechanisms of action. The tonus
of vascular smooth muscle can be decreased
by various means. ACE inhibitors,
antagonists at AT1-receptors and
antagonists at "-adrenoceptors protect
against the effects of excitatory mediators
such as angiotensin II and norepinephrine,
respectively. Prostacyclin analogues
such as iloprost, or prostaglandin
E1 analogues such as alprostanil,
mimic the actions of relaxant mediators.
Ca2+ antagonists reduce depolarizing inward
Ca2+ currents, while K+-channel activators
promote outward (hyperpolarizing)
K+ currents. Organic nitrovasodilators
give rise to NO, an endogenous
activator of guanylate cyclase.
Individual vasodilators. Nitrates
Ca2+-antagonists. "1-
antagonists, ACE-inhibitors, AT1-
antagonists; and sodium nitroprusside
are discussed elsewhere.
Dihydralazine and minoxidil (via
its sulfate-conjugated metabolite) dilate
arterioles and are used in antihypertensive
therapy. They are, however, unsuitable
for monotherapy because of compensatory
circulatory reflexes. The
mechanism of action of dihydralazine is
unclear. Minoxidil probably activates K+
channels, leading to hyperpolarization
of smooth muscle cells. Particular adverse
reactions are lupus erythematosus
with dihydralazine and hirsutism
with minoxidil—used topically for the
treatment of baldness (alopecia androgenetica).
Diazoxide given i.v. causes prominent
arteriolar dilation; it can be employed
in hypertensive crises. After its
oral administration, insulin secretion is
inhibited. Accordingly, diazoxide can be
used in the management of insulin-secreting
pancreatic tumors. Both effects
are probably due to opening of (ATPgated)
K+ channels.
The methylxanthine theophylline,
the phosphodiesterase inhibitor
amrinone, prostacyclins,
and nicotinic acid derivatives
also possess vasodilating activity.

Organic Nitrates
Various esters of nitric acid (HNO3) and
polyvalent alcohols relax vascular
smooth muscle, e.g., nitroglycerin (glyceryltrinitrate)
and isosorbide dinitrate.
The effect is more pronounced in venous
than in arterial beds.
These vasodilator effects produce
hemodynamic consequences that can
be put to therapeutic use. Due to a decrease
in both venous return (preload)
and arterial afterload, cardiac work is
decreased. As a result, the cardiac
oxygen balance improves. Spasmodic
constriction of larger coronary
vessels (coronary spasm) is prevented.
Uses. Organic nitrates are used
chiefly in angina pectoris,
less frequently in severe forms of chronic
and acute congestive heart failure.
Continuous intake of higher doses with
maintenance of steady plasma levels
leads to loss of efficacy, inasmuch as the
organism becomes refractory (tachyphylactic).
This “nitrate tolerance” can
be avoided if a daily “nitrate-free interval”
is maintained, e.g., overnight.
At the start of therapy, unwanted
reactions occur frequently in the form
of a throbbing headache, probably
caused by dilation of cephalic vessels.
This effect also exhibits tolerance, even
when daily “nitrate pauses” are kept.
Excessive dosages give rise to hypotension,
reflex tachycardia, and circulatory
collapse.
Mechanism of action. The reduction
in vascular smooth muscle tone is
presumably due to activation of guanylate
cyclase and elevation of cyclic GMP
levels. The causative agent is most likely
nitric oxide (NO) generated from the organic
nitrate. NO is a physiological messenger
molecule that endothelial cells
release onto subjacent smooth muscle
cells (“endothelium-derived relaxing
factor,” EDRF). Organic nitrates would
thus utilize a pre-existing pathway,
hence their high efficacy. The generation
of NO within the smooth muscle
cell depends on a supply of free sulfhydryl
(-SH) groups; “nitrate-tolerance”
has been attributed to a cellular exhaustion
of SH-donors but this may be not
the only reason.
Nitroglycerin (NTG) is distinguished
by high membrane penetrability
and very low stability. It is the drug
of choice in the treatment of angina pectoris
attacks. For this purpose, it is administered
as a spray, or in sublingual or
buccal tablets for transmucosal delivery.
The onset of action is between 1 and
3 min. Due to a nearly complete presystemic
elimination, it is poorly suited
for oral administration. Transdermal delivery
(nitroglycerin patch) also avoids
presystemic elimination. Isosorbide
dinitrate (ISDN) penetrates well
through membranes, is more stable
than NTG, and is partly degraded into
the weaker, but much longer acting, 5-
isosorbide mononitrate (ISMN). ISDN
can also be applied sublingually; however,
it is mainly administered orally in
order to achieve a prolonged effect.
ISMN is not suitable for sublingual use
because of its higher polarity and slower
rate of absorption. Taken orally, it is absorbed
and is not subject to first-pass
elimination.
Molsidomine itself is inactive. After
oral intake, it is slowly converted
into an active metabolite. Apparently,
there is little likelihood of "nitrate tolerance”.
Sodium nitroprusside contains a
nitroso (-NO) group, but is not an ester.
It dilates venous and arterial beds
equally. It is administered by infusion to
achieve controlled hypotension under
continuous close monitoring. Cyanide
ions liberated from nitroprusside can be
inactivated with sodium thiosulfate
(Na2S2O3).

