Pharmacology II

CH 38: Antiviral Drugs I

Study Guide

TREATMENT OF RESPIRATORY VIRUS INFECTIONS

Treatments only exist for Influenza A and B and RSV Neuraminidase inhibitors Oseltamivir Tamiflu Zanamivir Relenza -influenzaorthomyoxovirus; contain neuroamidinase enzymes -prevents release of new virons and their spread from cell to cell -effective against Influenza A and B -Administered PRIOR to exposure prevent infection -Administered WITHIN 24-48 hrs after onset of infection reduces intensity and duration of Sx MOA -osteltamivir is a transition state analog of salic acid substrate and serves as INHIBITORS of enzyme activity -inhibits viral neuroamidase OsteltamivirOral prodrug Zanamivir inhaled or activated by liver intranasal Ribavirin Virazole

General

Pharmokinetics

Adverse Effects

Osteltamivir -GI discomfort -Nausea **TAKE WITH FOOD

Zanamivir -irritation to respiratory tract -AVOID in pts with SEVERE REACTIVE ASTHMA or COPD broncospasm can occur w/ fatality

-synthetic guanosine analog -tx of infants and young children with SEVERE RSV infection -NOT FOR ADULTS -effective in chronic hep C when combined w/ interferon-a-2b -may reduce mortality and viremia of Lassa fever -prevents viral mRNA capping and blocking RNA-dependent RNA polymerase -INTERFERES w/ protein synthesis -Oral and IV absorption increased w/ fatty meal -Aerosol used in certain respiratory viral conditions -Dose dependent transient anemia w/ IV -AEROSOL MAY BE SAFERbut respiratory function can deteriorate quickly after initiation of aerosol tx -CONTRAINDICATED in pregnancy

TREATMENT of HEPATIC VIRAL INFECTIONS

Hep B and C are most common causes chronic hep, cirrhosis, hepatocellular carcinoma Only hepatic viral infxns with tx available

Interferon IFN General

-inducible glycoproteins interferes w/ ability of virus to infect cell -interferon--2a approved for tx of hep B and C, condylomata acuminata, cancers (hairy cell leukemia and Kaposis sarcoma)

pegylated formulations (Pegasys) bismonomethoxy polyethylene glycol covalently attached to increase size of molecule -decreases rate of absorption -decreases renal clearance -decreased immunogenicity -LENGTHENS DURATION OF ACTION

MOA Pharmokinetics Adverse Effects

-degradation of viral mRNA and tRNA -SubQ -cellular uptake and metabolism by liver and kidneyno active compound in plasma -flu-like sx on injection (myalgias, arthralgias, GI *BLACK BOX WARNING*DISCONTINUE DRUG IF disturbances, fever, chills) worsening of: -FATIGUE and DEPRESSION COMMONdecrease with -autoimmune disorders subsequent injections -thyroiditis -Bone marrow Suppression -TTP -ITP *BLACK BOX WARNING*may cause severe -RA depression and suicidal thoughts -Interstitial nephritis -SLE -Psorias

Interferon IFN Drug Interactions

-interferes w/ hepatic drug metabolism -toxic accumulations of thiophylline reported

Lamivudine Epivir General -inhibitor of HBV DNA polymerase (Hbv Epivir) and HIV reverse transcriptase (Epivir) -inexpensive -high rate of drug resistance -role diminishing due to new drugs MOA -competitively at concentrations that have negligible to host DNA polymerase -inhibits reverse transcriptase Pharmokinetics -intracellular half-life much longer than plasma half-lifeINFREQUENT dosing -absorbed orally -excreted unchanged in urine Adverse Effects -WELL TOLERATED -HA and dizziness

TREATMENT of HERPESVIRUS INFECTIONS

Includes: cold sores, viral encephalitis, genital infxns, Drugs exert actions during acute phase NO EFFECT during LATENT phase (except for foscarnet) inhibits HBV polyermase

Acyclovir Zovirax General -prototypic antiherpetic therapeutic agent -DRUG OF CHOICE for HSV encephalopathy -effective against HSV 1 & 2, VZV, some Esptein-commonly used in GENITAL HERPES Barr virus-mediated infxns MOA -guanisine analong lacks true sugar moiety -causes premature DNA-chain termination -virus-infected cells most susceptible Pharmokinetics -IV, oral, topical -accumulates in pts w/ renal failure Adverse Effects -depend on route -Oral HA, diarrhea, N/V -Topicallocal irritation -IV transient renal dysfunction in high doses or in dehydrated pt Resistance -usually found in HIV pts -cross-resistance w/ other cyclovirs Foscarnet General

Pharmokinetics

Adverse Effects Resistance

-NOT purine and pyrimidine analog -Phosphonoformate (physrophosphate derivative) -broad in vitro antiviral activity -approved for CMV retinitis in immunocompromised hosts and acyclovir-resistant HSV and herpes zoster infxns -must be injected IV -must be given frequently to avoid relapse when plasma levels fall -excreted through glomerular filtration and tubular secretion into urine -Nephrotoxicity -nausea -anemia -fever -cross-resistance btwn foscarnet and ganciclovir or acyclovir is UNCOMMON

Ganciclovir Cytovene (or Valganciclovir) General -analog of acyclovir 8-20x greater activity against CMV (only approved for CMV) -tx of CMV retinitis in immunocompromised pts and CMV prophylaxsis in transplant pts MOA -nucleotide competitively inhibits viral DNA polymerase and can be incorporated into the DNA (decreases rate if chain elongation) Pharmokinetics -Gangciclovir IV; accumulates in pts w/ renal failure -Valganciclovir Oral Adverse Effects -dose dependent neutropenia -carcinogenic, embryotoxic, teratogenic in experimental animals

General

MOA Pharmokinetics

Penciclovir (Denavir) -acyclic guanosine nucleoside derivative active against HSV-1, HSV-2, VZV - Cold sores and labialis -inhibits HSV DNA polymerase - topical -Bone pain and healing shortened approx. day in duration

Famiciclovir (Famvir) -prodrug of penciclovir -approved for tx of acute herpes zoster -metabolized to active penciclovir -orally

Adverse Effects

-HA -nausea