Edrophonium and Atropine (Systemic)


BAN:
Atropine sulfate—Atropine sulphate

VA CLASSIFICATION
Primary: AU300
Secondary: AD900

Commonly used brand name(s): Enlon-Plus.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Cholinergic (cholinesterase inhibitor)—

antidote (to nondepolarizing neuromuscular blockade)—

Indications

Accepted

Neuromuscular blockade, nondepolarizing (treatment)—Edrophonium and atropine combination is indicated to reverse the neuromuscular blockade produced by many nondepolarizing agents, including atracurium {09} {22}, gallamine {22}, metocurine {22}, mivacurium {22} {23} {24} {25}, pancuronium {10} {22}, rocuronium {22}, tubocurarine {03} {22}, and vecuronium {01} {09} {22}.
—Edrophonium is not effective against depolarizing agents such as decamethonium and succinylcholine {01}.

Toxicity, curare (treatment adjunct)—Edrophonium and atropine combination is indicated as an adjunct in the treatment of respiratory depression caused by curare overdosage {01}.

Unaccepted
Edrophonium and atropine combination is not recommended for use in the differential diagnosis of myasthenia gravis {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Edrophonium chloride: 201.7 {05}
    Atropine sulfate: 694.85 {05}


pH
    Edrophonium chloride and atropine sulfate: 4.4 to 4.6 {01}.

Mechanism of action/Effect:

Edrophonium—Since nondepolarizing neuromuscular blocking agents combine reversibly with the receptors, preventing access of acetylcholine, antagonism can be overcome by increasing the amount of agonist at the receptors; therefore, muscle paralysis induced by nondepolarizing neuromuscular blocking agents is reversed by edrophonium, which increases the concentration of acetylcholine at the receptors {01}.

Atropine—An accumulation of acetylcholine at the sites of muscarinic cholinergic transmission occurs at the parasympathetic postganglionic receptors of the autonomic nervous system, which may cause parasympathomimetic side effects, such as bradycardia, bronchoconstriction, or increased secretions {01}. The anticholinergic activity of atropine counteracts these muscarinic side effects {01}.


Other actions/effects:

A local and direct action on smooth muscle to reduce tone and motility of the gastrointestinal tract has been suggested to explain the apparent gastrointestinal antispasmodic effect of atropine {20} {21}.

Distribution:

Vol D

Edrophonium: 1.1 ± 0.2 L per kg of body weight (L/kg) {11} {12}.

Atropine: 1.6 ± 0.4 L/kg {01} {14}.

Protein binding:

Atropine—Low (14%) {01} {14} {22}.

Biotransformation:

Atropine—Hepatic; primarily to tropine (30%) {01} {13}.

Half-life:

Elimination—

Edrophonium: Approximately 108 minutes {01} (range, 33 to 110 minutes) {12}.

Atropine: Approximately 180 minutes {01} {14} {22}.

Onset of action:

Edrophonium—

Intramuscular: 2 to 10 minutes {16}.

Intravenous: Within 30 to 60 seconds {15}. Reversal of skeletal muscle relaxant–induced depression in twitch tension occurs within 3 minutes {01}.

Time to peak effect:

Edrophonium—Following a 0.5- to 1-mg-per-kg-of-body-weight (mg/kg) intravenous dose: Within 1.2 minutes {01}.

Atropine—Following a 0.02-mg/kg intravenous dose (effect on heart rate): 2 to 16 minutes {01}.

Duration of action:

Edrophonium—Following a 0.5- to 1-mg/kg intravenous dose: 70 minutes {01} {03}.

Atropine—Following a 0.02-mg/kg dose (effect on heart rate): 170 minutes {01}.

Elimination:
    Edrophonium—Renal: 67% unchanged {01}. The clearance of edrophonium is approximately 0.5 L/kg/hour {01} {12}.
    Atropine—Renal: 57% unchanged {01}. The clearance of atropine is approximately 0.4 L/kg/hour {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to edrophonium or atropine may be sensitive to the edrophonium and atropine combination {01}.