Calcium Antagonists
During electrical excitation of the cell
membrane of heart or smooth muscle,
different ionic currents are activated,
including an inward Ca2+ current. The
term Ca2+ antagonist is applied to drugs
that inhibit the influx of Ca2+ ions without
affecting inward Na+ or outward K+
currents to a significant degree. Other
labels are Ca-entry blocker or Ca-channel
blocker. Therapeutically used Ca2+ antagonists
can be divided into three
groups according to their effects on
heart and vasculature.
I. Dihydropyridine derivatives.
The dihydropyridines, e.g., nifedipine,
are uncharged hydrophobic substances.
They induce a relaxation of vascular
smooth muscle in arterial beds. An effect
on cardiac function is practically absent
at therapeutic dosage. (However, in
pharmacological experiments on isolated
cardiac muscle preparations a clear
negative inotropic effect is demonstrable.)
They are thus regarded as vasoselective
Ca2+ antagonists. Because of
the dilatation of resistance vessels,
blood pressure falls. Cardiac afterload is
diminished and, therefore, also
oxygen demand. Spasms of coronary arteries
are prevented.
Indications for nifedipine include
angina pectoris and, — when applied
as a sustained release preparation,
— hypertension. In angina pectoris,
it is effective when given either
prophylactically or during acute attacks.
Adverse effects are palpitation (reflex
tachycardia due to hypotension), headache,
and pretibial edema.
Nitrendipine and felodipine are used
in the treatment of hypertension. Nimodipine
is given prophylactically after
subarachnoidal hemorrhage to prevent
vasospasms due to depolarization by
excess K+ liberated from disintegrating
erythrocytes or blockade of NO by free
hemoglobin.
II. Verapamil and other catamphiphilic
Ca2+ antagonists. Verapamil contains
a nitrogen atom bearing a positive
charge at physiological pH and thus represents
a cationic amphiphilic molecule.
It exerts inhibitory effects not only on
arterial smooth muscle, but also on heart
muscle. In the heart, Ca2+ inward currents
are important in generating depolarization
of sinoatrial node cells (impulse
generation), in impulse propagation
through the AV- junction (atrioventricular
conduction), and in electromechanical
coupling in the ventricular cardiomyocytes.
Verapamil thus produces
negative chrono-, dromo-, and inotropic
effects.
Indications. Verapamil is used as
an antiarrhythmic drug in supraventricular
tachyarrhythmias. In atrial flutter
or fibrillation, it is effective in reducing
ventricular rate by virtue of inhibiting
AV-conduction. Verapamil is also employed
in the prophylaxis of angina pectoris
attacks and the treatment
of hypertension. Adverse effects:
Because of verapamil’s effects on
the sinus node, a drop in blood pressure
fails to evoke a reflex tachycardia. Heart
rate hardly changes; bradycardia may
even develop. AV-block and myocardial
insufficiency can occur. Patients frequently
complain of constipation.
Gallopamil (= methoxyverapamil) is
closely related to verapamil in both
structure and biological activity.
Diltiazem is a catamphiphilic benzothiazepine
derivative with an activity
profile resembling that of verapamil.
III. T-channel selective blockers.
Ca2+-channel blockers, such as verapamil
and mibefradil, may block both Land
T-type Ca2+ channels. Mibefradil
shows relative selectivity for the latter
and is devoid of a negative inotropic effect;
its therapeutic usefulness is compromised
by numerous interactions
with other drugs due to inhibition of cytochrome
P450-dependent enzymes
(CYP 1A2, 2D6 and, especially, 3A4).

Cardiac Drugs

Overview of Modes of Action (A)
1. The pumping capacity of the heart is
regulated by sympathetic and parasympathetic
nerves. Drugs capable
of interfering with autonomic
nervous function therefore provide a
means of influencing cardiac performance.
Thus, anxiolytics of the benzodiazepine
type, such as diazepam,
can be employed in myocardial infarction
to suppress sympathoactivation
due to life-threatening distress.
Under the influence of antiadrenergic
agents, used to lower an elevated
blood pressure, cardiac work is decreased.
Ganglionic blockers
are used in managing hypertensive
emergencies. Parasympatholytics
and !-blockers prevent the
transmission of autonomic nerve impulses
to heart muscle cells by blocking
the respective receptors.
2. An isolated mammalian heart
whose extrinsic nervous connections
have been severed will beat spontaneously
for hours if it is supplied with a
nutrient medium via the aortic trunk
and coronary arteries (Langendorff
preparation). In such a preparation, only
those drugs that act directly on cardiomyocytes
will alter contractile force and
beating rate.
Parasympathomimetics and sympathomimetics
act at membrane receptors
for visceromotor neurotransmitters.
The plasmalemma also harbors
the sites of action of cardiac glycosides
(the Na/K-ATPases), of Ca2+ antagonists
(Ca2+ channels ), and of
agents that block Na+ channels (local
anesthetics). An intracellular
site is the target for phosphodiesterase
inhibitors (e.g., amrinone).
3. Mention should also be made of
the possibility of affecting cardiac function
in angina pectoris or congestive
heart failure by reducing
venous return, peripheral resistance,
or both, with the aid of vasodilators;
and by reducing sympathetic drive
applying !-blockers.
Events Underlying Contraction and
Relaxation (B)
The signal triggering contraction is a
propagated action potential (AP) generated
in the sinoatrial node. Depolarization
of the plasmalemma leads to a rapid
rise in cytosolic Ca2+ levels, which
causes the contractile filaments to
shorten (electromechanical coupling).
The level of Ca2+ concentration attained
determines the degree of shortening,
i.e., the force of contraction. Sources of
Ca2+ are: a) extracellular Ca2+ entering
the cell through voltage-gated Ca2+
channels; b) Ca2+ stored in membranous
sacs of the sarcoplasmic reticulum (SR);
c) Ca2+ bound to the inside of the plasmalemma.
The plasmalemma of cardiomyocytes
extends into the cell interior
in the form of tubular invaginations
(transverse tubuli).
The trigger signal for relaxation is
the return of the membrane potential to
its resting level. During repolarization,
Ca2+ levels fall below the threshold for
activation of the myofilaments (3 10–7
M), as the plasmalemmal binding sites
regain their binding capacity; the SR
pumps Ca2+ into its interior; and Ca2+
that entered the cytosol during systole
is again extruded by plasmalemmal
Ca2+-ATPases with expenditure of energy.
In addition, a carrier (antiporter),
utilizing the transmembrane Na+ gradient
as energy source, transports Ca2+ out
of the cell in exchange for Na+ moving
down its transmembrane gradient
(Na+/Ca2+ exchange).


Cardiac Glycosides
Diverse plants (A) are sources of sugarcontaining
compounds (glycosides) that
also contain a steroid ring (structural
formulas ) and augment the contractile
force of heart muscle (B): cardiotonic
glycosides. cardiosteroids, or “digitalis.”
If the inotropic, “therapeutic” dose
is exceeded by a small increment, signs
of poisoning appear: arrhythmia and
contracture (B). The narrow therapeutic
margin can be explained by the mechanism
of action.
Cardiac glycosides (CG) bind to the
extracellular side of Na+/K+-ATPases of
cardiomyocytes and inhibit enzyme activity.
The Na+/K+-ATPases operate to
pump out Na+ leaked into the cell and to
retrieve K+ leaked from the cell. In this
manner, they maintain the transmembrane
gradients for K+ and Na+, the negative
resting membrane potential, and
the normal electrical excitability of the
cell membrane. When part of the enzyme
is occupied and inhibited by CG,
the unoccupied remainder can increase
its level of activity and maintain Na+ and
K+ transport. The effective stimulus is a
small elevation of intracellular Na+ concentration
(normally approx. 7 mM).
Concomitantly, the amount of Ca2+ mobilized
during systole and, thus, contractile
force, increases. It is generally
thought that the underlying cause is the
decrease in the Na+ transmembrane
gradient, i.e., the driving force for the
Na+/Ca2+ exchange (p. 128), allowing the
intracellular Ca2+ level to rise. When too
many ATPases are blocked, K+ and Na+
homeostasis is deranged; the membrane
potential falls, arrhythmias occur.
Flooding with Ca2+ prevents relaxation
during diastole, resulting in contracture.
The CNS effects of CG (C) are also
due to binding to Na+/K+-ATPases. Enhanced
vagal nerve activity causes a decrease
in sinoatrial beating rate and velocity
of atrioventricular conduction. In
patients with heart failure, improved
circulation also contributes to the reduction
in heart rate. Stimulation of the
area postrema leads to nausea and vomiting.
Disturbances in color vision are
evident.
Indications for CG are: (1) chronic
congestive heart failure; and (2) atrial
fibrillation or flutter, where inhibition of
AV conduction protects the ventricles
from excessive atrial impulse activity
and thereby improves cardiac performance
(D). Occasionally, sinus rhythm
is restored.
Signs of intoxication are: (1) cardiac
arrhythmias, which under certain
circumstances are life-threatening, e.g.,
sinus bradycardia, AV-block, ventricular
extrasystoles, ventricular fibrillation
(ECG); (2) CNS disturbances — altered
color vision (xanthopsia), agitation,
confusion, nightmares, hallucinations;
(3) gastrointestinal — anorexia, nausea,
vomiting, diarrhea; (4) renal — loss of
electrolytes and water, which must be
differentiated from mobilization of accumulated
edema fluid that occurs with
therapeutic dosage.
Therapy of intoxication: administration
of K+, which inter alia reduces
binding of CG, but may impair AV-conduction;
administration of antiarrhythmics,
such as phenytoin or lidocaine
; oral administration of colestyramine
for binding and preventing
absorption of digitoxin present
in the intestines (enterohepatic cycle);
injection of antibody (Fab) fragments
that bind and inactivate digitoxin and
digoxin. Compared with full antibodies,
fragments have superior tissue penetrability,
more rapid renal elimination,
and lower antigenicity.


