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.

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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. <>

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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.

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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.

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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).

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