Chapter 41

Antiviral and Antifungal Agents

Anti-HIV Agents

Anti-HIV agents

• Nucleoside reverse transcriptase inhibitors(Nucleoside reverse transcriptase inhibitors(NRTIs, NRTIs, 核苷类逆转录酶抑制剂核苷类逆转录酶抑制剂））

• Non-nucleoside reverse transcriptase inhibitNon-nucleoside reverse transcriptase inhibitors (NNRTIs, ors (NNRTIs, 非非核苷类逆转录酶抑制剂核苷类逆转录酶抑制剂））

• Protease inhibitorProtease inhibitor((PIPI, , 蛋白酶抑制剂）蛋白酶抑制剂）

• Cocktail therapyCocktail therapy

Nucleoside reverse transcriptase inhibitors (NRTIs)

• Zidovudine Zidovudine （齐多夫定，（齐多夫定， AZT, ZDVAZT, ZDV ））• Lamivudine(Lamivudine( 拉米夫定拉米夫定 ,3TC),3TC)

• StavudineStavudine （司他夫定（司他夫定 , d4T, d4T ））• Zalcitabine (Zalcitabine ( 扎西他宾扎西他宾 , ddC, ddC ））• Didanosine (Didanosine ( 去羟肌苷去羟肌苷 , ddI, ddI ））• Abacavir (Abacavir ( 阿巴卡韦阿巴卡韦 , ABC), ABC)

Zidovudine （齐多夫定， AZT, ZDV ）

– The first reverse transcriptase inhibitor for treaThe first reverse transcriptase inhibitor for treatment of AIDStment of AIDS

– Treatment of AIDS and HIV-associated dementTreatment of AIDS and HIV-associated dementia(ia( 痴呆痴呆 ) and thrombocytopenia() and thrombocytopenia( 血小板减少症血小板减少症))

– Mechanism: Mechanism: – Toxicity: myelosuppression(Toxicity: myelosuppression( 骨髓抑制骨髓抑制 ))

Non-nucleoside reverse transcriptase inhibitors

• Delavirdine(Delavirdine( 地拉韦定）地拉韦定）• NevirapineNevirapine （奈韦拉平）（奈韦拉平）• Efavirenz Efavirenz （依法韦恩茨）（依法韦恩茨）• Mechanism: different with NRTIsMechanism: different with NRTIs

• Used in combination with NRTIs and PI Used in combination with NRTIs and PI

• Toxicity: rashToxicity: rash

Protease inhibitor

• DrugsDrugs :saquinavir:saquinavir （沙奎那韦）（沙奎那韦） , ritonavi, ritonavir(r( 利托那韦）利托那韦） ,indinavir,indinavir （英地那韦）（英地那韦） , nel, nelfinavirfinavir （奈非地韦）（奈非地韦）

• Mechanism:Mechanism: inhibit precursor molecules c inhibit precursor molecules convert to mature virions(onvert to mature virions( 病毒颗粒病毒颗粒 ) during ) during HIV replicationHIV replication

Protease inhibitor

Clinical usesClinical uses: in combination with othe: in combination with other agents to treat AIDSr agents to treat AIDS

ToxicityToxicity abnormality in metabolism include altereabnormality in metabolism include altere

d body fat distribution, insulin resistance d body fat distribution, insulin resistance and hyperlipidemia(and hyperlipidemia( 高脂血症高脂血症 ))

Cocktail therapy

• 将将 2-32-3 种药物联合应用，以减少耐药性种药物联合应用，以减少耐药性的产生。的产生。

• 优点：（优点：（ 11 ）疗效）疗效 （（ 22 ）延缓耐药性）延缓耐药性 • 缺点：（缺点：（ 11 ）毒性）毒性 （（ 22 ）服药次数多）服药次数多 （（ 33 ）价格）价格

Other Antiviral agentsOther Antiviral agents

Antiviral agents• Acyclovir (ACV)Acyclovir (ACV)

– Active against HSV-1 , HSV-2Active against HSV-1 , HSV-2– Convert to ACV triphosphate and inhibit viral DNA polConvert to ACV triphosphate and inhibit viral DNA pol

ymeraseymerase– Treatment of a variety of herpes infections include primTreatment of a variety of herpes infections include prim

ary and recurrent genital herpes(ary and recurrent genital herpes( 生殖器疱疹生殖器疱疹 )) (one of the most effective)(one of the most effective)

• Valacyclovir Valacyclovir (( 伐昔洛韦）伐昔洛韦）– Higher blood concentrationHigher blood concentration

• Ganciclovir(Ganciclovir( 更昔洛韦更昔洛韦 ) CMV) CMV

Antiviral agents• Vidarabine Vidarabine （阿糖腺苷（阿糖腺苷 ,Ara-A,Ara-A ））

– Convert to Ara-A triphosphate and inhibit DNA polymConvert to Ara-A triphosphate and inhibit DNA polymeraseerase

– Active against HSV, VZV(Active against HSV, VZV( 水痘带状疱疹病毒水痘带状疱疹病毒 ), CMV, ), CMV, HBV etcHBV etc

