The pharmacology of atropine, scopolamine, and glycopyrrolate

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The pharmacology of atropine, scopolamine, and glycopyrrolate

Niki M. Dietz, MD

Atropine

Atropine is a naturally occurring tertiary amine capable of inhibiting the activation of muscarinic receptors that are found primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves but also present in ganglia and on some cells. At usual doses of the drug, the principal effect of atropine is competitive antagonism of cholinergic stimuli at muscarinic receptors, with little or no effect at nicotinic receptors.

Atropine is derived from flowering plants in the family Solanaceae (e.g., deadly nightshade [Atropa belladonna, named for Atropos, the Fate of Greek mythology who cuts the thread of life], mandrake [Mandragora officinarum], or jimsonweed [Datura stramonium]). Venetian women dropped the juice of deadly nightshade into their eyes to produce mydriasis, which was thought to enhance beauty (hence, the name belladonna, which, translated from Italian, is beautiful woman). Though atropine is used today to treat pesticide poisoning, Solanaceae plants have been used since 200 AD as a biologic weapon to poison, among other substances, wells and wine.

Pharmacokinetics

Absorption

Atropine is well absorbed from the gastrointestinal tract (i.e., from the upper small intestine). It is also well absorbed following intramuscular administration or from the tracheobroncheal tree following inhalation.

Distribution

Atropine undergoes rapid distribution throughout the body, and 50% is plasma protein bound. Atropine crosses the blood-brain barrier and the placenta.

Elimination

The plasma half-life of atropine is 2 to 3 h; it is metabolized in the liver, with 30% to 50% of the drug excreted unchanged in the urine.

Pharmacologic properties

Gastrointestinal system

Atropine reduces the volumes of saliva and gastric secretions. The motility of the entire gastrointestinal tract, from esophagus to colon, is decreased, prolonging transit time. Atropine causes lower esophageal sphincter relaxation through an antimuscarinic mechanism.

Cardiovascular system

The effect of atropine on the heart is dose dependent. An intravenously administered dose of 0.4 to 0.6 mg causes a transient decrease in heart rate of about 8 beats/min, which was once thought to be due to central vagal stimulation but is now known to be mediated through an unknown mechanism. Larger doses of atropine cause progressively increasing tachycardia by blocking vagal effects on M₂ receptors on the sinoatrial node; by the same mechanism, atropine can reverse sinus bradycardia secondary to extracardiac causes but has little or no effect on sinus bradycardia caused by intrinsic disease of the sinoatrial node. Atropine at high doses (>3 mg) may cause cutaneous vasodilation.

Respiratory system

Atropine reduces the volume of secretions from the nose, mouth, pharynx, and bronchi. Along with many other anticholinergic drugs (e.g., ipratropium), it relaxes smooth muscles of bronchi and bronchioles, with resultant decreases in airway resistance.

Central nervous system

Atropine is one of the few anticholinergic agents that crosses the blood-brain barrier, stimulating the medulla and higher cerebral centers. Higher doses are associated with restlessness, irritability, disorientation, and delirium. Even higher doses produce hallucinations and coma. This constellation of symptoms and signs, called central anticholinergic syndrome, can be treated with physostigmine.

Genitourinary system

Atropine decreases the tone and amplitude of ureter and bladder contractions, one of the reasons that belladonna and opium suppositories are administered to patients who have bladder spasms in response to a urinary catheter. The relaxation effect is more pronounced in neurogenic bladders. Bladder capacity is increased and incontinence is relieved as uninhibited contractions are reduced. The renal pelves, calyces, and ureters are dilated.

Ophthalmic response

Atropine blocks responses of the sphincter muscle of the iris and the accommodative muscle of the ciliary body of the lens to cholinergic stimulation, resulting in mydriasis (pupil dilation) and cycloplegia (paralysis of lens accommodation). It usually has little effect on intraocular pressure except in patients with angle-closure glaucoma, in whom intraocular pressure may increase.

Scopolamine

Scopolamine, another belladonna alkaloid, sometimes referred to as hyoscine, has stronger antisalivary actions and much more potent central nervous system effects than does atropine (Table 84-1). It is a strong amnesic that usually also produces sedation. Restlessness and delirium are not unusual and can make patients difficult to manage. Elderly patients who take scopolamine are at risk for incurring injury from falls when unsupervised. Scopolamine produces less cardiac acceleration than does atropine, and both drugs can produce paradoxical bradycardia when used in low doses, possibly through a weak peripheral cholinergic agonist effect.

Table 84-1

Duration of Action and Effects of Atropine, Scopolamine, and Glycopyrrolate

	Duration	Effect
Drug	IV	IM	CNS	GI Tone	Antisialagogue	HR
Atropine	5-30 min	2-4 h	Stimulation	– –	+	+++*
Scopolamine	0.5-1 h	4-6 h	Sedation^†	−	+++	0/+*
Glycopyrrolate	2-4 h	6-8 h	None	– – –	++++	+

CNS, Central nervous system; GI, gastrointestinal; HR, heart rate; IM, intramuscular; IV, intravenous.

^*May decelerate initially.

^†CNS effects often manifest as sedation before stimulation.

Adapted, with permission, from Lawson NW, Meyer J. Autonomic nervous system physiology and pharmacology. In: Barash PG, Cullen BF, Stoelting RF, eds. Clinical Anesthesia. 3rd ed. Philadelphia; Lippincott Williams & Wilkins: 1997:243-327.

Scopolamine in a transdermal patch has become popular as a treatment for motion sickness. The proposed mechanism for motion sickness is a disturbance in the balance between the cholinergic and adrenergic systems in the central nervous system. Because the vomiting center is activated by stimulation of cholinergic receptors in the vestibular nuclei and reticular formation neurons by impulses transmitted in response to vestibular stimulation, drugs that inhibit the cholinergic system have been proved to be effective in preventing motion sickness and are occasionally used to prevent or treat postoperative nausea and vomiting.

Glycopyrrolate

Glycopyrrolate is a synthetic antimuscarinic with a quaternary ammonium with anticholinergic properties similar to those of atropine (see Table 84-1); however, unlike atropine, glycopyrrolate is completely ionized at physiologic pH.

Pharmacokinetics

Absorption

With intravenous injection, the typical onset of action of glycopyrrolate occurs within 1 min; with intramuscular administration, it is approximately 15 to 30 min, with peak effects occurring within approximately 30 to 45 min. Compared with atropine and scopolamine, glycopyrrolate is a more potent antisialogogue (effects persisting for up to 7 h) and has a longer duration of action (vagal-blocking effects persist for 2-3 h).

Distribution

The in vivo metabolism of glycopyrrolate in humans has not been studied.

Elimination

After intravenous administration, the mean half-life of glycopyrrolate is 45 to 60 min, and after intramuscular administration, it is 30 to 75 min.

Pharmacologic properties

Gastrointestinal system

Glycopyrrolate completely inhibits gastrointestinal motility but does not change gastric pH or the volume of gastric secretions.

Cardiovascular system

Glycopyrrolate has minimal effects on heart rate.

Central nervous system

The structure of glycopyrrolate prevents it from crossing lipid barriers; therefore, unlike atropine and scopolamine, glycopyrrolate does not cross the blood-brain barrier, and the resultant effects on the central nervous system are limited.

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