Course content

Chemotherapeutic agents

Mechanism of actions

Indications

Contraindications/Cautions

Drug interactions

Side-effects/Adverse reactions

Dosage regimen (occasionally)

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Reference Books

Pharmacology by Rang, Dale, Ritter, Gardner

Clinical Pharmacology textbooks

British National Formulary (BNF)

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Antifungal

agents

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Most fungi are commensals or live in the environment.

But increasing incidence and severity of human fungal infections

Fungal infections are termed mycoses and in Generally can be divided into:

1) Superficial infections

2) Cutaneous infections

3) Sub-cutaneous infections

4) Systemic infections

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candidiasis

ringworm

histoplasmosis

blastomycosis

mucorymycosis

FUNGAL INFECTIONS

Factors increasing incidence and severity

of human fungal infections

Widespread use of broad-spectrum antibiotics (antimicrobial drugs)

Reduced immune responses caused by AIDS

Use of immunosuppressant drugs

Administration of anticancer drugs (cancer chemotherapy)

Chronic use of steroids (spreading of an infection)

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FUNGAL INFECTIONS

Fungal infections are usually more difficult to

treat than bacterial infections

Fungal organisms grow slowly

Fungal infections often occur in tissues that

are poorly penetrated by antimicrobial agents

Eg: devitalized or avascular tissues

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ANTIFUNGAL AGENTS

The Azoles

Griseofulvin

Flucytosine

The polyenes

Echinocandin antifungals (new)

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I. Antifungals damaging permeability of the cell

membrane

• Imidazoles: Bifonazole, Clotrimazole, Econazole,

Ketoconazole, Miconazole

• Triazoles: Fluconazole, Itraconazole, Voriconazole

• Allylamines: Terbinafine, Naftifine

• Morpholines: Amorolfine

• Thiocarbamates: Tolciclate, Tolnaftate

• Substituted pyridones: Ciclopirox

• Polyene antibiotics: Amphotericin B, Nystatin

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II. Antifungals inhibiting cell wall synthesis

• Echinocandins: Caspofungin, anidulafungin and

micafungin

III. Antifungals inhibiting synthesis of nucleic acids

• Flucytosine

• Griseofulvin?????

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AZOLES Comprise the imidazoles and triazoles

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Imidazoles:

Miconazole Bifonazole

Ketoconazole Butoconazole

Clotrimazole Econazole

Fenticonazole Tioconazole

Isoconazole Oxiconazole

Sertaconazole Sulconazole

Triazoles:

Fluconazole

Itraconazole

Ravuconazole

Posaconazole

Voriconazole

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Mechanism of action

Azoles inhibit the enzyme cytochrome P450 14α-

demethylase. This enzyme converts lanosterol to

ergosterol, and is required in fungal cell

membrane synthesis

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Azoles

Reduced fungal membrane ergosterol concentrations result in damaged, leaky cell membranes

Azoles inhibiting cytochrome P450 enzymes (inhibits biosynthesis of adrenal and gonadal steroid hormones)

The toxicity of these drugs depends on their relative affinities for mammalian and fungal cytochrome P450 enzymes.

The triazoles tend to have fewer side effects, better absorption, better drug distribution in body tissues, and fewer drug interactions.

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KETOCONAZOLE

Spectrum of activity includes

٭ Candida species

٭ Coccidioides immitis

٭ Cryptococcus neoformans

* Dermatophytes & Pityriasis versicolor

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Pharmacokinetics An acid environment is necessary for

ketoconazole absorption

Administration of food with ketoconazole appears

to increase absorption due possibly to:

1) increased bile secretions

2) delayed gastric emptying

Does not cross the intact blood-brain barrier except in meningitis.

Urinary concentrations of ketoconazole are

usually low, but vaginal and vaginal tissue

concentrations correlate with those in serum.

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Metabolized through

oxidation,

dealkylation,

aromatic hydroxylation.

