Antifungal Agents & Antiviral drugs

1. Antifungal Agents & Antiviral drugs Huifang Tang tanghuifang@zju.edu.cn

2. Part1 Antifungal Agents Mycotic infections Categories: Deep mycosis(深部真菌病)： • vaginal candidiasis(阴道念珠菌) • histoplasm caspsulatum (组织胞浆菌) • cryptococcal meningitis(隐球菌性脑膜炎) • coccidioidomycosis(球孢子菌病) Superficial Mycosis（浅部真菌病）: • dermatophyte （皮肤癣菌）infections

3. Categories 1、Antibiotic (抗生素类): Amphotericin B(两性霉素B ); Nystatin（制霉菌素） Griseofulvin(灰黄霉素) 2、Azole (唑类) : Imidazoles （咪唑类）：ketoconazole(酮康唑), Triazoles（三唑类）: Itraconazole(伊曲康唑), 3、Allylamine(丙烯胺类): Terbinafine （特比萘芬） 4、Pyrimidine (嘧啶类) : Flucytosine (氟胞嘧啶) 5、Echinocandins(棘白菌素类) Caspofungin(卡泊芬净)

4. Mechanism of action 壳多糖 4.嘧啶类 葡聚糖合成酶 1.抗生素类 3.丙烯胺类 麦角固醇 2.唑类 羊毛甾醇 角鲨烯环氧化酶 5.棘白菌素类

5. 1、Antibiotic (抗生素类): • Amphotericin B(两性霉素B ); • Nystatin（制霉菌素） • Griseofulvin(灰黄霉素)

6. AmphotercinB Amphotericin B Mechanism of antifungal action

7. AmphotercinB Mechanism of Action • Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. • Ergosterol(麦角固醇),a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol(胆固醇). • Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin Bassociated pores in the cell membrane .

8. AmphotercinB Antifungal Activity • Broadest spectrum. • Candida albicans and Cryptococcus neoformans (白色念珠菌和新型隐球菌); • Endemic mycoses(地方性真菌病 ): Histoplasma capsulatum(组织胞浆菌), Blastomyces dermatitidis(皮炎芽生菌), and Coccidioides immitis（粗球孢子菌）; • Pathogenic molds（致病霉菌）, such as Aspergillus fumigatus（曲霉）and mucor（毛霉）.

9. AmphotercinB 2. Clinical uses • Deep mycosis(深部真菌病) iv • candidiasis(念珠菌病) • Histoplasm caspsulatum (组织胞浆菌) • Cryptococcal meningitis(隐球菌性脑膜炎) • Coccidioidomycosis(球孢子菌病) • aspergillus infections(曲霉菌感染 ).

10. AmphotercinB Pharmacokinetics • Poorly absorbed from the gastrointestinal tract.Oral amphotericin B cannot be used for treatment of systemic disease. • >90% bound by serum proteins • Excreted slowly in the urine over a period of several days. • The serum t1/2 is approximately 15 days. • Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations, and therefore no dose adjustment is required. • The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.

11. AmphotercinB Adverse Effects • INFUSION-RELATED TOXICITY (输液相关性毒性) • Fever, chills, muscle spasms, vomiting, headache, and hypotension. • Prevention : (1)They can be ameliorated by slowing the infusion rate or decreasing the daily dose. (2)Pretreatment with oral acetaminophen(醋氨酚), or use of intravenous hydrocortisone hemisuccinate (氢化可的松半琥酯) at the start of the infusion decreases reaction; (3)Supplemental K+ is required; • CUMULATIVE TOXICITY(蓄积毒性) • Renal damage is the most significant toxic reaction. • Abnormalities of liver function tests are occasionally seen. • After intrathecal therapy (鞘内注射 )with amphotericin, seizures and a chemical arachnoiditis(蛛网膜炎) may develop, often with serious neurologic sequelae. • Hematological toxicity: hypochromic(低血红蛋白性) and normocytic(正常细胞) anemia, etc.

