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Monoamine oxidase inhibitors (Detail)

GENERAL

The monoamine oxidase inhibitors used in the management of depressive disorders consist of a group of older drugs, which tend to be non-selective and irreversible inhibitors of both monoamine oxidase (MAO) A and B, and a second group of compounds that reversibly inhibit only MAO A (RIMAs). There are also MAO inhibitors that are both selective and irreversible (e.g. clorgyline [MAO A], rasagiline [MAO B]) that will not be discussed here as they are now used only experimentally (clorgyline (1)) or as an anti-Parkinson drug (rasagiline (2)).

The older, non-selective, irreversible drugs have very severe and prolonged toxicity in overdose and potentially life-threatening interactions with tyramine in food and many drugs. The newer, selective, reversible drugs have a much more benign profile in overdose, are safe with food, but may still have life-threatening toxicity when combined with serotonergic drugs and deaths have also been recorded. The fatal toxicity index (FTI) of the monoamine oxidase inhibitors as a group (27.03 deaths per million prescriptions) in England, Scotland and Wales between 1985 and 1989 was significantly lower than the mean of all drugs (35.6) although that of tranylcypromine was higher (3).

STRUCTURE AND CLASSIFICATION/USES

Some aspects of the chemistry of these drugs are shown in Table 1 and structural diagrams are found here.

Table 1. Chemistry of monoamine oxidase inhibitors

Compound MW SI Conversion Therapeutic, toxic concentrations*United States Pharmacopoeia Dictionary of Drug Names
Iproniazid179.2mg/L x 5.58 = micromol/L5 mg/L, N/A2-(1-methylethyl)hydrazide-4-pyridinecarboxylic acid
Isocarboxazid231.3mg/L x 4.32 = micromol/LN/A, N/A5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide
Phenelzine136.2mg/L x 7.34 = micromol/L0.02 mg/L, 0.5 mg/L(2-phenylethyl)-hydrazine
Tranylcypromine133.2mg/L x 7.51 = micromol/L0.1 mg/L, 0.3 mg/L2-phenyl-, trans-(+-)-cyclopropanamine
Befloxatone349.3mg/L x 2.86 = micromol/LN/A, N/A(R)-5-(methoxymethyl)-3-{p-[(R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl}-2-oxazolidinone
Brofaromine310.2mg/L x 3.22 = micromol/LN/A, N/A4-(7-bromo-5-methoxy-2-benzofuranyl)piperidine
Moclobemide268.8mg/L x 3.72 = micromol/L2 mg/L, 20 mg/Lp-chloro-N-(2-morpholinoethyl)benzamide
Pirlindole226.3mg/L x 4.42 = micromol/LN/A, N/A2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino(3,2,1-jk)carbazole
Toloxatone207.2mg/L x 4.83 = micromol/LN/A, N/A5-(hydroxymethyl)-3-m-tolyl-2-oxazolidinone

MW, molecular weight
N/A, Not available
*From Flanagan RJ. Guidelines for the interpretation of analytical toxicology results and unit of measurement conversion factors. Ann Clin Biochem 1998;35 ( Pt 2):261-7

Tranylcypromine is a chiral cyclopropylamine derivative used as a racemic mixture (4), while the other older MAO inhibitors (iproniazid, isocarboxazid and phenelzine) are all hydrazine derivatives. Iproniazid is the isopropyl derivative of isoniazid (5) developed for use in tuberculosis (6) and found to be beneficial when depression complicated the disease (7). It has been withdrawn from use, even as an antidepressant, in most countries because of its tendency to produce a fulminant or subfulminant autoimmune hepatitis (8). The irreversible, non-selective MAO inhibitors are primarily indicated in major depression (9) but have found use in anxiety and phobic states, panic disorder, obsessive/compulsive disorders, chronic pain, bulimia nervosa and narcolepsy (10).

The RIMAs are less structurally related than the traditional MAO inhibitors (Table 1 and Figure) . Nevertheless, comparative analysis of these drugs reveals all such inhibitors have a phenolic ring with a neighboring negatively charged nitrogen or oxygen atom; the phenol ring is an ultimate precondition for the manifestation of MAO A inhibitory activity (11). Befloxatone and toloxatone are oxazolidinone derivatives while brofaromine is a brominated piperidine derivative that bears some resemblance to the analgesic tramadol. Moclobemide is a benzamide and pirlindole a chiral pyrazinocarbazole derivative. By far the most clinical experience has been with moclobemide which is indicated in the treatment of depression and social phobia and has been used in post-traumatic stress disorder, panic disorder and smoking cessation (9).

