Antiviral agents & Antifungal agents & Antifungal agents Chapter 44 Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]

Antiviral agentsAntiviral agents & Antifungal agents& Antifungal agents

Chapter 44Chapter 44

Yun-Bi Lu, PhDYun-Bi Lu, PhD卢韵碧卢韵碧

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

[email protected]@zju.edu.cn

2013.12.30

Antiviral agentsAntiviral agents

Essential Characteristics of VirusesEssential Characteristics of Viruses

• Genome (Genome (RNA or DNARNA or DNA) packaged in a ) packaged in a protein coreprotein core

• Intracellular parasitismIntracellular parasitism– No ribosomes or mitochondriaNo ribosomes or mitochondria– Utilize cellular machinery for synthesis of Utilize cellular machinery for synthesis of

macromoleculesmacromolecules

• Antiviral therapies targetAntiviral therapies target– Entry into cellsEntry into cells– Virus utilization of cellular machineryVirus utilization of cellular machinery– Or stimulate immune clearanceOr stimulate immune clearance

Specific Antiviral Therapy forSpecific Antiviral Therapy for

• Respiratory VirusesRespiratory Viruses– Influenza, Respiratory SyncInfluenza, Respiratory Syncyytial Virustial Virus ( ( 呼吸道合呼吸道合

胞病毒胞病毒 ))• Herpesviruses Herpesviruses (( 疱疹病毒疱疹病毒 ))

– HSV 1 & 2, VZV HSV 1 & 2, VZV (( 水痘水痘 -- 带状疱疹带状疱疹病毒病毒 )), CMV, EBV, CMV, EBV• Chronic HepatitisChronic Hepatitis

– Hepatitis B and CHepatitis B and C ( ( 肝炎病毒肝炎病毒 ))

• PapillomavirusesPapillomaviruses ( ( 乳头瘤病毒乳头瘤病毒 ))• RetrovirusesRetroviruses

– HIV-1, HIV-2, HTLV-1HIV-1, HIV-2, HTLV-1(( 人类嗜人类嗜 TT 细胞病毒细胞病毒 ))

General schema of virus replication

Attachment

Penetration

Uncoating

Protein and nucleic acid synthesis

Assembly

Release

Target cell

Virus particle

Specific Antiviral Therapy forSpecific Antiviral Therapy for

• Respiratory VirusesRespiratory Viruses– Influenza, Respiratory SyncInfluenza, Respiratory Syncyytial Virustial Virus ( ( 呼吸道合呼吸道合

胞病毒胞病毒 ))• Herpesviruses Herpesviruses (( 疱疹病毒疱疹病毒 ))

– HSV 1 & 2, VZV HSV 1 & 2, VZV (( 水痘水痘 -- 带状疱疹带状疱疹病毒病毒 )), CMV, EBV, CMV, EBV• Chronic HepatitisChronic Hepatitis

– Hepatitis B and CHepatitis B and C ( ( 肝炎病毒肝炎病毒 ))

• PapillomavirusesPapillomaviruses ( ( 乳头瘤病毒乳头瘤病毒 ))• RetrovirusesRetroviruses

– HIV-1, HIV-2, HTLV-1HIV-1, HIV-2, HTLV-1(( 人类嗜人类嗜 TT 细胞病毒细胞病毒 ))

Antiretroviral therapy

for HIV Infection: principles

•In the absence of treatment, HIV replication is a

continuous process

•Plasma HIV RNA concentrations are prognostic and

represent a useful 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

General Schema of HIV replication

General Schema of HIV replication

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 )

Nucleoside Analogue Reverse transcriptase inhibitors ( 核苷反转录酶抑制剂， NRTI)

Azidothymidine (AZT) = Zidovudine Azidothymidine (AZT) = Zidovudine (ZDV)(ZDV)Azidothymidine (AZT) = Zidovudine Azidothymidine (AZT) = Zidovudine (ZDV)(ZDV)

AbacavirAbacavir

Mechanism of ActionMechanism of ActionChain Termination of DNA by Chain Termination of DNA by triphosphorylated formstriphosphorylated forms

ToxicitiesToxicities: Numerous: NumerousZidovudine (AZT)Zidovudine (AZT) 齐多夫定齐多夫定

