• Muscarinic receptors belong to the class of G protein–coupled
receptors. These receptors, in addition to binding ACh, have
distinguished five subclasses of muscarinic receptors: M1, M2, M3,
M4, and M5. Although five muscarinic receptors have been
identified by gene cloning, only M1, M2, and M3 receptors have
been functionally characterized. M1 receptors are also found on
gastric parietal cells, M2 receptors on cardiac cells and smooth
muscle, and M3 receptors on the bladder, exocrine glands, and
• In neurochemistry, a muscarinic receptor antagonist (MRA) is an
agent that blocks the activity of the muscarinic acetylcholine
receptor. Acetylcholine (often abbreviated ACh) is a
neurotransmitter, whose receptor is a protein found in synapses
and other cell membranes.
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
• 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-
Mechanism of Action
• The muscarinic blocking agents act like
competitive (surmountable) pharmacologic
antagonists; their blocking effects can be
overcome by increased concentrations of
• The peripheral actions of muscarinic blockers are mostly
predictable effects derived from cholinoceptor blockade
.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.
• The muscarinic blockers have several useful therapeutic
applications in the CNS, eye, bronchi, gut, and urinary
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 ,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.
• 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 plant to dilate the pupils. They also cause cycloplegia and
paralyze accommodation. In descending order of duration of action, these drugs
are atropine (>72 h), homatropine (24 h), cyclopentolate (2–12 h), and
tropicamide (0.5–4 h). These agents are all well absorbed from the conjunctival sac
into the eye.
• Parenteral atropine has long been used to reduce airway secretions during general
anesthesia. Ipratropium is a quaternary antimuscarinic agent used by inhalation to
promote bronchodilation in asthma and chronic obstructive pulmonary disease
(COPD). Although not as efficacious as agonists, ipra-tropium is less likely to cause
tachycardia and cardiac arrhythmias in sensitive patients. It has very few
antimuscarinic effects outside the lungs because it is poorly absorbed and rapidly
metabolized. Tiotropium is a newer analog with a longer duration of action.
• Atropine, methscopolamine, and propantheline were used
in the past to reduce acid secretion in acid-peptic disease,
but are now obsolete for this indication because they are
not as effective as H2 blockers and proton pump
inhibitors ,and they cause far more frequent and severe
adverse effects. The M1-selective inhibitor pirenzepine is
available in Europe for the treatment of peptic ulcer.
Muscarinic blockers can also be used to reduce cramping
and hypermotility in transient diarrheas, but drugs such as
diphenoxylate and loperamide are more effective.
• Oxybutynin, tolterodine, or similar agents may be used to reduce
urgency in mild cystitis and to reduce bladder spasms after urologic
surgery. Tolterodine, darifenacin, solifenacin, and fesoterodine are
promoted for the treatment of stress incontinence.
• A traditional mnemonic for atropine toxicity is "Dry as a bone, red
as a beet, mad as a hatter." This description reflects both
predictable antimuscarinic effects and some unpredictable actions.
• Antimuscarinic actions lead to several important and potentially
dangerous effects. Blockade of thermoregulatory sweating may
result in hyperthermia or "atropine fever." This is the most
dangerous effect of the antimuscarinic drugs in children and is
potentially lethal in infants. Atropine toxicity is described as feeling
"dry as a bone" because sweating, salivation, and lacrimation are all
significantly reduced or stopped. Moderate tachycardia is common,
and severe tachycardia or arrhythmias are common with large
overdoses. In the elderly, important additional targets of toxicity
include the eye (acute angle-closure glaucoma may occur) and the
bladder (urinary retention is possible, especially in men with
prostatic hyperplasia). Constipation and blurred vision are common
adverse effects in all age groups.
Toxicities not predictable from peripheral autonomic actions
include the following.
•CNS toxicity includes sedation, amnesia, and delirium or
hallucinations ("mad as a hatter"); convulsions may also occur. Central
muscarinic receptors are probably involved. Other drug groups with
antimuscarinic effects, for example, tricyclic antidepressants, may
cause hallucinations or delirium in the elderly, who are especially
susceptible to antimuscarinic toxicity.
• At very high doses, intraventricular conduction
may be blocked; this action is probably not
mediated by muscarinic blockade and is difficult
to treat. Dilation of the cutaneous vessels of the
arms, head, neck, and trunk also occurs at these
doses; the resulting "atropine flush" ("red as a
beet") may be diagnostic of overdose with these
drugs. The mechanism is unknown.
• The antimuscarinic agents should be used
cautiously in infants because of the danger of
hyperthermia. The drugs are relatively
contraindicated in persons with glaucoma,
especially the closed-angle form, and in men
with prostatic hyperplasia.