Patients sensitive to sulfites may be sensitive to edrophonium and atropine combination because of the sulfite preservatives present.

Carcinogenicity/Mutagenicity

Studies evaluating the carcinogenic or mutagenic potential of edrophonium and atropine combination have not been done {01}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Studies have not been done in animals {01}.


Atropine

Atropine crosses the placenta. Well-controlled studies in humans have not been done. Intravenous administration of atropine during pregnancy or near term may produce tachycardia in the fetus. Studies in mice have not shown that atropine given in doses of 50 mg per kg of body weight (mg/kg) has adverse effects on the fetus. {18}



Edrophonium

Studies in humans or animals have not been done {15}.


FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether edrophonium and atropine combination is distributed into breast milk. However, problems in humans have not been documented {01}.


Atropine:

Atropine is distributed into breast milk. Although amounts have not been quantified, the long-term use of atropine should be avoided during nursing since infants are usually very sensitive to the effects of anticholinergics.



Edrophonium:

It is not known whether edrophonium is distributed into breast milk. However, problems in humans have not been documented.


Pediatrics

Limited information is available on the relationship of age to the effects of edrophonium and atropine combination in pediatric patients. Safety and efficacy have not been established {01}.


Geriatrics


Extensive studies on the relationship of age to the effects of the edrophonium and atropine combination have not been done in the geriatric population {01}. However, no geriatrics-specific problems have been documented.


Edrophonium:

In two studies comparing small numbers of patients 76 to 87 years of age with younger adults, the onset of action and the duration of antagonism of neuromuscular blockade by edrophonium in the older group were no different than in younger patients {17}.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, inhalation, especially with the combination of an opioid analgesic and nitrous oxide or{01}
» Beta-adrenergic blocking agents, systemic{01}    (concurrent use with edrophonium and atropine combination may increase the risk of excessive bradycardia; administration of atropine alone prior to the combination edrophonium and atropine is recommended {01}; caution is also recommended when administering edrophonium and atropine combination in patients with cardiovascular disease who are receiving anesthesia with an opioid (narcotic) analgesic and nitrous oxide without a potent inhalational anesthetic)


Digitalis glycosides{15}    (when used concurrently with edrophonium, the additive vagomimetic effects may cause excessive slowing of the heart rate)


Cholinesterase inhibitors, other, including antimyasthenics, demecarium, echothiophate, and isoflurophate, and possibly topical malathion in excessive quantities{01}    (caution is recommended when administering edrophonium and atropine combination to patients with symptoms of myasthenic weakness who are also receiving these medications, since symptoms of cholinergic crisis [overdosage] may be similar to those occurring with myasthenic crisis [underdosage]; the patient's condition may be worsened by use of the edrophonium and atropine combination)

{01}
» Neuromuscular blocking agents{01}    (edrophonium and atropine combination should not be administered prior to the administration of any nondepolarizing muscle relaxant)

{01}    (concurrent use of edrophonium and atropine combination with vecuronium may be associated with bradycardia and first-degree heart block, due to the lack of vagolytic activity of the skeletal muscle relaxant)

{01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiac dysrhythmias, such as bradycardia and atrioventricular (AV) block{01}    (increased risk of arrhythmias; it is recommended that additional doses of atropine be available for immediate use to counteract severe cholinergic reactions that may occur)

{01}
Sensitivity to edrophonium and atropine{01}
Risk-benefit should be considered when the following medical problems exist
» Asthma, bronchial{01}{22}    (increase in bronchial secretions and other respiratory effects of edrophonium may aggravate the condition)


» Glaucoma, angle-closure    (mydriatic effect resulting in increased intraocular pressure may precipitate an acute attack of angle-closure glaucoma)


» Intestinal or urinary tract obstruction, mechanical or{01}
» Pyloric stenosis    (may be aggravated)


