UHN Maret 2011,Pharmacology of antifungal drugs

8/7/2019 UHN Maret 2011,Pharmacology of antifungal drugs

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Pharmacology of antifungal drugs

Dr.Datten Bangun MSc.SpFK

Dept.Farmakologi & TerapeutikFakultas Kedokteran U H N

M E D A N


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Fungal Infection in Humans =

Mycosis

Fungal Infection in Humans =

Mycosis

Major Types of Mycoses

superficial

cutaneous

subcutaneous

systemic

opportunistic

Symptoms vary from cosmetic

to life threatening


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Fungal infectionsFungal infections

Superficial mycosesSuperficial mycoses hair, skin, mucous membraneshair, skin, mucous membranes egegdermatophytosisdermatophytosis (ringworm),(ringworm), candidacandida (thrush,(thrush, intertrigointertrigo))

andand malasseziamalassezia furfurfurfur ((pityriasispityriasis versicolorversicolor))

Subcutaneous mycosesSubcutaneous mycoses dermis,dermis, subcutsubcut and adjacentand adjacentbonesbones egeg mycetomamycetoma,, chromoblastomycosischromoblastomycosis,, sporotrichosissporotrichosis

Systemic mycosesSystemic mycoses

1.1. Inhalation =>pulmonary infection=>disseminated (Inhalation =>pulmonary infection=>disseminated (egeghistoplasmosishistoplasmosis,, coccidioidomycosiscoccidioidomycosis,, blastomycosisblastomycosis))

2.2. OpportunistOpportunist aspergillusaspergillus,, candidacandida,, crytococcuscrytococcus. Patients. Patients

compromised by disease, drugscompromised by disease, drugs


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4

FUNGAL INFECTIONS

Incidence ; increasing trend

Slow onset

Difficult to diagnose & eradicate

Long duration of therapy


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BackgroundBackground -- FungiFungi

3 main groups:3 main groups:

MouldsMoulds reproduce by spores, which may producereproduce by spores, which may produce

mycotoxinsmycotoxins

YeastsYeasts grow by budding, ferment sugarsgrow by budding, ferment sugars

Dimorphic fungiDimorphic fungi capable of changing growthcapable of changing growth


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Facts on Fungi

= Fungal cell membranes have a unique sterol,ergosterol, which replaces cholesterol found inmammalian 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 littlerepetitive DNA.

= Mitosis is generally accomplished withoutdissolution of the nuclear envelope.


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Fungal cell


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BackgroundBackground -- fungifungi

May be:May be:

= pathogenic in all exposed patients (= pathogenic in all exposed patients (egeg

histoplasmahistoplasma capsulatumcapsulatum,, coccidioidescoccidioides immitisimmitis))

= opportunists (= opportunists (egeg candidacandida,, aspergillusaspergillus))

= or cause illness via= or cause illness via mycotoxinsmycotoxins or allergicor allergic

reaction after inhalation of sporesreaction after inhalation of spores


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Fungal infectionsFungal infections

Risks:Risks:

= Exposure (living conditions, occupation and leisure= Exposure (living conditions, occupation and leisure

activities), animal contact, warm climates,activities), animal contact, warm climates,

geographygeography

= AIDS= AIDS

== ImmunosupressionImmunosupression (transplant)(transplant)

= Broad spectrum antibiotics= Broad spectrum antibiotics


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FUNGAL INFECTIONS

SYSTEMIC

HISTOPLASMOSIS

ASPERGILLOSIS

CRYPTOCOCCOSI

BLASTOMYCOSIS

MUCORMYCOSIS CANDIDIASIS

LOCAL

DERMATOPHYTOSIS

SPOROTRICHIOSIS

ZYGOMYCOSIS

CHROMOMYCOSIS

RHINOSPOIDIOSIS


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Common fungal infections

Pityriasis versicolor

Candidiasis : intertrigo,

paronychia , stomatitis,vulvovaginitis

Tinea: corpis, cruris,

barbae, capitis, pedis,

manum, unguium

Histoplasmosis

coccidoiomycosis

blastomycosis

cryptococcosis

aspergillosis

mucormicosis mycetoma


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How do they work?

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

Polyenes, triazoles, and imidazoles

target ergosterol destroying the cell

membranes integrity.

Allylamines inhibit ergosterol

synthesis.

-3-glucan synthase inhibitorblock

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.

Other antifungals such as flucytosine

inhibit DNA/RNA synthesis and

griseofulvin inhibit fungal cell mitosis

preventing cell proliferation and

function.

