Orphenadrine - Muscle Relaxants

Orphenadrine

·              Orphenadrine is a tertiary amine antimuscarinic agent closely related to diphenhydramine.

Uses

■■   Orphenadrine is used in the treatment of painful skeletal muscle disorders.

■■   It is also used to treat drug induced extrapyramidal reactions and Parkinson's disease.

Toxicokinetics

■■  Orphenadrine is rapidly and completely absorbed from the stomach and intestines, peak plasma levels are reached in 2 to 4 hours, and after undergoing an enterohepatic cycle is almost entirely metabolised by first-order kinetics to eight metabolites, the most important among which is N-demethylorphenadrine (NDO). Absorption may be delayed due to the drug’s anticholinergic effects on gastric motility.

■■Approximately 50 to 60% is excreted as metabolites in the urine, about 8% is excreted unchanged, while the remainder gets eliminated in the faeces. Elimination half-life is 14 hours after therapeutic doses.

Mode of Action

·              Orphenadrine has certain central effects on muscle tone, and is anticholinergic and antihistamininc, with some local anaes-thetic effects.

·              The usual oral dose of orphenadrine is 100 mg twice a day, while the usual parenteral dose is 60 mg IV or IM twice a day.

Adverse Effects

·              Dry mouth, nausea, blurred vision, mydriasis, tachycardia, urinary retention, headache, vertigo, agitation, tremors, and mental confusion. Constipation is a common anticholin- ergic side effect.

·              Rarely aplastic anaemia or anaphylactic reactions may occur.

Drug Interactions

·              Potentiation of the effects of alcohol, anticholinergics, antidepressants, MAOIs, and CNS depressants.

·              Propoxyphene may aggravate tremors and confusion.

·              There is synergistic effect with levodopa.

Clinical (Toxic) Features

·      Overdose results in mydriasis, tachycardia, dry hot skin, decreased gastrointestinal motility, athetoid movements, agitation, confusion, hallucinations, convulsions, urinary retention, hypokalaemia, hypoglycaemia, hypotension, ventricular arrhythmias, respiratory depression, and cardiac arrest.

·      Bradycardia has been reported with severe overdose.

Usual Fatal Dose

·              Therapeutic blood levels should be below 0.2 mg/L. Blood levels of over this are associated with toxicity, and levels over 4 to 8 mg/L may be fatal.

·              In a review of orphenadrine toxicity, the minimum lethal dose was between 2 to 3 grams for adults.

·              Death has been reported in children ingesting as little as 400 mg of orphenadrine.

Treatment

·            Continuous ECG monitoring, pulse, respiration, and temperature measurements.

·            Monitor blood glucose; follow serum electrolytes, renal function and CPK levels in patients with prolonged seizures or hypotension.

·            Stomach wash can be beneficial upto 4–6 hours of inges-tion.

·            Activated charcoal is said to help in the prevention of absorption of orphenadrine, and is administered in the usual dose.

·            Correct hypoglycaemia with intravenous dextrose, 50 ml of 50% dextrose in adults; 2 to 4 ml/kg of 25% or 10% dextrose in children. Follow blood glucose carefully and repeat as needed.

·              Physostigmine is the antidote and effectively reverses the anticholinergic manifestations. However it should be used with caution, since its cardiotoxic effects can aggravate the cardiac depressant property of orphenad-rine. The dose recommended is 2 mg IV for an adult and 0.5 mg for a child. Dilute the dose of physostigmine in 10 ml of dextrose 5% in water or normal saline. Give over 5 minutes. This can be repeated after 15–20 minutes if required. Atropine at a dose of 0.5 mg per 1 mg of physo-stigmine (of the last dose administered) should be avail-able to reverse life-threatening physostigmine induced, toxic cholinergic effects such as bronchoconstriction.

·            Attempt initial control of convulsions with a benzodi-azepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbitone.

·            For hypotension: Infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·            Lignocaine, phenytoin, esmolol, isoproterenol, amio-darone, or magnesium sulfate may be used to treat cardiac conduction disorders. Quinidine, disopyramide, and procainamide are contraindicated as their effects on myocardial conduction are similar to that of other sodium blocking drugs. Because orphenadrine has sodium blocking properties arrhythmias may respond to administration of sodium bicarbonate. An initial dose of 1 mEq/kg is appropriate, repeated as needed with careful monitoring of blood pH.

·            Convulsions usually respond to IV diazepam. Barbitu-rates are best avoided.

·            Hypokalaemia may require potassium replacement under strict ECG monitoring.

Forensic Issues

■■   Orphenadrine has mood elevating effects at therapeutic doses, and has been chronically abused for its euphoric effects.