Protease inhibitors

pharmacological perspective

1. PROTEASE INHIBITORS ANTI HIV DRUGS

2. PROTEASE IN HIV When viral RNA is translated into a polypeptide sequence, that sequence is assembled in a long chain that includes several individual proteins (reverse transcriptase, protease, integrase ). Before these enzymes become functional, they must be cut from the longer polypeptide chain. Viral protease cuts the long chain into its individual enzyme components which then facilitate the production of new viruses.

3. PROTEASE INHIBITORS They bind reversibly to active sites of HIV aspartic protease enzyme and interfere with its cleaving function. Because they act at a late step of viral cycle, they are effective against both newly and chronically infected cells. Hence HIV produce noninfectious viral progeny

4. Protease inhibitors were the second class of antiretroviral drugs developed. The first members of this class, saquinavir and ritonavir were approved in late 1995-1996. Later indinavir, nelfinavir,  amprenavir boceprevir ,  telaprevir were intoduced

5. PHARMACOKINETICS High-fat meals substantially increase the bioavailability of some PIs, such as nelfinavir and saquinavir , whereas the bioavailability of indinavir is decreased, and others are essentially unaffected. Metabolism is extensive, and very little of the PIs are excreted unchanged in urine. Dosage adjustments are unnecessary in renal impairment .

6. Adverse effects

7. DRUG INTERACTIONS Inhibitors and substrates of CYP450 isoenzymes . Potentially dangerous drug interactions Rhabdomylosis from simvastatin/lovastatin E xcessive sedation from midazolam/ triazolam Respiratory depression from Fentanyl Rifampin, Phenytoin, Warfarin are contraindicated for co-administration

8. RESISTANCE Resistance occurs as an accumulation of stepwise mutations of the protease gene. Initial mutations result in decreased ability of the virus to replicate, but as the mutations accumulate, virions with high levels of resistance to the protease inhibitors emerge.

9. Ritonavir Ritonavir [ ri -TOE- na -veer] is no longer used as a single PI but, instead , is used as a pharmacokinetic enhancer or “booster” of other PIs . Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir administration at low doses increases the bioavailability of the second PI, often allowing for longer dosing intervals.

10. OTHER USES Hepatitis C : boceprevir ,   telaprevir Anti Protozoal : saquinavir , ritonavir, and lopinavir have shown effectiveness against malaria and Giardia infections.

11. THERAPY AS SECOND LINE REGIMEN tenofovir + abacavir + lopinavir with low dose ritonavir Zidovudine + didanosine + atazanavir with LD ritonavir Post exposure prophylaxis(high risk) ( Zidovudine 300mg + lamivudine 150mg)twice daily and indinavir 800mg thrice daily. All for 4 weeks