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.
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.
