Chapter 41
Antiviral and Antifungal
Agents
Anti-HIV Agents
Anti-HIV agents
• Nucleoside reverse transcriptase
inhibitors(NRTIs, 核苷类逆转录酶抑制剂）
• Non-nucleoside reverse transcriptase
inhibitors (NNRTIs, 非核苷类逆转录酶抑制剂）
• Protease inhibitor(PI, 蛋白酶抑制剂）
• Cocktail therapy
Nucleoside reverse
transcriptase inhibitors
(NRTIs)
•
•
•
•
•
•
Zidovudine （齐多夫定，AZT, ZDV）
Lamivudine(拉米夫定,3TC)
Stavudine（司他夫定, d4T）
Zalcitabine (扎西他宾, ddC）
Didanosine (去羟肌苷, ddI）
Abacavir (阿巴卡韦, ABC)
Zidovudine （齐多夫定，AZT, ZDV）
– The first reverse transcriptase inhibitor for
treatment of AIDS
– Treatment of AIDS and HIV-associated
dementia(痴呆) and thrombocytopenia(血小板
减少症)
– Mechanism:
– Toxicity: myelosuppression(骨髓抑制)
Non-nucleoside reverse
transcriptase inhibitors
•
•
•
•
•
•
Delavirdine(地拉韦定）
Nevirapine（奈韦拉平）
Efavirenz （依法韦恩茨）
Mechanism: different with NRTIs
Used in combination with NRTIs and PI
Toxicity: rash
Protease inhibitor
• Drugs :saquinavir（沙奎那韦）, ritonavir(
利托那韦）,indinavir（英地那韦）,
nelfinavir（奈非地韦）
• Mechanism: inhibit precursor molecules
convert to mature virions(病毒颗粒) during
HIV replication
Protease inhibitor
 Clinical uses: in combination with
other agents to treat AIDS
 Toxicity
abnormality in metabolism include
altered body fat distribution, insulin
resistance and hyperlipidemia(高脂血症)
Cocktail therapy
• 将2-3种药物联合应用，以减少耐药性的
产生。
• 优点：（1）疗效 （2）延缓耐药性
• 缺点：（1）毒性 （2）服药次数多
（3）价格
Other Antiviral agents
Antiviral agents
• Acyclovir (ACV)
– Active against HSV-1 , HSV-2
– Convert to ACV triphosphate and inhibit viral DNA
polymerase
– Treatment of a variety of herpes infections include
primary and recurrent genital herpes(生殖器疱疹)
(one of the most effective)
• Valacyclovir (伐昔洛韦）
– Higher blood concentration
• Ganciclovir(更昔洛韦)
CMV
Antiviral agents
• Vidarabine （阿糖腺苷,Ara-A）
– Convert to Ara-A triphosphate and inhibit DNA
polymerase
– Active against HSV, VZV(水痘带状疱疹病毒), CMV,
HBV etc
– Toxicity : neurotoxicity
• Idoxuridine（碘苷,疱疹净,IDU）
– Inhibit DNA synthesis by blocking thymidylic acid(脱氧
胸苷酸) synthetase
– Topical use for treatment of HSV infections of the
eyelid, cornea(角膜) and skin
– High toxicity
Antiviral agents
• Ribavirin （利巴韦林,病毒唑,virazole）
– Inhibit replication of both DNA and RNA viruses
– Treatment of influenza A and B infections
– Teratogenesis(畸形)
• Lamivudine (拉米夫定,3TC)
– NRTIs: HIV-1
– One of the most effective drugs on HBV infection
Antiviral agents
• Amantadine and rimantadine
– Inhibit penetration of virus to cells and the
uncoating of certain virus
– Prevent diseases caused by influenza A
• Foscarnet( 磷甲酸)
• Interferon
• Polyinosinic polycytidylic acid
Antifungal agents
• Fungal infection
– Superficial infection
– Systemic infection
• Antifungal agents
– Antifungal antibiotics
– Azole(唑类): imidazole and triazole
– Others: terbinafine and flucytosine
Antifungal antibiotics
• Amphotericin B
• Nystatin
• Griseofuvin
Amphotericin B
• Antifungal activity
– Has the broadest spectrum of antifungal
action
– Active against candida albicans(白色念
珠菌), cryptococcus neoformans(新型隐
球菌), histoplasma capsulatum(夹膜组
织胞浆菌) etc
Amphotericin B
• Mechanism of action
– Bind to ergosterol(麦角固醇) on fungal cell
membrane and alter the permeability of the cell
by forming amphotericin B-associated pores in
