HIV Pharmacology Overview

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Questions and Answers

What are the main types of HIV drugs?

  • NRTIs, NNRTIs, PIs
  • NRTIs, NNRTIs, PIs, Integrase Inhibitors, CCR5 Antagonists
  • NRTIs, NNRTIs, PIs, Integrase Inhibitors, CCR5 Antagonists, Fusion Inhibitors (correct)
  • NRTIs, NNRTIs, PIs, Integrase Inhibitors

What does NRTI stand for?

Nucleoside Reverse Transcriptase Inhibitors

NRTIs require phosphorylation to be active.

True (A)

What is the mechanism of action of NNRTIs?

<p>They bind directly to reverse transcriptase, resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase. They do not require phosphorylation to be active.</p> Signup and view all the answers

Monotherapy with PIs is contraindicated.

<p>True (A)</p> Signup and view all the answers

Which of the following drugs is a CCR5 antagonist?

<p>Maraviroc (C)</p> Signup and view all the answers

What are the two main mechanisms of resistance to NRTIs?

<p>Mutations at or near the drug-binding site of the reverse transcriptase gene, and pyrophosphorolysis.</p> Signup and view all the answers

Dual-NRTI pairs are a preferred backbone for combination therapy due to their minimal drug interactions.

<p>True (A)</p> Signup and view all the answers

Which NRTI has the highest rate of lactic acidosis and hepatic steatosis?

<p>Stavudine (A)</p> Signup and view all the answers

What kind of analog is Abacavir?

<p>Guanosine analog</p> Signup and view all the answers

Abacavir is affected by food.

<p>False (B)</p> Signup and view all the answers

What is a serious side effect associated with abacavir?

<p>Hypersensitivity reaction (B)</p> Signup and view all the answers

What type of analog is Tenofovir?

<p>An acyclic nucleoside phosphonate, analog of adenosine</p> Signup and view all the answers

Tenofovir requires three phosphorylations to be activated.

<p>False (B)</p> Signup and view all the answers

Food can increase the bioavailability of tenofovir.

<p>True (A)</p> Signup and view all the answers

What is the recommended regimen for pre-exposure prophylaxis?

<p>Truvada: Emtricitabine + Tenofovir</p> Signup and view all the answers

Which drugs suppress both HBV and HIV?

<p>Lamivudine, Emtricitabine, Tenofovir (C)</p> Signup and view all the answers

What is the primary mutation associated with tenofovir resistance?

<p>K65R</p> Signup and view all the answers

Which NRTI has the highest rate of lipodystrophy?

<p>Stavudine (A)</p> Signup and view all the answers

What is the first FDA-approved ART?

<p>Zidovudine</p> Signup and view all the answers

Zidovudine is poorly distributed in body fluids.

<p>False (B)</p> Signup and view all the answers

Which drug should be avoided in combination with stavudine due to viral antagonism?

<p>Zidovudine (C)</p> Signup and view all the answers

Didanosine should be taken with a meal.

<p>False (B)</p> Signup and view all the answers

What is the main side effect associated with stavudine?

<p>Peripheral neuropathy</p> Signup and view all the answers

Stavudine is used as a first-line treatment for HIV.

<p>False (B)</p> Signup and view all the answers

What are the two first-generation NNRTIs?

<p>Efavirenz and Nevirapine</p> Signup and view all the answers

NNRTIs have a short half-life.

<p>False (B)</p> Signup and view all the answers

NNRTIs are affected by food.

<p>True (A)</p> Signup and view all the answers

Which NNRTI is highly albumin bound?

<p>Efavirenz (C)</p> Signup and view all the answers

Efavirenz is associated with an increased risk of Stevens-Johnson syndrome.

<p>True (A)</p> Signup and view all the answers

What is the main drug interaction associated with efavirenz?

<p>It is a substrate and inducer of CYP3A4, which can interact with the metabolism of many other drugs, such as anti-arrhythmics, antihistamines, sedative-hypnotics, neuroleptics, anticonvulsants, and oral contraceptives.</p> Signup and view all the answers

Delavirdine has a better resistance profile than first-generation NNRTIs.

<p>False (B)</p> Signup and view all the answers

Rilpivirine is highly bound to plasma proteins.

<p>True (A)</p> Signup and view all the answers

Nevirapine is effective in preventing vertical transmission of HIV.

<p>True (A)</p> Signup and view all the answers

Which drug is NOT used as an ARV but is solely used as a booster for other PIs?

<p>Ritonavir (A)</p> Signup and view all the answers

Which PI has a higher risk of hepatotoxicity?

<p>Ritonavir (B)</p> Signup and view all the answers

Atazanavir should be taken with a full meal.

<p>False (B)</p> Signup and view all the answers

Which PI is considered safe during pregnancy?

<p>Lopinavir (A)</p> Signup and view all the answers

Darunavir is generally considered safe for patients with sulfonamide allergy.

<p>False (B)</p> Signup and view all the answers

What is the prodrug of amprenavir?

<p>Fosamprenavir</p> Signup and view all the answers

Food can decrease the absorption of fosamprenavir.

