Antifungal

ANTIFUNGAL AGENTS.
Mocha Clifford.
Intro.
2
 Antifungal drugs are used for treatment

of superficial and deep (systemic) fungal
infections.
 Antifungal drugs available fall in several
categories namely:
 Systemic (oral or parenteral) for
systemic infections
 Topical drugs for mucontaneous
infections
Nmtc Series.Mocha Clifford 11/02/2024
Mode of action;
3
 Antifungals work by exploiting differences

between mammalian and fungal cells to kill
the fungal organism without dangerous
effects on the host.
 Unlike bacteria, both fungi and humans are
eukaryotes.
 Thus fungal and human cells are similar at
the molecular level.
Cont.
4
 This makes it more difficult to find or

design drugs that target fungi without
affecting human cells.
 Consequently, many antifungal drugs
cause side-effects.
 Some of these side-effects can be life-
threatening if the drugs are not used
properly.
Classification
 Antibiotic
 Polyenes
 Amphotericin B
 Nyastastin
 Heterocyclic benzofuran
 Grisefulvin
 Antimetabolites
 Flucytosine

Cont.
6
 Azoles
 Imidazoles
 Clotrimazole
 Econazole
 Miconazole
 Ketaconazole

Cont.
7
 Triazoles
 Fluconazole
 Itraconazole
 Voriconazole
 Allylamine
 Terbinafine
 Other topical agents

Polyene antifungals
 The polyene antimycotics bind with sterols in

the fungal cell membrane, principally
ergosterol.
 Animal cells contain cholesterol instead of
ergosterol and so they are much less
susceptible.
 As a polyene's hydrophobic chain is shortened,
its sterol binding activity is increased.
Therefore, further reduction of the hydrophobic
chain may result in it binding to cholesterol,
making it toxic to animals.
Cont.
9
 Examples include;
o Nystatin
o Amphotericin B
o Candicin
o Natamycin
o Rimocidin
o Filipin

Cont.
10
1. AMPHOTERICIN B
Pharmacokinetics
 Amphotericin B is poorly absorbed from the G.I.T.
 Oral amphotericin B is effective only on fungi within
the GIT lumen when given IV it is extensively bound to

plasma proteins.
 It is widely distributed in most tissues and only 3% of
blood level is attained in CSF.

 It is metabolised in the liver (60%) and slowly excreted
in urine over a period of several days. It is also

excreted in urine over a period of several days.
 It is also excrete in bile. Has a half life of 15 hours

Cont.
11
Mechanism of action
 It is a fungicidal drug which binds to
ergosterol cell membrane sterol and

alters the permeability of the cell
membrane through formation.
 The pores allow leakage of ions and
macromolecules resulting in cell death.

Cont.
12
Antifungal spectrum
 Candida albicans
 Histoplasma capsulatum
 Cryptococcus neoformans
 Blastomyces dermatitidis
 Coccidioides immitis
 Aspergillus
Indications
 Progrssive dismeminated mycotic infections
 leidimiasis

Cont.
13
Precautions Drug interactions
 Hepatic function  Enhances

tests nephrotoxitity of
 renal function tests drugs nephrotoxic
agents e.g
 renal impairment  antineoplastic drugs
 blood counts  corticosteroids
 breastfeeding  muscle relaxants
 avoid rapid infusion  digitalis glycosides
Cont.
14
Contraindications
 Allergy to amphotericin B
Side effects
 Anaphylactic shock
 Pseudomembranous colitis
 Nephrotoxicity
 GIT disturbances-anorexia, nausea,vomiting, diarrhoea
 hepatotoxicity
 chills
 febrile reactions fever
 headache
 encephalopathy

Cont.
15
Preparations
 Infusions 50mg/vial
 Tablets 100mg
Dose
 100 – 200mg QID(infant/neonate 100mg QID)
 infusion 0.25mg/kg increase by img/kg by
slow infusion of 5% glucose

Common names
 Fungizone, fungilin, tericin

Cont.
16
2. NYSTATIN
 Nystatin is a polyene macrolide obtained from
5. noursei.
 It has similar antifungal action and properties
with amphotericin B it has high systemic

toxicities hence it is used locally/topically only.
 It is not absorbed from the GIT when given
orally
Mechanism of Action
 As amphotericin B

Cont.
17
Indications
 Candidiasis
 Vaginal candidiasis
 Orophoryngeal thrus
 Intertriginous candidal infections
 Intestinal candidiasis
Preparations
 Creams
 Ointment
 Suppositories
 Pessaries
 Tablets 500000 iu
 Drops/suspension 100000iu/ml