ANTIFUNGAL AGENTS


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Antifungals

Polyenes Imidazoles Triazole

nystatin

amphotericin

B

miconazole

clotrimazole

ketoconazole

fluconazole

itraconazole

voriconazole

posaconazole

Allylamines

naftifine

terbinafine

butenafine

-3-glucan

synthase

inhibitors

caspofungin

micafungin

anidulafungin

Other

griseofulvin

flucytosine

tolnaftate

Classification in GeneMedRx


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Why is this important?

36% of drugs are

metabolized by

CYP3A4and

antifungals are

largely3A4

inhibitors

Antifungals can

effect up to 60%ofall drugs due

to inhibition of

3A4, 2C9, 2C19,

1A2.Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htmImage from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Antifungal metabolism


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ANTIFUNGALAGENTS

SYSTEMIC ANTIFUNGALS

TOPICAL ANTIFUNGALS

Some are fungistatic,while others are fungicidal


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PATKI 16

Systemic antifungals

1. GRISEOFULVIN

2. AMPHOTERICIN- B3. FLUCYTOSINE

4. IMIDAZOLES

5. TRIAZOLES


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GRISEOFULVIN

FUNGISTATIC :

- MIcrosporum, Epidermophyton Trichophytons

MECHANISM : Inhibition Of Fungal Mitosis , Disruption Of

Mitotic Spindles

KINETICS : Fatty Meal & Microsized Particles -

Increases Absorption, Deposition In Keratin

Cells


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PATKI 18

GRISEOFULVIN

INDICATIONS

Tenia Capitis,

Corporicruris Rubrum Athlets Foot

[Epidermophytosis]

DOSE-10-15 MG/Kg

ADRs-

Headache - 15%

Peripheral Neuropathy Confusion

Antabuse Reaction

Photo Sensitivity

Drug Interactions


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AMPHOTERICINE B

= Member of polyene class of antibiotics.

= Antifungal effect due to interaction with

sterols in membrane, making membranes leaky.

= Has high affinity forergosterol, but also bindsto cholesterol

= severe side effects.

Spectrum: ----

broad-spectrum= candida, Crypt. Blastomyces,Histoplasma,

Aspergillus.

= Limited Activity -Leishmania.

=

No Antibacterial


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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


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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


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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 amphotericin B to interact with the

fungal membrane


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INDICATIONS-DOSE-

0.5-0.6 MG/kg

mucormicosis aspergillosis

sporotrichosis

cryptococcosis


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Flucytosine

MOA Converted by cytosine

deaminase into 5-fluorouracil

which is then converted through

a series of steps to 5-fluorouridine 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

Fluorinated pyrimidine


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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 membraneproduced by amphotericin allows enhanced uptake offlucytosine


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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 activeforms that interfere with DNA synthesis

Resistance occurs frequently and rapidly when flucytosine isgiven as monotherapy

Combination therapy is necessary

Half-life:= 2 to 5 hours in normal renal function= 85 hours in patients with anuria

Distributes into tissues, CSF, and body fluids


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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 inpatients with changing renal function

Contraindicated in pregnancy


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AzolesKetoconazole

Have 5-membered organic rings that contain eithertwo 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 the biosynthesis of cell

membrane sterols.


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AzolesKetoconazole

Uses

Used in U.S. as an alternative Non-albicans candidiasis

Blastomycosis

Histoplasmosis

Not for immunocompromised hosts due to high failure rate

Coccidioidomycosis

Not for meningitis or for severely ill

Paracoccidioidomycosis

Inactive against non-albicans candida and Aspergillus

Needs acidic environment for absorption

Only available PO

Distributes into epidermis, synovial fluid, saliva, and lungs. Poordistribution into CSF and eye.

Dose

200 to 400 mg once daily

Decrease dose for severe liver failure


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AzolesKetoconazole

Adverse Effects

GI distress (17-43%) Rash (4-10%)

Increased transaminases (2-10%)

Hepatitis (1 in 10,000)

Can be fatal if drug is not DCd

Usually occurs within first 4 months of treatment Dose-dependent inhibition of synthesis of testosterone (5-21%

of patients will have symptoms such as impotence orgynecomastia)

Menstrual Irregularities (16% of women)

Alopecia (8%) Dose-related decrease in cortisol synthesis

Hypermineralocorticoid state

Can cause HTN in patients on long-term high doseketoconazole

Teratogenic in animals


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AzolesKetoconazole

Drug Interactions:=Antacids, H2 blockers, proton pump inhibitors,sucralfate----Decreases absorption ofketoconazole

= Rifampin decreases ketoconazole concentrations

by 33%= CYP inhibition-----

Cyclosporine levels increasedWarfarinPhenytoinMethylprednisolone

IsoniazidTerfenadineAstemizoleCisapride


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Triazoles MOA:

Inhibits 14--sterol demethylase, which is a microsomalCYP450 enzyme.

