7. Anti-viral Agents Flashcards
Classes of anti-HIV drugs
- Nucleoside reverse transcriptase inhibitors (NRTI): abacavir, emtricitabine, lamivudine, tenfovir, zidovudine
- Non-nucleoside reverse transcriptase inhibitors (NNRTI): efavirenz
- Integrase inhibitor: dolutegravir, ratelgravir, elvitegravir
- Protease inhibitors: darunavir, lopinavir
a. Booster - Ritonavir
b. Booster - Cobicistat - Inhibition of HIV fusion with host cells: Enfurvitide
- Chemokine receptor antagonist (CCR5): Maraviroc
Antiretroviral regimen for treatment-naive patient
2 nucleoside reverse transcriptase inhibitors (NRTIs) + ARV drug from one of 3 drug classes:
a. an integrase strand transfer inhibitor (INSTI)
b. a protease inhibitor (PI) with a pharmacokinetic (PK) enhancer (booster) (cobicistat or ritonavir)
3. or a non-nucleoside reverse transcriptase inhibitor (NNRTI)
MOA of nucleoside reverse transcriptase inhibitors (NRTI)
- NRTIs are analogs of native ribosomes, lacking a 3’- OH group
- Upon cell entry → phosphorylated to the corresponding triphosphate analog → preferentially incorporated into the viral DNA by RT
- Because the 3’-OH group is not present → a 3’, 5’-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed → DNA chain elongation is terminated
Which 3 NRTIs have additional hepatitis B anti-viral activity
Emtricitabine, Tenofovir, Lamivudine
Which 3 NRTIs are category C drugs for pregnancy
Abacavir, Lamivudine, Zidovudine
Adverse effects of Emtricitabine
- Minimal toxicity
- Hyperpigmentation
- Severe acute exacerbation of hepatitis may occur in HBV-coinfected patients who discontinue emtricitabine
- Risk of lactic acidosis
Do not coadminister with lamivudine! Both are cytosine analogs
Adverse effects of Tenofovir
- Nephrotoxic
- Osteomalacia
- Severe acute exacerbation of hepatitis may occur in HBV-coninfected patients who discontinue Tenofovir
- Headache, diarrhoea, nausea, vomiting, and flatulence
Adverse effects of Abacavir
- Approved for use in adults and children > 3 months old
- GI disturbances
- Increased risk of CVD
- CNS related: headache and dizziness
- Fatal hypersensitivity syndrome
- Only use in HLA-B*5701 - negative individuals
Adverse effects of Zidovudine
- Myelosuppression → anemia and neutropenia
- CNS related → headaches, insomnia
- GIT disturbances
- Lactic acidosis
Adverse effects of Lamivudine
- Least toxic antiretroviral drug
- GIT related: abdominal discomfort
- Risk of lactic acidosis in combination
- CNS related: headache and nausea at higher doses
- Severe acute exacerbation of hepatitis may occur in HBV-coinfected patients who discontinue
- Approved for use in adults and children > 3 months old
MOA of integrase inhibitor
Binds and inhibits the catalytic site of the HIV integrase, which terminates integration of HIV DNA into host genome
Adverse effects of integrase inhibitors
- Weight gain
- Hypersensitivity reaction including rash
- Insomnia
- Depression headaches
What is cobicistat used for?
Pharmacokinetic enhancer that acts by inhibiting cytochrome P450 3A (CYP3A) that is used with Elvitegravir (EVG)
MOA of protease inhibitors
Bind to the site where protein cutting occurs, and prevent the enzyme from releasing the individual core proteins → new viral proteins are unable to mature or become infectious
What is ritonavir used for?
Pharmacokinetic enhancer (combined with another PI) to help maintain conc. of PI
Adverse effects of protease inhibitors
- GI disturbances: nausea, vomiting, and diarrhoea
- Hyperglycaemia
- Hyperlipidemia
- Hepatic injury; hyperbilirubinemia, and elevated transaminase levels
- Chronic administration → fat maldistribution
- Skin rashes
Drug interactions with protease inhibitors
Substrates and potent inhibitors of CYP450 isoenzymes
- simvastatin/lovostatin, warfarin → CYP450 substrate drugs → accumulate to toxic levels
- rifampin and phenytoin → inducers of CYP450 isoenzymes → decrease PI plasma conc.
