Drugs Acting on the Sympathetic Nervous System I

Sympathetic Nervous System

In the course of phylogeny an efficient
control system evolved that enabled the
functions of individual organs to be orchestrated
in increasingly complex life
forms and permitted rapid adaptation
to changing environmental conditions.
This regulatory system consists of the
CNS (brain plus spinal cord) and two
separate pathways for two-way communication
with peripheral organs, viz.,
the somatic and the autonomic nervous
systems. The somatic nervous system
comprising extero- and interoceptive
afferents, special sense organs, and motor
efferents, serves to perceive external
states and to target appropriate body
movement (sensory perception: threat
response: flight or attack). The autonomic
(vegetative) nervous system
(ANS), together with the endocrine
system, controls the milieu interieur. It
adjusts internal organ functions to the
changing needs of the organism. Neural
control permits very quick adaptation,
whereas the endocrine system provides
for a long-term regulation of functional
states. The ANS operates largely beyond
voluntary control; it functions autonomously.
Its central components reside
in the hypothalamus, brain stem, and
spinal cord. The ANS also participates in
the regulation of endocrine functions.
The ANS has sympathetic and
parasympathetic branches. Both are
made up of centrifugal (efferent) and
centripetal (afferent) nerves. In many
organs innervated by both branches, respective
activation of the sympathetic
and parasympathetic input evokes opposing
responses.
In various disease states (organ
malfunctions), drugs are employed with
the intention of normalizing susceptible
organ functions. To understand the biological
effects of substances capable of
inhibiting or exciting sympathetic or
parasympathetic nerves, one must first
envisage the functions subserved by the
sympathetic and parasympathetic divisions
(A, Responses to sympathetic activation).
In simplistic terms, activation
of the sympathetic division can be considered
a means by which the body
achieves a state of maximal work capacity
as required in fight or flight situations.
In both cases, there is a need for
vigorous activity of skeletal musculature.
To ensure adequate supply of oxygen
and nutrients, blood flow in skeletal
muscle is increased; cardiac rate and
contractility are enhanced, resulting in a
larger blood volume being pumped into
the circulation. Narrowing of splanchnic
blood vessels diverts blood into vascular
beds in muscle.
Because digestion of food in the intestinal
tract is dispensable and only
counterproductive, the propulsion of intestinal
contents is slowed to the extent
that peristalsis diminishes and sphincteric
tonus increases. However, in order
to increase nutrient supply to heart and
musculature, glucose from the liver and
free fatty acid from adipose tissue must
be released into the blood. The bronchi
are dilated, enabling tidal volume and
alveolar oxygen uptake to be increased.
Sweat glands are also innervated by
sympathetic fibers (wet palms due to
excitement); however, these are exceptional
as regards their neurotransmitter
(ACh).
Although the life styles of modern
humans are different from those of
hominid ancestors, biological functions
have remained the same.

Structure of the Sympathetic Nervous
System

The sympathetic preganglionic neurons
(first neurons) project from the intermediolateral
column of the spinal gray
matter to the paired paravertebral ganglionic
chain lying alongside the vertebral
column and to unpaired prevertebral
ganglia. These ganglia represent
sites of synaptic contact between preganglionic
axons (1st neurons) and
nerve cells (2nd neurons or sympathocytes)
that emit postganglionic axons
terminating on cells in various end organs.
In addition, there are preganglionic
neurons that project either to peripheral
ganglia in end organs or to the adrenal
medulla.
Sympathetic Transmitter Substances
Whereas acetylcholine
serves as the chemical transmitter at
ganglionic synapses between first and
second neurons, norepinephrine
(= noradrenaline) is the mediator at
synapses of the second neuron (B). This
second neuron does not synapse with
only a single cell in the effector organ;
rather, it branches out, each branch
making en passant contacts with several
cells. At these junctions the nerve axons
form enlargements (varicosities) resembling
beads on a string. Thus, excitation
of the neuron leads to activation of
a larger aggregate of effector cells, although
the action of released norepinephrine
may be confined to the region
of each junction. Excitation of preganglionic
neurons innervating the adrenal
medulla causes a liberation of acetylcholine.
This, in turn, elicits a secretion
of epinephrine (= adrenaline) into the
blood, by which it is distributed to body
tissues as a hormone (A).
Adrenergic Synapse
Within the varicosities, norepinephrine
is stored in small membrane-enclosed
vesicles (granules, 0.05 to 0.2 μm in diameter).
In the axoplasm, L-tyrosine is
converted via two intermediate steps to
dopamine, which is taken up into the
vesicles and there converted to norepinephrine
by dopamine-!-hydroxylase.
When stimulated electrically, the sympathetic
nerve discharges the contents
of part of its vesicles, including norepinephrine,
into the extracellular space.
Liberated norepinephrine reacts with
adrenoceptors located postjunctionally
on the membrane of effector cells or
prejunctionally on the membrane of
varicosities. Activation of presynaptic
"2-receptors inhibits norepinephrine
release. By this negative feedback, release
can be regulated.
The effect of released norepinephrine
wanes quickly, because approx.
90 % is actively transported back into
the axoplasm, then into storage vesicles
(neuronal re-uptake). Small portions of
norepinephrine are inactivated by the
enzyme catechol-O-methyltransferase
(COMT, present in the cytoplasm of
postjunctional cells, to yield normetanephrine),
and monoamine oxidase
(MAO, present in mitochondria of nerve
cells and postjunctional cells, to yield
3,4-dihydroxymandelic acid).
The liver is richly endowed with
COMT and MAO; it therefore contributes
significantly to the degradation of
circulating norepinephrine and epinephrine.
The end product of the combined
actions of MAO and COMT is vanillylmandelic
acid.


Adrenoceptor Subtypes and Catecholamine Actions
Adrenoceptors fall into three major
groups, designated !1, !2, and ", within
each of which further subtypes can be
distinguished pharmacologically. The
different adrenoceptors are differentially
distributed according to region and
tissue. Agonists at adrenoceptors (direct
sympathomimetics) mimic the actions
of the naturally occurring catecholamines,
norepinephrine and epinephrine,
and are used for various therapeutic
effects.
Smooth muscle effects. The opposing
effects on smooth muscle (A) of
!-and "-adrenoceptor activation are
due to differences in signal transduction.
This is exemplified by vascular
smooth muscle (A). !1-Receptor stimulation
leads to intracellular release of
Ca2+ via activation of the inositol trisphosphate
(IP3) pathway. In concert
with the protein calmodulin, Ca2+ can
activate myosin kinase, leading to a rise
in tonus via phosphorylation of the contractile
protein myosin. cAMP inhibits
activation of myosin kinase. Via the former
effector pathway, stimulation of !-
receptors results in vasoconstriction;
via the latter, "2-receptors mediate vasodilation,
particularly in skeletal muscle
— an effect that has little therapeutic
use.
Vasoconstriction. Local application of
!-sympathomimetics can be employed
in infiltration anesthesia or for
nasal decongestion (naphazoline, tetrahydrozoline,
xylometazoline).
Systemically administered epinephrine
is important in the treatment
of anaphylactic shock for combating hypotension.
Bronchodilation. "2-Adrenoceptor-
mediated bronchodilation (e.g., with
terbutaline, fenoterol, or salbutamol)
plays an essential part in the treatment
of bronchial asthma.
Tocolysis. The uterine relaxant effect
of "2-adrenoceptor agonists, such as
terbutaline or fenoterol, can be used to
prevent premature labor. Vasodilation
with a resultant drop in systemic blood
pressure results in reflex tachycardia,
which is also due in part to the "1-stimulant
action of these drugs.
Cardiostimulation. By stimulating
"1-receptors, hence activation of adenylatcyclase
(Ad-cyclase) and cAMP
production, catecholamines augment all
heart functions, including systolic force
(positive inotropism), velocity of shortening
(p. clinotropism), sinoatrial rate
(p. chronotropism), conduction velocity
(p. dromotropism), and excitability (p.
bathmotropism). In pacemaker fibers,
diastolic depolarization is hastened, so
that the firing threshold for the action
potential is reached sooner (positive
chronotropic effect, B). The cardiostimulant
effect of "-sympathomimetics
such as epinephrine is exploited in the
treatment of cardiac arrest. Use of "-
sympathomimetics in heart failure carries
the risk of cardiac arrhythmias.
Metabolic effects. "-Receptors mediate
increased conversion of glycogen to
glucose (glycogenolysis) in both liver
and skeletal muscle. From the liver, glucose
is released into the blood, In adipose
tissue, triglycerides are hydrolyzed
to fatty acids (lipolysis, mediated by "3-
receptors), which then enter the blood
(C). The metabolic effects of catecholamines
are not amenable to therapeutic
use.


Structure – Activity Relationships of
Sympathomimetics

Due to its equally high affinity for all !-
and "-receptors, epinephrine does not
permit selective activation of a particular
receptor subtype. Like most catecholamines,
it is also unsuitable for oral
administration (catechol is a trivial
name for o-hydroxyphenol). Norepinephrine
differs from epinephrine by its
high affinity for !-receptors and low affinity
for "2-receptors. In contrast, isoproterenol
has high affinity for "-receptors,
but virtually none for !-receptors
(A).
norepinephrine ! !, "1
epinephrine ! !, "1, "2
isoproterenol ! "1, "2
Knowledge of structure–activity
relationships has permitted the synthesis
of sympathomimetics that display
a high degree of selectivity at
adrenoceptor subtypes.
Direct-acting sympathomimetics
(i.e., adrenoceptor agonists) typically
share a phenylethylamine structure. The
side chain "-hydroxyl group confers affinity
for !- and "-receptors. Substitution
on the amino group reduces affinity
for !-receptors, but increases it for "-receptors
(exception: !-agonist phenylephrine),
with optimal affinity being
seen after the introduction of only one
isopropyl group. Increasing the bulk of
the amino substituent favors affinity for
"2-receptors (e.g., fenoterol, salbutamol).
Both hydroxyl groups on the aromatic
nucleus contribute to affinity;
high activity at !-receptors is associated
with hydroxyl groups at the 3 and 4 positions.
Affinity for "-receptors is preserved
in congeners bearing hydroxyl
groups at positions 3 and 5 (orciprenaline,
terbutaline, fenoterol).
The hydroxyl groups of catecholamines
are responsible for the very low
lipophilicity of these substances. Polarity
is increased at physiological pH due
to protonation of the amino group. Deletion
of one or all hydroxyl groups improves
membrane penetrability at the
intestinal mucosa-blood and the bloodbrain
barriers. Accordingly, these noncatecholamine
congeners can be given
orally and can exert CNS actions; however,
this structural change entails a loss
in affinity.
Absence of one or both aromatic
hydroxyl groups is associated with an
increase in indirect sympathomimetic
activity, denoting the ability of a substance
to release norepinephrine from
its neuronal stores without exerting an
agonist action at the adrenoceptor.
An altered position of aromatic hydroxyl
groups (e.g., in orciprenaline, fenoterol,
or terbutaline) or their substitution
(e.g., salbutamol) protects
against inactivation by COMT. Indroduction
of a small alkyl residue at
the carbon atom adjacent to the amino
group (ephedrine, methamphetamine)
confers resistance to degradation by
MAO, as does replacement on the
amino groups of the methyl residue
with larger substituents (e.g., ethyl in
etilefrine). Accordingly, the congeners
are less subject to presystemic inactivation.
Since structural requirements for
high affinity, on the one hand, and oral
applicability, on the other, do not
match, choosing a sympathomimetic is
a matter of compromise. If the high affinity
of epinephrine is to be exploited,
absorbability from the intestine must be
foregone (epinephrine, isoprenaline). If
good bioavailability with oral administration
is desired, losses in receptor affinity
must be accepted (etilefrine).


Indirect Sympathomimetics
Apart from receptors, adrenergic neurotransmission
involves mechanisms
for the active re-uptake and re-storage
of released amine, as well as enzymatic
breakdown by monoamine oxidase
(MAO). Norepinephrine (NE) displays
affinity for receptors, transport systems,
and degradative enzymes. Chemical alterations
of the catecholamine differentially
affect these properties and result
in substances with selective actions.
Inhibitors of MAO (A). The enzyme
is located predominantly on mitochondria,
and serves to scavenge axoplasmic
free NE. Inhibition of the enzyme causes
free NE concentrations to rise. Likewise,
dopamine catabolism is impaired, making
more of it available for NE synthesis.
Consequently, the amount of NE stored
in granular vesicles will increase, and
with it the amount of amine released
per nerve impulse.
In the CNS, inhibition of MAO affects
neuronal storage not only of NE
but also of dopamine and serotonin.
These mediators probably play significant
roles in CNS functions consistent
with the stimulant effects of MAO inhibitors
on mood and psychomotor drive
and their use as antidepressants in the
treatment of depression (A). Tranylcypromine
is used to treat particular forms
of depressive illness; as a covalently
bound suicide substrate, it causes longlasting
inhibition of both MAO isozymes,
(MAOA, MAOB). Moclobemide reversibly
inhibits MAOA and is also used
as an antidepressant. The MAOB inhibitor
selegiline (deprenyl) retards the catobolism
of dopamine, an effect used in
the treatment of parkinsonism.
Indirect sympathomimetics (B)
are agents that elevate the concentration
of NE at neuroeffector junctions,
because they either inhibit re-uptake
(cocaine), facilitate release, or slow
breakdown by MAO, or exert all three of
these effects (amphetamine, methamphetamine).
The effectiveness of such
indirect sympathomimetics diminishes
or disappears (tachyphylaxis) when vesicular
stores of NE close to the axolemma
are depleted.
Indirect sympathomimetics can
penetrate the blood-brain barrier and
evoke such CNS effects as a feeling of
well-being, enhanced physical activity
and mood (euphoria), and decreased
sense of hunger or fatigue. Subsequently,
the user may feel tired and depressed.
These after effects are partly
responsible for the urge to re-administer
the drug (high abuse potential). To
prevent their misuse, these substances
are subject to governmental regulations
(e.g., Food and Drugs Act: Canada; Controlled
Drugs Act: USA) restricting their
prescription and distribution.
When amphetamine-like substances
are misused to enhance athletic performance
(doping), there is a risk of dangerous
physical overexertion. Because
of the absence of a sense of fatigue, a
drugged athlete may be able to mobilize
ultimate energy reserves. In extreme
situations, cardiovascular failure may
result (B).
Closely related chemically to amphetamine
are the so-called appetite
suppressants or anorexiants, such as
fenfluramine, mazindole, and sibutramine.
These may also cause dependence
and their therapeutic value and safety
are questionable.