Lung disease, chronic, especially in debilitated patients{01}    (increase in bronchial secretions and other respiratory effects of edrophonium may aggravate the condition)


Prostatic hypertrophy{01}    (urinary retention may be aggravated or precipitated)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Arrhythmias{01}{03}{04}{09}{10} (irregular heartbeat)

Note: Of the patients in whom arrhythmias occurred, 85% experienced onset within 2 minutes; 74% of these patients no longer had any arrhythmias after 10 minutes. Arrhythmias related to increased vagal tone, bradycardia, or second- and third-degree heart block responded to treatment with 0.2 to 0.4 mg of intravenous atropine {01}.


Incidence rare
    
Muscarinic effects{01} (shortness of breath, troubled breathing, wheezing, or tightness in chest; slow heartbeat; unusual tiredness or weakness)
    
nicotinic effects{01} (muscle weakness, cramps, or twitching)

Note: Cholinergic reaction includes severe muscarinic side effects in addition to nicotinic effects.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Dry skin{01} —dose-related
    
muscarinic effects{01} (blurred vision; diarrhea; frequent urge to urinate; increased sweating; increased watering of eyes or mouth; increase in mucus in the lungs; nausea or vomiting; stomach cramps or pain)
    
restlessness with asthenia{01} (restlessness with muscle weakness)
    
skin rash{01} —dose-related
    
speech disturbances{01} (changes in speech)





Overdose
For specific information on the agents used in the management of edrophonium and atropine combination overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Physostigmine (Systemic) monograph; and/or
   • Pralidoxime (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
Edrophonium
    
Muscarinic effects{01} (diarrhea; bradycardia; increased bronchial and salivary secretions; nausea and/or vomiting; sweating)

Atropine
    
Delirium{01}
    
dryness of mouth{01}
    
fever{01}
    
tachycardia{01}



Treatment of overdose
Specific treatment—

Use of atropine or pralidoxime for the treatment of muscarinic symptoms {01}. See package insert or Atropine in Anticholinergics/Antispasmodics (Systemic) or Pralidoxime (Systemic) for specific dosing guidelines.

Physostigmine must be administered with caution to reverse anticholinergic symptoms. See package insert or Physostigmine (Systemic) monograph for specific dosing guidelines.

Treatment of seizures or shock as appropriate {01}.

Monitoring—Monitoring cardiac function {01}.

Supportive care—May include maintaining an open airway and possible suctioning of bronchial secretions {01}.


General Dosing Information
Atropine slows gastric emptying and gastrointestinal activity, which may interfere with the absorption of other medications {01}.

It is recommended that atropine be immediately available to counteract severe cholinergic reactions that may occur in patients hypersensitive to edrophonium {01}.

After administration of edrophonium and atropine combination, the patient's response should be carefully monitored and ventilation secured {01}.


Parenteral Dosage Forms

EDROPHONIUM AND ATROPINE SULFATE INJECTION

Usual adult dose
Reversal of nondepolarizing neuromuscular blockade
Intravenous, 0.05 to 0.1 mL per kg of body weight given slowly over forty-five seconds to one minute at a point of at least 5% recovery of twitch response to neuromuscular stimulation (95% block) {01}.


Note: The dosage delivered is 0.5 to 1 mg per kg of body weight of edrophonium and 0.007 to 0.014 mg per kg of body weight of atropine {01}.


Usual adult and prescribing limits
Edrophonium—1 mg per kg of body weight per dose {01} {02}.

Pediatric prescribing limits
Safety and efficacy have not been established.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


10 mg per mL of edrophonium chloride and 0.14 mg per mL of atropine sulfate (Rx) [Enlon-Plus{01} (0.2% sodium sulfite) (sodium citrate) (citric acid—in 5-mL ampuls) (0.2% sodium sulfite) (sodium citrate) (citric acid) (phenol 0.45%—in 15-mL ampuls)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 ºC (104 ºF), preferably between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer.

Protect from freezing.