Cont.
18
Dose
 500000-100000IU QID(I – iiQID)
 Children 100000IU QID
Side effects
 Nausea/vomiting
 Diarrhoea – high doses
 Oral irritation and sensitization
 Urticaisa/rash
 Steven-Johnson syndrome (rare)
Common names
 Labstain, Mycostatin, nystatin, unistatin, mycodeal

Heterocyclic benzofurancs
19
1. GRISEOFULVIN
 Griseofulvin is an insoluble fungistatic drug derived from
penicillum griseofulvum.
 It is active against most darmatopytes including
epidermopluyton,
 Trichopyture and microsporum.
 It is not active against candida and other fungi causing deep
mycosis.
Mechanism of action
 It interferes with mitosis resulting in multinucleated and
stunted fungal hyphae.

 It also causes abnormal metaphase but does not arrest the
process of metaphase. It disorientates microtubules during

polymerization.
Cont.
20
 Griseofulovin does not kill fungus already established

but prevents infection of new keratin where it binds and
protects the tissue from new infection.
 It is normally deposited in keratin of newly forming
skin.
 This is the reason why it must be administered for 4-6
weeks for skin and hair infections to allow replacement
of infected keratin by the resistant structures.
 Nail infections will require longer periods of treatment
to allow regrowth of new protected nail.
 Treatment should be continued for a few weeks after
visual and macrosscospic evidence of infection
disappeared.
Cont.
21
Pharmacokmetics
 It is absorbed irregularly form the GIT due to its
nary low solubility in water.

 This can be improved by taking it with fat.
 It gets deposited in keratin forming cells of the
slain, hairs and nails. It is we concentrated and

retained in tenia infected cells.
 It is metabolized in the liver primarily by
methylation and induces hepatic enzymes.

 Has a plasma t1d/2 of 24 hours but it persists for
weeks in the skin and keratin. Excreted in urine.

Cont.
22
Indications
 Fungal infections of ski, hair and nails
 It is ineffective against pityriasis vesicular, superficial
candidiasis and all systemic mycoses.
Precautions
 Hepatic disorder.
Contraindications
 Severe Liver Disease
 Pregnancy (During And 1 Month After)
 Men Should Not Father Children Within 6 Months Of Treatment.
 Brend Feeding
 S.L.E
 Porphyria.

Cont.
23
Drug interaction
 Enhance alcohol effects/intolerance
 reduce response to barbiturates (reduces
oral absorption) and anticoagulants

(induces warfarin metabolism)
 Reduces efficacy of oral contraceptives.

Cont.
24
Side effects Side effects

 GIT disturbances-  Oral contraceptive failure
nausea, vomiting,
 Blood dysciasice
 Break through bleeding.
diarrhoea,  Confusion
 Skin rordies  Impaired
 photosensitivity judgement/coordination.
 Hepatotoxicity.
 Headache  Oral throash
 Dizziness  sleep disturbances
 Fatigue
 peripheral nueropthy

Cont.
25
Preparation
 Tables 125 mg. 250, mg & 500mg
Dose
 500-1000 mg 00
Children 10mg/kg
 Duration of treatment depends on site of infection,
thickness of infected keratin and turnover of the

keratin.
 Thus body skin (3/52) palms and soles (4-6/52), finger
nails (4-6/12 and toe nails (8-12/12)

Common names
 Griseofulvin fulcin, griseofil, grisovin grise

Anti-metabolites
26
1. FLUCYTOSINE (5 – FC)
 Is a pynocidine analogue antimetabolic which is related to
fluorouracil (5 – FU). Its spectrum is narrower than
amphotericins B
Mechanism of action
 Flucytosine (5FC) is metabolized in the fungal cell to 5 –
fluouracil (5FU) which inhibits nucleic acid synthesis. It is a

narrow spectrum fungistatic agent
Spectrum
 Cryptococcus neoformans
 Torula
 Chlomoblastomyces
 Few species of candida

Cont.
27
Pharmacokinetics
 It is well absorbed from the gut and penetrates
effectively into almost all tissues.

