antiviral drugs

Antiviral Drugs

PharmaIdea Publications ©

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

Antiviral Drugs


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

Antiviral Drugs


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

Antiviral Drugs


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 keratoconjunctivitis

-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,

Antiviral Drugs


-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

Antiviral Drugs


-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

Antiviral Drugs


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

Antiviral Drugs


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

Antiviral Drugs


-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

antiviral drugs

Documents