The pharmacokinetics of cardiac
glycosides (A) are dictated by their polarity,
i.e., the number of hydroxyl
groups. Membrane penetrability is virtually
nil in ouabain, high in digoxin,
and very high in digitoxin. Ouabain (gstrophanthin)
does not penetrate into
cells, be they intestinal epithelium, renal
tubular, or hepatic cells. At best, it is
suitable for acute intravenous induction
of glycoside therapy.
The absorption of digoxin depends
on the kind of galenical preparation
used and on absorptive conditions in
the intestine. Preparations are now of
such quality that the derivatives methyldigoxin
and acetyldigoxin no longer offer
any advantage. Renal reabsorption is incomplete;
approx. 30% of the total
amount present in the body (s.c. full
“digitalizing” dose) is eliminated per
day. When renal function is impaired,
there is a risk of accumulation. Digitoxin
undergoes virtually complete reabsorption
in gut and kidneys. There is
active hepatic biotransformation: cleavage
of sugar moieties, hydroxylation at
C12 (yielding digoxin), and conjugation
to glucuronic acid. Conjugates secreted
with bile are subject to enterohepatic
cycling; conjugates reaching the
blood are renally eliminated. In renal insufficiency,
there is no appreciable accumulation.
When digitoxin is withdrawn
following overdosage, its effect
decays more slowly than does that of digoxin.
Other positive inotropic drugs.
The phosphodiesterase inhibitor amrinone
(cAMP elevation ) can be
administered only parenterally for a
maximum of 14 d because it is poorly
tolerated. A closely related compound is
milrinone. In terms of their positive inotropic
effect, !-sympathomimetics,
unlike dopamine, are of little
therapeutic use; they are also arrhythmogenic
and the sensitivity of the !-receptor
system declines during continuous
stimulation.
Treatment Principles in Chronic Heart
Failure
Myocardial insufficiency leads to a decrease
in stroke volume and venous
congestion with formation of edema.
Administration of (thiazide) diuretics
offers a therapeutic approach of
proven efficacy that is brought about by
a decrease in circulating blood volume
(decreased venous return) and peripheral
resistance, i.e., afterload. A similar
approach is intended with ACE-inhibitors,
which act by preventing the synthesis
of angiotensin II (!vasoconstriction)
and reducing the secretion of aldosterone
(! fluid retention). In severe
cases of myocardial insufficiency, cardiac
glycosides may be added to augment
cardiac force and to relieve the
symptoms of insufficiency.
In more recent times !-blocker on a
long term were found to improve cardiac
performance — particularly in idiopathic
dilating cardiomyopathy — probably
by preventing sympathetic overdrive.

Antiarrhythmic Drugs

The electrical impulse for contraction
(propagated action potential)
originates in pacemaker cells of the sinoatrial
node and spreads through the
atria, atrioventricular (AV) node, and
adjoining parts of the His-Purkinje fiber
system to the ventricles (A). Irregularities
of heart rhythm can interfere dangerously
with cardiac pumping function.
I. Drugs for selective control of sinoatrial
and AV nodes. In some forms
of arrhythmia, certain drugs can be used
that are capable of selectively facilitating
and inhibiting (green and red arrows,
respectively) the pacemaker function
of sinoatrial or atrioventricular
cells.
Sinus bradycardia. An abnormally
low sinoatrial impulse rate (<60/min)
can be raised by parasympatholytics.
The quaternary ipratropium is preferable
to atropine, because it lacks CNS
penetrability. Sympathomimetics
also exert a positive chronotropic action;
they have the disadvantage of increasing
myocardial excitability (and
automaticity) and, thus, promoting ectopic
impulse generation (tendency to
extrasystolic beats). In cardiac arrest
epinephrine can be used to reinitiate
heart beat.
Sinus tachycardia (resting rate
>100 beats/min). !-Blockers eliminate
sympathoexcitation and decrease cardiac
rate.
Atrial flutter or fibrillation. An excessive
ventricular rate can be decreased
by verapamil or cardiac
glycosides. These drugs inhibit
impulse propagation through the AV
node, so that fewer impulses reach the
ventricles.
II. Nonspecific drug actions on
impulse generation and propagation.
Impulses originating at loci outside the
sinus node are seen in supraventricular
or ventricular extrasystoles, tachycardia,
atrial or ventricular flutter, and fibrillation.
In these forms of rhythm disorders,
antiarrhythmics of the local anesthetic,
Na+-channel blocking type (B) are
used for both prophylaxis and therapy.
Local anesthetics inhibit electrical excitation
of nociceptive nerve fibers
; concomitant cardiac inhibition
(cardiodepression) is an unwanted effect.
However, in certain types of arrhythmias
(see above), this effect is useful.
Local anesthetics are readily cleaved
(arrows) and unsuitable for oral administration
(procaine, lidocaine). Given judiciously,
intravenous lidocaine is an effective
antiarrhythmic. Procainamide
and mexiletine, congeners endowed
with greater metabolic stability, are examples
of orally effective antiarrhythmics.
The desired and undesired effects
are inseparable. Thus, these antiarrhythmics
not only depress electrical
excitability of cardiomyocytes (negative
bathmotropism, membrane stabilization),
but also lower sinoatrial rate (neg.
chronotropism), AV conduction (neg.
dromotropism), and force of contraction
(neg. inotropism). Interference with normal
electrical activity can, not too paradoxically,
also induce cardiac arrhythmias–
arrhythmogenic action.
Inhibition of CNS neurons is the
underlying cause of neurological effects
such as vertigo, confusion, sensory disturbances,
and motor disturbances
(tremor, giddiness, ataxia, convulsions).


