september 15, 1997copyright robert rapp, university of kentucky college of pharmacy viral infections...

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

Viral InfectionsPart 1 and 2

Robert P. Rapp, Pharm. D.

Professor

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)


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)


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


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


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.


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 intravitreal implant


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


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


Antiviral Drugs ofChoice(Cont)

• Influenza A virus - amantadine or rimantadine - P.O.

• Papillomavirus - Interferon a-2b - Interlesional.

• Respiratory syncytial virus - ribaviron - inhalation.


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.


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!!!


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.


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.)


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.


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.


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.


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.


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


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%


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.


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.


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.


Famciclovir

• The diacetyl ester prodrug of penciclovir and it lacks any antiviral activity until it is converted in-vivo.


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.


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.


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.


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.


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.


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.


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%)


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.


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.


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 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


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.


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.


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


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.


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, 1997copyright robert rapp, university of kentucky college of pharmacy viral infections...

Documents

copyright robert rapp

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