!-Sympathomimetics,
!-Sympatholytics
!-Sympathomimetics can be used
systemically in certain types of hypotension
and locally for nasal or conjunctival
decongestion or
as adjuncts in infiltration anesthesia
for the purpose of delaying the removal
of local anesthetic. With local
use, underperfusion of the vasoconstricted
area results in a lack of oxygen
(A). In the extreme case, local hypoxia
can lead to tissue necrosis. The appendages
(e.g., digits, toes, ears) are particularly
vulnerable in this regard, thus precluding
vasoconstrictor adjuncts in infiltration
anesthesia at these sites.
Vasoconstriction induced by an !-
sympathomimetic is followed by a
phase of enhanced blood flow (reactive
hyperemia, A). This reaction can be observed
after the application of !-sympathomimetics
(naphazoline, tetrahydrozoline,
xylometazoline) to the nasal mucosa.
Initially, vasoconstriction reduces
mucosal blood flow and, hence, capillary
pressure. Fluid exuded into the
interstitial space is drained through the
veins, thus shrinking the nasal mucosa.
Due to the reduced supply of fluid, secretion
of nasal mucus decreases. In coryza,
nasal patency is restored. However,
after vasoconstriction subsides, reactive
hyperemia causes renewed exudation
of plasma fluid into the interstitial
space, the nose is “stuffy” again, and the
patient feels a need to reapply decongestant.
In this way, a vicious cycle
threatens. Besides rebound congestion,
persistent use of a decongestant entails
the risk of atrophic damage caused by
prolonged hypoxia of the nasal mucosa.
!-Sympatholytics (B). The interaction
of norepinephrine with !-adrenoceptors
can be inhibited by !-sympatholytics
( !-adrenoceptor antagonists, !-
blockers). This inhibition can be put to
therapeutic use in antihypertensive
treatment (vasodilation ! peripheral
resistance ", blood pressure ").
The first !-sympatholytics blocked the
action of norepinephrine at both postand
prejunctional !-adrenoceptors
(non-selective !-blockers, e.g., phenoxybenzamine,
phentolamine).
Presynaptic !2-adrenoceptors function
like sensors that enable norepinephrine
concentration outside the
axolemma to be monitored, thus regulating
its release via a local feedback
mechanism. When presynaptic !2-receptors
are stimulated, further release
of norepinephrine is inhibited. Conversely,
their blockade leads to uncontrolled
release of norepinephrine with
an overt enhancement of sympathetic
effects at #1-adrenoceptor-mediated
myocardial neuroeffector junctions, resulting
in tachycardia and tachyarrhythmia.
Selective !-Sympatholytics
!-Blockers, such as prazosin, or the
longer-acting terazosin and doxazosin,
lack affinity for prejunctional !2-adrenoceptors.
They suppress activation of
!1-receptors without a concomitant enhancement
of norepinephrine release.
!1-Blockers may be used in hypertension.
Because they prevent
reflex vasoconstriction, they are likely
to cause postural hypotension with
pooling of blood in lower limb capacitance
veins during change from the supine
to the erect position (orthostatic
collapse: " venous return, " cardiac output,
fall in systemic pressure, " blood
supply to CNS, syncope).
In benign hyperplasia of the prostate,
!-blockers (terazosin, alfuzosin)
may serve to lower tonus of smooth
musculature in the prostatic region and
thereby facilitate micturition.




!-Sympatholytics (!-Blockers)
!-Sympatholytics are antagonists of
norepiphephrine and epinephrine at !-
adrenoceptors; they lack affinity for "-
receptors.
Therapeutic effects. !-Blockers
protect the heart from the oxygenwasting
effect of sympathetic inotropism
(p. 306) by blocking cardiac !-receptors;
thus, cardiac work can no longer
be augmented above basal levels (the
heart is “coasting”). This effect is utilized
prophylactically in angina pectoris
to prevent myocardial stress that could
trigger an ischemic attack (p. 308, 310).
!-Blockers also serve to lower cardiac
rate (sinus tachycardia, p. 134) and elevated
blood pressure due to high cardiac
output (p. 312). The mechanism underlying
their antihypertensive action via
reduction of peripheral resistance is unclear.
Applied topically to the eye, !-
blockers are used in the management of
glaucoma; they lower production of
aqueous humor without affecting its
drainage.
Undesired effects. The hazards of
treatment with !-blockers become apparent
particularly when continuous
activation of !-receptors is needed in
order to maintain the function of an organ.
Congestive heart failure: In myocardial
insufficiency, the heart depends on
a tonic sympathetic drive to maintain
adequate cardiac output. Sympathetic
activation gives rise to an increase in
heart rate and systolic muscle tension,
enabling cardiac output to be restored
to a level comparable to that in a
healthy subject. When sympathetic
drive is eliminated during !-receptor
blockade, stroke volume and cardiac
rate decline, a latent myocardial insufficiency
is unmasked, and overt insufficiency
is exacerbated (A).
On the other hand, clinical evidence
suggests that !-blockers produce favorable
effects in certain forms of congestive
heart failure (idiopathic dilated cardiomyopathy).
Bradycardia, A-V block: Elimination
of sympathetic drive can lead to a
marked fall in cardiac rate as well as to
disorders of impulse conduction from
the atria to the ventricles.
Bronchial asthma: Increased sympathetic
activity prevents bronchospasm
in patients disposed to paroxysmal
constriction of the bronchial tree
(bronchial asthma, bronchitis in smokers).
In this condition, !2-receptor
blockade will precipitate acute respiratory
distress (B).
Hypoglycemia in diabetes mellitus:
When treatment with insulin or oral hypoglycemics
in the diabetic patient lowers
blood glucose below a critical level,
epinephrine is released, which then
stimulates hepatic glucose release via
activation of !2-receptors. !-Blockers
suppress this counter-regulation; in addition,
they mask other epinephrinemediated
warning signs of imminent
hypoglycemia, such as tachycardia and
anxiety, thereby enhancing the risk of
hypoglycemic shock.
Altered vascular responses: When
!2-receptors are blocked, the vasodilating
effect of epinephrine is abolished,
leaving the "-receptor-mediated vasoconstriction
unaffected: peripheral
blood flow # – “cold hands and feet”.
!-Blockers exert an “anxiolytic“
action that may be due to the suppression
of somatic responses (palpitations,
trembling) to epinephrine release that
is induced by emotional stress; in turn,
these would exacerbate “anxiety” or
“stage fright”. Because alertness is not
impaired by !-blockers, these agents are
occasionally taken by orators and musicians
before a major performance (C).
Stage fright, however, is not a disease
requiring drug therapy.



Types of !-Blockers
The basic structure shared by most !-
sympatholytics is the side chain of !-
sympathomimetics (cf. isoproterenol
with the !-blockers propranolol, pindolol,
atenolol). As a rule, this basic structure
is linked to an aromatic nucleus by
a methylene and oxygen bridge. The
side chain C-atom bearing the hydroxyl
group forms the chiral center. With
some exceptions (e.g., timolol, penbutolol),
all !-sympatholytics are brought as
racemates into the market (p. 62).
Compared with the dextrorotatory
form, the levorotatory enantiomer possesses
a greater than 100-fold higher affinity
for the !-receptor and is, therefore,
practically alone in contributing to
the !-blocking effect of the racemate.
The side chain and substituents on the
amino group critically affect affinity for
!-receptors, whereas the aromatic nucleus
determines whether the compound
possess intrinsic sympathomimetic
activity (ISA), that is, acts as a
partial agonist (p. 60) or partial antagonist.
In the presence of a partial agonist
(e.g., pindolol), the ability of a full agonist
(e.g., isoprenaline) to elicit a maximal
effect would be attenuated, because
binding of the full agonist is impeded.
However, the !-receptor at which such
partial agonism can be shown appears
to be atypical (!3 or !4 subtype). Whether
ISA confers a therapeutic advantage
on a !-blocker remains an open question.
As cationic amphiphilic drugs, !-
blockers can exert a membrane-stabilizing
effect, as evidenced by the ability
of the more lipophilic congeners to inhibit
Na+-channel function and impulse
conduction in cardiac tissues. At the
usual therapeutic dosage, the high concentration
required for these effects will
not be reached.
Some !-sympatholytics possess
higher affinity for cardiac !1-receptors
than for !2-receptors and thus display
cardioselectivity (e.g., metoprolol, acebutolol,
bisoprolol). None of these
blockers is sufficiently selective to permit
its use in patients with bronchial
asthma or diabetes mellitus (p. 92).
The chemical structure of !-blockers
also determines their pharmacokinetic
properties. Except for hydrophilic
representatives (atenolol), !-sympatholytics
are completely absorbed from the
intestines and subsequently undergo
presystemic elimination to a major extent
(A).
All the above differences are of
little clinical importance. The abundance
of commercially available congeners
would thus appear all the more curious
(B). Propranolol was the first !-blocker
to be introduced into therapy in 1965.
Thirty-five years later, about 20 different
congeners are being marketed in different
countries. This questionable development
unfortunately is typical of any
drug group that has major therapeutic
relevance, in addition to a relatively
fixed active structure. Variation of the
molecule will create a new patentable
chemical, not necessarily a drug with a
novel action. Moreover, a drug no longer
protected by patent is offered as a generic
by different manufacturers under dozens
of different proprietary names.
Propranolol alone has been marketed by
13 manufacturers under 11 different
names.



Antiadrenergics
Antiadrenergics are drugs capable of
lowering transmitter output from sympathetic
neurons, i.e., “sympathetic
tone”. Their action is hypotensive (indication:
hypertension, p. 312); however,
being poorly tolerated, they enjoy only
limited therapeutic use.
Clonidine is an !2-agonist whose
high lipophilicity (dichlorophenyl ring)
permits rapid penetration through the
blood-brain barrier. The activation of
postsynaptic !2-receptors dampens the
activity of vasomotor neurons in the
medulla oblongata, resulting in a resetting
of systemic arterial pressure at a
lower level. In addition, activation of
presynaptic !2-receptors in the periphery
(pp. 82, 90) leads to a decreased release
of both norepinephrine (NE) and
acetylcholine.
Side effects. Lassitude, dry mouth;
rebound hypertension after abrupt cessation
of clonidine therapy.
Methyldopa (dopa = dihydroxyphenylalanine),
as an amino acid, is
transported across the blood-brain barrier,
decarboxylated in the brain to !-
methyldopamine, and then hydroxylated
to !-methyl-NE. The decarboxylation
of methyldopa competes for a portion of
the available enzymatic activity, so that
the rate of conversion of L-dopa to NE
(via dopamine) is decreased. The false
transmitter !-methyl-NE can be stored;
however, unlike the endogenous mediator,
it has a higher affinity for !2- than
for !1-receptors and therefore produces
effects similar to those of clonidine. The
same events take place in peripheral adrenergic
neurons.
Adverse effects. Fatigue, orthostatic
hypotension, extrapyramidal Parkinson-
like symptoms (p. 88), cutaneous
reactions, hepatic damage, immune-hemolytic
anemia.
Reserpine, an alkaloid from the
Rauwolfia plant, abolishes the vesicular
storage of biogenic amines (NE, dopamine
= DA, serotonin = 5-HT) by inhibiting
an ATPase required for the vesicular
amine pump. The amount of NE released
per nerve impulse is decreased.
To a lesser degree, release of epinephrine
from the adrenal medulla is also
impaired. At higher doses, there is irreversible
damage to storage vesicles
(“pharmacological sympathectomy”),
days to weeks being required for their
resynthesis. Reserpine readily enters
the brain, where it also impairs vesicular
storage of biogenic amines.
Adverse effects. Disorders of extrapyramidal
motor function with development
of pseudo-Parkinsonism (p. 88),
sedation, depression, stuffy nose, impaired
libido, and impotence; increased
appetite. These adverse effects have
rendered the drug practically obsolete.
Guanethidine possesses high affinity
for the axolemmal and vesicular
amine transporters. It is stored instead
of NE, but is unable to mimic the functions
of the latter. In addition, it stabilizes
the axonal membrane, thereby impeding
the propagation of impulses into
the sympathetic nerve terminals. Storage
and release of epinephrine from the
adrenal medulla are not affected, owing
to the absence of a re-uptake process.
The drug does not cross the blood-brain
barrier.
Adverse effects. Cardiovascular crises
are a possible risk: emotional stress
of the patient may cause sympathoadrenal
activation with epinephrine release.
The resulting rise in blood pressure
can be all the more marked because
persistent depression of sympathetic
nerve activity induces supersensitivity
of effector organs to circulating
catecholamines.

Drug-independent Effects II

Homeopathy is an alternative
method of therapy, developed in the
1800s by Samuel Hahnemann. His idea
was this: when given in normal (allopathic)
dosage, a drug (in the sense of
medicament) will produce a constellation
of symptoms; however, in a patient
whose disease symptoms resemble just
this mosaic of symptoms, the same drug
(simile principle) would effect a cure
when given in a very low dosage (“potentiation”).
The body’s self-healing
powers were to be properly activated
only by minimal doses of the medicinal
substance.
The homeopath’s task is not to diagnose
the causes of morbidity, but to
find the drug with a “symptom profile”
most closely resembling that of the
patient’s illness. This drug is then applied
in very high dilution.
A direct action or effect on body
functions cannot be demonstrated for
homeopathic medicines. Therapeutic
success is due to the suggestive powers
of the homeopath and the expectancy of
the patient. When an illness is strongly
influenced by emotional (psychic) factors
and cannot be treated well by allopathic
means, a case can be made in favor
of exploiting suggestion as a therapeutic
tool. Homeopathy is one of several
possible methods of doing so.

Drug-independent Effects I

Placebo
A placebo is a dosage form devoid of an
active ingredient, a dummy medication.
Administration of a placebo may elicit
the desired effect (relief of symptoms)
or undesired effects that reflect a
change in the patient’s psychological
situation brought about by the therapeutic
setting.
Physicians may consciously or unconsciously
communicate to the patient
whether or not they are concerned
about the patient’s problem, or certain
about the diagnosis and about the value
of prescribed therapeutic measures. In
the care of a physician who projects
personal warmth, competence, and confidence,
the patient in turn feels comfortable
and less anxious and optimistically
anticipates recovery.
The physical condition determines
the psychic disposition and vice versa.
Consider gravely wounded combatants
in war, oblivious to their injuries while
fighting to survive, only to experience
severe pain in the safety of the field hospital,
or the patient with a peptic ulcer
caused by emotional stress.
Clinical trials. In the individual
case, it may be impossible to decide
whether therapeutic success is attributable
to the drug or to the therapeutic
situation. What is therefore required is a
comparison of the effects of a drug and
of a placebo in matched groups of patients
by means of statistical procedures,
i.e., a placebo-controlled trial. A
prospective trial is planned in advance, a
retrospective (case-control) study follows
patients backwards in time. Patients
are randomly allotted to two
groups, namely, the placebo and the active
or test drug group. In a double-blind
trial, neither the patients nor the treating
physicians know which patient is
given drug and which placebo. Finally, a
switch from drug to placebo and vice
versa can be made in a successive phase
of treatment, the cross-over trial. In this
fashion, drug vs. placebo comparisons
can be made not only between two patient
groups, but also within either
group itself.

Adverse Drug Effects V

Drug Toxicity in Pregnancy and
Lactation
Drugs taken by the mother can be
passed on transplacentally or via breast
milk and adversely affect the unborn or
the neonate.
Pregnancy
Limb malformations induced by the
hypnotic, thalidomide, first focused attention
on the potential of drugs to
cause malformations (teratogenicity).
Drug effects on the unborn fall into two
basic categories:
1. Predictable effects that derive from
the known pharmacological drug
properties. Examples are: masculinization
of the female fetus by androgenic
hormones; brain hemorrhage
due to oral anticoagulants; bradycardia
due to !-blockers.
2. Effects that specifically affect the developing
organism and that cannot
be predicted on the basis of the
known pharmacological activity profile.
In assessing the risks attending
drug use during pregnancy, the following
points have to be considered:
a) Time of drug use. The possible sequelae
of exposure to a drug depend on
the stage of fetal development, as
shown in A. Thus, the hazard posed
by a drug with a specific action is limited
in time, as illustrated by the tetracyclines,
which produce effects on
teeth and bones only after the third
month of gestation, when mineralization
begins.
b) Transplacental passage. Most drugs
can pass in the placenta from the maternal
into the fetal circulation. The
fused cells of the syncytiotrophoblast
form the major diffusion barrier.
They possess a higher permeability to
drugs than is suggested by the term
“placental barrier”.
c) Teratogenicity. Statistical risk estimates
are available for familiar, frequently
used drugs. For many drugs,
teratogenic potency cannot be demonstrated;
however, in the case of
novel drugs it is usually not yet possible
to define their teratogenic hazard.
Drugs with established human teratogenicity
include derivatives of vitamin
A (etretinate, isotretinoin [used
internally in skin diseases]), and oral
anticoagulants. A peculiar type of damage
results from the synthetic estrogenic
agent, diethylstilbestrol, following its
use during pregnancy; daughters of
treated mothers have an increased incidence
of cervical and vaginal carcinoma
at the age of approx. 20.
In assessing the risk: benefit ratio, it is
also necessary to consider the benefit
for the child resulting from adequate
therapeutic treatment of its mother. For
instance, therapy with antiepileptic
drugs is indispensable, because untreated
epilepsy endangers the infant at least
as much as does administration of anticonvulsants.
Lactation
Drugs present in the maternal organism
can be secreted in breast milk and thus
be ingested by the infant. Evaluation of
risk should be based on factors listed in
B. In case of doubt, potential danger to
the infant can be averted only by weaning.

