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What is the MOA of acyclovir?
- Guanosine analogue that is activated by viral thymidine kinase
- Inhibits DNA synthesis by competing c dGTP
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How does resistance develop?
? viral thymidine kinase
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What are its pharmacokinetics?
- Oral, IV, or topical
- Excreted by kidney (adjust dose c impaired renal fxn)
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What is the preferred oral form of acyclovir?
Valacyclovir (pro-Rx has higher bioavailability)
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What are the uses of acyclovir?
- Genital herpes, herpes keratitis (ocular), herpes zoster
- IV for herpes encephalitis and VZV
- Prophylaxis in organ transplant and immunocompromise
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What are the acyclovir side effects?
- Generally mild and safe in pregnancy
- Nephrotoxic c high IV doses
- Somnolence when given c zidovudine in HIV
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What are the alternatives for Tx of HSV?
Famciclovir/Penciclovir (the oral pro-Rx form)
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What topical agent can be used?
Docosanol (Abreva)
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What is its MOA?
Inhibits viral fusion to cell membrane
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What is used for Tx of CMV?
- Ganciclovir (IV)/Valganciclovir (oral)
- -->they are also active against HSV
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What is the MOA?
Inhibits DNA replication
-
When is ganciclovir used?
- Rx or prophylaxis of CMV in immunocompromised or transplant pt
- CMV retinitis (give in ocular transplant)
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What are the toxic effects? (worse than acyclovir)
- Neutropenia (especially when given IV c zidovudine in HIV)
- Abnormal LFTs
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What Rx can be used in resistant CMV and HSV but are more toxic?
- Cidofovir_renal toxicity (use probenecid and hydrate)
- Foscarnet_renal toxicity
- Inhibits DNA and RNA polymerase, reverse transcriptase
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What is the MOA of oseltamivir and zanamivir?
Neuraminidase inhibitors_block release of virus from cell
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When are the used?
For influenza A and B
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How are oseltamivir and zanamivir administered?
- Start w/in 48hrs of onset
- Oseltamavir_oral;
- zanamivir_nasal or inhaled
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What are the adverse effects of zanamivir?
- May worsen resp fxn in COPD
- May cause bronchospasm in asthmatics
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Of oseltamivir?
Nausea and vomiting, better if taken c food
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What are amantadine and rimantidine used for?
Influenza A only
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What is their MOA?
Blocks uncoating of virus
-
What are the adverse effects of amantadine?
Causes release of DA ? hallucinations (used in Parkinson's)
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How does rimantidine differ?
Same mechanism, but doesn't cross BBB ? no hallucinations
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When is ribavirin used?
RSV and Hep C
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What is its MOA?
Purine analogue phosphorylated by virus that inhibits RNA polymerase and synthesis of GTP
-
How is it given?
Aerosol (for RSV), IV, and oral
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When is it give IV?
Lassa fever and SARS
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How is it given in Hep C?
combined c interferon
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What are the adverse effects?
Dyspnea, anemia, depression, TERATOGENIC!
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What is the DOC for chronic Hep B?
Lamivudine (don't treat acute Hep B)
-
What is its MOA?
Inhibits HBV polymerase and reverse transcriptase (HIV)
-
What are other Rx used?
- Adefovir_renal toxicity and lactic acidosis
- Entacavir
- Telbivudine_similar to lamivudine
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What are the antiviral mechanisms of the interferons?
- A,B: blocks viral entry
- 1: blocks transcription and translation of mRNA
- 2: blocks viral replication
- 3: blocks viral processing
- 4,5: blocks viral assembly and release
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How is Hep C treated?
Alfa-2b c ribavirin
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What are the side effects of interferon therapy?
- Flu-like: aches, pains, nausea
- Depression, suicide (use an antidepressant)
- Anemia (worse when combined c ribavirin, telaprevir, or boceprevir)
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What are boceprevir and telaprevir?
Protease inhibitors against Hep C
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When are they used?
- For pts c type 1 Hep C genotype when interferon/ribavirin is not effective
- What are their side effects?
- Strong inhibition of CYP3A4_many Rx interactions
- Pancytopenia, rash
-
What is the MOA of the HIV reverse transcriptase inhibitors?
