DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

and do not readily cross the axonal membrane into the
nerve ending. The latrotoxins from black widow spider
venom and stonefish are known to promote neuroexocytosis
by binding to receptors on the neuronal membrane.
Adrenergic. Several drugs that promote the release of
the adrenergic mediator already have been discussed.
On the basis of the rate and duration of the druginduced
release of norepinephrine from adrenergic terminals,
one of two opposing effects can predominate.
Thus tyramine, ephedrine, amphetamine, and related
drugs cause a relatively rapid, brief liberation of the
transmitter and produce a sympathomimetic effect. On
the other hand, reserpine, by blocking the vesicular
amine transporter (VAMT2) uptake of amines, produces
a slow, prolonged depletion of the adrenergic
transmitter from adrenergic storage vesicles, where it
is largely metabolized by intraneuronal MAO. The
resulting depletion of transmitter produces the equivalent
of adrenergic blockade. Reserpine also causes the
depletion of 5-HT, DA, and possibly other, unidentified
amines from central and peripheral sites, and many of
its major effects may be a consequence of the depletion
of transmitters other than NE.
As discussed earlier, deficiencies of tyrosine hydroxylase in
humans cause a neurologic disorder (Carson and Robertson, 2002)
that can be treated by supplementation with the dopamine precursor
levodopa.
A syndrome caused by congenital DβH deficiency has been
described; this syndrome is characterized by the absence of NE and
epinephrine, elevated concentrations of DA, intact baroreflex afferent
fibers and cholinergic innervation, and undetectable concentrations of
plasma DβH activity (Carson and Robertson, 2002). Patients have
severe orthostatic hypotension, ptosis of the eyelids, and retrograde
ejaculations. Dihydroxyphenylserine (L-DOPS) has been shown to
improve postural hypotension in this rare disorder. This therapeutic
approach cleverly takes advantage of the nonspecificity of aromatic
L-amino acid decarboxylase, which synthesizes NE directly from this
drug in the absence of DβH (Man in’t Veld et al., 1988; Robertson
et al., 1991). Despite the restoration of plasma NE in humans with
L-DOPS, epinephrine levels are not restored, leading to speculations
that PNMT may require DβH for appropriate functioning (Carson and
Robertson, 2002).
Agonist and Antagonist
Actions at Receptors
Cholinergic. The nicotinic receptors of autonomic
ganglia and skeletal muscle are not identical; they
respond differently to certain stimulating and block -
ing agents, and their pentameric structures contain
different combinations of homologous subunits
(Table 8–2). Dimethylphenylpiperazinium (DMPP)
and phenyltrimethylammonium (PTMA) show some
selectivity for stimulation of autonomic ganglion
cells and end plates of skeletal muscle, respectively.
Trimethaphan and hexamethonium are relatively
selective competitive and noncompetitive ganglionic
blocking agents. Although tubocurarine effectively
blocks transmission at both motor end plates and
autonomic ganglia, its action at the former site predominates.
Succinylcholine, a depolarizing agent, produces
selective neuromuscular blockade. Transmission
at autonomic ganglia and the adrenal medulla is complicated
further by the presence of muscarinic receptors
in addition to the principal nicotinic receptors (see
Chapter 11).
Various toxins in snake venoms exhibit a high degree of
specificity toward cholinergic receptors. The α-neurotoxins from the
Elapidae family interact with the agonist-binding site on the nicotinic
receptor. α-Bungarotoxin is selective for the muscle receptor and
interacts with only certain neuronal receptors, such as those containing
α 7
through α 9
subunits. Neuronal bungarotoxin shows a wider
range of inhibition of neuronal receptors. A second group of toxins,
called the fasciculins, inhibits AChE. A third group of toxins, termed
the muscarinic toxins (MT 1
through MT 4
), includes partial agonists
and antagonists for the muscarinic receptors. Venoms from the
Viperidae family of snakes and the fish-hunting cone snails also have
relatively selective toxins for nicotinic receptors.
Muscarinic ACh receptors, which mediate the effects of ACh
at autonomic effector cells, now can be divided into five subclasses.
Atropine blocks all the muscarinic responses to injected ACh and
related cholinomimetic drugs whether they are excitatory, as in the
intestine, or inhibitory, as in the heart. Newer muscarinic agonists,
pirenzepine for M 1
, tripitramine for M 2
, and darifenacin for M 3
,
show selectivity as muscarinic blocking agents. Several muscarinic
antagonists show sufficient selectivity in the clinical setting to minimize
the bothersome side effects seen with the nonselective agents
at therapeutic doses (see Chapter 9).
Adrenergic. A vast number of synthetic compounds that
bear structural resemblance to the naturally occurring
catecholamines can interact with α and β adrenergic
receptors to produce sympathomimetic effects (see
Chapter 12). Phenylephrine acts selectively at α 1
receptors,
whereas clonidine is a selective α 2
adrenergic
agonist. Isoproterenol exhibits agonist activity at both
β 1
and β 2
receptors. Preferential stimulation of cardiac
β 1
receptors follows the administration of dobutamine.
Terbutaline is an example of a drug with relatively
selective action on β 2
receptors; it produces effective
bronchodilation with minimal effects on the heart. The
main features of adrenergic blockade, including the
selectivity of various blocking agents for α and β adrenergic
receptors, are considered in detail in Chapter 12.
Partial dissociation of effects at β 1
and β 2
receptors has
been achieved by subtype-selective antagonists, as
exemplified by the β 1
receptor antagonists metoprolol
211
CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS