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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Drugs Used in Psychiatry

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Monoamine Oxidase Inhibitors (MAOIs) - Antidepressants

Today MAOIs have been largely replaced by the cyclic antide-pressants for the treatment of a variety of psychiatric disorders, but continue to be used in certain types of anxiety and phobias as well as treatment-resistant depression.

Monoamine Oxidase Inhibitors (MAOIs)

·              Today MAOIs have been largely replaced by the cyclic antide-pressants for the treatment of a variety of psychiatric disorders, but continue to be used in certain types of anxiety and phobias as well as treatment-resistant depression.

·              Examples of MAOIs include clorgyline, isocarboxacid, iproniazid, lazabemide, moclobemide, pargyline, phenel-zine, pimozide, selegiline, toloxatone, and tranylcypromine. Irreversible MAOIs such as clorgyline, isocarboxacid, phenel-zine, tranylcypromine, and selegiline are used in the treatment of Parkinsonism. Procarbazine, an antineoplastic agent used in Hodgkin’s disease has weak MAOI activity.

Uses

Monoamine oxidase inhibitors (MAOIs) are useful in the treat-ment of depression, agoraphobia, anxiety disorders, bulimia, migraine, panic disorders, obsessive-compulsive disorders, phobic disorders, narcolepsy and Parkinson’s disease.

Toxicokinetics

Monoamine oxidase inhibitors (MAOIs) are rapidly absorbed on oral administration and are metabolised by acetylation, followed by urinary excretion.

Mode of Action

·            The MAOIs act (obviously) by inhibiting monoamine oxidase which is a flavin-containing enzyme located in the mitochondrial membrane of liver and central as well as peripheral sympathetic nerve terminals. Monoamine oxidase oxidatively deaminates and inactivates mono-amines, some of which are essential as neurotransmit-ters or modulators of nervous system transmission, e.g.noradrenaline, dopamine, adrenaline, and serotonin. As a result of MAO inhibition, the pool of noradrenaline in the presynaptic sympathetic nerve terminal is expanded which causes the elevation of CNS noradrenaline and dopamine. This is presumed to be the reason for the antidepressant effect of MAOIs.

·            Some MAOIs are selective for the monoamine oxidase-A enzyme, located primarily in the placenta, intestines and liver. Others are selective for the monoamine oxidase enzyme B, located primarily in the platelets, brain and liver.

·            Others are non-selective. Selectivity is lost in overdose.

o     Meclobemide (reversible) and clorgyline (irreversible) are selective MAO-A inhibitors.

o     Lazabemide, pargyline and selegiline are selective MAO B inhibitors.

o     Phenelzine, tranylcypromine and isocarboxazid are non-selective MAOIs.

Adverse Effects and Drug Interactions

·            Patients taking MAOIs are prone for multiple food and drug interactions some of which are life-threatening. Many such reported instances involve the concomitant intake of sympathomimetic agents such as ephedrine and phenylpro- panolamine, or the ingestion of foods containing tyramine.* Sympathomimetic agents act by causing the release of noradrenaline stored in the peripheral sympathetic nerve terminals. The already expanded pool of noradrenaline arising out of MAO inhibition is greatly aggravated by this release, resulting in hypertension, tachycardia, (sometimes bradycardia), severe occipital headache, hyperthermia, altered mental status, convulsions, and even intracranial haemorrhage and death.

·            While most sympathomimetic agents are capable of producing this reaction, there are exceptions, e.g. adrenaline, noradrenaline and isoproterenol, which do not release a stored pool of noradrenaline, but instead bind directly with postsynaptic alpha- and beta-adrenergic receptors. Apart from sympathomimetic drugs, there are a number of other drugs with which the MAOIs interact adversely (Table 19.7).


·            Combination of MAOIs with indirect acting sympatho- mimetic drugs can cause severe hypertension. Drugs with the potential to cause this reaction include amphetamines, dopamine, cocaine, phentermine, ephedrine, metaraminol, and phenylpropanolamine.

·              With reference to the reaction with tyramine, a similar mechanism is postulated. Pharmacologically­ active dietary monoamines are found in substantial quantities in protein foods which contain decarboxylating bacteria. Amino acids are converted to monoamines (tyramines, histamine, phenylethylamine) which are normally degraded in the GI tract and liver by MAO, but in the setting of MAO inhibition large amounts of these mono-amines enter the systemic circulation, release stored noradrenaline, and cause a severe hypertensive crisis. Foods capable of producing this tyramine reaction are listed in Table 19.8.


·              It must be mentioned that the tyramine reaction is mainly associated with irreversible MAOIs, while reversible MAOIs do not normally induce such a reaction, e.g. brofaromine, cimoxatone and moclobemide.

