Azoles , Imidazoles , Triazoles

Azoles

·        A group of synthetic fungistatic agents with a broad spectrum of activity.

·        They have antibacterial, antiprotozoal anthelminthic & antifungal activity.

Mechanism of Action

1-    Inhibit the fungal cytochrome P450 enzyme, (α-demethylase) which is responsible for converting lanosterol to ergosterol (the main sterol in fungal cell membrane).

2-    Inhibition of mitochondrial cytochrome oxidase leading to accumulation of peroxides that cause autodigestion of the fungus.

3-    Imidazoles may alter RNA& DNA metabolism.

Imidazoles

·        Ketoconazole

·        Miconazole

·        Clotrimazole

They lack selectivity, they inhibit human gonadal and steroid synthesis leading to decrease testosterone & cortisol production. Also, inhibit human P-450 hepatic enzyme.

Ketoconazole

·        Well absorbed orally.

·        Bioavailability is decreased with antacids, H₂ blockers, proton pump inhibitors & food.

·        Half-life increases with the dose, it is (7-8 hrs).

·        Inactivated in liver & excreted in bile (feces) & urine.

·        Does not cross BBB.

Clinical uses

Used topically or systematic (oral route only) to treat:

1- Oral & vaginal candidiasis.

2- Dermatophytosis.

3- Systemic mycoses & mucocutaneous candidiasis.

Adverse Effects

·        Nausea, vomiting ,anorexia

·        Hepatotoxic

·        Inhibits human P 450 enzymes

·        Inhibits adrenal & gonadal steroids leading to :

·        Menstrual irregularities

·        Loss of libido

·        Impotence

·        Gynaecomastia in males

Triazoles

·        Fluconazole

·        Itraconazole

·        Voriconazole

They are: Selective, Resistant to degradation, and Causing less endocrine disturbance.

Fluconazole

·        Water soluble

·        Completely absorbed from GIT

·        Excellent bioavailability  after oral administration

·        Bioavailability is not affected by food or gastric PH

·        Conc. in plasma is same by oral or IV route

·        Has the least effect on hepatic microsomal enzymes

·        Drug interactions are less common

·        Penetrates well BBB so, it is the drug of choice of cryptococcal meningitis

·        Safely given in patients receiving bone marrow transplants (reducing fungal infections)

·        Excreted mainly through kidney

·        Half-life 25-30 hours

·        Resistance is not a problem

Clinical uses

·        Candidiasis

·        ( is effective in all forms of mucocutaneous candidiasis)

·        Cryptococcus meningitis

·        Histoplasmosis, blastomycosis, ring worm.

·        Not effective in aspergillosis

Side effects

·        Nausea, vomiting, headache, skin rash, diarrhea, abdominal pain, reversible alopecia.

·        Hepatic failure may lead to death

·        Highly teratogenic ( as other azoles)

·        Inhibit P450 cytochrome

·        No endocrine side effects

Flucytosine

·        Synthetic pyrimidine antimetabolite (cytotoxic drug) often given in combination with amphotericin B & itraconazole.

·        Systemic fungistatic

Mechanism of action

·        Converted within the fungal cell to 5- fluorouracil (Not in human cell), that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis.

·        (Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell, they are synergistic).

Pharmacokinetics

·        Rapidly & well absorbed orally

·        Widely distributed including CSF.

·        Mainly excreted unchanged through kidney

·        Half-life 3-6 hours

Clinical uses

·        Severe deep fungal infections as in meningitis

·        Generally given with amphotericin B

·        For cryptococcal meningitis in AIDS patients

Adverse Effects

·        Nausea, vomiting , diarrhea, severe enterocolitis

·        Reversible neutropenia, thrombocytopenia, bone marrow depression

·        Alopecia

·        Elevation in hepatic enzymes

·        (some adverse effects related to 5-Fu formed by intestinal organisms from5-FC)

Griseofulvin

·        Fungistatic, has a narrow spectrum

·        Given orally (Absorption increases with fatty meal )

·        Half-life 24 hours

·        Taken selectively by newly formed skin & concentrated in the keratin.

·        Induces cytochrome P450 enzymes

·        Should be given for 2-6weeks for skin & hair infections to allow replacement of infected keratin by the resistant structure

·        Inhibits fungal mitosis by interfering with microtubule function

·        Used to treat dermatophyte infections (ring worm of skin, hair, nails).

·        Highly effective in athletes foot.

·        Ineffective topically.

·        Not effective in subcutaneous or deep mycosis.

Adverse effects;

·        Peripheral neuritis, mental confusion, fatigue, vertigo,GIT upset,enzyme inducer, blurred vision.

·        Increases alcohol intoxication. Decreased effectiveness of cyclosporine (↓40%), estrogens, warfarin,