Electrophysiological Actions of
Antiarrhythmics of the Na+-Channel
Blocking Type
Action potential and ionic currents.
The transmembrane electrical potential
of cardiomyocytes can be recorded
through an intracellular microelectrode.
Upon electrical excitation, a characteristic
change occurs in membrane potential—
the action potential (AP). Its underlying
cause is a sequence of transient
ionic currents. During rapid depolarization
(Phase 0), there is a short-lived influx
of Na+ through the membrane. A
subsequent transient influx of Ca2+ (as
well as of Na+) maintains the depolarization
(Phase 2, plateau of AP). A delayed
efflux of K+ returns the membrane
potential (Phase 3, repolarization) to its
resting value (Phase 4). The velocity of
depolarization determines the speed at
which the AP propagates through the
myocardial syncytium.
Transmembrane ionic currents involve
proteinaceous membrane pores:
Na+, Ca2+, and K+ channels. In A, the
phasic change in the functional state of
Na+ channels during an action potential
is illustrated.
Effects of antiarrhythmics. Antiarrhythmics
of the Na+-channel blocking
type reduce the probability that Na+
channels will open upon membrane depolarization
(“membrane stabilization”).
The potential consequences are
(A, bottom): 1) a reduction in the velocity
of depolarization and a decrease in
the speed of impulse propagation; aberrant
impulse propagation is impeded. 2)
Depolarization is entirely absent; pathological
impulse generation, e.g., in the
marginal zone of an infarction, is suppressed.
3) The time required until a
new depolarization can be elicited, i.e.,
the refractory period, is increased; prolongation
of the AP (see below) contributes
to the increase in refractory period.
Consequently, premature excitation
with risk of fibrillation is prevented.
Mechanism of action. Na+-channel
blocking antiarrhythmics resemble
most local anesthetics in being cationic
amphiphilic molecules ( exception:
phenytoin). Possible molecular
mechanisms of their inhibitory effects
are outlined in more detail.
Their low structural specificity is
reflected by a low selectivity towards
different cation channels. Besides the
Na+ channel, Ca2+ and K+ channels are also
likely to be blocked. Accordingly, cationic
amphiphilic antiarrhythmics affect
both the depolarization and repolarization
phases. Depending on the substance,
AP duration can be increased
(Class IA), decreased (Class IB), or remain
the same (Class IC).
Antiarrhythmics representative
of these categories include: Class IA—
quinidine, procainamide, ajmaline, disopyramide,
propafenone; Class IB—lidocaine,
mexiletine, tocainide, as well as
phenytoin; Class IC—flecainide.
Note: With respect to classification,
!-blockers have been assigned to Class
II, and the Ca2+-channel blockers verapamil
and diltiazem to Class IV.
Commonly listed under a separate
rubric (Class III) are amiodarone and the
!-blocking agent sotalol, which both inhibit
K+-channels and which both cause
marked prolongation of the AP with a
lesser effect on Phase 0 rate of rise.
Therapeutic uses. Because of their
narrow therapeutic margin, these antiarrhythmics
are only employed when
rhythm disturbances are of such severity
as to impair the pumping action of
the heart, or when there is a threat of
other complications. The choice of drug
is empirical. If the desired effect is not
achieved, another drug is tried. Combinations
of antiarrhythmics are not customary.
Amiodarone is reserved for special
cases.

Biogenic Amines

Biogenic Amines — Actions and
Pharmacological Implications
Dopamine A. As the precursor of norepinephrine
and epinephrine,
dopamine is found in sympathetic (adrenergic)
neurons and adrenomedullary
cells. In the CNS, dopamine itself serves
as a neuromediator and is implicated in
neostriatal motor programming,
the elicitation of emesis at the level of
the area postrema, and inhibition
of prolactin release from the anterior
pituitary.
Dopamine receptors are coupled to Gproteins
and exist as different subtypes.
D1-receptors (comprising subtypes D1
and D5) and D2-receptors (comprising
subtypes D2, D3, and D4). The aforementioned
actions are mediated mainly by
D2 receptors. When given by infusion,
dopamine causes dilation of renal and
splanchnic arteries. This effect is mediated
by D1 receptors and is utilized in the
treatment of cardiovascular shock and
hypertensive emergencies by infusion of
dopamine and fenoldopam, respectively.
At higher doses, !1-adrenoceptors
and, finally, "-receptors are activated, as
evidenced by cardiac stimulation and
vasoconstriction, respectively.
Dopamine is not to be confused with dobutamine
which stimulates "- and !-adrenoceptors
but not dopamine receptors.
Dopamine-mimetics. Administration
of the precursor L-dopa promotes
endogenous synthesis of dopamine (indication:
parkinsonian syndrome.
The ergolides, bromocriptine,
pergolide, and lisuride, are ligands at Dreceptors
whose therapeutic effects are
probably due to stimulation of D2 receptors
(indications: parkinsonism, suppression
of lactation, infertility, acromegaly.
Typical adverse effects of
these substances are nausea and vomiting.
As indirect dopamine-mimetics, (+)-
amphetamine and ritaline augment dopamine
release.
Inhibition of the enzymes involved
in dopamine degradation, catecholamine-
oxygen-methyl-transferase
(COMT) and monoamineoxidase (MAO),
is another means to increase actual
available dopamine concentration
(COMT-inhibitors, p. 188), MAOB-inhibitors.
Dopamine antagonist activity is the
hallmark of classical neuroleptics. The
antihypertensive agents, reserpine (obsolete)
and "-methyldopa, deplete neuronal
stores of the amine. A common adverse
effect of dopamine antagonists or
depletors is parkinsonism.
Histamine (B). Histamine is stored
in basophils and tissue mast cells. It
plays a role in inflammatory and allergic
reactions and produces
bronchoconstriction, increased intestinal
peristalsis, and dilation and increased
permeability of small blood vessels.
In the gastric mucosa, it is released
from enterochromaffin-like cells and
stimulates acid secretion by the parietal
cells. In the CNS, it acts as a neuromodulator.
Two receptor subtypes (G-protein-
coupled), H1 and H2, are of therapeutic
importance; both mediate vascular
responses. Prejunctional H3 receptors
exist in brain and the periphery.
Antagonists. Most of the so-called
H1-antihistamines also block other receptors,
including M-cholinoceptors and
D-receptors. H1-antihistamines are used
for the symptomatic relief of allergies
(e.g., bamipine, chlorpheniramine, clemastine,
dimethindene, mebhydroline
pheniramine); as antiemetics (meclizine,
dimenhydrinate, as overthe-
counter hypnotics (e.g., diphenhydramine).
Promethazine represents
the transition to the neuroleptic
phenothiazines. Unwanted effects
of most H1-antihistamines are lassitude
(impaired driving skills) and atropine-
like reactions (e.g., dry mouth, constipation).
At the usual therapeutic doses,
astemizole, cetrizine, fexofenadine,
and loratidine are practically devoid of
sedative and anticholinergic effects. H2-
antihistamines (cimetidine, ranitidine,
famotidine, nizatidine) inhibit gastric
acid secretion, and thus are useful in the
treatment of peptic ulcers.


