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

212 and atenolol, which antagonize the cardiac actions of
catecholamines while causing somewhat less antagonism
at bronchioles. Prazosin and yohimbine are representative
of α 1
and α 2
receptor antagonists, respectively,
although prazosin has a relatively high affinity at
α 2B
and α 2C
subtypes compared with α 2A
receptors.
Several important drugs that promote the release of norepinephrine
or deplete the transmitter resemble, in their
effects, activators or blockers of postjunctional receptors
(e.g., tyramine and reserpine, respectively).
SECTION II
NEUROPHARMACOLOGY
Interference with the Destruction
of the Transmitter
Cholinergic. The anti-ChE agents (see Chapter 10) constitute
a chemically diverse group of compounds, the
primary action of which is inhibition of AChE, with
the consequent accumulation of endogenous ACh. At
the neuromuscular junction, accumulation of ACh
produces depolarization of end plates and flaccid paralysis.
At postganglionic muscarinic effector sites, the
response is either excessive stimulation resulting in
contraction and secretion or an inhibitory response
mediated by hyperpolarization. At ganglia, depolarization
and enhanced transmission are observed.
Adrenergic. The reuptake of NE by the adrenergic nerve
terminals by means of NET is the major mechanism for
terminating its transmitter action. Interference with this
process is the basis of the potentiating effect of cocaine on
responses to adrenergic impulses and injected catecholamines.
It also has been suggested that the antidepressant
actions and some of the adverse effects of imipramine
and related drugs are due to a similar action at adrenergic
synapses in the CNS (Chapter 15).
Entacapone and tolcapone are nitro catechol-type COMT
inhibitors. Entacapone is a peripherally acting COMT inhibitor,
whereas tolcapone also inhibits COMT activity in the brain. COMT
inhibition has been shown to attenuate levodopa toxicity on dopamine
neurons and enhance dopamine action in the brain of patients with
Parkinson disease (Chapter 22). On the other hand, nonselective
MAO inhibitors, such as tranylcypromine, potentiate the effects of
tyramine and may potentiate effects of neurotransmitters. While most
MAO inhibitors used as antidepressants inhibit both MAO-A and
MAO-B, selective MAO-A and MAO-B inhibitors are available.
Selegiline is a selective and irreversible MAO-B inhibitor that also
has been used as an adjunct in the treatment of Parkinson disease.
OTHER AUTONOMIC
NEUROTRANSMITTERS
The vast majority of neurons in both the central and
peripheral nervous systems contain more than one
substance with potential or demonstrated activity at relevant
postjunctional sites (see Chapter 14). In some
cases, especially in peripheral structures, it has been
possible to demonstrate that two or more such substances
are contained within individual nerve terminals
and are released simultaneously on nerve stimulation.
Although the anatomic separation of the parasympathetic
and sympathetic components of the autonomic
nervous system and the actions of ACh and NE (their
primary neurotransmitters) still provides the essential
framework for studying autonomic function, a host of
other chemical messengers such as purines,
eicosanoids, NO, and peptides modulate or mediate
responses that follow stimulation of the autonomic
nervous system. An expanded view of autonomic neurotransmission
has evolved to include instances where
substances other than ACh or NE are released and may
function as co-transmitters, neuromodulators, or even
primary transmitters. For example, it appears that some
postganglionic parasympathetic nerves utilize NO as a
neurotransmitter (Toda and Okamura, 2003).
The evidence for co-transmission in the autonomic
nervous system usually encompasses the following
considerations:
• A portion of responses to stimulation of preganglionic
or postganglionic nerves or to field stimulation
of target structures persists in the presence of
concentrations of muscarinic or adrenergic antagonists
that completely block their respective agonists.
• The candidate substance can be detected within
nerve fibers that course through target tissues.
• The substance can be recovered on microdialysis or
in the venous or perfusion effluent following electrical
stimulation; such release often can be blocked
by tetrodotoxin.
• Effects of electrical stimulation are mimicked by the
application of the substance and are inhibited in the
presence of specific antagonists, neutralizing antibodies,
or selective desensitization produced by prior
exposure to the substance.
A more recent approach to this challenging problem
is the use of knockout mice that do not express the
putative co-transmitter.
A number of problems confound interpretation of such evidence.
It is particularly difficult to establish that substances that fulfill
all the listed criteria originate within the autonomic nervous
system. In some instances, their origin can be traced to sensory
fibers, to intrinsic neurons, or to nerves innervating blood vessels.
Also, there may be marked synergism between the candidate substance