Download Protocol for Monoamine oxidase inhibitors (MAOIs) management

Protocol for Monoamine oxidase inhibitors (MAOIs) management
Category/Use: Used as an antidepressant / antianxiety
Specific substances: Specific substance are mentioned in range of toxicity table
Range of toxicity:
Specific
Maximum tolerated dose
Minimum lethal dose
substances
Phenelezine
Adults have survived after ingestion of Reported to result in death
2250mgs and 990 mgs
with doses ranging from
375mg to 1500mg.
Ingestion of 4 to 6 mg/kg
was fatal.
Nialamide
Not established
Tranylcypromine
An
adult
who
5gms was fatal in an adult
ingested
250mgs Not established
survived
Pargyline
150 to 175 mgs was ingested with Not established
survival in a 2.5 year old boy
Isocarboxazid
Survival was reported in a 48 year old Not established
woman who ingested 300mgs.
Ingestion of greater than 2 to 3 mg/kg of an MAOI should be considered potentially lifethreatening and 4 to 6 mg/kg or greater is consistent with reported fatalities.
Mortality rate/survival rate: Not available
Clinical presentation:
Patients with early or mild intoxication may experience drowsiness, dizziness (sometimes
severe), ataxia, headache (sometimes severe), insomnia, restlessness, anxiety, and irritability.
Other reported effects associated with severe overdosage include mental confusion, incoherence,
tachycardia, rapid and irregular pulse, hypotension, coma, seizures, respiratory depression,
hyporeflexia or hyperreflexia, fever, diaphoresis (sometimes perfuse and associated with cool,
clammy skin), precordial pain, and shock. A few patients have developed hypertension, which
rarely may be associated with twitching or myoclonic fibrillation of skeletal muscles and with
hyperpyrexia, sometimes progressing to generalized rigidity and coma. In addition, trismus and
opisthotonus have been reported to occur in some patients. Hyperactivity with marked agitation
may occur. Signs and symptoms following acute overdosage may be delayed for 12–24 hours.
Although signs and symptoms usually resolve within 3–4 days, they may persist for up to 2
weeks in some patients. Careful observation of patients for at least 1 week after overdosage is
generally recommended.
Mechanism of toxicity:
MAOIs exert their toxic effects by delaying the metabolism of sympathomimetic amines and 5hydroxytryptophan and by decreasing the norepinephrine stores in post ganglionic sympathetic
neurons. MAOIs inhibit the enzymes other than monoamine oxidase that is dopamine- B –
oxidase, diamine oxidase, amino acid decarboxylase and choline dehydrogenase. Inhibition
occurs only in very high doses and may be responsible for some of the toxic effects of MAOIs.
Pharmaco kinetics:
Absorption: rapidly and completely absorbed from GI tract.
Distribution:
Peak plasma levels: for tranylcypromine , peak plasma concentrations of 100 to 150 ng/ml were
reached 2 hours after a 20 mg oral dose of tranylcypromine in 10 healthy adult volunteers.
Distribution kinetics: Vd of tranylcypromine following a single oral dose of 20 mg of
tranylcypromine sulphate in patients with normal hepatic and renal function, the mean apparent
Vd was 3.09 L/kg.
Metabolism: hepatic
Excretion: kidney through urine
Elimination half life:
Tranylcypromine: single oral dose of tranylcypromine 20 mg/kg in patients with normal hepatic/
renal function, the elimination half life of tranylcypromine averaged 2.5 hours. In healthy
volunteers, terminal half life of the same drug was approximately 1.5 hours. Acute overdose with
250mg tranylcypromine in a 50 year old man, reported a terminal elimination half life of 3.5
hours.
Criteria for hospital admission:
Due to potential for delayed and severe toxicity, any patient with history of acute MAOI
overdose, even in the absence of symptoms in the first 4 to 6 hours, should be admitted for ICU
monitoring and remain until stable for 24 hours.
Monitoring parameters:
Monitor liver and renal function , CPK and fluid and electrolyte balance.
First aid measures:Same as decontamination method given in treatment.
Treatment
Decontamination method
Emesis: Ipecac-induced emesis is not recommended because of the potential for CNS depression
and seizures.
Activated charcoal
Dose: minimum of 240 milliliters of water per 30 grams charcoal.
Adult and adolescents: 25 to 100 grams
Children aged 1 to 12 years: 25 to 50 grams (0.5 to 1 gm/kg body weight)
Infants up to 1 year old: 0.5 to 1 gm/kg
Gastric lavage
Consider lavage more than 60 minutes after ingestion of sustained-release formulations and
substances known to form bezoars or concretions.
