A Power point presentation on "Antifungals' suitable for reading by MBBS UG students.

1. Dr. D. K. BrahmaDr. D. K. Brahma
Department of PharmacologyDepartment of Pharmacology
NEIGRIHMS, ShillongNEIGRIHMS, Shillong
Antifungal DrugsAntifungal Drugs

2. Introduction -Introduction - Also called antimycoticAlso called antimycotic
drugsdrugs
 Used to treat two types of fungal infection:Used to treat two types of fungal infection:
– Superficial fungal infections - skin or mucous membraneSuperficial fungal infections - skin or mucous membrane
– Systemic fungal infections - lungs or central nervousSystemic fungal infections - lungs or central nervous
systemsystem
 Fungi causing mycosis live as commensally or are
present in the environment.
 Earlier superficial infections were uncommon and
systemic rather rare.
 Recently there is increase in local as well as
systemic fungal infections.
 Reason for this is opportunistic infections

3. Opportunistic infectionsOpportunistic infections
 Immuno-suppression due to
- Cancer chemotherapy
- AIDS
– Corticosteroid overuse
 Indiscriminate use of broad spectrum
antibiotics

4. Fungal infections
 Superficial
– Skin
– Hair
– Nails
– Mucous membrane
 Deep
– Tissues (muscle &
connective tissue)
– Organs
Images of some superficial skin infections

5. Types of fungal infections - MycosesTypes of fungal infections - Mycoses
 Superficial mycosesSuperficial mycoses
– Affect the skin, hair and nails – ringworm/tinea orAffect the skin, hair and nails – ringworm/tinea or
onychomycosisonychomycosis
 Subcutaneous mycoses (tropical)Subcutaneous mycoses (tropical)
– Affect the muscle and connective tissue immediatelyAffect the muscle and connective tissue immediately
below the skinbelow the skin
 Systemic (invasive) mycosesSystemic (invasive) mycoses
– Involve the internal organsInvolve the internal organs
 Allergic mycosesAllergic mycoses
– Affect lungs or sinusesAffect lungs or sinuses
– Patients may have chronic asthma, cystic fibrosis or sinusitisPatients may have chronic asthma, cystic fibrosis or sinusitis
There is some overlap between these groups

6. MOST COMMON FUNGALMOST COMMON FUNGAL
PATHOGENSPATHOGENS
 DermatophytesDermatophytes –– Microsporum,Microsporum,
Epidermophyton and TrichophytonEpidermophyton and Trichophyton
 CandidaCandida –– C.C. albicans, C. glabrata, C.albicans, C. glabrata, C.
tropicalistropicalis
 AspergillusAspergillus
 CryptococcusCryptococcus
 RhizopusRhizopus

7. Causative fungiCausative fungi
 Superficial infections by
– Dermatophytes (ring worms): athlete`s foot or tinea
pedis, jock itch or tinea cruris, tinea capitis etc.
– Candida:Candida: oral thrush, vaginitis and diaper candidiasis
etc.
 Deep infections are
– Candidiasis: Chronic mucocutaneous candidiasis,
systemic candidiasis etc.
– Aspergillosis: broncho-pulmonary aspergillosis
– Coccidiomycosis: pulmonary and disseminated
(complications – pneumonia)
– Histoplasmosis:Histoplasmosis: H. capsulatum (common in HIV)H. capsulatum (common in HIV)

8. What are the targets for antifungal therapy?What are the targets for antifungal therapy?
Cell membrane
Fungi use principally ergosterol
instead of cholesterol
Cell Wall
Unlike mammalian cells, fungi
have a cell wall
DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.

