High-Yield Terms to Learn

Anticholinergic A drug that blocks muscarinic or nicotinic receptors, but commonly used to mean antimuscarinic Antimuscarinic A drug that blocks muscarinic but not nicotinic receptors Atropine fever Hyperthermia induced by antimuscarinic drugs; caused mainly by inhibition of sweating Atropine flush Marked cutaneous vasodilation of the arms and upper torso and head by antimuscarinic drugs; mechanism unknown Cholinesterase regenerator A chemical antagonist that binds the phosphorus of organophosphates and displaces acetylcholinesterase Cycloplegia Paralysis of accommodation; inability to focus on close objects Depolarizing blockade Flaccid skeletal muscle paralysis caused by persistent depolarization of the neuromuscular end plate Miotic A drug that constricts the pupil Mydriatic A drug that dilates the pupil Nondepolarizing blockade Flaccid skeletal muscle paralysis caused by blockade of the nicotinic receptor and prevention of end plate depolarization Parasympatholytic, parasympathoplegic A drug that reduces the effects of parasympathetic nerve stimulation, usually by blockade of the muscarinic receptors of autonomic effector tissues

Muscarinic Antagonists

Classification and Pharmacokinetics

Classification of the Muscarinic Antagonists

Muscarinic antagonists can be subdivided according to their selectivity for specific M receptors or their lack of such selectivity. Although the division of muscarinic receptors into subgroups is well documented (Chapters 6 and 7), only 2 receptor-selective M1 antagonists have reached clinical trials (eg, pirenzepine, telenzepine). However, as noted later, several agents in use in the United States are somewhat selective for the M3 subtype. Most of the drugs in general use in the United States are relatively nonspecific. The muscarinic blockers can also be subdivided on the basis of their primary clinical target organs (central nervous system [CNS], eye, bronchi, or gastrointestinal and genitourinary tracts). Drugs used for their effects on the CNS or the eye must be sufficiently lipid-soluble to cross lipid barriers. A major determinant of this property is the presence or absence of a permanently charged (quaternary) amine group in the drug molecule. This is because charged molecules are more polar and therefore less likely to penetrate a lipid barrier such as the blood-brain barrier or the cornea of the eye.

Pharmacokinetics of Atropine

Atropine is the prototypical nonselective muscarinic blocker. This alkaloid is found in Atropa belladonna and many other plants. Because it is a tertiary amine, atropine is relatively lipid-soluble and readily crosses membrane barriers. The drug is well distributed into the CNS and other organs and is eliminated partially by metabolism in the liver and partially unchanged in the urine. The elimination half-life is approximately 2 h, and the duration of action of normal doses is 4-8 h except in the eye, where effects last for 72 h or longer.

Pharmacokinetics of Other Muscarinic Blockers

In ophthalmology, topical activity (the ability to enter the eye after conjunctival administration) and duration of action are important in determining the usefulness of several antimuscarinic drugs (see Clinical Uses). Similar ability to cross lipid barriers is essential for the agents used in parkinsonism. In contrast, the drugs used for their antisecretory or antispastic actions in the gut, bladder, and bronchi are often selected for minimum CNS activity; these drugs may incorporate quaternary amine groups to limit penetration through the blood-brain barrier.

Mechanism of Action

The muscarinic blocking agents act like competitive (surmountable) pharmacologic antagonists; their blocking effects can be overcome by increased concentrations of muscarinic agonists.

Effects

The peripheral actions of muscarinic blockers are mostly predictable effects derived from cholinoceptor blockade (Table 8-1). These include the ocular, gastrointestinal, genitourinary, and secretory effects. The CNS effects are less predictable. CNS effects seen at therapeutic concentrations include sedation, reduction of motion sickness, and, as previously noted, reduction of some of the signs of parkinsonism. Cardiovascular effects at therapeutic doses include an initial slowing of heart rate caused by central or presynaptic vagal effects followed by the tachycardia and decreased atrioventricular conduction time that would be predicted from peripheral vagal blockade. It has been claimed that the M1-selective agents (not currently available in the United States) are somewhat selective for the gastrointestinal tract.

TABLE 8-1 Effects of muscarinic blocking drugs.

Organ Effect Mechanism CNS Sedation, anti-motion sickness action, antiparkinson action, amnesia, delirium Block of muscarinic receptors, several subtypes Eye Cycloplegia, mydriasis Block of M3 receptors

Bronchi Bronchodilation, especially if constricted Block of M3 receptors

Gastrointestinal tract Relaxation, slowed peristalsis, reduced salivation Block of M1, M3 receptors

Genitourinary tract Relaxation of bladder wall, urinary retention Block of M3 and possibly M1 receptors

Heart Initial bradycardia, especially at low doses, then tachycardia Tachycardia from block of M2 receptors in the sinoatrial node

Blood vessels Block of muscarinic vasodilation; not manifest unless a muscarinic agonist is present Block of M3 receptors on endothelium of vessels

Glands Marked reduction of salivation; moderate reduction of lacrimation, sweating; less reduction of gastric secretion Block of M1, M3 receptors

Skeletal muscle None

Clinical Uses

The muscarinic blockers have several useful therapeutic applications in the CNS, eye, bronchi, gut, and urinary bladder. These uses are listed in the Drug Summary table at the end of this chapter.

CNS

Scopolamine is standard therapy for motion sickness; it is one of the most effective agents available for this condition. A transdermal patch formulation is available. Benztropine, biperiden, and trihexyphenidyl are representative of several antimuscarinic agents used in parkinsonism. Although not as effective as levodopa (see Chapter 28), these agents may be useful as adjuncts or when patients become unresponsive to levodopa. Benztropine is sometimes used parenterally to treat acute dystonias caused by antipsychotic medications.

Eye

Antimuscarinic drugs are used to cause mydriasis, as indicated by the origin of the name belladonna (“beautiful lady”) from the ancient cosmetic use of extracts of the Atropa belladonna

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