药理学教学课件：Chapter 41 Antifungal Drugs

Chapter40:AntifungalDrugsFungalinfectionstraditionallyhavebeendividedtotwodistinctclasses:systemicandsuperficial.So,themajorantifungalagentsaredescribedwith“systemic”and“topical”.FungaldiseasesTypicalsystemicdisease(meningitis脑膜炎)

Histoplasmosis

(组织胞浆菌病),

Coccidioidomycosis

(球孢子菌病),

Blastomycosis

(芽生菌病),

Paracoccidiomycosis

(类球孢子菌病),

Cryptococcosis

(隐球菌病),

Sporotrichosis

(孢子丝菌病),

Candidiasis

(念珠菌病),

Aspergillosis

(曲霉病),

Mucormycosis

(毛霉菌病),etc.Typicaldermatosis(hair,skin,nails)

Epidermophytosis

表皮癣菌病

Trichophytosis

发癣菌病

Microsporosis

小孢子菌病

Classification1.Systemicantifungalagents:

AmphotercinB（两性霉素B）,

Flucytosine（氟胞嘧啶）;2.Topicalantifungalagents:

Nystatin（制霉菌素）,

Griseofulvin（灰黄霉素）,

Terbinafine（特比萘芬）;3.Azolesantifungalagents:

Ketoconazole（酮康唑）,

Fluconazol（氟康唑）.I.SystemicantifungalagentsAmphotercinB1.Mechanismofaction:bindtoergosterol

(麦角固醇)andalterthepermeabilityofthefungalcellmembranebyformingpore,andtheporeallowstheleakageofintracelluarionsandmacromolecules,eventuallyleadingtoFungalcelldeath.2.ClinicalUse:Owingtoitsbroadspectrumofactivityandfungicidalaction,amphotericinBremainsthedrugofchoiceforalllife-theatening

mycotic霉菌性infections.Itisoftenastheinitialregimenforseriousfungalinfections,eg.Cryptococcalmeningitis(隐球菌性脑膜炎）.3.Adversereaction:(1)Fever,chill,hyperpnea喘息,respiratorystridor呼吸喘鸣andhypotension,etc.(2)Nephrotoxic(3)RenaltubularacidosisandrenalwastingK+andMg2+，lowK+andMg2+(4)HematologicalToxicity:

hypochromic低色素andnormocytic正常红血球anemia,etc.(5)Hepatotoxicity

(6)Cardiactoxicity(7)CNSsideeffects.(8)Hypersensitivereaction4.Preventionofadversereaction:(1)Pretreatmentwithoralacetaminophenoruseofintravenoushydrocortisonehemisuccinate半琥珀酸酯atthestartoftheinfusiondecreasesreaction.(2)SupplementalK+isrequired.(3)Dophysicalexaminationtermly.5.Newformulations:(1)AmphotercinBlipidcomplex,ABLC(脂质复合体)(2)AmphotercinB

collcodaldispersion,ABCD(胶质分散体)(3)Liposomal

AmphotercinB,L-AMPHB(脂质体)Flucytosine

(氟胞嘧啶)1.Mechanismofaction:

takenupbyfungalcells.Itisconvertedintracellularlyfirstto5-FUandthento5-fluorodeoxyuridinemonophosphate(F-dUMP)andfluorouridine

triphosphate(FUTP),whichinhibitDNAandRNAsynthesis,respectively.(1)Humancellsareunabletoconverttheparentdrugtoitsactivemetabolites.(2)SynergywithamphotericinB:

Flucytosinemayenhancepenetrationoftheflucytosine

(3)Resistanceismediatedthroughalteredmetabolismofflucytosine.2.ClinicalUse:Flucytosineisa

norrow-spectrumantifungaldrug.Drugresistanceoccursrapidlywhenflucytosineisusedalone.FlucytosineisusedpredominantlyincombinationwithamphotericinBforthearpyofcryptococcal

(隐球菌性)meningitisinAIDSpatient,etc.3.Adversereactions:depressingthefunctionofbonemarrow(leadingtoleukopeniaandthrombocytopenia,etc.).Plasmalevelsofhepaticenzymesareelevated(reversible).Othereffect,includingrash,nausea,vomiting,diarrheaandsevereentercolitis,havebeennoted.

1.Classification: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）II.Azoles（唑类）antifungalagents

2.Mechanismofaction:Themajoreffectofazolesonfungiisinhibitionofsterol14-a-demethylase,amicrosomal

cytochromeP450-dependentenzymessystem.Azolesthusimpairthebiosynthesisofergosterol

(麦角固醇)forthecytoplasmicmembraneandleadtotheaccumulationof14-a-methylsterols.Thesemethylsterolsmaydisruptthefunctionsofmembrane-boundenzymessystemandthusinhibitinggrowthofthefungi.3.Antifungalactivity:

Theseantifungalagentsmaybeusedeithersystemicallyortopicall.(1)Ketoconazlewasthefirstoralazloeintroducedintoclinicaluse.ItislessselectiveforfungalP450thanthenewerazoles.So,ithasbeenlimitedbyendocrinesideeffectsandthedruginteractions,replacedbyitraconazoleor

fluconazole.(2)Itraconazoleisabroad-spectrumnewerantifungalazoles.Itsantifungalspectrumisbroaderthankotoconazole,anditssideeffectsislessthankotoconazole.Sometimes,itisthereplacerofkotoconazoleforpatient.(3)FluconazoleisdistinguishedfromtheotherazolesbyitswatersolubilityandgoodCSFpenetration.Druginteractonandsideeffectsarealsolessbecauseofitsleasteffectonhepaticenzymeofalltheazoles.Beusedin:①Candidiasis（念珠菌病）;②Cryptococcosis（隐球菌病）;③othermycosis(霉菌病).Nystatin（制霉菌素）Griseofulvin（灰黄霉素）Terbinafine（特比萘芬）Amorolfine

(阿莫罗芬)III.TopicalantifungalagentsIthasbee