Atropine is the prototypical antimuscarinic xenobiotic. It is a competitive antagonist at both central and peripheral muscarinic receptors, used to treat patients with symptoms following exposures to muscarinic agonists such as pilocarpine, and acetylcholinesterase inhibitors and Clitocybe mushrooms. The latter group includes pesticides, such as carbamate and organic phosphorous (OP) compounds, OP chemical warfare nerve agents, and some xenobiotics used to treat patients with Alzheimer disease (eg, donepezil, rivastigmine).
Many plants contain the 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 dilated pupils.8 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 involving various organs such as the heart and the eye.16 Experiments in the 1940s with cholinesterase inhibitors demonstrated that atropine reversed many of the effects of these xenobiotics and protected against doses two to three times the LD50 (median lethal dose in 50% of test subjects) in animals.43
Atropine (dl-hyoscyamine), like scopolamine (l-hyoscine), is a tropane alkaloid with a tertiary amine structure that allows central nervous system (CNS) penetration. Tropane alkaloids are bicyclic nitrogen-containing compounds that are naturally found in the plants of the families Solanaceae (eg, deadly nightshade, datura) and Erythroxylaceae (eg, coca) and have a long history of use as poisons and therapeutic agents. Only l-hyoscyamine is active and found in nature. The process of isolation results in racemization and forms dl-hyoscyamine. Quaternary amine antimuscarinic agents such as glycopyrrolate, ipratropium, tiotropium, methylhomatropine bromide, and methylatropine bromide do not cross the blood–brain barrier into the CNS.
Cholinergic receptors consist of muscarinic and nicotinic subtypes. Muscarinic receptors are coupled to G proteins and either inhibit adenylyl cyclase (M2, M4) or increase phospholipase C (M1, M3, M5). Muscarinic receptors are widely distributed throughout the peripheral and central nervous systems.19
The competitive blockade of muscarinic receptors in normal individuals results in dose-dependent clinical effects that vary by organ system based on the degree of endogenous parasympathetic tone.8,19 In adults, low doses (0.5 mg) of atropine cause a paradoxical bradycardia, and some drying of the mouth and sweat glands. Higher doses of atropine (2 mg) produce noticeable dryness; subjective feeling of warmth; slight flushing; slight tachycardia; reactive, slightly dilated pupils; blurred near vision; mild drowsiness; some postural hypotension; and urinary hesitation. At higher doses of 3 to 5 mg of atropine all the aforementioned symptoms are exaggerated, with escalating degrees of hyperthermia, tachycardia, drowsiness, difficulty voiding, prolonged gastrointestinal (GI) transit time, and decreased GI tone. Doses of greater than or equal to 10 ...