Anticholinergic drugs

Anticholinergic drugs

Muscarinic Receptor Antagonists

The class of drugs referred to here as muscarinic receptor antagonists includes (1) the naturally occurring alkaloids, atropine and scopolamine; (2) semisynthetic derivatives of these alkaloids, which primarily differ from the parent compounds in their disposition in the body or their duration of action; and (3) synthetic congeners, some of which show selectivity for particular subtypes of muscarinic receptors. Noteworthy agents among the synthetic derivatives are homatropine and tropicamide, which have a shorter duration of action than atropine, and methylatropine, ipratropium, and tiotropium, which are quaternized and do not cross the blood–brain barrier or readily cross membranes. The latter two agents are given by inhalation in the treatment of chronic obstructive pulmonary disease and are pending approval for use in bronchial asthma. Ipratropium also has an FDA-approved indication for perennial- and common cold–associated rhinorrhea. The synthetic derivatives possessing partial receptor selectivity include pirenzepine, used in the treatment of acid-peptic disease in some countries, and tolterodine, oxybutynin, and several others, used in the treatment of urinary incontinence.

Muscarinic receptor antagonists prevent the effects of ACh by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells; in peripheral ganglia; and in the CNS. In general, muscarinic receptor antagonists cause little blockade at nicotinic receptor sites. However, the quaternary ammonium antagonists generally exhibit a greater degree of nicotinic blocking activity, and consequently are more likely to interfere with ganglionic or neuromuscular transmission.

Cholinergic transmission appears to be both muscarinic and nicotinic at spinal, subcortical, and cortical levels in the brain (see Chapter 12). At high or toxic doses, central effects of atropine and related drugs are observed, generally consisting of CNS stimulation followed by depression. Since quaternary compounds penetrate the blood–brain barrier poorly, they have little or no effect on the CNS.

Parasympathetic neuroeffector junctions in different organs vary in their sensitivity to muscarinic receptor antagonists (Table 7–2). Small doses of atropine depress salivary and bronchial secretion and sweating. With larger doses, the pupil dilates, accommodation of the lens to near vision is inhibited, and vagal effects on the heart are blocked so that the heart rate is increased. Larger doses antagonize parasympathetic control of the urinary bladder and gastrointestinal tract, thereby inhibiting micturition and decreasing the tone and motility of the gut. Still larger doses are required to inhibit gastric motility and particularly secretion. Thus, doses of atropine and most related muscarinic receptor antagonists that depress gastric secretion also almost invariably affect salivary secretion, ocular accommodation, micturition, and gastrointestinal tone. This hierarchy of relative sensitivities is not a consequence of differences in the affinity of atropine for the muscarinic receptors at these sites because atropine lacks selectivity toward different muscarinic receptor subtypes. More likely determinants include the degree to which the functions of various end organs are regulated by parasympathetic tone and the involvement of intramural neurons and reflexes.

Table 7–2 Effects of Atropine in Relation to Dose



DOSE EFFECTS
0.5 mg Slight cardiac slowing; some dryness of mouth; inhibition of sweating
1 mg Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils
2 mg Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision
5 mg All the above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition; reduced intestinal peristalsis
10 mg and more Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma




The actions of most clinically available muscarinic receptor antagonists differ only quantitatively from those of atropine, considered below as the prototype of the group. No antagonist in the receptor-selective category, including pirenzepine, is completely selective (i.e., can be used to define a single receptor subtype relative to all other receptor subtypes). In fact, clinical efficacy of some agents may arise from a balance of antagonistic actions on two or more receptor subtypes