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INTRODUCTION

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Atropine is the prototypical antimuscarinic xenobiotic. It is a competitive antagonist at both central and peripheral muscarinic receptors that is used to treat patients with symptoms following exposures to muscarinic agonists such as pilocarpine, Clitocybe and Inocybe mushroom species, and acetylcholinesterase inhibitors. The latter group includes pesticides, such as carbamate and organic phosphorus compounds, chemical weapons nerve agents, and some xenobiotics used to treat patients with Alzheimer disease, such as donepezil and rivastigmine.

HISTORY

Many plants contain the tropane alkaloids atropine and/or scopolamine. One notable example is Atropa belladonna, named by Linnaeus after Atropos, the goddess of fate in Greek mythology who could cut short a person’s life. Belladonna means beautiful woman in Italian and comes from the practice by Italian women of placing belladonna extract in their eyes to produce aesthetically pleasing mydriasis.14 In the early 1800s, atropine was isolated and purified from plants. In the 1860s, Fraser experimented with the dose–response relationship between atropine and physostigmine in various organs such as the heart and the eye.28 Experiments in the 1940s with cholinesterase inhibitors demonstrated that atropine reversed many of the effects of these xenobiotics and protected animals against doses 2 to 3 times the dose necessary to kill 50% of the animals (LD50).62

PHARMACOLOGY

Chemistry

Tropane alkaloids are bicyclic nitrogen-containing compounds that are naturally found in the plants of the families Solanaceae (eg, Datura stramonium) and Erythroxylaceae (eg, Erythroxycom coca) and have a long history of use as poisons and medicinals. Atropine (D,L-hyoscyamine), like scopolamine (L-hyoscine), is a tropane alkaloid with a tertiary amine structure that allows central nervous system (CNS) penetration. Only L-hyoscyamine is active and found in nature. Quaternary amine antimuscarinics such as glycopyrrolate, ipratropium, tiotropium, methylhomatropine, and methylatropine bromide are charged and do not cross the blood–brain barrier into the CNS (Fig. A35–1). The process of isolation results in racemization and forms D,L-hyoscyamine.

FIGURE A35–1.

The comparison of atropine, a tertiary amine structure which permits central nervous penetration, and glycopyrrolate, which is a quaternary amine structure and thus does not cross the blood–brain barrier.

Mechanism of Action

Centrally acting muscarinic antagonists include atropine, scopolamine, and homatropine. Glycopyrrolate, ipratropium, and tiotropium act peripherally. Scopolamine is approximately 10 times more potent than atropine.40 Homatropine is approximately one-tenth as potent as atropine, depending on the measured outcome and route of administration.38 Cholinergic receptors consist of muscarinic and nicotinic subtypes. Muscarinic receptors are coupled to G proteins and either inhibit adenylate cyclase (M2, M4) or increase phospholipase C (M1, M3, M5). Muscarinic receptors are widely distributed throughout the peripheral and ...

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