9. Cell Membrane Active AntifungalCell Membrane Active Antifungal
Cell membrane
1. Polyene antibiotics
- Amphotericin B, lipid
formulations
- Nystatin (topical)
2. Azole antifungals
Imidazoles:
• Topical: Clotrimazole,
econazole, miconazole
• Systemic: Ketoconazole
Triazoles: Fluconazole,
itraconazole and voriconazole

10. Polyene antibiotics-Polyene antibiotics-Amphotericin BAmphotericin B
 Fermentation product ofFermentation product of Streptomyces nodususStreptomyces nodusus
 High affinity for ergosterol present in fungal cell membraneHigh affinity for ergosterol present in fungal cell membrane
 Hydrophilic polyhydroxyl chain along one side and a lipophilicHydrophilic polyhydroxyl chain along one side and a lipophilic
polyene hydrocarbon chain on the otherpolyene hydrocarbon chain on the other
 Binds sterols in fungal cell membrane –Binds sterols in fungal cell membrane –
– high affinity for ergosterol present in fungal cell membranehigh affinity for ergosterol present in fungal cell membrane
– affinity is less for host cell membrane although closely resemblesaffinity is less for host cell membrane although closely resembles
 Creates transmembrane channel and electrolyte leakage.Creates transmembrane channel and electrolyte leakage.
 Active against most fungi exceptActive against most fungi except Aspergillus terreusAspergillus terreus,,
ScedosporiumScedosporium sppspp..
 Bacteria lack sterols so insensitive to polyenesBacteria lack sterols so insensitive to polyenes

11. Antifungal spectrumAntifungal spectrum
 Most Toxic antifungalMost Toxic antifungal
 Fungicide at high and static at low conc.Fungicide at high and static at low conc.
 Effective againstEffective against
– Candida albicansCandida albicans
– Histoplasma capsulatumHistoplasma capsulatum
– CryptococcusCryptococcus

12. PharmacokineticsPharmacokinetics
 Insoluble in waterInsoluble in water
 Unstable at 37degreeUnstable at 37degree
 Poorly absorbed from GITPoorly absorbed from GIT
 Cannot cross BBBCannot cross BBB
 Highly bound to plasma proteinsHighly bound to plasma proteins
 Takes 2 months for complete clearance of drugTakes 2 months for complete clearance of drug
 Given as I/V infusionGiven as I/V infusion
 For fungal meningitis given intrathecallyFor fungal meningitis given intrathecally
 Has immuno-stimulant action alsoHas immuno-stimulant action also
 Given in immuno-compromised patients for fungalGiven in immuno-compromised patients for fungal
infectionsinfections

13. UsesUses
 Broad spectrum antifungalBroad spectrum antifungal
 Useful forUseful for
1. Candida that causes1. Candida that causes
– oraloral
– vaginalvaginal
– cutaneous candidiasiscutaneous candidiasis
2. Cryptococcus2. Cryptococcus
3. Histoplasma3. Histoplasma
4. Aspergillosis4. Aspergillosis
5. Also effective for Leishmaniasis(Reserve drug for resistant5. Also effective for Leishmaniasis(Reserve drug for resistant
cases of Kala Azar)cases of Kala Azar)

14. ADRsADRs
1.1. Acute reactions -Acute reactions - occurs with each infusionoccurs with each infusion
– Chills, Nausea, Vomiting, Pain, Fever, Aches, DyspnoeaChills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea
– So corticosteroids are administered along with the drugSo corticosteroids are administered along with the drug
1.1. ThrombophlebitisThrombophlebitis
2.2. Bone marrow depressionBone marrow depression - Reversible anemia- Reversible anemia
3.3. On intrathecal injectionOn intrathecal injection – Headache, Vomiting,– Headache, Vomiting,
Nerve paralysisNerve paralysis
4.4. Renal toxicity leading toRenal toxicity leading to – Azotemia, Decreased– Azotemia, Decreased
GFR, Acidosis, Hypokalemia, Inability to conc.GFR, Acidosis, Hypokalemia, Inability to conc.
urineurine

15. Newer Amphotericin BNewer Amphotericin B
They are developed to overcomeThey are developed to overcome
1. Side effects1. Side effects
2. To improve tolerability2. To improve tolerability
3. To get the drug at site of action3. To get the drug at site of action
4. To reduce the toxicity i.e.. Less nephrotoxic and minimal4. To reduce the toxicity i.e.. Less nephrotoxic and minimal
anemiaanemia
Formulations are:Formulations are:
1. Amphotericin B lipid complex1. Amphotericin B lipid complex
2. Amphotericin B colloidal dispersion2. Amphotericin B colloidal dispersion
3. Liposomal Amphotericin B3. Liposomal Amphotericin B
(Only drawback of these formulations is less efficacy)(Only drawback of these formulations is less efficacy)

