Antiviral agents & Antifungal agents

1. Chapter 44 Antiviral agents & Antifungal agents Yun-Bi Lu, PhD卢韵碧Dept. of Pharmacology, School of Medicine, Zhejiang Universityyunbi@zju.edu.cn 2013.12.30

2. Antiviral agents

3. Essential Characteristics of Viruses • Genome (RNA or DNA) packaged in a protein core • Intracellular parasitism • No ribosomes or mitochondria • Utilize cellular machinery for synthesis of macromolecules • Antiviral therapies target • Entry into cells • Virus utilization of cellular machinery • Or stimulate immune clearance

4. Specific Antiviral Therapy for • Respiratory Viruses • Influenza, Respiratory Syncytial Virus (呼吸道合胞病毒) • Herpesviruses (疱疹病毒) • HSV 1 & 2, VZV (水痘-带状疱疹病毒), CMV, EBV • Chronic Hepatitis • Hepatitis B and C (肝炎病毒) • Papillomaviruses (乳头瘤病毒) • Retroviruses • HIV-1, HIV-2, HTLV-1(人类嗜T细胞病毒)

5. Attachment Virus particle Penetration Uncoating Target cell Protein and nucleic acid synthesis Assembly Release General schema of virus replication

6. Specific Antiviral Therapy for • Respiratory Viruses • Influenza, Respiratory Syncytial Virus (呼吸道合胞病毒) • Herpesviruses (疱疹病毒) • HSV 1 & 2, VZV (水痘-带状疱疹病毒), CMV, EBV • Chronic Hepatitis • Hepatitis B and C (肝炎病毒) • Papillomaviruses (乳头瘤病毒) • Retroviruses • HIV-1, HIV-2, HTLV-1(人类嗜T细胞病毒)

7. Antiretroviral therapyfor HIV Infection:principles • In the absence of treatment, HIV replication is a continuous process • Plasma HIV RNA concentrations are prognostic and represent auseful marker of clinical efficacy of a treatment regimen • Multidrug therapy is essential for maximal suppression • Stabilization and improvement of immune function is possible • Is HIV Infection Curable?Today: No

8. General Schema of HIV replication

9. General Schema of HIV replication

10. Fusion Inhibitors (膜融合抑制剂) – Enfuvirtide (恩夫韦肽) • Enfuvirtide (formerly called T-20), a synthetic 36-amino-acid peptide, binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes. • ADME: administered by subcutaneous injection. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours. • Resistance to enfuvirtide can occur. However, enfuvirtide lacks cross-resistance to the other currently approved antiretroviral drug classes. • Adverse effects: local injection site reactions (the most common) Hypersensitivity reactions (rarely) Eosinophilia (嗜酸粒细胞增多症)

11. Nucleoside AnalogueReverse transcriptase inhibitors (核苷反转录酶抑制剂，NRTI) • Mechanism of Action • Chain Termination of DNA by triphosphorylated forms • Toxicities: Numerous • Zidovudine (AZT)齐多夫定 • Anemia（贫血） • Neutropenia（中性粒细胞减少） Thrombocytopenia（血小板减少） • Asthenia (无力) • Headache（头痛） • GI upset（胃肠道反应） • Stavudine (D4T)司他夫定 • Peripheral neuropathy（外周神经炎） • Lipodystrophy （脂肪代谢障碍） • Pancreatitis （胰腺炎） • Lactic acidosis （乳酸性酸中毒） withhepatic steatosis (肝脂肪变） • Hyperlipidemia （高脂血症） Abacavir Azidothymidine (AZT) = Zidovudine (ZDV)

12. 嘧啶衍生物 嘌呤衍生物 非核苷反转录酶抑制剂 阿巴卡韦 依法韦恩茨 地拉韦定 奈韦拉平 拉米夫定 去羟肌苷 司他夫定 扎西他宾 齐多夫定

13. Non-Nucleoside Reverse transcriptase inhibitors(非核苷反转录酶抑制剂NNRTI) • Mechanism of action • Bind in a pocket approximately 10 Å away from the catalytic site where nucleotides bind. • Non-competitive inhibitors of template and substrate binding. • Adverse effects • Stevens-Johnson Syndrome • Rash and hypersensitivity reactions (NVP>EFV) • Liver dysfunction (NVP>EFV) Nevirapine 奈韦拉平 Efavirenz 依法韦恩茨 Delavridine 地拉韦定

14. HIV Protease Inhibitors Polypeptide chain Nelfinavir 奈非那韦 Adverse effects: Nelfinavir - diarrhea Ritonavir - GI intolerance, hepatitis Indinavir - nephrolithiasis, GI intolerance Ritonavir 利多那韦 Saquinavir 沙奎那韦 Indinavir 英地那韦

