Sildenafil or other phosphodiesterase type-5 inhibitors may potentiate the hypotensive effects of organic nitrates, and are therefore contra-indicated in patients receiving such drugs. Sildenafil may also enhance the hypotensive effect of nicorandil and Use of the two drugs together should be avoided. Symptomatic hypotension may also occur when phosphodiesterase types inhibitors are given with alpha blockers. Generally, the patient should be stabilised on alpha blocker therapy before the phosphodiesterase type-5 inhibitor is started at a low dose and adjusted according to response. Drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, such as cimetidine, delavirdine, erythromycin, itraconazole, and ketoconazole, may reduce the clearance of phosphodiesterase type-5 inhibitors, necessitating a reduction in dosage. Plasma concentrations of phosphodiesterase type-5 inhibitors are significantly increased by HIV-protease inhibitors, and particularly so by ritonavir-boosted regimens. Such combinations should not be given unless absolutely essential. Grapefruit juice should be avoided with sildenafil or other phosphodiesterase type-5 inhibitors as it may increase their plasma concentrations. Inducers of CYP3A4, such as rifampicin, are likely to decrease plasma concentrations of phosphodiesterase type-5 inhibitors. Bosentan also reduces exposure to sildenafil. Specific dosage recommendations have been made for the use of phosphodiesterase type-5 inhibitors with many of these drugs.
Antivirals: Rises in sildenafil concentrations after use of saquinavir or ritonavir were consistent with inhibition of metabolism mediated by the cytochrome P450 isoenzyme CYP3A. The larger increases seen with ritonavir may be due to its additional inhibition of the isoenzyme CYP2C9. Fatal myocardial infarction has been reported in a 47-year-old patient who took sildenafil 25 mg with ritonavir and saquinavir. In a study of 6 HIV- positive men being treated with triple antiretroviral therapy that included indinavir, plasma concentrations of sildenafil were found to be significantly increased compared with historical controls.
Cardiovascular drugs: For the effects of sildenafil in men stabilised on anti-hypertensives in general.
The plasma concentration of sildenafil was reduced by bosentan in a study of 10 patients with pulmonary hypertension, probably by induction of the cytochrome P450 isoenzyme CYP3A4, which would increase the metabolism of sildenafil. The use of bosentan with sildenafil in pulmonary hypertension has been reported and this potential interaction should be taken into account If men with stable angina given sildenafil and sublingual glyceryl trinitrate, hypotensive symptoms occurred for at least 8 hours after dosing; the interaction was not considered synergistic after 6 hours, although there were still additive effects on blood pressure. It was suggested that this data might support the cautious use of glyceryl trinitrate in patients hospitalised for angina who were haemodynamically stable but had taken sildenafil at least 6 hours previously.
Dihydrocodeine: The use of dihydrocodeine with sildenafil was associated with priapism in 2 men who had previously been treated successfully with sildenafil. The first patient had two prolonged erections, lasting 4 and 5 hours, and the effect did not recur when the dihydrocodeine was stopped. The second patient had priapism on 3 occasions in the first week of dihydrocodeine treatment, but not in the subsequent 2 weeks despite continuing both drugs.
Food: Grapefruit juice has been shown to increase bioavailability but delay absorption of sildenafil in healthy subjects.
Immunosuppressants: Studies in men with erectile dysfunction who were receiving tacrolimus after kidney transplantation found that sildenafil had no effect on tacrolimus pharmacokinetics. However, the pharmacokinetic profile of sildenafil differed from that reported in healthy subjects; the maximal plasma concentration was higher, the area under the concentration-time curve was increased, and the elimination half-life was prolonged. Reductions in blood pressure were also found when sildenafil was given, although this may have been due to an interaction with verapamil. It was suggested that an initial dose of 25 mg sildenafil should be used, and that on the days of sildenafil use the doses of antihypertensive drugs may need to be adjusted according to blood pressure response.
Nitrates: Giving sildenafil 50 mg to patients receiving isosorbide mononitrate, or sublingual glyceryl trinitrate given I hour after sildenafil, resulted in substantially greater decreases in blood pressure than when the nitrate was given alone in 2 crossover studies in patients with angina. Treatment-related adverse effects were reported in 8 of 16 patients who received sildenafil with isosorbide mononitrate and 3 of l5 who took sildenafil with glyceryl trinitrate. It was confirmed that sildenafil should not be taken with nitrates.