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Viral Infections
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Robert P. Rapp, Pharm. D.
Professor
College of Pharmacy
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Antiviral Agents
• There has been slow but steady progress in the
development of antiviral chemotherapy.
• There are currently Drugs Approved for:
– Influenza
– Respiratory syncytial virus
– herpes simplex virus
– Varicella-zoster virus
– Hepatitis
– Cytomagalovirus
– HIV (covered by Dr. Liter - not in this section)
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Antiviral Agents Classification
• Agents that directly inactivate intact viruses
– Ether, chloroform, UV light, podophyllin
• Agents that inhibit viral replication at the cellular level.
– Acyclovir, ganciclovir, AZT, etc. (where all the drugs
are right now)
• agents that augment or modify the host response to
infection (immunomodulators)
– Ampligen, ditiocarb, (none marketed at this time)
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Susceptibility Testing - Antiviral Drugs
• Presently not standardized
• Many variable factors
– Assay system, viral innoculum, laboratory
• Rapidly developing and presently
somewhat effective for:
– HIV
– Herpes viruses
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Viral Infection and Immunity
• We remain dependent upon our
immune system for recovery from viral
infections.
• If immunity does not recover.
– Mortality is increased
– Response to therapy is usually delayed.
– Risk of selecting resistant viruses may be
higher in such patients.
• Mutations within the viral genome
• Usually detected only by a lack of clinical response
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Drug efficacy
• Depends on achieving effective antiviral
concentrations at the site of infection.
– Adequate intracellular concentrations of the
drug or active metabolites.
– Many antiviral drugs are inactive until
metabolized within cells to phosphorylated
derivatives that compete with natural
nucleosides for viral and sometimes host
enzyme systems.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Drug Efficacy(Continued)
• Predictive relationships between drug
concentrations active in-vitro and those
achieved in blood or other body fluids,
and clinical response have not been
established for most antiviral agents.
• Topical/local administration - becoming
more important - examples:
– Inhalation ribavirin (Virazole)
– Ganciclovir
implant
September
15, 1997
Copyright Robertintravitreal
Rapp, University of Kentucky
College of Pharmacy
Antiviral Drugs of Choice
• CMV
– Retinitis - ganciclovir I.V. or insert
– Pneumonia - ganciclovir - I.V.
– Others - ganciclovir - I.V.
• Hepatitis virus
– Hepatitis C - Interferon-a-2-b - SC/IM
– Hepatitis B - Interfron -a-2-b - SC/IM
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Antiviral Drugs of Choice(cont)
• Herpes simplex virus (HSV)
–
–
–
–
–
Genital 1st episode- acyclovir - P.O.
Genital recurrence - acyclovir - P.O.
Suppression - acyclovir - P.O.
Encephalitis - acyclovir - I.V.
Mucocutaneous disease in the
immunocompromised patient - acyclovir - I.V.
– Neonatal - acyclovir - I.V.
– Conjunctivitis - trifluridine or vidarabine topical
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Antiviral Drugs ofChoice(Cont)
• Influenza A virus - amantadine or
rimantadine - P.O.
• Papillomavirus - Interferon a-2b Interlesional.
• Respiratory syncytial virus - ribaviron inhalation.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Antiviral Drugs of choice(Cont)
• Varicella-zoster virus.
– Varcella in normal children - acyclovir - P.O.
– Varicella in immunocompromised - acyclovir I.V.
– Herpes-Zoster in immunocompromosed acyclovir - P.O.
– Herpes-Zoster in normal hosts - acyclovir P.O.
or famciclovir P.O.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Amandatine and Rimantadine
• Indication - prevention and treatment of
influenza A.
• Mechanism - Inhibits viral replication by
preventing uncoating of the virus after
entering the cell.
• Approximately 70% effective as
prophylaxis taken during an outbreak.
However - 1st line is vaccination!!!
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Amantadine - adverse effects
• Primary adverse effects - nausea,
vomiting, other GI disturbances, CNS
effects.
• Rimantadine is even more potent on a
weight basis and has less CNS effects.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Amantadine
• Pharmacokinetics
– High oral bioavailability
– T 1/2 - 12-18 hours.
– Excreted as parent drug in the urine with major
dosing adjustment required in renal failure (CC
< 10 ml/minute T 1/2 - 30 days - not cleared by
hemodialysis.)
