Drugs Metabolized by P450 2D6 ¾ The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors: CONTRAINDICATIONS
Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram (see WARNINGS
When amitriptyline HCl is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required.
Hyperpyrexia has been reported when amitriptyline HCl is administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.
Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine. Increases in plasma levels of tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been reported when cimetidine was added to the drug regimen. Discontinuation of cimetidine in well-controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants.
Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 - 150 mg of ELAVIL (amitriptyline HCl).
ELAVIL should not be given concurrently with Cisapride due to the potential for increased QT interval and increased risk for arrhythmia
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible.
Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indictors of tricyclic antidepressant toxicity.
Other signs of overdose may include: impaired myocardial contractility, confusion, disturbed concentration, transient visual hallucinations, dilated pupils, disorders of ocular motility, agitation, hyperactive reflexes, polyradiculoneuropathy, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS.
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish and intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death, and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.
All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impared, the airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED.
A maximal limb-lead QRS duration of ³0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45-7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type IA and IC antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.
In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
The principles of management of pediatric and adult overdosages are similiar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
ELAVIL is contraindicated in patients who have shown prior hypersensitivity to it.
It should not be given concomitantly with monoamine oxidase inhibitors. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting drugs simultaneously. When it is desired to replace a monoamine oxidase inhibitor with amitriptyline HCl, a minimum of 14 days should be allowed to elapse after the former is discontinued. Amitriptyline HCl should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.
ELAVIL should not be given concurrently with Cisapride due to the potential for increased QT interval and increased risk for arrhythmia.
This drug is not recommended for use during the acute recovery phase following myocardial infarction.
Ayd FJ Jr: Amitriptyline (ELAVIL) therapy for depressive reactions. Psychosomatics 1960;1:320-325.
Diamond S: Human metabolizer of amitriptyline tagged with carbon 14. Curr Ther Res, Mar 1965, pp 170-175.
Dorfman W: Clinical experiences with amitriptyline (ELAVIL): A preliminary report. Psychosomatics 1960;1:153-155.
Fallette JM, Stasney CR, Mintz AA: Amitriptyline poisoning treated with physostigmine. South Med J 1970;63:1492-1493.
Hollister LE, Overall JE, Johnson M, et al: Controlled comparison of amitriptyline, imipramine and placebo in hospitalized depressed patients. J Nerv Ment Dis 1964;139:370-375.
Hordern A, Burt CG, Holt NF:
Depressive states: A pharmacotherapeutic study, Springfield study. Springfield, Ill, Charles C. Thomas, 1965.
Treatment of Affective Illness in the Elderly with Drugs and Electroconvulsive Therapy. J Geriatr Psychiatry 1989;22(1):77-112.
Klerman GL, Cole JO:
Clinical pharmacology of imipramine and related antidepressant compounds. Int J Psychiatry 1976;3:267-304.
Liu B, Anderson G, Mittman N, et al:
Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998; 351(9112):1303-1307.
McConaghy N, Joffe AD, Kingston WR, et al:
Correlation of clinical features of depressed out-patients with response to amitriptyline and protriptyline. Br J Psychiatry 1968;114:103-106.
McDonald IM, Perkins M, Marjerrison G, et al:
A controlled comparison of amitriptyline and electroconvulsive therapy in the treatment of depression. Am J Psychiatry 1966;122:1427-1431.
Slovis T, Ott J, Teitelbaum D, et al:
Physostigmine therapy in acute tricyclic antidepressant poisoning. Clin Toxicol 1971;4:451-459.
Symposium on depression with special studies of a new antidepressant, amitriptyline. Dis Nerv Syst, (Sect 2) May 1961, pp 5-56.
* Registered trademark of AstraZeneca.
** Based on a maximum recommended amitriptyline dose of 150 mg/day or 3 mg/kg/day for a 50 kg patient.
*** Hollister LE: Monitoring Tricyclic Antidepressant
Plasma Concentrations. JAMA 1979;241(23):2530-2533.
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