Module 7 Lesson 7.1 Antiviral and Antifungal Drugs PDF

Module 7: Antiviral and Antifungal Drugs Lesson 7.1: Antiviral Drugs Acyclovir Guanosine derivative; selective for herpesviruses Metabolized to monophosphate via thymidine kinase  conversion of monophosphate to triphosphate Acyclovir triphosphate inhibits viral DNA polymerase ...

Module 7: Antiviral and Antifungal Drugs Lesson 7.1: Antiviral Drugs Acyclovir Guanosine derivative; selective for herpesviruses Metabolized to monophosphate via thymidine kinase  conversion of monophosphate to triphosphate Acyclovir triphosphate inhibits viral DNA polymerase Acyclovir Widely distributed throughout body tissues and fluids, including the brain, semen, and CSF Excreted by kidneys: GF, tubular secretion Tx: ocular and respiratory infxns of herpes virus 1 of cats active against equine herpes virus type-l in vitro, but poor oral absorption Acyclovir caused by Psittacid herpesvirus * treatment of Pacheco’s parrot disease Adverse side effects -low WBC Cats : leukopenia; anemia Birds: necrosis at injection site Amantadine 1-aminoadamantane Binds to M2 protein and blocks its ion channel activity inhibits viral uncoating and replication N-methyl-D-aspartate (NMDA) receptor antagonist NMDA receptors are important in pain sensation influenza viruses replicate within host cell  M2 protein Amantadine Therapeutic Use Primary use: adjunct treatment to chronic pain in dogs and cats; used in treatment of equine-2 influenza via IV Rimantadine: also a water-soluble cyclic amine Amantadine is no longer recommended for treatment of flu virus in USA Amantadine Pharmacokinetics Adverse effects Not described in dogs and cats Dogs Only in horses Agitation Variable absorption (PO) Loose Bioavailability: 40-60% stools Excretion: renal Flatulence Half-life: ~3.5 hrs Diarrhea Amantadine Contraindications Hypersensitivity to amantadine or rimantadine Patients with untreated angle-closure glaucoma With caution: liver and renal diseases, CHF, active psychoses, eczematoid dermatitis, seizure disorders Amantadine Drug Interactions Anticholinergics CNS stimulants Urinary Acidifiers (methionine, ascorbic acid, ammonium chloride) Increase excretion TMPS Decrease excretion Famciclovir For feline herpes (FHV-1); converted into penciclovir Cells infected with susceptible Herpes virus or varicella zoster virus  thymidine kinase phosphorylates penciclovir to penciclovir monophosphate  penciclovir triphosphate  inhibits herpes virus DNA polymerase via competition with deoxyguanosine triphosphate  inhibiting herpes viral DNA synthesis Famciclovir Pharmacokinetics Cats require higher doses because of poor conversion to penciclovir Contraindication Hypersensitivity With caution in patients with renal problems Adverse effects Not well documented Well tolerated when used up to three weeks Interferons Human recombinant IFN-α Feline recombinant IFN-ω MOA: Released by host cells in response to viral infection Attached to receptors on adjacent cells  IFNs increase transcription of host cell DNA and activate endonuclease in cell  increasing cell resistance to virus infection They stimulate cell-mediated lysis of virus-infected cells Interferon Alfa-2A, Human recombinant Use in Veterinary Medicine For non-neoplastic Feline Leukemia (FeLV) disease Oral administration- ocular herpes infection Effects Antiviral- due to inhibition of RNA, DNA and cellular protein synthesis (+antiproliferative) Antiproliferative Immunomodulating Well distributed throughout the body except in CNS Interferon Alfa-2A, Human recombinant Adverse effects (dose-related) Cats: PO uncommon but parenterally at high dosages may lead to: Malaise general discomfort uneasiness. feeling of a a Fever Allergic reactions Myelotoxicity Bone - marrow suppression Myalgia pain muscle in Interferon-ω (omega) /Cat omega interferon Produced by genetic engineering and is a type 1 interferon closely related to alpha interferon t ½: 1–2 hours in dogs and cats MOA: Acts on virus-infected cells by inhibiting mRNA synthesis and translation proteins  inhibition of viral replication Interferon-ω (omega) /Cat omega interferon Well-tolerated in cats used to treat cat viral infections, including calici virus, FeLV, Feline Immunodeficiency Virus (FIV), Feline Infectious Peritonitis (FIP) and others; as well as canine parvovirus Canine distemper Acute feline calicivirus infections Topical: feline herpetic keratitis (less data) Interferon-ω (omega) /Cat omega interferon Adverse effects Hyperthermia & vomiting Decrease RBCs, platelets, WBCs (myelotoxicity) Increase ALT Soft feces/ mild diarrhea Transient fatigue, anorexia and weight loss Development of Abs (dogs) Oseltamivir phosphate Ester prodrug that is converted by hepatic esterases to its active metabolite, oseltamivir carboxylate Competitive inhibitor of the enzyme neuraminidase Neuraminidase: influenza viruses use as part of the process of budding of the replicative viral particles from infected cells Oseltamivir phosphate May be effective for parvovirus infections in dogs (@ 2.2 mg/kg PO q12h) or other mixed bacterial/viral infections Public health issues, use in veterinary medicine is controversial  prohibited by the FDA for extralabel drug use in poultry this is in fear of resistance that avian influenza virus would develop against oseltamivir Tamiflu® brand for humans Zidovudine (AZT) Analog of thymidine MOA: phosphorylated by host cell enzymes to AZT 5- triphosphate, which competes with host 5-thymidine which is essential for proviral DNA formation by reverse transcriptase of the virus The incorporation of the 5-triphosphate zidovudine into the viral DNA chain produces the termination of viral DNA synthesis Zidovudine (AZT) Antiretroviral agent  virustatic effect Converted to active metabolite- triphosphate: inhibits viral RNA-directed DNA polymerase Has activity against bacteria (G-) and cytotoxic Useful for treating FIV Clinical improvement 14 days after the start of tx Adjunct treatment for FeLV Zidovudine (AZT) Pharmacokinetics Well absorbed orally; 90% bioavailability in cats Widely distributed including the CSF Metabolized in liver by glucuronide conjugation and excreted in urine t ½ = 1.5 hours (~2hrs; Hsu) Zidovudine (AZT) Adverse effects: (Non-regenerative) Anemia and reduction in hemoglobin Diarrhea and weakness Use with caution in patients with bone marrow, renal or hepatic dysfunction Zidovudine (AZT) Drug Interactions Antifungals, azole: increase level Atovaquone: increase level Doxorubicin: antagonism Interferon alfa: increase risk of hematologic and hepatotoxicity Zidovudine (AZT) Drug Interactions Probenecid: increase level Rifampin: May decrease blood levels (AUC) Myelo-/cytotoxic drugs (chloramphenicol, flucytosine, vincristine and vinblastine): May increase the risk of hematologic activity Other Antiviral Agents Trifluorothymidine (TFT) thought to have higher affinity for viral DNA than mammalian, and so is more potent Idoxuridine: thymidine analogs active against DNA viruses; herpesvirus and poxvirus References Hsu, W.H. (2008). Handbook Of Veterinary Pharmacology. Wiley Blackwell. Plumbs, D.C. (2008). Plumb's Veterinary Drug Handbook. (6th ed.). Blackwell Publishing. Riviere, J.E. & Papich, M.G. (2009). Veterinary Pharmacology and Therapeutics. (9th Edition). Wiley- blackwell, Iowa.