Table 2. Typical therpaeutic doses of monoamine oxidase inhibitors for major depression (9)

Drug Adult Dose*
Iproniazid50 to 150 mg daily, some patients may respond to 25 to 50 mg daily or every other day
Isocarboxazid30 mg daily in single or divided doses, some patients may respond to 10 to 20 mg daily. Half the normal maintenance dose may be adequate in the elderly
Phenelzine15 mg three times daily, some patients may respond to 15 mg on alternate days
Tranylcypromine10 mg in the morning and 10 mg in the afternoon, some patients may continue to respond to 10 mg daily
BefloxatoneInvestigational, suggested dose 20 mg/day (106)
Brofaromine50 to 150 mg/day
Moclobemide300 mg by mouth in divided doses. This may be increased to up to 600 mg daily according to response. In some patients, a maintenance dose of 150 mg daily may be sufficient
PirlindoleUp to a maximum of 400 mg daily
Toloxatone200 mg three times daily

* Pediatric use not reported

TOXIC DOSE

Non-selective, irreversible monoamine oxidase inhibitors

These drugs have potentially fatal interactions with food containing tyramine (12-14) and some other foodstuffs, and a variety of drugs. Knowledge of the food-drug interaction has even led to attempted suicide by cheese in a patient on a MAO inhibitor (15). Despite the increase in use of alternative and safer antidepressants, MAO inhibitor drug interactions still occur and unless they are managed appropriately, remain potentially fatal (16). Of particular importance is the interaction between MAO inhibitors and analgesics with serotonergic activity such as meperidine (pethidine) (17;18), dextromethorphan (19) and tramadol (20). Drugs of abuse are also a significant problem with a typical reaction occurring with 3,4-methylene-dioxy-methamphetamine (MDMA) and phenelzine (21).

There has been concern about increased adverse effects when switching patients from a tricyclic antidepressant to a traditional MAO inhibitor although in a limited retrospective study there were no problems (22). In another retrospective study (chart review), the use of a MAO inhibitor-tricyclic antidepressant combination in therapeutic doses appeared to be relatively safe (23). However, the efficacy of this combination has not yet been proven, and it may be particularly toxic if taken in an overdose (24). One prominent exception to the relatively safe therapeutic use of a tricyclic and a MAO inhibitor is clomipramine which is by far the most serotonergic of the tricyclics (25). The therapeutic combination of clomipramine with tranylcypromine can cause severe serotonin toxicity (26;27), which may be fatal (28). The combination in overdose is also associated with severe toxicity (29).

The use of therapeutic doses of fluoxetine with a monoamine oxidase inhibitor was accompanied by a very high incidence of adverse effects (30), especially serotonin toxicity and the combination of any serotonin uptake inhibitor (31) with any MAO inhibitor cannot be recommended. Fluoxetine (and presumably other serotonin uptake inhibitors) may precipitate serotonin toxicity even when initiated two weeks after ceasing treatment with a MAO inhibitor (32). Serotonin toxicity (often life-threatening) from a combination of venlafaxine with an irreversible MAO inhibitor seems a particular problem with cases reported with isocarboxazid (33), phenelzine (34) even after abstinence from phenelzine for more than two weeks (35) and tranylcypromine (36) even after a single therapeutic dose of venlafaxine (37).

Iproniazid

There is little information available on toxic doses of iproniazid although death has occurred (38). In the context of an overdose with another serotonergic agent, even therapeutic doses of iproniazid may combine to produce life-threatening toxicity.

Isocarboxazid

Ingestion of 300 mg of isocarboxazid was survived by a 48-year old woman (39). A 35-year old woman took 1 gram of isocarboxazid with suicidal intent and became comatose with poor ventilation, increasing rigidity of all muscles and temperature rising to 41.1 degrees C requiring intubation and ventilation (40). In the context of an overdose with another serotonergic agent, even therapeutic doses of isocarboxazid may combine to produce life-threatening toxicity.

Phenelzine

Psychotic phenomena (particularly delusional parisitosis (41;42)) can occur on therapeutic doses of phenelzine (43) as well as being a feature of phenelzine withdrawal (44).

A 2-year old child survived ingestion of 150 to 225 mg (45), while adults have survived doses of 900 (46) to 2250 mg (47). On the other hand, overdoses of 375 mg to 1500 mg have resulted in death (48) leading to the suggestion that more than 2 to 3 mg/kg may be life-threatening and more than 4 to 6 mg/kg may be fatal (49). In the context of an overdose with another serotonergic agent, even therapeutic doses of phenelzine may combine to produce life-threatening toxicity.