·              The MAOIs are also capable of causing the serotonin syndrome, especially when combined with selective serotonin reuptake inhibitors (SSRIs). At least 14 days should elapse between the discontinu-ation of an MAOI and the initiation of SSRI therapy. In some cases, e.g. fluoxetine, this interval may have to be prolonged upto 4 to 5 weeks. Combination of MAOIs with tricyclics can also produce serious (even fatal) reactions, though the practice of combined therapy is actually quite common.

·              Addicts who abuse cocaine are at special risk of suffering a severe reaction when they are on MAOI medication. Features include severe headache, hyperthermia, tremor, convulsions, and death.

Clinical (Toxic) Features

·      Overdose is characterised by an initial delay in presentation of upto 12 hours or more.

·      Symptoms include anxiety, flushing, headache, nausea, tachycardia/bradycardia, hypertension/hypotension, agita-tion, delirium, hallucinations, nystagmus, tremors, muscle rigidity, trismus, opisthotonus, convulsions, hyperthermia, profuse sweating, tachypnoea, respiratory depression, and cardiovascular collapse.

·      Pupils may be dilated and minimally reactive to light after MAOI overdose or MAOI-induced serotonin syndrome. Ping pong gaze (rhythmic and pendular, conjugate horizontal eye movements) has been described in some cases of MAOI overdose.

·      Death occurs in some cases from complications such as ARDS, DIC, and myoglobinuric renal failure.

·      Overdose complicated by rhabdomyolysis or hypotension often leads to myoglobinuria, acute tubular necrosis and renal failure.

·      Coagulopathy, haemolysis and thrombocytopenia may develop with MAOI overdose.

·              The newer reversible, selective inhibitors of MAO-A (e.g. moclobemide) appear to have a less severe toxicity profile when used in overdose. They have also been suggested to interact less with tyramine than traditional MAOIs and thus may have less potential to cause hypertensive crisis when tyramine-containing foods are ingested.

·              Chronic use of these drugs (especially phenelzine and tranylcypromine) can lead to withdrawal reaction on abrupt cessation, characterised by anxiety, depression, confusion, hallucinations, nausea, vomiting, diarrhoea and chills.

Usual Fatal Dose

Ingestion of greater than 2 to 3 mg/kg of an MAOI should be considered potentially life-threatening, and 4 to 6 mg/kg or greater is consistent with reported fatalities.

Treatment

·              Due to the potential for delayed and severe toxicity, any patient with a 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. The following measures are suggested for the treatment of adverse as well as toxic effects of MAOIs:

·            Maintenance of airway, oxygen, assisted ventilation, etc. (as needed).

·            Cardiac monitoring.

·            Electrolytes should be monitored closely, particularly for hyperkalaemia.

·            Monitor liver and renal function, and CPK level.

·            Severe hypertension should be treated with IV sodium nitroprusside or phentolamine. Methyldopa and guanethi-dine are contraindicated as they may potentiate hyper-tensive crises.

·              Hypotension (or shock) can be managed by IV fluids, and vasopressors such as noradrenaline or dopamine, i.e. direct-acting alpha-adrenergic agonists.

·            Ventricular tachyarrhythmias usually respond to ligno-caine, phenytoin, or procainamide.

·            If the patient is seen within a short time of overdosing, gut decontamination must be carried out—lavage, activated charcoal, cathartics.

·            Acidic diuresis and haemodialysis have been tried with varying degree of success but are probably best avoided. Although MAO inhibitor excretion is enhanced by forced acid diuresis, there is no evidence that it is effective in reducing the severity of an overdose. In fact, such a procedure may be dangerous in this situation because of the instability of the cardiovascular system.

·            Muscle rigidity and agitation may respond to phenothi-azines such as chlorpromazine. Diazepam is however safer, and phenytoin is a good alternative. In the presence of intractable muscle rigidity, neuromuscular paralysis with pancuronium may be necessary.*

·            Seizures are best treated with benzodiazepines or barbi-turates.

·            Hyperthermia can be managed with paracetamol and external cooling. In severe cases (malignant hyperthermia-type), IV dantrolene is given at a dose of 2.5 mg/kg, every 6 hours, for 24 hours. As an alternative, bromocriptine can be administered.

·            For 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 alka-linisation is not routinely recommended. Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalaemia, hyperthermia, and hypovolaemia. Control seizures, agitation, and muscle contractions.

·            Serotonin syndrome must be treated on the recommended lines outlined under SSRIs.

·            Patients should be placed on special diets low in tyra-mine-containing foods for at least 2 weeks post-exposure.

 

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