Inhibitors of histamine release: One
of the effects of the so-called mast cell
stabilizers cromoglycate (cromolyn)
and nedocromil is to decrease the release
of histamine from mast cells.
Both agents are applied topically.
Release of mast cell mediators can
also be inhibited by some H1 antihistamines,
e.g., oxatomide and ketotifen,
which are used systemically.
Serotonin
Occurrence. Serotonin (5-hydroxytryptamine,
5-HT) is synthesized from Ltryptophan
in enterochromaffin cells of
the intestinal mucosa. 5-HT-synthesizing
neurons occur in the enteric nerve
plexus and the CNS, where the amine
fulfills a neuromediator function. Blood
platelets are unable to synthesize 5HT,
but are capable of taking up, storing,
and releasing it.
Serotonin receptors. Based on biochemical
and pharmacological criteria,
seven receptor classes can be distinguished.
Of major pharmacotherapeutic
importance are those designated 5-HT1,
5-HT2, 5-HT4, and 5-HT7, all of which are
G-protein-coupled, whereas the 5-HT3
subtype represents a ligand-gated nonselective
cation channel.
Serotonin actions. The cardiovascular
effects of 5-HT are complex, because
multiple, in part opposing, effects are
exerted via the different receptor subtypes.
Thus, 5-HT2A and 5-HT7 receptors
on vascular smooth muscle cells mediate
direct vasoconstriction and vasodilation,
respectively. Vasodilation and
lowering of blood pressure can also occur
by several indirect mechanisms: 5-
HT1A receptors mediate sympathoinhibition
(! decrease in neurogenic vasoconstrictor
tonus) both centrally and
peripherally; 5-HT2B receptors on vascular
endothelium promote release of
vasorelaxant mediators (NO, p. 120;
prostacyclin) 5-HT released from
platelets plays a role in thrombogenesis,
hemostasis, and the pathogenesis of
preeclamptic hypertension.
Ketanserin is an antagonist at 5-
HT2A receptors and produces antihypertensive
effects, as well as inhibition of
thrombocyte aggregation. Whether 5-
HT antagonism accounts for its antihypertensive
effect remains questionable,
because ketanserin also blocks !-adrenoceptors.
Sumatriptan and other triptans are
antimigraine drugs that possess agonist
activity at 5-HT1 receptors of the B, D
and F subtypes and may thereby alleviate
this type of headache.
Gastrointestinal tract. Serotonin
released from myenteric neurons or enterochromaffin
cells acts on 5-HT3 and
5-HT4 receptors to enhance bowel motility
and enteral fluid secretion. Cisapride
is a prokinetic agent that promotes
propulsive motor activity in the
stomach and in small and large intestines.
It is used in motility disorders. Its
mechanism of action is unclear, but
stimulation of 5HT4 receptors may be
important.
Central Nervous System. Serotoninergic
neurons play a part in various
brain functions, as evidenced by the effects
of drugs likely to interfere with serotonin.
Fluoxetine is an antidepressant
that, by blocking re-uptake, inhibits inactivation
of released serotonin. Its activity
spectrum includes significant psychomotor
stimulation, depression of appetite,
and anxiolysis. Buspirone also has
anxiolytic properties thought to be mediated
by central presynaptic 5-HT1A receptors.
Ondansetron, an antagonist at
the 5-HT3 receptor, possesses striking
effectiveness against cytotoxic drug-induced
emesis, evident both at the start
of and during cytostatic therapy. Tropisetron
and granisetron produce analogous
effects.
Psychedelics (LSD) and other psychotomimetics
such as mescaline and
psilocybin can induce states of altered
awareness, or induce hallucinations and
anxiety, probably mediated by 5-HT2A
receptors. Overactivity of these receptors
may also play a role in the genesis
of negative symptoms in schizophrenia
and sleep disturbances.

Nicotine

Ganglionic Transmission
Whether sympathetic or parasympathetic,
all efferent visceromotor nerves
are made up of two serially connected
neurons. The point of contact (synapse)
between the first and second neurons
occurs mainly in ganglia; therefore, the
first neuron is referred to as preganglionic
and efferents of the second as
postganglionic.
Electrical excitation (action potential)
of the first neuron causes the release
of acetylcholine (ACh) within the
ganglia. ACh stimulates receptors located
on the subsynaptic membrane of the
second neuron. Activation of these receptors
causes the nonspecific cation
channel to open. The resulting influx of
Na+ leads to a membrane depolarization.
If a sufficient number of receptors
is activated simultaneously, a threshold
potential is reached at which the membrane
undergoes rapid depolarization in
the form of a propagated action potential.
Normally, not all preganglionic impulses
elicit a propagated response in
the second neuron. The ganglionic synapse
acts like a frequency filter (A). The
effect of ACh elicited at receptors on the
ganglionic neuronal membrane can be
imitated by nicotine; i.e., it involves nicotinic
cholinoceptors.
Ganglionic action of nicotine. If a
small dose of nicotine is given, the ganglionic
cholinoceptors are activated. The
membrane depolarizes partially, but
fails to reach the firing threshold. However,
at this point an amount of released
ACh smaller than that normally
required will be sufficient to elicit a
propagated action potential. At a low
concentration, nicotine acts as a ganglionic
stimulant; it alters the filter
function of the ganglionic synapse, allowing
action potential frequency in the
second neuron to approach that of the
first (B). At higher concentrations, nicotine
acts to block ganglionic transmission.
Simultaneous activation of many
nicotinic cholinoceptors depolarizes the
ganglionic cell membrane to such an extent
that generation of action potentials
is no longer possible, even in the face of
an intensive and synchronized release
of ACh (C).
Although nicotine mimics the action
of ACh at the receptors, it cannot
duplicate the time course of intrasynaptic
agonist concentration required for
appropriate high-frequency ganglionic
activation. The concentration of nicotine
in the synaptic cleft can neither
build up as rapidly as that of ACh released
from nerve terminals nor can
nicotine be eliminated from the synaptic
cleft as quickly as ACh.
The ganglionic effects of ACh can be
blocked by tetraethylammonium, hexamethonium,
and other substances (ganglionic
blockers). None of these has intrinsic
activity, that is, they fail to stimulate
ganglia even at low concentration;
some of them (e.g., hexamethonium)
actually block the cholinoceptor-linked
ion channel, but others (mecamylamine,
trimethaphan) are typical receptor
antagonists.
Certain sympathetic preganglionic
neurons project without interruption to
the chromaffin cells of the adrenal medulla.
The latter are embryologic homologues
of ganglionic sympathocytes. Excitation
of preganglionic fibers leads to
release of ACh in the adrenal medulla,
whose chromaffin cells then respond
with a release of epinephrine into the
blood (D). Small doses of nicotine, by inducing
a partial depolarization of adrenomedullary
cells, are effective in liberating
epinephrine.