Tranylcypromine

Tranylcypromine has been marketed as a combination product with trifluoperazine [Jatrosom (FM), Parmodalin, Parstelin, Parstelin (FM), Stelapar] (9). Therapy with twice the usual dose of this combination has resulted in severe neuroleptic malignant syndrome (50), while overdose of the product produces severe poisoning (51) which may be fatal in adults (52;53) and children (54). Even accidental poisoning in childhood is problematic (55).

Ingestion of 400 mg of tranylcypromine resulted in only mild symptoms of intoxication (56), while regular ingestion of 440 mg (57) to 600 mg (58) of tranylcypromine daily in patients with a dependence on MAOIs may be tolerated without side-effects until abruptly ceased (58). Doses of 200 – 900 mg have been survived (59-62) with varying degrees of toxicity while doses of 130 – 850 mg (> 2 to 3 mg/kg) have resulted in death (52;53;63-66). More than 1 mg/kg is likely to be a significant poisoning but, in the context of an overdose with another serotonergic agent, even therapeutic doses of tranylcypromine may combine to produce life-threatening toxicity.

Reversible inhibitors of monoamine oxidase A

In contrast to the irreversible non-selective MAO inhibitors, the potential for an interaction between a RIMA and tyramine appears very small (67-71).

There is little information about toxic doses of befloxatone, brofaromine or pirlindole.

Moclobemide

Serotonin toxicity has been reported with therapeutic doses of various serotonergic drugs in combination with moclobemide including fluoxetine (72), meperidine (73) and citalopram (74). In one case, serotonin toxicity with trismus developed on moclobemide alone and was fatal (75).

A small series of 11 patients suggested an SSRI and moclobemide might be well tolerated in therapeutic use(76). However, in a series of 50 depressed patients, moclobemide (up to 600 mg/day) was added to paroxetine or fluoxetine (20 mg/day) for 6 weeks to assess tolerability. There was a high rate of serotonergic adverse events (77), many severe and in the absence of convincing evidence for efficacy of such a combination there is no indication to prescribe these drugs together (78).

A review of single-drug intoxications with moclobemide at doses of up to 20.55 g revealed no deaths due solely to moclobemide overdose. All patients recovered fully within 1 to 7 days (79).

In a single toxicology treatment centre study, there were no deaths, complications or major toxic effects in 33 patients who took moclobemide alone despite a median ingested dose of 6 g (range 0.9 - 18 g). The patient who ingested 18 g developed hyperreflexia, tachycardia and a temperature of 37.4ºC but no other significant effects (80). All major complications in the 73 other patients who took moclobemide with a co-ingestant, including seizures and coma, could be accounted for by the coingested drug (80). The median dose of moclobemide in the patients coingesting other drugs was 4g (IQR 2.3 – 6.7) (80). The combination of moclobemide with other serotonergic drugs caused serotonin toxicity in over half of cases and severe serotonin toxicity in 29% of cases necessitating intubation, paralysis and sedation. The odds of developing serotonin toxicity in moclobemide plus a serotonergic drug overdose was 35 times that of moclobemide alone overdoses (80).

Despite blood concentrations of fluoxetine within the therapeutic range after an overdose, severe serotonin toxicity ensued, later attributed to concomitant ingestion of moclobemide (81). Overdoses of paroxetine (82;83), clomipramine (84) and venlafaxine (80;85) in combination with moclobemide have resulted in severe serotonin toxicity. Moclobemide overdose in combination with tricyclic antidepressants may also result in serious poisoning even when the moclobemide overdose is modest (86).

Fatalities from the combination of moclobemide taken in overdose with another serotonergic drug (87) have occurred with clomipramine (88-91), clomipramine with tramadol (92), clomipramine with fluoxetine (93), citalopram (88;91;94), paroxetine (95), sertraline (96) and, most recently, MDMA (ecstasy) (97). In the context of an overdose with another serotonergic agent, even therapeutic doses of moclobemide may combine to produce life-threatening toxicity.

Death has been reported due to deliberate ingestion of moclobemide alone (98;99), in one case the estimated dose was 4.5 g (100).

Toloxatone

Fulminant and ultimately fatal hepatitis has been reported on toloxatone therapy (101).
In a large series of 122 overdose cases, the minimal toxic dose was 2 g (102). Two of the patients died, one ingested 6 g of toloxatone together with clomipramine and lorazepam, became comatose, developed bilateral mydriasis and hyperthermia, and died in asystole (102). In the context of an overdose with another serotonergic agent, even therapeutic doses of toloxatone may combine to produce life-threatening toxicity.

