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Viral Infections

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					                         Viral Infections
                          Part 1 and 2
                  Robert P. Rapp, Pharm. D.
                          Professor
                    College of Pharmacy



                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                        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)

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                     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)



                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
        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

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
    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
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                            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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
      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)
     – 15, 1997
              Copyright Robert Rapp, University of implant
SeptemberGanciclovir intravitrealKentucky 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

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
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 Robert Rapp, University of Kentucky College of Pharmacy
                 Copyright
September 15, 1997
Antiviral Drugs ofChoice(Cont)
• Influenza A virus - amantadine or
  rimantadine - P.O.
• Papillomavirus - Interferon a-2b -
  Interlesional.
• Respiratory syncytial virus - ribaviron -
  inhalation.


                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
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.

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
 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!!!
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
  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.




                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                              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.)


                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                             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.



                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
 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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                  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.




                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                    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.




                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                  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



                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                  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%
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                  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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                  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.

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                               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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                               Famciclovir
• The diacetyl ester prodrug of penciclovir
  and it lacks any antiviral activity until it is
  converted in-vivo.




                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                 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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                 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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                 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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                 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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                               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.


                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                               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.



                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                        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 Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                 Copyright Robert
                                  unmetabolized by kidney (> 90%)
                               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.


                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                               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.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                      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
                  Copyright Robert activity
    have antiviralRapp, University of Kentucky College of Pharmacy
 September 15, 1997
                                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

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                Interferons
• Indications
     –   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.

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                              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 - 12-
    22 hour exposure daily for 3-6 days.
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                   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
                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                   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.

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997
                                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.

                 Copyright Robert Rapp, University of Kentucky College of Pharmacy
September 15, 1997

				
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