15. HIV Integrase Inhibitors (HIV 整合酶抑制剂) • Raltegravir (雷特格韦), is marketed on Oct. 2007. • HIV Integrase inhibitor, EC95 0.32nmol/L (in vitro) • ADME: administered p.o., t1/2 7-12 hours. • To avoid resistance, drug combination is suggested. • Clinical uses: against multi-resistant viruses in adult HIV patient. • Adverse effects: GI effects Liver dysfunction Rash…

16. NRTI(核苷反转录酶抑制剂) Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Tenofovir TDF NNRTI (非核苷反转录酶抑制剂) Delavirdine DLV Efavirenz EFV Nevirapine NVP Current Antiretroviral Medications PI(蛋白酶抑制剂) • Amprenavir APV • Atazanavir ATV • Darunavir DRV • Fosamprenavir FPV • Indinavir IDV • Lopinavir LPV • Nelfinavir NFV • Ritonavir RTV • Saquinavir SQV • hard gel HGC • tablet INV • Tipranavir TPV Fusion Inhibitor • Enfuvirtide T-20 • INTI (Integrase inhibitor) • HIV整合酶抑制剂raltegravir

17. Initial Treatment: Preferred Components *Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa. NNRTI Option NRTI Options • Tenofovir + emtricitabine** • Zidovudine + lamivudine** OR + PI Options

18. Ribavirin (利巴韦林) • Synthetic guanosine analog • Once phosphorylated, interferes with transcription of viral mRNA and synthesis of viral ribonucleoprotein complexes • Available as aerosol for treatment of respiratory syncitial virus (RSV), oral tablet for Hepatitis A • Toxicity • Bronchospasm (when used in inhaled formulation) • Anemia • Teratogenicity (致畸)

19. Acyclovir (阿昔洛韦) • Used in high dose IV formulation in HSV neonatal infection, CNS infection in adults • Used in lower dose for HSV or VZVmucocutaneous disease treatment and prophylaxis • Frequent oral dosing necessary • Toxicities more likely with high dose • Nausea, headache, crystal formation in renal tubules

20. Mechanism of Action of Acyclovir in Cells Infected by Herpes Simplex Virus Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255

21. Structure of acyclovir and related nucleoside analogues 阿昔洛韦 更昔洛韦 贲昔洛韦 利巴韦林 For comparison only; not related to acyclovir Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255

22. Ganciclovir (更昔洛韦) • Approved for treatment, prevention of CMV disease • Toxicities mostly related to bone marrow suppression • Anemia, neutropenia, thrombocytopenia • CNS effects

23. Foscarnet (磷甲酸盐) • Organic analogue of pyrophosphosphate焦磷酸盐衍生物 • (Trisodium phosphonoformate，磷酸三钠甲酸盐) • Interferes with viral DNA synthesis: Blocks cleavage of • pyrophosphates • Use for treatment of CMV disease, Active against acyclovir-resistant HSV and ganciclovir-resistant CMV • Toxicity • Renal toxicity (dose-dependent) • Electrolyte abnormalities • (drug chelates divalent cations): e.g. hypocalcemia

24. Vidarabine (阿糖腺苷，Ara-A) • Nucleotide analogues (purine nucleoside) • HSV neonatal infection, CNS infection in adults and VZV infection in AIDS • Acyclovir (阿昔洛韦) has replaced Ara-A in treatment of HSV and VZV infection.

25. Idoxuridine (碘苷，IDUR) • Nucleotide analogues (thymidine) • Topical use for Ophthalmological infections caused by Herpes Simplex viruses (HSV, 单纯疱疹病毒) or Varicella Zoster Virus (VZV，水痘病毒) • Severe toxic effects caused by systemic use

26. Amantadine (金刚烷胺) • Inhibitors of Viral Uncoating (Adamantane derivatives) • Active against Influenza A only • Prophylaxis and Treatment of Influenza A • CNS excitation (Dizziness, insomnia(失眠), anxiety); mild GI side effects

28. TREATMENT OF HEPATITIS B VIRUS INFECTION

29. TREATMENT OF HEPATITIS C VIRUS INFECTION

30. Amantidine (A) (金刚烷胺) Rimantidine (A) (金刚乙胺) Sites of Antiviral Drug Action Docosonal (H) Chemokine receptor blocking agents-(HIV) Attachment Penetration Nucleoside analogues (H, HBV, HIV) Nucleotide analogues (CMV, HBV, HIV) Non-nucleoside Reverse transcriptase inhibitors (HIV) Antisense oligonucleotides (CMV) Uncoating Protein, nucleic acid synthesis Assembly HIV Protease inhibitors Release A Influenza A E Enteroviruses I Influenza A or B H Herpes viruses CMV Cytomegalovirus HBV Hepatitis B virus HIV HIV Oseltamivir (I) (奥司他韦) Zanamivir (I) (扎那米韦)