Lavage fluid: Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius)
or saline per wash (in older children or adults) and 10 milliliters/kg body weight of normal saline
in young children and repeat until lavage return is clear.
Specific treatment/Antidote:
No specific antidote
Supportive treatment:
Agitation
Severe: incremental doses of intravenous diazepam
Adult: 2 to 10 milligrams slowly, repeat if necessary
Child: 0.1 milligram/kilogram
Unresponsive: Amobarbital has been recommended. Sedative hypnotic agents should be used
with caution due to possible potentiation of CNS depression due to MAOI overdose.
Phenothiazines should be avoided due to possible hypotension.
Seizure: Monitor for respiratory depression, hypotension and dysrhythmias. Endotracheal
intubation should be performed in patients with persistent seizures. Evaluate for hypoxia,
electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not
available, treat with intravenous dextrose Adult: 50 milliliters IV, Child: 2 milliliters/kilogram
25% dextrose).
Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or
recur administer Phenobarbital.
Diazepam
Adult dose: 5 to 10 milligrams initially, repeat every 5 to 10 minutes as needed.
Monitor for hypotension, respiratory depression and the need for endotracheal intubation.
Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
Paediatric diazepam dose: 0.2 to 0.5 milligram/kg (5 milligrams maximum); repeat every 5 to
10 minutes as needed. Monitor for hypotension, respiratory depression and the need for
endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10
milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
Maximum rate: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5
milligrams/minute).
No intravenous access
Diazepam may be given per rectum or intramuscularly. Recommended rectal dose is 0.2 mg/kg
in adults and 0.5 mg/kg in children.
Midazolam used intramuscularly and intranasal, particularly in children when intravenous access
has not been established.
Paediatric dose
Intramuscular: 0.2 milligram/kilogram (maximum 7 milligrams)
Intranasal: 0.2 milligram/kilogram
Buccal: 10 milligrams, has been used in adolescents and older children (5-years-old or more) to
control seizures when intravenous access was not established.
Lorazepam: may also be given intramuscularly or rectally.
Maximum rate: Rate of intravenous administration of lorazepam should not exceed 2
milligrams/minute.
Adult dose: 2 to 4 milligrams intravenously. Initial doses may be repeated in 10 minutes if
seizures persist.
Paediatric dose: 0.05 to 0.1 milligram/kilogram intravenously, (maximum 4 milligrams/dose)
repeated twice at intervals of 10 to 15 minutes if seizures persist.
Phenobarbital
Adult loading dose: 20 milligrams per kilogram diluted in 0.9 percent saline given at 25 to 50
milligrams per minute.
Adult repeat dose: An additional 10 milligrams/kilogram may be given if seizures persist or
recur.
Maximum safe dose: No maximum safe dose has been established. Patients in status epilepticus
have received as much as 100 milligrams/minute until seizure control was achieved. Patients
receiving high doses will require endotracheal intubation and may require vasopressor support.
Paediatric loading dose: 15 to 20 milligrams per kilogram of phenobarbital intravenously given
at a maximum rate of 25 to 50 milligrams per minute.
Pediatric repeat dose: Repeat doses of 5 to 10 milligrams per kilogram may be given every 20
minutes if seizures persist.
Maximum safe dose: No maximum safe dose has been established. Children in status
epilepticus have received doses of 30 to 120 milligrams/kilogram within 24 hours. Vasopressors
and mechanical ventilation were needed in many patients receiving these doses.
Neonatal loading dose: 20 to 30 milligrams/kilogram intravenously at a rate of no more than 1
milligram/kilogram per minute in patients with no preexisting phenobarbital serum levels.
Neonatal maintenance dose: Repeat doses of 2.5 milligrams/kilogram every 12 hours may be
given; adjust dosage to maintain serum levels of 20 to 40 micrograms/milliliter.
Maximum safe neonatal dose: Doses of up to 20 milligrams/kilogram/minute up to a total of 30
milligrams/kilogram have been tolerated in neonates.
Cautions: Adequacy of ventilation must be continuously monitored in children and adults.
Intubation will be necessary with increased doses. Hypotension may develop with large doses
and vasopressors may be required. Monitor serum levels over next 12 to 24 hours for
maintenance of therapeutic levels (20 to 40 micrograms per milliliter).
