Chapter 8.

Cholinoceptor-Blocking Drugs
Cholinoceptor-Blocking Drugs: Introduction
Cholinoceptor antagonists, like agonists, are divided into muscarinic and
nicotinic subgroups on the
basis of their specific receptor affinities. The antinicotinic drugs consist of
ganglion-blockers and
neuromuscular junction blockers. The ganglion-blocking drugs have little
clinical use and are
discussed at the end of this chapter. The neuromuscular blockers are discussed
in Chapter 27:
Skeletal Muscle Relaxants. This chapter emphasizes drugs that block muscarinic
cholinoceptors.
As noted in Chapter 6: Introduction to Autonomic Pharmacology and Chapter 7:
Cholinoceptor-
Activating & Cholinesterase-Inhibiting Drugs, five subtypes of muscarinic
receptors have been
described, primarily on the basis of data from ligand-binding and cDNA-
cloning experiments. A
standard terminology (M1 through M5) for these subtypes is now in common
use, and evidence,
based mostly on selective agonists and antagonists, indicates that functional
differences exist
between several of these subtypes.
As suggested in Chapter 6: Introduction to Autonomic Pharmacology, the M1
receptor subtype
appears to be located on central nervous system neurons, sympathetic
postganglionic cell bodies,
and many presynaptic sites. M2 receptors are located in the myocardium,
smooth muscle organs,
and some neuronal sites. M3 receptors are most common on effector cell
membranes, especially
glandular and smooth muscle cells.
Basic Pharmacology of the Muscarinic Receptor-Blocking Drugs
Muscarinic antagonists are often called parasympatholytic because they block
the effects of
parasympathetic autonomic discharge. However, they do not "lyse"
parasympathetic nerves, and
they have some effects that are not predictable from block of the
parasympathetic nervous system.
For these reasons, the term "antimuscarinic" is preferable.
Naturally occurring compounds with antimuscarinic effects have been known
and used for
millennia as medicines, poisons, and cosmetics. Atropine is the prototype of
these drugs. Many
similar plant alkaloids are known, and hundreds of synthetic antimuscarinic
compounds have been
prepared.
Chemistry & Pharmacokinetics
Source and Chemistry
Atropine and its naturally occurring congeners are tertiary amine alkaloid esters
of tropic acid
(Figure 81). Atropine (hyoscyamine) is found in the plant Atropa belladonna, or
deadly
nightshade, and in Datura stramonium, also known as jimsonweed (Jamestown
weed) or thorn
apple. Scopolamine (hyoscine) occurs in Hyoscyamus niger, or henbane, as the
l() stereoisomer.
Naturally occurring atropine is l()-hyoscyamine, but the compound readily
racemizes, so the
commercial material is racemic d,l-hyoscyamine. The l() isomers of both
alkaloids are at least 100
times more potent than the d(+) isomers.
Figure 81.
The structure of atropine (oxygen at [1] is missing) or scopolamine (oxygen
present). In
homatropine, the hydroxymethyl at [2] is replaced by a hydroxyl group, and the
oxygen at [1] is
absent.
A variety of semisynthetic and fully synthetic molecules have antimuscarinic
effects.
The tertiary members of these classes (Figure 82) are often used for their
effects on the eye or the
central nervous system. Many antihistaminic (see Chapter 16: Histamine,
Serotonin, & the Ergot
Alkaloids), antipsychotic (see Chapter 29: Antipsychotic Agents & Lithium), and
antidepressant
(see Chapter 30: Antidepressant Agents) drugs have similar structures and,
predictably, significant
antimuscarinic effects.
Figure 82.
Structures of some semisynthetic and synthetic antimuscarinic drugs.
Quaternary amine antimuscarinic agents (Figure 82) have been developed to
produce more
peripheral effects with reduced central nervous system effects.
Absorption
The natural alkaloids and most tertiary antimuscarinic drugs are well absorbed
from the gut and
conjunctival membranes. When applied in a suitable vehicle, some (eg,
scopolamine) are even
absorbed across the skin (transdermal route). In contrast, only 1030% of a
dose of a quaternary
antimuscarinic drug is absorbed after oral administration, reflecting the
decreased lipid solubility of
the charged molecule.
Distribution
Atropine and the other tertiary agents are widely distributed in the body.
Significant levels are
achieved in the central nervous system within 30 minutes to 1 hour, and this
may limit the dose
tolerated when the drug is taken for its peripheral effects. Scopolamine is
rapidly and fully
distributed into the central nervous system where it has greater effects than
most other
antimuscarinic drugs. In contrast, the quaternary derivatives are poorly taken
up by the brain and
therefore are relatively freeat low dosesof central nervous system effects.
Metabolism and Excretion
Atropine disappears rapidly from the blood after administration, with a half-life
of 2 hours. About
60% of the dose is excreted unchanged in the urine. Most of the rest appears in
the urine as
hydrolysis and conjugation products. The drug's effect on parasympathetic
function declines rapidly
in all organs except the eye. Effects on the iris and ciliary muscle persist for 72
hours.