A32: Antidotes in Depth

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 mushrooms, and acetylcholinesterase inhibitors. The latter group includes pesticides, such as carbamate and organic phosphorous compounds, chemical warfare nerve agents, and some xenobiotics used to treat patients with Alzheimer disease, such as donepezil and 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.¹⁰ 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.²⁰ Experiments in the 1940s with cholinesterase inhibitors demonstrated that atropine reversed many of the effects of these xenobiotics and protected animals against doses two to three times the LD₅₀.⁵⁰

Chemistry

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.

Mechanism of Action

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

One of the earliest descriptions of the effectiveness of atropine in parathion and tetraethylpyrophosphate insecticide poisoning was published in 1955.²¹ Atropine improved survival when administered early and continued with adequate maintenance doses, intubation, and ventilation. Parathion and tetraethylpyrophosphate insecticide exposure led to heart block and bronchoconstriction in dogs, whereas humans were more likely to develop a relative bradycardia. Humans were more likely to die from respiratory causes resulting from central apnea, diaphragmatic weakness, and bronchorrhea.

In 1971, a landmark case series and review of organic phosphorus compound (OP) insecticide poisonings was published. Included was a table classifying the severity of poisoning along with treatment protocols for each level of severity.³⁶ This regimen served as the foundation of treatment regimens (atropine and pralidoxime) for many years.

In the 1930s and 1940s, the Germans synthesized OP insecticides (acetylcholinesterase inhibitors) that were further developed as chemical warfare nerve agents (Chap. 132).⁴⁵ Although these xenobiotics inhibit acetylcholinesterase in a manner similar to traditional OP insecticides, these so-called “nerve agents” also affect other cholinesterases, and at high doses directly affect nicotinic and muscarinic receptors. Atropine was chosen in the late 1940s as the standard antidote for these nerve agents. The dose of atropine needed to antagonize these nerve agents is much less than that needed to effectively antagonize traditional OP insecticides, largely because of differences in pharmacokinetics. The benefits of adding pralidoxime to atropine were noted in the 1950s, and in the 1960s, pralidoxime was established as a standard antidote in addition to atropine for these xenobiotics (Antidotes in Depth: A33).

When atropine is used in the absence of a xenobiotic that increases or mimics acetylcholine, adverse effects begin at 0.5 mg IV in the adult and include dry mouth and decreased sweat. However, in the presence of muscarinics or anticholinesterases, these effects may not occur until many milligrams of atropine are administered.

Intravenous doses of greater than 10 mg of atropine and oral doses of 500 to 1000 mg have been administered with full recovery. Deaths from atropine use are usually correlated with hyperthermia.

An unintentional atropine dose of one thousand milligrams orally resulted in typical manifestations of anticholinergic poisoning that began within a short time and lasted 4 days.¹ In 2 hours the patient went from feeling hot and flushed with blurred vision to stupor. Over the ensuing 24 hours he became tachycardic, hyperthermic, and comatose with dilated, nonreactive pupils and shallow respirations. By 40 hours he started to respond to his name and his temperature had normalized, but he had dry mucous membranes with dilated and nonreactive pupils. He went from coma to restlessness, hallucinations, and paranoia. At 4 days he regained a normal mental status with amnesia for the previous 4 days.

A survey of pediatric emergency departments in Israel reported on 240 children who were unintentionally injected by atropine autoinjections or autoinjector systems, triggering unintended administration, self administration, needle injury, or delivery to an unintended site during the Persian Gulf crisis.⁴ Half of the children developed systemic effects that correlated with the doses of atropine administered. Eight percent of effects were serious, but there were no seizures or deaths.

Systemic atropine toxicity may occur when too large a dose of atropine, scopolamine, or homatropine is instilled in the eye, especially in children.³⁸ Excessive absorption from other routes of administration such as rectal or inhalation would also be expected to result in toxicity.⁴⁴ In the event of an atropine overdose, physostigmine, a reversible, CNS active, cholinesterase inhibitor, is the antidote of choice (Antidotes in Depth: A9).³⁷ Schizophrenic patients in the 1950s were often given atropine as a treatment. Within 15 to 20 minutes of getting 32 to 212 mg of IM atropine, patients become restless and often confused. This progressed to muscular incoordination, ataxia, weakness, and garbled speech.¹⁹ The patients then progressed to disorientation with illusions, visual hallucinations, and delirium, to coma. The coma often lasted for 4 to 6 hours, and then patients recovered in a manner that in some respects is the reverse of poisoning. Regardless of the dose of atropine required to induce the coma, physostigmine 4 mg IM completely reversed the toxicity within 20 minutes, although the reversal only lasted for 30 to 45 minutes.^19,37

Other precautions or contraindications to consider when administering atropine include those associated with all antimuscarinics and include narrow angle closure glaucoma, obstructive uropathy, gastroparesis, pylorospasm, relaxation of the lower esophageal sphincter, and myasthenia gravis. Of course these complications must be weighed against the possible life-threatening nature of OP, carbamate, and chemical nerve agent poisoning.