– Toxicity : neurotoxicityToxicity : neurotoxicity• IdoxuridineIdoxuridine （碘苷（碘苷 ,, 疱疹净疱疹净 ,,IDUIDU ））

– Inhibit DNA synthesis by blocking thymidylic acid(Inhibit DNA synthesis by blocking thymidylic acid( 脱脱氧胸苷酸氧胸苷酸 ) synthetase) synthetase

– Topical use for treatment of HSV infections of the eyeliTopical use for treatment of HSV infections of the eyelid, cornea(d, cornea( 角膜角膜 ) and skin) and skin

– High toxicity High toxicity

Antiviral agents

• Ribavirin Ribavirin （利巴韦林（利巴韦林 ,, 病毒唑病毒唑 ,virazole,virazole ））– Inhibit replication of both DNA and RNA virusesInhibit replication of both DNA and RNA viruses– Treatment of influenza A and B infectionsTreatment of influenza A and B infections– Teratogenesis(Teratogenesis( 畸形畸形 ) )

• Lamivudine (Lamivudine ( 拉米夫定拉米夫定 ,3TC),3TC)– NRTIs: HIV-1NRTIs: HIV-1– One of the most effective drugs on HBV infectionOne of the most effective drugs on HBV infection

Antiviral agents

• Amantadine and rimantadineAmantadine and rimantadine– Inhibit penetration of virus to cells and the Inhibit penetration of virus to cells and the

uncoating of certain virusuncoating of certain virus– Prevent diseases caused by influenza APrevent diseases caused by influenza A

• Foscarnet(Foscarnet( 磷甲酸磷甲酸 ))

• InterferonInterferon• Polyinosinic polycytidylic acidPolyinosinic polycytidylic acid

Antifungal agents

• Fungal infectionFungal infection– Superficial infectionSuperficial infection– Systemic infectionSystemic infection

• Antifungal agentsAntifungal agents– Antifungal antibioticsAntifungal antibiotics– Azole(Azole( 唑类唑类 ): imidazole and triazole): imidazole and triazole– Others: terbinafine and flucytosineOthers: terbinafine and flucytosine

Antifungal antibiotics

• Amphotericin BAmphotericin B

• Nystatin Nystatin

• GriseofuvinGriseofuvin

Amphotericin B

• Antifungal activityAntifungal activity– Has the broadest spectrum of antifungaHas the broadest spectrum of antifunga

l actionl action

– Active against candida albicans(Active against candida albicans( 白色念白色念珠菌珠菌 ), cryptococcus neoformans(), cryptococcus neoformans( 新型新型隐球菌隐球菌 ), histoplasma capsulatum(), histoplasma capsulatum( 夹膜夹膜组织胞浆菌组织胞浆菌 ) etc) etc

Amphotericin B

• Mechanism of actionMechanism of action– Bind to ergosterol(Bind to ergosterol( 麦角固醇麦角固醇 ) on fungal cell me) on fungal cell me

mbrane and alter the permeability of the cell by mbrane and alter the permeability of the cell by forming amphotericin B-associated pores in the forming amphotericin B-associated pores in the cell membrane, allow the leakage of intra-cellulcell membrane, allow the leakage of intra-cellular ions(Kar ions(K++) and molecules leading to cell death) and molecules leading to cell death

Amphotericin B

• Clinical usesClinical uses– Drug of choice for nearly all life-threDrug of choice for nearly all life-thre

atening mycotic(atening mycotic( 霉菌霉菌 ) infections in) infections include severe fungal pneumonia, crypclude severe fungal pneumonia, crypotoccal meningitis(otoccal meningitis( 隐球菌性脑膜炎隐球菌性脑膜炎) or sepsis syndrome() or sepsis syndrome( 败血症败血症 ))

Amphotericin B• Adverse reactionsAdverse reactions

– Infusion-related toxicity: fever, chills, musInfusion-related toxicity: fever, chills, muscle spasm, headache, hypotensioncle spasm, headache, hypotension

– Renal damage: azotemia(Renal damage: azotemia( 氮质血症 ), K), K++ ,M ,Mgg2+2+ wasting wasting

– Others: Liver damage, arrhythmia, anemiOthers: Liver damage, arrhythmia, anemiaa

New preparation• Liposomal amphotericin BLiposomal amphotericin B (( 两性霉素两性霉素 BB 脂质体）脂质体）• Amphotericin B lipid complexAmphotericin B lipid complex （两性霉素（两性霉素 BB 脂质复合体）脂质复合体）• Amphotericin B colloidal dispersion Amphotericin B colloidal dispersion (( 两性霉素两性霉素 BB 胶质复合体）胶质复合体）• Lower renal toxicityLower renal toxicity

Nystatin

• Has the same mechanism with amphHas the same mechanism with amphotericin Botericin B

• Only used topically for suppression oOnly used topically for suppression of local candidal infectionf local candidal infection