12. Amphotercin B 5.NewformulationsofamphotercinB (1)Liposomal Amphotercin B(L-AMPH B, 两性霉素B脂质体); (2)Amphotercin B lipid complex(ABLC, 两性霉素B脂质复合体); (3)Amphotercin B collcodal dispersion (ABCD, 两性霉素B胶质分散体).

13. Nystatin（制霉菌素） • Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration（肠外给药 ） and is only used topically. • Formulation: creams, ointments, suppositories • Pharmacokinetics: • Poorly absorbed from the gastrointestinal tract. • It is not absorbed to a significant degree from skin, mucous membranes. • Spectrum: most Candida sp(念珠菌属). • Cinical indications: • oropharyngeal thrush（鹅口疮） • vaginal candidiasis • intertriginous candidal infections.

14. Griseofulvin(灰黄霉素) (1) Mechanism of action :Mitotic inhibitors Binds to microtubules and prevents mitosis in fungi. • It is deposited in newly forming skin where it binds to keratin（角质 ）, protecting the skin from new infection. Because its action is to prevent infection of these new skin structures, • Administered for 2–6 weeks for skin and hair infections • Nail infections may require therapy for months . • It is a cytochrome p450 enzyme inducer (2) Clinical uses: Oral long-term therapy for dermatophyte, hair and nail infections （3）Adverse effects • An allergic syndrome much like serum sickness(血清病 ), hepatitis, • Drug interactions with warfarin and phenobarbital.

15. Azoles 2、Azoles（唑类） • Imidazoles （咪唑类）: • ketoconazole(酮康唑), • Miconazole(咪康唑), • clotrimazole (克霉唑) • Triazoles（三唑类）: • Itraconazole(伊曲康唑), • Fluconazole(氟康唑), • Voriconazole(伏立康唑), • Posaconazole(泊沙康唑).

16. Azoles Mechanism of Action • Inhibition of Lanosterol 14alpha-demethylase ( 羊毛甾醇14 -脱甲基酶)--> Inhibition of fungal cytochrome P450 enzymes--> Reduction of ergosterol synthesis . • The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. • Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and side effects. • Resistance to azoles occurs via multiple mechanisms. • The spectrum of action of azole is broad

17. Mechanism of action 壳多糖 4.嘧啶类 葡聚糖合成酶 1.抗生素类 3.丙烯胺类 麦角固醇 2.唑类 羊毛甾醇 角鲨烯环氧化酶 5.棘白菌素类

18. Azoles Clinical Use • Many candida species(念珠菌 ), C neoformans(新型隐球菌), the endemic mycoses (地方性真菌病 ), blastomycosis(芽生菌 ), coccidioidomycosis(球孢子菌病 ), histoplasmosis(组织胞浆菌病 ), the dermatophytes(皮肤癣菌 ), and, in the case of itraconazole and voriconazole, even aspergillus infections(曲霉菌感染 ). • They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii(波氏假霉样真菌).

19. Azoles Adverse Effects • The most common adverse reaction is relatively minor gastrointestinal upset. • All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. • All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent, and consequently they are prone to drug interactions.

20. Azoles Ketoconazole(酮康唑) • Ketoconazole was the first oral azole introduced into clinical use. • Less selective for fungal P450 than newer azoles. • Greater propensity to inhibit mammalian cytochrome P450 enzymes, block both testicular and adrenal androgen biosynthesis, and compete with androgens such as testosterone and DHT for androgen receptor binding. Clinical Uses: 1. Cutaneous candidiasis(皮肤念珠菌病): vaginal 2. Dermatophytosis(皮肤癣菌病 ) 3. Histoplasmosis(组织胞浆菌病)

21. Azoles Itraconazole(伊曲康唑) • Oral and intravenous formulations. Drug absorption is increased by food and by low gastric pH. • Penetrates poorly into the cerebrospinal fluid. Clinical uses • Dermatophytoses(皮肤癣菌)and onychomycosis(甲癣). • Dimorphic fungi histoplasma(组织胞浆菌), Blastomyces(芽生菌 ), and sporothrix(孢子丝菌). • Aspergillosis(曲霉菌病): but it has been replaced by voriconazole

