Page 490 - Basic _ Clinical Pharmacology ( PDFDrive )

476 SECTION V Drugs That Act in the Central Nervous System

■ BASIC PHARMACOLOGY OF
NEUROMUSCULAR BLOCKING N CH 3 HO OCH 3
DRUGS O
H
H
Chemistry
HO N +
All of the available neuromuscular blocking drugs bear a struc- CH 3 O O
tural resemblance to acetylcholine. For example, succinylcholine Tubocurarine CH 3 CH 3
is two acetylcholine molecules linked end-to-end (Figure 27–2).
In contrast to the linear structure of succinylcholine and other O O
depolarizing drugs, the nondepolarizing agents (eg, pancuronium) CH 3 O OCH 3
conceal the “double-acetylcholine” structure in one of two types of CH 2 CH 2 CO(CH 2 ) 5 OCCH 2 CH 2 +
+
bulky, semi-rigid ring systems (Figure 27–2). Examples of the two CH 3 O N N OCH 3
CH 3 H 3 C
CH 2 H 2 C

CH 3 O OCH 3
O CH 3
OCH 3 OCH 3
CH 3 C O CH 2 CH 2 + N CH 3 Atracurium
CH 3
FIGURE 27–3 Structures of two isoquinoline neuromuscular
Acetylcholine
blocking drugs. These agents are nondepolarizing muscle relaxants.

O CH 3 major families of nondepolarizing blocking drugs—the isoquino-
CH 2 C O CH 2 CH 2 + N CH 3 line and steroid derivatives—are shown in Figures 27–3 and 27–4.
Another feature common to all currently used neuromuscular
CH 3 blockers is the presence of one or two quaternary nitrogens, which
makes them poorly lipid soluble and limits entry into the CNS.
O CH 3

CH 2 C O CH 2 CH 2 + N CH 3 Pharmacokinetics of Neuromuscular
Blocking Drugs
CH 3
Succinylcholine All of the neuromuscular blocking drugs are highly polar
compounds and inactive orally; they must be administered
CH 3 parenterally.

C O
A. Nondepolarizing Relaxant Drugs
O The rate of disappearance of a nondepolarizing neuromuscular
CH 3 blocking drug from the blood is characterized by a rapid ini-
12 17 +
11 16 N tial distribution phase followed by a slower elimination phase.
CH 3 CH Neuromuscular blocking drugs are highly ionized, do not readily
+ 3 14 CH
N 1 9 3 cross cell membranes, and are not strongly bound in peripheral
2 8 H
O tissues. Therefore, their volume of distribution (80–140 mL/kg)
3 7 is only slightly larger than the blood volume.
H C C O 6
3
H The duration of neuromuscular blockade produced by non-
depolarizing relaxants is strongly correlated with the elimina-
Pancuronium
tion half-life. Drugs that are excreted by the kidney typically
have longer half-lives, leading to longer durations of action
(>35 minutes). Drugs eliminated by the liver tend to have
FIGURE 27–2 Structural relationship of succinylcholine, a shorter half-lives and durations of action (Table 27–1). All
depolarizing agent, and pancuronium, a nondepolarizing agent,
to acetylcholine, the neuromuscular transmitter. Succinylcholine, steroidal muscle relaxants are metabolized to their 3-hydroxy,
originally called diacetylcholine, is simply two molecules of acetyl- 17-hydroxy, or 3,17-dihydroxy products in the liver. The
choline linked through the acetate methyl groups. Pancuronium may 3-hydroxy metabolites are usually 40–80% as potent as the
be viewed as two acetylcholine-like fragments (outlined in color) parent drug. Under normal circumstances, metabolites are not
oriented on a steroid nucleus. formed in sufficient quantities to produce a significant degree of