Griseofulvin• Antifungal activityAntifungal activity

– inihibit the growth of dermatophytes include epidinihibit the growth of dermatophytes include epidermophytonermophyton （表皮癣菌）（表皮癣菌） , microsporum, microsporum （小孢子（小孢子菌）菌） and trichophytonand trichophyton （发癣菌属）（发癣菌属）

– no effect on bacteria and systemic infections of funo effect on bacteria and systemic infections of fungi ngi

• Mechanism of actionMechanism of action– interfere with fungal nucleic acid synthesisinterfere with fungal nucleic acid synthesis

Griseofulvin• Clinical useClinical use

– it is only used in the systemic treatment oit is only used in the systemic treatment of dermatophotosis include skin, hair and nf dermatophotosis include skin, hair and nailsails

• Adverse effectsAdverse effects– Nausea, vomiting ,headacheNausea, vomiting ,headache– Allergic reaction: fever, skin rash and leukopenAllergic reaction: fever, skin rash and leukopen

iaia– TeratogenesisTeratogenesis

Azole

•ImidazoleImidazole– Clotrimazole, miconazole, Clotrimazole, miconazole, ketoconketocon

azoleazole

•TriazoleTriazole – Fluconazole, itraconazoleFluconazole, itraconazole

Azole

• Mechanism of actionMechanism of action– Reduction of ergosterol synthesis by inhibition Reduction of ergosterol synthesis by inhibition

of fungal cytochrome P450-dependent 14 -demof fungal cytochrome P450-dependent 14 -demethylase ethylase

• Clinical usesClinical uses– Broad-spectrum: candida species, cryptococcuBroad-spectrum: candida species, cryptococcu

s neoformans, and dermatophytess neoformans, and dermatophytes

Topical azoles: clotrimazole and miconazole( 达克宁 )

– Broad spectrumBroad spectrum

– Poorly absorbed Poorly absorbed

– Too toxic for systemic usesToo toxic for systemic uses– Topical use in treatment of dermatophytosisTopical use in treatment of dermatophytosis

Ketoconazole– The first broad-spectrum oral azole introducThe first broad-spectrum oral azole introduc

ed into clinical useed into clinical use– Treatment of mucocutaneous candidisis and Treatment of mucocutaneous candidisis and

dermatophytosisdermatophytosis– Major toxicity:Major toxicity:

• Endocrine disturbance: infertility, gynecomastia Endocrine disturbance: infertility, gynecomastia and menstrual irregularityand menstrual irregularity

• Hepatoxicity: hepatitisHepatoxicity: hepatitis• Drug interactionDrug interaction

Itraconazole• Absorbed well F 55%Absorbed well F 55%

• Clinical usesClinical uses– Systemic fungal infectionSystemic fungal infection

– Choice in the treatment of dermatophytosChoice in the treatment of dermatophytosis and onychomycosisis and onychomycosis

• Lower toxicity than ketoconazole Lower toxicity than ketoconazole

• Can not penetrate BBBCan not penetrate BBB

Fluconazole( 大扶康 )

Can be adminstered orally and intravenouCan be adminstered orally and intravenously , high bioavalibility 95%sly , high bioavalibility 95%

Least effect on hepatic microsomal enzymeLeast effect on hepatic microsomal enzymeDrug of choice in the treatment of Drug of choice in the treatment of cyrptococyrptoco

ccal menigitisccal menigitis (( 隐球菌性脑膜炎）隐球菌性脑膜炎） of AIDSof AIDS and otheand other systemic fungal infectionsr systemic fungal infections

High concentration in CSFHigh concentration in CSF

Voriconazole

• Broad spectrum and higher activityBroad spectrum and higher activity

• Effective on fluconazole and amphoterin Effective on fluconazole and amphoterin B-resistant fungiB-resistant fungi

• po & iv F 90%po & iv F 90%

• Lower toxicityLower toxicity

Other antifungal agents• Terbinafine(Terbinafine( 丁克）丁克）

– Inhibit fungal squalene epoxidase and interfere witInhibit fungal squalene epoxidase and interfere with ergosterol biosynthesish ergosterol biosynthesis

– High effect and low toxicity High effect and low toxicity – Treatment of dermatophytoses especially onychomyTreatment of dermatophytoses especially onychomy

cosis(cosis( 甲癣）甲癣）• Flucytosine Flucytosine

– Effective against cryptococcus and candida speciesEffective against cryptococcus and candida species– Convert to 5-FU, inhibit DNA synthesisConvert to 5-FU, inhibit DNA synthesis– Synergism with Amphotericin BSynergism with Amphotericin B

羟甲戊二酰辅酶A（HMG-CoA）

甲羟戊酸

角鲨烯

羊毛甾醇烯丙胺类（特比奈芬） ×

14-去甲基羊毛甾醇

14-α -去甲基酶

唑类

麦角二烯醇

麦角二烷醇

麦角固醇

14-还原酶吗啉类

△ 8 → △ 7异构酶

多烯类（两性霉素B） ×

14-甲基麦角二烯醇

14-还原酶

吗啉类

角鲨烯环氧酶

×

何大一