Effects of Nicotine on Body Functions
At a low concentration, the tobacco alkaloid
nicotine acts as a ganglionic stimulant
by causing a partial depolarization
via activation of ganglionic cholinoceptors.
A similar action is evident
at diverse other neural sites, considered
below in more detail.
Autonomic ganglia. Ganglionic
stimulation occurs in both the sympathetic
and parasympathetic divisions of
the autonomic nervous system. Parasympathetic
activation results in increased
production of gastric juice
(smoking ban in peptic ulcer) and enhanced
bowel motility (“laxative” effect
of the first morning cigarette: defecation;
diarrhea in the novice).
Although stimulation of parasympathetic
cardioinhibitory neurons
would tend to lower heart rate, this response
is overridden by the simultaneous
stimulation of sympathetic cardioaccelerant
neurons and the adrenal medulla.
Stimulation of sympathetic
nerves resulting in release of norepinephrine
gives rise to vasoconstriction;
peripheral resistance rises.
Adrenal medulla. On the one hand,
release of epinephrine elicits cardiovascular
effects, such as increases in heart
rate und peripheral vascular resistance.
On the other, it evokes metabolic responses,
such as glycogenolysis and lipolysis,
that generate energy-rich substrates.
The sensation of hunger is suppressed.
The metabolic state corresponds
to that associated with physical
exercise – “silent stress”.
Baroreceptors. Partial depolarization
of baroreceptors enables activation
of the reflex to occur at a relatively
smaller rise in blood pressure, leading
to decreased sympathetic vasoconstrictor
activity.
Neurohypophysis. Release of vasopressin
(antidiuretic hormone) results
in lowered urinary output.
Levels of vasopressin necessary for vasoconstriction
will rarely be produced
by nicotine.
Carotid body. Sensitivity to arterial
pCO2 increases; increased afferent input
augments respiratory rate and depth.
Receptors for pressure, temperature,
and pain. Sensitivity to the corresponding
stimuli is enhanced.
Area postrema. Sensitization of
chemoceptors leads to excitation of the
medullary emetic center.
At low concentration, nicotine is also
able to augment the excitability of
the motor endplate. This effect can be
manifested in heavy smokers in the
form of muscle cramps (calf musculature)
and soreness.
The central nervous actions of nicotine
are thought to be mediated largely
by presynaptic receptors that facilitate
transmitter release from excitatory
aminoacidergic (glutamatergic) nerve
terminals in the cerebral cortex. Nicotine
increases vigilance and the ability
to concentrate. The effect reflects an enhanced
readiness to perceive external
stimuli (attentiveness) and to respond
to them.
The multiplicity of its effects makes
nicotine ill-suited for therapeutic use.


Consequences of Tobacco Smoking
The dried and cured leaves of the nightshade
plant Nicotiana tabacum are
known as tobacco. Tobacco is mostly
smoked, less frequently chewed or taken
as dry snuff. Combustion of tobacco
generates approx. 4000 chemical compounds
in detectable quantities. The
xenobiotic burden on the smoker depends
on a range of parameters, including
tobacco quality, presence of a filter,
rate and temperature of combustion,
depth of inhalation, and duration of
breath holding.
Tobacco contains 0.2–5 % nicotine.
In tobacco smoke, nicotine is present as
a constituent of small tar particles. It is
rapidly absorbed through bronchi and
lung alveoli, and is detectable in the
brain only 8 s after the first inhalation.
Smoking of a single cigarette yields peak
plasma levels in the range of 25–50
ng/mL. The effects described on p. 110
become evident. When intake stops,
nicotine concentration in plasma shows
an initial rapid fall, reflecting distribution
into tissues, and a terminal elimination
phase with a half-life of 2 h. Nicotine
is degraded by oxidation.
The enhanced risk of vascular disease
(coronary stenosis, myocardial infarction,
and central and peripheral ischemic
disorders, such as stroke and
intermittent claudication) is likely to be
a consequence of chronic exposure to
nicotine. Endothelial impairment and
hence dysfunction has been proven to
result from smoking, and nicotine is
under discussion as a factor favoring
the progression of arteriosclerosis. By
releasing epinephrine, it elevates plasma
levels of glucose and free fatty acids
in the absence of an immediate physiological
need for these energy-rich metabolites.
Furthermore, it promotes
platelet aggregability, lowers fibrinolytic
activity of blood, and enhances coagulability.
The health risks of tobacco smoking
are, however, attributable not only to
nicotine, but also to various other ingredients
of tobacco smoke, some of which
possess demonstrable carcinogenic
properties.
Dust particles inhaled in tobacco
smoke, together with bronchial mucus,
must be removed from the airways by
the ciliated epithelium. Ciliary activity,
however, is depressed by tobacco
smoke; mucociliary transport is impaired.
This depression favors bacterial infection
and contributes to the chronic
bronchitis associated with regular
smoking. Chronic injury to the bronchial
mucosa could be an important causative
factor in increasing the risk in
smokers of death from bronchial carcinoma.
Statistical surveys provide an impressive
correlation between the number
of cigarettes smoked a day and the
risk of death from coronary disease or
lung cancer. Statistics also show that, on
cessation of smoking, the increased risk
of death from coronary infarction or
other cardiovascular disease declines
over 5–10 years almost to the level of
non-smokers. Similarly, the risk of developing
bronchial carcinoma is reduced.
Abrupt cessation of regular smoking
is not associated with severe physical
withdrawal symptoms. In general,
subjects complain of increased nervousness,
lack of concentration, and weight
gain.

