I am Dr. Anil. this is my Lecture delivered to 3rd year MBBS for the subject of Pharmacology. These slides cover basics of Antifungal drugs mainly its pharmacology.

1. ANTI FUNGALANTI FUNGAL

7. MYCOSIS ?MYCOSIS ?

8. SUPERFICIAL MYCOSIS
SYSTEMIC MYCOSIS

9. CLASSIFICATIONCLASSIFICATION
 DRUGS FOR SYSTEMIC MYCOSISDRUGS FOR SYSTEMIC MYCOSIS
1. Amphotericin B 3. Flucytosine
2. AZOLES 4.Echinocandins
Fluconazole
Itraconazole
ketoconazole
Flucytosine

10. DRUGS FOR MUCOCUTANOUES MYCOSISDRUGS FOR MUCOCUTANOUES MYCOSIS
GRISEOFULVIN
TERBINAFINE

11. DRUGS FOR SUPERFICIAL MYCOSISDRUGS FOR SUPERFICIAL MYCOSIS
Nystatin
Clotrimazole
Miconazole
Econazole

12. •Cutaneous
•Moucosa Alimetary tract.
• vaginal
SUPERFICIAL MYCOSESSUPERFICIAL MYCOSES
Dermatophyte infectionsDermatophyte infections
 Ring wormsRing worms
 tineatinea
Candida infectionsCandida infections

13. Superficial mycoses
Infection Drugs Route
Ring worm
Tinea
Imidazoles Topical
Clotrimazole Topical
Econazole Topical
Miconazole Topical
Sulconazole Topical

14. Candida Infections
Cutaneous
amphotericin Topical
Clotrimazole Topical
Econazole Topical
Miconazole Topical
Nystatin Topical

15. Candida Infections
Mucosa
Alimentary
tract
amphotericin IV
Fluconazole Orally / IV
ketoconazole Only Orally
Miconazole Lozenges / Gel /
Suspension or
tablets
Nystatin

16. Candida Infections
Vaginal
Clotrimazole
Pessaries
Vaginal tablets
cream
Econazole
Isoconazole
ketoconazole
Miconazole
Nystatin

17. Systemic mycosis
Aspergillosis
Candidiasis
Coccidiodoidomycosis
Cryptococcosis
Histoplasmosis
Sporotrichosis

18. Classification of anti fungal drugsClassification of anti fungal drugs
according toaccording to
Mechanism of actionMechanism of action
Drugs that disrupt the cell membrane
Drugs that inhibit mitosis

19. Drugs that disrupt cell membranesDrugs that disrupt cell membranes
 Polyene antibioticsPolyene antibiotics
•Amphotericin B
•Nystatin

20. AZOLESAZOLES
Imidazoles Ketoconazole
Miconazole
Clotrimazole
Isoconazole
Ticonazole
Triazoles Fluconazole
Itraconazole

21. Binds to sterols (ergo sterol) present
in the cell Membranes Leakage
of intracellular ions & enzymes
Cell death
Mechanism of actionMechanism of action
 Polyene antibioticsPolyene antibiotics

22. AzolesAzoles
 ImidazolesImidazoles (KIMC)(KIMC)
Interfere with fungal oxidative
enzymes Lethal accumulation of
hydrogen peroxide
Triazoles (FI)
Inhibit demethylase enzyme
damage cell membrane

23.  GriseofulvinGriseofulvin
 FlucytosineFlucytosine
Drugs that inhibit MitosisDrugs that inhibit Mitosis
Flutycosine 5 flurouracil
Inhibit nucleic acid synthesis

24. Amphotericin –BAmphotericin –B
(Polyene macrolide antibiotic)(Polyene macrolide antibiotic)

25. PharmacokineticsPharmacokinetics::
• AdministrationAdministration
 Given I/V or topically (large hydrophilicGiven I/V or topically (large hydrophilic
molecule not absorbed from gut)molecule not absorbed from gut)
 Slow infusion, Ventricular FibrillationSlow infusion, Ventricular Fibrillation
• DistributionDistribution
 90% protein bound90% protein bound
 Some crosses BBBSome crosses BBB
• EliminationElimination
 No Metabolism,No Metabolism,
 slow Renal eliminationslow Renal elimination

26. + a polyene
(Amphotericin B
& Nystatin)
ergosterol
ergosterol with
pore
Mechanism of action

27. Fungal susceptibilityFungal susceptibility
 Candida speciesCandida species
 Histoplasma capsulatumHistoplasma capsulatum
 Cryptococcus neoformansCryptococcus neoformans
 Coccidioides imitansCoccidioides imitans
Blastomyces dermatidisBlastomyces dermatidis
 ParacoccidioidesParacoccidioides
 SporotrichumSporotrichum
 AspergillusAspergillus

