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
|
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
|
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
|
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
(65-75 yrs)
|
10.0±7.3
|
1.8±1.2
|
2.9±1.9
|
10
|
7
|
|