Nucleoside analogs incorporated into DNA that inhibit viral reverse transcriptase and prevent conversion of RNA ? DNA
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What can happen if they inhibit human mitochondrial DNA polymerase?
Anemia, peripheral neuropathy, and pancreatitis
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What are non-HIV uses of zidovudine?
Psoriasis and T-cell leukemia
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What are its side effects?
- Neutropenia, anemia-->caution if bone marrow is compromised
- Lactic acidosis or hepatotoxicity-->STOP if these develop
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What are the Rx interactions?
- Synergistic toxicity c neurotoxic, nephrotoxic, or myelosuppressive Rxs
- Cimetidine, benzos inhibit metabolism
- Probenecid ? elimination
- Acetaminophen, ganciclovir ? risk of granulocytopenia
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What is the 1st choice combo in Tx of HIV?
Tenofovir/emtricitabine
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What is the 2nd choice?
Zidovudine/lamivudine
-
What is the MOA of lamivudine?
Inhibits HIV RT and HBV polymerase (can be used as monotherapy in Hep B)
-
What other antiretroviral is used for Hep B?
Emtricitabine
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Which anti-RVs cause peripheral neuropathy?
Didanosine, stavudine, zalcitabine
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Which cause lactic acidosis?
Didanosine, stavudine, zalcitabine, zidovudine
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Which cause anemia, agranulocytopenia?
Zidovudine, didanosine
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What are the non-nucleotide RTIs?
Efavirenz, nevirapine, delaviridine, etravirine
-
What is their MOA?
Bind directly to, and inhibit viral RT
-
How are they given?
ONLY c nucleoside analogues (rapid resistance occurs)
-
What are the Rx interactions?
Interact c protease inhibitors
-
What is the preferred Rx?
Efavirenz
-
When is it NOT the 1st choice?
Pregnancy
-
Which other non-nucleotide RTI is teratogenic?
Delavirdine
-
Which non-nucleoside RTI can cause hepatitis and Stevens-Johnson syndrome?
Nevirapine
-
How are the protease inhibitors used?
In combo c NRTIs
-
What are their Rx interactions?
- Metabolized by CYP3A4:
- Rx that inhibit CYP3A4:
- Rx that induce CYP3A5: St. Johns wort, rifampin, phenytoin, barbiturates
-
What are their side effects?
- Altered body fat distribution: buffalo hump, truncal obesity, facial atrophy
- Insulin resistance and hyperglycemia
- ? cholesterol, TGs, atherosclerosis, CVAs, MIs
- Due to inhibition of CYP --> DO NOT combine c statins
-
What is the 1st choice protease inhibitor and why?
Atazanavir: dosed 1X/day, less effect on lipoproteins
-
What is its major side effect?
? bilirubin due to inhibition of UGT-A1
-
What is the PI of 2nd choice?
Darunavir (combined c ritonavir)
-
What effect does ritonavir have when combined c other PIs?
? their bioavailability
-
What are the adverse effects?
- Inhibits CYP3A4 --> many interactions
- Contains EtOH --> caution when using c metronidazole
-
What ? the bioavailability of saquinavir?
High fat foods, grapefruit, ritonavir
-
What are the adverse effects of indinavir?
- Cross resistance c ritonavir
- Nephrolithiasis, hyperbilirubinemia
-
What are the side effects of amprenavir/fosamprenavir?
- Contains propylene glycol --> avoid metronidazole
- Stevens-Johnson syndrome
-
What is the non-pepiditic protease inhibitor?
Tipranavir
-
What are the fusion inhibitors?
Enfuviritide and maraviroc
-
What is their MOA?
Bind viral envelope and prevent fusion
-
When are they used?
In advanced disease when other Rx are beginning to fail
-
How is enfuvirtide given?
SC
-
What is the major side effect?
? risk of pneumonia
-
What is the only integrase inhibitor?
Raltegravir (used when others stop working)
-
What are the current Tx guidelines?
- Tenofovir or emtricatibine
- ZDV+lamivudine (2nd choice)
- Efavirenz (switch to nevirapine in pregnancy)
- Atazanavir
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