Adverse Drug Effects IV

Type 2, cytotoxic reaction. Drugantibody
(IgG) complexes adhere to the
surface of blood cells, where either circulating
drug molecules or complexes already
formed in blood accumulate.
These complexes mediate the activation
of complement, a family of proteins that
circulate in the blood in an inactive
form, but can be activated in a cascadelike
succession by an appropriate stimulus.
“Activated complement” normally
directed against microorganisms, can
destroy the cell membranes and thereby
cause cell death; it also promotes phagocytosis,
attracts neutrophil granulocytes
(chemotaxis), and stimulates other
inflammatory responses. Activation
of complement on blood cells results in
their destruction, evidenced by hemolytic
anemia, agranulocytosis, and
thrombocytopenia.
Type 3, immune complex vasculitis
(serum sickness, Arthus reaction).
Drug-antibody complexes precipitate on
vascular walls, complement is activated,
and an inflammatory reaction is triggered.
Attracted neutrophils, in a futile
attempt to phagocytose the complexes,
liberate lysosomal enzymes that damage
the vascular walls
. Symptoms may include fever,
exanthema, swelling of lymph
nodes, arthritis, nephritis, and neuropathy.
Type 4, contact dermatitis. A cutaneously
applied drug is bound to the
surface of T-lymphocytes directed specifically
against it. The lymphocytes release
signal molecules (lymphokines)
into their vicinity that activate macrophages
and provoke an inflammatory
reaction.

Adverse Drug Effects III

Drug Allergy
The immune system normally functions
to rid the organism of invading foreign
particles, such as bacteria. Immune responses
can occur without appropriate
cause or with exaggerated intensity and
may harm the organism, for instance,
when allergic reactions are caused by
drugs (active ingredient or pharmaceutical
excipients). Only a few drugs, e.g.
(heterologous) proteins, have a molecular
mass (> 10,000) large enough to act
as effective antigens or immunogens,
capable by themselves of initiating an
immune response. Most drugs or their
metabolites (so-called haptens) must
first be converted to an antigen by linkage
to a body protein. In the case of penicillin
G, a cleavage product (penicilloyl
residue) probably undergoes covalent
binding to protein. During initial contact
with the drug, the immune system
is sensitized: antigen-specific lymphocytes
of the T-type and B-type (antibody
formation) proliferate in lymphatic tissue
and some of them remain as socalled
memory cells. Usually, these processes
remain clinically silent. During
the second contact, antibodies are already
present and memory cells proliferate
rapidly. A detectable immune response,
the allergic reaction, occurs.
This can be of severe intensity, even at a
low dose of the antigen. Four types of
reactions can be distinguished:
Type 1, anaphylactic reaction.
Drug-specific antibodies of the IgE type
combine via their Fc moiety with receptors
on the surface of mast cells. Binding
of the drug provides the stimulus for the
release of histamine and other mediators.
In the most severe form, a lifethreatening
anaphylactic shock develops,
accompanied by hypotension,
bronchospasm (asthma attack), laryngeal
edema, urticaria, stimulation of gut
musculature, and spontaneous bowel
movements .

Adverse Drug Effects II

Increased Sensitivity . If certain
body functions develop hyperreactivity,
unwanted effects can occur even at normal
dose levels. Increased sensitivity of
the respiratory center to morphine is
found in patients with chronic lung disease,
in neonates, or during concurrent
exposure to other respiratory depressant
agents. The DRC is shifted to the left
and a smaller dose of morphine is sufficient
to paralyze respiration. Genetic
anomalies of metabolism may also lead
to hypersensitivity. Thus, several drugs
(aspirin, antimalarials, etc.) can provoke
premature breakdown of red blood cells
(hemolysis) in subjects with a glucose-
6-phosphate dehydrogenase deficiency.
The discipline of pharmacogenetics deals
with the importance of the genotype for
reactions to drugs.
The above forms of hypersensitivity
must be distinguished from allergies involving
the immune system .
Lack of selectivity . Despite appropriate
dosing and normal sensitivity,
undesired effects can occur because the
drug does not specifically act on the targeted
(diseased) tissue or organ. For instance,
the anticholinergic, atropine, is
bound only to acetylcholine receptors of
the muscarinic type; however, these are
present in many different organs.
Moreover, the neuroleptic, chlorpromazine,
formerly used as a neuroleptic,
is able to interact with several
different receptor types. Thus, its action
is neither organ-specific nor receptorspecific.
The consequences of lack of selectivity
can often be avoided if the drug
does not require the blood route to
reach the target organ, but is, instead,
applied locally, as in the administration
of parasympatholytics in the form of eye
drops or in an aerosol for inhalation.
With every drug use, unwanted effects
must be taken into account. Before
prescribing a drug, the physician should
therefore assess the risk: benefit ratio.

Adverse Drug Effects I

Adverse Drug Effects
The desired (or intended) principal effect
of any drug is to modify body function
in such a manner as to alleviate
symptoms caused by the patient’s illness.
In addition, a drug may also cause
unwanted effects that can be grouped
into minor or “side” effects and major or
adverse effects. These, in turn, may give
rise to complaints or illness, or may
even cause death.
Causes of adverse effects: overdosage
. The drug is administered in
a higher dose than is required for the
principal effect; this directly or indirectly
affects other body functions. For instances,
morphine , given in the
appropriate dose, affords excellent pain
relief by influencing nociceptive pathways
in the CNS. In excessive doses, it
inhibits the respiratory center and
makes apnea imminent. The dose dependence
of both effects can be graphed
in the form of dose-response curves
(DRC). The distance between both DRCs
indicates the difference between the
therapeutic and toxic doses. This margin
of safety indicates the risk of toxicity
when standard doses are exceeded.
“The dose alone makes the poison”
(Paracelsus). This holds true for both
medicines and environmental poisons.
No substance as such is toxic! In order to
assess the risk of toxicity, knowledge is
required of) the effective dose during
exposure) the dose level at which
damage is likely to occur) the duration
of exposure.

Drug-Receptor Interaction IX

Time Course of Plasma Concentration
and Effect
After the administration of a drug, its
concentration in plasma rises, reaches a
peak, and then declines gradually to the
starting level, due to the processes of
distribution and elimination.
Plasma concentration at a given point in
time depends on the dose administered.
Many drugs exhibit a linear relationship
between plasma concentration and
dose within the therapeutic range
(dose-linear kinetic ; note different
scales on ordinate). However, the
same does not apply to drugs whose
elimination processes are already sufficiently
activated at therapeutic plasma
levels so as to preclude further proportional
increases in the rate of elimination
when the concentration is increased
further. Under these conditions,
a smaller proportion of the dose administered
is eliminated per unit of time.
The time course of the effect and of
the concentration in plasma are not
identical, because the concentrationeffect
relationships obeys a hyperbolic
function. This means
that the time course of the effect exhibits
dose dependence also in the presence
of dose-linear kinetics .
In the lower dose range (example
1), the plasma level passes through a
concentration range (0 ! 0.9) in which
the concentration effect relationship is
quasi-linear. The respective time courses
of plasma concentration and effect
are very similar.
However, if a high dose (100) is applied,
there is an extended period of time during
which the plasma level will remain
in a concentration range (between 90
and 20) in which a change in concentration
does not cause a change in the size
of the effect. Thus, at high doses (100),
the time-effect curve exhibits a kind of
plateau. The effect declines only when
the plasma level has returned (below
20) into the range where a change in
plasma level causes a change in the intensity
of the effect.
The dose dependence of the time
course of the drug effect is exploited
when the duration of the effect is to be
prolonged by administration of a dose
in excess of that required for the effect.
This is done in the case of penicillin G
, when a dosing interval of 8 h is
being recommended, although the drug
is eliminated with a half-life of 30 min.
This procedure is, of course, feasible only
if supramaximal dosing is not associated
with toxic effects.
Futhermore it follows that a nearly
constant effect can be achieved, although
the plasma level may fluctuate
greatly during the interval between
doses.
The hyperbolic relationship be
tween plasma concentration and effect
explains why the time course of the effect,
unlike that of the plasma concentration,
cannot be described in terms of
a simple exponential function. A halflife
can be given for the processes of
drug absorption and elimination, hence
for the change in plasma levels, but generally
not for the onset or decline of
the effect.

Drug-Receptor Interaction VIII

Mode of Operation of G-Protein-
Coupled Receptors
Signal transduction at G-protein-coupled
receptors uses essentially the same
basic mechanisms . Agonist binding
to the receptor leads to a change in receptor
protein conformation. This
change propagates to the G-protein: the
!-subunit exchanges GDP for GTP, then
dissociates from the two other subunits,
associates with an effector protein, and
alters its functional state. The !-subunit
slowly hydrolyzes bound GTP to GDP.
G!-GDP has no affinity for the effector
protein and reassociates with the " and
subunits . G-proteins can undergo
lateral diffusion in the membrane; they
are not assigned to individual receptor
proteins. However, a relation exists
between receptor types and G-protein
types . Furthermore, the !-subunits
of individual G-proteins are distinct in
terms of their affinity for different effector
proteins, as well as the kind of influence
exerted on the effector protein. G-
GTP of the GS-protein stimulates adenylate
cyclase, whereas G-GTP of the Giprotein
is inhibitory. The G-proteincoupled
receptor family includes muscarinic
cholinoceptors, adrenoceptors
for norepinephrine and epinephrine, receptors
for dopamine, histamine, serotonin,
glutamate, GABA, morphine, prostaglandins,
leukotrienes, and many other
mediators and hormones.
Major effector proteins for G-protein-
coupled receptors include adenylate
cyclase (ATP ! intracellular messenger
cAMP), phospholipase C (phosphatidylinositol
intracellular messengers
inositol trisphosphate and diacylglycerol),
as well as ion channel
proteins. Numerous cell functions are
regulated by cellular cAMP concentration,
because cAMP enhances activity of
protein kinase A, which catalyzes the
transfer of phosphate groups onto functional
proteins. Elevation of cAMP levels
inter alia leads to relaxation of smooth
muscle tonus and enhanced contractility
of cardiac muscle, as well as increased
glycogenolysis and lipolysis .
Phosphorylation of cardiac calcium-
channel proteins increases the
probability of channel opening during
membrane depolarization. It should be
noted that cAMP is inactivated by phosphodiesterase.
Inhibitors of this enzyme
elevate intracellular cAMP concentration
and elicit effects resembling those
of epinephrine.
The receptor protein itself may
undergo phosphorylation, with a resultant
loss of its ability to activate the associated
G-protein. This is one of the
mechanisms that contributes to a decrease
in sensitivity of a cell during prolonged
receptor stimulation by an agonist
(desensitization).
Activation of phospholipase C leads
to cleavage of the membrane phospholipid
phosphatidylinositol-4,5 bisphosphate
into inositol trisphosphate (IP3)
and diacylglycerol (DAG). IP3 promotes
release of Ca2+ from storage organelles,
whereby contraction of smooth muscle
cells, breakdown of glycogen, or exocytosis
may be initiated. Diacylglycerol
stimulates protein kinase C, which
phosphorylates certain serine- or threonine-
containing enzymes.
The subunit of some G-proteins
may induce opening of a channel protein.
In this manner, K+ channels can be
activated (e.g., ACh effect on sinus node,
; opioid action on neural impulse
transmission).

Drug-Receptor Interaction VII

The insulin receptor protein represents
a ligand-operated enzyme , a
catalytic receptor. When insulin binds
to the extracellular attachment site, a
tyrosine kinase activity is “switched on”
at the intracellular portion. Protein
phosphorylation leads to altered cell
function via the assembly of other signal
proteins. Receptors for growth hormones
also belong to the catalytic receptor
class.
Protein synthesis-regulating receptors
for steroids, thyroid hormone,
and retinoic acid are found in the
cytosol and in the cell nucleus, respectively.
Binding of hormone exposes a normally
hidden domain of the receptor
protein, thereby permitting the latter to
bind to a particular nucleotide sequence
on a gene and to regulate its transcription.
Transcription is usually initiated or
enhanced, rarely blocked.

Drug-Receptor Interaction VI

Receptor Types
Receptors are macromolecules that bind
mediator substances and transduce this
binding into an effect, i.e., a change in
cell function. Receptors differ in terms
of their structure and the manner in
which they translate occupancy by a ligand
into a cellular response (signal
transduction).
G-protein-coupled receptors
consist of an amino acid chain that
weaves in and out of the membrane in
serpentine fashion. The extramembranal
loop regions of the molecule may
possess sugar residues at different Nglycosylation
sites. The seven !-helical
membrane-spanning domains probably
form a circle around a central pocket
that carries the attachment sites for the
mediator substance. Binding of the mediator
molecule or of a structurally related
agonist molecule induces a change
in the conformation of the receptor protein,
enabling the latter to interact with
a G-protein (= guanyl nucleotide-binding
protein). G-proteins lie at the inner
leaf of the plasmalemma and consist of
three subunits .
There are various G-proteins that differ
mainly with regard to their !-unit. Association
with the receptor activates the
G-protein, leading in turn to activation
of another protein (enzyme, ion channel).
A large number of mediator substances
act via G-protein-coupled receptors.
An example of a ligand-gated ion
channel is the nicotinic cholinoceptor
of the motor endplate. The receptor
complex consists of five subunits, each
of which contains four transmembrane
domains. Simultaneous binding of two
acetylcholine (ACh) molecules to the
two !-subunits results in opening of the
ion channel, with entry of Na+ (and exit
of some K+), membrane depolarization,
and triggering of an action potential .
The ganglionic N-cholinoceptors
apparently consist only of ! and " subunits
. Some of the receptors for
the transmitter #-aminobutyric acid
(GABA) belong to this receptor family:
the GABAA subtype is linked to a chloride
channel (and also to a benzodiazepine-
binding site). Glutamate
and glycine both act via ligandgated
ion channels.

