Tricyclic antidepressants INDEX

Tricyclic antidepressants are cardiotoxic, inducing tachycardias and an increased tendency for ventricular arrhythmias with high doses. This dose dependent cardiotoxicity gives these agents a low therapeutic index. Overdoses are characterized by cardiac conduction disturbances, hyperpyrexia, hypertension, confusion, hallucinations, seizures and coma and there is a high mortality rate in suicide attempts. Depressed patients should therefore not be given more than one week supply of these drugs. 

Fluoxetine is a selective serotonin-reuptake inhibitor (SSRI) that produces a net increase in (post-synaptic motor neuron) serotonin delivery after 4-6 weeks of use. A double-blind, randomized cross-over trial compared fluoxetine to the tricyclic antidepressant agent protriptyline and placebo in 12 patients with sleep-disordered breathing [52], The group apnea-hypopnea index (AHI) improved with fluoxetine compared to placebo, but there was great variability of response and other measures of disordered sleep did not change. These potentially beneficial results in a small number of patients need to be replicated in well-designed larger studies to support a useful role in clinical practice. 

Precautions The tricyclic antidepressants should be used with caution in manic-depressive patients, since they may unmask manic behavior. The tricyclic antidepressants have a narrow therapeutic index for example, 5 to 6 times the maximal daily dose of imipramine can be lethal. Depressed patients who are suicidal should be given only limited quantities of these drugs and should be monitored closely. Drug interactions with the tricyclic antidepressants are shown in Figure 12.5. 

The majority of all deaths from antidepressant poisoning in Scotland, England, and Wales, during 1975-1984 and 1985-1989 were due to two tricyclic drugs, amitriptyline and dosulepin, and they, as well as the entire group of older tricyclic antidepressants, had a fatality index (deaths per million prescriptions) significantly higher than the mean (150). 

Sertraline has a relatively low risk of toxicity. It is less sedating and has fewer cardiovascular effects than the tricyclic antidepressants. It has a high therapeutic index, which is consistent with other serotonin uptake inhibitors. 

Drug-Drug and Drug-Food Interactions. Since cinacalcet is metabolized by multiple hepatic enzymes there is potential for drug interactions. Cinacalcet is also a potent inhibitor of the enzyme CYP2D6. As a result, dose adjustments of concomitant medications that are predominantly metabolized by this enzyme and have a narrow therapeutic index such as flecainide, thioridazine, vinblastine, and most tricyclic antidepressants (i.e., amitriptyline) may be required. ... 

Potentially clinically significant interactions include the tendency for fluvoxamine to increase circulating concentrations of oxidatively metabolized benzodiazepines, clozapine, theophylline, and warfarin. Sertraline and fluoxetine can increase levels of benzodiazepines, clozapine, and warfarin. Paroxetine increases levels of clozapine, theophylline, and warfarin. Fluoxetine also potentiates tricyclic antidepressants and some class 1C antiarrhythmics with a narrow therapeutic index (including encainide, flecainide, and propafenone). Nefazodone potentiates benzodiazepines other than lorazepam and oxazepam. 

II. Toxic dose. Most of the tricyclic antidepressants have a narrow therapeutic index so that doses of less than 10 times the therapeutic daily dose may produce severe intoxication. In general, ingestion of 10-20 mg/kg Is potentially life threatening. 

MHPG, a metabolite of norepinephrine, has been studied as a biochemical lug lui niuniiuriiig depressed and alcoholic individuals. In conjunction with an LCEC assay for certain tricyclic antidepressants, the MHPG procedure may offer an index of therapeutic reqx>nse to a particular drug r men. 

In the present review of recent developments in those so-called non-tricyclic antidepressants , the test methods on which the conclusion of probably therapeutically active is based are evaluated. Then the activities of the various new structures, classified by structural resemblance, are discussed. Finally an attempt is made to derive some general structure-activity relations (SAR) and to draw some final conclusions about the whole subject. An index of compound names has been added as an aid to finding information about individual compounds and comparing the phases of development of these. 

However, the use of antidepressants in completed suicide showed an upward trend, while the use of more violent methods (gassing, hanging) fell During this time prescription of moclobemide and two SSRIs (citalopram and fluoxetine) increased, while that of tricyclics (mainly doxepin and amitriptyline) remained steady. The mean annual fatal toxicity index was highest for tricyclics, such as doxepin, trimipramine, and amitripyline, and lowest for SSRIs. 

---