TOXICOKINETICS/TOXICODYNAMICS

Table 3. Pharmacokinetics of the monoamine oxidase inhibitors in theapeutic doses(10;118)

Drug Bioavailability (F) (%) Time to peak after oral dosing (h) Volume of distribution (L/kg) Clearance (L/h/kg) Half-life (h) Protein binding (%) Active metabolites
IproniazidNRNRNRNRNRNRhydrazine (hepatotoxic)
Isocarboxazidprobably significant first pass metabolism4NRNR36NRbenzylhydrazine
PhenelzineNR2 - 4NRNR1.5 - 4NRß-phenylethylamine
TranylcypromineNR0.7 - 3.52.71 (1.11 - 5.68)0.85 (0.38 - 2.4)2.45 (1.54 - 3.15)NRN-acetyl- tranylcypromine, N,O-diacetyl-p-hydroxy- tranylcypromine
Befloxatone (106)NR2NRNR11.1 ± 0.858o-desmethyl-befloxatone (22.2 ±2.3)
Brofaromine9023.290.1714.2 (12 - 15)NRo-desmethyl-brofaromine
Moclobemide49 - 90 saturable first pass metabolism1 - 210.73 - 1.291.6 (0.8 - 2.0)50ring-opened M4 and N-oxidized M5 metabolites
Pirlindole~ 301 - 2NRNR2.03 (0.98 - 6.51)NRdehydropirlindole
Toloxatone (113)50 - 620.5 - 11.09 - 1.6400.46 - 0.861 - 350NR

NR, not reported

The time course of action of the irreversible agents is dependent on the kinetics of monoamine oxidase so there is no correlation between plasma concentrations and primary effect for these agents. There is, however, some evidence that some of the other effects may be correlated with plasma concentration. For example, standing systolic blood pressure is negatively correlated with plasma concentration after a dose of tranylcypromine with the blood pressure minimum occurring at the time of peak concentration (103).

There is little information available on iproniazid or isocarboxazid.

Phenelzine

After a single oral dose of 30 mg, the peak plasma phenelzine concentration was 0.002 mg/L (104). Phenelzine concentrations of 1.5 and 2.0 mg/L were seen after overdose in two of three cases (105).

Tranylcypromine

After a single oral dose of 20 mg, mean peak plasma concentration in 9 subjects was 0.112 mg/L (range 0.0645 – 0.190 mg/L) (103). Tranylcypromine concentration in a case of fatal tranylcypromine-food interaction was 0.102 mg/L (14). After ingestion of 400 mg of tranylcypromine, blood concentration was 0.5 mg/L with mild symptoms of intoxication (56). In a fatal overdose estimated at 550 mg, antemortem tranylcypromine blood concentration was 0.611 mg/L (66).

Befloxatone

After a single dose of 10 mg, peak befloxatone concentration was 0.03 mg/L (106).

Brofaromine

After a single dose of 75 mg, peak brofaromine concentration was 0.37 mg/L (107).

Moclobemide

After a single dose of 300 mg, peak moclobemide concentrations were 1.46 – 2.96 mg/L (108).

In 3 cases of moclobemide overdose, plasma moclobemide was 2.8 mg/L at 2 h in the first case; in case 2, 18 mg/L; in case 3 60.9 mg/L at 2 h and 4.6 mg/L 12 hours later. None of the patients showed serious effects during 24 hours of observation (109). Seizures, tachycardia and hyperthermia were seen after a 10 g ingestion with a plasma moclobemide concentration of 36.5 mg/L 6 hours post-ingestion (110).

In five cases with estimated doses of 1.8, 3, 6, 9 and 12 g, the peak concentrations were 25, 8, 28, 30 and 50 mg/L respectively (80). Overall, moclobemide metabolism and elimination does not appear to be saturable, even with extreme doses and very high plasma concentrations (80). Nevertheless, because of the considerable interindividual variation in clearance with moclobemide, some individuals will have prolonged elimination half-lives (80;93;111) and consequently prolonged clinical effects as these correlate with plasma moclobemide concentrations (80).

Pirlindole

After a single dose of 75 mg, median peak plasma pirlindole concentration was 0.045 mg/l (range 0.017 – 0.149 mg/L) (112).

Toloxatone

After a single dose of 1 mg/kg orally, peak toloxatone concentration ranged from 0.384 to 0.640 mg/l (113). In acute overdose the toxicokinetic parameters (half life, 1.5 hours; total body clearance, 0.56 L/kg/h) were not significantly different from those reported with usual therapeutic doses (114).

PATHOPHYSIOLOGY

Monoamine oxidase catalyzes the oxidative deamination of a number of biogenic amines in the brain and peripheral tissues by the production of hydrogen peroxide (115). There are known to be two forms of MAO, A and B. They are made up of different polypeptides and coded by two genes located on the X chromosome but are structurally and functionally very close (115). MAO A preferentially metabolizes serotonin (5-HT), norepinephrine (NE) and dopamine (DA) while MAO B metabolizes phenylethylamine (PEA) and benzylamine although at high substrate concentrations there is considerable cross metabolism (115). Tyramine is deaminated by both MAO A and B, thus inhibiting only one of the enzymes allows for continued, albeit reduced, metabolism.

