Enlon-Plus

Pharmacodynamics

Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection is a combination of an anticholinesterase agent, which antagonizes the action of nondepolarizing neuromuscular blocking drugs, and a parasympatholytic (anticholinergic) drug, which prevents the muscarinic effects caused by inhibition of acetylcholine breakdown by the anticholinesterase. Edrophonium chloride antagonizes the effect of nondepolarizing neuromuscular blocking agents primarily by inhibiting or inactivating acetylcholinesterase. By inactivating the acetylcholinesterase enzyme, acetylcholine is not hydrolyzed as rapidly by acetylcholinesterase and is thereby allowed to accumulate. The greater quantity of acetylcholine reaching the sites of nicotinic cholinergic postjunctional receptors improves transmission of impulses across the myoneural junction. The concomitant, unavoidable accumulation of acetylcholine at the sites of muscarinic cholinergic transmission occurring at the parasympathetic, postganglionic receptors of the autonomic nervous system, may cause bradycardia, bronchoconstriction, increased secretions, and other parasympathomimetic side effects. The magnitude of these muscarinic side effects can be expected to vary from patient to patient depending upon the amount of vagal nerve activity present. Atropine sulfate counteracts these side effects.

Intravenous edrophonium chloride in doses of 0.5 to 1.0 mg/kg promptly antagonizes the effects of nondepolarizing muscle relaxants reaching the maximum antagonism within 1.2 minutes. A plateau of maximal antagonism is sustained for 70 minutes1. Intravenous atropine sulfate has an immediate effect on heart rate which reaches a peak in 2 to 16 minutes and lasts 170 minutes after an average 0.02 mg/kg dose.

Pharmacokinetics

Edrophonium chloride given intravenously shows first order elimination in a two compartment open pharmacokinetic model3. Onset of reversal of muscle relaxant induced depression in twitch tension occurs within three minutes. Edrophonium is primarily renally excreted with 67% of the dose appearing in the urine4. Hepatic metabolism and biliary excretion have also been demonstrated in animals4,8. While infants and children have been shown to have a reduced plasma half-life and an increased clearance of edrophonium, doses in children are not significantly different from adults on a mg/kg basis although they are more variable in effect. Conversely, elderly subjects (>75 years old) have a prolonged plasma half-life and a reduced clearance. Studies have shown that in spite of these changes the onset and duration of action is unchanged in these patients.

Atropine sulfate given intravenously shows first order elimination in a two compartment open model7. Approximately 57% of a dose of atropine appears in the urine as unchanged drug. Tropine is the primary hepatic metabolite of atropine and it accounts for approximately 30% of the dose2. Atropine is only 14±9% bound to plasma proteins7. Atropine clearance in children under 2 years old and in the elderly is decreased in relation to normal healthy adults.

Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection is not to be used in patients with known hypersensitivity to either of the components, or in patients with intestinal or urinary obstruction of mechanical type. Atropine sulfate is contraindicated in the presence of acute glaucoma, adhesions (synechiae) between the iris and lens of the eye, and pyloric stenosis.

General

As with any antagonist of nondepolarizing muscle relaxants, adequate recovery of voluntary respiration and neuromuscular transmission must be obtained prior to the discontinuation of respiratory assistance. Should a patient develop "anticholinesterase insensitivity" for brief or prolonged periods, the patient should be carefully monitored and the dosage of anticholinesterase drugs reduced or withheld until the patient again becomes sensitive to them. Use with caution in patients with prostatic hypertrophy and in debilitated patients with chronic lung disease.

When used in therapeutic doses, atropine can cause dryness of the mouth. This effect is additive when the product is administered with other drugs that can cause dryness of the mouth.

Since atropine sulfate slows gastric emptying and gastrointestinal motility, it may interfere with the absorption of other medications. The effect of atropine on dryness of the mouth may be increased if it is given with other drugs that have anticholinergic action (tricyclic antidepressants, antipsychotics, some antihistamines, and antiparkinsonism drugs).

Drug Interactions

Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection should not be administered prior to the administration of any nondepolarizing muscle relaxants. It should be administered with caution to patients with symptoms of myasthenic weakness who are also on anticholinesterase drugs. Anticholinesterase overdosage (cholinergic crisis) symptoms may mimic underdosage (myasthenic weakness), so the use of this drug may worsen the condition of these patients (see OVERDOSAGE section for treatment).

Narcotic analgesics, except when combined with potent inhaled anesthetics, appear to potentiate the effect of edrophonium on the sinus node and conduction system, increasing both the frequency and duration of bradycardia. In patients with cardiovascular disease, given anesthesia with narcotic and nitrous oxide without a potent inhalational agent, there is increased risk for clinically significant bradycardia. In patients receiving beta-adrenergic blocking agents there is increased risk for excessive bradycardia from unopposed parasympathetic vagal tone. Such patients should receive atropine sulfate alone prior to Enlon-Plus.

Compared to muscle relaxants with some vagolytic activity, muscle relaxants with no vagolytic effects, i.e. vecuronium, may be associated with a slightly higher incidence of vagotonic effects such as bradycardia and first-degree heart block when reversed with Enlon-Plus.

Pregnancy Category C

Animal reproduction studies have not been conducted with Enlon-Plus. It is also not known whether Enlon-Plus can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Enlon-Plus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of Enlon-Plus on the mother and fetus, on the duration of labor or delivery, in the possibility that a forceps delivery or other intervention or resuscitation of the newborn will be necessary, is not known. The effect of the combination drug on the later growth, development and functional maturation of the child is also unknown.

Nursing Mothers

The safety of Enlon-Plus during lactation in humans has not been established.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric patients may have increased vagal tone. The effect of fixed ratios of edrophonium and atropine on heart rate in such patients has not been evaluated.

Geriatric Use

Clinical studies of Enlon-Plus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.