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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