Flavin adenine dinucleotide (FAD) is an essential cofactor for both forms of monoamine oxidase and the site of action of the monoamine oxidase inhibitors. The irreversible inhibitors first bind reversibly to FAD then, by the same catalytic process as for substrates, are transformed into intermediate reactive species which bind covalently to the enzyme through a reduced form of FAD (117). Moclobemide is also transformed by the flavin cofactor into a new reactive chemical entity after forming a reversible complex with the cofactor, but the new entity is unstable and rapidly disappears (117). The other reversible inhibitors form a weak reversible charge-transfer complex with FAD which inhibits the enzyme activity (117).

Inhibition of MAO results in elevation of the relevant neurotransmitters and consequent therapeutic effect, and in excess, toxicity. Thus, the selective MAO A inhibitors exhibit predominantly serotonergic toxicity with some features of central norepinephrine and dopamine excess but not as much as might be expected because of remaining MAO B activity. The non-selective agents have greater toxicity because of the lack of alternative pathways of metabolism. Phenylethylamine is increased as a result of inhibition of monoamine oxidase B and may contribute to the clinical manifestations of toxicity (62). Phenelzine as also metabolized in part to PEA (118). High concentrations of PEA, injected into mice, induce convulsions through unclear mechanisms that do not involve the benzodiazepine receptor (119).

The hepatotoxicity of iproniazid is mediated by mechanisms similar to that of isoniazid (120). Iproniazid is metabolized to isopropylhydrazine which is further metabolized to highly reactive acylating and alkylating agents that covalently bind to liver macromolecules (121) resulting in an autoimmune hepatic injury (8) via a reactive metabolite/enzyme haptenization mechanism (122).
In addition to their effects on MAO A, brofaromine has some serotonin uptake inhibitory effect (123) while pirlindole inhibits serotonin and norepinephrine uptake (68).

PREGNANCY AND LACTATION

The U.S. Federal Drug Administration (FDA) and Australian Drug Evaluation Committee (ADEC) pregnancy risk categories (where known) are shown in Table 4.

Table 4. U.S. FDA and ADEC Risk Category and Breast Milk Distribution of the monoamine oxidase inhibitors

Drug FDA* (ADEC) Pregnancy Risk CategoryDistribution into breast milk
IproniazidNR (NR)NR
IsocarboxazidC (NR)NR
PhenelzineC (B3)NR
TranylcypromineC (B2)detectable in breast milk, significance unknown (124)
BefloxatoneNR (NR)NR
BrofaromineNR (NR)NR
MoclobemideNR (B3)1% of the weight-adjusted maternal daily dose (125).
PirlindoleNR (NR)NR
ToloxatoneNR (NR)NR

NR, not reported
*U.S. FDA pregnancy categories
ADEC, Australian Drug Evaluation Committee pregnancy categories

For most of these drugs, there are no data on distribution into breast milk. Tranylcypromine is detectable in milk (124) but the significance of this is unknown. The small amounts of moclobemide found in breast milk suggest the drug would be unlikely to be hazardous to suckling infants (125).

CLINICAL PRESENTATION

Acute Overdose

Non-selective, irreversible monoamine oxidase inhibitors

A significant overdose (> 1 mg/kg of tranylcypromine, > 2 mg/kg of phenelzine or any dose with another serotonergic agent) with one of the non-selective, irreversible MAO inhibitors resembles severe serotonin toxicity with additional CNS and severe cardiovascular compromise (both hyper- and hypotension). After a “latent” period of some hours (up to 6 – 12), patients may progressively develop restlessness, agitation, violent motor activity with moaning and grimacing, hyperreflexia and myoclonus, profuse sweating, and hallucinations. Other features of the CNS stimulation can include nystagmus, generalized hypertonia (126), jaw trismus (40) and an unusual periodic alternating gaze disturbance (alternating skew deviation) known as “ping-pong” gaze (29;127;128). At some stage during this process the patients will usually become comatose and may remain so for prolonged periods (129). Patients may present with seriously elevated blood pressure which may be followed by cardiovascular collapse (49) with hypotension (46) that may be unresponsive to fluids. ECG abnormalities are unusual although peaked T waves (in the absence of hyperkalaemia) have been reported after tranylcypromine overdose (130). Intracranial hemorrhage may occur during the hypertensive phase. Severe, life-threatening hyperthermia (60;131) accompanied by tachycardia, tachypnoea, metabolic acidosis and hypercapnea, temperatures exceeding 40oC and muscle rigidity may peak as late as 24 hours post presentation. Multi-organ failure (38) with rhabdomyolysis and a consumptive coagulopathy, thrombocytopenia and haemolysis (disseminated intravascular coagulation) (132) may ensue and, if so, is usually fatal (49).