16. Drug Interactions of Amphotericin BDrug Interactions of Amphotericin B
 With Flucytocin-synergistic actionWith Flucytocin-synergistic action
 Rifampicin and Minocyclin –Rifampicin and Minocyclin –
– Both potentiate Amphotericin BBoth potentiate Amphotericin B
 Vancomycin and Aminoglycoside –Vancomycin and Aminoglycoside –
– Both increase risk of nephrotoxicityBoth increase risk of nephrotoxicity
 Preparation and doses:Preparation and doses:
– 50 – 100 mg four times a day orally50 – 100 mg four times a day orally
– 3% ear drops3% ear drops
– Systemic: 50 mg vial (one vial diluted in 500 ml of 5%Systemic: 50 mg vial (one vial diluted in 500 ml of 5%
glucose and initially 1 mg test dose followed by infusionglucose and initially 1 mg test dose followed by infusion
for 4 – 8 Hrs)for 4 – 8 Hrs)

17. NystatinNystatin
 Similar to Amphotericin B but moreSimilar to Amphotericin B but more toxictoxic thanthan
Amphotericin BAmphotericin B
 Used only for superficial candidiasis ofUsed only for superficial candidiasis of
Skin, Mouth, Vagina, IntestineSkin, Mouth, Vagina, Intestine
 As ointment ,oral tablets & suppositoriesAs ointment ,oral tablets & suppositories
 Available as tablets and ointments (1 to 5 lacs U)Available as tablets and ointments (1 to 5 lacs U)
– also vaginal tablets– also vaginal tablets
 Orally not absorbed but can be used in monilialOrally not absorbed but can be used in monilial
diarrhoeadiarrhoea

18. Other PolyenesOther Polyenes
Hamycin:
 Water soluble
 Absorption from GIT not reliable
 Not used for systemic fungal infections
 Used topically for Aspergillus, Candida, Monilial,
Trichomonas vaginalis infections
Natamycin:
 Broad spectrum
 Used topically for – Keratitis, Monilial infections,
Trichomonas vaginalis

19. Imidazoles and TriazolesImidazoles and Triazoles
Azole antifungals
 Imidazoles:
– Topical: Clotrimazole, econazole, miconazole
– Systemic: Ketoconazole
 Triazoles: Fluconazole, itraconazole and
voriconazole
 Remember that among imidazoles, onlyRemember that among imidazoles, only
ketocanazole is systemic, other 3 are topical onlyketocanazole is systemic, other 3 are topical only
 While, Triazoles are used systemically and largelyWhile, Triazoles are used systemically and largely
replacing ketoconazolereplacing ketoconazole

20. Azole StructuresAzole Structures
Fluconazole Ketoconazole

21. AzolesAzoles – Common Mechanism– Common Mechanism
• In fungi, the cytochrome P450-
enzyme lanosterol 14-alpha
demethylase is responsible for the
conversion of lanosterol to
ergosterol
• Azoles bind to lanosterol 14α-
demethylase inhibiting the
production of ergosterol
– Some cross-reactivity is seen with
mammalian cytochrome p450 enzymes
leading to
• Drug Interactions
• Impairment of steroidneogenesis
(ketoconazole, itraconazole)

22. Effect of azoles on C. albicansEffect of azoles on C. albicans
Before exposure After exposure
Decreased budding from the parent cells

23. Individual AgentsIndividual Agents
Ketoconazole:Ketoconazole:
 Spectrum: yeasts and moulds - poor absorptionSpectrum: yeasts and moulds - poor absorption
limits its role for severe infections, generally usedlimits its role for severe infections, generally used
in mucosal infections only (dematophytosis)in mucosal infections only (dematophytosis)
 PharmacokineticsPharmacokinetics
– Variable oral absorption, dependent on pH (often givenVariable oral absorption, dependent on pH (often given
with cola or fruit juice)with cola or fruit juice)
– T1/2 = 7-10 hoursT1/2 = 7-10 hours
– Protein binding > 99%Protein binding > 99%
– Hepatic, bile and kidney eliminationHepatic, bile and kidney elimination