MOA of non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Highly selective, non-competitive inhibitors of HIV-1 reverse transcriptase. Not used against HIV-2
- Bind to HIV RT at an allosteric hydrophobic site adjacent to the active site, inducing a conformational change that results in enzyme inhibition
Drug interactions with NNRTIs
Efavirenz induces CYP3A4 → lower plasma conc. of CYP3A4 substrates (e.g. warfarin, darunavir, maraviroc, hormonal contraceptives, clarithromycin)
Adverse effects of Efavirenz
- Can be used in infants > 3 years old / 10kg
- Most adverse effects are tolerable and are associated with CNS including dizziness, headache, vivid dreams, and loss of concentration
- Rash
- Pregnancy: Cat D → contraindicated in pregnancy
MOA of entry inhibitors
- enfuvirtide inhibits fusion of the viral and cell membranes mediated by gp41 and CD4 interactions. Not used against HIV-2
- maraviroc is a chemokine receptor antagonist → binds the host cell CCR5 receptor → block binding of viral gp120
Adverse effects of enfuvirtide
Related to injection: pain, erythema, induration, and nodules
Resistance to enfuvirtide
Specific mutations in the enfuvirtide-binding domain of gp41
MOA of maraviroc
Blocks the binding of the HIV outer envelop protein gp120 to the CCR5 chemokine receptor
Adverse effects of maraviroc
Generally well-tolerated. Side effects include allergic rash, hepatic toxicity, cardiotoxicity
Resistance to maraviroc
Develop resistance via a shift of tropism to CXCR4- or dual/mixed-tropism predominance or HIV can retain its CCR5-tropism but gain resistance to the drug through specific mutations in gp120 that allow virus binding in the presence of inhibitor
Types of non-retroviral agents
- Acyclovir
2. Ganciclovir
MOA of acyclovir
- Acyclovir is a nucleoside analogue that is phosphorylated by viral thymidine kinase to acyclovir monophosphate, and host cell enzymes to acyclovir triphosphate form
- Stops replication of herpes viral DNA in 3 ways
- Competitively inhibits viral DNA polymerase
- Incorporates into and terminates the growing viral DNA chain
- Inactivates the viral DNA polymerase
Indications for acyclovir
- HSV1, HSV2, VZV, some EBV
- Treatment of choice for HSV encephalitis and commonly used for genital herpes infection
- Given prophylactically to seropositive patients before bone marrow transplant and post-heart transplant to protect against herpetic infections
Adverse effects of acyclovir
- Local irritation may occur from topical application; headache, diarrhoea, nausea and vomiting may result from oral administration
- Transient renal dysfunction may occur at high doses or in dehydrated patient receiving the drug IV
Resistance to acyclovir
Altered (point mutations and base insertions or deletions in genes) or deficient thymidine kinase and DNA polymerase
MOA of ganciclovir
- Inhibits viral DNA synthesis → monophosphorylated intracellularly by viral thymidine kinase and viral phosphotransferase during HSV and CMV infection respectively
- Ganciclovir diphosphate and triphosphate are formed by cellular enzymes. The triphosphate is a competitive inhibitor of deoxyguanosine triphosphate for incorporation into DNA and, preferentially inhibits viral rather than host cellular DNA synthesis.
- Incorporation into viral DNA causes eventual cessation of DNA chain elongation
Indications for ganciclovir
All herpesvirus, especially active against CMV
Adverse effects of ganciclovir
- Myelosuppression: particularly neutropenia
- GIT-related: diarrhoea, nausea, vomiting
- Irreversible aspermatogenesis at high doses
- Potential mutagenicity and carcinogenesis, teratogenicity and possible embryo toxicity
Resistance to ganciclovir
- Reduced intracellular ganciclovir phosphorylation owing to mutations in the viral phosphotransferase (UL97 gene), and mutations in viral DNA polymerase
- Ganciclovir also is much less active against acyclovir-resistant thymidine kinase-deficient HSV strains
