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

258 abundance in muscle, along with β, δ, and γ or ε. At least eight subtypes
of α (α2 through α9) and three of the non-α type (designated
as β2 through β4) are found in neuronal tissues (Figure 11–2).
Studies of neuronal receptor subunit abundance and associations in
brain and the periphery have enabled investigators to identify subunit
combinations that confer function. Although not all permutations of
α and β subunits lead to functional receptors, the diversity in subunit
composition is large and exceeds the capacity of ligands to distinguish
subtypes on the basis of their selectivity. For example, the
α3/β4 and α3/β2 subtypes are prevalent in peripheral ganglia,
whereas the α4/β2 subtype is most prevalent in brain. The subtypes
α2 through α6 and β2 through β4 associate as heteromeric pentamers
composed of two or three distinct subtypes, whereas α7
through α9 often are seen as homomeric associations. Distinctive
selectivities of the receptor subtypes for Na + and Ca 2+ suggest that
certain subtypes may possess functions other than rapid trans-synaptic
signaling.
NEUROMUSCULAR BLOCKING AGENTS
chemical identification of the curare alkaloids are presented in previous
editions of this book.
King established the essential structure of tubocurarine in
1935 (Figure 11–3). A synthetic derivative, metocurine (formerly
called dimethyl tubocurarine), contains three additional methyl
groups and possesses two to three times the potency of tubocurarine
in human beings. The most potent curare alkaloids are the toxiferines,
obtained from Strychnos toxifera. A semisynthetic derivative,
alcuronium chloride (N,N´-diallylnortoxiferinium dichloride), was
widely used clinically in Europe and elsewhere. The seeds of the
trees and shrubs of the genus Erythrina, widely distributed in tropical
and subtropical areas, contain erythroidines that possess curarelike
activity. Gallamine is one of a series of synthetic substitutes for
curare described by Bovet and co-workers in 1949.
Early structure-activity studies led to the development of the
polymethylene bis-trimethyl-ammonium series (referred to as the
methonium compounds). The most potent of these agents at the neuromuscular
junction was the compound with 10 carbon atoms
between the quaternary nitrogens: decamethonium (C10)
(Figure 11–3). The compound with 6 carbon atoms in the chain,
hexamethonium (C6), was found to be essentially devoid of neuromuscular
blocking activity but particularly effective as a ganglionic
blocking agent (see following discussion).
SECTION II
NEUROPHARMACOLOGY
The classical neuromuscular blocker, curare, was the
tool that Claude Bernard used in the mid-19th century
to demonstrate a locus of drug action at or near the neuromuscular
junction. Modern-day neuromuscular
blocking agents fall generally into two classes, depolarizing
and competitive/non-depolarizing. At present,
only a single depolarizing agent, succinylcholine
(ANECTINE, QUELICIN), is in general clinical use, whereas
multiple competitive or non-depolarizing agents are
available (Figure 11–3).
History, Sources, and Chemistry. Curare is a generic term for various
South American arrow poisons. The drug has been used for centuries
by Indians along the Amazon and Orinoco Rivers for
immobilizing and paralyzing wild animals used for food; death
results from paralysis of skeletal muscles. The preparation of curare
was long shrouded in mystery and was entrusted only to tribal witch
doctors. Soon after the discovery of the American continent,
European explorers and botanists became interested in curare, and
late in the 16th century, samples of the native preparations were
brought to Europe. Following the pioneering work of the
scientist/explorer von Humboldt in 1805, the botanical sources of
curare became the object of much field research. The curares from
eastern Amazonia come from Strychnos species; these and other
South American species of Strychnos contain chiefly quaternary neuromuscular-blocking
alkaloids. The Asiatic, African, and Australian
species nearly all contain tertiary strychnine-like alkaloids.
The modern clinical use of curare apparently dates from
1932, when West employed highly purified fractions in patients with
tetanus and spastic disorders. Research on curare was accelerated
greatly by the work of Gill, who, after prolonged and intimate study
of the native methods of preparing curare, brought to the U.S. a sufficient
amount of the authentic drug to permit chemical and pharmacological
investigations. Griffith and Johnson reported the first
trial of curare for promoting muscular relaxation in general anesthesia
in 1942. Details of the fascinating history of curare and the
Structure-Activity Relationships. Several structural features distinguish
competitive and depolarizing neuromuscular blocking
agents. The competitive agents (e.g., tubocurarine, the benzylisoquinolines,
the ammonio steroids, and the asymmetric mixed-onium
chlorofumarates) are relatively bulky, rigid molecules, whereas the
depolarizing agents (e.g., decamethonium [no longer marketed in
the U.S. and succinylcholine) generally have more flexible structures
that enable free bond rotations (Figure 11–3). While the distance
between quaternary groups in the flexible depolarizing agents
can vary up to the limit of the maximal bond distance (1.45 nm for
decamethonium), the distance for the rigid competitive blockers is
typically 1.0 ± 0.1 nm. L-Tubocurarine is considerably less potent
than D-tubocurarine, perhaps because the D-isomer has all the
hydrophilic groups localized uniquely to one surface.
Pharmacological Properties
Actions on Organ Systems
Skeletal Muscle. Claude Bernard first described a localized
paralytic action of curare in the 1850s. The site of
action of D-tubocurarine and other competitive blocking
agents was identified as the motor end plate (a thickened
region of postjunctional membrane) by fluorescence
and electron microscopy, micro-iontophoretic
application of drugs, patch-clamp analysis of single
channels, and intracellular recording. Competitive
antagonists combine with the nicotinic ACh receptor at
the end plate and thereby competitively block the binding
of ACh. When the drug is applied directly to the end
plate of a single isolated muscle fiber, the muscle cell
becomes insensitive to motor-nerve impulses and to
directly applied ACh; however, the end-plate region