24. Ketoconazole – contd.Ketoconazole – contd.
 Adverse effectsAdverse effects
– N&V, worse with higher doses (800 mg/day)N&V, worse with higher doses (800 mg/day)
– Hepatoxicity (2-8%), increase in transaminases,Hepatoxicity (2-8%), increase in transaminases,
hepatitishepatitis
– Dose related inhibition of CYP P450 responsibleDose related inhibition of CYP P450 responsible
for testosterone synthesisfor testosterone synthesis
 Gynecomastia, oligosperma, decreased libidoGynecomastia, oligosperma, decreased libido
– Dose-related inhibition of CYP P450Dose-related inhibition of CYP P450
responsible for adrenal cortisol synthesisresponsible for adrenal cortisol synthesis

25. Ketoconazole – contd.Ketoconazole – contd.
Drug Interaction:Drug Interaction:
 Potent inhibitor of cytochrome P450 3A4Potent inhibitor of cytochrome P450 3A4
– Rifampin and phenytoin decrease ketoconazole levelsRifampin and phenytoin decrease ketoconazole levels
– Ketoconazole increases cyclosporin, waKetoconazole increases cyclosporin, warrfarin, astemizole,farin, astemizole,
corticosteroid, and theophylline levelscorticosteroid, and theophylline levels
– Many of these drug interactions are severeMany of these drug interactions are severe
 Drugs that increase gastric pH will decrease blood levels ofDrugs that increase gastric pH will decrease blood levels of
ketoconazoleketoconazole
– Antacids, omeprazole, H2 blockersAntacids, omeprazole, H2 blockers
 Doses:Doses:
– Serious infections 800 mg/day POSerious infections 800 mg/day PO
– Other: 200-400 mg/day POOther: 200-400 mg/day PO

27. FluconazoleFluconazole
 Water soluble having wider range of activity thanWater soluble having wider range of activity than
KetoconazoleKetoconazole
 Good activity against C. albicans and CryptococcusGood activity against C. albicans and Cryptococcus
neoformansneoformans
 Non-albicans Candida species more likely to exhibitNon-albicans Candida species more likely to exhibit
primary resistanceprimary resistance
Always resistant Sometimes resistant
C. krusei > C. glabrata > C. parapsilosis
C. tropicalis
C. kefyr

28. ResistanceResistance
 Primary resistancePrimary resistance (seen in severely ill or(seen in severely ill or
immunocompromised patients)immunocompromised patients)
– Selection of resistant species or subpopulationsSelection of resistant species or subpopulations
– Replacement with more resistant strainReplacement with more resistant strain
 Secondary resistanceSecondary resistance (seen in patients with(seen in patients with
AIDS who experienced recurrent orophayrngealAIDS who experienced recurrent orophayrngeal
candidiasis and received long-term fluconazolecandidiasis and received long-term fluconazole
therapy)therapy)
– Genetic mutationGenetic mutation
– Upregulation of efflux pumpsUpregulation of efflux pumps

29. Mechanisms of antifungal resistanceMechanisms of antifungal resistance
 Target enzymeTarget enzyme
modificationmodification
 ErgosterolErgosterol
biosyntheticbiosynthetic
pathwaypathway
 Efflux pumpsEfflux pumps
 Drug importDrug import

