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

270 that are selective for M 1
muscarinic receptors (Chapter 9). The slow
EPSP has a longer latency and greater duration (10-30 seconds) than
the initial EPSP. Slow EPSPs result from decreased K + conductance,
the M current that regulates the sensitivity of the cell to repetitive
fast-depolarizing events (Adams et al., 1982). In contrast, the late
slow EPSP lasts for several minutes and is mediated by peptides
released from presynaptic nerve endings or interneurons in specific
ganglia, as discussed in the next section. The peptides and ACh may
be co-released at the presynaptic nerve terminals; the relative stability
of the peptides in the ganglion extends its sphere of influence to
postsynaptic sites beyond those in the immediate proximity of the
nerve ending.
The secondary synaptic events modulate the initial EPSP. The
importance of the secondary pathways and the nature of the modulating
transmitters appear to differ among individual ganglia and
between parasympathetic and sympathetic ganglia. A variety of peptides,
including gonadotropin-releasing hormone, substance P,
angiotensin, calcitonin gene–related peptide, vasoactive intestinal
polypeptide, neuropeptide Y, and enkephalins, have been identified
in ganglia by immunofluorescence. They appear localized to particular
cell bodies, nerve fibers, or SIF cells, are released on nerve stimulation,
and are presumed to mediate the late slow EPSP (Elfvin
et al., 1993). Other neurotransmitter substances, such as 5-hydroxytryptamine
and γ-aminobutyric acid, are known to modify ganglionic
transmission. Precise details of their modulatory actions are
not understood, but they appear to be most closely associated with
the late slow EPSP and inhibition of the M current in various ganglia.
Conventional ganglionic blocking agents can inhibit ganglionic
transmission completely; the same cannot be said for muscarinic
antagonists or α adrenergic receptor agonists (Volle, 1980).
SECTION II
NEUROPHARMACOLOGY
GANGLIONIC STIMULATING DRUGS
Drugs that stimulate cholinergic receptor sites on autonomic
ganglia have been essential for analyzing the
mechanism of ganglionic function; however, these ganglionic
agonists have very limited therapeutic use. They
can be grouped into two categories. The first group consists
of drugs with nicotinic specificity, including nicotine,
itself, which millions of tobacco users ingest on a
daily basis. Nicotine’s excitatory effects on ganglia are
rapid in onset, are blocked by ganglionic nicotinic-receptor
antagonists, and mimic the initial EPSP. The second
group consists of muscarinic receptor agonists such as
muscarine, McN-A-343, and methacholine (Chapter 9);
their excitatory effects on ganglia are delayed in onset,
blocked by atropine-like drugs, and mimic the slow EPSP.
History. Two natural alkaloids, nicotine and lobeline, exhibit
peripheral actions by stimulating autonomic ganglia. Nicotine
(Figure 11–6) was first isolated from leaves of tobacco, Nicotiana
tabacum, by Posselt and Reiman in 1828; Orfila initiated the first
pharmacological studies of the alkaloid in 1843. Langley and
Dickinson painted the superior cervical ganglion of rabbits with
nicotine and demonstrated that its site of action was the ganglion
rather than the preganglionic or postganglionic nerve fiber. Lobeline,
N
NICOTINE
CH 3
O
CH 3
CCH 2 N CH 2 CHOH
C 6 H 5
TETRAMETHYLAMMONIUM (TMA)
1,1-DIMETHYL-4-PHENYLPIPERAZINIUM (DMPP)
Figure 11–6. Ganglionic stimulants.
N
from Lobelia inflata, has many of the same actions as nicotine but is
less potent.
Other ganglionic stimulants include tetramethylammonium
(TMA) and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)
(Figure 11–6). Stimulation of ganglia by TMA or DMPP differs
from that produced by nicotine in that the initial stimulation is not
followed by a dominant blocking action. DMPP is about three times
more potent and slightly more ganglion-selective than nicotine.
Although parasympathomimetic drugs stimulate ganglia, their
effects usually are obscured by stimulation of other neuroeffector
sites. McN-A-343 represents an exception: in certain tissues its primary
action appears to occur at muscarinic M 1
receptors in ganglia.
Nicotine
Nicotine is of considerable medical significance
because of its toxicity, presence in tobacco, and propensity
for conferring a dependence on its users. The
chronic effects of nicotine and the untoward effects of
the chronic use of tobacco are considered in
Chapter 24. Nicotine is one of the few natural liquid
alkaloids. It is a colorless, volatile base (pK a
= 8.5)
that turns brown and acquires the odor of tobacco on
exposure to air.
Pharmacological Actions. The complex and often
unpredictable changes that occur in the body after
administration of nicotine are due not only to its actions
on a variety of neuroeffector and chemosensitive sites
but also to the fact that the alkaloid can both stimulate
N
C 6 H 5
LOBELINE
H 3 C
N + CH 3
H 3 C CH 3
+ CH 3
N
CH 3