Stages in viral replication:

• Attachment and penetration (stage 1);
  
• uncoating (stage 2);
  
• components of virus are synthesized (stage 3);
  
• virus particles are assembled (stage 4);
  
• virus is released (stage 5).

Gamma globulin (IgG) – Assumed to block penetration of virus (stage 1); anaphylactoid shock should always be considered.

Amantadine & Rimantadine

MOA: Prevent viral uncoating (stage 2).

Toxicity: CNS (dizziness, confusion, seizures).

Therapeutic place: Antiparkinsonian agent; prophylaxis of influenza A2 virus.

Contraindications: Epileptics, pregnancy.

Idoxuridine – antimetabolite; (thymidine analogue)

MOA: Disrupts DNA synthesis (stage 3). Only active against DNA viruses.

Pharmacokinetics: Prodrug that must be triphosphorylated by virus. Inactivated by liver.

Toxicity: Associated with IV administration – hepatotoxic, teratogenic, mutagenic, carcinogenic. Minimal toxicity when used topically.

Therapeutic place: Only approved for treatment of HSV infections of the eyelid, conjunctiva, and cornea.

Vidarabine – antimetabolite; purine analogue

MOA: Inhibits viral DNAP (stage 3). Only effective against DNA viruses.

Pharmacokinetics: Topical and IV. Prodrug that must be metabolized to a triphosphate. Reduce dose if patient is taking allopurinol for gout.

Toxicity: Topical adminstration is okay. Systemically causes GI and CNS toxicity, hepatotoxicity, carcinogenic/teratogenic/mutagenic.

Therapeutic place: Used primarily for topical ophthalmic administration (HSV keratoconjunctivitis). Used systemically for HSV encephalitis. Effective against HSV, VZV, and vaccinia.

Interferon

MOA: Cellular cytokines with antiviral activity that bind to receptors to stimulate the synthesis of proteins that interfere with all stages of viral replication.

Therapeutic place: Useful for some melanomas, chronic hepatitis B & C, Kaposi’s sarcoma.

Acyclovir – antimetabolite; guanosine analogue

MOA: Inhibits DNAP (stage 3)

Pharmacokinetics: Prodrug that must be triphosphorylated. Excreted by the kidney (probenecid inhibits secretion).

Resistance: Becoming a problem.

Toxicities: Low

Therapeutic place: EBV, VZV, HSV keratitis, HSV

Gangiclovir – Used to treat CMV in AIDS patients.

Cidofovir – Antimetabolite; cytosine analogue; disphosphate is the active drug; nephrotoxicity limited with concomitant use of probenecid and IV saline.

Sorivudine – Antimetabolite; pyrimidine analogue; used to treat VZV; will cause severe bone marrow depression when administered with 5-fluorouracil.

Ribavirin

MOA: Inhibits viral RNA synthesis (stage 3)

Pharmacokinetics: Prodrug that must be triphosphorylated.

Toxicity: Death, diminished pulmonary function, and CV problems in patients with CHF.

Therapeutic place: Aerosol used to treat severe lower respiratory tract infections due to syncytial virus. Also used in combination with interferon to treat hepatitis C.

Trifluridine – Antimetabolite; thymidine analogue

MOA: Stage 3 inhibitor of viral DNA synthesis by virtue of its incorporation into viral DNA.

Pharmacokinetics: Topical agent only. Very short half-life (20-30 min).

Toxicity: Palpebral edmea and transient burning of the eyes.

Therapeutic place: Topical treatment of epithelial keratitis of HSV.

Contraindications: Pregnancy

Foscarnet

MOA: Inhibits RNA polymerase and reverse transcriptase (stage 3)

Pharmacokinetics: Deposits into bone (binds with calcium)

Toxicity: Hypocalcemia and hypomagnesia.

Therapeutic place: IV adminstration for CMV retinitis.

Drug interactions

Vidarabine-Allopurinol – severe neurotoxicity

Acyclovir-Probenecid – decrease in acyclovir elimination

Category: Pharmacology Notes