Reversible inhibitors of monoamine oxidase A

There is little information available on the acute toxicity of befloxatone, brofaromine, or pirlindole.

Moclobemide

Moclobemide as a sole agent in overdose presents with a much more benign toxicity profile than that of the irreversible, non-selective MAO inhibitors even when very large doses are taken (80). Many patients will be asymptomatic, while in symptomatic patients, tachycardia, mild gastrointestinal symptoms, a slight increase in blood pressure, fatigue and agitation may occur. In a series of 33 moclobemide alone overdoses, no patients developed coma, seizures or arrhythmias, 21% developed a tachycardia and 3% developed serotonin toxicity, which was not severe (80).

In contrast, when patients co-ingested a serotonergic drug, 52% developed serotonin toxicity (see Chapter 28, Serotonin Toxicity) of which half were severe (with temperature > 38.5°C and muscle rigidity interfering with ventilation requiring intubation and paralysis) (80). The incidence of serotonin toxicity where moclobemide was taken with non-serotonergic co-ingestants (4%) was similar to that of moclobemide alone (80).

Case reports of severe serotonin toxicity from moclobemide in combination with a serotonergic drug are common (82-85). The serotonin toxicity may be severe enough to be fatal (87-97) (see Toxic dose for details of involved drugs).

Very occasionally, moclobemide alone can produce severe symptoms such as convulsions, coma, muscle rigidity, respiratory failure, cardiovascular collapse and hyperthermia (133) and death from moclobemide alone has been reported (98-100).

Toloxatone

In a large series of 122 cases, the first symptoms appeared about one hour after ingestion. In most cases, only drowsiness and mild adrenergic effects (sinus tachycardia) were observed (102). In a few of these cases with very large doses, coma, hypertonia and myoclonic jerks occurred. In 3 cases of severe poisoning, toloxatone was taken with tricyclic antidepressants including clomipramine. Symptoms in these severe cases were muscular rigidity, hyperthermia and cardiovascular collapse (102). Two of these severely poisoned patients died, one in asystole (102).

Acute Withdrawal

Symptoms associated with withdrawal of irreversible non-selective MAO inhibitors appear much sooner (hours to days (134)) than would be expected given the slow offset of the MAO inhibition. Symptoms may include anxiety, depression, confusion, hallucinations, psychosis (44), tremulousness, nausea, vomiting, diarrhea, and chills (135). Moclobemide is also associated with a withdrawal syndrome which may present as a flu-like illness (136). The discontinuation syndrome does not respond to serotonin uptake inhibitors (136) nor does moclobemide alleviate the discontinuation syndrome of serotonin uptake inhibitors (137).

Adverse Reactions

MAO inhibitors may induce euphoriant-stimulating type and psychotomimetic effects in certain individuals and the use of MAO inhibitors can be associated with dependence-tolerance (57;138). Rapid switching (with little or no antidepressant period) between irreversible MAO inhibitors may be dangerous (139) particularly if switching to tranylcypromine (140), however, others have suggested that there is no (141) or little problem (142).

Non-selective, irreversible monoamine oxidase inhibitors
The adverse effect profile of these agents is similar apart from the increased risk of auto-immune hepatitis associated with iproniazid (8). Common adverse effects include orthostatic hypotension, sleep disturbances (including insomnia and less commonly hypersomnia), headache, drowsiness, fatigue, weakness, agitation, tremors, twitching, myoclonus, hyperreflexia, constipation, dry mouth, weight gain, impotence, loss of libido and elevated serum transaminases (143). Infrequent effects include itch, rash, sweating, blurred vision, peripheral edema and mania, while hypertensive crisis (tyramine or medication interactions), hepatocellular damage, leucopenia and SIADH occur rarely (143). The hypertensive crisis is characterized by severe occipital headache and a rapid and sometimes prolonged rise in blood pressure, which may result in intracranial hemorrhage or acute cardiac failure. If treatment is required, use phentolamine 2 – 5 mg IV, nifedipine 10 mg orally, or chlorpromazine 50 mg IV, repeated as necessary (143).

Reversible inhibitors of monoamine oxidase A Befloxatone

The most frequent adverse effects reported on befloxatone were drowsiness (6.8%), headache (6.8%) and asthenia (6.8%). Nervousness and euphoria occurred in 1.5% with no complaints of insomnia (106).

