HIV protease inhibitors

Mechanism of Action - Clipping the Virus's Wings

• Competitively inhibit viral aspartyl protease, an enzyme crucial for HIV maturation.
• Prevents cleavage of precursor gag-pol polyproteins into functional structural proteins (e.g., capsid, reverse transcriptase).

• Results in the production of immature, non-infectious virions.
• 📌 -navir suffix: Think "Navir (never) cleave the protein."

⭐ Ritonavir Boost: Ritonavir is a potent CYP3A4 inhibitor, used in low doses to "boost" levels of other PIs, increasing their efficacy and allowing for lower dosing.

PK & Interactions - The Cytochrome P450 Story

• All protease inhibitors (PIs) are metabolized by and are potent inhibitors of Cytochrome P450 (CYP3A4).
  • This creates a high potential for drug-drug interactions (DDIs).
  • ⚠️ Avoid co-administration with highly CYP3A4-dependent drugs (e.g., certain statins, sedatives, antiarrhythmics).
• Pharmacokinetic Boosting:
  • This effect is leveraged by co-administering a potent CYP3A4 inhibitor (a "booster") with another PI.
  • Ritonavir (a PI itself) is the most common booster, used at sub-therapeutic doses.
  • Cobicistat is a newer, dedicated booster with no anti-HIV activity.

⭐ Exam Favorite: Rifampin, a potent CYP3A4 inducer, is contraindicated with most PIs. It dramatically ↓ PI plasma concentrations, risking virologic failure.

The '-navir' Lineup - Meet the Inhibitors

• Mechanism: All protease inhibitors (PIs) reversibly inhibit HIV aspartate protease, an enzyme essential for cleaving the viral Gag-Pol polyprotein into mature, functional proteins. This prevents the assembly of new, infectious virions.

• 📌 Mnemonic: "-navir tease a protease"

• Key Agents & Distinctions:

  • Atazanavir (ATV): Causes indirect hyperbilirubinemia and jaundice (scleral icterus) due to UGT1A1 inhibition. "Bananavir."
  • Darunavir (DRV): Often used for treatment-experienced patients with drug-resistant HIV. Contains a sulfa moiety-use with caution in sulfa allergy.
  • Lopinavir (LPV): Commonly co-formulated with Ritonavir.
  • Ritonavir (RTV): Primarily used in low doses as a pharmacokinetic enhancer (booster) for other PIs.

⭐ Exam Favorite: Ritonavir is a potent inhibitor of Cytochrome P450 (specifically CYP3A4), leading to numerous drug-drug interactions but also boosting the levels of other PIs, allowing for lower dosing and improved efficacy.

Adverse Effects - The Unwanted Baggage

• Metabolic Complications: A defining feature.

  • Lipodystrophy: Redistribution of fat leading to central obesity, buffalo hump, and peripheral wasting. 📌 Mnemonic: "Protease Paunch."
  • Hyperglycemia: Due to insulin resistance.
  • Dyslipidemia: Elevated triglycerides and LDL cholesterol.

• Hepatotoxicity: Monitor liver function tests.

• GI Distress: Nausea, vomiting, and diarrhea are common.

• Drug-Specific Effects:

  • Indinavir: Associated with nephrolithiasis and crystalluria; adequate hydration is key.

⭐ Because they are metabolized by CYP450, protease inhibitors are susceptible to many drug-drug interactions. Ritonavir, a potent inhibitor, is often used as a "booster" to ↑ levels of other PIs.

High‑Yield Points - ⚡ Biggest Takeaways

• All protease inhibitors end in "-navir"; they block the cleavage of Gag-Pol polyproteins, resulting in immature, non-infectious virions.
• As cytochrome P450 inhibitors, they have significant drug-drug interactions.
• Ritonavir is a potent inhibitor used to "boost" other PIs.
• Class-wide metabolic side effects include hyperglycemia, dyslipidemia, and lipodystrophy.
• Indinavir can cause nephrolithiasis; advise hydration.
• Atazanavir can cause benign indirect hyperbilirubinemia.
• Darunavir contains a sulfa moiety; use cautiously in sulfa allergy.