Atropine is classified by the Food and Drug Administration (FDA) as pregnancy category C. Atropine crosses the placenta and may cause tachycardia in the fetus near term. Human data suggest low risk, and atropine should be used when indicated.^9,47 The American Academy of Pediatrics classifies atropine to be as compatible with breast-feeding.⁹

The dosage regimen of atropine for pesticide poisoning in adults has never been evaluated in a randomized, controlled trial, and there is considerable variation in recommendations in the literature.¹⁶ A prospective, observational study suggested that a dose doubling, titrated protocol provided equal efficacy with less atropine toxicity compared with a less preplanned ad hoc dosing protocol.⁴⁰ Experience suggested that atropine should be initiated in adults in doses of 1 to 2 mg IV for mild to moderate poisoning and 3 to 5 mg IV for severe poisoning with unconsciousness.³⁶ This dose can be doubled every 3 to 5 minutes until improvement has begun, at which time dose doubling can stop and similar or smaller doses can be used.^17,42 We believe that the most important end point for adequate atropinization is the resolution of bronchorrhea and the reversal of the muscarinic toxic syndrome. However, it is important not to confuse abnormal focal ausculatory sounds associated with pulmonary aspiration with those of extensive bronchorrhea.^17,42 Some authors suggest clear lungs, heart rate greater than or equal to 80 beats/min, and systolic blood pressure exceeding 80 mm Hg as the most important goals of therapy, and dry axillae and wider than pinpoint pupils as additional goals.¹⁸ Once these end points are achieved, a maintenance dose of atropine needs to be started. One group suggests administering 10% to 20% of the loading dose as an IV infusion every hour as a starting point with meticulous, frequent reevaluation and titration.^16,17 Atropine can be diluted in 0.9% sodium chloride, with rates of 0.5 to 1.5 mg/h of atropine commonly used.⁴⁰ For example, if a patient received atropine 2 mg IV, then 4 mg in 5 minutes, and 8 mg in 5 minutes, when improvement in bronchorrhea is noticeable, the total loading dose to initial control would be 14 mg in 10 minutes. The initial IV infusion dose of atropine would be 1.4 mg/h. This could be achieved by mixing 10 mg of atropine in 100 mL of 0.9% sodium chloride to make a concentration of 0.1 mg/mL and infusing it at 14 mL (1.4 mg)/h. If too much atropine is administered, the patient demonstrates classic signs of peripheral and central anticholinergic toxicity as described above.

The IV/IO starting dose of atropine in children is 0.02 mg/kg up to the adult dose.^39,42,49 A continuous infusion of 0.025 mg/kg/h was successfully used in a 2 year-old child following a fenthion poisoning.⁸ Although a minimum dose of 0.1 mg has been advocated, this dose would be toxic to infants <5 kg and is not recommended.⁶

In the event that a person is exposed to a chemical warfare nerve agent, atropine should be administered in a dosage suitable for both the severity of the poisoning and the age of the patient. In a conscious adult with mild to moderate cholinergic effects, 2 mg of atropine IV or IM should be administered every 5 to 10 minutes until shortness of breath improves and drying of secretions occurs.⁴⁵ One adult autoinjector of atropine for IM administration, Mark 1 Nerve Agent Antidote Kit (NAAK), contains 2 mg of atropine, and therefore multiple injectors may be required. Total doses of 2 to 4 mg of atropine are usually all that is needed, which is much lower than the dose for most OP pesticide exposures. Patients who are unconscious or apneic require higher total doses, with 5 to 15 mg usually sufficing.⁴⁵

