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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
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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
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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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