Protease inhibitors Calcium-channel blockers

CYP3A4 Midazolam, triazolam, cyclosporine, erythromycin, HIV protease inhibitors, calcium channel blockers Polymorphic... 

PROTEASE INHIBITORS CALCIUM CHANNEL BLOCKERS Plasma concentrations of calcium channel blockers are t by protease inhibitors Protease inhibitors inhibit CYP3A4-mediated metabolism of calcium channel blockers Monitor PR, BP and ECG closely 1 dose of calcium channel blocker if necessary (e.g. manufacturers of diltiazem suggest starting at 50% of the standard dose and titrating to effect)... 

Drugs affected by voriconazole include the following benzodiazepines, calcium channel blockers, cisapride, coumarin anticoagulants, cyclosporine, ergot alkaloids, HMG-CoA reductase inhibitors, NNRTIs, phenytoin, protease inhibitors, pimozide, proton pump inhibitors, quinidine, prednisolone, rifabutin, sirolimus, sulfonylureas, tacrolimus, vinca alkaloids. 

Drugs that might be affected by lopinavir/ritonavir include ergot derivatives, oral contraceptives, antiarrhythmics, HMG-CoA reductase inhibitors, HIV protease inhibitors, atovaquone, calcium channel blockers, ketoconazole, itraconazole, pimozide, cisapride, clarithromycin, disulfiram, metronidazole, immunosuppressants, midazolam, triazolam, narcotic analgesics, rifabutin and rifabutin metabolite, sildenafil, warfarin, bupropion, clozapine, desipramine, piroxicam, quinidine, theophylline, and zolpidem. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Takei, Y., Marzi, I., Kauffman, F.C. et al.. Increase in survival time of liver transplants by protease inhibitors and a calcium channel blocker, nisolidpine. Transplantation 50, 14—20, 1990. 

CYP3A4 alprazolam, calcium channel blockers, cisapride, clarithromycin, cyclosporin A, erythromycin, HIV protease inhibitors, lidocaine, midazolam, simvastatin, terfenadine carbamazepine, dexamethsone, phenobarbital, phenytoin, rifampicin, St John s wort cimetidine, erythromycin, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole... 

A4 Barbiturates, carbamazepine, corticosteroids, efavirenz, phenytoin, rifampin, troglitazone Antiarrhythmics, antidepressants, azole antifungals, benzc iazepines, calcium channel blockers, cyclosporine, delavirdine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazodone, paclitaxel, proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca anticancer agents... 

Modafinil is an inducer of the cytochrome P450 isoenzyme CYP3A4. The manufacturers therefore predict that it may reduce the levels of drugs that are CYP3A4 substrates. They specifically name the protease inhibitors, buspirone, calcium-channel blockers, ciclosporin, midazolam, and the statins [note that only some statins, namely atorvastatin, lovastatin and... 

Symptomatic orthostasiisi occurred in a patient taking nelfinavir or ritonavir/indinavir and nifedipine. Another patient had similar symptoms when nelfinavir was added to felodipine therapy. Atazanavir markedly increased diltiazem bioavailability with an increase in cardiac effects in healthy subjects. Similarly, ritonavir/indinavir caused a modest to marked increase in diltiazem levels, and a 1.9-fold increase in amlodipine levels. Based on this evidence, raised calcium-channel blocker levels are predicted when any calcium-channel blocker is given with a protease inhibitor, especially ritonavir. Caution is required. 

Protease inhibitors, particularly ritonavir (see Antivirals , (p.772)), are potent inhibitors of cytochrome P450 isoenzyme CYP3A4, by which all the calcium-channel blockers are extensively metabolised. It appears that some protease inhibitors can cause a clinically relevant increase in calcium-channel blocker levels. In addition, verapamil, diltiazem and nicardipine can also inhibit CYP3A4, and might therefore theoretically reduce the metabolism of the protease inhibitors. However, the effect might depend on which is the more potent inhibitor, since, in the studies above, diltiazem did not affect atazanavir, indinavir or ritonavir levels. 

Although information is limited, these pharmacokinetic interactions are predictable, and potentially serious. To date, clinically relevant increases in calcium-channel blocker levels or effects have been shown for nelfinavir with nifedipine or felodipine, indinavir/ritonavir with amlodipine, diltiazem or nifedipine, and atazanavir with diltiazem. Caution would be required with any of these combinations, anticipating the need to use lower doses of the calcium-channel blocker. The manufacturers specifically recommend that if diltiazem is given with atazanavir the initial dose of diltiazem should be reduced by 50% with subsequent dose titration and ECG monitoring. They also note that verapamil levels may be raised and therefore advise caution. Similarly, the manufaeturers of nifedipine say that blood pressure monitoring is required and a reduction in nifedipine dose may be neeessary if it is given with HIV-protease inhibitors. However, some UK manufacturers (e.g. felodipine, lercanidipine, nimodipine ) recommend avoiding the concurrent use of ritonavir and other protease inhibitors if possible. 

Until more is known, caution is warranted with any combination of a calcium-channel blocker and a protease inhibitor. 

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