AnemiaAnemia （贫血）（贫血）NeutropeniaNeutropenia （中性粒细胞减少）（中性粒细胞减少） ThrombocytopeniaThrombocytopenia （血小板减少）（血小板减少）Asthenia (Asthenia ( 无力无力 ))HeadacheHeadache （头痛）（头痛）GI upsetGI upset （胃肠道反应）（胃肠道反应）

Stavudine (Stavudine (DD4T)4T) 司他夫定司他夫定Peripheral neuropathyPeripheral neuropathy （外周神经（外周神经炎）炎） Lipodystrophy Lipodystrophy （脂肪代谢障碍）（脂肪代谢障碍）Pancreatitis Pancreatitis （胰腺炎）（胰腺炎）Lactic acidosis Lactic acidosis （乳酸性酸中毒）（乳酸性酸中毒） withwith hepatic steatosis (hepatic steatosis ( 肝脂肪变）肝脂肪变） Hyperlipidemia Hyperlipidemia （高脂血症）（高脂血症）

嘧啶衍生物嘌呤衍生物

非核苷反转录酶抑制剂

齐多夫定扎西他宾

司他夫定拉米夫定

去羟肌苷

阿巴卡韦

奈韦拉平

地拉韦定依法韦恩茨

Non-Nucleoside Reverse transcriptase inhibitors

( 非核苷反转录酶抑制剂 NNRTI)

Nevirapine

Delavridine

EfavirenzEfavirenz

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)

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)

奈韦拉平奈韦拉平

依法韦恩茨依法韦恩茨

地拉韦定地拉韦定

HIV Protease Inhibitors

Polypeptide chainPolypeptide chain

NelfinavirNelfinavir

RitonavirRitonavir

SaquinavirSaquinavir

IndinavirIndinavir

Adverse effects:Adverse effects:

Nelfinavir - diarrheaRitonavir - GI intolerance,

hepatitis Indinavir - nephrolithiasis, GI

intolerance

奈非那韦奈非那韦

利多那韦利多那韦

沙奎那韦沙奎那韦

英地那韦英地那韦

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…

Current Antiretroviral MedicationsNRTI( 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

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

Initial Treatment: Initial Treatment: Preferred ComponentsPreferred Components

*Avoid in pregnant women and women with significant pregnancy potential.**Emtricitabine can be used in place of lamivudine and vice versa.

•Efavirenz* 依法韦恩茨依法韦恩茨

OR

•Atazanavir + ritonavir

•Fosamprenavir + ritonavir (BID)

•Lopinavir/ritonavir (BID)

NNRTI Option

PI Options

Tenofovir + emtricitabine**

Zidovudine + lamivudine**

+

NRTI Options

Ribavirin ( 利巴韦林 )• Synthetic guanosine analog Synthetic guanosine analog

• Once phosphorylated, interferes with Once phosphorylated, interferes with transcription of viral mRNA and synthesis of transcription of viral mRNA and synthesis of viral ribonucleoprotein complexesviral ribonucleoprotein complexes

• Available as aerosol for treatment of Available as aerosol for treatment of respiratory syncitial virus (RSV), oral tablet respiratory syncitial virus (RSV), oral tablet for Hepatitis for Hepatitis AA

• ToxicityToxicity– Bronchospasm (when used in inhaled Bronchospasm (when used in inhaled

formulation)formulation)– AAnemianemia– TeratogenicityTeratogenicity ( ( 致畸致畸 ))

AcyclovirAcyclovir ( ( 阿昔洛韦 )

• Used in high dose IV formulation in Used in high dose IV formulation in HSV HSV neonatal infection, CNS infection in adultsneonatal infection, CNS infection in adults

• Used in lower dose for Used in lower dose for HSVHSV or or VZVVZV mucocutaneous disease treatment and mucocutaneous disease treatment and prophylaxisprophylaxis

• Frequent oral dosing necessaryFrequent oral dosing necessary• Toxicities more likely with high doseToxicities more likely with high dose

– Nausea, headache, crystal formation in renal Nausea, headache, crystal formation in renal tubulestubules