Drugs Acting on the Parasympathetic Nervous System

Parasympathetic Nervous System
Responses to activation of the parasympathetic
system. Parasympathetic
nerves regulate processes connected
with energy assimilation (food intake,
digestion, absorption) and storage.
These processes operate when the body
is at rest, allowing a decreased tidal volume
(increased bronchomotor tone)
and decreased cardiac activity. Secretion
of saliva and intestinal fluids promotes
the digestion of foodstuffs; transport
of intestinal contents is speeded up
because of enhanced peristaltic activity
and lowered tone of sphincteric muscles.
To empty the urinary bladder (micturition),
wall tension is increased by
detrusor activation with a concurrent
relaxation of sphincter tonus.
Activation of ocular parasympathetic
fibers (see below) results in narrowing
of the pupil and increased curvature
of the lens, enabling near objects to
be brought into focus (accommodation).
Anatomy of the parasympathetic
system. The cell bodies of parasympathetic
preganglionic neurons are located
in the brainstem and the sacral spinal
cord. Parasympathetic outflow is channelled
from the brainstem (1) through
the third cranial nerve (oculomotor n.)
via the ciliary ganglion to the eye; (2)
through the seventh cranial nerve (facial
n.) via the pterygopalatine and submaxillary
ganglia to lacrimal glands and
salivary glands (sublingual, submandibular),
respectively; (3) through the
ninth cranial nerve (glossopharyngeal
n.) via the otic ganglion to the parotid
gland; and (4) via the tenth cranial
nerve (vagus n.) to thoracic and abdominal
viscera. Approximately 75 % of all
parasympathetic fibers are contained
within the vagus nerve. The neurons of
the sacral division innervate the distal
colon, rectum, bladder, the distal ureters,
and the external genitalia.
Acetylcholine (ACh) as a transmitter.
ACh serves as mediator at terminals
of all postganglionic parasympathetic
fibers, in addition to fulfilling its transmitter
role at ganglionic synapses within
both the sympathetic and parasympathetic
divisions and the motor endplates
on striated muscle. However, different
types of receptors are present at
these synaptic junctions:


Cholinergic Synapse
Acetylcholine (ACh) is the transmitter
at postganglionic synapses of parasympathetic
nerve endings. It is highly concentrated
in synaptic storage vesicles
densely present in the axoplasm of the
terminal. ACh is formed from choline
and activated acetate (acetylcoenzyme
A), a reaction catalyzed by the enzyme
choline acetyltransferase. The highly
polar choline is actively transported into
the axoplasm. The specific choline transporter
is localized exclusively to membranes
of cholinergic axons and terminals.
The mechanism of transmitter release
is not known in full detail. The vesicles
are anchored via the protein synapsin
to the cytoskeletal network. This arrangement
permits clustering of vesicles
near the presynaptic membrane, while
preventing fusion with it. During activation
of the nerve membrane, Ca2+ is
thought to enter the axoplasm through
voltage-gated channels and to activate
protein kinases that phosphorylate synapsin.
As a result, vesicles close to the
membrane are detached from their anchoring
and allowed to fuse with the
presynaptic membrane. During fusion,
vesicles discharge their contents into the
synaptic gap. ACh quickly diffuses
through the synaptic gap (the acetylcholine
molecule is a little longer than
0.5 nm; the synaptic gap is as narrow as
30–40 nm). At the postsynaptic effector
cell membrane, ACh reacts with its receptors.
Because these receptors can also
be activated by the alkaloid muscarine,
they are referred to as muscarinic
(M-)cholinoceptors. In contrast, at ganglionic
and motor endplate
cholinoceptors, the action of ACh is
mimicked by nicotine and they are,
therefore, said to be nicotinic cholinoceptors.
Released ACh is rapidly hydrolyzed
and inactivated by a specific acetylcholinesterase,
present on pre- and postjunctional
membranes, or by a less specific
serum cholinesterase (butyryl cholinesterase),
a soluble enzyme present in
serum and interstitial fluid.
M-cholinoceptors can be classified
into subtypes according to their molecular
structure, signal transduction, and
ligand affinity. Here, the M1, M2, and M3
subtypes are considered. M1 receptors
are present on nerve cells, e.g., in ganglia,
where they mediate a facilitation of
impulse transmission from preganglionic
axon terminals to ganglion cells.
M2 receptors mediate acetylcholine effects
on the heart: opening of K+ channels
leads to slowing of diastolic depolarization
in sinoatrial pacemaker cells
and a decrease in heart rate. M3 receptors
play a role in the regulation of
smooth muscle tone, e.g., in the gut and
bronchi, where their activation causes
stimulation of phospholipase C, membrane
depolarization, and increase in
muscle tone. M3 receptors are also
found in glandular epithelia, which similarly
respond with activation of phospholipase
C and increased secretory activity.
In the CNS, where all subtypes are
present, cholinoceptors serve diverse
functions, including regulation of cortical
excitability, memory, learning, pain
processing, and brain stem motor control.
The assignment of specific receptor
subtypes to these functions has yet to be
achieved.
In blood vessels, the relaxant action
of ACh on muscle tone is indirect, because
it involves stimulation of M3-cholinoceptors
on endothelial cells that respond
by liberating NO (= endotheliumderived
relaxing factor). The latter diffuses
into the subjacent smooth musculature,
where it causes a relaxation of
active tonus.



Parasympathomimetics
Acetylcholine (ACh) is too rapidly hydrolyzed
and inactivated by acetylcholinesterase
(AChE) to be of any therapeutic
use; however, its action can be mimicked
by other substances, namely direct
or indirect parasympathomimetics.
Direct Parasympathomimetics.
The choline ester, carbachol, activates
M-cholinoceptors, but is not hydrolyzed
by AChE. Carbachol can thus be effectively
employed for local application to
the eye (glaucoma) and systemic administration
(bowel atonia, bladder atonia).
The alkaloids, pilocarpine (from Pilocarpus
jaborandi) and arecoline (from
Areca catechu; betel nut) also act as direct
parasympathomimetics. As tertiary
amines, they moreover exert central effects.
The central effect of muscarinelike
substances consists of an enlivening,
mild stimulation that is probably
the effect desired in betel chewing, a
widespread habit in South Asia. Of this
group, only pilocarpine enjoys therapeutic
use, which is limited to local application
to the eye in glaucoma.
Indirect Parasympathomimetics.
AChE can be inhibited selectively, with
the result that ACh released by nerve
impulses will accumulate at cholinergic
synapses and cause prolonged stimulation
of cholinoceptors. Inhibitors of
AChE are, therefore, indirect parasympathomimetics.
Their action is evident
at all cholinergic synapses. Chemically,
these agents include esters of carbamic
acid (carbamates such as physostigmine,
neostigmine) and of phosphoric
acid (organophosphates such as paraoxon
= E600 and nitrostigmine = parathion
= E605, its prodrug).
Members of both groups react like
ACh with AChE and can be considered
false substrates. The esters are hydrolyzed
upon formation of a complex with
the enzyme. The rate-limiting step in
ACh hydrolysis is deacetylation of the
enzyme, which takes only milliseconds,
thus permitting a high turnover rate
and activity of AChE. Decarbaminoylation
following hydrolysis of a carbamate
takes hours to days, the enzyme
remaining inhibited as long as it is carbaminoylated.
Cleavage of the phosphate
residue, i.e. dephosphorylation,
is practically impossible; enzyme inhibition
is irreversible.
Uses. The quaternary carbamate
neostigmine is employed as an indirect
parasympathomimetic in postoperative
atonia of the bowel or bladder. Furthermore,
it is needed to overcome the relative
ACh-deficiency at the motor endplate
in myasthenia gravis or to reverse
the neuromuscular blockade (p. 184)
caused by nondepolarizing muscle relaxants
(decurarization before discontinuation
of anesthesia). The tertiary
carbamate physostigmine can be used
as an antidote in poisoning with parasympatholytic
drugs, because it has access
to AChE in the brain. Carbamates
(neostigmine, pyridostigmine, physostigmine)
and organophosphates (paraoxon,
ecothiopate) can also be applied
locally to the eye in the treatment of
glaucoma; however, their long-term use
leads to cataract formation. Agents from
both classes also serve as insecticides.
Although they possess high acute toxicity
in humans, they are more rapidly degraded
than is DDT following their
emission into the environment.
Tacrine is not an ester and interferes
only with the choline-binding site of
AChE. It is effective in alleviating symptoms
of dementia in some subtypes of
Alzheimer’s disease.