Revised: 08/08/1997



References
  1. Enlon-Plus package insert (Ohmeda—US), Rev 4/95, Rec 9/96.
  1. Heijke SA, Smith G, Key A. Comparison of the combined effects of atropine and neostigmine with atropine and edrophonium on the lower oesophageal sphincter. Anesthesiology 1991; 46(8): 628-31.
  1. Cronnelly R, Morris RB, Miller RD. Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia. Anesthesiology 1982; 57: 261-6.
  1. Naguib M, Gomaa M, Absood GH. Atropine-edrophonium mixture: a dose-response study. Anesth Analg 1988; 67: 650-5.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD. The United States Pharmacopeial Convention, Inc; 1996. p. 67, 259.
  1. Kopman AP. The current status of edrophonium: have we come “full circle”? Can J Anaesth 1991; 38: 145-50.
  1. Rupp SM, McChristen J, Miller RD. Neostigmine and edrophonium antagonism of varying intensity of neuromuscular blockade by atracurium, pancuronium or vecuronium. Anesthesiology 1988; 64: 711-7.
  1. Donati F, Smith CE, Bevan DR. Dose-response relationships for edrophonium and neostigmine as antagonists of moderate and profound atracurium blockade. Anesth Analg 1989; 68: 13-9.
  1. Mirakhur RK. Antagonism of the muscarinic effects of edrophonium with atropine and glycopyrrolate. A comparative study. Br J Anaesth 1985; 57: 1213-6.
  1. Azar I, Pham AN, Karamelkar DJ, et al. The heart rate following edrophonium-atropine and edrophonium-glycopyrrolate mixtures. Anesthesiology 1983; 59: 139-41.
  1. Morris RB, Cronnelly R, Miller RD, et al. Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man. Anesthesiology 1981; 54: 399-402.
  1. Aquilonius SM, Hartvig P. Clinical pharmacokinetics of cholinesterase inhibitors. Clin Pharmacokinet 1986; 11: 236-49.
  1. Hinderling PH, Gundert-Remy U, Schmidlin O, et al. Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. I: Pharmacokinetics; II: Pharmacodynamics. J Pharm Sci 1985; 74: I-703-10; II-711-7.
  1. Virtanen R, Kanto J, Iisalo O, et al. Pharmacokinetics studies on atropine with special reference to age. Acta Anaesthesiol Scand 1982; 26: 297-300.
  1. Enlon package insert (Ohmeda—US), Rev 4/95, Rec 10/96.
  1. Tensilon package insert (ICN—Canada), Rev 7/89, Rec 10/96.
  1. Matteo RS, Young WL, Ornstein E, et al. Pharmacokinetics and pharmacodynamics of edrophonium in elderly surgical patients. Anesth Analg 1990; 71: 334-9.
  1. Atropine sulfate injection package insert (LyphoMed—US), Rev 2/90, Rec 11/90.
  1. Aust J Hosp Pharm 1988; 18(2): 162.
  1. Fry E. Postoperative gastric aspirations reduced by glycopyrrolate during upper abdominal surgery. J R Soc Med 1986; 79: 334-5.
  1. Randell T, Saarnivaara L, Oikkonen M, et al. Oral atropine enhances the risk of acid aspiration in children. Acta Anaesthesiol Scand 1991; 35: 651-3.
  1. Reviewers' consensus on monograph revision of 8/97.
  1. Miller DR, Bryson G, Martineau RJ, et al. Edrophonium requirements for reversal of deep neuromuscular block following infusion of mivacurium. Can J Anaesth 1995; 42(11): 996-1002.
  1. Brandom BW, Taiwo OO, Woelfel SK. Spontaneous versus edrophonium-induced recovery from paralysis with mivacurium. Anesth Analg 823(5): 999-1002.
  1. Devcic A, Monshi CA, Ghandi DK, et al. Mivacurium neuromuscular block: neostigmine versus edrophonium. Anesth Analg 1995; 81: 1005-9.
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