Nefazodone Antihistamines

These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients. 

Drugs that may affect antihistamines include aluminum/magnesium-containing acids, cimetidine, erythromycin, ketoconazole, MAO inhibitors, and rifamycins (eg, rifampin). Drugs that may be affected by antihistamines include alcohol and CNS depressants, beta-blockers, MAO inhibitors, metyrapone, nefazodone, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine. 

Antihistamines, nonsedating/Cisapride/Pimozide- Cisapride and pimozide are metabolized by the cytochrome P-450 3A4 isozyme inhibitors of 3A4 can block the metabolism of these drugs, resulting in increased plasma concentrations of parent drug, which is associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, because of ventricular tachycardia of the torsades de pointes type. In vitro, nefazodone inhibits 3A4. It is recommended that nefazodone not be used in combination with cisapride or pimozide. 

Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTC interval. This can cause potentially dangerous interactions. In a double-blind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTC interval (27). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTC interval. This effect of nefazodone on... 

Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE. Loratadine and terfenadine interaction with nefazodone both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001 69(3) 96-103. 

A randomised, placebo-controlled study in healthy subjects found that when they were given nefazodone 300 mg twice daily with loratadine 20 mg once daily, the loratadine AUC was increased by 39%. Similarly, the QTc interval was increased by 21.6 milliseconds by the combination, which was about half the increase seen with terfenadine 60 mg twice daily given with the same dose of nefazodone. Neither nefazodone, loratadine nor terfenadine alone prolonged the QTc interval. The findings for loratadine in this study were unexpected, since this antihistamine was considered to have no clinically relevant effect on the QT interval (but see also Table 15.2 , (p.583)). The use of the Bazett formula to calculate QTc has... 

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