AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Generic Name(s):

• Atropine

• Atropine Sulfate

Atropine ( dl -hyoscyamine) is a naturally occurring tertiary amine antimuscarinic.

Surgery

Atropine sulfate is used parenterally as a preoperative medication to inhibit salivation and excessive secretions of the respiratory tract (antisialagogue);196,198,200 however, the current surgical practice of using general anesthetics that do not stimulate the production of salivary and tracheobronchial secretions has reduced the need to control excessive respiratory secretions during surgery. Although atropine has been used prophylactically to prevent acid-aspiration pneumonitis during surgery, antimuscarinics, including atropine, have not been shown to be effective for this use.

Atropine also may be used to prevent other cholinergic effects during surgery, such as cardiac arrhythmias, hypotension, and bradycardia, which may result from excessive vagal stimulation, from stimulation of the carotid sinus, or as a pharmacologic effect of some drugs (e.g., succinylcholine).196,200,402 Atropine is administered concurrently with anticholinesterase agents (e.g., neostigmine, pyridostigmine) to block the adverse muscarinic effects of these latter agents when they are used after surgery to reverse the effects of neuromuscular blocking agents.120,121,196

Atropine has been used prophylactically to prevent reflex bradycardia in pediatric patients undergoing emergency intubation; however, there is no evidence that atropine reduces the risk of cardiac arrest or improves survival in this setting.402 Because of the lack of supporting evidence, preintubation use of atropine is not routinely recommended, but may be considered in situations where there is an increased risk of bradycardia (e.g., when succinylcholine is used to facilitate intubation).402

Advanced Cardiovascular Life Support and Bradyarrhythmias

Atropine sulfate is used in advanced cardiovascular life support (ACLS) for the management of symptomatic bradycardia.400,401,403 The drug reverses cholinergically mediated decreases in heart rate, systemic vascular resistance, and blood pressure, and is considered the initial drug of choice in adults with unstable bradycardia (e.g., that which is accompanied by altered mental status, cardiac ischemia, acute heart failure, hypotension, or other signs of shock).106,400,401 In pediatric advanced life support (PALS), atropine is used for the treatment of bradycardia secondary to increased vagal activity or primary atrioventricular (AV) block when bradycardia persists despite initial management with adequate oxygenation, ventilation, and chest compressions (if indicated).403

Atropine was previously included in ACLS guidelines for the treatment of asystole or pulseless electrical activity (PEA) during cardiopulmonary resuscitation (CPR);106 however, routine use of the drug during cardiac arrest is no longer recommended because of the lack of evidence demonstrating clinical benefit.400,401,402,403 High-quality CPR and defibrillation are integral components of ACLS and the only proven interventions to increase survival to hospital discharge.400,401 Other resuscitative efforts including drug therapy are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.400,401 The principal goal of pharmacologic therapy during cardiac arrest is to facilitate the return of spontaneous circulation (ROSC), and epinephrine is considered the drug of choice for this use.400,401 (See Uses: Advanced Cardiovascular Life Support and Cardiac Arrhythmias, in Epinephrine 12:12.12.)

Because atropine can increase conduction through the AV node, the drug also may be beneficial in the management of AV nodal block.401,403 However, atropine is not likely to be effective in patients with type II second-degree AV block or third-degree AV block, including third-degree AV block accompanied by a new wide QRS complex when the conduction block is at or below the His-Purkinje level; patients with these bradyarrhythmias are preferably treated with transcutaneous pacing or a rate-accelerating β-adrenergic drug (e.g., dopamine or epinephrine) until transvenous pacing can be performed.401 Atropine administration should not delay implementation of external pacing for patients with poor perfusion.401

Atropine also is used in patients with acute myocardial infarction (MI) who develop symptomatic or hemodynamically unstable sinus bradycardia.201,202 Sinus bradycardia caused by increased vagal tone commonly occurs after ST-segment-elevation MI (STEMI), particularly in patients with an inferior infarction.201 Other uses of atropine in the MI setting include treatment of sustained bradycardia and hypotension associated with nitroglycerin use, and treatment of nausea and vomiting associated with morphine use.202 Although atropine was previously used for the management of symptomatic type I second- or third-degree AV block associated with MI,202 the incidence of abnormal conduction in STEMI patients has decreased considerably in the current reperfusion era.201

Because heart rate is a major determinant of myocardial oxygen requirements, atropine should be used cautiously in the presence of acute myocardial ischemia or infarction. Excessive rate acceleration in patients with these conditions may worsen ischemia or increase the extent of infarction. In addition, ventricular fibrillation and tachycardia have occurred rarely following IV administration of atropine. Because transplanted hearts lack vagal innervation, atropine may not be effective in patients who have undergone cardiac transplantation.401 Paradoxical slowing of the heart rate and high-degree AV block have been reported in patients who have received atropine after cardiac transplantation.401