22. Azoles Fluconazole(氟康唑) • Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration, its oral bioavailability is high. • The drug is available in oral and intravenous formulations. • Drug interactions are also less common because fluconazole has the least effect of all the azoles on hepatic microsomal enzymes. Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections. • Fluconazole displays no activity against aspergillus(曲霉菌 ) or other filamentous fungi(丝状真菌). • Clinical use • cryptococcal meningitis(隐球菌性脑膜炎). • Mucocutaneous candidiasis(皮肤粘膜念珠菌病). • Coccidioidal disease(球孢子菌病)

23. Azoles Voriconazole(伏立康唑) • Voriconazole is available in intravenous and oral formulations. The drug is well absorbed orally, with a bioavailability exceeding 90%, and it exhibits less protein binding than itraconazole. • Metabolism is predominantly hepatic. Voriconazole is a clinically relevant inhibitor of mammalian CYP3A4. Adverse Effects • Observed toxicities include rash and elevated hepatic enzymes. • Visual disturbances are common, occurring in up to 30% of patients receiving intravenous voriconazole, and include blurring and changes in color vision or brightness. These visual changes usually occur immediately after a dose of voriconazole and resolve within 30 minutes. • Photosensitivity dermatitis is commonly observed in patients receiving chronic oral therapy. spectrum of action Excellent activity against Candida sp（假丝菌）(including fluconazole-resistant species such as C krusei) and the dimorphic fungi（双相真菌）。

24. Azoles Posaconazole(泊沙康唑 ) • Posaconazole is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation. • Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. • Posaconazole is the broadest spectrum member of the azole family, with activity against most species of candida (念珠菌)and aspergillus(曲霉菌). • It is the only azole with significant activity against the agents of zygomycosis and mucormycosis(毛霉菌病). Clinical use • Prophylaxis of invasive aspergillosis(侵袭性曲霉病), • Prophylaxis of fungal infections during induction chemotherapy for leukemia, allogeneic bone marrow transplant patients with graft-versus-host disease(异基因骨髓移植患者的移植物抗宿主病).

25. Azoles Pharmacokinetics

26. - = no inhibition.

27. 3、Allylamine（丙烯胺类）(squalene monooxygenase inhibitors角鲨烯环氧化酶抑制剂) Terbinafine （特比萘芬） • Terbinafine is a synthetic allylamine that is available in an oral formulation. • It is used in the treatment of dermatophytoses, especially onychomycosis (灰指甲). it is fungicidal. • It interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase (角鲨烯环氧化酶). This leads to the accumulation of the sterol squalene（甾醇角鲨烯）, which is toxic to the organism. Adverse effects ： rare • Primarily of gastrointestinal upset and headache. • Terbinafine does not seem to affect the P450 system and has demonstrated no significant drug interactions to date.

28. Mechanism of action 壳多糖 4.嘧啶类 葡聚糖合成酶 1.抗生素类 3.丙烯胺类 麦角固醇 2.唑类 羊毛甾醇 角鲨烯环氧化酶 5.棘白菌素类

29. Flucytosine 4、Flucytosine (氟胞嘧啶)Pyrimidine analogues/Thymidylate synthase inhibitors Mechanism of Action Flucytosine is taken up by fungal cells via the enzyme--cytosine permease(胞嘧啶渗透酶). It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

30. Flucytosine Mechanism of antifungal action: 胸腺嘧啶核苷合成酶

31. Flucytosine Clinical uses: Flucytosineis anarrow-spectrumanti-fungal drug. Drug resistance occurs rapidly whenflucytosineis used alone. So,flucytosineisused predominantlyin combination with amphotericin Bfor thearpy of crypotococcal meningitis in AIDS patient, etc. Adverse reactions: Depressing the function of bone marrow(leading to leukopenia and thrombocytopenia, etc.). Plasma levels of hepatic transminase are elevated(reversible). Other reaction: including rash, nausea, vomiting, diarrhea, etc.