Drug-Receptor Interaction V

Enantioselectivity of affinity. If a
receptor has sites for three of the substituents
(symbolized in B by a cone, a
sphere, and a cube) on the asymmetric
carbon to attach to, only one of the
enantiomers will have optimal fit. Its affinity
will then be higher. Thus, dexetimide
displays an affinity at the muscarinic
ACh receptors almost 10000 times
that of levetimide; and at !-
adrenoceptors, S(-)-propranolol has an
affinity 100 times that of the R(+)-form.
Enantioselectivity of intrinsic activity.
The mode of attachment at the
receptor also determines whether an effect
is elicited and whether or not a substance
has intrinsic activity, i.e., acts as
an agonist or antagonist. For instance,
(-) dobutamine is an agonist at "-adrenoceptors
whereas the (+)-enantiomer is
an antagonist.
Inverse enantioselectivity at another
receptor. An enantiomer may
possess an unfavorable configuration at
one receptor that may, however, be optimal
for interaction with another receptor.
In the case of dobutamine, the
(+)-enantiomer has affinity at !-adrenoceptors
10 times higher than that of the
(-)-enantiomer, both having agonist activity.
However, the "-adrenoceptor
stimulant action is due to the (-)-form
(see above).
As described for receptor interactions,
enantioselectivity may also be
manifested in drug interactions with
enzymes and transport proteins. Enantiomers
may display different affinities
and reaction velocities.
Conclusion: The enantiomers of a
racemate can differ sufficiently in their
pharmacodynamic and pharmacokinetic
properties to constitute two distinct
drugs.

Drug-Receptor Interaction IV

Enantioselectivity of Drug Action
Many drugs are racemates, including !-
blockers, nonsteroidal anti-inflammatory
agents, and anticholinergics (e.g.,
benzetimide A). A racemate consists of
a molecule and its corresponding mirror
image which, like the left and right
hand, cannot be superimposed. Such
chiral (“handed”) pairs of molecules are
referred to as enantiomers. Usually,
chirality is due to a carbon atom
linked to four different substituents
(“asymmetric center”). Enantiomerism is
a special case of stereoisomerism. Nonchiral
stereoisomers are called diastereomers
(e.g., quinidine/quinine).
Bond lengths in enantiomers, but
not in diastereomers, are the same.
Therefore, enantiomers possess similar
physicochemical properties (e.g., solubility,
melting point) and both forms are
usually obtained in equal amounts by
chemical synthesis. As a result of enzymatic
activity, however, only one of the
enantiomers is usually found in nature.
In solution, enantiomers rotate the
wave plane of linearly polarized light
in opposite directions; hence they are
refered to as “dextro”- or “levo-rotatory”,
designated by the prefixes d or (+) and l
or (-), respectively. The direction of rotation
gives no clue concerning the spatial
structure of enantiomers. The absolute
configuration, as determined by
certain rules, is described by the prefixes
S and R. In some compounds, designation
as the D- and L-form is possible
by reference to the structure of D- and
L-glyceraldehyde.
For drugs to exert biological actions,
contact with reaction partners in
the body is required. When the reaction
favors one of the enantiomers, enantioselectivity
is observed.

Drug-Receptor Interaction III

Agonist stabilizes spontaneously
occurring active conformation. The
receptor can spontaneously “flip” into
the active conformation. However, the
statistical probability of this event is
usually so small that the cells do not reveal
signs of spontaneous receptor activation.
Selective binding of the agonist
requires the receptor to be in the active
conformation, thus promoting its existence.
The “antagonist” displays affinity
only for the inactive state and stabilizes
the latter. When the system shows minimal
spontaneous activity, application
of an antagonist will not produce a measurable
effect. When the system has
high spontaneous activity, the antagonist
may cause an effect that is the opposite
of that of the agonist: inverse agonist.
A “true” antagonist lacking intrinsic
activity (“neutral antagonist”) displays
equal affinity for both the active and inactive
states of the receptor and does
not alter basal activity of the cell.
According to this model, a partial agonist
shows lower selectivity for the active
state and, to some extent, also binds
to the receptor in its inactive state.
Other Forms of Antagonism
Allosteric antagonism. The antagonist
is bound outside the receptor agonist
binding site proper and induces a decrease
in affinity of the agonist. It is also
possible that the allosteric deformation
of the receptor increases affinity for an
agonist, resulting in an allosteric synergism.
Functional antagonism. Two agonists
affect the same parameter (e.g.,
bronchial diameter) via different receptors
in the opposite direction (epinephrine
dilation; histamine ! constriction).

Drug-Receptor Interaction II

Agonists – Antagonists
An agonist has affinity (binding avidity)
for its receptor and alters the receptor
protein in such a manner as to generate
a stimulus that elicits a change in cell
function: “intrinsic activity“. The biological
effect of the agonist, i.e., the
change in cell function, depends on the
efficiency of signal transduction steps
initiated by the activated receptor.
Some agonists attain a maximal
effect even when they occupy only a
small fraction of receptors
. Other ligands , possessing
equal affinity for the receptor but lower
activating capacity (lower intrinsic activity),
are unable to produce a full maximal
response even when all receptors
are occupied: lower efficacy. Ligand B is
a partial agonist. The potency of an agonist
can be expressed in terms of the
concentration (EC50) at which the effect
reaches one-half of its respective maximum.
Antagonists attenuate the effect
of agonists, that is, their action is
“anti-agonistic”.
Competitive antagonists possess
affinity for receptors, but binding to the
receptor does not lead to a change in
cell function (zero intrinsic activity).
When an agonist and a competitive
antagonist are present simultaneously,
affinity and concentration of the two rivals
will determine the relative amount
of each that is bound. Thus, although the
antagonist is present, increasing the
concentration of the agonist can restore
the full effect . However, in the presence
of the antagonist, the concentration-
response curve of the agonist is
shifted to higher concentrations (“rightward
shift”).
Molecular Models of Agonist/Antagonist
Action
Agonist induces active conformation.
The agonist binds to the inactive receptor
and thereby causes a change from
the resting conformation to the active
state. The antagonist binds to the inactive
receptor without causing a conformational
change.

Drug-Receptor Interaction I

Types of Binding Forces
Unless a drug comes into contact with
intrinsic structures of the body, it cannot
affect body function.
Covalent bond. Two atoms enter a
covalent bond if each donates an electron
to a shared electron pair (cloud).
This state is depicted in structural formulas
by a dash. The covalent bond is
“firm”, that is, not reversible or only
poorly so. Few drugs are covalently
bound to biological structures. The
bond, and possibly the effect, persist for
a long time after intake of a drug has
been discontinued, making therapy difficult
to control. Examples include alkylating
cytostatics or organophosphates
. Conjugation reactions
occurring in biotransformation also
represent a covalent linkage (e.g., to
glucuronic acid).
Noncovalent bond. There is no formation
of a shared electron pair. The
bond is reversible and typical of most
drug-receptor interactions. Since a drug
usually attaches to its site of action by
multiple contacts, several of the types of
bonds described below may participate.
Electrostatic attraction. A positive
and negative charge attract each
other.
Ionic interaction: An ion is a particle
charged either positively (cation) or
negatively (anion), i.e., the atom lacks or
has surplus electrons, respectively. Attraction
between ions of opposite
charge is inversely proportional to the
square of the distance between them; it
is the initial force drawing a charged
drug to its binding site. Ionic bonds have
a relatively high stability.
Dipole-ion interaction: When bond
electrons are asymmetrically distributed
over both atomic nuclei, one atom
will bear a negative, and its partner
a positive partial charge. The molecule
thus presents a positive and a negative
pole, i.e., has polarity or a dipole. A
partial charge can interact electrostatically
with an ion of opposite charge.
Dipole-dipole interaction is the electrostatic
attraction between opposite
partial charges. When a hydrogen atom
bearing a partial positive charge bridges
two atoms bearing a partial negative
charge, a hydrogen bond is created.
A van der Waals’ bond is
formed between apolar molecular
groups that have come into close proximity.
Spontaneous transient distortion
of electron clouds (momentary faint dipole)
may induce an opposite dipole
in the neighboring molecule. The van
der Waals’ bond, therefore, is a form of
electrostatic attraction, albeit of very
low strength (inversely proportional to
the seventh power of the distance).
Hydrophobic interaction. The
attraction between the dipoles of water
is strong enough to hinder intercalation
of any apolar (uncharged) molecules. By
tending towards each other, H2O molecules
squeeze apolar particles from
their midst. Accordingly, in the organism,
apolar particles have an increased
probability of staying in nonaqueous,
apolar surroundings, such as fatty acid
chains of cell membranes or apolar regions
of a receptor.

Quantification of Drug Action V

Concentration-Binding Curves
In order to elicit their effect, drug molecules
must be bound to the cells of the
effector organ. Binding commonly occurs
at specific cell structures, namely,
the receptors. The analysis of drug binding
to receptors aims to determine the
affinity of ligands, the kinetics of interaction,
and the characteristics of the
binding site itself.
In studying the affinity and number
of such binding sites, use is made of
membrane suspensions of different tissues.
This approach is based on the expectation
that binding sites will retain
their characteristic properties during
cell homogenization. Provided that
binding sites are freely accessible in the
medium in which membrane fragments
are suspended, drug concentration at
the “site of action” would equal that in
the medium. The drug under study is radiolabeled
(enabling low concentrations
to be measured quantitatively),
added to the membrane suspension,
and allowed to bind to receptors. Membrane
fragments and medium are then
separated, e.g., by filtration, and the
amount of bound drug is measured.
Binding increases in proportion to concentration
as long as there is a negligible
reduction in the number of free binding
sites (c = 1 and B ! 10% of maximum
binding; c = 2 and B ! 20 %). As binding
approaches saturation, the number of
free sites decreases and the increment
in binding is no longer proportional to
the increase in concentration (in the example
illustrated, an increase in concentration
by 1 is needed to increase
binding from 10 to 20 %; however, an increase
by 20 is needed to raise it from 70
to 80 %).

The differing affinity of different ligands
for a binding site can be demonstrated
elegantly by binding assays. Although
simple to perform, these binding
assays pose the difficulty of correlating
unequivocally the binding sites concerned
with the pharmacological effect;
this is particularly difficult when more
than one population of binding sites is
present. Therefore, receptor binding
must not be implied until it can be
shown that
• binding is saturable (saturability);
• the only substances bound are those
possessing the same pharmacological
mechanism of action (specificity);
• binding affinity of different substances
is correlated with their pharmacological
potency.
Binding assays provide information
about the affinity of ligands, but they do
not give any clue as to whether a ligand
is an agonist or antagonist . Use of
radiolabeled drugs bound to their receptors
may be of help in purifying and
analyzing further the receptor protein.

Quantification of Drug Action IV

Disadvantages are:
1. Unavoidable tissue injury during dissection.
2. Loss of physiological regulation of
function in the isolated tissue.
3. The artificial milieu imposed on the
tissue.
Concentration-Effect Curves (B)
As the concentration is raised by a constant
factor, the increment in effect diminishes
steadily and tends asymptotically
towards zero the closer one comes
to the maximally effective concentration.
The concentration at which a maximal
effect occurs cannot be measured
accurately; however, that eliciting a
half-maximal effect (EC50) is readily determined.
It typically corresponds to the
inflection point of the concentration–
response curve in a semilogarithmic
plot (log concentration on abscissa).
Full characterization of a concentration–
effect relationship requires determination
of the EC50, the maximally
possible effect (Emax), and the slope at
the point of inflection.

Quantification of Drug Action III

Concentration-Effect Relationship (A)
The relationship between the concentration
of a drug and its effect is determined
in order to define the range of active
drug concentrations (potency) and
the maximum possible effect (efficacy).
On the basis of these parameters, differences
between drugs can be quantified.
As a rule, the therapeutic effect or toxic
action depends critically on the response
of a single organ or a limited
number of organs, e.g., blood flow is affected
by a change in vascular luminal
width. By isolating critical organs or tissues
from a larger functional system,
these actions can be studied with more
accuracy; for instance, vasoconstrictor
agents can be examined in isolated
preparations from different regions of
the vascular tree, e.g., the portal or
saphenous vein, or the mesenteric, coronary,
or basilar artery. In many cases,
isolated organs or organ parts can be
kept viable for hours in an appropriate
nutrient medium sufficiently supplied
with oxygen and held at a suitable temperature.
Responses of the preparation to a
physiological or pharmacological stimulus
can be determined by a suitable recording
apparatus. Thus, narrowing of a
blood vessel is recorded with the help of
two clamps by which the vessel is suspended
under tension.
Experimentation on isolated organs
offers several advantages:
1. The drug concentration in the tissue
is usually known.
2. Reduced complexity and ease of relating
stimulus and effect.
3. It is possible to circumvent compensatory
responses that may partially
cancel the primary effect in the intact
organism — e.g., the heart rate increasing
action of norepinephrine
cannot be demonstrated in the intact
organism, because a simultaneous
rise in blood pressure elicits a counter-
regulatory reflex that slows cardiac
rate.
4. The ability to examine a drug effect
over its full rage of intensities — e.g.,
it would be impossible in the intact
organism to follow negative chronotropic
effects to the point of cardiac
arrest.

Quantification of Drug Action II

To illustrate this point, we consider
an experiment in which the subjects individually
respond in all-or-none fashion,
as in the Straub tail phenomenon
. Mice react to morphine with excitation,
evident in the form of an abnormal
posture of the tail and limbs. The dose
dependence of this phenomenon is observed
in groups of animals (e.g., 10
mice per group) injected with increasing
doses of morphine. At the low dose,
only the most sensitive, at increasing
doses a growing proportion, at the highest
dose all of the animals are affected
. There is a relationship between the
frequency of responding animals and
the dose given. At 2 mg/kg, one out of 10
animals reacts; at 10 mg/kg, 5 out of 10
respond. The dose-frequency relationship
results from the different sensitivity
of individuals, which as a rule exhibits
a log-normal distribution (C, graph at
right, linear scale). If the cumulative frequency
(total number of animals responding
at a given dose) is plotted
against the logarithm of the dose (abscissa),
a sigmoidal curve results .
The inflection point of the curve lies at
the dose at which one-half of the group
has responded. The dose range encompassing
the dose-frequency relationship
reflects the variation in individual sensitivity
to the drug. Although similar in
shape, a dose-frequency relationship
has, thus, a different meaning than does
a dose-effect relationship. The latter can
be evaluated in one individual and results
from an intraindividual dependency
of the effect on drug concentration.
The evaluation of a dose-effect relationship
within a group of human subjects
is compounded by interindividual
differences in sensitivity. To account for
the biological variation, measurements
have to be carried out on a representative
sample and the results averaged.
Thus, recommended therapeutic doses
will be appropriate for the majority of
patients, but not necessarily for each individual.
The variation in sensitivity may be
based on pharmacokinetic differences
(same dose ! different plasma levels)
or on differences in target organ sensitivity
(same plasma level !different effects).

Quantification of Drug Action I

Dose–Response Relationship
The effect of a substance depends on the
amount administered, i.e., the dose. If
the dose chosen is below the critical
threshold (subliminal dosing), an effect
will be absent. Depending on the nature
of the effect to be measured, ascending
doses may cause the effect to increase in
intensity. Thus, the effect of an antipyretic
or hypotensive drug can be quantified
in a graded fashion, in that the extent
of fall in body temperature or blood
pressure is being measured. A dose-effect
relationship is then encountered.
The dose-effect relationship may
vary depending on the sensitivity of the
individual person receiving the drug,
i.e., for the same effect, different doses
may be required in different individuals.
Interindividual variation in sensitivity is
especially obvious with effects of the
“all-or-none” kind.

Pharmacokinetics VIII

Change in Elimination Characteristics
During Drug Therapy
With any drug taken regularly and accumulating
to the desired plasma level, it
is important to consider that conditions
for biotransformation and excretion do
not necessarily remain constant. Elimination
may be hastened due to enzyme
induction (p. 32) or to a change in urinary
pH (p. 40). Consequently, the
steady-state plasma level declines to a
new value corresponding to the new
rate of elimination. The drug effect may
diminish or disappear. Conversely,
when elimination is impaired (e.g., in
progressive renal insufficiency), the
mean plasma level of renally eliminated
drugs rises and may enter a toxic concentration
range.

