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Atropine
Indications
Atropine sulfate was initially synthesized from the plant Atropa belladonna, from which the drug derives its name. The FDA-approved indications for atropine are discussed below.
FDA-Approved Indications
The FDA has approved atropine as a treatment for anti-sialagogue or anti-vagal effects, organophosphate/muscarinic poisoning, and bradycardia.[1][2]
Anti-sialagogue effects
While atropine can be used independently for anti-salivation effects, it is not formally recommended for routine use in controlled airways, though it can be used off-label to minimize secretions in the intubated patient.[3][4] Glycopyrrolate is at least 5 times more potent than atropine in its anti-sialagogue effect.
Anticholinesterase poisoning
Acetylcholine works on 3 different receptors during nerve agent poisonings. Atropine is only helpful to counter muscarinic effects at these receptors (pralidoxime and benzodiazepines act on the others).[3] If there are local symptoms in the eyes or respiratory tract, atropine is not indicated. Intravenous (IV) atropine indications include patients with hypersalivation, bronchial secretions, or bradycardia. Large doses and repeat doses may be required. Ingestions especially require higher doses (up to 20 mg). These doses should be titrated to effect by monitoring the patient's ability to clear excess secretions. Pupils and heart rate are poor indications of appropriate dosing in these patients.
Bradycardia
Atropine is the first-line therapy (Class IIa) for symptomatic bradycardia in the absence of reversible causes. Treatments for bradydysrhythmias are indicated when there is a structural disease of the infra-nodal system or if the heart rate is less than 50 bpm with unstable vital signs. Approximately 20% of bradydysrhythmias are due to endogenous cardiac electrical systems. The structural disease may or may not require resuscitation and should be closely monitored with medication and pacing readily available. If there is no improvement in the patient's condition after repeat doses of atropine, additional treatments with atropine are unlikely to be effective. However, transient improvements with repeat dosing indicate continuing treatment with atropine (which may exceed standard cumulative dosing maximums). Pediatric bradycardia is rarely cardiac in origin and often secondary to hypoxia and hypoventilation. If bradycardia persists despite adequate respiratory support, atropine is indicated. According to the ACC/AHA guidelines, atropine is a reasonable first-line option for increasing the sinus rate in patients with symptomatic bradycardia or hemodynamic compromise due to sinus node dysfunction (SND). However, in patients who have undergone heart transplants and lack autonomic reinnervation, atropine should be avoided for treating sinus bradycardia, as it is ineffective due to the absence of vagal tone.[4] Also, it is appropriate to administer atropine for bradycardia caused by high vagal tone or cholinergic drug toxicity.[5] Under current ACLS protocols, atropine is indicated for symptomatic bradycardia and not in a pulseless patient.
Rapid sequence intubation (RSI) pretreatment
Although not recommended as a routine agent, atropine may be used 3 to 5 minutes before initiation of RSI to prevent bradycardia. In the setting of post-intubation-related bradycardia, atropine is indicated. Post-induction bradycardia is more commonly observed in the pediatric population due to the predominance of vagal response, even without the use of succinylcholine.
Amblyopia (ocular atropine)
According to the American Academy of Ophthalmology (AAO), children with amblyopia respond to treatment with 2 hours of daily patching or weekend atropine. Atropine 1% may be administered as a cycloplegic due to its relatively long 24 to 48-hour duration. Other cycloplegics, like cyclopentolate and tropicamide, are less effective due to their shorter durations (4 to 24 hours) and require more frequent dosing. While atropine may have some ocular and systemic adverse effects, its superior efficacy and longer-lasting effect make it the preferred choice for amblyopia treatment.[6][7][8] https://www.aaojournal.org/action/showPdf?pii=S0161-6420%2822%2900865-X
Cycloplegia (ocular atropine)
Cycloplegic refraction is the gold standard for determining refractive errors. Atropine is the most potent cycloplegic agent. However, the longer duration of action and potential adverse effects of atropine make alternative agents, such as cyclopentolate and tropicamide, preferable.[10] Atropine can also be used to break posterior synechiae and provide symptomatic relief; however, drugs with short half-lives are preferred for these patients as well.[11]
Off-Label Uses
Atropine/diphenoxylate is an antimotility agent that can be administered as second-line therapy for diarrhea. This medication allows the central-acting opioid effect of diphenoxylate and capitalizes on its anticholinergic mechanism to slow gastrointestinal motility. Subtherapeutic amounts of atropine are included in the dosage form to discourage diphenoxylate abuse. This combination may potentiate barbiturates, alcohol, or tranquilizers, and therefore, its administration requires caution.