<p>True (A)</p> Signup and view all the answers

Fosamprenavir is contraindicated in children.

<p>True (A)</p> Signup and view all the answers

Flashcards

NRTI drugs

Abacavir (ABC), Didanosine (ddI), Emtricitabine (FTC), Lamivudine (3TC), Stavudine (d4T), Tenofovir (TDF), Zidovudine (AZT, ZDV)

NNRTI drugs

Delavirdine (DLV), Efavirenz (EFV), Etravirine (ETR), Nevirapine (NVP), Rilpivirine (RPV)

PI drugs

Atazanavir (ATV), Darunavir (DRV), Fosamprenavir (FPV), Indinavir (IDV), Lopinavir (LPV), Nelfinavir (NFV), Ritonavir (RTV), Saquinavir (SQV), Tipranavir (TPV)

Integrase Inhibitor drugs

Raltegravir (RAL), Elvitegravir* (EVG), Dolutegravir** (DTG)

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CCR5 Antagonist drugs

Maraviroc (MVC)

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Fusion Inhibitor drugs

Enfuvirtide (ENF, Fuzeon)

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Nucleoside reverse transcriptase inhibitors MOA

Competitive inhibition of HIV reverse transcriptase. It incorporates into viral DNA chain which results in a premature chain termination due to inhibition of binding with the incoming nucleotide. Require phsophorylation to the triphosphate form to be active.

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NRTI mechanism of resistance

Main mechanisms: Mutations at or near the drug-binding site of the reverse transcriptase gene, M184V, L74V, D67N, and M41L. Key mutations that essentially work to undo the action of these drugs, even if they do manage to bind correctly within the RT gene. Reverse reaction of DNA polymerization, termed pyrophosphorolysis, enables reverse transcription and DNA synthesis to resume.

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Dual-NRTI Pairs advantages and disadvantages

ADVANTAGES: Established backbone of combination therapy, Minimal drug interactions. DISADVANTAGES: Lactic acidosis and hepatic steatosis reported with most NRTIs (rare)

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Adverse Effects: NRTIs

Lactic acidosis and hepatic steatosis, Lipodystrophy

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Which NRTIs have highest and lowest rate of lactic acidosis and hepatic steatosis?

Highest incidence with Stavudine (d4T), than Didanosine (ddI) and Zidovudine (AZT, ZDV). Lower with Tenofovir (TDF), Abacavir (ABC), Lamivudine (3TC), and Emtricitabine (FTC)

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Which NRTI has highest rate of lipodystrophy?

Higher incidence with stavudine, d4T

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Abacavir is what kind of analog?

Guanosine analog

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Is abacavir affected by food?

Unaffected by food

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Side effects of abacavir

Hypersensitivity Reaction = serious and sometimes fatal - High risk if HLA-B*5701 allele (screen prior) - Rash - Possible increased risk of MI D/C ASAP if S/Sx in 2 or more of the following groups: -Group 1: fever -Group 2: rash -Group 3: GI Effects n/v/d/abdominal pain -Group 4: Constitutional malaise/fatigue/achiness -Group 5: Respiratory dyspnea/cough/pharyngitis Onset: 9 days within 6 was of starting. Never re-challenge!

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What type of screening is needed with abacavir?

Screen for HLA-B5701allele before treatment with ABC; ABC should not be given to patients who test positive for HLA-B5701 (5-6%) = ABC allergy

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What kind of analog is Tenofovir?

An acyclic nucleoside phosphonate (ie, nucleotide) Analog of adenosine

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how many phosphorylations are needed to activate Tenofovir?

Only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis

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How does food affect tenofovir?

oral bioavailabilty increases after high fat meal

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how is tenofovir administered?

Is often co-administered with emtricitabine, and a combination formulation is available. Also part of Atripla®, and the Quad Pill, Stribild®.

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which drug suppresses Hep B as well as HIV?

Lamuvudine (preferred for HIV/HBV co-infected), Emtricitabine, Tenofovir

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Tenofovir resistance

K65R is the primary mutation associated to resistance. Higher threshold of resistant than other NRTIs

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Tenofovir side effects

Renal impairment, decrease in bone mineral density, headache, GI intolerance

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Emtricitabine is structurally similar to...

lamivudine A fluorinated analog of lamivudine

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Is emtricitabine affected by food?

Bioavailability is 93%, unaffected by food (CSF penetration is poor)

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what is recommended by the CDC for pre-exposure prophylaxis?

Truvada®: Emtricitabine + Tenofovir

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emtricitabine side effects

Headache, Darkening of palms and soles skin pigmentation GI upset, but well tolerated otherwise

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what kind of analog is Lamivudine?

A cytosine analog with synergistic activity with a variety of other NRTIs including zidovudine-sensitive or -resistant HIV-1

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Is lamivudine affected by food?

no

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which is safe for mother and infant?

lamivudine used in combination with zidovudin A regimen used in pregnancy beginning 14-34 weeks of gestation, oral.; i.v. during labor; syrup for neonate from birth through 6 weeks of age reduces vertical transmission by up to 23% (only in certain circumstances)

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Study Notes

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.

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.

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