Mechanism of Action of Acyclovir in Cells Infected by Herpes Simplex Virus

Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255

Structure of acyclovir and related nucleoside analogues

Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255

For comparison only; not related to acyclovir

利巴韦林

阿昔洛韦更昔洛韦

贲昔洛韦

GanciclovirGanciclovir ( ( 更昔洛韦 )

• Approved for treatment, prevention of Approved for treatment, prevention of CMV diseaseCMV disease

• Toxicities mostly related to bone Toxicities mostly related to bone marrow suppressionmarrow suppression– Anemia, neutropenia, thrombocytopeniaAnemia, neutropenia, thrombocytopenia– CNS effectsCNS effects

Foscarnet ( 磷甲酸盐 )

• Organic analogue of pyrophosphosphateOrganic analogue of pyrophosphosphate 焦磷酸盐衍生物焦磷酸盐衍生物 ((Trisodium phosphonoformateTrisodium phosphonoformate ，，磷酸三钠甲酸盐磷酸三钠甲酸盐 ))• Interferes with viral DNA synthesis: Blocks cleavage of Interferes with viral DNA synthesis: Blocks cleavage of pyrophosphatespyrophosphates• UseUse for treatment of CMV disease for treatment of CMV disease, , Active against Active against

acycloviracyclovir--resistant HSV and ganciclovir-resistant CMVresistant HSV and ganciclovir-resistant CMV• ToxicityToxicity

Renal toxicityRenal toxicity (dose-dependent) (dose-dependent) Electrolyte abnormalities Electrolyte abnormalities (drug chelates divalent cations)(drug chelates divalent cations): e.g. hypocalcemia: e.g. hypocalcemia

Vidarabine (Vidarabine ( 阿糖腺苷，阿糖腺苷， Ara-A)Ara-A)

• Nucleotide analoguesNucleotide analogues ( (purine purine nucleosidenucleoside))

• HSV HSV neonatal infection, CNS neonatal infection, CNS infection in adultsinfection in adults and VZV and VZV infectioninfection in AIDS in AIDS

• Acyclovir (Acyclovir ( 阿昔洛韦阿昔洛韦 )) has replaced has replaced Ara-A in treatment of HSV and VZAra-A in treatment of HSV and VZV infection.V infection.

Idoxuridine (Idoxuridine ( 碘苷，碘苷， IDUR)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 systemisystemic usec use

AAmantadinemantadine ( ( 金刚烷胺金刚烷胺 ))

• Inhibitors of Viral Uncoating (Adamantane Inhibitors of Viral Uncoating (Adamantane

derivatives)derivatives)

• Active Active against Influenzaagainst Influenza A only A only• Prophylaxis and Treatment of Influenza AProphylaxis and Treatment of Influenza A• CNS excitation (Dizziness, insomniaCNS excitation (Dizziness, insomnia(( 失失

眠眠 ),), anxiety); mild GI side effects anxiety); mild GI side effects

TREATMENT OF HEPATITIS B VIRUS INFECTION

TREATMENT OF HEPATITIS C VIRUS INFECTION

Attachment

Penetration

Uncoating

Protein, nucleic acid synthesis

Assembly

Release

Sites of Antiviral Drug ActionDocosonal (H)Chemokine receptor

blocking agents-(HIV)

Amantidine (A)( 金刚烷胺 )

Rimantidine (A)( 金刚乙胺 )

Nucleoside analogues(H, HBV, HIV)

Nucleotide analogues(CMV, HBV, HIV)

Non-nucleoside Reverse transcriptase inhibitors

(HIV)Antisense oligonucleotides

(CMV)

Oseltamivir (I)( 奥司他韦 )

Zanamivir (I)( 扎那米韦 )

A Influenza AE EnterovirusesI Influenza A or BH Herpes virusesCMV CytomegalovirusHBV Hepatitis B virusHIV HIV

HIV Protease inhibitors

Antifungal agentsAntifungal agents

Antifungal agentsAntifungal agentsOnychomycosisOnychomycosis

(( 甲癣甲癣 ))

Fungal infections traditionally have been diviFungal infections traditionally have been divided to ded to two distinct classes: systemic(two distinct classes: systemic( 系统性系统性 //深部深部 ) and superficial() and superficial( 体表体表 // 表浅部表浅部 ).). So, the m So, the major antifungal agents are described with ajor antifungal agents are described with “sys“systemic” and “topical”temic” and “topical”..