the cell membrane, allow the leakage of intracellular ions(K+) and molecules leading to cell
death
Amphotericin B
• Clinical uses
– Drug of choice for nearly all lifethreatening mycotic(霉菌) infections
include severe fungal pneumonia,
crypotoccal meningitis(隐球菌性脑
膜炎) or sepsis syndrome(败血症)
Amphotericin B
• Adverse reactions
– Infusion-related toxicity: fever, chills,
muscle spasm, headache, hypotension
– Renal damage: azotemia(氮质血症), K+
,Mg2+ wasting
– Others: Liver damage, arrhythmia, anemia
New preparation
• Liposomal amphotericin B
(两性霉素B脂质体）
• Amphotericin B lipid complex
（两性霉素B脂质复合体）
• Amphotericin B colloidal dispersion
(两性霉素B胶质复合体）
• Lower renal toxicity
Nystatin
• Has the same mechanism with
amphotericin B
• Only used topically for suppression
of local candidal infection
Griseofulvin
•
Antifungal activity
– inihibit the growth of dermatophytes include
epidermophyton（表皮癣菌）, microsporum（小孢
子菌） and trichophyton（发癣菌属）
– no effect on bacteria and systemic infections of
fungi
• Mechanism of action
– interfere with fungal nucleic acid synthesis
Griseofulvin
• Clinical use
– it is only used in the systemic treatment of
dermatophotosis include skin, hair and
nails
• Adverse effects
– Nausea, vomiting ,headache
– Allergic reaction: fever, skin rash and
leukopenia
– Teratogenesis
Azole
•Imidazole
– Clotrimazole, miconazole,
ketoconazole
•Triazole
– Fluconazole, itraconazole
Azole
• Mechanism of action
– Reduction of ergosterol synthesis by inhibition
of fungal cytochrome P450-dependent 14 demethylase
• Clinical uses
– Broad-spectrum: candida species,
cryptococcus neoformans, and dermatophytes
Topical azoles: clotrimazole and
miconazole(达克宁)
– Broad spectrum
– Poorly absorbed
– Too toxic for systemic uses
– Topical use in treatment of dermatophytosis
Ketoconazole
– The first broad-spectrum oral azole
introduced into clinical use
– Treatment of mucocutaneous candidisis and
dermatophytosis
– Major toxicity:
• Endocrine disturbance: infertility, gynecomastia
and menstrual irregularity
• Hepatoxicity: hepatitis
• Drug interaction
Itraconazole
• Absorbed well
• Clinical uses
F 55%
– Systemic fungal infection
– Choice in the treatment of
dermatophytosis and onychomycosis
• Lower toxicity than ketoconazole
• Can not penetrate BBB
Fluconazole(大扶康)
Can be adminstered orally and
intravenously , high bioavalibility 95%
Least effect on hepatic microsomal enzyme
Drug of choice in the treatment of
cyrptococcal menigitis (隐球菌性脑膜炎）of AIDS
and other systemic fungal infections
High concentration in CSF
Voriconazole
• Broad spectrum and higher activity
• Effective on fluconazole and amphoterin
B-resistant fungi
• po & iv F 90%
• Lower toxicity
Other antifungal agents
• Terbinafine(丁克）
– Inhibit fungal squalene epoxidase and interfere
with ergosterol biosynthesis
– High effect and low toxicity
– Treatment of dermatophytoses especially
onychomycosis(甲癣）
• Flucytosine
– Effective against cryptococcus and candida species
– Convert to 5-FU, inhibit DNA synthesis
– Synergism with Amphotericin B
羟甲戊二酰辅酶A（HMG-CoA）
甲羟戊酸
角鲨烯
烯丙胺类（特比奈芬） ×
角鲨烯环氧酶
羊毛甾醇
14-还原酶
唑类
×
14-α-去甲基酶
14-去甲基羊毛甾醇
14-甲基麦角二烯醇
吗啉类
14-还原酶
麦角二烯醇
△8 →△7异构酶
吗啉类
麦角二烷醇
多烯类（两性霉素B）
×
麦角固醇
何大一