Toxicity MAOIs

Normally, dietary tyramine is broken down in the gastrointestinal tract by MAO and is not absorbed. In the presence of MAOI, however, all of its potent sympathomimetic actions are seen. Other side effects of MAOI include excessive CNS stimulation, orthostatic hypotension, weight gain, and in rare cases hepatotoxicity. Because the monoamine oxidase inhibitors exhibit greater toxicity, yet no greater therapeutic response than other, newer agents, clinical use has been markedly curtailed. The primary use for MAOIs is in the treatment of atypical depressions, eg, those associated with increased appetite, phobic anxiety, hypersomnolence, and fatigues, but not melancholia (2). 

Use of die MAOIs must be discontinued 2 weeks before the administration of die SSRIs. When the SSRIs are administered witii die tricyclic antidepressants, tiiere is an increased risk of toxic effects and an increased tiierapeutic effect. When sertraline is administered witii a MAOI, a potentially fatal reaction can occur. Sjymptoms of a serious reaction include hyper-tiiermia, rigidity, autonomic instability witii fluctuating vital signs and agitation, delirium, and coma Sertraline blood levels are increased when administered witii cimetidine. 

The effects of buspirone are decreased when the drug is administered with fluoxetine Increased serum levels of buspirone occur if the drug is taken with erythromycin or itraconazole Should any of these combinations be required, the dosage of buspirone is decreased to 2.5 mg BID, and the patient is monitored closely. Venlafaxine blood levels increase with a risk of toxicity when administered witii MAOIs or cimetidine There is an increased risk of toxicity when trazodone is administered with the phenothiazines and decreased effectiveness of trazodone when it is administered with carbamazepine Increased serum digoxin levels have occurred when digoxin is administered with trazodone There is a risk for increased phenytoin levels when phenytoin is administered witii trazodone... 

Additive sympathomimetic effects may develop when decongestants are administered with other sympathomimetic drug s (see Chap. 22). Use of the nasal decongestants with the MAOIs may cause hypertensive crisis. Use of a decongestant with beta-adrenergic blocking dragp may cause hypertension or bradycardia. When ephedrine is administered with theophylline, the patient is at increased risk for theophylline toxicity. 

The clinician should bear in mind the toxic potential for the various antidepressant medications when patients already have or develop suicidality. The TCAs and MAOIs have narrow therapeutic indices, whereas the SSRIs, SNRIs, nefa-zodone, and mirtazapine have wide therapeutic indices.22... 

The MAO enzymes, which come in two types known as MAO-A and MAO-B, perform a scavenger function by metabolizing and thereby eliminating certain molecules from nerve cells. This prevents the accumulation of toxic levels of these substances. In the brain, the MAO-A enzyme metabolizes a variety of substances including norepinephrine and serotonin, and the MAO-B enzyme metabolizes dopamine and several other substances. The effectiveness of MAOIs primarily comes from their ability to inhibit the MAO-A enzyme and thereby boost the availability of norepinephrine and serotonin. 

More concerning are the less common but potentially dangerous interactions of the MAOis with certain foods and medications. Because the MAOis permanently disable the MAO enzymes (until the body is able over the course of several weeks to produce a new supply of the enzymes), taking a medication or eating a food that contains one of the substances eliminated by the MAO enzymes can cause toxic accumulation. The result is a so-called hypertensive crisis in which the blood pressure is uncontrollably elevated, risking heart attack, stroke, or death. 

In Enrope and Canada, reversible MAOIs such as moclobemide are available. Because these medications do not permanently disable the supply of MAO enzymes, the potential for toxic accumulation of substances is greatly reduced. It appears that patients taking these reversible MAOIs may eat tyramine-containing foods without problems. None are currently available in the United States. 

The toxic effects of the MAOIs are more varied and potentially more serious than those of the other classes of antidepressants in common use. Hepatotoxicity has been reported to occur with the older hydrazine type of MAOIs and led to the early demise of iproniazid the hepatotoxicity does not appear to be related to the dose or duration of the drug administered. 

Cydobenzaprine (Flexeril) [Skeletal Muscle Relaxant/ANS A nt] Uses Relief of muscle spasm Action Centrally acting skeletal muscle relaxant reduces tonic somatic motor activity Dose 5-10 mg PO bid-qid (2-3 wk max) Caution [B, ] Shares the toxic potential of theTCAs urinary hesitancy, NAG Contra Do not use concomitantly or w/in 14 d of MAOIs hyperthyroidism heart failure arrhythmias Disp Tabs SE Sedation anticholinergic effects Interactions t Effects of CNS d ression W/ CNS dqjressants, TCAs, barbiturates, EtOH t risk of HTN convulsions W/MAOIs EMS Use caution w/ other CNS depressants concurrent EtOH use can t CNS d ession OD May cause N/V,... 