Antifungal agentsAntifungal agentsOnychomycosisOnychomycosis （甲癣）（甲癣）

Oral infection with Candida (Thrush 鹅口疮鹅口疮 )

www.thachers.org/ internal_medicine.htm http://vasculitis.med.jhu.edu/treatments/cytoxan.html

Invasive fungal diseaseInvasive fungal disease

Ubiquitous pathogens act as opportunistsUbiquitous pathogens act as opportunists(( 机机会菌感染会菌感染 ))

CandidaCandida species species (( 念珠菌属念珠菌属 )) Aspergillus Aspergillus species species (( 曲霉菌属曲霉菌属 ))

Cryptococcus Cryptococcus (( 隐球菌属隐球菌属 ))

Endemic mycosesEndemic mycoses(( 地方性的霉菌病地方性的霉菌病 ) ) HistoplasmosisHistoplasmosis (( 组织胞浆菌病组织胞浆菌病 )) CoccidioidomycosisCoccidioidomycosis (( 球孢子菌病球孢子菌病 )) BlastomycosisBlastomycosis (( 芽生菌病芽生菌病 ))

Invasive Aspergillosis( 侵袭性曲霉菌病 )

AA= aortic arch, a = aneurysmSC = 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.

• 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）

Classification of Classification of antifungal agents

Antifungal MedicationsAntifungal Medications

Allylamine

丙烯胺类Echinocandins

棘白菌素类Inhibition of cell wall biosynthesis

唑类嘧啶类多烯类

Polyenes: Amphotercin BAmphotercin B （两性霉素（两性霉素 BB ））broad-spectrumbroad-spectrum

Antibiotics

1. Mechanism of action1. Mechanism of action

Amphotercin BAmphotercin B

2. Clinical Uses2. Clinical Uses::• Amphotericin B remains the drug of choice for all Amphotericin B remains the drug of choice for all

life-threatening mycotic infections (It is often as tlife-threatening mycotic infections (It is often as the initial regimen). (he initial regimen). ( 首选药物之一首选药物之一 ) )

e.g. Cryptococcal meningitis (e.g. Cryptococcal meningitis ( 隐球菌性脑膜炎隐球菌性脑膜炎 ))

CandidiasisCandidiasis ( 念珠菌病念珠菌病 )

HistoplasmosisHistoplasmosis ( ( 组织胞浆菌病组织胞浆菌病 ))

CoccidioidomycosisCoccidioidomycosis ( ( 球孢子菌病球孢子菌病 ) )

InvasiveInvasive aspergillosis (aspergillosis ( 侵袭性曲霉菌病侵袭性曲霉菌病 ))


3. Adverse reactions:3. Adverse reactions:(1) fever, chill, hyperpnea(1) fever, chill, hyperpnea （喘息）（喘息） , ,

myalgiamyalgia （肌痛）（肌痛） and hypotension, and hypotension, etetcc.. （（ ~75%~75% ））

(2) nephrotoxic(2) nephrotoxic(3) renal tubular acidosis(3) renal tubular acidosis （肾小管酸化）（肾小管酸化）

and renal wasting Kand renal wasting K++ and Mg and Mg 2+2+

(4) hematological Toxicity(4) hematological Toxicity:: hypochromic hypochromic （低血红蛋白性）（低血红蛋白性） and normocyticand normocytic （正（正常色素性）常色素性） anemia, anemia, etcetc..


3. Adverse reactions3. Adverse reactions::

(5) hepatotoxicity (5) hepatotoxicity

(6) cardiac toxicity(6) cardiac toxicity

(7) CNS side effects (7) CNS side effects

(8) hypersensitive reaction(8) hypersensitive reaction


4. Prevention of adverse reaction4. Prevention of adverse reaction::

(1) Pretreatment with oral (1) Pretreatment with oral acetaminophacetaminophen en or use of intravenous or use of intravenous hydrocortisohydrocortisone hemisuccinatene hemisuccinate. .

(2) Supplemental K(2) Supplemental K+ + is required. is required.

(3) Do physical examination termly. (3) Do physical examination termly.

