Antiviral Agents

Antiviral agents
Introduction
• Viruses are obligate intracellular parasites,
– the replication of viruses depends on synthetic processes of the host
cell.
– Common viruses:
– Herpes viruses:
– Herpes simplex virus (HSV); has two types- HSV 1 and HSV 2
– Herpes simplex infection causes blisters in the skin or mucous membranes of the mouth,
lips or genitals:
– HSV 1- oral herpes
– HSV2- Genital herpes
– Varicella Zoster Virus (VZV)-chicken pox and shingles (herpes zoster)
– Cytomegalovirus
– A common virus particularly among immuno-compromised patients and infants
– Influenza virus- causes respiratory illness (flu)
– Hepatitis viruses- cause inflammation of the liver; Include- Hepatitis A
Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and others
– Human Immunodeficiency Virus (HIV)
Antiviral agents: classification
• Antiviral drugs:
• Drugs for herpes:
– Acyclovir
– Ganciclovir
– Foscarnet
– Drugs for influenza:
• Amantadine
• Zinamivir
– Drugs for HBV and HCV:
• IFN- alpha
• Lamivudine
• Ribavirin
Antiviral agents: classification
• Antiretroviral drugs:
– Drugs for HIV
• Reverse transcriptase inhibitors: nucleoside and non-
nucleoside
• Protease inhibitors
Antiherpes drugs
• Drugs:
– Acyclovir
– Valacyclovir (prodrug)
– Penciclovir
– Famciclovir (prodrug)
• Mechanism of action
– Activated by viral thymidine kinase (TK) to forms that inhibit viral DNA
polymerase
• Clinical use:
– Treatment and prophylaxis for Herpes Simplex Virus Infection (HSV-I, HSV-2)
and Varicella Zoster Virus (VZV)
• Pharmacokinetics:
– Acyclovir: Topical, oral, and IV
– Penciclovir: Topical
– Famciclovir and valcyclovir: Oral
• Adverse effects:
– Oral forms cause nausea, diarrhea, and headache
– IV acyclovir may cause renal and CNS toxicity
Drugs for cytomegalovirus
• Drugs:
– Ganciclovir
– Valganciclovir
– Cidofovir
– Foscarnet
• Mechanism of action:
– Ganciclovir requires activation to a form inhibiting DNA polymerase;
– No viral bioactivation of cidofovir and foscarnet is required
• Clinical use
– Treatment of CMV infections in immunosuppression (eg, AIDS) and organ
transplantation
– Ganciclovir: Oral, IV, intraocular forms
– Valganciclovir: Oral
– Cidofovir and foscarnet (IV)
• Adverse reactions:
– Ganciclovir: Bone marrow suppression, hepatic and neurologic dysfunction
– Cidofovir and foscarnet: Nephrotoxicity
– Foscarnet: CNS effects (headache, hallucinations, and seizures) and electrolyte
imbalance
Antihepatitis drugs
• Drugs:
– Interferon- (IFN- alpha)
– Adefovir-dipivoxil
– Entecavir
– Lamivudine
– Ribavirin
– Telbivudine
– Tenofovir
– IFN alpha;
• Degrades viral RNA via activation of host cell RNAase;
– The others inhibit HBV DNA polymerase
Antihepatitis drugs
• Clinical use
– Suppressive treatment of HBV (all drugs except ribavirin);
– Treatment of HCV (ribavirin +/– IFN-)
– IFN-alpha: Parenteral
– Adefovir, entacavir, lamivudine, and ribavirin: Oral
– Ribavirin: Inhalational
• Adverse reactions
– IFN-alpha: Alopecia, myalgia, depression, flu-like syndrome
– Adefovir: lactic acidosis, renal and hepatic toxicity
– Ribavirin: Anemia, teratogen
Anti-influenza drugs
• Drugs:
– Amantadine
– Rimantadine
– Oseltamivir
– Zanamivir
– Amantadine and rimantidine: block M2 proton channels, preventing viral
uncoating
– Oseltamivir and zanamivir: inhibit neuraminidase, preventing viral cleavage and
release
• Clinical use
– M2 blockers are virtually obsolete;
– others are used in:
• Prophylaxis against most current flu strains; used to shorten symptoms
– All given orally except zanamivir, which is inhalational
• Adverse reactions
– Oseltamivir: Gastrointestinal effects
– Zanamivir: Bronchospasm in asthmatics
Antiretroviral Drugs
Nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs)
– Abacavir
– Didanosine
– Emtricitabine
– Lamivudine
– Stavudine
– Tenofovir
– Zalcitabine
– Zidovudine
– Inhibit HIV reverse transcriptase after phosphorylation by cellular enzyme
– most undergo renal elimination especially, didanosine, emtricitabine,
lamivudine, stavudine, tenofovir, and zidovudine
– Zidovudine: Bone marrow suppression
– Abacavir: Hypersensitivity
– Didanosine: Pancreatitis
– Stavudine, zalcitabine: Peripheral neuropathy, Lactic
acidosis with hepatic steatosis
• Drug interactions:
– Most NRTIs are not extensively metabolized by
hepatic enzymes such as the CYP450 isoforms,
• so they have few interactions that concern their
pharmacokinetic characteristics
• Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
– Delavirdine
– Efavirenz
– Etravirine
– Nevirapine
• Mechanism of acion:
– Inhibit HIV reverse transcriptase; no phosphorylation required;
• Pharmacokinetics
– All current NNRTIs are metabolized via CYP450 isozymes;
– Delavirdine, nevirapine: Rash, increased liver enzymes
– Efavirenz: Teratogenicity
• Interactions:
– Inducers of CYP450 isozymes (eg, phenytoin, rifampin) and inhibitors
(eg, azoles, PIs) alter NNRTI duration of action
Protease inhibitors (PIs)
– Atazanavir
– Darunavir
– Fosamprenavir
– Indinavir
– Nelfinavir
– Ritonavir
– Saquinavir
– Tipranavir
– Inhibit viral protein processing;
• Pharmacokinetics
– Elimination mainly via metabolism by CYP450 isozymes;
– GI distress and diarrhea associated with:
• Atazanavir,
• fosamprenavir,
• lopinavir,
• nelfinavir,
• saquinavir:
– Atazanavir: Peripheral neuropathy
– Amprenavir: Rash
– Indinavir: Hyperbilirubinemia and nephrolithiasis
• Effects on Carbohydrate and Lipid Metabolism
– The use of PIs in HAART drug combinations has led to the
development of disorders in carbohydrate and lipid metabolism:
• hyperglycemia and insulin resistance or hyperlipidemia,
• altered body fat distribution;
– Buffalo hump (accumulation of fat on the back of the neck), gynecomastia,
– truncal obesity
• Interactions:
– Ritonavir and other PIs can inhibit CYP450
metabolism of many drugs including:
• antihistamines,
• antiarrhythmics,
• oral contraceptives
• sedative-hypnotics
– Drugs known to induce or inhibit CYP450 isoforms
may alter the plasma levels of PIs
Bibliography
– Anthony J. Trevor, Bertram G. Katzung & Susan B.
Masters (2013) Pharmacology- Examination And
Board Review 10th ed., McGraw Hill, Lange
– Katzung B.G (2007) Basic & Clinical Pharmacology,
11th ed, McGraw Hill, Lange

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