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Rimantadine
• Pharmacokinetics
– Extensively metabolized and < 15% of the
drug is excreted unchanged in the urine.
– T 1/2 - 24-36 hours.
– Dose reduction is required for severe renal and
hepatic failure.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Amantadine and Rimantadine
• Almost all the toxicities are seen in the
setting of renal failure when the dose
has not been adjusted.
– Neurotoxic reactions - tremor, seizures, coma.
– Cardiac - arrhythmias
• With normal dosing - nervousness,
lightheadedness, insomnia, loss of
appetite - all are usually mild.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Acyclovir
• The prototype of a group of antiviral agents that is activated by
viral thymidine kinases to become inhibitors of viral DNA
polymerases and block viral DNA synthesis.
• Acyclovir uptake and intracellular phosphorylation to the
monophosphate derivative is facilitated by sHSV thymidine
kinase.
• Cellular enzymes then convert the monophosphate to acyclovir
triphosphate which is present in 40-100 fold higher
concentations in HSV-infected cells than in uninfected cells.
• The triphosphate then is incorporated into viral DNA which leads
to irreversible inactivation of DNA polymerase.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Acyclovir
• Resistance
– Defined in-vitro by concentration > 3 mcg/ml
– Always present in a native viral population at very low levels.
(about 1%)
– Several mechanisms identified most common is thymidine kinase
deficiency.
– Recovered uncommonly from normal hosts.
– Now occurring frequently in patients with AIDS and in transplant
patients.
• 1 in 52 first treatment courses and 2 of 22 second treatment
courses.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Acyclovir
• When resistance occurs.
– Optimal management is not certain.
– In patients with progressive disease - I.V.
foscarnet therapy is usually effective but
vidarabine is not and ganciclovir is not.
– Other options
• High dose continuous-infusion acyclovir
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Acyclovir
• Pharmacokinetics
– Oral bioavailability - 15-21%
– Prodrug valaciclovir - (L-valine ester of
acyclovir) - 3-5 x greater oral bioavailibility
compared to acyclovir.
– Protein binding - < 20%
– CSF - 1/2 of plasma levels.
– t1/2 - 2.5 - 3 hours.
– Renal excretion - 60-91%
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Acyclovir
• Adverse effects - I.V. (most of these
associated with decreased renal
function - serum conc > 25 mcg/ml)
– CNS - lethargy, confusion, tremor - 1-3%
– Reversible renal dysfunction - 5%
– Oral acyclovir - nausea, vomiting, rash,
headache - infrequent.
– Appears to be safe in pregnancy.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Acyclovir
• Dosing regimens
– Oral - 200 - 4000 mg/day in divided doses.
– I.V. - 5-20 mg/kg - every 8 hours.
• Drug interactions
– AZT - increased CNS toxicity
– Cyclosporin - increased renal toxicity
– Decreases renal clearance of other drugs.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Penciclovir
• Similar to acyclovir in spectrum of
antiviral activity.
• Inhibitory activity about twofold higher
than for acyclovir and the triphosphate
is 100 fold less active.
• T 1/2 intracellular - 7-20 hours - less
infrequent dosing compared to
acyclovir.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Famciclovir
• The diacetyl ester prodrug of penciclovir
and it lacks any antiviral activity until it is
converted in-vivo.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Foscarnet
• Inhibitory for all HSV and HIV.
• Inhibitory for most ganciclovir - resistant
CMV and acyclovir-resistant HSV and
VSZ
• Also acts synergistically with ganciclovir
• An inorganic pyrophosphate analog and
unlike nucleosides, directly inhibits the
virus by blocking the pyrophosphate
binding site of viral polymerase.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Foscarnet
• Resistance does occur and is
associated with poor clinical response.
• Pharmacokinetics
– Low oral bioavailabilty - < 20% - therefore
usually given by the I.V. route.
– Renal elimination - 80% of dose - must adjust
does in renal failure.
– T 1/2 - 4-8 hours, secondary prolonged T 1/2 88 hours - sequestration in bone.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Foscarnet
• Toxicity
– Renal toxicity - the major dose limiting side
effect - ATN. Crystalluria and interstitial
nephritis. Increases in creatinine occurs in 50%
of patients treated.
– Metabolic - hypo and hypercalcemia, hypo, and
hyperphosphatemia
– CNS - headache in 25% of patients, tremor,
irritability, seizures in 10% of patients.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Foscarnet
• Approved for the treatment of CMV
retinitis in AIDS patients.
