Pharmacology of

antifungal drugs

Dr GEORGE KASONDA
MMED PAEDIATRIC
STUDENTS

Fungal
Fungal Infection
Infection in
in
Humans
Humans =
= Mycosis
Mycosis
Major Types of Mycoses
superficial
cutaneous
subcutaneous
systemic
opportunistic

Symptoms vary from cosmetic

to life threatening

Fungal infections
Superficial mycoses hair, skin, mucous
membranes eg dermatophytosis
(ringworm), candida (thrush, intertrigo)
and malassezia furfur (pityriasis
versicolor)

Subcutaneous mycoses dermis, subcut

and adjacent bones eg mycetoma,
chromoblastomycosis, sporotrichosis

Systemic mycoses
1. Inhalation =>pulmonary
infection=>disseminated (eg
histoplasmosis, coccidioidomycosis,

FUNGAL INFECTIONS
Incidence ; increasing
trend
Slow onset
Difficult to diagnose &
eradicate
Long duration of
therapy
4

Background - Fungi
3 main groups:
Moulds

reproduce by spores, which may

produce mycotoxins

Yeasts

grow by budding, ferment sugars

Dimorphic fungi
growth

capable of changing

Facts on Fungi
= Fungal cell membranes have a
unique sterol, ergosterol, which
replaces cholesterol found in
mammalian cell membranes
= Tubule proteinproduction of a
different type in microtubules
formed during nuclear division.
= Chitin biosynthesis occurs in fungi.
= Most fungi have very small nuclei,
with little repetitive DNA.
= Mitosis is generally accomplished
without dissolution of the nuclear
envelope.

Fungal cell

Background - fungi
May be:
= pathogenic in all exposed patients (eg
histoplasma capsulatum, coccidioides
immitis)
= opportunists (eg candida, aspergillus)
= or cause illness via mycotoxins or
allergic reaction after inhalation of
spores

Fungal infections
Risks:
= Exposure (living conditions, occupation
and leisure activities), animal contact,
warm climates, geography
= AIDS
= Immunosupression (transplant)
= Broad spectrum antibiotics

FUNGAL INFECTIONS
SYSTEMIC
HISTOPLASMOS
IS
ASPERGILLOSIS
CRYPTOCOCCOS
I
BLASTOMYCOSI
S
MUCORMYCOSIS
CANDIDIASIS

LOCAL
DERMATOPHYT
OSIS
SPOROTRICHIO
SIS
ZYGOMYCOSIS
CHROMOMYCOS
IS
RHINOSPOIDIOS
IS

Common fungal
infections
Pityriasis
versicolor
Candidiasis :
intertrigo,
paronychia ,
stomatitis,
vulvovaginitis
Tinea: corpis,
cruris, barbae,
capitis, pedis,
manum, unguium

Histoplasmosis
coccidoiomycosi
s
blastomycosis
cryptococcosis
aspergillosis
mucormicosis
mycetoma

ANTIFUNGAL AGENTS

do they work?
Polyenes, triazoles, and imidazoles
target ergosterol destroying the cell
membranes integrity.
Allylamines inhibit ergosterol
synthesis.
-3-glucan synthase inhibitor block
the production of the -(1,3)-glucan
protein damaging the cell wall.
Every component of the cell wall and
membrane can be targeted. Drugs not
available in the market such as
Nikkomycin and Polyoxin target chitin
synthase. Mannoproteins are another
potential target.

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Other antifungals such as flucytosine

inhibit DNA/RNA synthesis and
griseofulvin inhibit fungal cell mitosis
preventing cell proliferation and
function.

Classification in GeneMedRx
Antifungals
Polyenes Imidazoles Triazole

-3-glucan
Allylaminessynthase
inhibitors

Other

nystatin miconazolefluconazolenaftifine caspofungingriseofulvin

amphotericin
clotrimazoleitraconazole
terbinafinemicafunginflucytosine
voriconazole
butenafine
tolnaftate
ketoconazole
anidulafungin
posaconazole

Antifungal metabolism
Why is this important?

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

36% of drugs
are
metabolized
by CYP 3A4
and
antifungals
are largely
3A4 inhibitors
Antifungals can
effect up to
60% of all
drugs due to
inhibition of

ANTIFUNGAL AGENTS
SYSTEMIC ANTIFUNGALS
TOPICAL ANTIFUNGALS
Some are fungistatic,
while others are fungicidal

Systemic antifungals
1. GRISEOFULVIN
2. AMPHOTERICINB
3. FLUCYTOSINE
4. IMIDAZOLES
5. TRIAZOLES
GEORGE

16

GRISEOFULVIN
FUNGISTATIC :
- MIcrosporum, Epidermophyton
Trichophytons

MECHANISM :
Inhibition Of Fungal Mitosis ,
Disruption Of Mitotic Spindles
KINETICS :
Fatty Meal & Microsized
Particles - Increases
Absorption, Deposition In