Pharmacokinetics VII

Accumulation: Dose, Dose Interval, and
Plasma Level Fluctuation
Successful drug therapy in many illnesses
is accomplished only if drug concentration
is maintained at a steady high
level. This requirement necessitates
regular drug intake and a dosage schedule
that ensures that the plasma concentration
neither falls below the therapeutically
effective range nor exceeds
the minimal toxic concentration. A constant
plasma level would, however, be
undesirable if it accelerated a loss of effectiveness
(development of tolerance),
or if the drug were required to be
present at specified times only.
A steady plasma level can be
achieved by giving the drug in a constant
intravenous infusion, the steadystate
plasma level being determined by
the infusion rate, dose D per unit of time
and the clearance
This procedure is routinely used in
intensive care hospital settings, but is
otherwise impracticable. With oral administration,
dividing the total daily
dose into several individual ones, e.g.,
four, three, or two, offers a practical
compromise.
When the daily dose is given in several
divided doses, the mean plasma
level shows little fluctuation. In practice,
it is found that a regimen of frequent
regular drug ingestion is not well
adhered to by patients. The degree of
fluctuation in plasma level over a given
dosing interval can be reduced by use of
a dosage form permitting slow (sustained)
release .
The time required to reach steadystate
accumulation during multiple
constant dosing depends on the rate of
elimination. As a rule of thumb, a plateau
is reached after approximately
three elimination half-lives (t1/2).
For slowly eliminated drugs, which
tend to accumulate extensively (phenprocoumon,
digitoxin, methadone), the
optimal plasma level is attained only after
a long period. Here, increasing the
initial doses (loading dose) will speed
up the attainment of equilibrium, which
is subsequently maintained with a lower
dose (maintenance dose).

Pharmacokinetics VI

Time Course of Drug Plasma Levels
During Irregular Intake
In practice, it proves difficult to achieve
a plasma level that undulates evenly
around the desired effective concentration.
For instance, if two successive doses
are omitted, the plasma level will
drop below the therapeutic range and a
longer period will be required to regain
the desired plasma level. In everyday
life, patients will be apt to neglect drug
intake at the scheduled time. Patient
compliance means strict adherence to
the prescribed regimen. Apart from
poor compliance, the same problem
may occur when the total daily dose is
divided into three individual doses (tid)
and the first dose is taken at breakfast,
the second at lunch, and the third at
supper. Under this condition, the nocturnal
dosing interval will be twice the
diurnal one. Consequently, plasma levels
during the early morning hours may
have fallen far below the desired or,
possibly, urgently needed range.

Pharmacokinetics V

Time Course of Drug Plasma Levels
During Repeated Dosing
When a drug is administered at regular
intervals over a prolonged period, the
rise and fall of drug concentration in
blood will be determined by the relationship
between the half-life of elimination
and the time interval between
doses. If the drug amount administered
in each dose has been eliminated before
the next dose is applied, repeated intake
at constant intervals will result in similar
plasma levels. If intake occurs before
the preceding dose has been eliminated
completely, the next dose will add on to
the residual amount still present in the
body, i.e., the drug accumulates. The
shorter the dosing interval relative to
the elimination half-life, the larger will
be the residual amount of drug to which
the next dose is added and the more extensively
will the drug accumulate in
the body. However, at a given dosing
frequency, the drug does not accumulate
infinitely and a steady state (Css) or
accumulation equilibrium is eventually
reached. This is so because the activity
of elimination processes is concentration-
dependent. The higher the drug
concentration rises, the greater is the
amount eliminated per unit of time. After
several doses, the concentration will
have climbed to a level at which the
amounts eliminated and taken in per
unit of time become equal, i.e., a steady
state is reached. Within this concentration
range, the plasma level will continue
to rise (peak) and fall (trough) as dosing
is continued at a regular interval.
The height of the steady state (Css) depends
upon the amount administered
per dosing interval and the
clearance (Cltot)

Pharmacokinetics IV

Drug entry into hepatic and renal
tissue constitutes movement into the
organs of elimination. The characteristic
phasic time course of drug concentration
in plasma represents the sum of
the constituent processes of absorption,
distribution, and elimination,
which overlap in time. When distribution
takes place significantly faster than
elimination, there is an initial rapid and
then a greatly retarded fall in the plasma
level, the former being designated
the !-phase (distribution phase), the
latter the "-phase (elimination phase).
When the drug is distributed faster than
it is absorbed, the time course of the
plasma level can be described in mathematically
simplified form by the Bateman
function (k1 and k2 represent the
rate constants for absorption and elimination,
respectively).
B. The velocity of absorption depends
on the route of administration.
The more rapid the administration, the
shorter will be the time (tmax) required
to reach the peak plasma level (cmax),
the higher will be the cmax, and the earlier
the plasma level will begin to fall
again.
The area under the plasma level time
curve (AUC) is independent of the route
of administration, provided the doses
and bioavailability are the same (Dost’s
law of corresponding areas). The AUC
can thus be used to determine the bioavailability
F of a drug. The ratio of AUC
values determined after oral or intravenous
administration of a given dose of a
particular drug corresponds to the proportion
of drug entering the systemic
circulation after oral administration.
The determination of plasma levels affords
a comparison of different proprietary
preparations containing the same
drug in the same dosage. Identical plasma
level time-curves of different
manufacturers’ products with reference
to a standard preparation indicate bioequivalence
of the preparation under
investigation with the standard.

Pharmacokinetics III

Time Course of Drug Concentration in
Plasma
A. Drugs are taken up into and eliminated
from the body by various routes. The
body thus represents an open system
wherein the actual drug concentration
reflects the interplay of intake (ingestion)
and egress (elimination). When an
orally administered drug is absorbed
from the stomach and intestine, speed
of uptake depends on many factors, including
the speed of drug dissolution (in
the case of solid dosage forms) and of
gastrointestinal transit; the membrane
penetrability of the drug; its concentration
gradient across the mucosa-blood
barrier; and mucosal blood flow. Absorption
from the intestine causes the
drug concentration in blood to increase.
Transport in blood conveys the drug to
different organs (distribution), into
which it is taken up to a degree compatible
with its chemical properties and
rate of blood flow through the organ.
For instance, well-perfused organs such
as the brain receive a greater proportion
than do less well-perfused ones. Uptake
into tissue causes the blood concentration
to fall. Absorption from the gut diminishes
as the mucosa-blood gradient
decreases. Plasma concentration reaches
a peak when the drug amount leaving
the blood per unit of time equals that
being absorbed.

Pharmacokinetics II

The constancy of the process permits
calculation of the plasma volume
that would be cleared of drug, if the remaining
drug were not to assume a homogeneous
distribution in the total volume
(a condition not met in reality).
This notional plasma volume freed of
drug per unit of time is termed the
clearance. Depending on whether plasma
concentration falls as a result of urinary
excretion or metabolic alteration,
clearance is considered to be renal or
hepatic. Renal and hepatic clearances
add up to total clearance (Cltot) in the
case of drugs that are eliminated unchanged
via the kidney and biotransformed
in the liver. Cltot represents the
sum of all processes contributing to
elimination; it is related to the half-life
(t1/2) and the apparent volume of distribution
Vapp (p. 28) by the equation:
Vapp t1/2 = In 2 x ––––
Cltot
The smaller the volume of distribution
or the larger the total clearance, the
shorter is the half-life.
In the case of drugs renally eliminated
in unchanged form, the half-life of
elimination can be calculated from the
cumulative excretion in urine; the final
total amount eliminated corresponds to
the amount absorbed.
Hepatic elimination obeys exponential
kinetics because metabolizing
enzymes operate in the quasilinear region
of their concentration-activity
curve; hence the amount of drug metabolized
per unit of time diminishes
with decreasing blood concentration.
The best-known exception to exponential
kinetics is the elimination of alcohol
(ethanol), which obeys a linear
time course (zero-order kinetics), at
least at blood concentrations > 0.02 %. It
does so because the rate-limiting enzyme,
alcohol dehydrogenase, achieves
half-saturation at very low substrate
concentrations, i.e., at about 80 mg/L
(0.008 %). Thus, reaction velocity reaches
a plateau at blood ethanol concentrations
of about 0.02 %, and the amount of
drug eliminated per unit of time remains
constant at concentrations above
this level.

Pharmacokinetics I

Drug Concentration in the Body
as a Function of Time. First-Order
(Exponential) Rate Processes
Processes such as drug absorption and
elimination display exponential characteristics.
As regards the former, this follows
from the simple fact that the
amount of drug being moved per unit of
time depends on the concentration difference
(gradient) between two body
compartments (Fick’s Law). In drug absorption
from the alimentary tract, the
intestinal contents and blood would
represent the compartments containing
an initially high and low concentration,
respectively. In drug elimination via the
kidney, excretion often depends on glomerular
filtration, i.e., the filtered
amount of drug present in primary
urine. As the blood concentration falls,
the amount of drug filtered per unit of
time diminishes. The resulting exponential
decline is illustrated in . The
exponential time course implies constancy
of the interval during which the
concentration decreases by one-half.
This interval represents the half-life
(t1/2) and is related to the elimination
rate constant k by the equation t1/2 = ln
2/k. The two parameters, together with
the initial concentration co, describe a
first-order (exponential) rate process.

Drug Elimination X

Lipophilic drugs that are converted
in the liver to hydrophilic metabolites
permit better control, because the
lipophilic agent can be eliminated in
this manner. The speed of formation of
hydrophilic metabolite determines the
drug’s length of stay in the body.
If hepatic conversion to a polar metabolite
is rapid, only a portion of the
absorbed drug enters the systemic circulation
in unchanged form, the remainder
having undergone presystemic
(first-pass) elimination. When biotransformation
is rapid, oral administration
of the drug is impossible (e.g.,
glyceryl trinitate). Parenteral or,
alternatively, sublingual, intranasal, or
transdermal administration is then required
in order to bypass the liver. Irrespective
of the route of administration,
a portion of administered drug may be
taken up into and transiently stored in
lung tissue before entering the general
circulation. This also constitutes presystemic
elimination.
Presystemic elimination refers to
the fraction of drug absorbed that is
excluded from the general circulation
by biotransformation or by first-pass
binding.
Presystemic elimination diminishes
the bioavailability of a drug after its
oral administration. Absolute bioavailability
= systemically available amount/
dose administered; relative bioavailability
= availability of a drug contained
in a test preparation with reference to a
standard preparation.

Drug Elimination IX

Elimination of Lipophilic and
Hydrophilic Substances
The terms lipophilic and hydrophilic
(or hydro- and lipophobic) refer to the
solubility of substances in media of low
and high polarity, respectively. Blood
plasma, interstitial fluid, and cytosol are
highly polar aqueous media, whereas
lipids — at least in the interior of the lipid
bilayer membrane — and fat constitute
apolar media. Most polar substances
are readily dissolved in aqueous media
(i.e., are hydrophilic) and lipophilic
ones in apolar media. A hydrophilic
drug, on reaching the bloodstream,
probably after a partial, slow absorption
(not illustrated), passes through the liver
unchanged, because it either cannot,
or will only slowly, permeate the lipid
barrier of the hepatocyte membrane
and thus will fail to gain access to hepatic
biotransforming enzymes. The unchanged
drug reaches the arterial blood
and the kidneys, where it is filtered.
With hydrophilic drugs, there is little
binding to plasma proteins (protein
binding increases as a function of lipophilicity),
hence the entire amount
present in plasma is available for glomerular
filtration. A hydrophilic drug is
not subject to tubular reabsorption and
appears in the urine. Hydrophilic drugs
undergo rapid elimination.
If a lipophilic drug, because of its
chemical nature, cannot be converted
into a polar product, despite having access
to all cells, including metabolically
active liver cells, it is likely to be retained
in the organism. The portion filtered
during glomerular passage will be
reabsorbed from the tubules. Reabsorption
will be nearly complete, because
the free concentration of a lipophilic
drug in plasma is low (lipophilic substances
are usually largely proteinbound).
The situation portrayed for a
lipophilic non-metabolizable drug
would seem undesirable because pharmacotherapeutic
measures once initiated
would be virtually irreversible (poor
control over blood concentration).

Drug Elimination VIII

During passage down the renal tubule,
urinary volume shrinks more than
100-fold; accordingly, there is a corresponding
concentration of filtered drug
or drug metabolites . The resulting
concentration gradient between urine
and interstitial fluid is preserved in the
case of drugs incapable of permeating
the tubular epithelium. However, with
lipophilic drugs the concentration gradient
will favor reabsorption of the filtered
molecules. In this case, reabsorption
is not based on an active process
but results instead from passive diffusion.
Accordingly, for protonated substances,
the extent of reabsorption is
dependent upon urinary pH or the degree
of dissociation. The degree of dissociation
varies as a function of the urinary
pH and the pKa, which represents
the pH value at which half of the substance
exists in protonated (or unprotonated)
form. This relationship is graphically
illustrated with the example of
a protonated amine having a pKa of 7.0.
In this case, at urinary pH 7.0, 50 % of the
amine will be present in the protonated,
hydrophilic, membrane-impermeant
form (blue dots), whereas the other half,
representing the uncharged amine
(orange dots), can leave the tubular lumen
in accordance with the resulting
concentration gradient. If the pKa of an
amine is higher (pKa = 7.5) or lower (pKa
= 6.5), a correspondingly smaller or
larger proportion of the amine will be
present in the uncharged, reabsorbable
form. Lowering or raising urinary pH by
half a pH unit would result in analogous
changes for an amine having a pKa of
7.0.
The same considerations hold for
acidic molecules, with the important
difference that alkalinization of the
urine (increased pH) will promote the
deprotonization of -COOH groups and
thus impede reabsorption. Intentional
alteration in urinary pH can be used in
intoxications with proton-acceptor substances
in order to hasten elimination of
the toxin (alkalinization ! phenobarbital;
acidification !amphetamine).

Drug Elimination VII

The Kidney as Excretory Organ
Most drugs are eliminated in urine either
chemically unchanged or as metabolites.
The kidney permits elimination
because the vascular wall structure in
the region of the glomerular capillaries
allows unimpeded passage of blood
solutes having molecular weights (MW)
<> 70000. With
few exceptions, therapeutically used
drugs and their metabolites have much
smaller molecular weights and can,
therefore, undergo glomerular filtration,
i.e., pass from blood into primary
urine. Separating the capillary endothelium
from the tubular epithelium, the
basal membrane consists of charged
glycoproteins and acts as a filtration
barrier for high-molecular-weight substances.
The relative density of this barrier
depends on the electrical charge of
molecules that attempt to permeate it.
Apart from glomerular filtration
, drugs present in blood may pass
into urine by active secretion. Certain
cations and anions are secreted by the
epithelium of the proximal tubules into
the tubular fluid via special, energyconsuming
transport systems. These
transport systems have a limited capacity.
When several substrates are present
simultaneously, competition for the
carrier may occur .