Atropine is not indicated in β-blocker-induced bradycardias or hypotension, though its use is unlikely harmful. Glucagon is the first line to treat β-blockade-induced symptoms.
Spinal cord injury-induced bradycardia can be treated with atropine.[12]
Atropine can also be used as a diagnostic agent during dobutamine stress echocardiography.[13]
According to ACC/AHA guidelines for patients with second-degree AV block, carotid sinus massage or challenge with atropine, procainamide, or isoproterenol may be considered to determine the block's level and whether these patients may benefit from permanent pacing.[14]
The AAO suggests that low-dose ocular atropine and increased outdoor time can be strategies for myopia prevention in young children at risk.[9][10] Atropine 1% solution is suitable for children who do not improve with refractive correction alone. This approach may also be considered when latent nystagmus or occlusion failure is present.[11][12][13][14]
Mechanism of Action
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Mechanism of Action
Atropine is an antimuscarinic that works through competitive inhibition of postganglionic acetylcholine receptors and direct vagolytic action, which leads to parasympathetic inhibition of the acetylcholine receptors in smooth muscle. The end effect of increased parasympathetic inhibition allows for preexisting sympathetic stimulation to predominate, creating increased cardiac output and other associated antimuscarinic adverse effects, as described herein.[15]
Pharmacokinetics
Absorption: After parental administration, atropine achieves peak concentration at 30 minutes. The systemic bioavailability of l-hyoscyamine (enantiomer) after ocular administration of atropine ophthalmic solution is approximately 64% (±29%), ranging from 19% to 95%.[16] The time to maximum plasma concentration (Tmax) of l-hyoscyamine is about 28 min (±27), ranging from 3 to 60 minutes. Ocular atropine is absorbed systemically through the conjunctiva and the lacrimal drainage system after intraocular administration.[17]
Distribution: Atropine distributes throughout the body with a plasma protein binding of about 44%. The apparent volume of distribution of atropine ranges from 1.0 to 1.7 L/kg. The corneal penetration of ocular atropine can differ based on preservatives like benzalkonium chloride and the concentration of atropine.[18]
Metabolism: The metabolites of atropine are atropin-n-oxide, noratropine, and tropic acid. Organophosphate inhibits the metabolism of atropine. The majority of the drug is eliminated by enzymatic hydrolysis.
Elimination: The pharmacokinetics of atropine are nonlinear after parenteral administration. The plasma half-life ranges from 2 to 4 hours. About 13% to 50% of atropine is excreted unchanged in the urine. The plasma half-life of ocular atropine is approximately 2.5 hours (± 0.8).
Administration
Available Dosage Forms and Strengths
Atropine can be administered by intravenous (IV), subcutaneous, intramuscular, or endotracheal (ET) methods; IV is preferred. For ET administration, 1 to 2 mg may be diluted in 10 mL of sterile water or normal saline before administration. For a pediatric endotracheal administration, the usual IV dose should be doubled and diluted in 3 to 5 mL of sterile water. Ocular atropine is available as a 1% solution.
Dosing
- Anti-sialagogue/anti-vagal: 0.5 mg to 1 mg every 1 to 2 hours
- Organophosphate or muscarinic poisoning: 2 mg to 3 mg every 20 to 30 minutes (may require doses up to 20 mg, titrate to effect for secretion control)
- Bradycardia: 1 mg every 3 to 5 minutes (3 mg max), repeat until obtaining desired heart rate, most effective for sinus and AV nodal disease
- Pediatric: 0.01 mg/kg to 0.03 mg/kg every 3 to 5 minutes. The pediatric minimum dose is 0.1 mg, the maximum dose is 0.5 mg (child) and 1.0 mg (adolescent), and the maximum cumulative dose is 1 mg (child) and 2 mg (adolescent).
- Rapid sequence intubation pretreatment: 0.01 mg/kg IV for adults with bradycardia secondary to repeat dosing of succinylcholine. Pediatric 0.02 mg/kg IV, minimum dose 0.1 mg. Not recommended as a routine treatment.
