Protease inhibitors, inhibition

In the life cycle of HIV, its RNA is translated into a polypeptide chain that is composed of several individual proteins including protease, integrase and reverse transcriptase, but in this form these enzymes are not functional. They must be cleaved by viral proteases from the assembled sequence in order for them to become functional. These posttranslational modifications allow the enzymes to facilitate the production of new viruses. The protease itself is made up of two 99-amino-acid monomers, and an aspartic acid residue in the monomer is required for the cleavage. The protease inhibitors inhibit the enzyme protease and consequently interfere with viral replication and maturation by preventing proteases from cleaving proteins into peptides. In humans, these drugs inhibit cleavage of HIV gag and pol polyproteins, which are part of the essential viral structural components, P7, P9, P17 and P24, and... 

Doh-ura K., Iwaki T., and Caughey B. (2000). Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J. Virol. 74 4894 1897. 

In an in vitro study of the effects of the HIV-1 protease inhibitors, ritonavir, indinavir, and saquinavir, which are metabolized by the liver CYP3A4, all three protease inhibitors inhibited methadone demethylation and buprenor-phine dealkylation in rank order of potency ritonavir > indinavir > saquinavir (53). Clinical studies are required to establish the further relevance of these observations. 

DISOPYRAMIDE ANTIVIRALS Disopyramide levels may be t by protease inhibitors Inhibition of CYP3A4-mediated metabolism of disopyramide Watch closely for disopyramide toxicity... 

CALCIUM CHANNEL BLOCKERS ANTIVIRALS-PROTEASE INHIBITORS Plasma concentrations of calcium channel blockers are t by protease inhibitors Protease inhibitors inhibit CYP3A4-mediated metabolism of calcium channel blockers. Also, ritonavir inhibits CYP2C9-mediated metabolism of verapamil, and ritonavir and saquinavir both inhibit intestinal P-gp, which may T the bioavailability of verapamil Monitor PR, BP and ECG closely 1 dose of calcium channel blocker if necessary (e.g. the manufacturers of diltiazem suggest starting at 50% of the standard dose and titrating to effect)... 

CILOSTAZOL ANTIVIRALS-PROTEASE INHIBITORS Amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir t cilostazol levels These protease inhibitors inhibit CYP3A4-mediated metabolism of cilostazol Avoid co-administration... 

SYMPATHOMIMETICS ANTIVIRALS-PROTEASE INHIBITORS 1. Risk of serotonin syndrome when dexamfetamine is administered with ritonavir 2. Indinavir may t phenylpropanolamine levels 1. Protease inhibitors inhibit CYP2D6-mediated metabolism 2. Likely inhibition of phenylpropanolamine metabolism 1. Avoid co-administration 2. Monitor BP closely watch for marked t BP... 

TOLTERODINE PROTEASE INHIBITORS Possibly t adverse effects, including ariythmias, with protease inhibitors Inhibition of CYP2D6- and 3A4-mediated metabolism of tolterodine Avoid co-administration... 

Some antiretroviral protease inhibitors inhibit CYP3A4, which is mostly responsible for the metabolism of carbamazepine. 

Ritonavir, and all protease inhibitors, inhibit the cytochrome P450 isoenzyme CYP3A4 to varying degrees. Fluticasone is metabolised by this isoenzyme and therefore the protease inhibitors cause its plasma levels to rise. The active metabolite of ciclesonide is also metabolised by CYP3A4, and is therefore similarly affected. 

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