Antiviral drugs

Mr. OLORO JOSEPH.

Viruses Obligate intracellular parasites Consist of a core genome in a protein shell and

some are surrounded by a lipoprotein lack a cell wall and cell membrane do not carry out metabolic processes Replication depends on the host cell

machinery

Viruses Steps for Viral Replication

1) adsorption and penetration into cell 2) uncoating of viral nucleic acid 3) synthesis of regulatory proteins 4) synthesis of RNA or DNA 5) synthesis of structural proteins 6) assembly of viral particles 7) release from host cell

Antiviral Agents General mechanism of action Block viral entry into the cell Inhibits uncoating Inhibit synthesis of nucleic acid Inhibit release of new virions

Most agents are pyrimidine or purine nucleoside analogs

Sites of Drug Action

Antiherpes Agents

Acyclovir- prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine

Acyclovir

• An acyclic guanosine derivatives.

• Mechanism of action• Undergoes initial phosphorylation by viral specific

thymidine kinase enzyme• Then di- and triphosphate by host cell enzymes• Triphosphate inhibit viral replication by;

Competition with dGTP. Chain termination following icoporation

Mechanism of Resistance toAcyclovir Alteration in viral thymidine kinase

Alteration in viral DNA polymerase

Cross-resistance with valacyclovir, famciclovir, and ganciclovir

Acyclovir Oral, IV, and Topical formulations Cleared by glomerular filtration and tubular

secretion Uses:

Herpes Simplex Virus 1 and 2 (HSV) Varicella-zoster virus (VZV)

Side Effects: nausea, diarrhea, headache, tremors, and delirium

Valacyclovir L-valyl ester of acyclovir Converted to acyclovir when ingested M.O.A.: same as acyclovir Uses:

1) recurrent genital herpes 2) herpes zoster infections

Side Effects: nausea, diarrhea, and headache

Famciclovir Prodrug of penciclovir (a guanosine analog)

M.O.A.: same as acyclovir does not cause chain termination

Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B

Side Effects: nausea, diarrhea, and headache

Trifluridine

Trifluridine- fluorinated pyrimidine inhibits viral DNA synthesis same as acyclovir incorporates into viral and cellular DNA Uses: HSV-1 and HSV-2 (topically)

Vidarabine

An adenosine analog inhibits viral DNA polymerase incorporated into viral and cellular DNA metabolized to hypoxanthine arabinoside Side Effects: GI intolerance and

myelosuppression

Anti-Cytomegalovirus Agents

Gancyclovir Valgancyclovir Cidofovir Foscarnet Fomivirsen

Ganciclovir An acyclic guanosine analog requires a 3 step phosphorylation for activation monophosphorylation is catalyzed by a

phosphotransferase in CMV and by thymidine kinase in HSV cells

M.O.A.: same as acyclovir Uses: CMV*, HSV, VZV,and EBV Side Effect: myelosuppression

Valgancyclovir Monovalyl ester prodrug of gancyclovir Metabolized by intestinal and hepatic esterases

when administered orally

M.O.A.: same as gancyclovir Uses: CMV* Side Effect: myelosuppression

Cidofovir [si-DOE-foe-veer] A cytosine analog phosphorylation not dependent on viral

enzymes Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6,

adenovirus, and human papillomavirus Side Effects: nephrotoxicity (prevented by

admin. of probenecid) Resistance: mutation in DNA polymerase gene

Foscarnet[fos-KAR-net] An inorganic pyrophosphate inhibits viral DNA polymerase, RNA polymerase, and HIV

reverse transcriptase Does not undergo phosphorylation.

Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV

Resistance: due to mutations in DNA polymerase gene

Side Effects: hypo- or hypercalcemia and phosphotemia

Fomivirsen

[foe-MI-veer-sen] An antisense oligonucleotide M.O.A.: binds to mRNA and inhibits protein

synthesis and viral replication Uses: CMV retinitis in pts who cannot

tolerated other agents. Side effects: iritis and vitritis, and changes in

vision.

Neuraminidase inhibitors.

• Oseltamivir [os-el-TAM-i-veer] and Zanamivir [za-NA-mi-veer]

• Are sialic acid analogs• They prevent the release of new virions and

their spread from cell to cell.• are effective against both Type A and Type B

influenza viruses

Mode of action

• Inhibits neuraminidase, an enzyme necessary for the release of newly formed virions from infected cells

Resistance: due to Mutations of the neuraminidase

Pharmacokinetics• Oseltamivir, orally active pro-drug that is rapidly

hydrolyzed by the liver to its active form. • Zanamivir, is administered either inhaled or

intranasally. • Both are eliminated unchanged in urine

• Adverse effects: • Oseltamivir are gastrointestinal discomfort and

nausea, alleviated by taking the drug with food. • Zanamivir. Irritation of the respiratory tract does

occur, however. • Caution: avoid in individuals with severe reactive

asthma or chronic obstructive respiratory disease, because bronchospasm may occur with the risk of fatality.

• No clinically significant drug interactions reported on both drugs.

Ant influenza agents.

• Amantadine [a-MAN-ta-deen] and Rimantadine [ri-MAN-ta-deen]

• Their activity is limited to influenza A infections

• Mode of action: • Block the viral membrane matrix protein, M2, • A channel for hydrogen ion. • This channel is required for the fusion of the

viral membrane with the cell membrane forming the endosome

• Note: The acidic environment of the endosome is required for viral uncoating.

• The drugs may also interfere with the release of new virions.

• Pharmacokinetics: • Both are well absorbed orally. Amantadine

distributes throughout the body including CNS, rimantadine does not cross the BBB.

• Amantadine is not extensively metabolized. • excreted into the urine and may accumulate to toxic

levels in patients with renal failure. • rimantadine is extensively metabolized by the liver,

metabolites and the parent drug are eliminated by the kidney

• Adverse effects:• insomnia, dizziness, and ataxia

Resistance: • Due to a change in one amino acid of the M2

matrix protein. • Cross-resistance occurs between the two drugs.

Drugs active against respiratory syncitial virus (RSV)

Ribavirin [rye-ba-VYE-rin]

• A synthetic guanosine analog.

• Mode of action: converted to ribavirin-triphosphate, which inhibits guanosine triphosphate formation, preventing viral mRNA capping, and blocking RNA-dependent RNA polymerase.

• [Note: Rhinoviruses and enteroviruses, which contain preformed mRNA and do not need to synthesize mRNA in the host cell to initiate an infection, are relatively resistant to the action of ribavirin.]

Pharmacokinetics: • Effective p.o, iv & aerosol. • Absorption ↑sed if taken with a fatty meal.• Retained in all tissues, except brain. • The drug and its metabolites are eliminated in

the urine

Clinical use• Treatment of RSV infection

• Adverse effects: • oral or parenteral: included dose-dependent

transient anemia, elevated bilirubin has been reported. The

• Aerosol: safer, but respiratory function in infants can deteriorate quickly after initiation of aerosol treatment.

• Contraindication: pregnancy (teratogenic)

Reference

• Lippincotts illustrated review pharmacology 4th edition.

• B. G. Katzung: Basic & Clinical Pharmacology• Katzung & Trevor; Examination review

Pharmacology.

THANKS