30. Fluconazole - KineticsFluconazole - Kinetics
 Available as both IV and POAvailable as both IV and PO
– Bioavailibility > 90%Bioavailibility > 90%
 PharmacokineticsPharmacokinetics
– t 1/2 = ~24 hourst 1/2 = ~24 hours
– Protein binding < 12%Protein binding < 12%
– Vd 0.85 L/kg (widely distributed)Vd 0.85 L/kg (widely distributed)
– >90% excreted unchanged through the kidney>90% excreted unchanged through the kidney
 DosingDosing
1.1. Mucosal candidiasisMucosal candidiasis
 100-200 mg/day (150 mg tablet vulvovaginal candidiasis)100-200 mg/day (150 mg tablet vulvovaginal candidiasis)
1.1. Systemic fungal infectionsSystemic fungal infections
 400-800 mg q24h400-800 mg q24h
 >> 800 mg q24h in unstable patient, S-DD isolate, or if non-800 mg q24h in unstable patient, S-DD isolate, or if non-albicansalbicans spp.spp.
(except(except C. kruseiC. krusei))
1.1. Maintenance for cryptococcal meningitisMaintenance for cryptococcal meningitis
 400 mg q24h400 mg q24h

31. Fluconazole - ADRsFluconazole - ADRs
 N&V, rash:N&V, rash:
– More likely with high doses and in AIDS patientsMore likely with high doses and in AIDS patients
– Asymptomatic increase in LFTs (7%)Asymptomatic increase in LFTs (7%)
 Drug interactions:Drug interactions:
– May increase phenytoin, cyclosporin, rifabutin,May increase phenytoin, cyclosporin, rifabutin,
warfarin, and zidovudine concentrationswarfarin, and zidovudine concentrations
– Rifampin reduced fluconazole levels to halfRifampin reduced fluconazole levels to half
(even though FLU is not a major substrate)(even though FLU is not a major substrate)

32. ItraconazoleItraconazole
Some Features:Some Features:
 Newer orally active triazoleNewer orally active triazole
 Broader spectrun than KTZ and FCZ –Broader spectrun than KTZ and FCZ –
includes moulds like aspergillusincludes moulds like aspergillus
 Fungistatic action but very effective inFungistatic action but very effective in
immunocompromizrd patientsimmunocompromizrd patients
 Steroid hormone synthesis inhibition isSteroid hormone synthesis inhibition is
absent and no serious hepatotoxicityabsent and no serious hepatotoxicity

33. KetoconazoleKetoconazole FluconazoleFluconazole ItraconazoleItraconazole
11 Broad spectrumBroad spectrum Still wider rangeStill wider range Fungi staticFungi static
22 DermatophyteDermatophyte
& deep mycosis& deep mycosis
Cryptococcal & coccidialCryptococcal & coccidial
meningitismeningitis
immunocompromisedimmunocompromised
patientspatients
33 Absorbed at low pHAbsorbed at low pH Good oral absorptionGood oral absorption Varies with food & pHVaries with food & pH
44 Highly bound to PPHighly bound to PP Not muchNot much Highly boundHighly bound
55 More S/E, headache, androgenMore S/E, headache, androgen
inhibitioninhibition
Less S/E, headache & rashLess S/E, headache & rash Hypokalemia, pruritis &Hypokalemia, pruritis &
dizzinessdizziness
66 Causes hepatic impairmentCauses hepatic impairment MildMild Not hepatotoxicNot hepatotoxic
77 Inhibit cytochrome P450Inhibit cytochrome P450 Inhibit only fungal P450Inhibit only fungal P450 No effectNo effect
88 Used for Monilial vaginitis.Used for Monilial vaginitis.
Cushing’s synCushing’s syn
Candidiasis, Keratitis,Candidiasis, Keratitis,
Cryptococcal meningitisCryptococcal meningitis
Mycosis, meningitisMycosis, meningitis
Chromo & paracocciChromo & paracocci

34. Local azolesLocal azoles
 Very popular local azoles are – Clotrimazole, Econazole
and Miconazole
 (For Tinea, Ring worm, Athlete’s foot, otomycosis, oral,
cutaneous & vaginal candidiasis)
 Mechanism of action is same as that of Ketoconazole i.e.
ergosterol inhibition by inhibiting CYP450
 Clotrimazole is favoured in vaginitis because of long lasting
residual effect and once daily dosing
 Miconazole causes frequently vaginal irritation & pelvic
cramp.
 Available s lotion, cream, powder, vaginal tablet etc.Available s lotion, cream, powder, vaginal tablet etc.