 It has a half life of 4 hours and excreted unchanged
in urine. It is advisable to reduce the dose in renal

failure
Indications
 Systemic yeast and fungal infections
 adjuvant to amphotericin B or fluconazole in
cryptoccoccal meningitis
 Adjuvant to amphotericin B in severe systemic
candidiasis
Cont.
28
Precautions Side effects

 renal impairment  GIT disturbances
 blood disorders –
 elderly leucopenia, mild anaemia
 blood disorders and thrombocytopaia
 hepatic impairment
 convulsions
 confusion
 weekly blood counts  hallucinations
 pregnancy  headache
 lactation  sedation
 vertigo
Cont.
29
2) Azole Antifungals
 Imidazole
 triazole, and
 thiazole antifungals;
 Azole antifungal drugs inhibit the enzyme
cytochrome P450 CYP51 and14α-demethylase;
the enzyme necessary to convert lanosterol to
ergosterol.
 Depletion of ergosterol in fungal membrane
disrupts the structure and many functions of
fungal membrane leading to inhibition of fungal
growth
Imidazoles;
30
 Miconazole
 Ketoconazole
 Clotrimazole
 Econazole
 Bifonazole
 Isoconazole

Cont.
31
1. KETACONAZOLE (Nizoral)
 It as the first oral azole introduced into clinical
use.
 It is useful in both dermatophytes and deep
mycoses.
Mechanism of action
 Impairs synthesis of orgostarol, the reainstrerol
of fungal cell rembrases causing increased

permeability and leakage of cellular components
leading to cell death.
 This results from inhibition of cyp 450 enzymes.

Cont.
32
Indications
 Fungal infections (deep or superficial) due to
dermatophytes and yeasts.

 Advanced cancer of the prostate inhibits testicular and
adoenal steroid synthesis.

 Adjurant in management of D/C association with
prostatic cancer.
 Systemic mycoses
 Serios chromic resistant mucotaneous cardidiasis.

 Serios resistant vaginal condidiasis. Gift mycoses.
 Resistant dermatophyte infectionsofthe sian or finger nails.
 Prophylaxis of mycoses in immunosuppressed patients.

Cont.
33
Pharmacokinetics
 It is well absorbed from GIT (poor with hypoacidity)
and is well distributed in tissues but low

concentrations in csf and urine.
 Actions is terminated by metabolism by C4503A
( CYP 3A).. Inhibition of testosterone systhesis leads

to reduced bone pain in advanced androgenic
dependent prostatic cancer.
Precautions
 Monitor livers function.
 Avoid drugs that reduced gastric secretions.
 Adrenal insufficiency.

Cont.
34
Contraindications
 Pregnancy
 Lactation.
 Hepatic disorders
 Concomittant admistration with terfenadine.
Drug Interaction
 Ritampian, phenytoin, alcohol.
 Drugs that reduce gastric acidity antalids, h2 receptor
 Antagonists reduce absorption of ketaconazole.
 Ketaconazole blinds strongly to cp 450 180 enzymes and
thus inhibit metabolism (and increased effects) of oral

anticoaglants and phenytoin.
 Increases risk of cordiac arrhythmias with terfenarine.

Cont.
35
Side Effects
 GIT Disturbances – Nausea/vomiting.
 Headache.
 Rashes
 Anaphylatis.
 Gynaecomastia.
 Dizzines.
 Alopecia
 Reduced libids.
 Photophosia.
 Thrombocytopenia.
 Impaired hepatic.

Cont.
36
Preparations
 Tablets 200mg.
 Cream
 Oritment
 Shampoo.
Dose
 200-400 mg (MAX 1.2gm) Daily
 Resistant vaginal candidiasis 200-400mg 00x1/52
 Children 3mg 1kg/day
 NOTE: Take after meals.
Common names
 Nizoral, Hitoral, Ketaconazole, ketocos, ketasin, Aquaisus.

Miconazole (daktarin)
37
 Miconazole is a highly efficacious drug for tinea, pityriasis,

versicolor, otomycosis, cutaneous and vulvovaginal
candidiasis.
 It is administered as a topical application
Indications
 Fungal infections – skin oropharynx
Preparations
 Cream
 oral gel
 spray
 vaginal pessaries
Contraindications
 Hepatic impairment

Cont.
38
Precautions
 pregnancy
 lactation
 porplyia
Side effects
 GIT disturbances – nausea, vomiting, diarrhoea
 local irritation
 hypersensitivity reactions
Dose
 Apply OD or BD x 2/52 then upto 10/7 after the lesions disappear
Daktarin
 Miconazole, Micogel, micarin,fungistat, dermidex CLOTRIMAZOLE
(canesten)
 Clotrimazole is an effective topical azole for dermatophytes, yeast and
other fungal infections such as intertrigo, athlete’s foot, ring worm,

potyriasis, versicolor and fungal happy rash
Cont.
39
Preparations
 Cream
 Pessaries
 vaginal tablets
 vaginal cream
Common names
 Bulkot, candid, candistan, canesten,
habesten, candistat, candid V6

combination
Triazoles;
40
Newer, less toxic and more effective.