Pesticide Poisoning

Atropine is used to reverse the muscarinic effects associated with toxic exposure to organophosphate or carbamate anticholinesterase pesticides.103,105,197,200 For the treatment of toxic exposure to organophosphate pesticides, atropine may be used concomitantly with a cholinesterase reactivator (pralidoxime chloride). 103,105 Concomitant therapy with pralidoxime chloride may not be necessary in patients with carbamate anticholinesterase pesticide poisoning.197 Antidotes such as atropine and pralidoxime should not be solely relied upon to provide complete protection against the toxic effects of insecticide poisoning and should be used in conjunction with other protective measures (e.g., decontamination, immediate evacuation, specialized masks and clothing) and treatments (e.g., an anticonvulsant for seizures).105 Some clinicians have suggested a challenge (test) dose of atropine to aid in the diagnosis of cholinergic poisoning†; failure of the test dose to elicit typical antimuscarinic effects (e.g., mydriasis, tachycardia, dry mucous membranes) strongly suggests the presence of organophosphate or carbamate poisoning.197

Chemical Warfare Agent Poisoning

Atropine is used concomitantly with a cholinesterase reactivator (pralidoxime chloride) for the treatment of nerve agent poisoning in the context of chemical warfare or terrorism.101,102,103,104,105 The most toxic of the known chemical warfare agents are the nerve agents.101 Most nerve agents are liquid at room temperature (although most are volatile at ambient temperatures, the term “nerve gas” is a misnomer); nerve agents are readily absorbed after inhalation of aerosols (e.g., following an explosion), ingestion, or dermal contact.101,102,103,104 Nerve agents (e.g., sarin, soman, tabun, VX [methylphosphonothioic acid]) are chemically similar to the organophosphate pesticides and exert their biologic effects by inhibiting acetylcholinesterase enzymes.101,102,103,104 Nerve agents alter cholinergic synaptic transmission at neuroeffector junctions (muscarinic effects), at skeletal myoneural junctions and autonomic ganglia (nicotinic effects), and in the CNS.101,102,103 Manifestations of nerve agent exposure include rhinorrhea, chest tightness, pinpoint pupils, dyspnea, excessive salivation and sweating, nausea, vomiting, abdominal cramps, involuntary defecation and/or urination, muscle twitching, confusion, seizures, flaccid paralysis, coma, respiratory failure, and death.101,102,103,104 While initial effects of nerve agent exposure depend on dose and route of exposure, signs and symptoms generally are similar regardless of the route of exposure.101 Manifestations may not be apparent until as long as 18 hours following dermal exposure, and CNS effects (e.g., fatigue, irritability, nervousness, memory impairment) may persist as long as 6 weeks following recovery from the acute effects of nerve agent exposure.101

Initial management of nerve agent poisoning includes aggressive airway control and ventilation (administration of nebulized β-adrenergic agonist [e.g., albuterol] and antimuscarinics [e.g., ipratropium bromide] may be necessary), and administration of atropine and pralidoxime chloride.101,102,103 Diazepam may be needed for seizure control.101 Rapid decontamination using standard hazardous materials (HAZMAT) procedures is important to prevent further absorption by the victim and to prevent contamination of others (e.g., emergency personnel, health-care workers) by direct contact or off-gassing of nerve agents from contaminated clothing.101,102,103 Following initial therapy and decontamination, additional treatment with atropine and supportive measures in a hospital setting are likely to be necessary.101,102,103

Mushroom Poisoning

Atropine sulfate also is used for the treatment of muscarinic effects associated with toxic ingestion of mushrooms containing muscarine (e.g., certain members of the Clitocybe and Inocybe genera); however, substantial toxicity is uncommon and supportive symptomatic care (e.g., atropine) rarely is necessary.197,200

GI Disorders

Atropine sulfate has been used as an adjunct in the treatment of peptic ulcer disease; although synthetic or semisynthetic antimuscarinics, especially quaternary ammonium compounds, have generally replaced atropine in the treatment of peptic ulcer disease, none of these antimuscarinics has been shown to be therapeutically superior to atropine. (See Uses: Peptic Ulcer Disease and GI Hypersecretory States, in the Antimuscarinics/Antispasmodics General Statement 12:08.08) As with other antimuscarinics, there are no conclusive data from well-controlled studies which indicate that, in usually recommended dosage, atropine aids in the healing, decreases the rate of recurrence, or prevents complications of peptic ulcers. In addition, in patients with gastric ulcer, antimuscarinics may delay gastric emptying and result in antral stasis. With the advent of more effective therapies for the treatment of peptic ulcer disease, antimuscarinics have only limited usefulness in this condition. Current epidemiologic and clinical evidence supports a strong association between gastric infection with Helicobacter pylori and the pathogenesis of duodenal and gastric ulcers, and the American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, see Uses: Helicobacter pylori Infection and Duodenal Ulcer Disease, in Clarithromycin 8:12.12.92.

Atropine has been used in the treatment of functional disturbances of GI motility such as irritable bowel syndrome. As with other antimuscarinics, atropine has limited efficacy in the treatment of these disorders and should be used only if other measures (e.g., diet, sedation, counseling, amelioration of environmental factors) have been of little or no benefit.