35. Heterocyclic Nitrofurans -Heterocyclic Nitrofurans -
GriseofulvinGriseofulvin
 Used for superficial fungal infections byUsed for superficial fungal infections by
dermatophytesdermatophytes
 Derived from Penicillium griseofulvum butDerived from Penicillium griseofulvum but
no antibacterial activityno antibacterial activity
 Effective against most dermatophytes, butEffective against most dermatophytes, but
not against candida causing deep mycosisnot against candida causing deep mycosis
 Dermatophytes actively concentrate it –Dermatophytes actively concentrate it –
accounts for selective toxicity against themaccounts for selective toxicity against them
 Taken up by newly formed keratinTaken up by newly formed keratin

36. Griseofulvin - MOAGriseofulvin - MOA
 Interferes with mitosis – results inInterferes with mitosis – results in
multinucleated and stuntedmultinucleated and stunted hyphaehyphae
((In most fungi, hyphae are the main mode of vegetative growth, and areIn most fungi, hyphae are the main mode of vegetative growth, and are
collectively called a mycelium yeasts are unicellular fungi that do notcollectively called a mycelium yeasts are unicellular fungi that do not
grow as hyphae)grow as hyphae)
 Abnormal metaphase configurations leadingAbnormal metaphase configurations leading
to failure of daughter nuclei to fall apartto failure of daughter nuclei to fall apart
(Colchicine and vinca alkloids also mitotic inhibitors but they cause(Colchicine and vinca alkloids also mitotic inhibitors but they cause arrestarrest
of mitosis)of mitosis)
 Disorientation of polymerized microtubulesDisorientation of polymerized microtubules

37. Griseofulvin – contd.Griseofulvin – contd.
Pharmacokinetics:Pharmacokinetics:
 Given orally and fats improve absorptionGiven orally and fats improve absorption
 Absorption depends on the particle sizeAbsorption depends on the particle size
 Duration of treatment depends upon tissue turn overDuration of treatment depends upon tissue turn over
1. 3-6 wks for skin & hair1. 3-6 wks for skin & hair
2. 3-6 months for nails2. 3-6 months for nails
 Treatment should continue till whole infected tissue is shedTreatment should continue till whole infected tissue is shed
off.off.
Doses:Doses: Used orally only for dermatophytosis (125 to 250 mgUsed orally only for dermatophytosis (125 to 250 mg
4 times daily, but depends on site of infection4 times daily, but depends on site of infection

38. Griseofulvin - ADRsGriseofulvin - ADRs
 Safe with mild side effectsSafe with mild side effects
1. GIT upsets1. GIT upsets
2. CNS symptoms2. CNS symptoms
3. Hepatotoxicity3. Hepatotoxicity
4. Leucopenia4. Leucopenia
5. Photosensitivity5. Photosensitivity
6. Allergy etc.6. Allergy etc.
 Microsomal enzyme inducerMicrosomal enzyme inducer
 Causes decrease in activity of anticoagulantsCauses decrease in activity of anticoagulants
 Cause intolerance to alcoholCause intolerance to alcohol
 Phenobarbitone reduces its oral absorption so failure ofPhenobarbitone reduces its oral absorption so failure of
therapytherapy

39. FlucytosinFlucytosin
 Fluorinated pyrimidine related to flurouracilFluorinated pyrimidine related to flurouracil
 Restricted spectrum of activity.Restricted spectrum of activity.
 Acquired Resistance due to > result of monotherapyAcquired Resistance due to > result of monotherapy
 Due to:Due to:
1) Decreased uptake (permease activity)1) Decreased uptake (permease activity)
2) Altered 5-FC metabolism (cytosine deaminase or UMP2) Altered 5-FC metabolism (cytosine deaminase or UMP
pyrophosphorylase activity)pyrophosphorylase activity)
Kinetics:Kinetics:
 Orally absorbedOrally absorbed
 Widely distributed even in CSFWidely distributed even in CSF
 Exc. in urine.Exc. in urine.
 Converted in fungal cell to 5-FU which is antimetabolite.Converted in fungal cell to 5-FU which is antimetabolite.
 Mammalian cells remain unaffected except few bone marrow cellsMammalian cells remain unaffected except few bone marrow cells