(4) drug interactions(4) drug interactions



(( 脂质复合体脂质复合体 ))

(( 胶质分散体胶质分散体 ))

(( 脂质体脂质体 ))

5. New formulations of Amphotercin B :5. New formulations of Amphotercin B :

Antibiotics:Antibiotics:nystatinnystatin （制霉菌素）（制霉菌素）griseofulvingriseofulvin （灰黄霉素）（灰黄霉素） Allylamines:Allylamines:terbinafineterbinafine （特比萘芬）（特比萘芬） - - squalene epoxidase inhibitor ( 角鲨烯环氧化酶抑制剂 )

Topical antifungal agentsTopical 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）

Azoles antifungal agentsAzoles antifungal agents

Mechanism of action:Mechanism of action:• reduce ergosterol reduce ergosterol (( 麦角固醇麦角固醇 )) synthesis by synthesis by

interfering with lanosterol interfering with lanosterol ((1414) –) –demethylasedemethylase ( ( 羊毛固醇羊毛固醇 1414-- 去甲基酶去甲基酶 ))

• inhibition of fungal cytochrome P450 enzymeinhibition of fungal cytochrome P450 enzyme

Antifungal activity:Antifungal activity:• Systemically (kSystemically (ketoconazle, fluconazole, itrac

onazole) or topically (miconazole, clotrimazol) or topically (miconazole, clotrimazole). e).


Ketoconazle Ketoconazle （酮康唑）（酮康唑） ::• the first oral azoles introduced into clinical use (sthe first oral azoles introduced into clinical use (systyst

emically or topically)emically or topically). .

• less selective for fungal P450 less selective for fungal P450

• clinical use has been clinical use has been limited by endocrine side effectlimited by endocrine side effect

ss, , liver toxicityliver toxicity and the and the drug interactionsdrug interactions. .

• itraconazole itraconazole （伊曲康唑）（伊曲康唑） or or fluconazole fluconazole （氟康唑）（氟康唑） has replaced ketoconazle for patients who can afford has replaced ketoconazle for patients who can afford

the more expensive, newer product.the more expensive, newer product.


Itraconazole Itraconazole （伊曲康唑）（伊曲康唑） • Its antifungal spectrum is broader than kotoconazole, and its side Its antifungal spectrum is broader than kotoconazole, and its side

effects is less than kotoconazole. effects is less than kotoconazole.

• p.o. iv., tp.o. iv., t1/21/2 15~20 h 15~20 h

• Drug absorption is increased by food and by low gastric pH. Drug absorption is increased by food and by low gastric pH. • penetrates poorly into the CSF penetrates poorly into the CSF • interacts with hepatic microsomal enzymes (to a lesser degrinteracts with hepatic microsomal enzymes (to a lesser degr

ee than ketoconazole)ee than ketoconazole)• used in the treatment of dermatophytoses(used in the treatment of dermatophytoses( 皮癣皮癣 ) and onycho) and onycho

mycosis(mycosis( 甲癣甲癣 ).).• for treatment of disease due to the dimorphic fungi histoplafor treatment of disease due to the dimorphic fungi histopla

sma (sma ( 组织胞浆菌组织胞浆菌 ), blastomyces(), blastomyces( 芽生菌芽生菌 ), and sporothrix (), and sporothrix ( 孢子孢子丝菌丝菌 ). ).


FFluconazole luconazole （氟康唑）（氟康唑） • good water solubility and good CSF penetratgood water solubility and good CSF penetrat

ionion• drug interactions and side effects are also ledrug interactions and side effects are also le

ssss because of its least effect on hepatic enzy because of its least effect on hepatic enzyme of all the azoles. me of all the azoles.

• Be used in:Be used in:

(1) Candidiasis(1) Candidiasis （念珠菌病）（念珠菌病） , ,

(2) Cryptococcosis(2) Cryptococcosis （隐球菌病）（隐球菌病） , ,

(3) others.(3) others.


FlucytosineFlucytosine （氟胞嘧啶）（氟胞嘧啶）

5-FC

5-FC

5-FU

FdUMP

dUMP

dTMP

Inhibition of DNA synthesisInhibition of DNA synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

FdUMP

FUTP

5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine;FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate;FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate;dTMP, deoxythymidine monophosphate

5-FC

FlucytosineFlucytosine ：： Mechanism of actionMechanism of action

Cytosine permease

Cytosine deaminase

Phosphorylation

Conversion to deoxynucleosides

Ihibition of thymidylate synthaseIhibition of thymidylate synthase

Substitution for uracilSubstitution for uracil

• a a wide-spectrumwide-spectrum antifungal drug. antifungal drug.

