Antiviral Chemotherapy And Prophylaxis

Front 1

Selective toxicity of antiviral drugs depends on?

Back 1

greater susceptibility of viral enzymes to their inhibitory actions than host cell enzymes

Front 2

Why combination drug therapy?

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greater clinical effectiveness and prevention, or delay, of emergence of resistance

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Most drugs active against herpes viruses are?

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antimetabolites bioactivated by viral or host cell kinases to form compounds that inhibit viral DNA polymerases

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MOA of acyclovir

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guanosine analog active against HSV 1/2 and VZV

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Acyclovir activated to form what

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acyclovir triphosphate which interferes with viral synthesis

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Two ways in which Acyclovir interferes with viral synthesis?

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competitive substrate for DNA polymerase, and chain termination after incorporation into viral DNA

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HSV resistance to Acyclovir?

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changes in viral DNA polymerase

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HSV resistant strains lack?

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thymidine kinase-enzyme involved in initial viral-specific phosphorylation of acyclovir

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pharmacokinetics of Acylcovir

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topical, oral, IV
short half life (oral needs multiple daily doses)

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Elimination of Acylcovir

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renal excretion

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Clinical uses of acyclovir?

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oral-mucocutaneous and genital herpes
IV-severe herpes disease including encephalitis, and neonatal infection

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Tox of acyclovir?

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oral: GI distress and headache
IV: delirium, tremor, seizures, hypotension, nephrotoxicity

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Valacyclovir

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prodrug converted to acyclovir by hepatic metabolism; reaches plasma levels 3-5x acyclovir and has longer duration of action

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Penciclovir

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activated by viral thymidine kinase and the triphosphate form inhibits DNA polymerase (no chain termination)

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Famciclovir

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prodrug of penciclovir (converted in liver)

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Docosanol

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aliphatic alcohol that inhibits fusion between HSV envelope and plasma membranes; prevents viral entry and replication; shortens healing time when used topically

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Ganciclovir MOA

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guanine derivative, triphosphorylated to form a nucleotide that inhibits DNA polymerases of CMV and HSV and causes chain termination

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First phosphorylation of ganciclovir catalyzed by?

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virus-specific enzymes in CMV and HSV infected cells

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CMV resistance to ganciclovir?

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mutations in genes that code for activating viral phosphotransferase and viral DNA polymerase

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Pharmacokinetics of ganciclovir

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IV-good penetration including eye and CNS

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Elimination of ganciclovir?

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renal elimination in direct proportion to creatinine clearance; oral bioavailability <10%

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Valgancivlovir

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prodrug of ganciclovir; high oral bioavailability; decreased use of IV ganciclovir for end-organ CMV disease

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Clinical uses of ganciclovir?

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prophylaxis and treatment of CMV retinitis

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Tox of ganciclovir?

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leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, seizures

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Ganciclovir with zidovudine?

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severe neurtropenia

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Cidofovir MOA

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activated by host cell kinases and the activated diphosphate inhibits DNA polymerase of HSV, CMV, adenovirus, and HPV; active against ganciclovir and acyclovir resistant strains

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Pharmacokinetics of cidofovir?

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given IV and renal elimination

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Clinical use of cidofovir?

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CMV retinitis, mucocutaneous HSV, genital warts

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Tox of cidofovir?

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nephrotoxicity

Front 30

Foscarnet

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phosphonoformate derivative that does not require phosphorylation for antiviral activity

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Foscarnet MOA?

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inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase

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Resistance to foscarnet?

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point mutations in DNA polymerase gene

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Pharmacokinetics of foscanet?

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IV; good penetration including CNS, renal elimination in direct proportion to creatinine clearance

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Clinical use of foscarnet?

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alternative for prophylaxis and treatment of CMV infections; has activity against ganciclovir-resistant strains; inhibits herpes DNA polymerase in acyclovir-resistant strains

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Tox of foscarnet?

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hephrotoxicity (30%), electrolyte imbalance (hypocalemia), GU ulceration, CNS effects

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Elimination of ganciclovir?

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renal elimination in direct proportion to creatinine clearance; oral bioavailability <10%

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Vidarabine

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adenine analog with activity against HSV, VZV, CMV

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Valgancivlovir

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prodrug of ganciclovir; high oral bioavailability; decreased use of IV ganciclovir for end-organ CMV disease

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Clinical uses of vidarabine?

