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

4. Mechanism of action

5. Amphotericin B Amphotericin B 1. Mechanism of action It bind to ergosterol and alter membrane to allow leakage of cellular contents cause damage of cells.

6. Amphotericin B 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, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol. • Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin Bassociated pores in the cell membrane .

7. Amphotericin B 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 ）.

8. Amphotericin B 2. Clinical uses fungal infections: • 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 infections

9. Amphotericin B Pharmacokinetics • Amphotericin B is poorly absorbed from the gastrointestinal tract. • Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease. • the drug is more than 90% bound by serum proteins • amphotericin B is 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.

10. Amphotericin B Adverse Effects • The toxicity of amphotericin B can be divided into two broad categories: • INFUSION-RELATED TOXICITY • Fever, chills, muscle spasms, vomiting, headache, and hypotension. • They can be ameliorated by slowing the infusion rate or decreasing the daily dose. • Premedication with antipyretics, antihistamines, meperidine, • corticosteroids can be helpful. • CUMULATIVE TOXICITY • 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.

11. Amphotericin B Liposomal amphotericin B • liposomal amphotericin B (AmBisome ,脂质体） • amphotericin B colloidal dispersion(ABCD,胶样分散体) • amphotericin B lipid complex（ABLC,脂质复合物）

12. 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. • Nystatin is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. • It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, nystatin has little toxicity, although oral use is often limited by the unpleasant taste. • Nystatin is active against most Candida sp and is most commonly used for suppression of local candidal infections. • Some common indications include oropharyngeal thrush（鹅口疮）, vaginal candidiasis, and intertriginous candidal infections.

13. Griseofulvin(灰黄霉素) (1) Mechanism of action :cellular level • 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, griseofulvin must be administered for 2–6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. • Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse. (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.

14. Azoles 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).

15. Azoles Mechanism of Action • The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. • 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.

16. Azoles Pharmacokinetics

17. Azoles Clinical Use • The spectrum of action of azole medications is broad, including 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.

18. Azoles Adverse Effects • the azoles are relatively nontoxic. 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.

19. Azoles Ketoconazole(酮康唑) • Ketoconazole was the first oral azole introduced into clinical use. • greater propensity to inhibit mammalian cytochrome P450 enzymes • less selective for fungal P450 than newer azoles. 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)

20. Azoles Itraconazole(伊曲康唑) • Itraconazole is available in oral and intravenous formulations. Drug absorption is increased by food and by low gastric pH. Like other lipid-soluble azoles, it interacts with hepatic microsomal enzymes, though to a lesser degree than ketoconazole. • Like ketoconazole, it penetrates poorly into the cerebrospinal fluid. Itraconazole is the azole of choice for treatment of disease due to the dimorphic fungi histoplasma(组织胞浆菌), Blastomyces(芽生菌 ), and sporothrix(孢子丝菌). • Itraconazole has activity against Aspergillus sp, but it has been replaced by voriconazole as the azole of choice for aspergillosis(曲霉菌病). • Itraconazole is used extensively in the treatment of dermatophytoses(皮肤癣菌)and onychomycosis(甲癣).

21. 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)

22. 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）。

23. 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). • It is the only azole with significant activity against the agents of zygomycosis and mucormycosis(毛霉菌病). Clinical use • Salvage therapy in 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).

24. Echinocandins Echinocandins（棘白菌素类） • Echinocandins are the newest class of antifungal agents to be developed. They are large cyclic peptides linked to a long-chain fatty acid. • Caspofungin(卡泊芬净) , micafungin(米卡芬净), and anidulafungin （阿尼芬净）are the only licensed agents in this category of antifungals, although other drugs are under active investigation. • Echinocandins are available only in intravenous formulations. • These agents are active against candida and aspergillus, but not C neoformans or the agents of zygomycosis and mucormycosis. Mechanism of Action • Echinocandins act at the level of the fungal cell wall by inhibiting the synthesis of (1–3)-glucan.

25. 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, 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.

26. Echinocandins Adverse Effects • Echinocandin agents are extremely well tolerated, with minor gastrointestinal sideeffects and flushing reported infrequently. • Elevated liver enzymes have been noted in several patients receiving caspofungin in combination with cyclosporine, and this combination should be avoided. • Micafungin has been shown to increase levels of nifedipine, cyclosporine, and sirolimus. Anidulafungin does not seem to have significant drug interactions, but histamine release may occur during intravenous infusion.

27. 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 that caspofungin is licensed for use in invasive aspergillosis（侵袭性曲霉病） only as salvage therapy 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.

28. Flucytosine (氟胞嘧啶) Mechanism of Action Flucytosine is taken up by fungal cells via the enzyme cytosine permease. 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. Human cells are unable to convert the parent drug to its active metabolites, resulting in selective toxicity. Clinical uses: Rarely used as a single drug but often used in combination with other antifungal agents

29. Allylamine（丙胺类） Terbinafine（特比萘芬） • Terbinafine is a synthetic allylamine that is available in an oral formulation. I • t 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.

