HIV Drug groups - Protease inhibitors

Protease inhibitors (PIs) are a class of medications used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new virons.

Protease inhibitors have been developed or are presently undergoing testing for treating various viruses:

HIV/AIDS: antiretroviral protease inhibitors such assaquinavir, ritonavir, indinavir, nelfinavir etc.

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Saquinavir

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Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:

a hard-gel capsule formulation of the mesylate, with trade name Invirase®, which requires combination with ritonavir to increase the saquinavir bioavailability; a soft-gel capsule formulation of saquinavir, with trade name Fortovase®. Both formulations are generally used as a component of highly active antiretroviral therapy (HAART). Ritonavir

Ritonavir, with trade name Norvir® (Abbott Laboratories), is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.

Ritonavir is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.

Indinavir

Indinavir (IDV; trade name Crixivan, manufactured by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy (HAART) to treat HIV infection and AIDS.

Nelfinavir

Nelfinavir (Viracept®) is an antiretroviral drug used in the treatment of the human immunodeficiency virus (HIV). Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is generally used in combination with other antiretroviral drugs. Nelfinavir is presented as the mesilate (mesylate) ester prodrug.

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki=2nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. Nelfinavir mesylate contains the Castor oil derivative Cremophor EL

Ritonavir

Ritonavir, with trade name Norvir (Abbott Laboratories), is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.

Ritonavir is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.

Method of action

Ritonavir was originally developed as an inhibitor of HIV protease. It is one of the most complex inhibitors. It is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[3] The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery, which has drastically reduced the adverse effects and improved the efficacy of PI's and HAART, was first communicated in an article published in the AIDS Journal in 1997 by the University of Liverpool. This effect does come with a price: it also affects the efficacy of numerous other medications, making it difficult to know how to administer them concurrently. In addition it can cause a large number of side-effects on its own.

Drug interactions
Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[4] These interactions can occur with strong inhibitors, strong or moderate inducers or substrates of hepatic cytochrome P450 CYP3A4 isoform.

The list of clinically significant interactions of ritonavir includes but is not limited to following drugs:

• amiodarone - decreased metabolism, possible toxicity
• midazolam and triazolam - contraindicated
• carbamazepine - decreased metabolism, possible toxicity
• cisapride - decreased metabolism, possible prolongation of Q-T interval and life-threatening arrythmias
• disulfiram (with ritonavir oral preparation) - decreased metabolism of ritonavir
• eplerenone
• etravirine
• flecainide - decreased metabolism, possible toxicity
• MDMA
• meperidine - build-up of toxic concentrations of a metabolite possible
• nilotinib
• nisoldipine
• pimozide
• quinidine
• ranolazine
• salmeterol
• St John's wort
• statins - decreased metabolism, without dosage modification increased risk of rhabomyolisis
• thioridazine
• topotecan
• voriconazole - ritonavir increases metabolism of voriconazole
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