These include;
 Fluconazole
 Itraconazole
 Isavuconazole
 Ravuconazole
 Posaconazole
 Voriconazole
 Terconazole

Cont.
41
1. FLUCONAZOLE
 Fluconazole is newer water soluble triazole
with a wider spectrum of activity them

ketaconazole.
Antifungal Spetrum
 Cryptococal meningitis.
 Systemic and mucosal candidiasis in both
normal and immune compromised patients

 Coccidioidal meningitis.
 Histoplasmosis.

Cont.
42
Pharmacokinetics
 Fluconazole is well absorbed from the GIT.
 It has high oral bisaxail ability and is not affected by food/gastric
PH.
 It is widely distributed in body tissues and paetrates the CSF well.
 Fungicidal concentrations are achieved in nails vagina and saliva.
 It is largely excreted unchanged in urine hence the dose should be
reduced in renal insufficiency.

Indications
 Persistent candidial and cryptococcal infections.
 Prophylaxis in corditions predisposing to candidial infections.
 Tinea, pedis,corporits, cures
 Pityriasis vericolor

Cont.
43
Precautions
 Renal impairment
 Breast feeding
 Pregnancy
 Hepatic impairment
 Concomittant administration with terfenadive.
Contrandications
 High doses in renal failure
Side effects
 GIT disturbances-nause, vomiting, abdominal pain, diarrhoea,
flatulence.
 Rash.
 Headache
 Renal disturbances

Cont.
44
 Haematological disturbances-laucopenia, prolonged

prothombin time, thrombocytopenia.
 Alopenia
 Anaphylaxis
 Steve-Johnson Syndrome (increased risk in HIV/AIDS)
 Taste disturbances.
Drug interactions
 High doses increase effects of plenytoin zidovudin and
warfarin, cyxloserine, sulphylureas

Preparations
 capsules 50mg ,150 mg, 200mg
 syrup 50 mg/5mls
 IV infusion 2mg/ml

Cont.
45
Dose
 Acute/recurrent vaginal candidiasis – 150mg stat
 Non – vaginal mucosal candidiosis – 50 g OD X 7 –
30/7
 Systemic candidiasis + cryptococcal infection IV or PO
400mg initially then 200 – 400mg OD X 6/52

 Prophylaxis after cytotoxic chemotherapy or
radiotheraphy 50 – 100mg OD
 Children >1 year 1 – 6 mg/kg
Common names
 Diconazol, Flucon, Fluconazole, Fluzone, Flucozal,
Zorcan, Jeflam, Triconazol

Cont.
46
2. ITRACONAZOLE
 Itraconazole is available in oral and intravenous
formulations and is used at a dosage of 100–400

mg/d.
 Drug absorption is increased by food and by low
gastric pH.
 Like other lipid-soluble azoles, it interacts with
hepatic microsomal enzymes, though to a lesser

degree than ketoconazole.
 An important drug interaction is reduced
bioavailability of itraconazole when taken with

rifamycins (rifampin,rifabutin,rifapentine).
Cont.
47
3. VORICONAZOLE
 Voriconazole is available in intravenous and
oral formulations.
 The recommended dosage is 400 mg/d. The
drug is well absorbed orally,with a

bioavailability exceeding 90%, and it exhibits
less protein binding than itraconazole.
 Metabolism is predominantly hepatic.
 Voriconazole is less toxic than amphotericin B
and is the treatment of choice for invasive

aspergillosis.
Cont.
48
 Thiazoles;
 Abafungin

Allylamines;
49
 Allylamines inhibit squalene epoxidase,

another enzyme required for ergosterol
synthesis: examples include;
o Terbinafine
o Amorolfine
o Naftifine
o Butenafine

Cont.
50
3. TERBINAFINE
 Terbinafine is a synthetic allylamine that
is available in an oral formulation and is

used at a dosage of 250 mg/d. It is used
in the treatment of dermatophytoses,
especially onychomycosis.
 One tablet given daily for 12 weeks
achieves acure rate of up to 90% for

onychomycosis and is more effective than
griseofulvin or itraconazole.
Cont.
51
4) Echinocandins;
 Echinocandins inhibit the synthesis of

glucan in the cell wall, probably via the
enzyme 1,3-β glucan synthase:
examples include;
o Anidulafungin
o Caspofungin
o Micafungin

