Protease inhibitors are a class of antiretroviral drugs that work by binding to and inhibiting the HIV protease enzyme. This prevents protease from cleaving polypeptide chains into functional viral enzymes, which stops the production of mature, infectious HIV virions. Some commonly used protease inhibitors include saquinavir, ritonavir, indinavir, and nelfinavir. Protease inhibitors must be carefully dosed due to interactions with other drugs and the development of viral resistance over time.

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.

4. 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

5. • 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

6. 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.

7. Adverse effects

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

10. 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.

11. • 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.

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

13. 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