First FDA approved antisense therapy Binding to target mRNA results in inhibiton of immediate early region 2 protein synthesis – inhibiting viral replication
Injected intravitreally in CMV retinitis
ANTIVIRAL DRUGS – DNA & RNA VIRUSES DRUG MECHANISM/ VIRAL SELECTIVITY CLINICAL USE VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS PHARMACOKINETICS NOTES Acylovir Metabolized by thymidine kinase to triphosphate Herpes simplex 1 & 2, varicella zoster Produce abnormal thymidine kinase Skin irritation, burning, crystalline nephropathy IV/PO. Administer slowly. CNS level=50% serum level. Decrease dose w/ kidney dysfunction Pencyclovir Oral HSV (coldsores) Topical Valacyclovir L-valyl ester of acyclovir converted to acyclovir Herpes zoster (shingles) Nausea, headache PO. Slightly better oral absorption than acyclovir No clear advantage over acyclovir Idoxuridine Phosphorylated metabolite incorporates into DNA causing strand breaks Herpes simplex keratitis. No effect on RNA viruses Resistance develops Photophobia, irritation of conjunctiva & eyelid Eyedrops Drug is a halogenated derivative of deoxyuridine Famciclovir Phosphorylated by viral thymidine kinase to penciclovir triiphosphate Shortens duration of herpes zoster & genital herpes Minimal toxicity. Headache PO. Decrease dose with renal dysfunction. Ganciclovir Metabolized by thymidine kinase to triphosphate . Preferentially phosphorylated to active drug in CMV infected cells CMV retinitis & severe systemic CMV infections Some resistant strains lack thymidine kinase. Cannot activate drug. Granulocytopenia, thrombocytopenia IV/PO. Excreted unchanged in urine. Decrease dose with renal dysfunction. Do not coadminister zidovudine (granulocytopenia) or imipenem-cilastatin (seizures)
Cidofovir Metabolized to diphosphate form. Otherwise like ganciclovir. CMV retinitis Nephrotoxicity may be reduced by hydration & coadministration of Probenicid. Neutropenia. Foscarnet Analog of pyrophosphate. Competes for pyrophosphate site in viral but not human, DNA polymerase & reverse transcriptase CMV retinitis Does not need phosphorylation, it is active against thymidine kinase –deficient strains Renal toxicity, seizures, hypocalcemia, fever, anemia, diarrhea, nausea IV. >80% excreted unchanged in the urine. CSF penetration variable. Reduce dose with renal dysfunction. Deposited in bone & teeth. Hydrate patient during therapy to protect the kidney Amantadine Prevents virus from entering susceptible cells Treatment & prophylaxis of influenza A Depression, CNS toxicity, CHF, orthostatic hypotension, urinary retention PO. Excreted unmetabolized. Rimantadine Analog of amantadine , inhibits viral uncoating Prophylaxis in children Fewer CNS side effects, risk of seizure PO. Prolonged elimination w/ renal or hepatic dysfunction Ribavirin Unknown mechanism RSV Decreased pulmonary function. Aerosol administration. Absorbed systemically. May precipitate in ventilator tubing.
Immune response modifier effective in topical treatment of external genitalia & perianal warts
ANTIVIRAL DRUGS - RETROVIRUSES DRUG MECHANISM & VIRAL SELECTIVITY CLINICAL USE VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS PHARMACOKINETICS NOTES Zidovudine (AZT) Thymidine analog is incorporated into DNA of hyman immunodeficiency viirus causing termination of the viral DNA chain HIV. Prevention of maternal-fetal transmission of HIV Mutations in reverse transcriptase Headaches, nausea, myalgias, anemia, neutropenia, macrocytosis PO. Well absorbed, rapidly metabolized by liver Acetaminophen increases risk of hematologic toxicity Didanosine (ddl) Zalcitabine (ddC) Lamivudine -Metabolized intracellularly to dideoxynucleotide triphosphate that inhibits reverse transcriptase & incorporates into viral DNA. -Nucleotides fail to bind to ddATP bec it lacks free 3’ OH group HIV Mutations in reverse transcriptase Peripheral neuropathy, pancreatitis, diarrhea, headache, insomnia, vomiting, nausea, rash, abdominal pain IV/PO. Partially metabolized in liver, excreted in the urine. Toxicity may be enhanced by renal or hepatic dysfunction. Limited utility as a single agent therapy because of viral resistance Stavudine Metabolized to stavudine triphosphate w/c inhibits HIV reverse transcriptase & DNA polymerase. Prevents DNA elongation. HIV Peripheral neuropathy PO Not indicated for initial monotherapy of HIV
