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CHAPTER 8 Cholinoceptor-Blocking Drugs 125

Naturally occurring atropine is l(−)-hyoscyamine, but the com-
pound readily racemizes, so the commercial material is racemic
Extracellular d,l-hyoscyamine. The l(−) isomers of both alkaloids are at least
vestibule
100 times more potent than the d(+) isomers.
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 sim-
Tyr lid ilar structures and, predictably, significant antimuscarinic effects.
Quaternary amine antimuscarinic agents (Figure 8–3) have
been developed to produce more peripheral effects and reduced
Orthosteric CNS effects.
binding site
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
FIGURE 8–1 Upper portion of the M 3 receptor with a “lid” absorbed across the skin (transdermal route). In contrast, only
formed by tyrosine (Tyr) residues separating the cavity into an upper 10–30% of a dose of a quaternary antimuscarinic drug is absorbed
portion called the vestibule from the lower portion, with the ortho- after oral administration, reflecting the decreased lipid solubility
steric binding site depicted as occupied by tiotropium. The recep- of the charged molecule.
tor is in black, tiotropium is in yellow, and the receptor surface is in
green. (Adapted, with permission, from Kruse AC et al: Structure and dynamics of
the M 3 muscarinic acetylcholine receptor. Nature 2012;482:552. Copyright © 2012 C. Distribution
Macmillan Publishers Ltd.) 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
plant alkaloids are known, and hundreds of synthetic antimusca- taken for its peripheral effects. Scopolamine is rapidly and fully
rinic compounds have been prepared. distributed into the CNS where it has greater effects than most
other antimuscarinic drugs. In contrast, the quaternary deriva-
Chemistry & Pharmacokinetics tives are poorly taken up by the brain and therefore are relatively
free—at low doses—of CNS effects.
A. Source and Chemistry
Atropine and its naturally occurring congeners are tertiary amine D. Metabolism and Excretion
alkaloid esters of tropic acid (Figure 8–2). Atropine (hyoscyamine) After administration, the elimination of atropine from the blood
is found in the plant Atropa belladonna, or deadly nightshade, and occurs in two phases: the half-life (t ) of the rapid phase is
1/2
in Datura stramonium, also known as jimson-weed (Jamestown 2 hours and that of the slow phase is approximately 13 hours.
weed), sacred Datura, or thorn apple. Scopolamine (hyoscine) About 50% of the dose is excreted unchanged in the urine. Most
occurs in Hyoscyamus niger, or henbane, as the l(−) stereoisomer. 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.
N CH
[2] 3
O Pharmacodynamics
HOCH 2 O
C A. Mechanism of Action
C O
[1] Atropine causes reversible (surmountable) blockade (see Chapter 2)
H of cholinomimetic actions at muscarinic receptors; that is, block-
ade by a small dose of atropine can be overcome by a larger
Tropic acid Base concentration of acetylcholine or equivalent muscarinic agonist.
Mutation experiments suggest that aspartate in the third trans-
FIGURE 8–2 The structure of atropine (oxygen [red] at [1] is membrane segment of the heptahelical receptor forms an ionic
missing) or scopolamine (oxygen present). In homatropine, the bond with the nitrogen atom of acetylcholine; this amino acid is
hydroxymethyl at [2] is replaced by a hydroxyl group, and the oxygen also required for binding of antimuscarinic drugs. When atropine
at [1] is absent. binds to the muscarinic receptor, it prevents actions such as the