1. ANTIFUNGAL DRUGS

2. Summary of antifungal drugs.
Drugs for subcutaneous
and systemic mycoses
Voriconazole
Posaconazole
Micafungin
Ketoconazole
Itraconazole
Flucytosine
Fluconazole
Caspofungin
Anidulafungin
Amphotericin B
Drugs for cutaneous mycoses
Terconazole
Terbinafine
Nystatin
Miconazole
Griseofulvin
Econazole
Clotrimazole
Butoconazole
(according to Lippincott´s Pharmacology, 2009)

3. Drugs for subcutaneous and systemic mycoses
1. Amphotericin B
polyene ATB
choice for life-threatening, systemic mycoses
sometimes in combination with flucytosine – (structurally related to the cytostatic fluorouracil)
binds to ergosterol in the plasma membranes - forms pores (channels) –
electrolytes (particularly K) and small molecules leak from the cell - cell death.
Against a wide range of fungi,
incl. Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, many strains of Aspergillus.
also protozoal infection, leishmaniasis.
Administered by slow, i.v. infusion.
Lipophilic – but no into CSF, cross placenta
3. Resistance: infrequent ( ergosterol content of the fungal membrane). The more dangerous intrathecal route.
Low levels of the drug and metabolites appear in the urine over a long period; some are also eliminated via the bile.
Dosage adjustment is not required in compromised renal or hepatic function.

4. Drugs for subcutaneous and systemic mycoses
Amphotericin B - AE
Fever and chills
liposomes or microemulsion
usually subside with repeated administration.
premedication with a corticosteroid or an antipyretic helps to prevent it.
anaphylaxis, convulsions
Small test dose initially
Renal impairment
Adequate hydration is necessary.
Hypotension
A shock-like fall in BP with hypokalemia requiring K supplementation
Anemia:
Normochromic, normocytic anemia (by reversible suppression of erythrocyte production).
Neurologic effects: Intrathecal administration - serious problems- convulsions, neuropathy.

5. Drugs for subcutaneous and systemic mycoses
2. Azole antimycotics
Ketoconazole, itraconazole, fluconazole, voriconazole
fungistatic - inhibit C-14 a-demethylase (P450)
block demethylation of lanosterol to ergosterol -
disruption of membrane structure and function
Spectrum
many fungi, incl. histoplasma, blastomyces, candida, coccidioides, but not aspergillus species.
Only orally (it requires gastric acid for dissolution - absorbed through the gastric mucosa). Drugs that raise gastric pH (antacids, H2-histamine receptor blockers, proton-pump inhibitors) - impair absorption. Extensively bound to plasma proteins
Rifampin (inducer of CYP450) can shorten the duration of action of azoles.
Drugs that decrease gastric acidity -  absorption of ketoconazole. Ketoconazole and amphotericin B should not be used together (decrease in ergosterol reduces action of amphotericin B).

6. Azole antimycotics – AE
Allergies
dose-dependent GI disturbances (nausea, anorexia, vomiting)
hepatotoxic - transient elevation of serum transaminases; hepatitis - rarely - immediate withdraw
endocrine effects (gynecomastia, impotence, menstrual irregularities)
via the block of androgen and adrenal (testosterone) synthesis - ketoconazol
Teratogenic in animals - not administer in pregnancy
Interactions
Inhibition of CYP450 !!! - ketoconazol

7. Drugs for subcutaneous and systemic mycoses
Ketoconasole
Absorption dependent on pH in stomach
Not into CNS
Extensive metabolism in the liver – bile
Enzyme inhibitor
Itraconasole
Broader spectrum - aspergillosis, and histoplasmosis
Similar PK to ketoconazole
Also P450 inhibitor but without endocrine effect
Fluconazole
Also for i.v – excellent CNS penetration - treatment of cryptococcal meningitis
Lack of P450 interactions incl endocrine
Kidney excretion
Voriconazole, posaconazole
New, broadest spectrum, resistant aspergilosis (vori),
prevention of candidosis in immunocpmpromised - posa

8. 3. Echinocandins Caspofungin, micafungin, anidulafungin
A second-line antifungal
for those who have failed or cannot tolerate amphotericin B or itraconazole.
against aspergillus and candida species
inhibit synthesis of the fungal cell wall
inhibiting the synthesis of b(1,3)-o-glucan – cell death
parenterally only
Lipophilic - slowly metabolized (hydrolysis and N-acetylation)
Adverse effects:
fever, rash, nausea, phlebitis
flushing due to histamine release
The first member of the echinocandins Elimination by urinary and fecal routes. should not be coadministered with cyclosporine.

9. Drugs for cutaneous mycotic infection
Terbinafine
Drug of choice for dermatophytosis and, esp. onychomycoses
E.g. Candida infection
unuseful for treatment of systemic aspergillosis.
Therapy is prolonged - usually about 3 months
Fungicidal - inhibits fungal squalene epoxidase
Only low affinity to human SE (cholesterol pathway)
deposited in the skin, nails, and fat
Orally active - More than 99 % bound to plasma proteins.
Half-life ( 200 to 400 hours ) - reflects the slow release from these tissues.
Accumulates in breast milk , should not be given to nursing mothers.
Extensively metabolized
deposited in the skin, nails, and fat
Orally active (BAV about 40 % - first-pass metabolism). More than 99 % bound to plasma proteins. Half-life ( 200 to 400 hours ) - reflects the slow release from these tissues.
Accumulates in breast milk  should not be given to nursing mothers.
Extensively metabolized (but probably no significant risk of reduced clearance of other drugs); urinary excretion – in renal impairment or hepatic cirrhosis reduced clearance.
Adverse effects: resolve upon drug discontinuation
- GI disturbances (diarrhea, dyspepsia, and nausea), headache, rash are common Taste and visual disturbances Transient elevations in serum liver enzyme Rarely hepatotoxicity and neutropenia.

10. Terbinafine - AE
GIT disturbances (taste, diarrhea, dyspepsia, and nausea),
headache
typical rash is common
visual disturbances
transient elevations in serum liver enzyme- rarely hepatotoxicity

11. Griseofulvin dermatophytic infections of the nails
Largely replaced by terbinafine for the treatment.
Fungistatic - requires treatment of months in duration
It accumulates in newly synthesized, keratin-containing tissue
causes disruption of the mitotic spindle and inhibition of fungal mitosis.
P.o. - absorption is enhanced by high-fat meals.
induces hepatic CYP450 activity
Number of interactions. e.g., oral anticoagulant drugs
Blockade of alcohol dehydrogenase
Patients should not drink alcoholic beverages during therapy
griseofulvin potentiates the intoxicating effects of alcohol

12. Others Nystatin - polyene antibiotic.
Its structure, chemistry, mechanism of action, and resistance resemble those of amphotericin.
Only for topical treatment of candida infections because of systemic toxicity
Not absorbed from GIT - Oral agent for the treatment of oral candidiasis.
Excretion in the feces.
Adverse effects: rare (nausea, vomiting).

13. Miconazole, clotrimazole - OTC, butoconazole, terconazole
topical azole formulations
AE - associated with contact dermatitis,
- vulvar irritation, and edema
miconazole is a potent inhibitor of warfarin metabolism (bleeding in warfarin-treated patients even when applied topically).
Th. of seborrheic dermatitis