Parasympatholytics
Excitation of the parasympathetic division
of the autonomic nervous system
causes release of acetylcholine at neuroeffector
junctions in different target organs.
The major effects are summarized
in A (blue arrows). Some of these effects
have therapeutic applications, as indicated
by the clinical uses of parasympathomimetics
(p. 102).
Substances acting antagonistically
at the M-cholinoceptor are designated
parasympatholytics (prototype: the alkaloid
atropine; actions shown in red in
the panels). Therapeutic use of these
agents is complicated by their low organ
selectivity. Possibilities for a targeted
action include:
• local application
• selection of drugs with either good or
poor membrane penetrability as the
situation demands
• administration of drugs possessing
receptor subtype selectivity.
Parasympatholytics are employed
for the following purposes:
1. Inhibition of exocrine glands
Bronchial secretion. Premedication
with atropine before inhalation anesthesia
prevents a possible hypersecretion
of bronchial mucus, which cannot
be expectorated by coughing during intubation
(anesthesia).
Gastric secretion. Stimulation of
gastric acid production by vagal impulses
involves an M-cholinoceptor subtype
(M1-receptor), probably associated with
enterochromaffin cells. Pirenzepine (p.
106) displays a preferential affinity for
this receptor subtype. Remarkably, the
HCl-secreting parietal cells possess only
M3-receptors. M1-receptors have also
been demonstrated in the brain; however,
these cannot be reached by pirenzepine
because its lipophilicity is too
low to permit penetration of the bloodbrain
barrier. Pirenzepine was formerly
used in the treatment of gastric and duodenal
ulcers (p. 166).
2. Relaxation of smooth musculature
Bronchodilation can be achieved by the
use of ipratropium in conditions of increased
airway resistance (chronic obstructive
bronchitis, bronchial asthma).
When administered by inhalation,
this quaternary compound has little effect
on other organs because of its low
rate of systemic absorption.
Spasmolysis by N-butylscopolamine
in biliary or renal colic (p. 126). Because
of its quaternary nitrogen, this
drug does not enter the brain and requires
parenteral administration. Its
spasmolytic action is especially marked
because of additional ganglionic blocking
and direct muscle-relaxant actions.
Lowering of pupillary sphincter tonus
and pupillary dilation by local administration
of homatropine or tropicamide
(mydriatics) allows observation
of the ocular fundus. For diagnostic uses,
only short-term pupillary dilation is
needed. The effect of both agents subsides
quickly in comparison with that of
atropine (duration of several days).
3. Cardioacceleration
Ipratropium is used in bradycardia and
AV-block, respectively, to raise heart
rate and to facilitate cardiac impulse
conduction. As a quaternary substance,
it does not penetrate into the brain,
which greatly reduces the risk of CNS
disturbances (see below). Relatively
high oral doses are required because of
an inefficient intestinal absorption.
Atropine may be given to prevent
cardiac arrest resulting from vagal reflex
activation, incident to anesthetic induction,
gastric lavage, or endoscopic
procedures.



4. CNS-dampening effects
Scopolamine is effective in the prophylaxis
of kinetosis (motion sickness, sea
sickness, see p. 330); it is well absorbed
transcutaneously. Scopolamine (pKa =
7.2) penetrates the blood-brain barrier
faster than does atropine (pKa = 9), because
at physiologic pH a larger proportion
is present in the neutral, membrane-
permeant form.
In psychotic excitement (agitation),
sedation can be achieved with
scopolamine. Unlike atropine, scopolamine
exerts a calming and amnesiogenic
action that can be used to advantage
in anesthetic premedication.
Symptomatic treatment in parkinsonism
for the purpose of restoring a
dopaminergic-cholinergic balance in
the corpus striatum. Antiparkinsonian
agents, such as benzatropine (p. 188),
readily penetrate the blood-brain barrier.
At centrally equi-effective dosage,
their peripheral effects are less marked
than are those of atropine.
Contraindications for
parasympatholytics
Glaucoma: Since drainage of aqueous
humor is impeded during relaxation of
the pupillary sphincter, intraocular
pressure rises.
Prostatic hypertrophy with impaired
micturition: loss of parasympathetic
control of the detrusor muscle exacerbates
difficulties in voiding urine.
Atropine poisoning
Parasympatholytics have a wide therapeutic
margin. Rarely life-threatening,
poisoning with atropine is characterized
by the following peripheral and
central effects:
Peripheral: tachycardia; dry
mouth; hyperthermia secondary to the
inhibition of sweating. Although sweat
glands are innervated by sympathetic
fibers, these are cholinergic in nature.
When sweat secretion is inhibited, the
body loses the ability to dissipate metabolic
heat by evaporation of sweat (p.
202). There is a compensatory vasodilation
in the skin allowing increased heat
exchange through increased cutaneous
blood flow. Decreased peristaltic activity
of the intestines leads to constipation.
Central: Motor restlessness, progressing
to maniacal agitation, psychic
disturbances, disorientation, and hallucinations.
Elderly subjects are more
sensitive to such central effects. In this
context, the diversity of drugs producing
atropine-like side effects should be
borne in mind: e.g., tricyclic antidepressants,
neuroleptics, antihistamines,
antiarrhythmics, antiparkinsonian
agents.
Apart from symptomatic, general
measures (gastric lavage, cooling with
ice water), therapy of severe atropine
intoxication includes the administration
of the indirect parasympathomimetic
physostigmine (p. 102). The most
common instances of “atropine” intoxication
are observed after ingestion of
the berry-like fruits of belladonna (children)
or intentional overdosage with
tricyclic antidepressants in attempted
suicide.