Atropine has been used in the treatment of GI hypermotility and diarrhea caused by reserpine, guanethidine, or cholinergic stimulation. Although antimuscarinics have been used in the treatment of diarrhea from other causes (e.g., ulcerative colitis, dysentery, shigellosis, Clostridium difficile -associated diarrhea and colitis [also known as antibiotic-associated pseudomembranous colitis]), they should be used with extreme caution, if at all, in patients with these conditions. (See Cautions: Precautions and Contraindications, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.)

Genitourinary Tract Disorders

Atropine sulfate has been used as adjunctive therapy in the management of hypermotility disorders of the lower urinary tract. Although atropine may provide symptomatic relief, the underlying cause should be determined and specifically treated. Appropriate anti-infective therapy should be initiated whenever urinary tract infection is present. With the exception of uninhibited or reflex neurogenic bladder, there is generally little evidence to support the use of antimuscarinics in the treatment of various genitourinary disorders. (See Uses: Genitourinary Tract Disorders, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.)

Bronchospasm

Because atropine sulfate is a potent bronchodilator, the drug has been used by oral inhalation for the short-term treatment and prevention of bronchospasm associated with chronic bronchial asthma, bronchitis, and chronic obstructive pulmonary disease; however, a solution of the drug for oral inhalation no longer is commercially available in the US. (See Uses: Bronchospasm, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.) Atropine has also been used as a drying agent in the relief of symptoms of acute rhinitis.

Other Uses

Atropine sulfate has been used in combination with other drugs (e.g., antihistamines, vasoconstrictors) for the symptomatic relief of cold and cough.

Atropine sulfate has been used to facilitate hypotonic duodenography or contrast examination of the colon by reducing duodenal or colonic motility and spasm; however, glucagon appears to be more effective and is generally preferred in these examinations. Atropine also has been used to increase visualization of the urinary tract in excretion urography.

Atropine sulfate has been used in conjunction with morphine or other opiates for the symptomatic relief of biliary or renal colic; however, since antimuscarinics exert only a weak biliary antispasmodic action, these drugs should not be relied on in the treatment of biliary tract disease. Atropine has also been used to reduce pain and hypersecretion in pancreatitis; however, there is little, if any, evidence that antimuscarinics improve the prognosis of the disease. (See Uses: Other Uses, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.)

For ophthalmic uses of atropine sulfate, see 52:24.For other uses of atropine sulfate, see Uses in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Administration

Atropine sulfate is administered by IM, subcutaneous, or direct IV administration.105,198,200 IV administration is preferred for the treatment of severe or life-threatening muscarinic effects.200

Atropine also has been administered by intraosseous (IO) injection† in the setting of advanced cardiovascular life support (ACLS), generally when IV access is not readily available; onset of action and systemic concentrations are comparable to those achieved with venous administration.401,403

Atropine may be administered via an endotracheal tube when vascular access (IV or IO) is not possible;200,403 however, IV or IO administration is preferred because of more predictable drug delivery and pharmacologic effect.403 (See Pharmacokinetics: Absorption.)

Atropine sulfate has been administered orally;199 however, an oral dosage form no longer is commercially available in the US.

Atropine sulfate has been administered by oral inhalation using a nebulizer solution; however, a solution for oral inhalation no longer is commercially available in the US.

Parenteral Administration

IM Administration

Atropine is commercially available in a prefilled auto-injector (e.g., AtroPen^®) for IM administration in the treatment of pesticide or nerve agent poisoning.105 The auto-injector should be used only by individuals who have received proper training in the recognition and treatment of pesticide poisoning.105 The AtroPen^® auto-injector may be self-administered by the patient or caregiver in an out-of-hospital setting to facilitate the initial treatment of muscarinic poisoning (usually breathing difficulty secondary to increased secretions); however, definitive medical care should be sought immediately.105

For self-administration or administration by a caregiver in an out-of-hospital setting in the event of pesticide or nerve agent poisoning, the appropriate dose of atropine injection (AtroPen^®) should be injected IM into the anterolateral aspect of the thigh.105 For very thin patients and small children, the thigh should be bunched up (to provide a thicker injection area) prior to administration of the drug.105 For additional instructions on proper use of atropine auto-injectors, the manufacturer's instructions should be consulted.105

IV Administration

Although at least one manufacturer recommends that atropine sulfate injection be administered slowly and with caution, the drug generally is given rapidly by direct IV injection since slow injection may cause a paradoxical slowing of the heart rate.