Brofaromine

Brofaromine has a similar side effect profile to moclobemide with dose-limiting side effects typically including nausea, insomnia and tremor (144).

Moclobemide

Common adverse effects include nausea, dry mouth, constipation, diarrhea, anxiety, restlessness, insomnia, dizziness and headache (143). Infrequent effects include visual disturbances, gastrointestinal complaints (feeling of fullness), rash, itch, urticaria and flushing, while sedation, hypertension, intrahepatic cholestasis and peripheral edema occur rarely (143).

Pirlindole

Adverse effect profile of pirlindole did not differ significantly from placebo in a small (n = 103) trial (145).

Toloxatone

Toloxatone had more sleep disturbance and anxiety but less hot flushes, dry mouth, constipation and headache than moclobemide in a comparison trial (146).

DIAGNOSTIC TESTS

There are no diagnostic tests specific to the MAO inhibitors. Quantitative drug estimation is not readily available for any of these agents and is not indicated for routine management.

Blood pressure should be monitored closely and if abnormal after a significant dose of an irreversible MAO should be measured invasively (arterial line). Core body temperature should be assessed as hyperthermia is common. Hepatic and renal function tests are indicated as are tests to assess for thrombocytopenia and disseminated intravascular coagulation in more severe cases. Measurement of creatine kinase in cases of coma will help in the assessment of rhabdomyolysis. Prolonged coma with life-threatening irreversible MAO inhibitor overdose may simply be a manifestation of the poisoning, but consideration should be given to CT head scan to look for intracerebral bleeding.

Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

POST-MORTEM CONSIDERATIONS

For many drugs, there is a post-mortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artefactual elevation of drug concentrations in blood (postmortem redistribution). Highest drug concentrations are found in central vessels such as pulmonary artery and vein, and lowest concentrations are found in peripheral vessels such as subclavian and femoral veins. This creates major difficulties in interpretation and undermines the reference value of data bases where the site of origin of post-mortem blood samples is unknown (147). It is widely agreed, however, that the femoral vein site represents the optimum sampling site and this site is standardized amongst forensic pathologists.

There is little information on postmortem examination after iproniazid, isocarboxazid, befloxatone, brofaromine, pirlindole or toloxatone.

Phenelzine

In two cases of phenelzine related death, concentrations in blood at autopsy were 10 – 50 times greater than therapeutic concentrations (0.002 – 0.02 mg/L) (148).

Tranylcypromine

Site and temporal changes in tranylcypromine concentrations in blood were studied in a human poisoning case (149). Tranylcypromine showed preferential concentration in liver (2.21 mg/kg) and brain stem (2.46 mg/kg). There was a moderate post mortem redistribution phenomenon with tranylcypromine concentrations lowest in peripheral blood (0.17 mg/L) at 0 h and highest in central vessels at 24 h (0.52 mg/L) (149). A femoral blood concentration of 3.7 mg/L was found in a fatality after 300 mg of tranylcypromine (150). In a fatal overdose estimated at 550 mg, femoral blood tranylcypromine was 0.57 mg/L with a subclavian blood concentration twice that of the antemortem blood (suggesting postmortem redistribution) (66). Other studies have shown concentrations varying from 0.25 to 9.1 mg/L (53;65;151).

Moclobemide

Postmortem redistribution of moclobemide was investigated in a rat model. Postmortem concentrations in blood from the vena cava and the heart were found to be in good accordance with antemortem concentrations (87).

In a fatality due to the combined ingestion of moclobemide and citalopram with lormetazepam and alcohol, the results obtained for blood and urine, respectively, were as follows: moclobemide 5.62 mg/L and 204 mg/L and citalopram 4.47 mg/L and 19.7 mg/L (94). Moclobemide (49.9 mg/L) and perazine (1.27 mg/L) were identified in a combined drug intoxication resulting in death (152).

In a case of moclobemide overdose due to a deliberate ingestion of 4.5 g of the drug, the post-mortem whole blood concentration was 15.5 mg/L (100). In a death attributed to moclobemide alone, the blood concentration of moclobemide was 137 mg/L and the liver concentration was 432 mg/kg (99).

TREATMENT

Overview

All serotonergic drugs should be withdrawn and the use of agents with serotonergic activity is absolutely contraindicated. Oral activated charcoal may be of value if given early (within 1 hour) in irreversible non-selective MAO inhibitor poisoning; it is unlikely decontamination would be of benefit in RIMA poisoning alone. The preferred treatment for RIMA poisoning is simple supportive care with IV access and fluids.