40. FlucytosinFlucytosin
Monotherapy : NeverMonotherapy : Never
 CandidiasisCandidiasis
 CryptococcosisCryptococcosis
 ?Aspergillosis?Aspergillosis
} In combination with amphotericin B or
fluconazole.
Doses:
1. Vaginal candidiasis: 200 mg OD for 3 days
2. Dermatophytosis; 100-200 mg OD for 7-15 days
3. Onychomycosis: 200 mg per day for 3 months
ADRs: 1.Mild BM depression
2. Loss of hair
3. Dose should be decreased in the presence of renal impairment

41. TerbinafineTerbinafine
 Belongs to a newer allylamine class of antifungalsBelongs to a newer allylamine class of antifungals
 Given both orally & locallyGiven both orally & locally
 Lipophillic so widely distributedLipophillic so widely distributed
 Fungicidal in contrast to azoles (fungistatic)Fungicidal in contrast to azoles (fungistatic)
 Acts by non-competitive inhibition ofActs by non-competitive inhibition of “squalene epoxidase”“squalene epoxidase”
(early step enzyme in ergosterol synthesis (Image in Slide(early step enzyme in ergosterol synthesis (Image in Slide
No. 22) – accumulation of squalene in fungal cells – cidalNo. 22) – accumulation of squalene in fungal cells – cidal
effecteffect
 Used for dermatophytes & candidaUsed for dermatophytes & candida
 Dose is 250mg OD for 2-6 wksDose is 250mg OD for 2-6 wks
 Locally 1% ointmentLocally 1% ointment.

42. Terbinafine – contd.Terbinafine – contd.
ADRsADRs
 With oralWith oral
– GIT upsetGIT upset
– Hepatic dysfunctionHepatic dysfunction
– RashRash
– Taste disturbanceTaste disturbance
– No interaction with CYP450No interaction with CYP450
 Preparations and doses:Preparations and doses:
– 1% cream 125/250 mg tablets etc.1% cream 125/250 mg tablets etc.
– Tinea pedis: 250 mg OD for 2-6 weeksTinea pedis: 250 mg OD for 2-6 weeks
– Onychmycosis: 3-12 months (alternative to fluconazole)Onychmycosis: 3-12 months (alternative to fluconazole)
• On local application -On local application -
ddryness, Erythemaryness, Erythema,, Rash,Rash,
itching etc.itching etc.

43. Expected QuestionsExpected Questions
 Classify antifungals. Write MOA, ADRs and Uses of Amphotericin BClassify antifungals. Write MOA, ADRs and Uses of Amphotericin B
 Classify azoles. Write briefly on MOA and Uses of azolesClassify azoles. Write briefly on MOA and Uses of azoles
 Write briefly on MOA and mechanism of resistance of azolesWrite briefly on MOA and mechanism of resistance of azoles
 MCQs:MCQs:
1.1. Amphotericin B is: fungistatic, fungicidal etc. and other choicesAmphotericin B is: fungistatic, fungicidal etc. and other choices
2.2. Azoles: inhibits ergosterol, inhibits nucleic acid, inhibits microtubule etc.Azoles: inhibits ergosterol, inhibits nucleic acid, inhibits microtubule etc.
3.3. Ketoconazole may cause: cortisol deficiency, testosterone deficiency etc.Ketoconazole may cause: cortisol deficiency, testosterone deficiency etc.
4.4. Griseofulvin causes: destruction of fungal microtubule, inhibits fungal cellGriseofulvin causes: destruction of fungal microtubule, inhibits fungal cell
membrane etc.membrane etc.
5.5. Griseofuvin is best administered: with fatty diet, in empty stomach etc.Griseofuvin is best administered: with fatty diet, in empty stomach etc.
 Short Notes:Short Notes:
– Fluconazole, Griseofulvin, Ketoconazole, Clotrimazole, TerbinafineFluconazole, Griseofulvin, Ketoconazole, Clotrimazole, Terbinafine

44. Thank youThank you