Cont.
52
5) Others;
 Benzoic acid – has antifugal properties but

must be combined with a keratolytic agent
such as salicylic acid (as in Whitfield's
Ointment)
 Other examples include;
o Ciclopirox – most useful against Tinea versicolour
o Tolnaftate
o Griseofulvin – binds to polymerized microtubules and
inhibits fungal mitosis
o Haloprogin – discontinued due to side effects
Anti-dandruff shampoos;
53
 Antifungal drugs (such as ketoconazole) are
often found in anti-dandruff shampoos.
 The antifungal drugs inhibit the yeast
Malassezia globosa which encourages
seborrhoeic dermatitis and tinea versicolor.

Mechanism of action;
54
Like amphotericin B and natamycin,


nystatin binds to ergosterol, a major

component of the fungal cell membrane.
When present in sufficient

concentrations, it forms pores in the

membrane that lead to K+ leakage and
death of the fungus.
Ergosterol is fairly unique to fungi, so the

drug does not have such catastrophic

effects on animals.
Topical antifungal therapy
55
1. NYSTATIN
 Nystatin is a polyene macrolide much like
amphotericin B. It is too toxic for parenteral

administration and is only used topically.
 Nystatin is currently available in creams,
ointments,suppositories, and other forms for

application to skin and mucous membranes.
 Nystatin is active against most Candida sp
and is most commonly used for suppression

of local candidal infections.
Cont.
56
2. TOPICAL AZOLES
 Oral clotrimazole troches are available
for treatment of oral thrush and are a

pleasant tasting alternative to nystatin
 In cream form, both agents are useful for
dermatophytic infections, including tinea

corporis, Tinea pedis, and tinea cruris.

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ANTIFUNGAL AGENTS.

 Antifungal drugs are used for treatment

 Antifungals work by exploiting differences

 This makes it more difficult to find or

Nmtc Series.Mocha Clifford 11/02/2024

Nmtc Series.Mocha Clifford 11/02/2024

Nmtc Series.Mocha Clifford 11/02/2024

 The polyene antimycotics bind with sterols in

Nmtc Series.Mocha Clifford 11/02/2024

 Oral amphotericin B is effective only on fungi within

the GIT lumen when given IV it is extensively bound to

blood level is attained in CSF.

in urine over a period of several days. It is also

Nmtc Series.Mocha Clifford 11/02/2024

ergosterol cell membrane sterol and

macromolecules resulting in cell death.

Nmtc Series.Mocha Clifford 11/02/2024

Nmtc Series.Mocha Clifford 11/02/2024

Precautions Drug interactions

 Hepatic function  Enhances

Nmtc Series.Mocha Clifford 11/02/2024

 infusion 0.25mg/kg increase by img/kg by

slow infusion of 5% glucose

Nmtc Series.Mocha Clifford 11/02/2024

with amphotericin B it has high systemic

Nmtc Series.Mocha Clifford 11/02/2024

Nmtc Series.Mocha Clifford 11/02/2024

 Children 100000IU QID

 Diarrhoea – high doses

 Oral irritation and sensitization

 Steven-Johnson syndrome (rare)

Nmtc Series.Mocha Clifford 11/02/2024

 It is not active against candida and other fungi causing deep

stunted fungal hyphae.

process of metaphase. It disorientates microtubules during

 Griseofulovin does not kill fungus already established

nary low solubility in water.

 It gets deposited in keratin forming cells of the

slain, hairs and nails. It is we concentrated and

methylation and induces hepatic enzymes.

weeks in the skin and keratin. Excreted in urine.

 Pregnancy (During And 1 Month After)

 Men Should Not Father Children Within 6 Months Of Treatment.

Nmtc Series.Mocha Clifford 11/02/2024

 reduce response to barbiturates (reduces

oral absorption) and anticoagulants

Nmtc Series.Mocha Clifford 11/02/2024

Side effects Side effects

Nmtc Series.Mocha Clifford 11/02/2024

thickness of infected keratin and turnover of the

nails (4-6/12 and toe nails (8-12/12)

Nmtc Series.Mocha Clifford 11/02/2024

fluouracil (5FU) which inhibits nucleic acid synthesis. It is a

 Few species of candida

Nmtc Series.Mocha Clifford 11/02/2024

effectively into almost all tissues.

in urine. It is advisable to reduce the dose in renal

 adjuvant to amphotericin B or fluconazole in

Precautions Side effects

Nmtc Series.Mocha Clifford 11/02/2024