1 / 30

Chapter 43 Antifungal and Antiviral Agents

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

les
Download Presentation

Chapter 43 Antifungal and Antiviral Agents

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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)

More Related