Antifungal Drugs Fungal infectious occur due to : 1- Abuse of broad spectrum antibiotics 2- Decrease in the patient immunity

Types of fungal infections 1. Superficial : Affect skin – mucous

membrane.e.g. Tinea versicolor Dermatophytes : Fungi that affect

keratin layer of skin, hair, nail.e.g.tinea pedis ,ring worm infection

Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.

2- Deep infections Affect internal organs as : lung ,heart ,

brain leading to pneumonia , endocarditis , meningitis.

Classification of Antifungal Drugs 1- Antifungal Antibiotics : Griseofulvin Polyene macrolide : Amphotericin- B &

Nystatin 2- Synthetic : Azoles : A) Imidazoles : Ketoconazole , Miconazole B) Triazoles : Fluconazole , Itraconazole

In Dermatophytes :

Squalene epoxidase inhibitors : Terbinafine &

Naftifine.

Amphotericin B Amphotericin A & B are antifungal

antibiotics. Amphotericin A is not used clinically. It is a natural polyene macrolide (polyene = many double bonds ) (macrolide = containing a large lactone ring )

Ergosterol Doesn't present in plant or animal cell .it is

present in fungal and yeast cell serving the same function of cholesterol in animal cells

Mechanism of action It is a selective fungicidal drug

Because of :…………………………...? Disrupt fungal cell membrane by binding to

ergosterol , so alters the permeability of the cell membrane leading to leakage of intracellular ions & macromolecules ( cell death ).

Nystatin It is a polyene macrolide ,similar in structure

& mechanism to amphotericin B. Too toxic for systemic use. Used only topically. It is available as creams, ointment ,

suppositories & other preparations. Not significantly absorbed from skin, mucous

membrane, GIT .

Azoles A group of synthetic fungistatic agents with a

broad spectrum of activity . They have antibacterial , antiprotozoal

anthelminthic & antifungal activity .

Cytochrome P450 : metabolic enzyme is a large and diverse group of enzymes

that catalyze the oxidation of organic substances.

The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones(in fungal is lanosterols), as well as xenobiotic substances such as drugs and other toxic chemicals.

Cont ..Cytochrome P 450 Is present both in human and fungal cell .

RH + O2 + NADPH + H+ → ROH + H2O + NADP+

Cytochrome

oxidase

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 (free radicals )that cause autodigestion of the fungus.

3- Imidazoles may alter RNA& DNA metabolism.

Azoles They are antibacterial , antiprotozoal,

anthelminthic & antifungal. They are fungistatic agents. They are classified into : Imidazole group Triazole group

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.(Non selective )

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).

Phrmacokinetics Rapidly & well absorbed orally Widely distributed including CSF. Mainly excreted unchanged through kidney Half-life 3-6 hours

Caspofungin Inhibits the synthesis of fungal cell wall by

inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis & cell death.

Given by IV route only Highly bound to plasma proteins Half-life 9-11 hours Slowly metabolized by hydrolysis & N-acetylation. Elimination is nearly equal between the urinary &

fecal routes.

Griseofulvin Fungistatic, has a narrow spectrum Given orally (Absorption increases with fatty

meal ) 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

Griseofulvin(cont.) Adverse effects ;(Not used adays) Peripheral neuritis, mental confusion, fatigue,

vertigo,GIT upset,enzyme inducer, blurred vision. Increases alcohol intoxication.