MAOI/RIMA Panic disorder Social anxiety disorder PTSD Significant short- and long-term side-effects special dietary requirements moclobemide better tolerated Significant overdose toxicity (less with moclobemide) Reported... 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

The potential for toxicity that is associated with the administration of the MAOIs restricts their use in major depression. Hepatotoxicity is likely to occur with isocarboxazid or phenelzine, since hydrazine compounds can cause damage to hepatic parenchymal cells. This is true particularly for patients identified as slow acetyla-tors (see Chapter 4) of hydrazine compounds. Fortunately, the incidence of hepatotoxicity is low with the available agents. 

C. Nortriptyline (Pamelor) is a TCA, and as a class these drugs require at least one steady-state blood level to safely and effectively use the medication. Paroxetine, venlafaxine, and bupropion have not had blood levels correlated to response, and their relatively low toxicity does not require therapeutic blood monitoring. Nardil is a MAOI, which can be... 

The most common reason for the underutilization of MAOIs is the potential for serious consequences of MAOI drug-food and drug-drug interactions. Combined MAOI treatment with (1) foods or medications involved in monoamine synthesis (2) monoamines themselves or (3) other sympathomimetics routinely found in over-the-counter medications can result in hy-peradrenergic crises or serotonin toxicity (Blackwell, 1991). 

The SSRIs also have a high rate of protein binding, which can lead to increased therapeutic or toxic effects of other protein-bound medications. The MAOIs should not be given within 5 weeks after stopping fluoxetine, and at least 2 weeks after other SSRIS, because of the possibility of inducing a serotonergic syndrome. 

Iproniazic was the first widely prescribed MAOI. Realization that this drug can produce rare but dangerous liver toxicity led to the synthesis of the other hydrazine MAOIs, such as isocarboxazid, nialamide, and phenelzine, as well as the nonhydrazine MAOIs, tranylcypromine, and pargyline. 

Compared with TCAs and MAOIs, BZDs have a rapid onset of action, have fewer unpleasant adverse effects, and are considerably less toxic. Despite these advantages, however, BZDs (with the possible exception of alprazolam, discussed later) generally appear devoid of true antidepressant effects. When the results of several well-controlled studies totalling 1,275 patients were summarized, the overall response to BZDs was 51% versus 73% for standard antidepressants. This generated a highly significant difference (p < 10 ) on the Mantel-Haenzsel test in favor of the antidepressants (Table 7-15). 

Similar to patients on other antidepressants, patients on MAOIs should be maintained on MAOIs for a period of at least 6 months. If there is a history of recurrent depressive episodes following discontinuation, MAOl therapy should be extended for 2 years or more, as long as the patient is closely supervised and shows no significant adverse effects or toxicity. There is evidence that a few patients maintained on MAOIs for periods of 6 months or more may experience loss of therapeutic effect, which correlates with a decrease in adverse effects such as anorexia and insomnia (277). Of note, tolerance to the hypotensive effects does not seem to develop. Waning of therapeutic efficacy can be compensated for by increasing the dose, but this strategy may be limited by adverse effects, particularly hypotension. 

Despite impressions to the contrary, MAOIs are generally well tolerated if patients observe the restricted diet and avoid medications that contain sympathomimetic amines. Adverse effects are rarely a treatment-limiting problem with the exception of hypotension. MAOIs also fall between TCAs and SSRIs in terms of overdose risk. Major toxic reactions to MAOIs are uncommon but require immediate discontinuation and symptomatic treatment. 

Co-administration with MAOIs can lead to a dangerous toxic interaction (see page 163). Though in the past such a combination might have been used for very treatment-resistant patients it would be very rare to consider it now. 

Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used for the treatment of Parkinson s disease (see Chapter 28). 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

It is unusual for the MAOIs to have a toxic effect. However, when it does occur the symptoms are severe and include dulled consciousness, seizures, shock, and hyperthermia (elevated temperature). Although some reactions with SSRIs—and even some fatalities—have occurred with overdoses, they are extremely rare. A reaction may be due to the combining of the SSRIs with other drugs. 

Patients should not use dextromethorphan if they are taking any drug in the class known as monoamine oxidase inhibitors (MAOI), including phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate), which are used in the treatment of depression. The combination of MAOIs with dextromethorphan can lead to toxic levels of dextromethorphan in the blood. 

Trazodone Hydrochloride Trazodone overdose causes severe toxic effects. These effects are severe if taken along with benzodiazepines or alcohol. Trazodone interacts with MAOIs, cardiovascular drugs, CNS depressants, and antiepileptics. 

MAOIs SSRIs t risk of serotonin syndrome >- For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome Additive inhibitory on serotonin reuptake Avoid co-administration. MAOIs should not be started for at least 1 week after stopping SSRIs (2 weeks after sertraline, S weeks after fluoxetine). Conversely, SSRIs should not be started for at least 2 weeks after stopping MAOIs... 

MAOIs TCAs-AMITRIPTYLINE CLOMIPRAMINE DESIPRAMINE IMIPRAMINE NORTRIPTYLINE t risk of stroke, hyperpyrexia and convulsions, t plasma concentrations of TCAs, with risk of toxic effects, t risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson s disease when used with selegiline TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can t risk of seizures Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest... 

---