Drug Elimination VI

Conjugations
The most important of phase II conjugation
reactions is glucuronidation. This
reaction does not proceed spontaneously,
but requires the activated form of
glucuronic acid, namely glucuronic acid
uridine diphosphate. Microsomal glucuronyl
transferases link the activated
glucuronic acid with an acceptor molecule.
When the latter is a phenol or alcohol,
an ether glucuronide will be
formed. In the case of carboxyl-bearing
molecules, an ester glucuronide is the
result. All of these are O-glucuronides.
Amines may form N-glucuronides that,
unlike O-glucuronides, are resistant to
bacterial !-glucuronidases.
Soluble cytoplasmic sulfotransferases
conjugate activated sulfate (3’-
phosphoadenine-5’-phosphosulfate)
with alcohols and phenols. The conjugates
are acids, as in the case of glucuronides.
In this respect, they differ from
conjugates formed by acetyltransferases
from activated acetate (acetylcoenzyme
A) and an alcohol or a phenol.
Acyltransferases are involved in the
conjugation of the amino acids glycine
or glutamine with carboxylic acids. In
these cases, an amide bond is formed
between the carboxyl groups of the acceptor
and the amino group of the donor
molecule (e.g., formation of salicyluric
acid from salicylic acid and glycine).
The acidic group of glycine or glutamine
remains free.

Drug Elimination V

Enterohepatic Cycle
After an orally ingested drug has been
absorbed from the gut, it is transported
via the portal blood to the liver, where it
can be conjugated to glucuronic or sulfuric
acid (shown in B for salicylic acid
and deacetylated bisacodyl, respectively)
or to other organic acids. At the pH of
body fluids, these acids are predominantly
ionized; the negative charge confers
high polarity upon the conjugated
drug molecule and, hence, low membrane
penetrability. The conjugated
products may pass from hepatocyte into
biliary fluid and from there back into
the intestine. O-glucuronides can be
cleaved by bacterial !-glucuronidases in
the colon, enabling the liberated drug
molecule to be reabsorbed. The enterohepatic
cycle acts to trap drugs in the
body. However, conjugated products
enter not only the bile but also the
blood. Glucuronides with a molecular
weight (MW) > 300 preferentially pass
into the blood, while those with MW >
300 enter the bile to a larger extent.
Glucuronides circulating in the blood
undergo glomerular filtration in the kidney
and are excreted in urine because
their decreased lipophilicity prevents
tubular reabsorption.
Drugs that are subject to enterohepatic
cycling are, therefore, excreted
slowly. Pertinent examples include digitoxin
and acidic nonsteroidal anti-inflammatory
agents .

Drug Elimination IV

Reduction reactions may occur at
oxygen or nitrogen atoms. Keto-oxygens
are converted into a hydroxyl
group, as in the reduction of the prodrugs
cortisone and prednisone to the
active glucocorticoids cortisol and prednisolone,
respectively. N-reductions occur
in azo- or nitro-compounds (e.g., nitrazepam).
Nitro groups can be reduced
to amine groups via nitroso and hydroxylamino
intermediates. Likewise, dehalogenation
is a reductive process involving
a carbon atom (e.g., halothane).
Methylations are catalyzed by a
family of relatively specific methyltransferases
involving the transfer of
methyl groups to hydroxyl groups (Omethylation
as in norepinephrine [noradrenaline])
or to amino groups (Nmethylation
of norepinephrine, histamine,
or serotonin).
In thio compounds, desulfuration
results from substitution of sulfur by
oxygen (e.g., parathion). This example
again illustrates that biotransformation
is not always to be equated with bioinactivation.
Thus, paraoxon (E600)
formed in the organism from parathion
(E605) is the actual active agent .

Drug Elimination III

Oxidation reactions can be divided
into two kinds: those in which oxygen is
incorporated into the drug molecule,
and those in which primary oxidation
causes part of the molecule to be lost.
The former include hydroxylations,
epoxidations, and sulfoxidations. Hydroxylations
may involve alkyl substituents
(e.g., pentobarbital) or aromatic
ring systems (e.g., propranolol). In both
cases, products are formed that are conjugated
to an organic acid residue, e.g.,
glucuronic acid, in a subsequent Phase II
reaction.
Hydroxylation may also take place
at nitrogen atoms, resulting in hydroxylamines
(e.g., acetaminophen). Benzene,
polycyclic aromatic compounds (e.g.,
benzopyrene), and unsaturated cyclic
carbohydrates can be converted by
mono-oxygenases to epoxides, highly
reactive electrophiles that are hepatotoxic
and possibly carcinogenic.
The second type of oxidative biotransformation
comprises dealkylations.
In the case of primary or secondary
amines, dealkylation of an alkyl
group starts at the carbon adjacent to
the nitrogen; in the case of tertiary
amines, with hydroxylation of the nitrogen
(e.g., lidocaine). The intermediary
products are labile and break up into the
dealkylated amine and aldehyde of the
alkyl group removed. O-dealkylation
and S-dearylation proceed via an analogous
mechanism (e.g., phenacetin and
azathioprine, respectively).
Oxidative deamination basically
resembles the dealkylation of tertiary
amines, beginning with the formation of
a hydroxylamine that then decomposes
into ammonia and the corresponding
aldehyde. The latter is partly reduced to
an alcohol and

Drug Elimination II

Drug Elimination II

Ester hydrolysis does not invariably
lead to inactive metabolites, as exemplified
by acetylsalicylic acid. The cleavage
product, salicylic acid, retains pharmacological
activity. In certain cases,
drugs are administered in the form of
esters in order to facilitate absorption
(enalapril ! enalaprilate; testosterone
undecanoate ! testosterone) or to reduce
irritation of the gastrointestinal
mucosa (erythromycin succinate !
erythromycin). In these cases, the ester
itself is not active, but the cleavage
product is. Thus, an inactive precursor
or prodrug is applied, formation of the
active molecule occurring only after hydrolysis
in the blood.
Some drugs possessing amide
bonds, such as prilocaine, and of course,
peptides, can be hydrolyzed by peptidases
and inactivated in this manner.
Peptidases are also of pharmacological
interest because they are responsible
for the formation of highly reactive
cleavage products (fibrin, p. 146) and
potent mediators (angiotensin II, p. 124;
bradykinin, enkephalin, p. 210) from
biologically inactive peptides.
Peptidases exhibit some substrate
selectivity and can be selectively inhibited,
as exemplified by the formation of
angiotensin II, whose actions inter alia
include vasoconstriction. Angiotensin II
is formed from angiotensin I by cleavage
of the C-terminal dipeptide histidylleucine.
Hydrolysis is catalyzed by “angiotensin-
converting enzyme” (ACE). Peptide
analogues such as captopril (p. 124)
block this enzyme. Angiotensin II is degraded
by angiotensinase A, which clips
off the N-terminal asparagine residue.
The product, angiotensin III, lacks vasoconstrictor
activity.

Drug Elimination I

The Liver as an Excretory Organ
As the chief organ of drug biotransformation,
the liver is richly supplied with
blood, of which 1100 mL is received
each minute from the intestines
through the portal vein and 350 mL
through the hepatic artery, comprising
nearly 1/3 of cardiac output. The blood
content of hepatic vessels and sinusoids
amounts to 500 mL. Due to the widening
of the portal lumen, intrahepatic
blood flow decelerates . Moreover,
the endothelial lining of hepatic sinusoids
contains pores large
enough to permit rapid exit of plasma
proteins. Thus, blood and hepatic parenchyma
are able to maintain intimate
contact and intensive exchange of substances,
which is further facilitated by
microvilli covering the hepatocyte surfaces
abutting Disse’s spaces.
The hepatocyte secretes biliary
fluid into the bile canaliculi (dark
green), tubular intercellular clefts that
are sealed off from the blood spaces by
tight junctions. Secretory activity in the
hepatocytes results in movement of
fluid towards the canalicular space.
The hepatocyte has an abundance of enzymes
carrying out metabolic functions.
These are localized in part in mitochondria,
in part on the membranes of the
rough (rER) or smooth (sER) endoplasmic
reticulum.

Drug Distribution in the Body V

Binding to Plasma Proteins
Having entered the blood, drugs may
bind to the protein molecules that are
present in abundance, resulting in the
formation of drug-protein complexes.
Protein binding involves primarily albumin
and, to a lesser extent, !-globulins
and acidic glycoproteins. Other
plasma proteins (e.g., transcortin, transferrin,
thyroxin-binding globulin) serve
specialized functions in connection
with specific substances. The degree of
binding is governed by the concentration
of the reactants and the affinity of a
drug for a given protein. Albumin concentration
in plasma amounts to
4.6 g/100 mL or O.6 mM, and thus provides
a very high binding capacity (two
sites per molecule). As a rule, drugs exhibit
much lower affinity (KD approx.
10–5 –10–3 M) for plasma proteins than
for their specific binding sites (receptors).
In the range of therapeutically relevant
concentrations, protein binding of
most drugs increases linearly with concentration
(exceptions: salicylate and
certain sulfonamides).
The albumin molecule has different
binding sites for anionic and cationic ligands,
but van der Waals’ forces also
contribute. The extent of binding
correlates with drug hydrophobicity
(repulsion of drug by water).
Binding to plasma proteins is instantaneous
and reversible, i.e., any
change in the concentration of unbound
drug is immediately followed by a corresponding
change in the concentration
of bound drug. Protein binding is of
great importance, because it is the concentration
of free drug that determines
the intensity of the effect. At an identical
total plasma concentration (say, 100
ng/mL) the effective concentration will
be 90 ng/mL for a drug 10 % bound to
protein, but 1 ng/mL for a drug 99 %
bound to protein. The reduction in concentration
of free drug resulting from
protein binding affects not only the intensity
of the effect but also biotransformation
(e.g., in the liver) and elimination
in the kidney, because only free
drug will enter hepatic sites of metabolism
or undergo glomerular filtration.
When concentrations of free drug fall,
drug is resupplied from binding sites on
plasma proteins. Binding to plasma protein
is equivalent to a depot in prolonging
the duration of the effect by retarding
elimination, whereas the intensity
of the effect is reduced. If two substances
have affinity for the same binding site
on the albumin molecule, they may
compete for that site. One drug may displace
another from its binding site and
thereby elevate the free (effective) concentration
of the displaced drug (a form
of drug interaction). Elevation of the
free concentration of the displaced drug
means increased effectiveness and accelerated
elimination.
A decrease in the concentration of
albumin (liver disease, nephrotic syndrome,
poor general condition) leads to
altered pharmacokinetics of drugs that
are highly bound to albumin.
Plasma protein-bound drugs that
are substrates for transport carriers can
be cleared from blood at great velocity,
e.g., p-aminohippurate by the renal tubule
and sulfobromophthalein by the
liver. Clearance rates of these substances
can be used to determine renal or hepatic
blood flow.

Drug distribution in the Body IV

Possible Modes of Drug Distribution
Following its uptake into the body, the
drug is distributed in the blood and
through it to the various tissues of the
body. Distribution may be restricted to
the extracellular space (plasma volume
plus interstitial space) or may also
extend into the intracellular space .
Certain drugs may bind strongly to tissue
structures, so that plasma concentrations
fall significantly even before
elimination has begun .
After being distributed in blood,
macromolecular substances remain
largely confined to the vascular space,
because their permeation through the
blood-tissue barrier, or endothelium, is
impeded, even where capillaries are
fenestrated. This property is exploited
therapeutically when loss of blood necessitates
refilling of the vascular bed,
e.g., by infusion of dextran solutions
. The vascular space is, moreover,
predominantly occupied by substances
bound with high affinity to plasma proteins
(determination of the plasma
volume with protein-bound dyes).
Unbound, free drug may leave the
bloodstream, albeit with varying ease,
because the blood-tissue barrier
is differently developed in different segments
of the vascular tree. These regional
differences are not illustrated in
the accompanying figures.
Distribution in the body is determined
by the ability to penetrate membranous
barriers . Hydrophilic
substances (e.g., inulin) are neither taken
up into cells nor bound to cell surface
structures and can, thus, be used to determine
the extracellular fluid volume
. Some lipophilic substances diffuse
through the cell membrane and, as a result,
achieve a uniform distribution .
Body weight may be broken down
as follows:
Further subdivisions are shown in
the table.
The volume ratio interstitial: intracellular
water varies with age and body
weight. On a percentage basis, interstitial
fluid volume is large in premature or
normal neonates (up to 50 % of body
water), and smaller in the obese and the
aged.
The concentration (c) of a solution
corresponds to the amount (D) of substance
dissolved in a volume (V); thus, c
= D/V. If the dose of drug (D) and its
plasma concentration (c) are known, a
volume of distribution (V) can be calculated
from V = D/c. However, this represents
an apparent volume of distribution
(Vapp), because an even distribution
in the body is assumed in its calculation.
Homogeneous distribution will not occur
if drugs are bound to cell membranes
or to membranes of intracellular
organelles or are stored within
the latter . In these cases, Vapp can exceed
the actual size of the available fluid
volume. The significance of Vapp as a
pharmacokinetic parameter is discussed

Drug distribution in the Body III

Transcytosis (vesicular transport).
When new vesicles are pinched off,
substances dissolved in the extracellular
fluid are engulfed, and then ferried
through the cytoplasm, vesicles (phagosomes)
undergo fusion with lysosomes
to form phagolysosomes, and the transported
substance is metabolized. Alternatively,
the vesicle may fuse with the
opposite cell membrane (cytopempsis).
Receptor-mediated endocytosis
. The drug first binds to membrane
surface receptors whose cytosolic
domains contact special proteins (adaptins,
). Drug-receptor complexes migrate
laterally in the membrane and aggregate
with other complexes by a
clathrin-dependent process. The affected
membrane region invaginates
and eventually pinches off to form a detached
vesicle . The clathrin coat is
shed immediately , followed by the
adaptins . The remaining vesicle then
fuses with an “early” endosome,
whereupon proton concentration rises
inside the vesicle. The drug-receptor
complex dissociates and the receptor
returns into the cell membrane. The
“early” endosome delivers its contents
to predetermined destinations, e.g., the
Golgi complex, the cell nucleus, lysosomes,
or the opposite cell membrane
(transcytosis). Unlike simple endocytosis,
receptor-mediated endocytosis is
contingent on affinity for specific receptors
and operates independently of concentration
gradients.

Drug distribution in the Body II

Membrane Permeation
An ability to penetrate lipid bilayers is a
prerequisite for the absorption of drugs,
their entry into cells or cellular organelles,
and passage across the bloodbrain
barrier. Due to their amphiphilic
nature, phospholipids form bilayers
possessing a hydrophilic surface and a
hydrophobic interior. Substances
may traverse this membrane in three
different ways.
Diffusion. Lipophilic substances
(red dots) may enter the membrane
from the extracellular space (area
shown in ochre), accumulate in the
membrane, and exit into the cytosol
(blue area). Direction and speed of permeation
depend on the relative concentrations
in the fluid phases and the
membrane. The steeper the gradient
(concentration difference), the more
drug will be diffusing per unit of time
(Fick’s Law). The lipid membrane represents
an almost insurmountable obstacle
for hydrophilic substances (blue triangles).
Transport . Some drugs may
penetrate membrane barriers with the
help of transport systems (carriers), irrespective
of their physicochemical
properties, especially lipophilicity. As a
prerequisite, the drug must have affinity
for the carrier (blue triangle matching
recess on “transport system”) and,
when bound to the latter, be capable of
being ferried across the membrane.
Membrane passage via transport mechanisms
is subject to competitive inhibition
by another substance possessing
similar affinity for the carrier. Substances
lacking in affinity (blue circles) are
not transported. Drugs utilize carriers
for physiological substances, e.g., L-dopa
uptake by L-amino acid carrier across
the blood-intestine and blood-brain
barriers, and uptake of aminoglycosides
by the carrier transporting
basic polypeptides through the luminal
membrane of kidney tubular cells
. Only drugs bearing sufficient resemblance
to the physiological substrate
of a carrier will exhibit affinity for it.
Finally, membrane penetration
may occur in the form of small membrane-
covered vesicles.

