Course content 1

Chemotherapeutic agents

 Mechanism of actions

 Indications

 Contraindications/Cautions

 Drug interactions

 Side-effects/Adverse reactions

 Dosage regimen (occasionally) Reference Books 2

 Pharmacology by Rang, Dale, Ritter, Gardner

 Clinical Pharmacology textbooks

 British National Formulary (BNF) 3

Antifungal agents 4

 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 FUNGAL INFECTIONS 5

blastomycosis candidiasis

histoplasmosis

mucorymycosis ringworm Factors increasing incidence and severity 6 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) FUNGAL INFECTIONS 7 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 ANTIFUNGAL AGENTS 8

 The Azoles

 Griseofulvin

 Flucytosine

 The polyenes

 Echinocandin antifungals (new) 9

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 10

 II. Antifungals inhibiting cell wall synthesis • Echinocandins: Caspofungin, anidulafungin and micafungin

 III. Antifungals inhibiting synthesis of nucleic acids • Flucytosine • Griseofulvin????? 11 AZOLES 12

 Comprise the imidazoles and triazoles 13

 Imidazoles:  Miconazole Bifonazole  Ketoconazole Butoconazole  Clotrimazole Econazole  Fenticonazole Tioconazole  Isoconazole Oxiconazole  Sertaconazole Sulconazole

 Triazoles:  Fluconazole  Itraconazole  Ravuconazole  Posaconazole  Voriconazole 14 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 Azoles 15

 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. KETOCONAZOLE 16

 Spectrum of activity includes Candida species ٭ Coccidioides immitis ٭ Cryptococcus neoformans ٭ * Dermatophytes & Pityriasis versicolor Pharmacokinetics 17

 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. KETOCONAZOLE 18

Metabolized through

 oxidation,

 dealkylation,

 aromatic hydroxylation.

Excreted into the bile, faeces and the urine

 Bile

 Faeces

 Urine Side effects 19

 Impotence

 Gynaecomastia

 Reduced sperm count

 Decreased libido

 Hepatotoxicity

 Nausea/vomiting

 Pruritis

 Dizziness

 Photophobia Contraindications/Precautions 20

 Achlorhydria

 Hypochlorhydria

 Alcoholism

 Breast-feeding

 Children

 Hepatic disease

 Pregnancy Drug interactions 21

 Antacids

 H2 blockers  Omeprazole  Isoniazid  Corticosteroids  Ethanol  Phenytoin  Rifampicin  Astemizole  Amphotericin B Miconazole, Econazole, Clotrimazole 22

 Bioavailability is low when administered orally

 Usually used topically. Fluconazole 23

 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. Fluconazole 24

 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 Itraconazole 25

 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 histoplasmosis in AIDS, nonmeningeal blastomycosis and sporotrichosis Itraconazole 26

 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. GRISEOFULVIN 27

 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, Microsporum and 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 Pharmacokinetics 28

 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 Drug Interactions 29

 Barbiturates ( e.g. Phenobarbitone)

 Warfarin

 Oestrogen

 Progesterone preparations Toxicity and Side Effects 30

 Headache

 Abdominal discomfort

 Rashes

 Fatigue, Dizziness (enhance effect of alcohol)

 Confusion and impaired co-ordination POLYENE ANTIFUNGALS 31

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 32 Toxic Effects 33

 Anorexia, Nausea, Vomiting, diarrhoea, epigastric pain

 Headache, Muscle and Joint pain

 Disturbances in renal and liver functions

 Neurological and blood disorders Clinical Uses 34

 Drug of choice in most systemic mycoses

 Candidiasis

 Cryptococcosis

 Aspergillosis

 Mucormycosis. Nystatin 35  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 Side Effects 36

 Nausea

 Vomiting and Diarrhoea (at high doses)

 Oral irritation

 Rashes (topical and vaginal forms) Flucytosine (5-flucytosine, 5-FC)

37

 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 thymidylate synthetase.  Incorporation of these metabolites into fungal RNA inhibits protein synthesis.

Indicated for :Crytococcus neoformans (Crytococcal), Candida infections (UTI’s) and Torulopsis glabrata 38 Pharmacokinetics 39

 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 Side Effects 40

 Leukopenia

 Thrombocytopenia

 Rash

 Nausea and vomiting

 diarrhoea.

 Severe enterocolitis

 Confusion, headache, sedation Drug Interactions 41

 Amphotericin

 Cytotoxics Allylamines 42

 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. 43 Terbinafine 44

 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 Drug interactions 45

 Rifampicin

 Cimetidine

 Famotidine Side effects 46

 Abdominal discomfort

 Anorexia

 Urticaria rash

 Taste disturbance

 Photosensitivity ECHINOCANDIN ANTIFUNGALS 47  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. 48 Caspofungin 49 Pharmacokinetics

 Administration: IV

 96% plasma protein bound

 Predominantly hepatic metabolism (hydrolysis and N-acetylation).

 Distribution: urinary concentration low, CSF concentration expected to be low Adverse effects 50

 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 Drug interactions 51  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 Micafungin 52 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 Clinical use 53

 Invasive aspergillosis

Drug interactions

 No interactions reported Adverse effects 54

 Phlebitis

 Abnormal liver function tests

 Rash (infrequent )

 Headache

 Fever uncommon

 Clinically significant haemolysis rare Pyridones 55

 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) Thiocarbamates 56

 Tolnaftate

 effective in the treatment of dermatophyte infections and tinea.

 Mechanism of action : not clear however, it is believed to inhibit squalene epoxidase, Haloprogin 57

 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 58

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