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Antiviral Drugs
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Drug Actions Therapeutic Uses Pharmacokinetics Adverse Effects Other
Neuraminidase Inhibitors
Oseltamivir Zanamivir
-Prevent the release of new virions and their spread from cell to cell -Given prior to exposure they prevent infection -Given24-48 hours after onset of infection, they effect intensity and duration of symptoms
-Type A and B influenza viruses
-Oseltamivir: orally active prodrug, hydrolyzed by liver to active form -Zanamivir: inhaled or administered intranasally -Eliminted unchanged in urine
-Oseltamivir: GI discomfort and nausea -Zanamivir: bronchospasm
-Orthomyxoviruses need neuraminidase for life cycle of the virus -Sialic acid analogs -Do not interfere with response immune response to influenza A vaccine -Zanamivir should be avoided in pts with severe reactive asthma or COPD
Amantadine Rimantadine
-Block the viral membrane matrix protein (M2) which is required for the fusion of viral membrane with cell membrane Preventing formation of endosome Interferes with viral uncoating -70 to 90% effective in preventing infection if tx begun at time of or prior to exposure to infection -Given w/in first 48 hours, they reduce duration and severity of systemic symptoms
-Influenza A viruses -Amantadine: Parkinson’s disease
-Can be given with vaccine to provide protection while Ab response occurs -Absorbed well orally -Amantadine: readily penetrates into CNS -Amantadine: excreted in urine -Rimantadine: extensively metabolized by liver and eliminated by kidneys
Amantadine: -Insomnia -Dizziness -Ataxia -Hallucinations -Seizures
-Do not impair the response of influenza A vaccine -Amantadine may accumulate to toxic levels in pts with renal failure -Cautious use in pregnant and nursing mothers (embryotoxic and teratogenic) -Cross-resistance occurs between the two drugs
-Both cause GI intolerance
Ribavirin -Converted to 5’-phosphate derivative forming ribavirin-triphosphate Inhibits guanosine triphosphate formation Prevents viral mRNA capping, blocking RNA-dependent RNA polymerase
-Infants and young children: severe RSV infections -Chronic hepatitis C (w/ IFN) -Reduces mortality and viremia of Lassa fever
-Effective orally and IV -Absorption increased if drug is taken w/ fatty meal -Aerosol -Eliminated in urine
-Transient anemia -Elevated bilirubin
-Guanosine analogs -Contraindicated in pregnancy due
Interferon -Interfere with ability of viruses to infect cells -Induce host cell enzymes that inhibit viral RNA translation Degradation of
-IFN-α-2b: hepatitis B, C -Condylomata acuminate
-Pegylated forms of the drug causes delayed absorption from drug site, increased duration of drug
-Flu-like symptoms (fever, chills, myalgias, arthalgia, GI disturbances)
-Interferes with metabolism of THEOPHYLLINE -Potentiates the bone marrow suppression caused by other
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viral mRNA and tRNA -Hairy cell leukemia -Kaposi’s sarcoma
actions, decrease clearance -Given intralesionally, SC, IV -Cellular uptake and metabolism by liver and kidney
-Fatigue -Mental depression -BM suppression (granulocytopenia) -Neurotoxicity (somnolence, behavioural disturbances, weight loss) -Autoimmune disorders -CV problems (CHF) -Acute hypersensitivity -Hepatic failure
agents
-IFN-β: MS
Lamivudine -Inhibitor of both HBV DNA polymerase and HIV reverse transcriptase -Must be phosphorylated by host cell enzymes to active form (triphosphate)
-HBV -HIV
-Intracellular ½ life is longer than plasma ½ life -Well absorbed orally -Plasma ½ life: 9 hours
-Headache -Dizziness
-Cytosine analog -Chronic treatment reduces hepatic inflammation -Dose reductions required in moderate renal insufficiency
Adefovir dipivoxil
-Phosphorylated to adefovir diphosphate Incorporated into viral DNA Termination of further DNA synthesis and prevents viral replication -Causes decreased viral load and improved liver function
-Given once a day -Excreted in urine
-Discontinuation leads to severe exacerbation of hepatitis
-Nucleotide analog -Cautious use in pts with existing renal disease
Entecavir -Intracellular phosphorylation to triphosphate Competes for viral reverse transcriptase
-LAMIVUDINE-resistant HBV
-Given once a day -Severe hepatitis may occur after discontinuation of therapy