• Useful for acyclovir-resistant HSV or
VZV, and ganciclovir resistant CMV
retinitis in immumocompromised
patients.
• Doses - 60 mg/kg every 8 hours, 90
mg/kg every 12 hours.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ganciclovir
• A oxyguanosine analog that differs
somewhat from acyclovir.
• Spectrum
– Inhibitory against all HSV.
– Uniqueness - potent inhibitory against CMV
replication. Compared to acyclovir, 10 - 100
fold lower inhibitory concentrations.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ganciclovir
• Mechanism
– Intracellular ganciclovir is phosphorylated to
the monophosphate derivative by thymidine
kinase - then to the di and triphosphates. At
least 10 fold higher ganciclovir triphosphate are
present in CMV infected cells compared with
uninfected cells.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ganciclovir
• Resistance
– Occurs and is recognized by progressive
disease and persistent CMV recovery despite
therapy.
– Pharmacokinetics
• Oral bioavailibility - < 10% - usually have to give
doses of 1000 mg every 6 hours.
• Low plasma protein binding.
• T 1/2 - 2-4 hours.
• High Vd - good tissue distribution
• Elimination
unmetabolized by kidney (> 90%)
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ganciclovir
• Indications
– Treatment of CMV retinitis in
immunocompromised patients.
– Prevention of CMV in transplant patients.
– Intravitreal implant now approved as well - cost
around $1500 per implant.
– Used for all forms of CMV disease.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ganciclovir
• Toxicity
– Myelosuppression - the major dose-limiting
toxicity of ganciclovir. 40% of patients will
have neutropenia (< 1000 cells /mm3) and
thrombocytopenia (< 50,000/mm3) - usually
occurs in the 2nd week of therapy and is
reversible. DC when the ANC < 500. GMCSF
may be helpful but expensive.
– Others - headache, behavorial changes,
confusion, psychosis.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Interferons
• Potent cytokines associated with
complex antiviral, immunomodulating,
and antiproliferative activity.
• Proteins, synthesized by erkaryotic cells
in response to various inducers and
each type if immunologically distinct.
• Not directly antiviral but cause
elaboration of effector proteins in
exposed cells - over 24 - many of which
September
15, 1997
Copyright Robert Rapp,
University of Kentucky College of Pharmacy
have
antiviral
activity
Interferons
• Pharmacokinetics
– Effect not directly related to serum levels.
– Given I.M/SC or interlesional (genital warts)
• Drug interactions - via cytochrome P450
• Adverse effects
– Acute influenza like activity.
– Major - BM suppression, neurotoxicity
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
• Indications
–
–
–
–
Interferons
Condyloma accuminatum
Chronic hepatitis C.
Chronic hepatitis B. (80% remissions)
Karposi’s sarcoma
• Dose and expense.
– Most indications require high doses for long
periods of time ( 10 MU 3 times a week for 4-6
months) and this is very expensive.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ribarvin
• A guanosine analog - inhibits the in-vitro
replication of RNA and DNA viruses
(specific mechanism at the cellular level
is not presently known)
• In the US - only the aerosolized form is
approved.
• Approved for RSV bronchiolitis and
pneumonia in hospitalized children - 122215,hour
exposure
daily
for
3-6
days.
September
1997
Copyright
Robert Rapp, University
of Kentucky
College
of Pharmacy
Ribavirin
• For influenza infection - 12-18 hour
exposure per day for 3 days. For use in
high risk patients (transplant) by
inhalation or by intravenous injection of
the inhaled product - may be effective
and the only therapy available.
• Intravenous form also used for Lassa
fever and other hemorrhagic fever.
• May be useful for Hanta virus infection
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Ribavirin
• Adverse effects
–
–
–
–
Marrow suppression
Increased bilirubin in 25% of patients.
Intravenous - acute flu like syndromes.
Pulmonary symptoms when given by inhalation
• Ribavirin exposure to health care
workers during aerolization is a very
major concern.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy
Vidarabine
• Antiviral activity against HSV, Zoster, or
varicella in immunocompromised
patients.
• Acyclovir has replaced it for most
indications because of greater efficacy
and safety.
• Many serious toxicities.
September 15, 1997
Copyright Robert Rapp, University of Kentucky College of Pharmacy