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Enlon Plus (Edrophonium Chloride / Atropine Sulfate) - Description and Clinical Pharmacology

 
 



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DESCRIPTION

ENLON-PLUS (edrophonium chloride, USP and atropine sulfate, USP) Injection, for intravenous use, is a sterile, nonpyrogenic, nondepolarizing neuromuscular relaxant antagonist. ENLON-PLUS is a combination drug containing a rapid acting acetylcholinesterase inhibitor, edrophonium chloride, and an anticholinergic, atropine sulfate. Chemically, edrophonium chloride is ethyl (m-hydroxyphenyl) dimethylammonium chloride; its structural formula is:

Molecular Formula: C10H16ClNO

Molecular Weight: 201.70

Chemically, atropine sulfate is: endo-(±)-alpha-(hydroxymethyl)-8-methyl-8-azabicyclo [3.2.1]oct-3-yl benzeneacetate sulfate (2:1) monohydrate. Its structural formula is:

Molecular Formula: (C17H23NO3)2•H2SO4•H2O

Molecular Weight: 694.84

ENLON-PLUS contains in each mL of sterile solution:

5 mL Ampule: 10 mg edrophonium chloride and 0.14 mg atropine sulfate compounded with 2.0 mg sodium sulfite as a preservative and buffered with sodium citrate and citric acid. The pH range is 4.0-5.0.

CLINICAL PHARMACOLOGY

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

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.

Table of Pharmacokinetic Values for Edrophonium Chloride
Population T1/2β
hr±S.D.
VD
L/kg±S.D.
Cl
mL/kg/min±S.D.
N Ref.
T1/2β = Elimination half-life
VD = Volume of distribution
Cl = Clearance

Adults

1.8±0.6

1.1±0.2

9.6±2.7

10

3

Anephric Patients 1 2

3.4±1.0

0.68±0.13

2.7±1.4

6

4

Infants (3 wks-11 mos)

1.2±0.5

1.2±0.2

17.8±1.2

4

5

Children (1-6 yr)

1.6±0.5

1.2±0.7

14.2±7.3

4

5

Adults

3 0.9±0.3

1.1±0.6

13.3±5

5

6

Elderly (over 75 yr)

1.4±0.3

0.6±0.1

5.1±1

5

6

1 No adjustments of edrophonium dosage are required because elimination of non-depolarizing muscle relaxants is similarly decreased.
2 Values for anephric patients were calculated using a non-compartmental model.
3 From a study using a different, less sensitive HPLC method and fitting C vs T data to a biexponential curve.

ATROPINE SULFATE

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.

Table of Pharmacokinetic Values for Atropine Sulfate
Population T1/2β
hr±S.D.
VD
L/kg±S.D.
Cl
mL/kg/min±S.D.
N Ref.
T1/2β = Elimination half-life
VD = Volume of distribution
Cl = Clearance

Adults

3.0±0.9

1.6±0.4

6.8±2.9

8

7

Children (0.08-10 yrs)

4.8±3.5

2.2±1.5

6.4±3.9

13

7

Elderly 1 (65-75 yrs)

10.0±7.3

1.8±1.2

2.9±1.9

10

7

1 No dose adjustment required because the cardiovascular effect of atropine is diminished in the elderly.

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