31. Part2 Antiviral drugs 合成病毒 核酸\蛋白质 病毒吸附侵入(attachment & penetration) 病毒脱壳(uncoating) 病毒颗粒 装配成熟(assembly) 从细胞内 释放(release) 合成 核酸多聚酶

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

33. Antiviral drugs • Anti-influenza virus agents • Amantadine(金刚烷胺)--influenza A • Target: viral protein, M2 • Oseltamivir(奥赛他米韦)；zanamivir（扎那米韦）--influenza A &B • Target: neuraminidase(神经氨酸酶) inhibitors • Antiherpes agents • idoxuridine(碘苷) -- HSV, VZV • Vidarabine(阿糖腺苷)—HSV,VZV,HBV,CMV • acyclovir（阿昔洛韦）; ganciclovir(更昔洛韦) ; valacyclovir(伐昔洛韦) • foscarnet (磷甲酸盐）--HSV, influenza ,CMV, HIV • cidofovir (西多福韦)—HSV,VZV,CMV

34. 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）

35. 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

36. 1 Anti-influenza virus agents • 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) Preventing influenza A infections during influenza season (2) Parkinson's disease (3) Off-label uses 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 Syndromeand suicidal ideation. (3) Livedo reticularis (网状青斑) is a possible side effect of amantadine use for Parkinson's disease.

37. 2. Antiherpes agents 胸苷激酶 • 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) • 碘苷(idoxuridine) • 阿昔洛韦（acyclovir） • 更昔洛韦(ganciclovir) • 伐昔洛韦(valacyclovir) • 磷甲酸盐（foscarnet） • 西多福韦 (cidofovir) • 屈氟尿苷(trifluridine)

38. 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.

39. Antiviral drugs2 Valganciclovir Acyclovir(阿昔洛韦,无环鸟苷) 1. Mechanism of action It inhibits viral DNA-polymerase, terminating the DNA- chain. • clinical activity --HSV-1, HSV-2, and VZV, but it is approximately 10 times more potent against HSV-1 and HSV-2 than against VZV. • In vitro activity -- Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) is present but weaker. 2. Clinical use: The bioavailability of oral acyclovir is low (15–20%) and is unaffected by food. An intravenous formulation is available. It is used to treat herps simplex viruses, varicella-zoster viruses. First choice --Herpes simplex viruses infection.

40. Antiviral drugs2 Valganciclovir Ganciclovir(更昔洛韦) • Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells. • The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation. • Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8. • Its activity against CMV is up to 100 times greater than that of acyclovir.

41. Antiviral drugs2 Valganciclovir Valganciclovir(伐昔洛韦) • Valganciclovir is an L-valyl ester prodrug of ganciclovir that exists as a mixture of two diastereomers. • After oral administration, both diastereomers are rapidly hydrolyzed to ganciclovir by intestinal and hepatic esterases. • Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir; • The absolute bioavailability of oral valganciclovir is 60%. The AUC0–24h resulting from valganciclovir (900 mg once daily) is similar to that after 5 mg/kg once daily of intravenous ganciclovir and approximately 1.65 times that of oral ganciclovir. • The major route of elimination is renal, through glomerular filtration and active tubular secretion. Clinical use • Cytomegalovirus(CMV) retinitis in patients with AIDS • prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas transplant patients.

42. Ribavirin Ribavirin（利巴韦林） (1) Action:It is effective against a broad spectrum of RNA and DNA viruses. (2) Uses:It is used in treating infants and young children infected with severe respiratory syncytial virus (呼吸道合胞病毒RSV)infections, actue hepatitis A virus, and influenza A and B infections.

43. Foscarnet Foscarnet(磷甲酸盐) • It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6(人类疱疹病毒), HHV-8, and HIV-1. • inhibits viral DNA polymerase, • inhibits RNA polymerase, • inhibits HIV reverse transcriptase • Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. • Foscarnet is available in an intravenous formulation only;

44. Foscarnet Adverse effects • Renal impairment, hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, and hypomagnesemia. • Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue • the risk of anemia may beadditive in patients receiving concurrent zidovudine. • Central nervous system toxicities include headache, hallucinations, and seizures; • Foscarnet caused chromosomal damage in preclinical studies.

45. Anti-HIV agents summary 马拉韦罗（maraviroc） Entry inhibitors(入胞抑制药) 恩夫韦地（enfuvrtide） 西夫韦肽（sifuvirtide） Integrase Inhibitors （整合酶抑制药）:雷特格韦（raltegravir） • NNRTI: • 地拉韦定(delavirdine) • 奈韦拉平(nevirapine) • 依法韦恩茨(efavirenz) • NRTI: • 齐多夫定(zidovudine，AZT) • 扎西他宾(zalcitabine，ddC) • 司他夫定(stavudine，d4T) • 拉米夫定(lamivudine，3TC) • 去羟肌苷(didanosine，ddI) • 阿巴卡韦(abacavir，ABC) • Protease inhibitor(蛋白酶抑制剂,PI) • 利托那韦(ritonavir) • 奈非那韦(nelfinavir) • 沙奎那韦(saquinavir) • 英地那韦(indinavir) • 安谱那韦(amprenavir)

46. Zidovudine Zidovudine(齐多夫定,zdv,azt) • Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including thecerebrospinal fluid, where drug levels are 60–65% of those in serum. • the serum half-life averages 1.1 hours, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing. • Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.

47. Zidovudine • Zidovudine is often co-administered with lamivudine, and a combination formulation is available. • Zidovudine was the first antiretroviral agent to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. • Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

48. Zidovudine Adverse effect • myelosuppression, resulting in macrocytic anemia (1–4%) or neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. • Extremity fat loss may be more common with zidovudine than with other agents. • Less common toxicities include thrombocytopenia, hyperpigmentation of the nails, and myopathy. High doses can cause anxiety, confusion, and tremulousness. • Zidovudine causes vaginal neoplasms in mice; however, no human cases of genital neoplasms have been reported to date. Short-term safety has been demonstrated for both mother and infant. • Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance. • Zidovudine may decrease phenytoin levels. Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. Combination regimens containing zidovudine and stavudine should be avoided due to in vitro antagonism