Excreted into the bile, faeces and the urine

Bile

Faeces

Urine

18KETOCONAZOLE

Side effects

Impotence

Gynaecomastia

Reduced sperm count

Decreased libido

Hepatotoxicity

Nausea/vomiting

Pruritis

Dizziness

Photophobia

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Contraindications/Precautions

Achlorhydria

Hypochlorhydria

Alcoholism

Breast-feeding

Children

Hepatic disease

Pregnancy

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Drug interactions

Antacids

H2 blockers

Omeprazole

Isoniazid

Corticosteroids

Ethanol

Phenytoin

Rifampicin

Astemizole

Amphotericin B

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Miconazole, Econazole, Clotrimazole

Bioavailability is low when administered orally

Usually used topically.

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Fluconazole

Does not require an acidic environment, as does

ketoconazole, for GI absorption.

About 80 to 90% absorbed from GIT.

Thet1/2 of the drug is 27 to 37 h, permitting once-daily

dosing in patients with normal renal function.

Only 11% of the circulating drug is bound to plasma

proteins.

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Fluconazole

The drug penetrates widely into most body tissues eg

CSF therefore effective for treating fungal meningitis.

About 80% of the drug is excreted unchanged in the

urine.

Dosage reductions are required in the presence of

renal insufficiency.

Alopecia and hepatic necrosis have been reported as adverse effects

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Itraconazole

Lipophilic and water insoluble

Requires a low gastric pH for absorption.

Oral bioavailability is variable (20 to 60%).

It is highly protein bound (99%)

Metabolized in the liver and excreted into the bile.

Useful in the treatment of disseminated histoplasmosisin AIDS, nonmeningeal blastomycosis and sporotrichosis

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Itraconazole

Contraindicated in conditions of hepatic and

renal impairment, pregnancy and breastfeeding

mothers

Side effects include nausea, abdominal pain and

rash.

Flatulence, constipation, menstrual disorders and

alopecia may occur.

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GRISEOFULVIN

Fermentation product of Penicillium griseofulvum

Mode of action not exactly understood but involves nucleic acid synthesis and cell mitosis

Dermatophyte infections of the skin, scalp, hair and nails

Infections where susceptible strains of Trichophyton, Microsporumand Epidermaphyte are implicated.

Griseofulvin also is deposited in keratin cells on the surface of the skin making it difficult for fungus to invade the skin and other tissues

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Pharmacokinetics

Well absorbed after oral administration.

Presence of fat in the diet appears increase absorption

of griseofulvin

Metabolized in the liver and then excreted in urine

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Drug Interactions Barbiturates ( e.g. Phenobarbitone)

Warfarin

Oestrogen

Progesterone preparations

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Toxicity and Side Effects

Headache

Abdominal discomfort

Rashes

Fatigue, Dizziness (enhance effect of alcohol)

Confusion and impaired co-ordination

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POLYENE ANTIFUNGALS

Amphotericin B Mechanism of Action: Destroys the integrity of cellular

membrane of susceptible organism by binding to

ergosterol

Active against most fungi and yeast

Treatment of systemic fungal infections.

Not absorbed from the gut

Given by IV infusion

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Toxic Effects

Anorexia, Nausea, Vomiting, diarrhoea, epigastric pain

Headache, Muscle and Joint pain

Disturbances in renal and liver functions

Neurological and blood disorders

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Clinical Uses

Drug of choice in most systemic mycoses

Candidiasis

Cryptococcosis

Aspergillosis

Mucormycosis.

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Nystatin Produced from Streptomyces noursei

Active against Candida albicans infections

of skin and mucous membranes

Not absorbed when given by mouth

Its activity is affected by long exposure to light, and heat

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Side Effects

Nausea

Vomiting and Diarrhoea (at high doses)

Oral irritation

Rashes (topical and vaginal forms)

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Flucytosine (5-flucytosine, 5-FC)

Fluorinated purimidine related to fluouracil and floxuridine

An analogue of cytosine that was originally synthesized for possible use as an antineoplastic agent.

5-FC is converted to 5-fluorouracil inside the cell by the fungal enzyme cytosine deaminase.