Atropine has occasionally been administered by IV infusion† for the management of muscarinic poisoning (e.g., organophosphate pesticides).197

Endotracheal Administration

For endotracheal administration, the appropriate dose of atropine sulfate should be diluted in 5-10 mL of sterile water or 0.9% sodium chloride injection in adults or followed by a flush with 5 mL of 0.9% sodium chloride injection in pediatric patients.200,401,403 Absorption of the drug may be greater when sterile water rather than 0.9% sodium chloride injection is used as the diluent (in adults).401

Dosage

Dosage of atropine sulfate should be individualized based on indication, patient characteristics, and response (e.g., heart rate, blood pressure); pediatric patients tend to be more susceptible than adults to the toxic effects of atropine overdosage.198,200

Parenteral Dosage

Surgery

For antisialagogue or antivagal effects during surgery, the usual initial adult dose of atropine sulfate is 0.5-1 mg by IV, IM, or subcutaneous injection 30-60 minutes prior to surgery; the dose may be repeated in 1-2 hours.195,200 Dosing in pediatric patients has not been well studied, but initial doses usually range from 0.01-0.03 mg/kg, administered 30-60 minutes prior to surgery; according to some clinicians, repeat doses may be given every 4-6 hours.195,198,200 Some clinicians recommend a minimum dose of 0.1 mg and maximum dose of 0.4 mg in children;195 however, doses up to 0.6 mg have been suggested in pediatric patients weighing more than 41 kg.198

The American Heart Association (AHA) guidelines for pediatric advanced life support (PALS) recommend a preintubation atropine sulfate dose of 0.02 mg/kg administered IV in infants and children undergoing emergency intubation.402 Although a minimum dose of 0.1 mg was previously recommended because of concerns about paradoxical bradycardia, current evidence suggests that no minimum dose is necessary.402

To block adverse muscarinic effects of anticholinesterase agents (e.g., neostigmine, pyridostigmine) when these agents are used to reverse the effects of neuromuscular blocking agents after surgery, the usual IV dose of atropine sulfate is 0.6-1.2 mg for each 0.5-2.5 mg of neostigmine methylsulfate or 10-20 mg of pyridostigmine bromide administered; atropine is administered concurrently with (but in a separate syringe) or a few minutes before the anticholinesterase agent. In the presence of bradycardia, atropine sulfate should be administered IV before the anticholinesterase agent to increase the pulse rate to about 80 beats/minute. Neonates and infants have been given a 0.02-mg/kg dose of atropine sulfate concomitantly with a 0.04-mg/kg dose of neostigmine methylsulfate. Children have been given a 0.01- to 0.04-mg/kg dose of atropine sulfate concomitantly with each 0.025- to 0.08-mg/kg dose of neostigmine methylsulfate.194

Advanced Cardiovascular Life Support and Bradyarrhythmias

For the treatment of symptomatic bradycardia in adults, AHA recommends an initial atropine sulfate dose of 0.5 mg by direct IV injection; the dose may be repeated every 3-5 minutes up to a maximum of 3 mg.401 Doses less than 0.5 mg may cause paradoxical slowing of the heart rate.401 In previous ACLS guidelines, an atropine sulfate dosage of 1 mg every 3-5 minutes up to a total of 3 doses by IV or IO injection† was recommended for the treatment of asystole and slow pulseless electrical activity (PEA) in adults;106 however routine use of atropine during cardiac arrest is no longer recommended.400,401 (See Uses: Advanced Cardiovascular Life Support and Bradyarrhythmias.)

In PALS guidelines, an atropine sulfate dose of 0.02 mg/kg by IV or IO injection† (repeated once if needed) is recommended in infants and children with symptomatic bradycardia secondary to increased vagal activity or primary atrioventricular (AV) block; a minimum dose of 0.1 mg and a maximum single dose of 0.5 mg is recommended.403 Larger doses may be required in special resuscitation situations (e.g., organophosphate toxicity or exposure to nerve gas agents); smaller doses (i.e., less than 0.1 mg) may cause paradoxical bradycardia.195,403

Hypotonic Radiography of the GI Tract

For hypotonic radiography of the GI tract (contrast examination of the duodenum or colon) in adults, the usual IM dose of atropine sulfate is 1 mg.

Pesticide Poisoning

Various atropine sulfate doses and dosing intervals have been recommended for the treatment of muscarinic toxicity resulting from exposure to organophosphate anticholinesterase pesticides; dosage requirements are based on the severity of poisoning and individual patient response.105,195,198,200

The usual initial dose of atropine sulfate for the treatment of muscarinic toxicity resulting from exposure to organophosphate anticholinesterase pesticides in adults is 1-2 mg, preferably administered IV. Some clinicians recommend that additional 2-mg doses may be administered IM or IV every 5-60 minutes until muscarinic signs and symptoms subside. In severe cases, 2-6 mg may be given initially, preferably administered IV, and repeated doses given every 5-60 minutes until muscarinic signs and symptoms subside. Mildly symptomatic poisoning may respond to 1-2 mg for reversal of muscarinic toxicity whereas moderate poisoning commonly requires total doses up to 40 mg.197 Some experts state that for severe poisoning, 5-mg doses may be repeated every 2-3 minutes for stabilization.197 Cumulative doses up to 1 g in 24 hours or 11 g over a course of treatment have been used.197 Atropine sulfate also has been administered by IV infusion† at an initial rate of 0.5-1 mg/hour in adults for muscarinic poisoning; the infusion rate should be adjusted according to response.197 In severe cases, atropine therapy should be gradually withdrawn to avoid abrupt recurrence of symptoms (e.g., pulmonary edema). Similar doses of atropine sulfate may be used in the treatment of muscarinic toxicity resulting from exposure to carbamate anticholinesterase pesticides.