Hypotensive episode
Administer intravenous fluids and keep the patient supine. If the patient is unresponsive to these
measures, administer norepinephrine or dopamine cautiously, monitoring for possible
exaggerated response.
Norepinephrine
Preparation: Add four milligram norepinephrine to 250 milliliters of dextrose 5% in water to
produce a concentration of 16 micrograms/milliliter.
Adult dose: begin infusion at 0.5 to 1 microgram/minute and titrate to maintain adequate blood
pressure.
Child dose: begin infusion at 0.1 microgram/kilogram/minute and titrate to maintain adequate
blood pressure.
Caution: Extravasation may cause local tissue ischemia, administration by central venous
catheter is advised.
Dopamine
Preparation: Add 400 milligrams to 250 milliliters of normal saline or dextrose 5% in water to
produce 1600 micrograms per milliliter or add 400 milligrams to 500 milliliters of normal saline
or dextrose 5% in water to produce 800 micrograms per milliliter.
Dose: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram
per minute increments as needed. Norepinephrine should be added if more than 20
micrograms/kilogram/minute of dopamine is needed.
Caution: If ventricular dysrhythmias occur, decrease rate of administration. Extravasation may
cause local tissue necrosis; administration through a central venous catheter is preferred.
Hypertensive episode
IV Nitroprusside
Adult and child: Initially 1 microgram/kilogram/minute by intravenous infusion; titrate up to 10
micrograms/kilogram/minute as needed to achieve desired effect
Phentolamine: Treat symptomatic hypertension with phentolamine
Adult: 2.5 to 5 milligrams every 5 minutes until hypertension is controlled then every 2 to 4
hours as needed;
Child: 0.05 to 0.1 milligram/kilogram/dose every 5 minutes until hypertension is controlled then
every 1 to 4 hours as needed.
Labetalol: Has been used to treat successfully one case of accelerated hypertension due to a
tranylcypromine-tyramine interaction.
Nifedipine: Two patients developed hypertension (BP 194/120, 182/112) following consumption
of food containing cheese. Both patients were treated by biting a nifedipine capsule and placing
it under the tongue. Within 7 to 10 minutes the headache had subsided and the blood pressure
dropped to 166/96 mmHg and 132/84, respectively. Both patients remained normotensive over 8
hours and symptoms did not recur.
Hyperthermia
Should be managed with external cooling. Acetaminophen may also be useful. Early
neuromuscular paralysis, intubation and ventilation in patients with a core temperature of greater
than 39 0C have been advocated by some authors.
Dantrolene
Therapeutic dose - Intravenously 2.5 milligrams/kilogram/day in divided doses.
Bromocriptine-An alternative drug used in cases of malignant hyperthermia.
Ventricular tachyarrhythmias
Lidocaine, phenytoin, and procainamide are the safest antiarrhythmic agents.
Rhabdomyolysis
Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal
insufficiency. Diuretics such as mannitol or furosemide may be needed to maintain urine output.
Urinary alkalinization is not routinely recommended. Initial treatment should be directed towards
controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia.
Control seizures, agitation, and muscle contractions.
Vigorous fluid replacement with 0.9% saline is necessary even if there is no evidence of
dehydration. Hypovolemia, increased insensible losses, and third spacing of fluid commonly
increase fluid requirements. Strive to maintain a urine output of at least 2 to 3 milliliters/kg per
hour. In severe cases 500 milliliters of fluid per hour may be required for the first several days.
Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid
overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
Alkalinization of the urine is not routinely recommended as it has never been documented to
reduce nephrotoxicity and may cause complications such as alkalemia, hypocalcemia, and
hypokalemia.
Elimination enhancement method:
There is no evidence documenting the efficacy of hemodialysis in reducing MAO inhibitor
toxicity.
Criteria for emergency department discharge: Not available/No specific guidelines
Complications: Not mentioned
Contraindications: Methyldopa and guanethidine are contraindicated as they may potentiate
hypertensive crises. Avoid phenothiazines since they can precipitate irreversible shock.
References:
1. David A Tenon. Monoamine oxidase inhibitors. In: Kent R Olson (ED.). Poisoning and drug
overdose, fifth edition, Mc Graw-Hill’S, 2007
2. Editorial Staff: Monoamine oxidase inhibitors (Management/Treatment Protocol). In:
Klasko RK (Ed): POISINDEX® System. Volume 143. Thomson Micromedex,
Greenwood Village, Colorado.
3. www.lexi.com