- Cycloplegia: 2 to 3 drops of atropine are instilled before the examination
Generally, the dosing of atropine is repeatable every 5 minutes until reaching a maximum of 0.04 mg/kg.
Adult doses >0.5 mg and slow IV pushes correlate with paradoxical bradycardia (though likely transient) and ventricular fibrillation (VF).
Specific Patient Populations
Hepatic impairment: No dosage adjustments have been provided in the product labeling.
Renal impairment: No dosage adjustments have been provided in the product labeling.
Pregnancy considerations: Atropine does cross the placenta and may lead to fetal tachycardia; however, it does not cause fetal abnormalities.[19] According to the American College of Obstetricians and Gynecologists (ACOG), atropine may be administered in cases of vasovagal reactions during office hysteroscopy, mainly if symptoms like bradycardia or hypotension persist.[20] According to the American College of Cardiology/American Heart Association (ACC/AHA), life-saving interventions, including defibrillation and medications, should not be withheld during pregnancy.[21]
Breastfeeding considerations: No information is available about the use of atropine during lactation. Although chronic administration of atropine decreases milk or letdown, a single dose of atropine systemically or topically will not be expected to affect breastfeeding. Mothers should be monitored for signs of decreased lactation, such as infant restlessness or failure to gain weight in chronic administration. Anticholinergics, such as atropine, suppress lactation in animal studies and decrease prolactin levels in nonlactating women. This is not expected to affect established breastfeeding.[19]
Pediatric patients: According to the American Heart Association guidelines, the Pediatric Advanced Life Support (PALS) guidelines state that when there is a higher risk of bradycardia (such as when giving succinylcholine), it may be reasonable for practitioners to use atropine as a premedication to prevent bradycardia during emergency intubations.[22]
Older patients: The American Geriatric Society has instated the Beers Criteria for potentially inappropriate medications (PIMs) in older adults. The AGS advises avoiding atropine due to its strong anticholinergic properties.[23] However, this should not discourage its use in emergencies. Ophthalmic atropine is excluded from this list.
Adverse Effects
The most common adverse effects are related to the drug's antimuscarinic properties, including xerostomia, blurred vision, photophobia, tachycardia, flushing, and hot skin. Constipation, difficulty with urination, and anhidrosis can occur, especially in at-risk populations (most notably, older adults). In rare cases, delirium or coma may occur. Hypersensitivity reactions may occur and are usually limited to a skin rash that could progress to exfoliation.[23] Ocular adverse reactions include photophobia, blurred vision, and central anticholinergic syndrome from systemic absorption.[24]
Drug-Drug Interactions
The majority of drug interactions are due to drugs with anticholinergic properties. Clinicians are advised to reconcile medications and prevent drug interactions.
- Eluxadoline: Eluxadoline is a locally-acting mixed μ-receptor and κ-receptor agonist/δ-receptor antagonist indicated for diarrhea-predominant irritable bowel syndrome. Coadministration can worsen constipation.[25]
- Glycopyrrolate/glycopyrronium: The administration should be avoided due to the synergistic anticholinergic properties.
- Mexiletine: Atropine decreases the rate of mexiletine absorption, which can be prevented by combined IV delivery of metoclopramide with atropine before anesthesia.
- Antipsychotics: Combining atropine with antipsychotics such as chlorpromazine, haloperidol, olanzapine, quetiapine, clozapine, and risperidone can lead to excessive anticholinergic effects.
- Gastrointestinal antispasmodic and muscle relaxants: Drugs such as dicyclomine and cyclobenzaprine, when combined with atropine, can significantly increase the risk of constipation and paralytic ileus.
- Antihistamines: Diphenhydramine, promethazine, hydroxyzine, and chlorpheniramine can also interact with atropine. This combination can enhance anticholinergic adverse effects such as sedation, confusion, dry mouth, and urinary retention.
- Antidepressants (with anticholinergic properties): Tricyclic antidepressants like amitriptyline, nortriptyline, and imipramine have anticholinergic properties. When administered with atropine, they can lead to confusion, blurred vision, sedation, and delirium.[26]
- Bladder relaxants: Atropine can interact with bladder relaxants like oxybutynin, solifenacin, and revefenacin. These may lead to urinary retention. Retention may be treated with catheterization and adjusting/discontinuing the medications.[27]
Contraindications
Atropine does not carry an FDA-issued box warning or any absolute contraindications. Multiple conditions carry a cautionary status. However, relative contraindications are overridden by the clinical need, especially in patients who are unstable or poisoned.