32. Antifungal agents

33. Antifungal agents Onychomycosis (甲癣)

34. Antifungal agents Fungal infections traditionally have been divided to two distinct classes: systemic(系统性/深部) and superficial(体表/表浅部). So, the major antifungal agents are described with “systemic” and “topical”. Onychomycosis （甲癣）

35. Oral infection with Candida (Thrush鹅口疮) http://vasculitis.med.jhu.edu/treatments/cytoxan.html www.thachers.org/ internal_medicine.htm

36. Invasive fungal disease • Ubiquitous pathogens act as opportunists(机会菌感染) • Candida species (念珠菌属) • Aspergillus species (曲霉菌属) • Cryptococcus (隐球菌属) • Endemic mycoses(地方性的霉菌病) • Histoplasmosis(组织胞浆菌病) • Coccidioidomycosis(球孢子菌病) • Blastomycosis(芽生菌病)

37. Invasive Aspergillosis(侵袭性曲霉菌病) AA= aortic arch, a = aneurysm SC = subclavian artery Silva ME, Malogolowkin MH, Hall TR, Sadeghi AM, Krogstad P.Mycotic aneurysm of the thoracic aorta due to Aspergillus terreus: case report and review. Clin Infect Dis. 2000 Nov;31(5):1144-8.

38. Classification of antifungal agents • Antibiotics 抗生素类 Amphotercin B（两性霉素B） • Azoles 唑类 Ketoconazole（酮康唑） Fluconazol（氟康唑） • Allylamine 丙烯胺类 Terbinafine（特比萘芬） • Pyrimidine analogues嘧啶类 Flucytosine（氟胞嘧啶） • Echinocandins 棘白菌素类 Caspofungin（卡泊芬净）

39. 嘧啶类 唑类 多烯类 Allylamine 丙烯胺类 Echinocandins 棘白菌素类 Inhibition of cell wall biosynthesis Antifungal Medications

40. Antibiotics Polyenes: Amphotercin B（两性霉素B） broad-spectrum

41. Amphotercin B 1. Mechanism of action

42. Amphotercin B 2. Clinical Uses: • Amphotericin B remains the drug of choice for all life-threatening mycotic infections (It is often as the initial regimen). (首选药物之一) e.g. Cryptococcal meningitis (隐球菌性脑膜炎) Candidiasis(念珠菌病) Histoplasmosis (组织胞浆菌病) Coccidioidomycosis (球孢子菌病) Invasiveaspergillosis (侵袭性曲霉菌病)

43. Amphotercin B 3. Adverse reactions: (1) fever, chill, hyperpnea（喘息）, myalgia（肌痛）and hypotension, etc.（~75%） (2) nephrotoxic (3) renal tubular acidosis（肾小管酸化） and renal wasting K+ and Mg 2+ (4) hematological Toxicity: hypochromic （低血红蛋白性）and normocytic（正常色素性） anemia, etc.

44. Amphotercin B 3. Adverse reactions: (5) hepatotoxicity (6) cardiac toxicity (7) CNS side effects (8) hypersensitive reaction

45. Amphotercin B 4. Prevention of adverse reaction: (1) Pretreatment with oral acetaminophen or use of intravenous hydrocortisone hemisuccinate. (2) Supplemental K+ is required. (3) Do physical examination termly. (4) drug interactions

46. (脂质复合体) (胶质分散体) (脂质体) Amphotercin B 5. New formulations of Amphotercin B :

47. Topical antifungal agents Antibiotics: nystatin（制霉菌素） griseofulvin（灰黄霉素） Allylamines: terbinafine（特比萘芬） - squalene epoxidase inhibitor (角鲨烯环氧化酶抑制剂)

48. Azoles antifungal agents Imidazoles (咪唑类) • ketoconazle （酮康唑） • miconazole（咪康唑） • clotrimazole（克霉唑） Triazoles(三唑类) • fluconazole （氟康唑） • itraconazole（伊曲康唑）

49. Azoles antifungal agents Mechanism of action: • reduce ergosterol (麦角固醇) synthesis by interfering with lanosterol (14a) –demethylase (羊毛固醇14a-去甲基酶) • inhibition of fungal cytochrome P450 enzyme Antifungal activity: • Systemically (ketoconazle, fluconazole, itraconazole) or topically (miconazole, clotrimazole).

50. Azoles antifungal agents Ketoconazle （酮康唑） : • the first oral azoles introduced into clinical use (systemically or topically). • less selective for fungal P450 • clinical use has been limited by endocrine side effects, liver toxicity and the drug interactions. • itraconazole （伊曲康唑）or fluconazole （氟康唑） has replaced ketoconazle for patients who can afford the more expensive, newer product.