32. Echinocandins 5、Echinocandins（棘白菌素类）（β-glucan synthase inhibitors β葡聚糖合成酶抑制剂） • Caspofungin(卡泊芬净) • Micafungin(米卡芬净) • Anidulafungin（阿尼芬净） • Echinocandins are available only in intravenous formulations. • Mechanism of Action • Act at the level of the fungal cell wall by inhibiting the synthesis of (1–3)-glucan（葡聚糖）.

33. Echinocandins • Spectrum of action • Active effect against candida （念珠菌）and aspergillus（曲霉菌）, but not C neoformans (隐球菌) or the agents of zygomycosis and mucormycosis(毛霉菌病). • Adverse Effects • Echinocandin agents are extremely well tolerated, with minor gastrointestinal side effects and flushing reported infrequently.

34. Echinocandins Pharmacokinetics • Caspofungin（卡泊芬净） is water-soluble and highly protein-bound. The half-life is 9–11 hours, and the metabolites are excreted by the kidneys and gastrointestinal tract. Dosage adjustments are required only in the presence of severe hepatic insufficiency. • Micafungin （米卡芬净）displays similar properties with a half-life of 11–15 hours for treatment of candida esophagitis（念珠菌食管炎）, candidemia, and prophylaxis of fungal infections. • Anidulafungin （阿尼芬净）has a half-life of 24–48 hours. For esophageal candidiasis, it is administered intravenously at 100 mg on the first day and 50 mg/d thereafter for 14 days. For candidemia, a loading dose of 200 mg is recommended with 100 mg/d thereafter for at least 14 days after the last positive blood culture.

35. Echinocandins Clinical Use • Caspofungin is currently licensed for disseminated and mucocutaneous candida infections（侵袭性和皮肤粘膜念珠菌病） • Note：caspofungin is licensed for use in invasive aspergillosis（侵袭性曲霉病） only as salvage therapy（抢救治疗）in patients who have failed to respond to amphotericin B, and not as primary therapy. • Micafungin is licensed for mucocutaneous candidiasis, candidemia, and prophylaxis of candida infections in bone marrow transplant patients. • Anidulafungin is approved for use in esophageal candidiasis and invasive candidiasis, including candidemia.

37. Part 2 Antiviral drugs • Anti-influenza virus agent • Antiherpes agents • Anti-HIV agents • Entry inhibitors(入胞抑制药) • Reverse transcriptase inhibitor(逆转录酶抑制剂) • Nonnucleoside reverse transcriptase inhibitor(非核苷逆转录酶抑制剂 , NNRTI); • Nucleoside reverse transcriptase inhibitor(核苷逆转录酶抑制剂 , NRTI); • Protease inhibitor(蛋白酶抑制剂,PI) • Integrase Inhibitors （整合酶抑制药）

38. Antiviral drugs Antiviral therapy 流感病毒 疱疹病毒 • Influenza—RNA virus • herpesviruses (HSV)—DNA virus • human immunodeficiency virus (HIV)- RNA Reverse transcript virus 艾滋病毒 肝炎病毒

39. Mechanism of Antiviral drug action 病毒侵入 病毒吸附 病毒脱壳 合成病毒 核酸\蛋白质 病毒颗粒 装配成熟 释放

40. Antiviral drugs1 1 Anti-influenza virus agents • M2蛋白抑制剂--influenza A • Amantadine(金刚烷胺) • Neuraminidase(神经氨酸酶,NA) inhibitors --influenza A &B • Oseltamivir(奥司他韦)； • zanamivir（扎那米韦） • 广谱抗病毒药--DNA &RNA viurs • Ribavirin(利巴韦林, virazole病毒唑）

41. Antiviral drugs1 Amantadine(金刚烷胺) • The mechanism of Amantadine's antiviral activity involves interference with a viral protein, M2 (an ion channel), which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosis. • The mechanism of its antiparkinsonian effect is poorly understood. The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist as well as an anticholinergic. • Clinical use (1) For 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes, Amantadine is no longer recommended for treatment of influenza A infection. (2) Parkinson's disease

42. Antiviral drugs1 Side effects: (1)CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease. (2)Rare cases of severe skin rashes such as Stevens Johnson Syndrome(皮肤黏膜眼综合征) and suicidal ideation. (3) Livedo reticularis (网状青斑) is a possible side effect of amantadine use for Parkinson's disease.