-Guanosine analog -Improves liver scarring and inflammation -Drugs that have renal toxicity should be avoided
Telbivudine -Phosphorylated intracellularly to triphosphate Competes with endogenous thymidine triphosphate for incorporation into DNA Terminates
-HBV -Administered orally -Once daily
-Thymidine analog -Dose should be adjusted in renal failure -Can be combined with
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further elongation of DNA LAMIVUDINE
Acyclovir -Monophosphorylated in cell by thby thymidine kinase -Acyclovir triphosphate: competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase Incorporates into viral DNA Premature DNA-chain termination
-HSV 1 and 2 -Varicella-Zoster virus -EBV -DOC: HSV encephalitis -Prophylactic to sero+ pts before BM or heart transplant
-Given IV, oral, topical -Partially metabolized to inactive product -Excretion into urine
-Local irritation -Headache -Diarrhea -Nausea -Vomiting -Transient renal dysfunction -Valacyclovir: GI problems, thrombotic thrombocytopenia purpura
-Accumulates in pts with renal failure -Valacyclovir: hydrolyzed to Acyclovir -Resistance occurs due to altered or deficient to thymidine kinase and DNA polymerase -Cross-resistance to other cyclovirs occurs
Cidofovir -Inhibits viral DNA synthesis -CMV-induced retinitis in pts w/ AIDS
-Slow elimination permits prolonged dosage intervals -Given intravenous, intravitreal, topical
-Renal toxicity -Neutropenia -Metabolic acidosis -Ocular hypotony
-Nucleotide analog -Eliminates the permanent venous access used for GANCICLOVIR therapy -CI in pts with renal impairment or taking nephrotoxic drugs -PROBENECID can be given to reduce risk of nephrotoxicity
Fomivirsen -Directed against CMV mRNA -CMV retinitis -Intravitreally -Iritis -Vitritis -Changes in vision
-Antisense oligonucleotide -Should be used 2-4 weeks after CIDOFOVIR to reduce toxicity
Foscarnet -Reversibly inhibits viral DNA and RNA polymerases Interferes with viral DNA and RNA synthesis
-CMV retinitis in immunocompromised pts -ACYCLOVIR-resistant HSV and Herpes Zoster infections
-Injected IV -Given frequently to avoid relapse when plasma levels fall
-Nephrotoxicity -Anemia -Nausea -Fever -Hypokalemia -Hypo- or hyperphosphatemia -Seizures -Arrhythmias
-Phosphonoformate
Ganciclovir -Activated through conversion to nucleotide triphosphate Nucleotide competitively inhibits viral DNA
-CMV retinitis in immunocompromised pts
-Given IV -Excreted into urine
-Severe neutropenia -Carcinogenic -Embryogenic
-Analog of ACYCLOVIR -Accumulates in pts with renal failure
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polymerase -CMV prophylaxis in transplant pts
-Teratogenic -Valganciclovir: rapid hydrolysis in intestine and liver
Peniciclovir
-Triphosphate inhibits HSV DNA polymerase -Pain and healing are shortened
-HSV 1 and 2 -Varicella Zoster
-Only given topically -Intracellular ½ life of 20-30x longer than ACYCLOVIR
-Acyclic guanosine nucleoside
Famciclovir -Prodrug metabolized to active PENCICLOVIR
-Acute herpes zoster -Orally effective -Headache -Nausea
-In animals: increased mammary adenocarcinomas and testicular toxicity
Vidarabine (ara-A)
-Converted in cells to ara-ATP Inhibit viral DNA synthesis
-Tx of immunocompromised pts with herpetic and vaccinial keratitis -HSV kerato- conjunctivitis
-Opthalmic ointment -Adenosine analog
Trifluridine -Converted to triphosphate Competitively inhibits incorporation of thymidine triphosphate into viral DNA Defective DNA -Irreversible inhibitor of viral thymidine synthase
-HSV 1 and 2 -Vaccina virus -DOC: HSV keratoconjunctivitis and recurrent epithelial keratitis
-Topic application as solution for eye -1/2 life of 12 minutes
-Transient irriation of eye -Palpebral edema
-Fluorinated pyrimidine nucleoside analog
NRTIs Zidovudine Stavudine
Didanosine Tenofovir
Lamivudine Emtricitabine
Zalcitabine Abacavir
-After entering a cell, they are phosphorylated to corresponding triphosphate analog which gets incorporated into the viral DNA DNA chain elongation is terminated -Mitochondrial DNA polymerase γ is also susceptible at therapeutic doses
-HIV -Renal excretion -Drug interactions are seen with Zidovudine and Tenofovir
-Peripheral neuropathies -Pancreatitis -Lipoatrophy -Potentially fatal liver toxicity: lactic acidosis and hepatomegaly with steatosis