GRISEOFULVIN
INDICATIONS
Tenia Capitis,
Corporicruris
Rubrum
Athlets Foot
[Epidermophyto
sis]
DOSE-10-15
MG/Kg
GEORGE

ADRs Headache - 15%

Peripheral
Neuropathy
Confusion
Antabuse
Reaction
Photo Sensitivity
Drug
Interactions
18

AMPHOTERICINE B
= Member of polyene class of antibiotics.
= Antifungal effect due to interaction with
sterols in membrane, making membranes leaky.
= Has high affinity for ergosterol, but also binds
to cholesterol
= severe side effects.
Spectrum: ---- broad-spectrum
= candida, Crypt. Blastomyces,Histoplasma,
Aspergillus.
= Limited Activity -Leishmania.
= No Antibacterial

AMPHOTERICINE B
KINETICS
= No Git absorption,--- digunakan
per-oral utk
infeksi jamur diusus
= 90% Bound To Proteins
= Un Changed Elimination,
= Elimination Half Life-15 Days

Adverse drug reactions

I.Infusion related toxicity:
-chills & fever ,muscle spasm
vomitting,headache,hypotension
II. Slower toxicity:
- renal damage is the most significant toxic rx.
-bronchospasm, azotemia, hypokalemia
- Liver function abnormalities

Amphotericin B
Resistance
Susceptibility testing methods have
not been standardized
Development of resistance in a
previously susceptible species is
uncommon
Mechanisms of Resistance
Reductions in ergosterol
biosynthesis
Synthesis of alternative sterols
that lessen the ability of

 INDICATIONSDOSE-0.5-0.6
MG/kg
mucormicosis
aspergillosis
sporotrichosis
cryptococcosis

mal to be reviewed

Flucytosine
MOA

Fluorinated pyrimidine

Converted by cytosine
deaminase into 5-fluorouracil
which is then converted through
a series of steps to 5fluorouridine triphosphate and
incorporated into fungal RNA
leading to miscoding
Also converted by a series of
steps to 5-fluorodeoxyuridine
monophosphate which is a
noncompetitive inhibitor of
thymidylate synthase, interfering
with DNA synthesis

Flucytosine
Spectrum of Activity
Active against
Candida species except C. krusei
Cryptococcus neoformans
Aspergillus species
Synergy with amphotericin B has been
demonstrated
The altered permeability of the fungal
cell membrane produced by
amphotericin allows enhanced uptake
of flucytosine

Flucytosine
Mechanisms of Resistance
Loss of cytosine permease that permits
flucytosine to cross the fungal cell
membrane
Loss of any of the enzymes required to
produce the active forms that interfere with
DNA synthesis
Resistance occurs frequently and rapidly
when flucytosine is given as monotherapy
Half-life:
Combination therapy is necessary

= 2 to 5 hours in normal renal function

= 85 hours in patients with anuria
Distributes into tissues, CSF, and body
fluids

Flucytosine
Toxicities
Bone marrow suppression (dose
dependent)
Hepatotoxicity (dose dependent)
Enterocolitis
Toxicities occur more commonly in patients
with renal impairment

Dose
Administered orally (available in 250 and
500 mg capsules)
100 to 150 mg/kg/day in 4 divided doses
Dose adjust for creatinine clearance
Flucytosine concentrations should be
monitored especially in patients with
changing renal function

AzolesKetoconazole
Have 5-membered organic rings that
contain either two or three nitrogen
molecules (the imidazoles and the
triazoles respectively).
= The clinically useful imidazoles are
clotrimazole, miconazole, and
ketoconazole.
=Two important triazoles are
itraconazole and fluconazole. In
general, the azole antifungal agents
are thought to inhibit cytochrome
P450-dependent enzymes involved in

AzolesKetoconazole
Drug Interactions:

= Antacids, H2 blockers, proton pump inhibitors,

sucralfate----Decreases absorption of
ketoconazole
= Rifampin decreases ketoconazole concentrations
by 33%
= CYP inhibition-----
Cyclosporine levels increased
Warfarin
Phenytoin
Methylprednisolone
Isoniazid
Terfenadine
Astemizole
Cisapride

Triazoles
MOA:

Inhibits 14--sterol demethylase, which

is a microsomal CYP450 enzyme.
This enzyme is responsible for
conversion of lanosterol to ergosterol,
the major sterol of most fungal cell
membranes

TriazolesADME
Fluconazole
Absorption

IV and PO
Good
bioavailability

Itraconazole
PO
Capsule Suspension

Capsules best
absorbed with food.
Suspension best
absorbed on empty
stomach.

