Page 147 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 8 Cholinoceptor-Blocking Drugs 133

Delayed-onset mushroom poisoning, usually caused by Amanita Recent evidence indicates that some centrally acting drugs
phalloides, Amanita virosa, Galerina autumnalis, or Galerina mar- (tricyclic antidepressants, selective serotonin reuptake inhibitors,
ginata, manifests its first symptoms 6–12 hours after ingestion. anti-anxiety agents, antihistamines) with antimuscarinic actions
Although the initial symptoms usually include nausea and vomit- impair memory and cognition in older patients.
ing, the major toxicity involves hepatic and renal cellular injury by
amatoxins that inhibit RNA polymerase. Atropine is of no value Contraindications
in this form of mushroom poisoning (see Chapter 58).
Contraindications to the use of antimuscarinic drugs are relative,
not absolute. Obvious muscarinic excess, especially that caused
H. Other Applications by cholinesterase inhibitors, can always be treated with atropine.
Hyperhidrosis (excessive sweating) is sometimes reduced by anti- Antimuscarinic drugs are contraindicated in patients with
muscarinic agents. However, relief is incomplete at best, probably glaucoma, especially angle-closure glaucoma. Even systemic use of
because apocrine rather than eccrine glands are usually involved. moderate doses may precipitate angle closure (and acute glaucoma)
in patients with shallow anterior chambers.
In elderly men, antimuscarinic drugs should always be used
Adverse Effects with caution and should be avoided in those with a history of
prostatic hyperplasia.
Treatment with atropine or its congeners directed at one organ
system almost always induces undesirable effects in other organ Because the antimuscarinic drugs slow gastric emptying, they
systems. Thus, mydriasis and cycloplegia are adverse effects when may increase symptoms in patients with gastric ulcer. Nonselective
an antimuscarinic agent is used to reduce gastrointestinal secretion antimuscarinic agents should never be used to treat acid-peptic
or motility, even though they are therapeutic effects when the drug disease (see Chapter 62).
is used in ophthalmology.
At higher concentrations, atropine causes block of all parasym-
pathetic functions. However, atropine is a remarkably safe drug in ■ BASIC & CLINICAL
adults. Atropine poisoning has occurred as a result of attempted PHARMACOLOGY OF THE
suicide, but most cases are due to attempts to induce hallucina- GANGLION-BLOCKING DRUGS
tions. Poisoned individuals manifest dry mouth, mydriasis, tachy-
cardia, hot and flushed skin, agitation, and delirium for as long as Ganglion-blocking agents competitively block the action of
1 week. Body temperature is frequently elevated. These effects are acetylcholine and similar agonists at neuronal nicotinic receptors
memorialized in the adage, “dry as a bone, blind as a bat, red as a of both parasympathetic and sympathetic autonomic ganglia.
beet, mad as a hatter.” Some members of the group also block the ion channel that is
Unfortunately, children, especially infants, are very sensitive to gated by the nicotinic cholinoceptor. The ganglion-blocking drugs
the hyperthermic effects of atropine. Although accidental admin- are important and used in pharmacologic and physiologic research
istration of over 400 mg has been followed by recovery, deaths because they can block all autonomic outflow. However, their lack
have followed doses as small as 2 mg. Therefore, atropine should of selectivity confers such a broad range of undesirable effects that
be considered a highly dangerous drug when overdose occurs in they have limited clinical use.
infants or children.
Overdoses of atropine or its congeners are generally treated
symptomatically (see Chapter 58). Poison control experts discour- Chemistry & Pharmacokinetics
age the use of physostigmine or another cholinesterase inhibitor All ganglion-blocking drugs of interest are synthetic amines.
to reverse the effects of atropine overdose because symptomatic Tetraethylammonium (TEA), the first to be recognized as hav-
management is more effective and less dangerous. When physo- ing this action, has a very short duration of action. Hexametho-
stigmine is deemed necessary, small doses are given slowly intrave- nium (“C6”) was developed and was introduced clinically as the
nously (1–4 mg in adults, 0.5–1 mg in children). Symptomatic first drug effective for management of hypertension. As shown in
treatment may require temperature control with cooling blankets Figure 8–7, there is an obvious relationship between the struc-
and seizure control with diazepam. tures of the agonist acetylcholine and the nicotinic antagonists
Poisoning caused by high doses of quaternary antimuscarinic tetraethylammonium and hexamethonium. Decamethonium, the
drugs is associated with all of the peripheral signs of parasympa- “C10” analog of hexamethonium, is a depolarizing neuromuscular
thetic blockade but few or none of the CNS effects of atropine. blocking agent.
These more polar drugs may cause significant ganglionic block- Mecamylamine, a secondary amine, was developed to improve
ade, however, with marked orthostatic hypotension (see below). the degree and extent of absorption from the gastrointestinal tract
Treatment of the antimuscarinic effects, if required, can be carried because the quaternary amine ganglion-blocking compounds were
out with a quaternary cholinesterase inhibitor such as neostig- poorly and erratically absorbed after oral administration. Trimeth-
mine. Control of hypotension may require the administration of aphan, a short-acting, polar, ganglion-blocking drug, is no longer
a sympathomimetic drug such as phenylephrine. available for clinical use.