To facilitate out-of-hospital administration, atropine injection may be administered using the commercially available prefilled auto-injector (e.g., AtroPen^®).105 For self-administration or administration by a caregiver, the dose of atropine (AtroPen^®) is based on severity of symptoms.105 Atropine should be administered as soon as symptoms of organophosphate or carbamate poisoning (e.g., tearing, excessive oral secretions, wheezing, muscle fasciculations) appear.105 For the treatment of adults with 2 or more mild symptoms of pesticide exposure (e.g., miosis or blurred vision, tearing, runny nose, hypersalivation or drooling, wheezing, muscle fasciculations, nausea/vomiting) when such exposure is known or suspected, one 2-mg IM dose of atropine sulfate should be administered.105 If the patient develops any severe symptoms (behavioral changes, severe breathing difficulty, severe respiratory secretions, severe muscle twitching, involuntary defecation or urination, seizures, unconsciousness), two additional 2-mg IM doses should be administered in rapid succession 10 minutes after the first dose.105 It is preferable that an individual other than the patient administer the second and third doses.105 For the treatment of adults who are either unconscious or present with any severe symptoms, three 2-mg doses should be administered IM in rapid succession.105 Additional treatment (i.e., supportive measures, additional doses of atropine, pralidoxime for organophosphate exposure, an anticonvulsant [e.g., diazepam] for seizures) generally is needed, and such treatment should be carried out under the supervision of trained medical personnel.105

In children, the usual IM or IV dose of atropine sulfate for the treatment of muscarinic toxicity resulting from exposure to organophosphate anticholinesterase pesticides is 0.05-0.1 mg/kg every 5-10 minutes until muscarinic signs and symptoms subside.195 The drug also has been given by IV infusion† at a rate of 0.025 mg/kg per hour; continuous infusions have been maintained for up to several weeks in severe cases.197 Similar doses of atropine sulfate may be used in the treatment of muscarinic toxicity resulting from exposure to carbamate anticholinesterase pesticides.

To facilitate out-of-hospital administration, atropine injection may be administered using the commercially available prefilled auto-injector (e.g., AtroPen^®).105 The AtroPen^® auto-injector containing atropine sulfate 0.25, 0.5, or 1 mg is intended for use in children weighing less than 7, 7-18, or 18-41 kg, respectively.105 When administered by a caregiver in an out-of-hospital setting, the dose of atropine (AtroPen^®) is based on severity of symptoms and body weight.105 Mild symptoms of pesticide exposure include miosis or blurred vision, tearing, runny nose, hypersalivation or drooling, wheezing, muscle fasciculations, and nausea/vomiting.105 Treatment with atropine is indicated in infants and children with 2 or more mild symptoms of pesticide exposure when such exposure is known or suspected.105 Severe symptoms of pesticide exposure include behavioral changes, severe breathing difficulty, severe respiratory secretions, severe muscle twitching, involuntary defecation or urination, seizures, and unconsciousness.105 Treatment is indicated in infants and children who are unconscious or have any severe symptoms of pesticide exposure.105 Atropine should be administered as soon as symptoms of organophosphate or carbamate poisoning (e.g., tearing, excessive oral secretions, wheezing, muscle fasciculations) appear.105 See Table 1 for specific dosage recommendations. Additional treatment (i.e., supportive measures, additional doses of atropine, pralidoxime for organophosphate exposure, an anticonvulsant [e.g., diazepam] for seizures) generally is needed, and such treatment should be carried out under the supervision of trained medical personnel.105

A cholinesterase reactivator (e.g., pralidoxime) is administered concomitantly with antimuscarinic therapy for the treatment of toxic exposure to organophosphate pesticides. For the treatment of muscarinic toxicity resulting from carbamate exposure, pralidoxime generally is not used unless exposure also included an organophosphate or unless respiratory depression and muscle weakness are severe manifestations of intoxication.

Chemical Warfare Agent Poisoning

Various atropine sulfate doses and dosing intervals have been recommended for the treatment of muscarinic toxicity resulting from exposure to nerve agent poisoning; dosage requirements are based on the severity of poisoning and individual patient response.101,105,195,198,200

The initial dose of atropine for the treatment of nerve agent (e.g., sarin, soman, tabun, VX [methylphosphonothioic acid]) poisoning in the context of chemical warfare or terrorism is based on the severity of symptoms (i.e., mild/moderate or severe) and the victim's age.101 Mild to moderate symptoms include localized sweating, muscle fasciculations, nausea, vomiting, weakness, dyspnea; severe symptoms include apnea, flaccid paralysis, seizures, and/or coma.101 When atropine is used for the immediate treatment of nerve agent poisoning in an out-of-hospital setting or in an emergency department, the drug is administered IM.101,105 The usual initial adult IM dose of atropine sulfate is 2-4 mg for those with mild to moderate symptoms and 5-6 mg for those with severe symptoms; frail geriatric patients with mild to moderate symptoms may receive atropine sulfate 1 mg and those with severe symptoms may receive atropine sulfate 2-4 mg.101,197

