CASE 3

A 53-year-old woman comes to see you for a consultation. She is scheduled to take a Caribbean cruise in 2 weeks but is concerned about sea sickness. She has been on boats before and is very sensitive to motion sickness. A friend mentioned to her that there is a patch that is effective for this problem. She is in good health and takes no medications regularly. Her examination is normal. You prescribe a scopolamine transdermal patch for her.

image What is the mechanism of action of scopolamine?

image What are the common side effects of this medication?

image What are some relative contraindications to its use?

ANSWERS TO CASE 3:

Muscarinic Cholinoreceptor Antagonists

Summary: A 53-year-old woman with motion sickness is prescribed transdermal scopolamine before she takes a sea cruise.

image Mechanism of action of scopolamine: Competitive antagonist of muscarinic cholinoreceptors in the vestibular system and the CNS.

image Common side effects: Mydriasis, dry mouth, tachycardia, urinary retention, confusion, drowsiness.

image Relative contraindications: Glaucoma, urinary obstruction, heart Disease.

CLINICAL CORRELATION

Scopolamine, like other antimuscarinic agents, including the prototype atropine, is a selective competitive (surmountable) antagonist of ACh at muscarinic cholinoreceptors. Its actions can be overcome by increased concentrations 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 (eg, benztropine) are used therapeutically to treat Parkinson disease. Short-acting topical agents or ointments are used to facilitate ophthalmoscopic examination (eg, cyclopentolate, tropicamide). Ipratropium bromide, a quaternary 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 (eg, trospium, tolterodine) are also used to treat certain bladder 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, which could increase intraocular pressure in a person with glaucoma. Cholinoreceptor blockade at the sinoatrial node results in tachycardia, which 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 (eg, prostatic hypertrophy), cardiac disease, and gastrointestinal infections, among other conditions. Elderly patients are particularly sensitive to CNS effects.

APPROACH TO:

Muscarinic Cholinoreceptor Antagonists

OBJECTIVES

1. Describe the mechanism of action of muscarinic cholinoreceptor antagonists.

2. Describe the physiologic effects of muscarinic cholinoreceptor antagonists.

3. List important therapeutic uses of muscarinic cholinoreceptor antagonists.

4. List the adverse effects and contraindications for muscarinic cholinoreceptor antagonists.

DEFINITIONS

Chronic obstructive pulmonary disease (COPD): Progressive, inflammatory lung conditions, including both chronic bronchitis and emphysema, 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.

Muscarinic cholinoreceptor antagonists: Drugs that block the actions of acetylcholine.

DISCUSSION

Class

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.

Structure

Like atropine, the prototype muscarinic cholinoreceptor antagonist scopolamine 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 combined 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 muscarinic cholinoreceptors prevents the typical actions of ACh, such as activation of G-proteins and subsequent production of IP3, and DAG that results in mobilization of calcium.

Administration

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.

Pharmacokinetics

The duration of action of antimuscarinic agents ranges from less than a day (tropicamide) to 3–10 days (scopolamine, atropine).

COMPREHENSION QUESTIONS

3.1 Prescription of a muscarinic cholinoreceptor antagonist with a quaternary amine group is most appropriate for the patient with which of the following conditions?

A. A 50-year-old woman with angle-closure glaucoma

B. A 34-year-old man with gastrointestinal infectious enteritis

C. A 66-year-old man with mild dementia

D. A 56-year-old diabetic woman with urinary tract obstruction

3.2 A 16-year-old teenager is going on his first deep sea fishing trip and is using a scopolamine patch to ward off sea sickness. Which of the following is the most likely adverse effect he will experience?

A. Bradycardia

B. Drowsiness

C. Miosis

D. Urinary urgency

3.3 Cholinergic excess resulting from organophosphate insecticide poisoning can be treated with which of the following?

A. Atropine

B. Digoxin

C. Ipratropium bromide

D. Tropicamide

ANSWERS

3.1 C. Muscarinic cholinoreceptor antagonists with quaternary amine groups do not penetrate the CNS and are therefore unlikely to impair memory. By blocking gastrointestinal motility, these agents can cause increased retention of infecting organisms.

3.2 B. Scopolamine penetrates the CNS and can cause drowsiness and sedation. It also can cause mydriasis, tachycardia, and urinary retention.

3.3 A. Atropine is a tertiary amine that can penetrate the CNS. In addition to its peripheral blocking actions, it can also block the adverse CNS effects as a result of cholinergic excess. Tropicamide is also a tertiary amine. However, it has a very short duration of action and would be an unsuitable antidote. Ipratropium bromide is a charged quaternary ammonium compound that does not penetrate the CNS.

PHARMACOLOGY PEARLS

image Many antihistaminic agents, antipsychotic agents, and antidepressant agents have muscarinic cholinoreceptor antagonist (antimuscarinic) activity.

image Scopolamine is a tertiary amine and has ready access to the CNS when administered parenterally, whereas quaternary amine antimuscarinic agents, such as ipratropium bromide, have limited access to the CNS.

image Scopolamine can cause drowsiness and sedation, as well as mydriasis, tachycardia, and urinary retention.

image Cholinoreceptor agonists cause symptoms of SLUD—salivation, lacrimation, urination, diarrhea—whereas cholinoreceptor antagonists have the opposite effects—dry mouth, dry eyes, urinary retention, constipation.

REFERENCES

Alhasso AA, McKinlay J, Patrick K, et al. Anticholinergic drugs versus non-drug active therapies for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2006;18(4):CD003193.

Eglen RM. Overview of muscarinic receptor subtypes. Handb Exp Pharmacol. 2012;(208):3–28.

Nachum Z, Shupak A, Gordon C. Transdermal scopolamine for prevention of motion sickness: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2006;45(6):543–66.

Sellers DJ, Chess-Williams R. Muscarinic agonists and antagonists: effects on the urinary bladder. Handb Exp Pharmacol. 2012;(208):375–400.