Drug distribution in the Body I

External Barriers of the Body
Prior to its uptake into the blood (i.e.,
during absorption), a drug has to overcome
barriers that demarcate the body
from its surroundings, i.e., separate the
internal milieu from the external milieu.
These boundaries are formed by
the skin and mucous membranes.
When absorption takes place in the
gut (enteral absorption), the intestinal
epithelium is the barrier. This singlelayered
epithelium is made up of enterocytes
and mucus-producing goblet
cells. On their luminal side, these cells
are joined together by zonulae occludentes
(indicated by black dots in the inset,
bottom left). A zonula occludens or
tight junction is a region in which the
phospholipid membranes of two cells
establish close contact and become
joined via integral membrane proteins
(semicircular inset, left center). The region
of fusion surrounds each cell like a
ring, so that neighboring cells are welded
together in a continuous belt. In this
manner, an unbroken phospholipid
layer is formed (yellow area in the schematic
drawing, bottom left) and acts as
a continuous barrier between the two
spaces separated by the cell layer – in
the case of the gut, the intestinal lumen
(dark blue) and the interstitial space
(light blue). The efficiency with which
such a barrier restricts exchange of substances
can be increased by arranging
these occluding junctions in multiple
arrays, as for instance in the endothelium
of cerebral blood vessels. The connecting
proteins (connexins) furthermore
serve to restrict mixing of other
functional membrane proteins (ion
pumps, ion channels) that occupy specific
areas of the cell membrane.
This phospholipid bilayer represents
the intestinal mucosa-blood barrier
that a drug must cross during its enteral
absorption. Eligible drugs are those
whose physicochemical properties allow
permeation through the lipophilic
membrane interior (yellow) or that are
subject to a special carrier transport
mechanism. Absorption of such drugs
proceeds rapidly, because the absorbing
surface is greatly enlarged due to the
formation of the epithelial brush border
(submicroscopic foldings of the plasmalemma).
The absorbability of a drug is
characterized by the absorption quotient,
that is, the amount absorbed divided
by the amount in the gut available
for absorption.
In the respiratory tract, cilia-bearing
epithelial cells are also joined on the
luminal side by zonulae occludentes, so
that the bronchial space and the interstitium
are separated by a continuous
phospholipid barrier.
With sublingual or buccal application,
a drug encounters the non-keratinized,
multilayered squamous epithelium
of the oral mucosa. Here, the cells
establish punctate contacts with each
other in the form of desmosomes (not
shown); however, these do not seal the
intercellular clefts. Instead, the cells
have the property of sequestering phospholipid-
containing membrane fragments
that assemble into layers within
the extracellular space (semicircular inset,
center right). In this manner, a continuous
phospholipid barrier arises also
inside squamous epithelia, although at
an extracellular location, unlike that of
intestinal epithelia. A similar barrier
principle operates in the multilayered
keratinized squamous epithelium of the
outer skin. The presence of a continuous
phospholipid layer means that
squamous epithelia will permit passage
of lipophilic drugs only, i.e., agents capable
of diffusing through phospholipid
membranes, with the epithelial thickness
determining the extent and speed
of absorption. In addition, cutaneous absorption
is impeded by the keratin
layer, the stratum corneum, which is
very unevenly developed in various areas
of the skin.

Sites of Action of drug

Potential Targets of Drug Action
Drugs are designed to exert a selective
influence on vital processes in order to
alleviate or eliminate symptoms of disease.
The smallest basic unit of an organism
is the cell. The outer cell membrane,
or plasmalemma, effectively demarcates
the cell from its surroundings,
thus permitting a large degree of internal
autonomy. Embedded in the plasmalemma
are transport proteins that
serve to mediate controlled metabolic
exchange with the cellular environment.
These include energy-consuming
pumps (e.g., Na, K-ATPase), carriers
(e.g., for Na/glucose-cotransport,),
and ion channels e.g., for sodium or calcium .
Functional coordination between
single cells is a prerequisite for viability
of the organism, hence also for the survival
of individual cells. Cell functions
are regulated by means of messenger
substances for the transfer of information.
Included among these are “transmitters”
released from nerves, which
the cell is able to recognize with the
help of specialized membrane binding
sites or receptors. Hormones secreted
by endocrine glands into the blood, then
into the extracellular fluid, represent
another class of chemical signals. Finally,
signalling substances can originate
from neighboring cells, e.g., prostaglandins
and cytokines.
The effect of a drug frequently results
from interference with cellular
function. Receptors for the recognition
of endogenous transmitters are obvious
sites of drug action (receptor agonists
and antagonists, p. 60). Altered activity
of transport systems affects cell function
(e.g., cardiac glycosides,;
loop diuretics,; calcium-antagonists,).
Drugs may also directly
interfere with intracellular metabolic
processes, for instance by inhibiting
(phosphodiesterase inhibitors,)
or activating (organic nitrates,)
an enzyme .
In contrast to drugs acting from the
outside on cell membrane constituents,
agents acting in the cell’s interior need
to penetrate the cell membrane.
The cell membrane basically consists
of a phospholipid bilayer (80Å =
8 nm in thickness) in which are embedded
proteins (integral membrane proteins,
such as receptors and transport
molecules). Phospholipid molecules
contain two long-chain fatty acids in ester
linkage with two of the three hydroxyl
groups of glycerol. Bound to the
third hydroxyl group is phosphoric acid,
which, in turn, carries a further residue,
e.g., choline, (phosphatidylcholine = lecithin),
the amino acid serine (phosphatidylserine)
or the cyclic polyhydric alcohol
inositol (phosphatidylinositol). In
terms of solubility, phospholipids are
amphiphilic: the tail region containing
the apolar fatty acid chains is lipophilic,
the remainder – the polar head – is hydrophilic.
By virtue of these properties,
phospholipids aggregate spontaneously
into a bilayer in an aqueous medium,
their polar heads directed outwards into
the aqueous medium, the fatty acid
chains facing each other and projecting
into the inside of the membrane.
The hydrophobic interior of the
phospholipid membrane constitutes a
diffusion barrier virtually impermeable
for charged particles. Apolar particles,
however, penetrate the membrane
easily. This is of major importance with
respect to the absorption, distribution,
and elimination of drugs.

Drug Administration part VII

From Application to Distribution
in the Body
As a rule, drugs reach their target organs
via the blood. Therefore, they must first
enter the blood, usually the venous limb
of the circulation. There are several possible
sites of entry.
The drug may be injected or infused
intravenously, in which case the drug is
introduced directly into the bloodstream.
In subcutaneous or intramuscular
injection, the drug has to diffuse
from its site of application into the
blood. Because these procedures entail
injury to the outer skin, strict requirements
must be met concerning technique.
For that reason, the oral route
(i.e., simple application by mouth) involving
subsequent uptake of drug
across the gastrointestinal mucosa into
the blood is chosen much more frequently.
The disadvantage of this route
is that the drug must pass through the
liver on its way into the general circulation.
This fact assumes practical significance
with any drug that may be rapidly
transformed or possibly inactivated in
the liver (first-pass hepatic elimination;).
Even with rectal administration,
at least a fraction of the drug enters the
general circulation via the portal vein,
because only veins draining the short
terminal segment of the rectum communicate
directly with the inferior vena
cava. Hepatic passage is circumvented
when absorption occurs buccally or
sublingually, because venous blood
from the oral cavity drains directly into
the superior vena cava. The same would
apply to administration by inhalation
. However, with this route, a local
effect is usually intended; a systemic action
is intended only in exceptional cases.
Under certain conditions, drug can
also be applied percutaneously in the
form of a transdermal delivery system
. In this case, drug is slowly released
from the reservoir, and then penetrates
the epidermis and subepidermal
connective tissue where it enters blood
capillaries. Only a very few drugs can be
applied transdermally. The feasibility of
this route is determined by both the
physicochemical properties of the drug
and the therapeutic requirements
(acute vs. long-term effect).
Speed of absorption is determined
by the route and method of application.
It is fastest with intravenous injection,
less fast which intramuscular injection,
and slowest with subcutaneous injection.
When the drug is applied to the
oral mucosa (buccal, sublingual route),
plasma levels rise faster than with conventional
oral administration because
the drug preparation is deposited at its
actual site of absorption and very high
concentrations in saliva occur upon the
dissolution of a single dose. Thus, uptake
across the oral epithelium is accelerated.
The same does not hold true for
poorly water-soluble or poorly absorbable
drugs. Such agents should be given
orally, because both the volume of fluid
for dissolution and the absorbing surface
are much larger in the small intestine
than in the oral cavity.
Bioavailability is defined as the
fraction of a given drug dose that reaches
the circulation in unchanged form
and becomes available for systemic distribution.
The larger the presystemic
elimination, the smaller is the bioavailability
of an orally administered drug.

Drug Administration part VI

Dermatologic Agents

Pharmaceutical preparations applied to
the outer skin are intended either to
provide skin care and protection from
noxious influences, or to serve as a
vehicle for drugs that are to be absorbed
into the skin or, if appropriate, into the
general circulation .

Skin Protection
Protective agents are of several kinds to
meet different requirements according
to skin condition (dry, low in oil,
chapped vs moist, oily, elastic), and the
type of noxious stimuli (prolonged exposure
to water, regular use of alcoholcontaining
disinfectants , intense solar irradiation).
Distinctions among protective
agents are based upon consistency, physicochemical
properties (lipophilic, hydrophilic),
and the presence of additives.

Dusting Powders are sprinkled onto
the intact skin and consist of talc,
magnesium stearate, silicon dioxide
(silica), or starch. They adhere to the
skin, forming a low-friction film that attenuates
mechanical irritation. Powders
exert a drying (evaporative) effect.

Lipophilic ointment (oil ointment)
consists of a lipophilic base (paraffin oil,
petroleum jelly, wool fat [lanolin]) and
may contain up to 10 % powder materials,
such as zinc oxide, titanium oxide,
starch, or a mixture of these. Emulsifying
ointments are made of paraffins and
an emulsifying wax, and are miscible
with water.

Paste (oil paste) is an ointment
containing more than 10 % pulverized
constituents.

Lipophilic (oily) cream is an emulsion
of water in oil, easier to spread than
oil paste or oil ointments.

Hydrogel and water-soluble ointment
achieve their consistency by
means of different gel-forming agents
(gelatin, methylcellulose, polyethylene
glycol). Lotions are aqueous suspensions
of water-insoluble and solid constituents.

Hydrophilic (aqueous) cream is an
emulsion of an oil in water formed with
the aid of an emulsifier; it may also be
considered an oil-in-water emulsion of
an emulsifying ointment.
All dermatologic agents having a
lipophilic base adhere to the skin as a
water-repellent coating. They do not
wash off and they also prevent (occlude)
outward passage of water from
the skin. The skin is protected from drying,
and its hydration and elasticity increase.
Diminished evaporation of water
results in warming of the occluded skin
area. Hydrophilic agents wash off easily
and do not impede transcutaneous output
of water. Evaporation of water is felt
as a cooling effect.
Dermatologic Agents as Vehicles
In order to reach its site of action, a drug
must leave its pharmaceutical preparation
and enter the skin, if a local effect
is desired (e.g., glucocorticoid ointment),
or be able to penetrate it, if a
systemic action is intended (transdermal
delivery system, e.g., nitroglycerin
patch, ). The tendency for the drug
to leave the drug vehicle is higher
the more the drug and vehicle differ in
lipophilicity (high tendency: hydrophilic
D and lipophilic V, and vice versa). Because
the skin represents a closed lipophilic
barrier, only lipophilic
drugs are absorbed. Hydrophilic drugs
fail even to penetrate the outer skin
when applied in a lipophilic vehicle.
This formulation can be meaningful
when high drug concentrations are required
at the skin surface (e.g., neomycin
ointment for bacterial skin infections).

Drug Administration part V

Drug Administration by Inhalation
Inhalation in the form of an aerosol
, a gas, or a mist permits drugs to
be applied to the bronchial mucosa and,
to a lesser extent, to the alveolar membranes.
This route is chosen for drugs intended
to affect bronchial smooth muscle
or the consistency of bronchial mucus.
Furthermore, gaseous or volatile
agents can be administered by inhalation
with the goal of alveolar absorption
and systemic effects (e.g., inhalational
anesthetics, ). Aerosols are
formed when a drug solution or micronized
powder is converted into a mist or
dust, respectively.
In conventional sprays (e.g., nebulizer),
the air blast required for aerosol
formation is generated by the stroke of a
pump. Alternatively, the drug is delivered
from a solution or powder packaged
in a pressurized canister equipped
with a valve through which a metered
dose is discharged. During use, the inhaler
(spray dispenser) is held directly
in front of the mouth and actuated at
the start of inspiration. The effectiveness
of delivery depends on the position
of the device in front of the mouth, the
size of aerosol particles, and the coordination
between opening of the spray
valve and inspiration. The size of aerosol
particles determines the speed at which
they are swept along by inhaled air,
hence the depth of penetration into
the respiratory tract. Particles >
100 μm in diameter are trapped in the
oropharyngeal cavity; those having diameters
between 10 and 60μm will be
deposited on the epithelium of the
bronchial tract. Particles < 2 μm in diameter
can reach the alveoli, but they
will be largely exhaled because of their
low tendency to impact on the alveolar
epithelium.
Drug deposited on the mucous lining
of the bronchial epithelium is partly
absorbed and partly transported with
bronchial mucus towards the larynx.
Bronchial mucus travels upwards due to
the orally directed undulatory beat of
the epithelial cilia. Physiologically, this
mucociliary transport functions to remove
inspired dust particles. Thus, only
a portion of the drug aerosol (~ 10 %)
gains access to the respiratory tract and
just a fraction of this amount penetrates
the mucosa, whereas the remainder of
the aerosol undergoes mucociliary
transport to the laryngopharynx and is
swallowed. The advantage of inhalation
(i.e., localized application) is fully exploited
by using drugs that are poorly
absorbed from the intestine (isoproterenol,
ipratropium, cromolyn) or are subject
to first-pass elimination (beclomethasone
dipropionate, budesonide,
flunisolide, fluticasone dipropionate).
Even when the swallowed portion
of an inhaled drug is absorbed in unchanged
form, administration by this
route has the advantage that drug concentrations
at the bronchi will be higher
than in other organs.
The efficiency of mucociliary transport
depends on the force of kinociliary
motion and the viscosity of bronchial
mucus. Both factors can be altered
pathologically (e.g., in smoker’s cough,
bronchitis) or can be adversely affected
by drugs (atropine, antihistamines).

Drug Administration part IV

Dosage Forms for Parenteral ,
Pulmonary , Rectal or Vaginal ,
and Cutaneous Application
Drugs need not always be administered
orally (i.e., by swallowing), but may also
be given parenterally. This route usually
refers to an injection, although enteral
absorption is also bypassed when
drugs are inhaled or applied to the skin.
For intravenous, intramuscular, or
subcutaneous injections, drugs are often
given as solutions and, less frequently,
in crystalline suspension for
intramuscular, subcutaneous, or intraarticular
injection. An injectable solution
must be free of infectious agents,
pyrogens, or suspended matter. It
should have the same osmotic pressure
and pH as body fluids in order to avoid
tissue damage at the site of injection.
Solutions for injection are preserved in
airtight glass or plastic sealed containers.
From ampules for multiple or single
use, the solution is aspirated via a
needle into a syringe. The cartridge ampule
is fitted into a special injector that
enables its contents to be emptied via a
needle. An infusion refers to a solution
being administered over an extended
period of time. Solutions for infusion
must meet the same standards as solutions
for injection.
Drugs can be sprayed in aerosol
form onto mucosal surfaces of body cavities
accessible from the outside (e.g.,
the respiratory tract). An aerosol
is a dispersion of liquid or solid particles
in a gas, such as air. An aerosol results
when a drug solution or micronized
powder is reduced to a spray on being
driven through the nozzle of a pressurized
container.
Mucosal application of drug via the
rectal or vaginal route is achieved by
means of suppositories and vaginal
tablets, respectively. On rectal application,
absorption into the systemic circulation
may be intended. With vaginal
tablets, the effect is generally confined
to the site of application. Usually the
drug is incorporated into a fat that solidifies
at room temperature, but melts in
the rectum or vagina. The resulting oily
film spreads over the mucosa and enables
the drug to pass into the mucosa.