Additional doses of atropine may be administered at 5- to 10-minute intervals until secretions have diminished and breathing is comfortable or airway resistance has returned to near normal.101 Some patients may require up to 15-20 mg of the drug within the first 3 hours,104 but most patients respond to less than 20 mg usually during the initial 24 hours.197 In a report of sarin poisoning, less than 20% of moderately symptomatic patients required more than 2 mg.197 Pralidoxime chloride is administered concomitantly with atropine.101 Diazepam may be administered for seizure control.101

To facilitate out-of-hospital administration, atropine injection may be administered using the commercially available prefilled auto-injector (e.g., AtroPen^®).105 For self-administration or administration by a caregiver in an out-of-hospital setting, the dose of atropine (AtroPen^®) is based on severity of symptoms.105 Atropine should be administered as soon as symptoms of nerve agent poisoning (e.g., tearing, excessive oral secretions, wheezing, muscle fasciculations) appear.105 For the treatment of adults with 2 or more mild symptoms of exposure (e.g., miosis or blurred vision, tearing, runny nose, hypersalivation or drooling, wheezing, muscle fasciculations, nausea/vomiting) when such exposure is known or suspected, one 2-mg IM dose of atropine sulfate should be administered.105 If the patient develops any severe symptoms (behavioral changes, severe breathing difficulty, severe respiratory secretions, severe muscle twitching, involuntary defecation or urination, seizures, unconsciousness), two additional 2-mg IM doses should be administered in rapid succession 10 minutes after the first dose.105 It is preferable that an individual other than the patient administer the second and third doses.105 For the treatment of adults who are either unconscious or present with any severe symptoms, three 2-mg doses should be administered IM in rapid succession.105 Additional treatment (i.e., supportive measures, additional doses of atropine, pralidoxime, an anticonvulsant [e.g., diazepam] for seizures) generally is needed, and such treatment should be carried out under the supervision of trained medical personnel.105

The usual initial IM dose of atropine sulfate for the treatment of nerve agent poisoning in children 0-2 years of age, 2-10 years of age, or older than 10 years of age with mild to moderate symptoms is 0.05 mg/kg, 1 mg, or 2 mg, respectively, and the usual initial dose for children 0-2 years of age, 2-10 years of age, or older than 10 years with severe symptoms is 0.1 mg/kg, 2 mg, or 4 mg, respectively.101 Children 0-2 years of age with mild to moderate or severe symptoms treated in an emergency department may receive atropine sulfate 0.02 mg/kg, administered IV.101

To facilitate out-of-hospital administration for infants and children, atropine injection may be administered using the prefilled auto-injector (e.g., AtroPen^®).105 The AtroPen^® auto-injector containing atropine sulfate 0.25, 0.5, or 1 mg is intended for use in children weighing less than 7, 7-18, or 18-41 kg, respectively.105 When administered by a caregiver in an out-of-hospital setting, the dose of atropine (AtroPen^®) is based on body weight and severity of symptoms.105 Mild symptoms of nerve agent exposure include miosis or blurred vision, tearing, runny nose, hypersalivation or drooling, wheezing, muscle fasciculations, and nausea/vomiting.105 Treatment with atropine is indicated in infants and children with 2 or more mild symptoms of nerve agent exposure when such exposure is known or suspected.105 Severe symptoms of nerve agent exposure include behavioral changes, severe breathing difficulty, severe respiratory secretions, severe muscle twitching, involuntary defecation or urination, seizures, and unconsciousness.105 Treatment is indicated in infants and children who are unconscious or have any severe symptoms of nerve agent exposure.105 Atropine should be administered as soon as symptoms of nerve agent poisoning (e.g., tearing, excessive oral secretions, wheezing, muscle fasciculations) appear.105 See Table 2 for specific dosage recommendations. Additional treatment (i.e., supportive measures, additional doses of atropine, pralidoxime, an anticonvulsant [e.g., diazepam] for seizures) generally is needed, and such treatment should be carried out under the supervision of trained medical personnel.105

Mushroom Poisoning

If atropine is needed for severe symptoms of mushroom poisoning (i.e., muscarine-containing Clitocybes and Inocybes ) in adults, some experts recommend an IV dose of 1-2 mg (minimum of 0.1 mg), repeated and titrated as needed according to response.197 If needed for severe symptoms in pediatric patients, an IV dose of 0.02 mg/kg (minimum of 0.1 mg) is recommended, repeated and titrated as needed according to response.197

