Chapter 43 Antifungal and Antiviral Agents

1. Chapter 43 Antifungal and Antiviral Agents Department of pharmacology Liu xiaokang(刘小康） 2010,3

2. Antifungal Agents • Drugs categorized multiple bases: (1) Type of infection: (a) Systemic (Deep) Fungal infections. (b) Topical (Dermatophytic) Fungal infections. (c) Mucous membranes -- Yeast infections. (2) Route/Site of action. (3) Mechanism of action. (4) Chemical nature.

3. ANTIFUNGAL DRUGS Drug Infection Type Route/Site Mechanism Chemical Group Amphotericin B Deep/Derm IV for Systemic/Topical Cell membrane Polyene Nystatin Derm/Yeast PO for GI/Topical/Vaginal Cell membrane Polyene Itraconazole Deep PO for Systemic Cell membrane Azole Fluconazole Deep IV,PO for Systemic Cell membrane Azole Ketoconazole Deep/Derm PO for Systemic/Topical Cell membrane Azole Miconazole Deep/Derm IV for Systemic/Topical Cell membrane Azole Sulconazole硫康唑 Derm Topical Cell membrane Azole

4. ANTIFUNGAL DRUGS Drug Infection Type Route/Site Mechanism Chemical Group Clotrimazole Derm/Yeast Topical/Vaginal Cell Membrane Azole Enilconazole恩康唑 Derm Topical Cell Membrane Azole Econazole益康唑 Derm/Yeast Topical/Vaginal Cell membrane Azole Oxiconazole奥昔康唑 Derm/Yeast Topical/Vaginal Cell membrane Azole Tioconazole噻康唑 Derm/Yeast Topical/Vaginal Cell membrane Azole Flucytosine Deep PO for Systemic Nuclear Pyrimidine Griseofulvin Derm PO for Topical Nuclear Other Terbinafine Derm Topical Cell membrane Allylamine

5. Basis for some selectivity: • Bacteria: Prokaryotes, Have cell wall, Key membrane lipid = hydroxylated glycerols • Fungi: Eukaryotes, Have cell wall, Key membrane lipid = ergosterol • Vertebrates: Eukaryotes, NO cell wall, Key membrane lipid = cholesterol

6. Amphotericin B • Structure and chemical characteristics: • (1) Poorly water soluble. • (2) Unstable in saline -- must use 5% dextrose. • (3) Large, charged molecule, polyene derivative. • (4) Nystatin related and similar, but more systemic toxicity

7. Mechanism of Action: • (1) Affinity for membranes with ergosterol. • (2) Forms channel through membrane. • (3) Small molecules leak. • (4) Cell dies. • (5) Resistance is rare and slow to develop.

8. Pharmacokinetics: • Crosses membranes poorly by diffusion and must inject where need, e.g., intrathecal, IV. • Clinical uses:Deep infection of various fungal. • Adverse Effects: Many adverse effects, some serious.

9. Azole Derivatives • Overview:Much less toxic than amphotericin B • Mechanism of Action: • Inhibit ergosterol synthesis: Inhibits key cytochrome P450 step and Lanosterol(羊毛甾醇)alpha-C14-demethylase

10. Ketoconazole Fluconazole Itraconazole Spectrum Narrow Expanded Expanded Route(s) of Adm Oral Oral, IV Oral t1/2 (hr) 6-9 30 30-40 CSF penetration No Yes No Renal excretion No Yes No Interaction with other drugs Frequent Occasional Occasional Inhibition of mammalian sterol synthesis Dose-dependent inhibitory effect No inhibition No inhibition Figure 34.5: Summary of azole fungistatic drugs. P342, Mycek, Harvey & Champe [Pcol-Lipp2nd97]

11. Ketoconazole • Broad spectrum antifungal agent. • Pharmacokinetics: Used PO for systemic effect. Dose-related kinetics, PO doses. Hepatic biotransforming enzymes approach saturation. Half-life after stated oral dose: 6.5 hr -- 100 mg tablet, 8.1 hr -- 200 mg tablet, 9.6 hr -- 300 mg tablet

12. Clinical uses:various fungal infection. • Adverse effects: • (1) Most common -- anorexia, nausea, vomiting. divided doses have been used to reduce GI side effects. • (2) Hepatocellular toxicity. • (3) Adrenocortical suppression

13. Itraconazole • Antifungal activity:5 - 100 times greater in vitro potency and broader antifungal activity than ketoconazole. Good activity againstAspergillus spp. Activity vs meningeal cryptococcus.