28. Adverse drug reactionsAdverse drug reactions
 Infusion reactionsInfusion reactions
• Fever, chills, headache, anorexia, nausea,Fever, chills, headache, anorexia, nausea,
vomiting & thrombophlebitisvomiting & thrombophlebitis
 Normocytic normochromic anemiaNormocytic normochromic anemia
(reversible & due to suppression of(reversible & due to suppression of
erythropoietin)erythropoietin)
 Thrombocytopenia has also been notedThrombocytopenia has also been noted
 Renal toxicityRenal toxicity
• ReversibleReversible
• Irreversible (Total Dose)Irreversible (Total Dose)
 hypokalemia, acidosishypokalemia, acidosis
 glomerular damageglomerular damage
 renal tubule degenerationrenal tubule degeneration
 Hypersensitity ReactionsHypersensitity Reactions

29. Drug InteractionsDrug Interactions
 Synergistic:Synergistic:
• Augments the actions of:Augments the actions of:
Rifampin, 5-FC, tetracyclinesRifampin, 5-FC, tetracyclines
(due to decreased renal clearance)(due to decreased renal clearance)
• Enhances the antifungal activity ofEnhances the antifungal activity of
FlucytosineFlucytosine
 Antagonistic:Antagonistic:
• ImidazolesImidazoles
 Drug Resistance:Drug Resistance:
• Rare due to altered sterolsRare due to altered sterols

30. NystatinNystatin
((Polyene macrolide antibiotic)Polyene macrolide antibiotic)

31. NystatinNystatin
 It is similar in structure to amphotericinIt is similar in structure to amphotericin
 It has same mechanism of actionIt has same mechanism of action
 No absorption from the gut & mucousNo absorption from the gut & mucous
membranes of the body or skinmembranes of the body or skin
 Very toxic therefore not given sytemicallyVery toxic therefore not given sytemically
 It used for the treatment of fungalIt used for the treatment of fungal
infections of the gutinfections of the gut

32. GriseofulvinGriseofulvin

33. PharmacokineticsPharmacokinetics
 Given orally absorption is variableGiven orally absorption is variable
depending on the particle size & type ofdepending on the particle size & type of
preparation, increased when given withpreparation, increased when given with
fatty meal.fatty meal.
 Peak plasma concentration in 5 hoursPeak plasma concentration in 5 hours
 It is taken up by the newly formed skinIt is taken up by the newly formed skin
and concentrated in keratinand concentrated in keratin
 t½ is 24 hours but retained in the skin fort½ is 24 hours but retained in the skin for
much longermuch longer
 It induces cytochrome p450It induces cytochrome p450

34. Pharmacodynamics & UsesPharmacodynamics & Uses
 It is a narrow spectrum antibioticIt is a narrow spectrum antibiotic
 It is fungistaticIt is fungistatic
 It interacts with microtubules andIt interacts with microtubules and
interferes with mitosisinterferes with mitosis
 Its only use is in the systematicIts only use is in the systematic
treatment of dermatophytosis(nailtreatment of dermatophytosis(nail
infection)infection)

35. AzolesAzoles

36. These are a group of synthetic fungistatic drugsThese are a group of synthetic fungistatic drugs
having a broad spectrum of activityhaving a broad spectrum of activity
Have 5-membered organic rings that contain eitherHave 5-membered organic rings that contain either
two or three nitrogen molecules (the imidazolestwo or three nitrogen molecules (the imidazoles
and the triazoles respectively)and the triazoles respectively)
The clinically useful imidazoles areThe clinically useful imidazoles are clotrimazole,clotrimazole,
miconazole, ketoconazole.miconazole, ketoconazole.
The important triazoles areThe important triazoles are itraconazoleitraconazole
fluconazolefluconazole
In general, the azole antifungal agents are thought toIn general, the azole antifungal agents are thought to
inhibit cytochrome P450-dependent enzymesinhibit cytochrome P450-dependent enzymes
involved in the biosynthesis of cell membraneinvolved in the biosynthesis of cell membrane
sterolssterols..

