ANSWERS TO CASE - 03 :
MUSCARINIC CHOLINORECEPTOR ANTAGONISTS
Summary: A 53-year-old woman with motion sickness is prescribed transder- mal scopolamine before she takes a sea cruise.
- Mechanism of action of scopolamine: Competitive antagonist of muscarinic cholinoreceptors in the vestibular system and the CNS
- Common side effects: Mydriasis, dry mouth, tachycardia, urinary retention, confusion, drowsiness
- Relative contraindications: Glaucoma, urinary obstruction, heart disease
Scopolamine, like other antimuscarinic agents, including the prototype atropine, is a selective competitive (surmountable) antagonist of ACh at mus- carinic cholinoreceptors. Its actions can be overcome by increased concentra- tions of ACh or other muscarinic cholinoreceptor agonists. Scopolamine blocks muscarinic cholinoreceptors in the vestibular system and CNS to prevent motion sickness. It has a relatively long duration of action and can be given as a transdermal patch, making it well suited for the treatment of motion sickness. Histamine H1-receptor antagonists, such as cyclizine, are also used to treat motion sickness.
In addition to motion sickness, muscarinic cholinoreceptor antagonists (e.g., benztropine) are used therapeutically to treat Parkinson disease. Short- acting topical agents or ointments are used to facilitate ophthalmoscopic examination (e.g., cyclopentolate, tropicamide). Ipratropium bromide, a qua- ternary ammonium compound that does not cross the blood-brain barrier, is used to treat asthma and has efficacy in chronic obstructive pulmonary disease (COPD). They (e.g., trospium, tolterodine) are also used to treat certain blad- der disorders. Because it penetrates the CNS, the tertiary amine atropine is used to counter the muscarinic cholinoreceptor effects of cholinergic excess resulting from organophosphate insecticide poisoning.
The adverse effects of scopolamine and other muscarinic cholinoreceptor antagonists are related to inhibition of muscarinic cholinoreceptors in organ systems of the body. Drowsiness and sedation are caused by actions on the CNS. Mydriasis is caused by blocking parasympathetic tone in the muscles of the cilia and iris. This could increase intraocular pressure in a person with glaucoma. Cholinoreceptor blockade at the sinoatrial node results in tachycardia. This could cause arrhythmias, especially in someone with underlying heart disease. The urinary bladder is relaxed and the urinary sphincter constricted, which may promote urinary retention. Blockade of muscarinic cholinoreceptors in the salivary glands reduces salivation, causing dry mouth. Blockade of other muscarinic cholinoreceptors in the CNS can lead to impairment of memory, confusion, restlessness, drowsiness, or hallucinations.
Muscarinic cholinoreceptor antagonist drugs are used cautiously in patients with angle-closure glaucoma (contraindicated), open-angle glaucoma, urinary tract obstruction (e.g., prostatic hypertrophy), cardiac dis- ease, and gastrointestinal infections, among other conditions. Elderly patients are particularly sensitive to CNS effects.
APPROACH TO MUSCARINIC CHOLINORECEPTOR ANTAGONISTS
Chronic obstructive pulmonary disease [COPD]: Progressive, inflam- matory lung conditions, including both chronic bronchitis and emphy- sema, which result in airway obstruction that is not fully reversible. Most COPD is due to smoking.
Asthma: An inflammatory lung condition characterized by reversible airway obstruction that can be precipitated by irritants such as environmental allergens, cigarette smoke, cold air or exercise.
Muscarinic Cholinoreceptor antagonists: Drugs that block the actions of acetylcholine.
Cholinoreceptor antagonists are distinguished by their specificity for muscarinic and nicotinic cholinoreceptors. Muscarinic cholinoreceptor antagonists block the effects of ACh at muscarinic cholinoreceptors in the parasympathetic autonomic nervous system and in the CNS. Nicotinic cholinoreceptor antagonists block the effects of ACh at ganglia of the parasympathetic and sympathetic nervous system (and medulla), and at the neuromuscular junction.
Like atropine, the prototype muscarinic cholinoreceptor antagonist scopo- lamine is a tertiary amine. As such, it has ready access to the CNS when administered parenterally, and it can be absorbed across the skin when com- bined with a suitable vehicle in a transdermal patch. Quaternary amine antimuscarinic agents, including tiotropium bromide, have limited access to the CNS and thus are used therapeutically for their peripheral effects.
Mechanism of Action
Interaction of scopolamine, atropine, or other antimuscarinic agents with mus- carinic cholinoreceptors prevents the typical actions of ACh, such as activation of G-proteins and subsequent production of IP3, and DAG that results in mobi- lization of calcium.
The patch formulation of scopolamine for motion sickness provides for up to 72 hours of pharmacologic activity. Scopolamine can also be administered IV, IM, or PO. Ipratropium bromide and tiotropium are administered topically to the airways as a metered-dose inhaler for COPD.
The duration of action of antimuscarinic agents ranges from less than a day (tropicamide) to 3–10 days (scopolamine, atropine).