• Drug resistanceDrug resistance occurs rapidly whe occurs rapidly whe

n flucytosine is used alone. n flucytosine is used alone.

• Clinical uses:Clinical uses: in in combination with a combination with a

mphotericin Bmphotericin B for therapy of crypot for therapy of crypot

ococcal meningitis (ococcal meningitis ( 隐球菌性脑膜隐球菌性脑膜炎炎 ) in AIDS patient, ) in AIDS patient, etcetc..

FlucytosineFlucytosine

Adverse effectsAdverse effects::• depressing the function of bone madepressing the function of bone ma

rrowrrow (leading to leukopenia and thr (leading to leukopenia and thrombocytopenia, ombocytopenia, etc.etc.). ).

• Plasma levels of hepatic enzymes aPlasma levels of hepatic enzymes are elevated (reversible).re elevated (reversible).

• rash, nausea, vomiting, diarrhea. rash, nausea, vomiting, diarrhea.

FlucytosineFlucytosine

caspofungincaspofungin （卡泊芬净）（卡泊芬净） - - inhibit the biosynthesis of fungal cell wall via inhibiting the synthesis inhibit the biosynthesis of fungal cell wall via inhibiting the synthesis

of b(1-3) glucan. of b(1-3) glucan.

• a widea wide-spectrum -spectrum fungicidalfungicidal drug. drug.

• ADME:ADME: water-soluble and highly protein-bound, administered in intr water-soluble and highly protein-bound, administered in intr

avenous forms (a loading dose is recommended), tavenous forms (a loading dose is recommended), t1/21/2 9-11 hours, ex 9-11 hours, ex

creted by the kidneys and gastrointestinal tract.creted by the kidneys and gastrointestinal tract.

• Clinical uses:Clinical uses: mucocutaneous candida infections, empiric antifungal mucocutaneous candida infections, empiric antifungal

disease, invasive aspergillosis (as salvage). disease, invasive aspergillosis (as salvage).

• Adverse effects:Adverse effects: well tolerated, with minor gastrointestinal side effec well tolerated, with minor gastrointestinal side effec

ts and flushing reported infrequently. Dosage adjustments are requirts and flushing reported infrequently. Dosage adjustments are requir

ed only in the presence of severe hepatic insufficiency. ed only in the presence of severe hepatic insufficiency.

• Drug interactions:Drug interactions: cyclosporine, Elevated liver enzymes cyclosporine, Elevated liver enzymes

Echinocandins Echinocandins (( 棘白菌素类棘白菌素类 ))

terbinafineterbinafine （特比萘芬）（特比萘芬） - - squalene epoxidase inhibitor ( 角鲨烯环氧化酶抑制剂 )

• a widea wide-spectrum, low toxicity,-spectrum, low toxicity, fungicidalfungicidal drug. drug.

• available in an oral formulation. One tablet given daily (2available in an oral formulation. One tablet given daily (2

50 mg/d) for 12 weeks achieves a cure rate of up to 90% 50 mg/d) for 12 weeks achieves a cure rate of up to 90%

for onychomycosis (for onychomycosis ( 甲癣 ) and is more effective than gri) and is more effective than gri

seofulvin or itraconazole.seofulvin or itraconazole.

• Clinical uses:Clinical uses: dermatophytoses( dermatophytoses( 皮肤癣菌病 ), especially ), especially

onychomycosis (onychomycosis ( 甲癣 ). ).

• Adverse effectsAdverse effects ：： rare, GI effects and headache, no sigrare, GI effects and headache, no sig

nificant drug interactions.nificant drug interactions.

Naftifine (Naftifine ( 萘替芬萘替芬 ), ), 布替萘芬布替萘芬 (butenafine)(butenafine)

Allylamines Allylamines (( 丙烯胺丙烯胺类类 ))

Thanks !

Documents

Antiviral agents & Antifungal agents & Antifungal agents Chapter 44 Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]