Warnings and Precautions
- Clinicians must exercise caution in patients with coronary heart disease, acute myocardial ischemia, congestive heart failure, tachycardia, or hypertension, as the increased cardiac demand and possible further worsening of tachycardia and hypertension can prove detrimental to patient outcomes.
- Caution is necessary when administering atropine to older patients, patients with chronic lung disease, acute angle closure glaucoma, obstructive diseases (uropathy, toxic megacolon, paralytic ileus, pyloric stenosis, prostatic hypertrophy), myasthenia gravis, or in situations with environmental heat exposure.
- Clinicians' understanding of the adverse reactions makes the above cautionary situations easily recognizable by compounding effects on preexisting conditions.
- Ocular atropine can cause blurred vision and photophobia.[28] Cycloplegia may last up to 2 weeks.
Monitoring
Tachycardia is the most common adverse effect; the dose should be titrated to effect when treating bradydysrhythmia in patients with coronary artery disease. Atropine may precipitate acute angle glaucoma, pyloric obstruction, urinary retention due to benign prostatic hyperplasia, or viscid plugs in patients with chronic lung diseases.[29][30] Ophthalmologists and optometrists should be monitored for any local or systemic adverse effects of ocular atropine.
Toxicity
Signs and Symptoms of Overdose
An overdose can lead to increased antimuscarinic adverse effects of dilated pupils, warm, dry skin, tachycardia, tremor, ataxia, delirium, and coma. In extreme toxicity, circulatory collapse secondary to respiratory failure may occur after paralysis and coma. Ten milligrams or less may be fatal to a child, while there is no known adult lethal dose.
All Datura plant species have endogenous atropine and other assorted anticholinergic alkaloids. These include Jimson weed and angel’s trumpet, typically seen in warm or temperate climate areas. These patients may have ingested it accidentally or intentionally smoked or ingested it for the goal of hallucinations. While treatment for ingestions is similar to other toxic overdoses of anticholinergics, whole-bowel irrigation is recommended after a large quantity of seed ingestion. Clinicians need to avoid using phenothiazines in these patients.
Central anticholinergic syndrome (CAS) has been described due to systemic absorption of ocular atropine. The clinical features are psychomotor agitation, acute psychosis, hallucinations, and mydriasis.[17][24]
Management of Overdose
Physostigmine is the basis of reversal. Treatment of overdose includes a short-acting barbiturate or diazepam as needed for convulsions or excitement. Avoid dosing for sedation as it can cause respiratory collapse. Physostigmine is useful as an antidote to treat delirium and coma. Repeat doses may be required as physostigmine has a shorter half-life. Monitor respiratory effort and supplement, if necessary.[31][32] Compressing the internal corner of the eye after administration and wiping off excess drops can help decrease systemic effects. Physostigmine should be administered for the central anticholinergic syndrome.[24]
Enhancing Healthcare Team Outcomes
Indications for atropine only include a few conditions, but this alkaloid is life-saving. All interprofessional healthcare team members should be aware of how to use atropine, the dose, and the method of administration. Clinicians can use this drug in patients with bradycardia and poisoning from cholinergic agents; atropine can immediately reverse the slow heart rate and reduce mortality. Nursing staff should always ensure that atropine is available in the cardiac arrest cart. More importantly, a syringe and needle should also be available as the drug can only be administered parenterally. Similarly, nurse anesthetists should ensure that atropine is available in the operating room at all times. On almost every cardiology and cardiac surgery floor, atropine may be necessary, so it should be readily available. Ophthalmologists should ensure strategies for minimal systemic absorption. Emergency medicine should stabilize patients who are experiencing atropine toxicity or overdose. The pharmacist is the team member responsible for ensuring that stock supplies of atropine are available in each department, verifying dosing, and performing medication reconciliation for drug-drug interactions.[33][34]
Outcomes
Atropine is a beneficial drug for reversing bradycardia from many causes. This medication works immediately and is relatively safe when used at therapeutic doses. There are countless reports on the number of lives saved through the use of atropine in patients with bradycardia or organophosphate poisoning.[35][36]
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