1. Course content Chemotherapeutic agents Mechanism of actions
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Chemotherapeutic agents
Mechanism of actions
Indications
Contraindications/Cautions
Drug interactions
Side-effects/Adverse reactions
Dosage regimen (occasionally)
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2. Reference Books Pharmacology by Rang, Dale, Ritter, Gardner
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Pharmacology by Rang, Dale, Ritter, Gardner
Clinical Pharmacology textbooks
British National Formulary (BNF)
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3. Antifungal agents
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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
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5. FUNGAL INFECTIONS blastomycosis candidiasis histoplasmosis
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blastomycosis
candidiasis
histoplasmosis
mucorymycosis
ringworm

6. 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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7. 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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8. ANTIFUNGAL AGENTS The Azoles Griseofulvin Flucytosine The polyenes
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The Azoles
Griseofulvin
Flucytosine
The polyenes
Echinocandin antifungals (new)
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9. 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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10. II. Antifungals inhibiting cell wall synthesis
Echinocandins: Caspofungin, anidulafungin and micafungin
III. Antifungals inhibiting synthesis of nucleic acids
Flucytosine
Griseofulvin?????
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12. AZOLES
Comprise the imidazoles and triazoles
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13. Miconazole Bifonazole Ketoconazole Butoconazole Clotrimazole Econazole
Imidazoles:
Miconazole Bifonazole
Ketoconazole Butoconazole
Clotrimazole Econazole
Fenticonazole Tioconazole
Isoconazole Oxiconazole
Sertaconazole Sulconazole
Triazoles:
Fluconazole
Itraconazole
Ravuconazole
Posaconazole
Voriconazole
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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
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15. 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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16. KETOCONAZOLE Spectrum of activity includes ٭ Candida species
٭ Coccidioides immitis
٭ Cryptococcus neoformans
* Dermatophytes & Pityriasis versicolor
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17. 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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18. KETOCONAZOLE Metabolized through oxidation, dealkylation,
aromatic hydroxylation.
Excreted into the bile, faeces and the urine
Bile
Faeces
Urine
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19. Side effects Impotence Gynaecomastia Reduced sperm count
Decreased libido
Hepatotoxicity
Nausea/vomiting
Pruritis
Dizziness
Photophobia
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20. Contraindications/Precautions
Achlorhydria
Hypochlorhydria
Alcoholism
Breast-feeding
Children
Hepatic disease
Pregnancy
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21. Drug interactions Antacids H2 blockers Omeprazole Isoniazid
Corticosteroids
Ethanol
Phenytoin
Rifampicin
Astemizole
Amphotericin B
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22. Miconazole, Econazole, Clotrimazole
Bioavailability is low when administered orally
Usually used topically.
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23. 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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24. 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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25. 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 histoplasmosis in AIDS, nonmeningeal blastomycosis and sporotrichosis
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26. 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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27. 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, 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
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28. 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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29. Drug Interactions Barbiturates ( e.g. Phenobarbitone) Warfarin
Oestrogen
Progesterone preparations
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30. Toxicity and Side Effects
Headache
Abdominal discomfort
Rashes
Fatigue, Dizziness (enhance effect of alcohol)
Confusion and impaired co-ordination
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31. 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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33. Toxic Effects Anorexia, Nausea, Vomiting, diarrhoea, epigastric pain
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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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34. Clinical Uses Drug of choice in most systemic mycoses Candidiasis
Cryptococcosis
Aspergillosis
Mucormycosis.
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35. 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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36. Side Effects Nausea Vomiting and Diarrhoea (at high doses)
Oral irritation
Rashes (topical and vaginal forms)
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37. 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 thymidylate synthetase.
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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39. 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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40. Side Effects Leukopenia Thrombocytopenia Rash Nausea and vomiting
diarrhoea.
Severe enterocolitis
Confusion, headache, sedation
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41. Drug Interactions
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Amphotericin
Cytotoxics
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42. 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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44. 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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45. Drug interactions
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Rifampicin
Cimetidine
Famotidine
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46. Side effects Abdominal discomfort Anorexia Urticaria rash
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Abdominal discomfort
Anorexia
Urticaria rash
Taste disturbance
Photosensitivity
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47. 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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49. 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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50. Adverse effects Fever Hepatotoxicity Headache Phlebitis
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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51. 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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52. 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 h
also adrenal and splenic metabolism
cannot be dialysed
Distribution: urinary concentration low, CSF concentration is low
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53. Clinical use Drug interactions Invasive aspergillosis
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Invasive aspergillosis
Drug interactions
No interactions reported
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54. Adverse effects Phlebitis Abnormal liver function tests
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Phlebitis
Abnormal liver function tests
Rash (infrequent )
Headache
Fever uncommon
Clinically significant haemolysis rare
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55. 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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56. 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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57. 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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58. Thanks for your attention
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