Anticholium (physostigmine salicylate)

The usual initial adult dose of physostigmine salicylate is 0.5-2 mg. When there is no response to the initial dose, it may be repeated every 20 minutes until response occurs or adverse cholinergic effects occur. If initial doses of the drug are effective in adults, additional doses of 1-4 mg may be given as necessary at intervals (usually 30-60 minutes) as life-threatening signs (e.g., arrhythmias, seizures, deep coma) recur.

In children, use of physostigmine should be reserved for life-threatening situations only. The initial pediatric IV or IM dose of physostigmine salicylate recommended by the manufacturers is 0.02 mg/kg. Additional doses may be repeated at 5- to 10-minute intervals until response occurs, adverse cholinergic effects develop, or a total dose of 2 mg has been administered. Alternatively, children may receive doses of 0.03 mg/kg or 0.9 mg/m2 as necessary.

To reverse the anticholinergic effects of atropine sulfate or scopolamine hydrobromide injections given as preanesthetic medications, physostigmine salicylate has been given IM or IV in a dose twice that of the anticholinergic drug, on a weight basis.

Additional study on the safety and efficacy of the drug is necessary (see Uses: Alzheimer's Disease), but an oral+ physostigmine salicylate dosage of 2-2.5 mg every 2 hours 6 or 7 times daily has been used in the management of dementia of the Alzheimer's type+ (Alzheimer's disease). Lower oral dosages may provide minimal benefit, while higher oral dosages may produce intolerable adverse effects (e.g., nausea, vomiting, excessive sweating). Oral dosage usually has been initiated at 0.5 mg every 2 hours 6 or 7 times daily until beneficial effect was achieved, intolerable adverse effects occurred, or a maximum total daily dose of 16 mg was achieved.

When physostigmine salicylate was used to stimulate peristalsis in patients with postoperative intestinal atony+, the usual adult dose was 0.5-2 mg given IV or IM.

Physostigmine salicylate is usually administered by slow IV injection or by IM injection; however, the drug has also been administered subcutaneously. When administered IV, the drug should be given at a slow, controlled rate not to exceed 1 mg/minute in adults and 0.5 mg/minute in children. (See Cautions: Precautions and Contraindications). The drug has also been administered orally+, but an oral dosage form is not currently commercially available.

Atropine sulfate injection should always be readily available when physostigmine is administered.

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No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Anticholinesterase/Corticosteroids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of these agents may contribute to increased muscle weakness and decreased response to anticholinesterases shortly after onset of corticosteroid therapy in the treatment of myasthenia gravis. Deterioration in muscle strength, including severe muscular depression, has been documented in patients with myasthenia gravis while receiving corticosteroids and anticholinesterases.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, hold anticholinesterase agents at least 24 hours before initiating corticosteroid therapy. If concurrent use is necessary, close observation of the patient is indicated and life support systems should be available.

DISCUSSION: Decreased effectiveness of anticholinesterases during the period of corticosteroid-induced increased weakness probably reflects a temporary increase in the severity of the disease process itself rather than a specific, direct interaction between the two drugs. Despite the initial adverse effect, glucocorticoid (or ACTH) therapy subsequently produces improvement, beyond pre-therapy muscle strength, in most myasthenia gravis patients. In an uncontrolled study involving nine patients receiving therapeutic doses of pyridostigmine, the concurrent administration of methylprednisolone resulted in a decrease in muscle strength in 71% of treatment courses. During 57% of treatment courses, severe muscle weakness occurred, necessitating mechanical ventilation. Improvement in muscle strength and response to pyridostigmine above baseline levels occurred after methylprednisolone was discontinued. Other clinical observations have indicated that the concomitant use of these agents can affect muscle strength, although each agent alone has been used successfully in treating myasthenia gravis.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticholinesterases/Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

CLINICAL EFFECTS: Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of anticholinesterases and beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1)

DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(2) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(3) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(4)

Anticholinesterases/Succinylcholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases, delaying succinylcholine hydrolysis and prolonging its duration of action.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects of succinylcholine, producing profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of anticholinesterases and succinylcholine in patients with depolarizing type (phase I) neuromuscular blockade. In addition, use with caution in the presence of a nondepolarizing type (phase II) blockade. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concomitant administration of anticholinesterases and succinylcholine has been associated with prolonged respiratory depression and apnea.

Cholinergics/Quinidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The anticholinergic properties of quinidine may oppose cholinergic drug effects.

CLINICAL EFFECTS: Quinidine may antagonize the effects of cholinergic drugs in the treatment of myasthenia gravis. Cardiac slowing secondary to cholinergic drugs would tend to be prevented by quinidine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, observe the myasthenic patient for signs and symptoms of the disease.

DISCUSSION: Caution is warranted in co-administration of these drugs due to their opposing pharmacologic properties.

There is no enhanced messaging for this drug.

• Asthma
• Bradycardia
• Coronary artery disease
• Diabetes mellitus
• Gangrene
• Gastrointestinal obstruction
• Peripheral vascular disease
• Urinary tract obstructive uropathy

There are no severe contraindications for this drug.

• Seizure disorder

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Rare or Very Rare

• Bradycardia
• Cardiac arrhythmia
• Chest tightness
• Dyspnea
• Fatigue
• Muscle fasciculation
• Seizure disorder
• Wheezing

More Frequent

• Abdominal pain with cramps
• Diarrhea
• Hyperhidrosis
• Nausea
• Sialorrhea
• Vomiting

Less Frequent

• Eye tearing
• Increased bronchial secretions
• Increased urinary frequency
• Miosis
• Nervousness

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No enhanced messaging available.

Little information is available regarding the effects of cholinesterase inhibitors, including physostigmine, on the fetus because of the rarity of maternal conditions requiring use of these drugs during pregnancy. Because physostigmine crosses the blood-brain barrier, it would be expected to cross the placenta. Transient muscular weakness has occurred in 10-20% of neonates whose mothers received anticholinesterases for the treatment of myasthenia gravis. Use of physostigmine in pregnant women requires that the potential benefit be weighed against the possible hazard to mother and fetus.

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No enhanced messaging available.