43. Antiviral drugs1 Rimantadine(金刚乙胺) • Rimantadine is four to ten times more active than amantadine in vitro. • Amantadine is well absorbed and 67% protein-bound. Its plasma half-life is 12–18 hours and varies by creatinine clearance. • Rimantidine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal secretion and salivary levels approximate those in the serum, and cerebrospinal fluid levels are 52–96% of those in the serum; nasal mucus concentrations of rimantidine average 50% higher than those in plasma. • Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion.

44. Neuraminidase(神经氨酸酶,NA) inhibitors • Oseltamivir(奥司他韦)； • Zanamivir（扎那米韦） • Both influenza A and influenza B viruses. • analogs of sialic acid • Mechanism: • Interfere with release of progeny influenza virus from infected to new host cells, thus halting the spread of infection within the respiratory tract. • Destroy the receptors recognized by viral hemagglutinin(血凝素) on cells, newly released virions, and respiratory tract mucins. • Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness.

45. Oseltamivir(奥司他韦) • Oseltamivir is FDA-approved for patients 1 year and older, • Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body. • Oral bioavailability is approximately 80%, plasma protein binding is low, and concentrations in the middle ear and sinus fluid are similar to those in plasma. • The half-life of oseltamivir is 6–10 hours, • Excretion is by glomerular filtration and tubular secretion in the urine. • Potential adverse effects include nausea, vomiting, and abdominal pain, which occur in 5–10% of patients early in therapy but tend to resolve spontaneously.

46. Zanamivir（扎那米韦） • Zanamivir is delivered directly to the respiratory tract via inhalation. 10%-20% of the active compound reaches the lungs, and the remainder is deposited in the oropharynx. • The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half-life is 2.8 hours. • 5%-15% of the total dose (10 mg twice daily for 5 days for treatment and 10 mg once daily for prevention) is absorbed and excreted in the urine with minimal metabolism. • Potential adverse effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort. • zanamivir is approved in patients 7 years or older.

47. Antiviral drugs1 Ribavirin（利巴韦林） Mechanism of action • Ribavirin is a guanosine analog (鸟苷类似物) that is phosphorylated intracellularly by host cell enzymes. • interfere with the synthesis of guanosine triphosphate, • inhibit capping of viral messenger RNA, • inhibit the viral RNA-dependent polymerase of certain viruses. Action: It is effective against a broad spectrum of RNA and DNA viruses. • Influenza A and B, • parainfluenza(副流感病毒) • respiratory syncytial virus(呼吸道合胞体病毒) • paramyxoviruses(副粘病毒) • HCV • HIV-1.

48. In addition to oral administration for hepatitis C infection in combination with interferon alfa, • Aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12–18 hours per day) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia to reduce the severity and duration of illness. • Aerosolized ribavirin has also been used to treat influenza A and B infections but has not gained widespread use. • Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation.

49. 2、Antiherpes agents • Herpessimplexvirus（疱疹病毒，HSV） • Varicella-zoster virus (水痘/带状疱疹病毒，VZV) • Cytomegalovirus(巨细胞病毒CMV) • Epstein-Barrvirus(EB病毒，EBV） • idoxuridine(碘苷) -- HSV, VZV • Vidarabine(阿糖腺苷)—HSV,VZV,HBV,CMV • acyclovir（阿昔洛韦）; Valacyclovir(伐阿昔洛韦)--HSV、VZV • ganciclovir(更昔洛韦) ; valacyclovir(伐昔洛韦)--HSV、VZV、CMV • foscarnet (磷甲酸盐）--HSV, influenza ,CMV, HIV • cidofovir (西多福韦)—HSV,VZV,CMV • Trifluridine(屈氟尿苷)--HSV-1和HSV-2,CMV

50. Antiviral drugs2 Idoxuridine(碘苷) Its main use is in treatment of herpes simplex and varicelly-zoster infections in eye. Being too toxic for systemic use, it is only used topically.