Endotracheal Dosage

Advanced Cardiovascular Life Support and Bradyarrhythmias

When atropine sulfate cannot be administered IV in emergent situations such as during ACLS, the drug may be administered via an endotracheal tube.200,401,403 Although the optimum endotracheal dose of atropine sulfate remains to be established, some experts state that typical doses of drugs administered via this route are 2-2.5 times those administered IV in adults and generally should be diluted in 5-10 mL of 0.9% sodium chloride or sterile water prior to direct injection into the endotracheal tube.401 One manufacturer recommends an endotracheal atropine sulfate dose of 1-2 mg (diluted in no more than 10 mL of sterile water or 0.9% sodium chloride injection) for the treatment of bradysystolic cardiac arrest in adults.200

The optimum dose(s) of atropine sulfate administered via an endotracheal tube in pediatric patients remains to be established; PALS guidelines suggest an endotracheal atropine sulfate dose of 0.04-0.06 mg/kg (repeated once if necessary) for the treatment of pediatric bradycardia, with a minimum dose of 0.1 mg and a maximum single dose of 0.5 mg.403 Larger doses may be required in special resuscitation situations (e.g., organophosphate toxicity or exposure to nerve gas agents).403 If cardiopulmonary resuscitation (CPR) is in progress, chest compressions should be interrupted briefly to administer atropine.403 Following administration, the endotracheal tube should be flushed with 5 mL of 0.9% sodium chloride injection and followed by 5 consecutive positive-pressure ventilations.403

Pesticide and Nerve Agent Poisoning

One manufacturer recommends an endotracheal atropine sulfate dose of 1-2 mg (diluted in no more than 10 mL of sterile water or 0.9% sodium chloride injection) in adults.200

The recommended endotracheal dose of atropine sulfate for the treatment of insecticide or nerve agent poisoning in pediatric patients is 0.05-0.1 mg/kg given every 5-10 minutes until muscarinic signs and symptoms disappear.195 The dose should be diluted in 1-2 mL of 0.9% sodium chloride injection for endotracheal administration.195

For a complete discussion of cautions, precautions, and contraindications associated with atropine, see Cautions in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Pharmacology

As the prototype of the antimuscarinics, atropine exhibits the pharmacologic actions associated with this group of drugs. The pharmacologic activity of atropine results almost completely from l -hyoscyamine; d -hyoscyamine has essentially no antimuscarinic activity. As a racemic mixture, atropine possesses about 50% of the antimuscarinic potency of l -hyoscyamine. In terms of central antimuscarinic activity, l -hyoscyamine is 8-50 times as potent as d -hyoscyamine. In general, atropine is more potent than scopolamine in its antimuscarinic action on the heart and on bronchial and intestinal smooth muscle, and less potent than scopolamine in its antimuscarinic action on the iris, ciliary body, and certain secretory (salivary, bronchial, sweat) glands. In contrast to scopolamine, atropine stimulates the CNS in usual doses.

For a complete discussion of the pharmacologic effects of atropine, see Pharmacology in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Pharmacokinetics

Absorption

Atropine is well absorbed from the GI tract. The drug appears to be absorbed principally from the upper small intestine. Atropine is also well absorbed following IM administration, oral inhalation, or endotracheal administration. Following oral administration of a single, radiolabeled, 2-mg dose of atropine in healthy, fasting adults, about 90% of the dose was absorbed. In this study, peak plasma concentrations were reached within 1 hour. Following IM administration, peak plasma concentrations are reached within 30 minutes. Following oral inhalation, atropine appears in serum within 15 minutes and peak concentrations are achieved within 1.5-4 hours. Endotracheal administration of the drug results in lower plasma concentrations than when the drug is given IV.401

Atropine-induced inhibition of salivation occurs within 30 minutes or 30 minutes to 1 hour and peaks within 1-1.6 or 2 hours after IM or oral administration, respectively; inhibition of salivation persists for up to 4 hours. Atropine-induced increase in heart rate occurs within 5-40 minutes or 30 minutes to 2 hours and peaks within 20 minutes to 1 hour or 1-2 hours after IM or oral administration, respectively. Following IV administration of the drug, peak increase in heart rate occurs within 2-4 minutes. Low doses of the drug cause a paradoxical decrease in heart rate. The ocular effects of atropine are delayed following systemic administration; in one study, near point of accommodation was increased within 2 or 4 hours after IM administration of a single 3-mg dose or oral administration of a single 4-mg dose, respectively. Bronchodilation (as determined by forced expiratory volume in 1 second [FEV₁]) occurs within 15 minutes and is maximal within 15 minutes to 1.5 hours after oral inhalation of atropine. Based on peak inhibition of salivation in one study, 0.9-1.4 mg of orally administered drug was estimated to be approximately equivalent in effect to 0.6 mg administered IM.

Distribution

Atropine is well distributed throughout the body. The drug crosses the blood-brain barrier. Following IV administration of a single 0.1 mg/kg dose of radiolabeled atropine in dogs, peak CSF concentrations of the drug were 10.3 ng/mL, about 90% of the peak serum concentration.

