HIV Pharmacology Overview

HIV Pharmacology Study Notes

• NRTIs (Nucleoside Reverse Transcriptase Inhibitors): Drugs that inhibit HIV reverse transcriptase. These drugs require phosphorylation to become active. Common examples include Abacavir (ABC), Didanosine (ddI), Emtricitabine (FTC), Lamivudine (3TC), Stavudine (d4T), Tenofovir (TDF), and Zidovudine (AZT, ZDV).

NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors): These drugs bind directly to reverse transcriptase, inhibiting its function. They include Delavirdine (DLV), Efavirenz (EFV), Etravirine (ETR), Nevirapine (NVP), and Rilpivirine (RPV).

PIs (Protease Inhibitors): Inhibit HIV protease, which is essential for viral replication. Key examples are Atazanavir (ATV), Darunavir (DRV), Fosamprenavir (FPV), Indinavir (IDV), Lopinavir (LPV), Nelfinavir (NFV), Ritonavir (RTV), and Saquinavir (SQV). Ritonavir often used as a booster for other PIs.

Integrase Inhibitors: These drugs interfere with the integrase enzyme essential for HIV's integration into host DNA. Examples include Raltegravir (RAL), Elvitegravir (EVG), and Dolutegravir (DTG).

CCR5 Antagonist: Blocks CCR5 receptor, preventing HIV's entry into cells. An example is Maraviroc (MVC).

Fusion Inhibitors: Interfere with the fusion process required for HIV entry into cells. An example is Enfuvirtide (ENF, Fuzeon).

NRTI Mechanisms of Resistance: Mutations in the reverse transcriptase gene, such as M184V, L74V, D67N, and M41L, allow HIV to resist NRTI drugs. Pyrophosphorolysis can resume DNA synthesis.

Dual-NRTI Pairs: Combinations of 2 NRTIs are common for HIV treatment. Advantages include fewer interactions and established therapy. Disadvantages include rare reports of lactic acidosis and hepatic steatosis.

NRTI Adverse Effects: Common side effects include lactic acidosis, hepatic steatosis, and lipodystrophy. Stavudine has the highest incidence of lactic acidosis and lipodystrophy, while Tenofovir, Abacavir, Lamivudine, and Emtricitabine have lower incidence.

Abacavir (ABC): A guanosine analog. Not affected by food. Serious hypersensitivity reactions can occur, requiring HLA-B*5701 screening before use.

Tenofovir (TDF): A nucleotide analog; lower risk of metabolic side effects than some other NRTIs. Absorption increases after a high-fat meal. Often used in combination with emtricitabine.

Emtricitabine (FTC): A fluorinated analog of lamivudine. Unaffected by food. Recommended pre-exposure prophylaxis (PrEP) drug combination with tenofovir.

Lamivudine (3TC): A cytosine analog. Safe for mothers and infants. Well-tolerated but can cause darkened skin pigmentation.

Zidovudine (AZT, ZDV): A thymidine analog; first ART (antiretroviral therapy) approved. Commonly used in pregnancy. Significant side effects include bone marrow suppression (anemia, neutropenia, and macrocytosis).

Didanosine (ddI): A deoxyadenosine analog. Taken on an empty stomach. Side effects include peripheral neuropathy and pancreatitis.

Stavudine (d4T): A thymidine analog. High risk of peripheral neuropathy, lipoatrophy, and pancreatitis.

NNRTI Advantages and Disadvantages: Long half-lives, reduced metabolic toxicity (vs. PIs), and good potency. Disadvantages include rapid resistance development, cross-resistance among many NNRTIs.

NNRTI Adverse Effects: Rash (including severe reactions like Stevens-Johnson syndrome) and hepatotoxicity (especially with nevirapine).

Efavirenz (EFV): A long-acting NNRTI. Avoid high-fat meals. Central nervous system effects (drowsiness, insomnia) are possible.

Delavirdine (DLV): An older NNRTI. It has a high incidence of skin rash, erythema multiforme, and Stevens-Johnson syndrome. This drug is not used frequently.

Etravirine (ETR): A second-generation NNRTI that boasts a better resistance profile than first generation NNRTIs.

Rilpivirine (RPV): A second-generation NNRTI, commonly used. Associated with depression, insomnia, and headache.

Nevirapine (NVP): A lipophilic NNRTI. Good for preventing vertical transmission. Risks of rash and liver toxicity.

PIs Adverse Effects: Metabolic complications (fat redistribution, dyslipidemia, insulin resistance) and GI intolerance are common. Liver toxicity is also possible.

Ritonavir (RTV): A PI often used as a booster to increase the levels of other PIs. Potential for numerous drug interactions.

Atazanavir (ATV): Taken with a light meal due to absorption concerns in acidic environments. Avoid omeprazole for this reason. No dyslipidemia (a significant advantage).

Lopinavir (LPV): Taken with ritonavir to enhance drug levels, preventing resistance. Food dependant for higher absorption.

Darunavir (DRV): Used for patients resistant to other PIs. Fewer metabolic side effects than other PIs.

Fosamprenavir (FPV): A prodrug of amprenavir. Food affects absorption.