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Topically against HSV keratitis

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Clinical uses of ganciclovir?

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prophylaxis and treatment of CMV retinitis

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Tox of ganciclovir?

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leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, seizures

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Tox of vidarabine?

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GI irritation, paresthesias, tremor, convulsions, hepatic dysfunction

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Ganciclovir with zidovudine?

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severe neurtropenia

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Two drugs used topically in herpes keratitis

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idoxuridine and trifluridine; pyrimidine analogs (too toxic for systemic use)

Front 45

Cidofovir MOA

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activated by host cell kinases and the activated diphosphate inhibits DNA polymerase of HSV, CMV, adenovirus, and HPV; active against ganciclovir and acyclovir resistant strains

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Fomivirsen

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antisense oligonucleotide that binds to mRNA of CMV; inhibits early protein synthesis

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Pharmacokinetics of cidofovir?

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given IV and renal elimination

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Clinical use of cidofovir?

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CMV retinitis, mucocutaneous HSV, genital warts

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Tox of cidofovir?

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nephrotoxicity

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Foscarnet

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phosphonoformate derivative that does not require phosphorylation for antiviral activity

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Tox of fomivirsen

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iritis, vitreitis, increased IOP, changes in vision

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primary drugs effective against HIV

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antimetabolite inhibitors of viral reverse transcriptase and inhibitors of viral aspartate protease

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Normal combination (3 drugs?)

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nucleoside reverse transcriptase inhibitors, inhibitors of HIV protease

Front 54

NRTIs

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prodrugs converted by host cell kinases to triphosphates, which competitively inhibit binding of natural nucleotides to dNTP-binding site of RT but also terminate chains via insertion into growing DNA chain

Front 55

Why is attachment of the next nucleotide impossible?

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NRTIs lack a 3'-hydroxyl group on the ribose ring

Front 56

Resistance to NRTIs via?

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mutations in the pol gene

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Abacavir

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guanosine analog; good oral bioavailability and an intracellular half-life of 12-24 hr; slow resistance

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Side effect of abacavir and frequency?

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Hypersensitivity reactions (sometimes fatal); 5% HIV patients

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Didanosine (ddI) reduced oral bioavailability?

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food and chelating agents

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ddI elimination

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kidney

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other ddI tox?

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peripheral neuropathy, diarrhea, hepatic dysfunction, hyperuricemia, CNS effects

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Emtricitabine

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good oral bioavailability; renal elimination with long half-life (once-daily dosing);

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Contraindications of emtricitabine?

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pregnancy and young children, patients with hepatic or renal dysfunction because contains propylene glycol

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adverse effects of emtricitabine?

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asthenia, GI distress, headache, hyperpigmentation of the palms/soles

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Lamivudine (3TC)

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80% oral bioavailability; eliminated almost exclusively by the kidney

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Lamivudine also effective in?

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HBV

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Stavudine (d4T)

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good oral bioavailability and good penetration including CNS;

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Tox of stavudine and exacerbated by?

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peripheral neuropathy; coadministration of didanosine or zalcitabine

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What side effect occurs more often with stavudine than other NRTIs?

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hepatic steatosis

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Tenofovir

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nucleotide; also has activity against HBV; oral bioavailability= 25-40%; intracellular half life >60 hrs; renal elimination

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Adverse effects of tenofovir?

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GI distress, asthenia, headache; rare acute renal failure and Fanconi's syndrome

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Zalcitabine (ddC)

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high oral bioavailability; renal elimination

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Side effects of zalcitabine (ddC)

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pancreatitis, esophageal ulceration, stomatitis, arthralgias

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Zidovudine (ZDV) [formerly AZT]

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active orally and distributed to most tissues including CNS;

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elimination of ZDV

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hepatic metabolism to glucuronides and renal excretion

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primary toxicity of ZDV

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bone marrow suppression leading to anemia and neutropenia

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other tox of ZDV

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thrombocytopenia, headaches, myalgia, acute cholestatic hepatitis, agitation, insomnia

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drugs that increase plasma levels of zidovudine

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azole antifungals and protease inhibitors

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drug that increases clearance of ZDV

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rifampin

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Global side effects of NRTIs

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lactic acidemia and severe hepatomegaly with steatosis

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Adverse effects of tenofovir?

