Atropine (dl-hyoscyamine), like scopolamine (l-hyoscine), is a tropane alkaloid with a tertiary amine structure that allows central nervous system (CNS) penetration. Quaternary amine antimuscarinics such as glycopyrrolate, ipratropium, tiotropium, methylhomatropine bromide, and methylatropine bromide do not cross the blood–brain barrier into the CNS. 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 medicinals. Only l-hyoscyamine is active and found in nature. The process of isolation results in racemization and forms dl-hyoscyamine.
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.23
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.10,23 In adults, low doses (0.5 mg) of atropine sometimes causes a paradoxical bradycardia of about 4 to 8 beats per minute, not evident with rapid IV administration. Higher doses of atropine (2 mg) produce noticeable dryness of the mouth and sweat glands, feeling of warmth, flushing, tachycardia, reactive dilated pupils, blurred near vision, drowsiness, postural hypotension, and urinary hesitation. At higher doses (3 to 5 mg) of atropine, all the aforementioned symptoms are exaggerated, with escalating degrees of hyperthermia, tachycardia, drowsiness, difficulty voiding, prolonged gastrointestinal transit time, and decreased peristalsis. Doses of greater than or equal to 10 mg of atropine produce incapacitation with hot, dry, flushed skin, dilated pupils, blurred vision, very dry mouth, tachycardia, urinary retention, constipation, increased drowsiness or disorientation, hallucinations, stereotypical movements, bursts of laughter, delirium, and finally, coma, and rarely death.10,22
The paradoxical bradycardia produced at low doses of atropine is thought to be a consequence of the inhibition of peripheral M1 presynaptic postganglionic parasympathetic neurons. Stimulation of these receptors by acetylcholine inhibits the further release of acetylcholine, and atropine interferes with this negative feedback.10,48 Not all studies, however, have shown this paradoxical decrease in heart rate.27
Centrally acting muscarinic antagonists include atropine, scopolamine, and homatropine. Glycopyrrolate, ipratropium, and tiotropium act peripherally. Scopolamine is approximately 10 times more potent than atropine.31 Homatropine is approximately one-tenth as potent as atropine, depending on the measured outcome and route of administration.29
Cholinesterase inhibitors prevent the breakdown of acetylcholine by acetylcholinesterase, thereby increasing the amount of acetylcholine available to stimulate cholinergic receptors at both muscarinic and nicotinic subtypes, although the degree of effect varies widely among the class. Atropine is a competitive antagonist of acetylcholine only at muscarinic receptors and not nicotinic receptors.13
Miosis from the topical instillation of a cholinesterase inhibitor into the eye will not be reversed by the systemic administration of atropine.22 The systemic administration of 354 mg of atropine made one patient floridly anticholinergic but did not counteract the ophthalmic effects of a previously instilled topical cholinesterase inhibitor.22
Pharmacokinetics and Pharmacodynamics
Atropine is absorbed rapidly from most routes of administration including inhalation, oral, and intramuscular (IM).3 Ingestion of 1 mg of atropine produces maximal effects on heart rate and on salivary secretions in 1 and 3 hours, respectively. The duration of action may last from 12 to 24 hours, depending on the dose.
The distribution half-life of atropine following intravenous (IV) administration is approximately one minute. The apparent volume of distribution (Vd) is about 2 to 2.6 L/kg.29 As a result of the rapid distribution, 10 minutes after IV administration less than 5% of the dose remains in the serum. The serum concentrations of atropine are similar at 1 hour following either 1 mg IV or IM in adults.3,7 The elimination half-life is 6.5 hours.41
Following IM administration of 0.02 mg/kg in adults, the absorption rate and elimination rates are comparable for the racemic dl-hyoscyamine and the active l-hyoscyamine at 8 minutes and 2.5 hours, respectively. The mean peak serum concentration and the area under the curve (AUC) are higher for the racemic mixture indicating a stereochemical difference in pharmacokinetics.29 Renal elimination accounts for 34% to 57% of the excretion of the dose, and the majority of renal elimination occurs within 6 hours.3 Serum concentrations of l-hyoscyamine correlate with effects on heart rate and the antisialagogue effects. Serum concentrations below 0.5 μg/L may cause bradycardia in adults, whereas higher concentrations cause tachycardia.29
A study of intraosseous (IO) administration in minipigs demonstrated a pharmacokinetic profile similar to IV atropine.35 The time to maximum concentration following a dose of 0.25 mg/kg was 2 minutes with both IV and IO injection, compared to 3.5 minutes for IM injection.
Atropine autoinjectors are now given to first responders for use during chemical terrorist attacks. The administration of 2 mg of atropine by autoinjector was compared with 2 mg administered by conventional needle and syringe into the deltoid of six adult subjects.46 The onset of tachycardia and the time to maximal increase in heart rate occurred sooner with the autoinjector (16 minutes versus 23 minutes, and 34 minutes versus 41 minutes, respectively). An analysis of radiographs of contrast material injected by autoinjector or conventional IM administration into the leg of a dog demonstrated that the autoinjector appeared to “spray” the material into a larger tissue area, accounting for a faster rate of absorption.46
Ophthalmic instillation of atropine causes cyclopegia and mydriasis by blocking the M3 muscarinic receptor on the iris sphincter muscle.34 The peak mydriatic effect occurs within 30 to 40 minutes and persists for 7 to 10 days. In contrast, the effects of topical homatropine on the eye occur sooner than topical atropine (10–30 minutes for mydriasis and 30–90 minutes for cycloplegia) and are shorter in duration (6–48 hours).
The effects on pupillary dilation after systemic atropine administration depend on the dose and route of administration. An IM dose of 0.01 mg/kg into the thigh of healthy adults produced no change in pupil size,14 while subcutaneous administration into the upper arm of doses of 0.5 mg, 1 mg, and 2 mg per 70 kg person produced a dose dependent increase in pupil size. An oral dose of 0.02 mg/kg also produced pupillary dilation.12,27
An investigation of the bioavailability of atropine eye drops in healthy adults revealed approximately a 65% systemic absorption, but with a wide individual variability.28 The time to maximum serum concentration was 30 minutes, and the apparent elimination half-life was 2.5 hours.
The pharmacokinetics of three inhaled doses of atropine from a metered dose nebulizer was compared with 2 mg of IM atropine in healthy adults.24 Peak concentrations were comparable for the 2 mg inhaled and 2 mg IM atropine doses. The time to peak concentration following inhalation averaged 1.3 hours. A novel nanoatropine dry powder inhaler is being evaluated to rapidly achieve blood concentrations of atropine in the hopes of circumventing IM administration.2