-Analogs of native ribosides -All except Abacavir require dose adjustments in renally insufficient patients -Mutation at viral codon 184 causes resistance to Lamivudine but restores sensitivity to Zidovudine and Tenofovir -Concomitant use of agents in same class is contraindicated
Zidovudine (AZT)
-Children and adults -Prevent prenatal infection in pregnancy
-Well absorbed after oral administration -Crosses the BBB -1/2 life of 1 hour
-Toxic to bone marrow -Headaches
-Pyrimidine analog -STAVUDINE and RIBAVARIN should not be used with AZT -Drugs like PROBENECID,
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-Prophylaxis in pts exposed to HIV
-Intracellular ½ life: 3 hours -Excreted in urine
ACETAMINOPHEN, LORAZEPAM, INDOMETHACIN, CIMETIDINE should be used cautiously
Stavudine (d4T) -Strong inhibitor of cellular enzymes such as β and γ DNA polymerases Reducing mitochondrial DNA synthesis
-HIV -Absorbed upon oral administration -Penetrates BBB
-Peripheral neuropathy -Lipoatrophy -Hyperlipidemia
-Thymidine analog -Renal impairment interferes with clearance
Didanosine (ddI)
-In host cell its transformed to ddATP Incorporation into DNA chain Termination of chain elongation
-HIV -Acid lability -Absorption is best if taken in fasting state
-Pancreatitis -Peripheral neuropathy
-Should not be used with STAVUDINE
Tenofovir (TDF) -Converted by cellular enzymes to diphosphate Inhibits HIV reverse transcriptase
-HIV -AZT-resistant strains of HIV
-Should be taken with a meal -Once daily dosing due to long ½ life -Found unchanged in urine
-Nausea -Diarrhea -Vomiting
-Nucleotide analog -Dose should be adjusted in renal insufficiency -Has significant drug interactins -If used with ddl, the dose of the drug needs to be decreased; not used together any longer -Decreases the concentration of ATAZANAVIR
Lamivudine (3TC)
-Terminates synthesis of proviral DNA chain -Inhibits reverse transcriptase of both HIV and HBV
-HIV (w/ AZT) -Oral administration -Excreted by kidneys
Emtricitabine (FTC)
-Inhibits both HIV and HBV reverse transcriptase
-HIV -Orally active -Plasma ½ life: 10 hours -Intracellular ½ life: 39 hours -Found unchanged in urine
-Headache -Diarrhea -Nausea -Rash -Hyperpigmentation of soles and palms -Lactic acidosis -Fatty liver -Hepatomegaly
-Derivative of LAMIVUDINE -Withdrawal in HBV-pts may lead to worsening of hepatitis
Abacavir (ABC) -Well absorbed orally -Metabolites appear in urine
-GI disturbances -Headache -Dizziness
-Guanosine analog -Sensitized pts should never be rechallenged because it may
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-Hypersensitivity reaction: drug fever, rash, GI symptoms, malaise, respiratory distress
cause death -HLA genetic test can be done to screen pts
NNRTIs Nevirapine Delavirdine Efavirenz
-Highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase -Bind to enzyme adjacent to active site, causing conformational change, resulting in enzyme inhibition
-Hypersensitivity reactions: rash
-Lack of cross-resistance with NRTIs -Cross-resistance within the NNRTIs
Nevirapine (NVP)
-HIV-1 in adults and children
-Orally absorbed -Enters fetus and mother’s milk -Excreted in urine -Inducer of CYP3A4
-Severe hepatotoxicity -Rash -Fever -Headache -Elevated serum transaminase -Stevens-Johnson syndrome -Toxic epidermal necrolysis
-Shouldn’t be used in women with CD4+ counts >250 or in men with counts >400 -14-dat titration period at ½ dose is mandatory to reduce risk of serious epidermal reactions
Delavirdine (DLV)
-Rapidly absorbed after oral administration -Extensively metabolized -Fecal and urinary excretion -Inhibitor of CYP450
-Rash
Efavirenz (EFV) -Treatment results in increases in CD4+ T cell counts and decrease in viral load
-Oral administration -Should be taken with high-fat meal -Bound to plasma proteins -1/2 life of more than 40 hours (once-daily dosing) -Inducer of CYP450
-Dizziness -Headache -Vivid dreams -Loss of concentration -Rash
-Should not be given to pregnant women
Etravirine -Active against 1st generation resistant
-Oral administration -1/2 life: 40 hours
-Rash -2nd generation NNRTI
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NNRTIs -HIV tx-experienced, multi-drug resistant adult pts who have evidence of ongoing viral replication
-Twice daily dosing -Inducer of CYP450
HIV Protease Inhibitors Ritonavir
Saquinavir Indinavir Nelfinavir
Fosamprenavir Lopinavir
Atazanavir Tipranavir Darunavir