14. Clinical uses: • Broad antifungal spectrum. Drug of choice for blastomycosis. May be effective in aspergillosis, candidemia, coccidioidomycosis, and cryptococcosis.

15. Adverse effects: • Fewer adverse side effects than ketoconazole. Nausea and vomiting, Rash (especially in immunocompromised patient), Hypokalemia, Hypertension, Edema, Headache.

16. Fluconazole • In vivo potencies are 100-fold ketoconazole. Similar with itraconazole

17. Antiviral Agents • Amantadine • Mechanism: Inhibit early viral processes. • Pharmacokinetics: PO, Well absorbed, Eliminated unchanged in urine. • Uses: Highly selective, Influenza A viruses (H1 N1, H2, N2, and H3 N2), NOT clinically active versus influenza B viruses. • Adverse Effects: Dose related and appear above 1-5 mcg/mL, CNS toxicity, nervousness, confusion, hallucinations, and coma.

18. Acyclovir • Antiviral activity: Effective against herpes simplex virus (HSV). • Mechanism of action: Relatively large margin of safety. It is a Prodrug -- must be activated. • (1) Activated by herpesvirus thymidine kinase (TK). • (2) Binds to herpes virus thymidine kinase 200 times more strongly than to host TK. • (3) Inhibits viral DNA polymerase.

19. Pharmacokinetics: PO and IV. Widely distributed, including CSF. • Therapeutic application: • (1) Essentially only for herpesviruses (especially H.simplex type 1). • (2) Topical, Mucotaneous herpesvirus infections, May be useful for primary genital herpes, less for recurrent (PO better), Herpes simplex keratitis.

20. Adverse effects: • Few side effects in humans, Nausea with PO, Tissue irritation if extravasation on IV.

21. Ganciclovir: • Conceptually similar to acyclovir. Lower margin of safety than acyclovir. Highly efficacious and important drug. • Mechanism of action: Prodrug, Activated drug incorporated into both host and viral DNA.

22. Adverse effects: • Predict toxicity by rapidly dividing tissues, bone marrow, GI mucosa, and gonads (at all doses tested).

23. Uses: • Potent and broad spectrum vs herpes viruses, especially Cytomegalovirus (CMV ).

24. Ribavarin: • Effective against BOTH DNA and RNA viruses. Prodrug that must be phosphorylated. Phosphorylated derivatives inhibit viral nucleic acid synthesis. Generally low toxicity.

25. Zidovudine: • The first and most important drug for palliation of AIDS, Active against HIV-1 and other mammalian retroviruses.

26. Mechanism of action: • (1) Decreases reverse transcriptase activity in cultured cells at 0.013 mcg/mL • (2) Inhibits replication of HIV-1 virus • (3) Prodrug that must be phosphorylated: Phosphorylated to triphosphate by cellular enzymes, inhibits viral RNA-directed DNA polymerase (transcriptase), Triphosphate binds more strongly to viral than eukaryotic DNA polymerase.

27. (4) DNA chain termination: azidothymidine triphosphate can be incorporated into DNA, hence nucleotides cannot be added to modified 3'-position. • (5) Mammalian DNA polymerases: Alpha-DNA polymerase relatively resistant to incorporating azido-TP, Gamma DNA polymerase in mitochondria does incorporate -- source of toxicity?

28. Resistant strains: Isolated from AIDs patients treated 6 months or more, Still sensitive to dideoxycytidine(双脱氧胞苷) and foscarnet (膦甲酸). • Pharmacokinetics: PO, F=60-65%. Peak concentration 30 to 90 minutes. Wide distribution. Usual dosage is 200 mg q4h!! continuously!!

29. Adverse effects: • (1) Hematologic: Granulocytopenia and anemia in up to 45% of patients. (2) Other effects: occur sometimes, Gastrointestinal disturbances, paresthesia, skin rash, insomnia, fever, headaches, abnormalities of liver function, Myopathy, Confusion, anxiety, depression, and flu-like syndrome

30. Clinical uses: • (1) HIV positive patients before onset of AIDS, Delays progession of disease by 12-18 months. (2) Patients with AIDS – can reduces opportunistic infections, e.g., Pneumocystis carinii pneumonia, stabilizes weight, reduces HIV-associated thrombocytopenia, stabilizes HIV-associated dementia. • (The end)