This enzyme is responsible for conversion of lanosterolto ergosterol, the major sterol of most fungal cellmembranes


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TriazolesADMEFluconazole Itraconazole Voriconazole Posaconazole

Absorption IV and PO

Goodbioavailability

PO

Capsule SuspensionCapsules best

absorbed with food.

Suspension best

absorbed on emptystomach.

IV and PO

90% oralbioavailability

PO--Absorption

enhanced withhigh fat meal

Distribution Wide.Good CNS

penetration

Low urinary levelsPoor CNS

penetration

Wide.Good CNS

penetration

Widelydistributed into

tissues

Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19,3A4

Saturablemetabolism

Not a substrate of

or metabolized by

P450, but it is anInhibitor of 3A4

Elimination 80% excreted

unchanged in the

urine

Excreted in feces Minimal renal

excretion

Minimal renal

excretion of parent

compound

66% excreted in

feces


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TriazolesFluconazole Dose

100 to 400 mg daily

Renal impairment:

CrCl >50 ml/min, give full dose

CrCl


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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

Rash

Hypokalemia

Nausea and vomiting


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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


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TriazolesVoriconazole

Common Adverse Effects

Peripheraledema

Rash (6%)

N/V/D Hepatotoxicity

Headache

Visual disturbance (30%)

Fever

Serious Adverse Events

Stevens-Johnson Syndrome

Live

r fa

ilure

Anaphylaxis

Renal failure

QTc prolongation

Drug InteractionsDrug Interactions

Major substrate ofCYP 2CD and 2C19Major substrate ofCYP 2CD and 2C19

Minor substrate ofCYP 3A4Minor substrate ofCYP 3A4

Weak inhibitor ofCYP 2C9 and 2C19Weak inhibitor ofCYP 2C9 and 2C19

Moderate inhibitor ofCYP 3A4Moderate inhibitor ofCYP 3A4

Dose AdjustmentsDose Adjustments

EfavirenzEfavirenz

PhenytoinPhenytoin

CyclosporineCyclosporine

WarfarinWarfarin

TacrolimusTacrolimus


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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 13days

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

GI: Diarrhea


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PATKI 39

TOPICAL ANTIFUNGAL

AZOLES-CLOTRIMAZOLE,ECONAZOLE,

MICONAZOLE,TERCONAZOLE

.BUTOCONAZOLE

CICLOPIROX OLAMINE

HALOPROGIN,BENZOIC+SALICYLIC,TOLN

AFTATE,TERBINAFINE, NYSTATIN

UNDECYLENIC ACID,


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PATKI 40

CLOTRIMAZOLE

fungicidal,1% cream,lotion,vaginal cream

100mg -vaginal tab-o.d-7 days

cure for dermatophytes ,vulvovaginitis, cut.candidiasis-80% success

ADRs-erythema,pruritis,burning sensations


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PATKI 41

Local antifungals

MICONAZOLE

Cream,powder,lotion

,100mg Pessaries, Teniasis,vulvovaginitis

,-80% Success.

Terconazole

Butoconazole-

CICLOPIROX

OLAMINE,

HALOPROGIN , TOLNAFTATE-

TRICHOPHYTONS

AND MICROSPORUM.

TERBINAFINE CREAM


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PATKI 42

NYSTATIN

Useful Only For Candidiasis-cutanious,Oral

Or Vaginal

100,000Units/GmCream,powder.

VaginalTab-twiceADay-2weeks

ADRs- RARE


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PATKI 43

OLDER LOCAL ANTIFUNGALS

BENZOIC ACID 6% &SALICYLIC ACID 3%-

WHITFIELD OINTMENT-TINEA PEDIS.

KERTOLYTIC TOO,

POTASSIUM IODIDE-1 GM/ML-CUTANIOUS

SPOROTRICHIOSIS

GENTIAN VOILET,IODINE,SULPHUR


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ANYQUESTION ??

Thank you

Documents

UHN Maret 2011,Pharmacology of antifungal drugs