The active metabolite 5-fluorouracil interferes with fungal DNA synthesis by inhibiting thymidylatesynthetase.

Incorporation of these metabolites into fungal RNA inhibits protein synthesis.

Indicated for :Crytococcus neoformans (Crytococcal), Candida infections (UTI’s) and Torulopsis glabrata

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Pharmacokinetics

Rapidly and well absorbed in GI tract

Widely distributed in the body

Minimally bound to proteins

Approximately 80% excreted in the urine

(unchanged)

Half-life 3-6 hours

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Side Effects

Leukopenia

Thrombocytopenia

Rash

Nausea and vomiting

diarrhoea.

Severe enterocolitis

Confusion, headache, sedation

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Drug Interactions

Amphotericin

Cytotoxics

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Allylamines

Reversible noncompetitive inhibitors of the fungal

enzyme squalene epoxidase, which converts

squalene to lanosterol.

These agents exhibit fungicidal activity against

dermatophytesand fungistatic activity against

yeasts.

Naftifine is available for topical use only in the

treatment of cutaneous dermatophyte and

Candida infections.

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Terbinafine Dermatophyte infections of the nails and

ringworm infections

Available for topical and systemic use

Lipophilic and highly binds to plasma protiens

Cautions Hepatic and renal impairment

Pregnancy

Breast feeding

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Drug interactions

Rifampicin

Cimetidine

Famotidine

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Side effects

Abdominal discomfort

Anorexia

Urticaria rash

Taste disturbance

Photosensitivity

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ECHINOCANDIN ANTIFUNGALS

Mode of action: inhibit ß-(1,3) glucan synthesis,

damaging fungal cell walls

no drug target in mammalian cells

Rapidly fungicidal against most Candida spp.

Fungistatic against Aspergillus spp.

Active against cyst form of Pneumocystis carinii.

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Caspofungin

Pharmacokinetics

Administration: IV

96% plasma protein bound

Predominantly hepatic metabolism (hydrolysis and N-acetylation).

Distribution: urinary concentration low, CSF

concentration expected to be low

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Adverse effects

Fever

Hepatotoxicity

raised transaminases common in patients receiving caspofungin

hepatic necrosis in animals given large doses (5-8 mg/kg)

Headache

Phlebitis

Rash (infrequent)

Haemolysis may occur but clinically significant haemolysis is rare

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Drug interactions Slight increases in clearance with co-

adminstration of:

phenytoin

carbamazepine

dexamethasone

efavirenz, nelfinavir, nevirapine

Rifampicin - concentrations of both drugs increased

Tacrolimus - concentration of tacrolimus decreased by ~20%

Cyclosporin - increased caspofungin plasma concentration

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Micafungin

Pharmacokinetics Administration: IV

99.8% plasma protein bound

Predominantly hepatic metabolism (hydrolysis and N-acetylation).

Hepatic uptake slow, leading to long terminal half-life of 11-17 h

also adrenal and splenic metabolism

cannot be dialysed

Distribution: urinary concentration low, CSF concentration is low

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Clinical use

Invasive aspergillosis

Drug interactions

No interactions reported

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Adverse effects

Phlebitis

Abnormal liver function tests

Rash (infrequent )

Headache

Fever uncommon

Clinically significant haemolysis rare

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Pyridones

Ciclopirox olamine is a pyridone derivative

Use for the treatment of cutaneous dermatophyte

infections, cutaneous C. albicans infections and tinea

versicolor caused by Malassezia furfur.

Mode of action: It interferes with fungal growth by

inhibiting macromolecule synthesis (blocks amino

acid synthesis)

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Thiocarbamates

Tolnaftate

effective in the treatment of dermatophyte

infections and tinea.

Mechanism of action : not clear however, it is

believed to inhibit squalene epoxidase,

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Haloprogin

Haloprogin is a halogenated phenolic ether

administered topically for dermotaphytic

(tinea)infections.

Mechanism of action is unknown, but it is thought to be via inhibition of oxygen uptake and

disruption of yeast membrane structure and

function

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Thanks for your attention

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