-Reversible inhibitors of HIV aspartyl protease Prevents maturation of viral particles Production of non-infectious virions -Greater affinity for HIV-1 and 2 enzymes than human proteases, causing selective toxicity
-HIV-1 and 2 -Naive pts: Protease Inhibitor + 2 NRTIs
-High-fat meals increase bioavailability of Nelfinavir and Saquinavir, but decrease it for Indinavir -Substrates for CYP3A4 -Extensive metabolism -Limited access to CNS -Bound to plasma proteins, specifically, α1-acid glycoprotein -Inhibitors of CYP enzymes
-Paraesthesias -Nausea -Vomiting -Diarrhea -Diabetes -Hypertriglyceridemia -Hypercholesterolemia -Fat redistribution to abdomen and back of neck -Breast enlargement
-Drug interaction: Rhabdomyolysis: SIMVASTATIN, LOVASTATIN Excressive sedation: MIDAZOLAM, TRIZOLAM Respiratory depression: FENTANYL Others: WARFARIN, SILENDAFIL, PHENYTOIN -RIFAMPIN AND ST.JOHN’S WORT contraindicated with these drugs
Ritonavir (RTV) -Allows for longer dosing of other protease inhibitors and also helps to prevent development of resistance
-Enhancer/booster of other protease inhibitors
-Inhibitor of CYP3A -Biliary excretion -1/2 life: 3-5 hours
-Nausea -Vomiting -Diarrhea -Headache -Circumoral paraesthesias
Saquinavir (SQV)
-High-fat meals enhance absorption -Biliary excretion -1/2 life: 7-12 hours -Multiple daily doses
-Headache -Fatigue -Diarrhea -Nausea -GI disturbances
-Given with low dose of RITONAVIR -Increased levels of hepatic aminotransferases may be seen in pts with HBV or HCV
Indinavir (IDV) -Well absorbed orally -Acidic gastric conditions required for absorption -w/ RITONAVIR: twice-daily dosing -1/2 life: 1.8 hours
-GI disturbance -Headache -Nephrolithiasis -Hyperbilirubinemia -Fat redistribution
-Dosage should be adjusted in pts with hepatic insufficiency -To avoid kidney stone formation, pts should drink 1.5 L of water per day
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Nelfinavir (NFV)
-Usually given with food -Well absorbed -Metabolism produces an active metabolite with antiviral activity -1/2 life: 5 hours
-Diarrhea (controlled with LOPERAMIDE)
-Non-peptide *Only protease inhibitor that can’t be boosted by RITONAVIR
Fosamprenavir (fAPV)
-Prodrug, metabolized to AMPRENAVIR -Oral administration -Twice-daily dosing
-Nausea -Vomiting -Diarrhea -Fatigue -Paraesthesias -Headache
-Coadministered with RITONAVIR -Can inhibit the metabolism of other drugs
Lopinavir (LPVr) -Very poor intrinsic bioavailability -Oral solution contains alcohol
-GI effects -Hypertriglyceridemia
-Peptidomimetic -Given with RITONAVIR -can inhibit the metabolism of other drugs -DISULFIRAM/METRONIDAZOLE: can cause unpleasant reactions
Atazanavir (ATV)
-inhibits HIV protease -Competitive inhibitor of glucuronyl transferase
-w/ RITONAVIR: once-daily dosing -well absorbed orally -Increased absorbed with food -Highly protein bound -1/2 life: 7 hours -Potent inhibitor of CYP3A4
-Benign hyperbilirubinemia -Jaundice -Prolongs PR interval -Slows the heart rate
-Contraindicated with PROTON-PUMP INHIBITORS
Tipranavir (TPV)
-Inhibits HIV protease in viruses that are resistant to other protease inhibitors
-Salvage regimens in pts with multidrug resistance
-Well absorbed with food -1/2 life: 6 hours -w/ RITONAVIR: twice daily
-Severe and fatal hepatitis -Faratl and nonfatal intracranial hemorrhages
Darunavir (DRV)
-Active against HIV protease that is resistant to other protease inhibitors
-Salvage regimens in pts with multidrug resistance
-Well absorbed w/ food -1/2 life: 15 hours w/ RITONAVIR
-Rash -There may be decreased risk of hyperlipidemia
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-Inhibitor of CYP3A4 and also metabolized by these enzymes
Enfuvirtide (Entry
Inhibitor)
-Fusion inhibitor -Binds to gp41 Prevents conformational change Preventing fusion of HIV membrane with host cell membrane
-Experienced pts with evidence of viral replication despite ongoing antiretroviral therapy
-Given SC -Pain -Erythema -Induration -Nodules
Maraviroc (Entry
Inhibitor)
-Blocks the CCR5 coreceptor that works together with gp41 to help HIV entry into cell
-Well absorbed orally -Metabolized by CYP450
-Dose should be reduced when given with PROTEASE INHIBITORS
Raltegravir (RAL)
-Integrase inhibitor -Inhibits the final step in integration of stand transfer of viral DNA into our own host cell
-Treatment-experienced pts with evidence of viral replication
-1/2 life: 9 hours -Twice-daily dosing -Metabolized by UGT1A1
-Nausea -Headache -Diarrhea