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GI distress, asthenia, headache; rare acute renal failure and Fanconi's syndrome

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Zalcitabine (ddC)

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high oral bioavailability; renal elimination

Front 83

Side effects of zalcitabine (ddC)

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pancreatitis, esophageal ulceration, stomatitis, arthralgias

Front 84

Zidovudine (ZDV) [formerly AZT]

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active orally and distributed to most tissues including CNS;

Front 85

elimination of ZDV

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hepatic metabolism to glucuronides and renal excretion

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primary toxicity of ZDV

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bone marrow suppression leading to anemia and neutropenia

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other tox of ZDV

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thrombocytopenia, headaches, myalgia, acute cholestatic hepatitis, agitation, insomnia

Front 88

drugs that increase plasma levels of zidovudine

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azole antifungals and protease inhibitors

Front 89

drug that increases clearance of ZDV

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rifampin

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Global side effects of NRTIs

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lactic acidemia and severe hepatomegaly with steatosis

Front 91

MOA of etravirine

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substrate and inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19

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Nevirapine

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good oral bioavailability; metabolized by hepativ CYP3A4

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Use of nevirapine

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effective in preventing HIV vertical transmission when given as single dose to mothers at the onset of labor

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Side effect of nevirapine

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hypersensitivity (15-20%); Stevens-Johnson syndrome, epidermal necrolysis

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Drugs that increase nevirapine blood levels?

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cimetidine and macrolides

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Drugs that decrease nevirapine blood levels?

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rifampin (enzyme inducers)

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pol gene encodes?

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aspartate protease essential for assembly of infectious HIV virions

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resistance to protease inhibitors via?

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point mutations in the pol gene

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MOA of PIs

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substrates and inhibitors of CYP3A4; ritonavir with most pronounced effect

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Atazanavir

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oral absorption requires acidic environment (no antacid ingestion)

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elimiation of atazanavir?

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biliary

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adverse effects of atazanavir?

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GI distress, peripheral neuropathy, skin rash, hyperbilirubinemia
*prolongation of QT interval at high doses

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Darunavir

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newer drug in combo with ritanovir in treatment of patients with resistance to other PIs; substrate of CYP3A4

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Darunavir special consideration?

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contains a sulfonamide moiety; cross reaction with sulfonamide allergy

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fosamprenavir

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prodrug forming amprenavir via hydrolysis in GI tract; used in combination with lose-dose ritonavir

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absorption and metabolism of fosamprenavir?

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absorption impeded by fatty foods; hepatic metabolisms

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Cross allergenicity of fosamprenavir?

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sulfonamides

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indinavir

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good oral bioavailability except in presence of food

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indinavir metabolism?

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hepatic and 10% renal

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adverse effects of indinavir?

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nausea, diarrhea, thrombocytopenia, hyperbilirubinemia, hephrolithiasis

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reduction of renal damage with indinavir

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hydration

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more common with indinavir than other PIs?

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insulin resistance

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Drugs that increase serum levels of indinavir?

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azole antifungals

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Drugs that decrease serum levels of indinavir?

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rifamycins

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Indinavir increases the serum levels of?

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antihistamines, benzodiazepines, rifampin

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Nelfinavir

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increased oral absorption in the presence of food; hepatic metabolism via CYP3A4, short half life

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When is nelfinavir favored?

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pregnancy

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Ritonavir

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good oral bioavailability; should be taken with meals

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Clearance of ritonavir?

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hepatic

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most common adverse effects of ritonavir

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GI irritation and bitter taste; also paresthesias and elevations of hepatic aminotransferases and triglycerides in plasma

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drugs that reduce serum levels of ritonavir?

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anticonvulsants, rifamycins (drugs that increase the activity of CYP3A4)

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drugs that increase serum levels of ritonavir?

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azole antifungals, cimetidine, erythromycin (drugs that inhibit CYP3A4)

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Ritonavir inhibits metabolism of?

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erythromycin, dronabinol, ketoconazole, prednisone, rifampin, saquinavir

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rationale for PI combinations that include ritonavir?