Intensive care admission for high level supportive care is indicated for significant ingestions of an irreversible, non-selective MAO inhibitor poisoning (> 1 mg/kg of tranylcypromine, > 2 mg/kg of phenelzine or any dose with another serotonergic agent). After the potential latent period of up to 6 – 12 h, the early features are consistent with serotonin toxicity and treatment is focused on controlling agitation, maintaining airway, reversing hyperthermia and symptomatic treatment. In view of the potential cardiovascular toxicity of the irreversible agents, in addition to maintenance of the airway and breathing, circulatory status warrants close attention. Temperature should be monitored closely as hyperthermia predicts worsening toxicity.

Milder serotonin toxicity from either group of MAO inhibitors may respond to specific serotonin antagonists but severe serotonin toxicity (often due to combined overdose with another serotonergic drug) has the potential for life-threatening outcomes that may require more aggressive intervention.

Supportive Care

Non-selective, irreversible monoamine oxidase inhibitors

The restlessness and agitation with hyperreflexia, myoclonus and profuse sweating with or without generalized hypertonia may be an indication for specific treatment with serotonin antagonists such as cyproheptadine or chlorpromazine (see Antidotes). Benzodiazepines may be helpful but antipsychotic medication that does not have significant serotonin antagonism (e.g. haloperidol) should not be used because of the effects of serotonin on dopamine release.

Hypertension may occasionally be very severe and warrant therapy in its own right. If treatment is required, use phentolamine 2 – 5 mg IV, nifedipine 10 mg orally, or chlorpromazine 50 mg IV, repeated as necessary (143). In the context of an overdose, treatment of the hypertension should be cautiously undertaken because of the possibility of cardiovascular collapse and hypotension. Hypotension may very severe and should be treated initially with a 10 to 20 mL/kg bolus of 0.9% NaCl followed by a vasopressor. A direct acting alpha adrenergic agonist (e.g. norepinephrine) should be used rather than any indirect acting agents for the treatment of hypotension unresponsive to fluids. Seizures are rare, if they occur, they should be treated with benzodiazepines as first line.

Severe hyperthermia with increasing muscular rigidity heralds life-threatening toxicity. Elective intubation, neuromuscular paralysis, mechanical ventilation and aggressive cooling measures are indicated. Organ failure should be treated along standard lines.

Reversible inhibitors of monoamine oxidase A

Overdoses of these agents without co-ingestion are unlikely to be associated with severe toxicity and the preferred treatment is simple supportive care with IV access and fluids. For cases after ingestion alone or with another serotonergic agent that develop more severe features of serotonin toxicity, treatment of serotonin toxicity should be instituted as for the irreversible agents.

Antidotes

Cyproheptadine has relatively high affinity for the 5-HT2 receptor (153) and is effective for milder cases of serotonin toxicity secondary to serotonin uptake inhibitor toxicity who are able to take oral medication (154-158). There is no experience with its use in irreversible MAO inhibitor overdose. If used, current experience suggests that 12 mg orally or by nasogastric tube, followed by 4 – 8 mg every four to six hours, is an appropriate dose range (159). For severe serotonin toxicity, chlorpromazine, also a potent 5HT2 antagonist (160), has been used in serotonin toxicity associated with irreversible MAO inhibitor drug interactions with apparent good effect (26;27). Chlorpromazine has also been used with some success in irreversible MAO inhibitor overdose (60;161;162) . Current experience indicates fluid resuscitation is required prior to administration of chlorpromazine and that the dose is probably in the range of 12.5 to 50 mg IV initially, followed by 25 – 50 mg orally or IV every six hours (159). Newer antipsychotic agents such as risperidone also have very potent 5HT2 antagonist activity (163) and may be beneficial in treating serotonin toxicity although there is no published experience of their use.

Elimination enhancement

The volumes of distribution for MAO inhibitors, where known, are uniformly high and extracorporeal techniques are unlikely to be of benefit.

Monitoring

Routine observation of vital signs, especially GCS, airway patency, blood pressure and temperature is indicated. Frequent assessment of mental status and neuromuscular function (hyperreflexia, hypertonia, myoclonus, clonus) should be made. All patients suspected of ingesting toxic doses (see above) of irreversible MAO inhibitors should be observed in a monitored setting for 24 hours because of the potential for delayed onset of reactions.

Patients should be placed on special diets low in tyramine containing foods. Sympathomimetic and serotonergic drugs should be avoided because of potentiation of MAO inhibitor overdose effects. Precautions for food and drug interactions should remain in effect for 1 to 2 weeks post exposure to the irreversible agents.

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IMW 1/2/04 This article has been used (with permission of MediTox Pty Ltd) as the basis of a chapter on monoamine oxidase inhibitor toxicity in the third edition of Medical Toxicology published by Lippincott Williams Wilkins, 2004.


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