37. In general, the azole antifungal agentsIn general, the azole antifungal agents
are thought to inhibit cytochromeare thought to inhibit cytochrome
P450-dependentP450-dependent
enzymes,enzymes,demethylasedemethylase, involved in, involved in
the demethylation of lanosterol tothe demethylation of lanosterol to
ergosterol---the principle sterol ofergosterol---the principle sterol of
fungal membrane structure andfungal membrane structure and
functionfunction

38. KetoconazoleKetoconazole
 Given orally, is well absorbed fromGiven orally, is well absorbed from
the gutthe gut
 It is distributed widely in the tissuesIt is distributed widely in the tissues
& fluids but not in CNS& fluids but not in CNS
 It is metabolised in the liverIt is metabolised in the liver
 t½ is 8 hourst½ is 8 hours
 Excreted thru bile & urineExcreted thru bile & urine

39. KetoconazoleKetoconazole
 Active againstActive against
 Histoplasma,Blastomyces,Candida,CoccidioidesHistoplasma,Blastomyces,Candida,Coccidioides
• Epidermophyton,Epidermophyton,
• MicrosporumMicrosporum
• TrichophytonTrichophyton
 Its use is limited because of toxicityIts use is limited because of toxicity
• Liver toxicityLiver toxicity
 Although rare can prove fatalAlthough rare can prove fatal
• GIT disturbanceGIT disturbance
• PruritisPruritis
 Drug interactions includeDrug interactions include
• Inhibition of synthesis of adrenal corticosteroids &Inhibition of synthesis of adrenal corticosteroids &
testosteronetestosterone
• Rifampicin, HRifampicin, H22 blockers & antacids decrese itsblockers & antacids decrese its
absorptionabsorption

40. FlucytosineFlucytosine

41. PharmacokineticsPharmacokinetics
 It is a synthetic antifungal agentIt is a synthetic antifungal agent
 Given I/V because orally absorptionGiven I/V because orally absorption
is limitedis limited
 It is widely distributed throughoutIt is widely distributed throughout
the body fluids including CSFthe body fluids including CSF
 90% excreted unchanged thru90% excreted unchanged thru
kidneyskidneys
 t½ is 3-5 hourst½ is 3-5 hours

42.  It is converted in fungal cells toIt is converted in fungal cells to 5-5-
Fluorodeoxyuridine 5Fluorodeoxyuridine 5
monophosphate(5FduMP),monophosphate(5FduMP),a falsea false
nucleotide which inhibits thymidylatenucleotide which inhibits thymidylate
sythetase and thus DNA synthesis issythetase and thus DNA synthesis is
inhibitedinhibited
 It should not be used alone as resistanceIt should not be used alone as resistance
develops rapidlydevelops rapidly
 Its use is limited because it is effectiveIts use is limited because it is effective
against yeast onlyagainst yeast only
 Unwanted effects areUnwanted effects are
• GI disturbancesGI disturbances
• Aanemia, neutropenia, thrombocytopeniaAanemia, neutropenia, thrombocytopenia
• AlopeciaAlopecia

43. TerbinafineTerbinafine

44.  It is highly lipophilic, keratinophilicIt is highly lipophilic, keratinophilic
fungicidalfungicidal
 Given orally & topically accumultes rapidlyGiven orally & topically accumultes rapidly
in skin & nailsin skin & nails
 Metabolised in the liver & excreted thruMetabolised in the liver & excreted thru
kidneyskidneys
 It is active against wide range of skinIt is active against wide range of skin
pathogenspathogens
 It acts selectively by inhibiting squaleneIt acts selectively by inhibiting squalene
epoxidase for synthesis of ergosterol fromepoxidase for synthesis of ergosterol from
sqalenesqalene
 Squalene accumulates & is toxic to the cellSqualene accumulates & is toxic to the cell
 Adverse effects includeAdverse effects include
• GIT disturbabce, rashes, pruritis, headache &GIT disturbabce, rashes, pruritis, headache &
dizzinessdizziness
• Joint & muscle pains ocassionallyJoint & muscle pains ocassionally

45. CaspofunginCaspofungin

46.  It comprises of 6-aminoacids linked toIt comprises of 6-aminoacids linked to
lipophilic side chainlipophilic side chain
 Oral absorption is poor, given I/VOral absorption is poor, given I/V
 Extensively protein boundExtensively protein bound
 t½ is 9-10 hourst½ is 9-10 hours
 It acts by inhibiting the synthesis ofIt acts by inhibiting the synthesis of ββ--
glucon(part of gungal cell wall), cell wallglucon(part of gungal cell wall), cell wall
loses integrity & lysis occursloses integrity & lysis occurs
 It is active in vitro against a wide varietyIt is active in vitro against a wide variety
of fungiof fungi
 It is used for the treatment of CandidiasisIt is used for the treatment of Candidiasis
& all forms of aspergilosis refractory to& all forms of aspergilosis refractory to
amphotericinamphotericin