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subtherapeutic doses inhibit CYP3A-mediated metabolism of other protease inhibitors; permits use of lower doses of other PIs

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Saquinavir

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extensive first-pass metabolism

Front 126

Tipranavir

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treatment-experienced patients with resistance to other PIs; substrate and inducer of CYP3A4 and induces P-glycoprotein transporters

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Association of tipranavir and side effects?

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increased blood levels of statins, increasing risk for myopathy and rhabdomyolysis

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PI effect on carbohydrate and lipid metabolism

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hyperglycemia and insulin resistance or hyperlipidemia (30-50%)

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Maraviroc

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Entry inhibitor-target is CCR5 (human protein); blocks viral attachment

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Enfuvirtide MOA

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peptide that binds to the gp41 subunit, preventing the conformational changes required for the fusion of the viral and cellular membranes

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resistance to enfuvirtide occurs via?

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mutation in env gene

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administration of enfuvirtide

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subcutaneously in combination with other anti-HIV drugs

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metabolism of enfuvirtide

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via hydrolysis and does not involved cytochrome P450 system

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Anti-Influenenza agents

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amantadine and rimantadine

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amantadine and rimantadine MOA

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inhibit and early step in replication of the influenza A virus; prevent "uncoating" by binding to a protein M2

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Function of M2 protein

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proton ion channel required at the onset of infection to permit acidification of the virus core--> activates viral RNA transcriptase

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Clinical uses of A and R?

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prophylactic against influenza A

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toxic effects of A and R?

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Gi irritation, dizziness, ataxia, slurred speech

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MOA of Oseltamivir and Zanamivir

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inhibitors of neuraminidases produced by influenza A and B; also currently active against H3N2 and H1N1 strains

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function of neuraminidases

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cleave sialic acid residues from viral proteins and surface proteins of infected cells; promote virion release

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Clinical use of oseltamivir and zanamivir

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O: prodrug used orally, activated int he gut and liver
Z: intransally

decrease the time of alleviation of symptoms after onset

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difference between agents of HBV and HCV

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HBV: goal is suppressive
HCV: goal is viral eradication

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INF-a

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cytokine that increases activity of JAKs

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How do JAKs work?

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phosphorylate signal transducers and activators of transcription (STATs) to increase the formation of antiviral proteins

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Clinical uses of INF-a

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chronic HBV; in combination with ribavirin for reduction in progression from acute to chronic HCV

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other uses of INF-a

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kaposi's sarcoma, papillomatosis, genital warts

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Toxicity of INF-a

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Gi irritation, flulike syndrome, neutropenia, alopecia, hearing loss, thyroid dysfunction, mental confusion, depression

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Contraindications for INF-a

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autoimmune disease, cardiac arrhythmias, pregnancy

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Adeforvir Dipivoxil MOA

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prodrug of adefovir; after being phosphorylated competitively inhibits HBV DNA polymerase and results in chain termination

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Pharmacokinetics and clinical use

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eliminated by the kidney; suppresses HBV replication and improves liver histology and fibrosis; active against lamivudine-resistant strains of HBV

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Entecavir

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guanosine nucleoside that inhibits HBV DNA polymerase; cross resistance with lamivudine

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Lamivudine

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nucleoside inhibitor of HIV reverse transcriptase; longer intracellular half-life in HBV-infected cells

Front 153

Monotherapy of lamivudine for HBV

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rapid suppression of replication and remarkably nontoxic; 20% increase in resistance each year

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Ribavirin MOA

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inhibits replication of wide range of DNA and RNA viruses (Influenza A and B, parainfluenza, RSV, paramyxoviruses, HCV, HIV); inhibits guanosine triphosphate formation, prevents capping of viral mRNA, can block RNA-dependent RNA polymerases

Front 155

Pharmacokinetics of ribavirin

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effective orally and eliminated via kidney; used adjunctively with IFN-a in chronic HCV

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Early administration (IV) of ribavirin

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decreases mortality in viral hemorrhagic fevers

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Toxicity of ribavirin

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dose-dependent hemolytic anemia; conjunctival and bronchial irritation; ABSOLUTELY CONTRAINDICATED IN PREGNANCY

Front 158

Telbivudine

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nucleoside analog; phosphorylated by cellular kinases to triphosphate form (inhibits HBV DNA polymerase)