A variety of semisynthetic and fully synthetic molecules have antimuscarinic effects. The tertiary members of these classes (Figure 8–3) are often used for their effects on the eye or the CNS. Many antihistaminic (see Chapter 16), antipsychotic (see Chapter 29), and antidepressant (see Chapter 30) drugs have similar structures and, predictably, significant antimuscarinic effects.
Quaternary amine antimuscarinic agents (Figure 8–3) have been developed to produce more peripheral effects and reduced CNS effects.
B. Absorption
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 10–30% of a dose of a quaternary antimuscarinic drug is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule.
C. Distribution
Atropine and the other tertiary agents are widely distributed in the body. Significant levels are achieved in the CNS within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects. Scopolamine is rapidly and fully distributed into the CNS 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 free—at low doses—of CNS effects.
D. Metabolism and Excretion
After administration, the elimination of atropine from the blood occurs in two phases: the half-life (t1/2) of the rapid phase is 2 hours and that of the slow phase is approximately 13 hours. About 50% 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.
A. Mechanism of Action
Atropine causes reversible (surmountable) blockade (see Chapter 2) of cholinomimetic actions at muscarinic receptors; that is, blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist. Mutation experiments suggest that aspartate in the third trans-membrane segment of the heptahelical receptor forms an ionic bond with the nitrogen atom of acetylcholine; this amino acid is also required for binding of antimuscarinic drugs. When atropine binds to the muscarinic receptor, it prevents actions such as the
Quaternary amines for gastrointestinal and pulmonary applications (peptic disease, COPD):
Tropicamide Dicyclomine (mydriatric, cycloplegic) (peptic disease, hypermotility)
Quaternary amine for use in asthma: Tertiary amine for Parkinson’s disease:
FIGURE 8–3 Structures of some semisynthetic and synthetic antimuscarinic drugs.
release of inositol trisphosphate (IP3) and the inhibition of adenylyl cyclase that are caused by muscarinic agonists (see Chapter 7). Muscarinic antagonists were traditionally viewed as neutral compounds that occupied the receptor and prevented agonist binding. Recent evidence indicates that muscarinic receptors are constitutively active, and most drugs that block the actions of acetylcholine are inverse agonists (see Chapter 1) that shift the equilibrium to the inactive state of the receptor. Muscarinic blocking drugs that are inverse agonists include atropine, pirenzepine, trihexyphenidyl, AF-DX 116, 4-DAMP, ipratropium, glycopyrrolate, and a methyl derivative of scopolamine (Table 8–1).