Atropine crosses the placental barrier. Following IV administration of a single 12.5 mcg/kg dose of atropine sulfate in pregnant women, mean fetal blood (from the placental side of the cord) concentrations of atropine were 1.2 times those of the mother between 5-15 minutes after administration of the drug. In another study, fetal venous blood (from the cord) concentrations of atropine were 12 and 93% of simultaneous maternal venous concentrations 1 and 5 minutes after administration of the drug, respectively; fetal arterial blood (from the cord) concentrations were approximately 50% of simultaneous fetal venous blood concentrations. Although atropine has been stated to distribute into milk in small quantities, there are minimal data to support this statement.

In one in vitro study, atropine was about 18% bound to serum albumin.

Elimination

Atropine has a plasma half-life of about 2-3 hours. Following IM administration of atropine in one study, elimination of the drug (determined by urinary excretion of radiolabeled drug) appeared to be biphasic, with a half-life in the initial phase of about 2 hours and a half-life in the terminal phase of 12.5 hours or longer.

Atropine is metabolized in the liver to several metabolites including tropic acid, tropine (or a chromatographically similar compound), and, possibly, esters of tropic acid and glucuronide conjugates. Atropine is excreted mainly in urine. Approximately 77-94% of an IM dose of atropine is excreted in urine within 24 hours. About 30-50% of a dose is excreted in urine unchanged. In one study, about 50% of the dose was excreted in urine unchanged; about 33% as unknown metabolites, possibly esters of tropic acid; and less than 2% as tropic acid. In another study, tropine or a chromatographically similar compound was the major metabolite in urine. Small amounts of atropine may also be eliminated in expired air as carbon dioxide and in feces.

Chemistry and Stability

Chemistry

Atropine ( dl -hyoscyamine) is a naturally occurring tertiary amine antimuscarinic. Atropine is the prototype of the antimuscarinics. The drug may be prepared synthetically but is usually obtained by extraction from various members of the Solanaceae genus of plants including Atropa belladonna (deadly nightshade), Datura stramonium (Jimson weed), or Duboisia myoporoides.

Atropine is a racemic mixture of d - and l -hyoscyamine, a tertiary amine organic ester formed by combining tropine and tropic acid. It is not clear whether atropine occurs naturally as a racemic mixture in plant tissues or is formed during extraction, a process known to cause racemization. Atropine occurs as white crystals, usually needle-like, or a white, crystalline powder; it is optically inactive, but usually contains a slight excess of l -hyoscyamine. Atropine has solubilities of approximately 2.17 mg/mL in water and 0.5 g/mL in alcohol at 25°C. The drug has a pK_a of 9.8. Atropine injection is commercially available as a sterile solution of the drug in water for injection and contains a citrate buffer, glycerin, and phenol as a preservative.

Atropine sulfate occurs as colorless crystals or a white, crystalline powder. Atropine sulfate has solubilities of approximately 2 g/mL in water and 0.2 g/mL in alcohol at 25°C. Atropine sulfate injection is commercially available as a sterile solution of the drug in water for injection or 0.9% sodium chloride injection; sulfuric acid may be added to adjust the pH to 3-6.5. The injection may also contain a preservative.

Stability

Atropine sulfate effloresces on exposure to dry air and is slowly affected by light. Atropine should be stored in tight, light-resistant containers. Atropine sulfate should be stored in tight containers. Atropine injection (AtroPen^® Auto-Injector) should be stored at 25°C but may be exposed to temperatures ranging from 15-30°C. Atropine sulfate injections should be stored in single-dose or multiple-dose containers, preferably of USP Type I glass, at a temperature less than 40°C, preferably between 15-30°C; freezing of the injections should be avoided.

When admixed in the same syringe at room temperature, atropine sulfate injection is reported to be physically compatible for at least 15 minutes with the following injections: chlorpromazine hydrochloride, cimetidine hydrochloride, dimenhydrinate, diphenhydramine hydrochloride, droperidol, fentanyl citrate, glycopyrrolate, hydroxyzine hydrochloride, hydroxyzine hydrochloride with meperidine hydrochloride, meperidine hydrochloride, meperidine hydrochloride with promethazine hydrochloride (Mepergan^®, no longer commercially available in the US), morphine sulfate, concentrated opium alkaloids hydrochlorides, pentazocine lactate, pentobarbital sodium, prochlorperazine edisylate, promazine hydrochloride, promethazine hydrochloride, propiomazine hydrochloride, or scopolamine hydrobromide. Atropine sulfate injection is also reported to be physically compatible with butorphanol tartrate injection. Since the compatibility of these and other admixtures with atropine sulfate injection depends on several factors (e.g., concentration of the drugs, resulting pH, temperature), specialized references should be consulted for specific compatibility information.

Atropine sulfate injection is reported to be physically incompatible with norepinephrine bitartrate, metaraminol bitartrate, and sodium bicarbonate injections. A haze or precipitate may form within 15 minutes when atropine sulfate injection is mixed with methohexital sodium solutions.

Additional Information

For further information on the chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of atropine sulfate, see the Antimuscarinics/Antispasmodics General Statement 12:08.08. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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