Ritonavir Indinavir Saquinavir Nelfinavir Inhibts HIV protease . Results in immature virion HIV Mutations in protease sequence reduce affinity of protease inhibitors GI distress, headache, neurologic symptoms. Indinavir associated w/ increase risk for kidney stones PO. Metabolized by P450 in liver. Reduce dose in patients with liver disease. Poor CNS penetration Potentially serious drug interactions due to P450 competition Nevirapine Delavirdene Nob-nucleoside inhibitor of HIV reverse transcriptase HIV. Never as monotherapy due to rapid development of resistance Rapid resistance develops due to mutations in reverse transcriptase Severe skin rash, fever, nausea, headache PO. Well absorbed. Nevirapine crosses placenta & has better CNS penetration than Delavirdene Delavirdene failed to show clinical efficacy when added to didanosine in clinical trial
Topical treatment of tinea cruris & tinea corporis
Cutaneous candidiasis & tinea versicolor
ANTIFUNGAL DRUGS DRUG ACTION CLINICAL USE UNDESIRABLE EFFECTS PHARMACOKINETICS NOTES Amphotericin B Disrupts plasma membrane of fungal cells, greater affinity for ergosterol DOC: systemic fungal infections, fungal meningitis & fungal urinary tract infections Poor therapeutic index (toxic at therapeutic dose). Fever & chills, nephrotoxicity, nausea, headache, thrombophlebitis, anemia, hepatotoxicity, cardiotoxicity Slow IV for systemic infections; intrathecal for meningitis, bladder irrigation for cystitis. No need to reduce dose with renal dysfunction. CBC, urinalysis, liver enzymes, BUN, Crea, & electrolytes should be checked before and during tx Nystatin DOC: Intestinal candidiasis or oral thrush Few adverse effects PO. Negligible absorption, fecal excretion . Ketoconazole Impairs synthesis pf ergosterol DOC: P. brasiliensis, thrush, chronic mucocutaneous candidiasis, dermatophytes Nausea, diarrhea, headaches, rsh, dizziness, fatal hepatic necrosis, gynecomastia. Risk of cardiac arrhythmia with Terfenadine PO. Acid pH required for dissolution. Absorption decreased by food, antacids, cimetidine Follow LFTs. Stop during signs of liver abnormalities Fluconazole Inhibits fungal cytochrome P450. Damages plasma membrane by inhibiting sterol demethylation Systemic histoplasmosis, blastomycosis, coccidiomycosis or sporotrichosis. Opportunistic cryptococcosis, candidiasis, candidal thrush, vaginitis, esophagitis Nausea, headache, rash, vomiting, diarrhea PO/IV. Long half life. Excellent penetration of CSF, eye, urine. Hepatic metabolism No effect on testosterone synthesis.
Itraconazole Aspergillosis, histoplasmosis, coccidiomycosis, sporotrichosis, paracoccidiomycosis, tinea or candidal infections Nausea, edema, hepatitis. No gynecomastia or breast pain. Risk of fatal cardiac arrhythmias w/ terfenadine PO. Requires acidic environment for absorption No effect on testosterone synthesis Clotrimazole unknown DOC: candida dermatophyte infections of the skin topical Miconazole Vaginal candidiasis, severe systemic fungal infections Phlebitis, pruritus, nausea, fever, rash, vomiting Vaginal suppositories/ topical/IV Flucytosine Deaminated to 5-FU by the fungus. Incorporated into RNA. Metabolized to 5-FdURD w/c inhibits thymidilate synthetase Leucopenia, nausea, diarrhea, Inc LFTs, bone marrow depression Easily penetrates CNS. Renal excretion Fungal resistance develops Griseofulvin Interferes w/ synthesis & polymerization of nucleic acids Dermatophytes of hair, skin, & nails. Up to 6 months tx may be required Headaches, GI upset, dec memory & judgement, leucopenia, teratogenic PO. Water insoluble, powder absorbed fairly well, administration w/ fatty meal aids absorption Contraindicated w/ pregnant women. Drug binds to keratin of growing tissues Terbinafine Inhibits squalene epoxidase that converts squalene to ergosterol in fungi Toenail infection due to trichophyton species Neutropenia, skin infections, ophthalmic toxicity PO. Long half life. Good tissue penetration Monitor blood counts