Powders, ointments, and pastes
are applied to the skin surface. In
many cases, these do not contain drugs
but are used for skin protection or care.
However, drugs may be added if a topical
action on the outer skin or, more
rarely, a systemic effect is intended.

Transdermal drug delivery
systems are pasted to the epidermis.
They contain a reservoir from which
drugs may diffuse and be absorbed
through the skin. They offer the advantage
that a drug depot is attached noninvasively
to the body, enabling the
drug to be administered in a manner
similar to an infusion. Drugs amenable
to this type of delivery must: (1) be capable
of penetrating the cutaneous barrier;
(2) be effective in very small doses
(restricted capacity of reservoir); and
(3) possess a wide therapeutic margin
(dosage not adjustable).

Drug Administration part III

matrix-type tablet,
the drug is embedded in an inert
meshwork from which it is released by
diffusion upon being moistened. In contrast
to solutions, which permit direct
absorption of drug , the use
of solid dosage forms initially requires
tablets to break up and capsules to open
(disintegration) before the drug can be
dissolved (dissolution) and pass
through the gastrointestinal mucosal
lining (absorption). Because disintegration
of the tablet and dissolution of the
drug take time, absorption will occur
mainly in the intestine . In
the case of a solution, absorption starts
in the stomach .
For acid-labile drugs, a coating of
wax or of a cellulose acetate polymer is
used to prevent disintegration of solid
dosage forms in the stomach. Accordingly,
disintegration and dissolution
will take place in the duodenum at normal
speed and drug liberation
per se is not retarded.
The liberation of drug, hence the
site and time-course of absorption, are
subject to modification by appropriate
production methods for matrix-type
tablets, coated tablets, and capsules. In
the case of the matrix tablet, the drug is
incorporated into a lattice from which it
can be slowly leached out by gastrointestinal
fluids. As the matrix tablet
undergoes enteral transit, drug liberation
and absorption proceed en route

coated tablets,
coat thickness can be designed such that
release and absorption of drug occur either
in the proximal or distal
bowel. Thus, by matching
dissolution time with small-bowel
transit time, drug release can be timed to occur
in the colon.

Drug liberation and, hence, absorption
can also be spread out when the
drug is presented in the form of a granulate
consisting of pellets coated with a
waxy film of graded thickness. Depending
on film thickness, gradual dissolution
occurs during enteral transit, releasing
drug at variable rates for absorption.
The principle illustrated for a capsule
can also be applied to tablets. In this
case, either drug pellets coated with
films of various thicknesses are compressed
into a tablet or the drug is incorporated
into a matrix-type tablet. Contrary
to timed-release capsules
, slow-release tablets have the advantage
of being dividable ad libitum;
thus, fractions of the dose contained
within the entire tablet may be administered.

Drug Administration part II

Solid dosage forms include tablets,
coated tablets, and capsules (B).

Tablets have a disk-like shape, produced
by mechanical compression of
active substance, filler (e.g., lactose, calcium
sulfate), binder, and auxiliary material
(excipients). The filler provides
bulk enough to make the tablet easy to
handle and swallow. It is important to
consider that the individual dose of
many drugs lies in the range of a few
milligrams or less. In order to convey
the idea of a 10-mg weight, two squares
are marked below, the paper mass of
each weighing 10 mg. Disintegration of
the tablet can be hastened by the use of
dried starch, which swells on contact
with water, or of NaHCO3, which releases
CO2 gas on contact with gastric acid.
Auxiliary materials are important with
regard to tablet production, shelf life,
palatability, and identifiability (color).

Effervescent tablets (compressed
effervescent powders) do not represent
a solid dosage form, because they are
dissolved in water immediately prior to
ingestion and are, thus, actually, liquid
preparations.


The coated tablet contains a drug within
a core that is covered by a shell, e.g., a
wax coating, that serves to: (1) protect
perishable drugs from decomposing; (2)
mask a disagreeable taste or odor; (3)
facilitate passage on swallowing; or (4)
permit color coding.

Capsules usually consist of an oblong
casing — generally made of gelatin
— that contains the drug in powder or
granulated form

Drug Administration part I

Dosage Forms for Oral, Ocular, and
Nasal Applications
A medicinal agent becomes a medication
only after formulation suitable for
therapeutic use (i.e., in an appropriate
dosage form). The dosage form takes
into account the intended mode of use
and also ensures ease of handling (e.g.,
stability, precision of dosing) by patients
and physicians. Pharmaceutical
technology is concerned with the design
of suitable product formulations and
quality control.
Liquid preparations (A) may take
the form of solutions, suspensions (a
sol or mixture consisting of small water-
insoluble solid drug particles dispersed
in water), or emulsions (dispersion
of minute droplets of a liquid agent
or a drug solution in another fluid, e.g.,
oil in water). Since storage will cause
sedimentation of suspensions and separation
of emulsions, solutions are generally
preferred. In the case of poorly
watersoluble substances, solution is often
accomplished by adding ethanol (or
other solvents); thus, there are both
aqueous and alcoholic solutions. These
solutions are made available to patients
in specially designed drop bottles, enabling
single doses to be measured exactly
in terms of a defined number of
drops, the size of which depends on the
area of the drip opening at the bottle
mouth and on the viscosity and surface
tension of the solution. The advantage
of a drop solution is that the dose, that
is, the number of drops, can be precisely
adjusted to the patient‘s need. Its disadvantage
lies in the difficulty that
some patients, disabled by disease or
age, will experience in measuring a prescribed
number of drops.
When the drugs are dissolved in a
larger volume — as in the case of syrups
or mixtures — the single dose is measured
with a measuring spoon. Dosing
may also be done with the aid of a
tablespoon or teaspoon (approx. 15 and
5 ml, respectively). However, due to the
wide variation in the size of commercially
available spoons, dosing will not
be very precise. (Standardized medicinal
teaspoons and tablespoons are
available.)
Eye drops and nose drops (A) are
designed for application to the mucosal
surfaces of the eye (conjunctival sac)
and nasal cavity, respectively. In order
to prolong contact time, nasal drops are
formulated as solutions of increased
viscosity.

Drug development picture

Drug Development

Drug Development
This process starts with the synthesis of
novel chemical compounds. Substances
with complex structures may be obtained
from various sources, e.g., plants
(cardiac glycosides), animal tissues
(heparin), microbial cultures (penicillin
G), or human cells (urokinase), or by
means of gene technology (human insulin).
As more insight is gained into structure-
activity relationships, the search
for new agents becomes more clearly
focused.
Preclinical testing yields information
on the biological effects of new substances.
Initial screening may employ
biochemical-pharmacological investigations
(e.g., receptor-binding assays
p. 56) or experiments on cell cultures,
isolated cells, and isolated organs. Since
these models invariably fall short of
replicating complex biological processes
in the intact organism, any potential
drug must be tested in the whole animal.
Only animal experiments can reveal
whether the desired effects will actually
occur at dosages that produce little
or no toxicity. Toxicological investigations
serve to evaluate the potential for:
(1) toxicity associated with acute or
chronic administration; (2) genetic
damage (genotoxicity, mutagenicity);
(3) production of tumors (onco- or carcinogenicity);
and (4) causation of birth
defects (teratogenicity). In animals,
compounds under investigation also
have to be studied with respect to their
absorption, distribution, metabolism,
and elimination (pharmacokinetics).
Even at the level of preclinical testing,
only a very small fraction of new compounds
will prove potentially fit for use
in humans.
Pharmaceutical technology provides
the methods for drug formulation.
Clinical testing starts with Phase I
studies on healthy subjects and seeks to
determine whether effects observed in
animal experiments also occur in humans.
Dose-response relationships are
determined. In Phase II, potential drugs
are first tested on selected patients for

therapeutic efficacy in those disease
states for which they are intended.
Should a beneficial action be evident
and the incidence of adverse effects be
acceptably small, Phase III is entered,
involving a larger group of patients in
whom the new drug will be compared
with standard treatments in terms of
therapeutic outcome. As a form of human
experimentation, these clinical
trials are subject to review and approval
by institutional ethics committees according
to international codes of conduct
(Declarations of Helsinki, Tokyo,
and Venice). During clinical testing,
many drugs are revealed to be unusable.
Ultimately, only one new drug remains
from approximately 10,000 newly synthesized
substances.
The decision to approve a new
drug is made by a national regulatory
body (Food & Drug Administration in
the U.S.A., the Health Protection Branch
Drugs Directorate in Canada, UK, Europe,
Australia) to which manufacturers
are required to submit their applications.
Applicants must document by
means of appropriate test data (from
preclinical and clinical trials) that the
criteria of efficacy and safety have been
met and that product forms (tablet, capsule,
etc.) satisfy general standards of
quality control.
Following approval, the new drug
may be marketed under a trade name
(p. 333) and thus become available for
prescription by physicians and dispensing
by pharmacists. As the drug gains
more widespread use, regulatory surveillance
continues in the form of postlicensing
studies (Phase IV of clinical
trials). Only on the basis of long-term
experience will the risk: benefit ratio be
properly assessed and, thus, the therapeutic
value of the new drug be determined.

Drug Sources

Until the end of the 19th century, medicines
were natural organic or inorganic
products, mostly dried, but also fresh,
plants or plant parts. These might contain
substances possessing healing
(therapeutic) properties or substances
exerting a toxic effect.
In order to secure a supply of medically
useful products not merely at the
time of harvest but year-round, plants
were preserved by drying or soaking
them in vegetable oils or alcohol. Drying
the plant or a vegetable or animal product
yielded a drug (from French
“drogue” – dried herb). Colloquially, this
term nowadays often refers to chemical
substances with high potential for physical
dependence and abuse. Used scientifically,
this term implies nothing about
the quality of action, if any. In its original,
wider sense, drug could refer equally
well to the dried leaves of peppermint,
dried lime blossoms, dried flowers
and leaves of the female cannabis plant
(hashish, marijuana), or the dried milky
exudate obtained by slashing the unripe
seed capsules of Papaver somniferum
(raw opium). Nowadays, the term is applied
quite generally to a chemical substance
that is used for pharmacotherapy.
Soaking plants parts in alcohol
(ethanol) creates a tincture. In this process,
pharmacologically active constituents
of the plant are extracted by the alcohol.
Tinctures do not contain the complete
spectrum of substances that exist
in the plant or crude drug, only those
that are soluble in alcohol. In the case of
opium tincture, these ingredients are
alkaloids (i.e., basic substances of plant
origin) including: morphine, codeine,
narcotine = noscapine, papaverine, narceine,
and others.
Using a natural product or extract
to treat a disease thus usually entails the
administration of a number of substances
possibly possessing very different activities.
Moreover, the dose of an individual
constituent contained within a
given amount of the natural product is
subject to large variations, depending


upon the product‘s geographical origin
(biotope), time of harvesting, or conditions
and length of storage. For the same
reasons, the relative proportion of individual
constituents may vary considerably.
Starting with the extraction of
morphine from opium in 1804 by F. W.
Sertürner (1783–1841), the active principles
of many other natural products
were subsequently isolated in chemically
pure form by pharmaceutical laboratories.
The aims of isolating active principles
are:
1. Identification of the active ingredient(
s).
2. Analysis of the biological effects
(pharmacodynamics) of individual ingredients
and of their fate in the body
(pharmacokinetics).
3. Ensuring a precise and constant dosage
in the therapeutic use of chemically
pure constituents.
4. The possibility of chemical synthesis,
which would afford independence from
limited natural supplies and create conditions
for the analysis of structure-activity
relationships.
Finally, derivatives of the original constituent
may be synthesized in an effort
to optimize pharmacological properties.
Thus, derivatives of the original constituent
with improved therapeutic usefulness
may be developed.

Pharmacology History

Since time immemorial, medicaments
have been used for treating disease in
humans and animals. The herbals of antiquity
describe the therapeutic powers
of certain plants and minerals. Belief in
the curative powers of plants and certain
substances rested exclusively upon
traditional knowledge, that is, empirical
information not subjected to critical examination.


Claudius Galen (129–200 A.D.) first attempted
to consider the theoretical
background of pharmacology. Both theory
and practical experience were to
contribute equally to the rational use of
medicines through interpretation of observed
and experienced results.
“The empiricists say that all is found by
experience. We, however, maintain that it
is found in part by experience, in part by
theory. Neither experience nor theory
alone is apt to discover all.”






The Impetus
Theophrastus von Hohenheim (1493–
1541 A.D.), called Paracelsus, began to
quesiton doctrines handed down from
antiquity, demanding knowledge of the
active ingredient(s) in prescribed remedies,
while rejecting the irrational concoctions
and mixtures of medieval medicine
medicine.
He prescribed chemically defined
substances with such success that professional
enemies had him prosecuted
as a poisoner. Against such accusations,
he defended himself with the thesis
that has become an axiom of pharmacology:
“If you want to explain any poison properly,
what then isn‘t a poison? All things
are poison, nothing is without poison; the
dose alone causes a thing not to be poison.”




Early Beginnings




Johann Jakob Wepfer (1620–1695)
was the first to verify by animal experimentation
assertions about pharmacological
or toxicological actions.
“I pondered at length. Finally I resolved to
clarify the matter by experiments.”


Foundation
Rudolf Buchheim (1820–1879) founded
the first institute of pharmacology at
the University of Dorpat (Tartu, Estonia)
in 1847, ushering in pharmacology as an
independent scientific discipline. In addition
to a description of effects, he
strove to explain the chemical properties
of drugs.
“The science of medicines is a theoretical,
i.e., explanatory, one. It is to provide us
with knowledge by which our judgement
about the utility of medicines can be validated
at the bedside.”
Consolidation – General Recognition
Oswald Schmiedeberg (1838–1921),
together with his many disciples (12 of
whom were appointed to chairs of pharmacology),
helped to establish the high
reputation of pharmacology. Fundamental
concepts such as structure-activity
relationship, drug receptor, and
selective toxicity emerged from the
work of, respectively, T. Frazer (1841–
1921) in Scotland, J. Langley (1852–
1925) in England, and P. Ehrlich
(1854–1915) in Germany. Alexander J.
Clark (1885–1941) in England first formalized
receptor theory in the early
1920s by applying the Law of Mass Action
to drug-receptor interactions. Together
with the internist, Bernhard
Naunyn (1839–1925), Schmiedeberg
founded the first journal of pharmacology,
which has since been published
without interruption. The “Father of
American Pharmacology”, John J. Abel
(1857–1938) was among the first
Americans to train in Schmiedeberg‘s
laboratory and was founder of the Journal
of Pharmacology and Experimental
Therapeutics (published from 1909 until
the present).
Status Quo
After 1920, pharmacological laboratories
sprang up in the pharmaceutical industry,
outside established university
institutes. After 1960, departments of
clinical pharmacology were set up at
many universities and in industry.