The appropriate total Mark 1 autoinjector doses of atropine for children depend on age and weight.^25,32 For ages 3 to 7 (13–25 kg), one autoinjector (2 mg) of atropine and one autoinjector of pralidoxime (600 mg) should be administered, resulting in a projected atropine dose of 0.08 to 0.15 mg/kg. For ages 8 to 14, two autoinjectors of atropine and two autoinjectors of pralidoxime should be administered, resulting in a projected atropine dose of 0.08 to 0.15 mg/kg. For patients older than 14 years of age, three autoinjectors of atropine and pralidoxime should be administered, resulting in a projected dose of atropine of less than 0.11 mg/kg. In an emergency for children younger than 3 years of age, a risk-to-benefit analysis would suggest injecting one autoinjector of atropine and one of pralidoxime. If time permits and only one autoinjector is available for use, its contents may be transferred to a small sterile vial for traditional IM administration with a needle and syringe.²⁶ Some experts recommend that children under the age of one year be administered one pediatric atropine autoinjector (0.5 mg), such as AtroPen (Meridian Medical Technologies, Inc.), if available, and children over the age of one year be administered the Mark 1 autoinjector as described above.

When IV administration is not feasible, atropine may also be administered IO at the standard IV dose. However, the dose for endotracheal administration in adults should be two to two-and-a-half times the IV dose, diluted in 5 to 10 mL of 0.9% sodium chloride solution or sterile water. For children, the 2010 American Heart Association guidelines for pediatric advanced life support recommend 0.04 to 0.06 mg/kg in a child endotracheally, followed by a flush of 5 mL of 0.9% sodium chloride solution and then five manual ventilations to enhance absorption.³⁹

Atropine sulfate injection is available in many different strengths, with the following concentrations in each 1 mL vial or ampule: 50 μg, 300 μg, 400 μg, 500 μg, 800 μg, and 1 mg. Atropine sulfate is also available in prefilled 5 mL or 10 mL syringes with a concentration of 0.1 mg/mL for adults and in 5 mL syringes with a concentration of 0.05 mg/mL for pediatrics.

The AtroPen Auto-Injector is a prefilled syringe designed for IM injection by an autoinjector into the outer thigh.⁵ It is available in four strengths: 0.25 mg, 0.5 mg (blue label), 1 mg (dark red label), and 2 mg (green label).

Atropine is also packaged in a kit designed for IM injection with a second autoinjector containing 600 mg of pralidoxime in 2 mL of sterile water for injection with 40 mg benzyl alcohol and 22.5 mg glycine. The pralidoxime injector is accompanied by an atropine autoinjector containing 2.1 mg of atropine in 0.7 mL of a sterile solution containing 12.47 mg glycerin and not more than 2.8 mg phenol. This particular combination kit is called a “Mark 1 Nerve Agent Antidote Kit” and is designed for IM use in case of a nerve agent attack. The needles are 0.8 inches in length.³³ The Mark 1 NAAK has recently been replaced by the DuoDote Autoinjector System and the analagous, military designated antidote treatment nerve agent, autoinjector (ATNAA), which use technology that sequentially administers 2.1 mg in 0.7 mL atropine followed by 600 mg in 2 mL pralidoxime chloride IM through the same syringe. The 23 gauge needle is 0.8 inches in length.

Atropine is available orally in 300 μg, 400 μg, and 600 μg tablets.

In case of a shortage during an emergency, large quantities of atropine syringes can be compounded by a pharmacist from atropine powder utilizing standard syringe batching system.³⁰ In vitro evidence suggests that outdated atropine retains its potency and that an extemporaneously prepared atropine solution from powder is stable for at least 3 days.^15,43 Other sources of atropine to consider in an emergency during a shortage would be atropine eye drops, which come as a 1% concentration (10 mg/mL). Homatropine, available as eye drops in a 2% or 5% concentration, compared favorably with atropine in preventing lethality when administered IM in a pretreatment rodent model using dichlorvos. In this experimental model, homatropine appeared to be half as potent as atropine.¹¹ Atropine is maintained as part of the Strategic National Stockpile (SNS) for formulary in repositories in numerous locations throughout the United States.

• Atropine has many clinical uses as a competitive antagonist at both central and peripheral muscarinic receptor sites.

• The use of atropine is extensive for patients with bradycardias, in advanced cardiac life support, and in those exposed to acetylcholinesterase inhibitors in the workplace, in the home, and potentially on the battlefield.

• Atropine should be dosed to the resolution of bronchorrhea caused by the muscarinic toxidome using a dose-titrated doubling protocol.

References