Voriconazole

Posaconazole

IV and PO
90% oral
bioavailability

PO--Absorption
enhanced with
high fat meal

Distribution Wide.
Good CNS
penetration

Low urinary levels

Poor CNS
penetration

Wide.
Good CNS
penetration

Widely
distributed into
tissues

Metabolism Hepatic/Renal

Hepatic

CYP 2C9, 2C19,

3A4
Saturable
metabolism

Not a substrate of
or metabolized by
P450, but it is an
Inhibitor of 3A4

Minimal renal
excretion

Minimal renal
excretion of parent
compound
66% excreted in
feces

Elimination 80% excreted

Excreted in feces
unchanged in the
urine

TriazolesFluconazole
Dose
100 to 400 mg daily
Renal impairment:
CrCl >50 ml/min, give full dose
CrCl<50 ml/min, give 50% of dose
Dialysis: replace full dose after each session

Drug Interactions
Minor inhibitor of CYP 3A4
Moderate inhibitor of CYP 2C9
Warfarin, phenytoin, cyclosporine, tacrolimus,
rifampin/rifabutin, sulfonylureas

Adverse Drug Reactions

Well tolerated
Nausea
Elevated LFTs

TriazolesItraconazole

Dose
200 to 400 mg/day (capsules)
doses exceeding 200 mg/day are given in 2 divided
doses
Loading dose: 200 mg 3 times daily can be given
for the first 3 days
Oral solution is 60% more bioavailable than the
capsules
Drug Interactions
Major substrate of CYP 3A4
Strong inhibitor of CYP 3A4
Many Drug Interactions
Adverse Drug Reactions
Contraindicated in patients with CHF due to negative
inotropic effects
QT prolongation, torsades de pointes, ventricular
tachycardia, cardiac arrest in the setting of drug
interactions
Hepatotoxicity

TriazolesVoriconazole
Dose
IV
6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV
every 12 hours

PO
> 40 kg200-300 mg PO every 12 hours
< 40 kg100-150 mg PO every 12 hours

Cirrhosis:
IV
6 mg /kg IV for 2 doses, then 2 mg/kg IV every
12 hours

PO
> 40 kg100 mg PO every 12 hours
< 40 kg 50 mg PO every 12 hours

Renal impairment:
if CrCl<50 ml/min, use oral formulation
to avoid accumulation of cyclodextrin

TriazolesVoriconazole
Drug Interactions
Major substrate of CYP 2CD and 2C19
Minor substrate of CYP 3A4
Weak inhibitor of CYP 2C9 and 2C19
Moderate inhibitor of CYP 3A4

Common Adverse
Effects
Peripheral edema
Rash (6%)
N/V/D
Hepatotoxicity
Headache
Visual disturbance
(30%)

Dose Adjustments
Efavirenz
Phenytoin
Cyclosporine
Warfarin
Tacrolimus

Serious Adverse Events

Stevens-Johnson Syndrom
Liver failure
Anaphylaxis
Renal failure
QTc prolongation

TriazolesPosaconazole

Dosing (only available PO)

Prophylaxis of invasive Aspergillus and Candida
species
200 mg 3 times/day
Treatment of oropharyngeal candidiasis
100 mg twice daily for 1 day, then 100 mg
once daily for 13 days
Treatment or refractory oropharyngeal
candidiasis
400 mg twice daily
Treatment of refractory invasive fungal
infections (unlabeled use)
800 mg/day in divided doses
Drug Interactions
Moderate inhibitor of CYP3A4
Adverse Reactions
Hepatotoxicity
QTc prolongation

TOPICAL ANTIFUNGAL
AZOLESCLOTRIMAZOLE,ECONAZOLE,
MICONAZOLE,TERCONAZOLE .
BUTOCONAZOLE
CICLOPIROX OLAMINE
HALOPROGIN,BENZOIC+SALIC
YLIC,TOLNAFTATE,TERBINAFI
NE, NYSTATIN
UNDECYLENIC ACID,
GEORGE

39

CLOTRIMAZOLE
fungicidal,1% cream,lotion,vaginal
cream
100 mg -vaginal tab-o.d-7 days
cure for dermatophytes
,vulvovaginitis,
cut.candidiasis-80% success
ADRs-erythema,pruritis,burning
sensations
GEORGE

40

Local antifungals
MICONAZOLE
Cream,powder,l
otion ,100mg
Pessaries,
Teniasis,vulvov
aginitis,-80%
Success.
Terconazole
ButoconazoleGEORGE

CICLOPIROX
OLAMINE,
HALOPROGIN ,
TOLNAFTATETRICHOPHYTON
S AND
MICROSPORUM.
TERBINAFINE
CREAM
41

NYSTATIN
Useful Only For Candidiasiscutanious, Oral Or Vaginal
100,000 Units/Gm Cream,powder.
Vaginal Tab-twice A Day-2weeks
ADRs- RARE

GEORGE

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OLDER LOCAL
ANTIFUNGALS
BENZOIC ACID 6% &SALICYLIC
ACID 3%-WHITFIELD OINTMENTTINEA PEDIS. KERTOLYTIC TOO,
POTASSIUM IODIDE-1 GM/MLCUTANIOUS SPOROTRICHIOSIS
GENTIAN
VOILET,IODINE,SULPHUR

GEORGE

43

ANY QUESTION ??

Thank

you