Lecture 4 Antimicrobial Chemotherapy Antifungal Drugs Antiprotozoan Drugs

Lecture 4 Antimicrobial Chemotherapy • Antifungal Drugs • Antiprotozoan Drugs • Antihelminthic Drugs Dr. : Abeer El-Sherbiny

Antifungal Drugs • Fungi are eukaryotes • Pathogenic fungi are often outside the body • More difficult to find point of selective toxicity in eukaryotes than in prokaryotes • Fungi have a rigid cell wall that is made up of chitin and various polysaccharides and a cell membrane that contains ergosterol.

Antifungal Drugs Fungal infectious occur due to : 1 - Abuse of broad spectrum antibiotics 2 - Decrease in the patient immunity 3

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, vulvovaginitis , nail infections. • 2 - Deep infections • Affect internal organs as : lung , heart , brain leading to pneumonia , endocarditis , meningitis 4

Classification of Antifungal Drugs 1 - Antifungal Antibiotics : A. Griseofulvin B. Polyene macrolide : Amphotericin- B & Nystatin 2 - Synthetic : • Azoles : A. Imidazoles : Ketoconazole , Miconazole B. Triazoles : Fluconazole , Itraconazole • Flucytosine • Terbinafine & Naftifine. 5

Targets of antifungal drugs • Agents affecting fungal sterols : destroying the cell membrane’s integrity such as triazoles, and imidazoles target ergosterol • Agents affecting fungal cell walls: damaging the cell wall • primary target of selective toxicity is β-glucan. Inhibition of synthesis of this glucan results in an incomplete cell wall, and results in lysis of the cell • Agents inhibiting nucleic acids: inhibit DNA/RNA synthesis such as flucytosine and griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function. 6

How do they work? Image from http: //www. doctorfungus. org/thedrugs/antif_pharm. htm 7

Classification According to Route of Administration • Systemic : • Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine. • Topical • In candidiasis : • Imidazoles : Ketoconazole , Miconazole. • Triazoles : Terconazole. • Polyene macrolides : Nystatin , Amphotericin-B • Gentian violet : Has antifungal & antibacterial. • In Dermatophytes : • Squalene epoxidase inhibitors : Terbinafine & • Naftifine, Tolnaftate 8

Agents affecting fungal sterols 1 -Amphotericin B Mechanism of action • It is a selective fungicidal drug. • 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 ). 9

Resistance to amphotericin B • If ergosterol binding is impaired either by : • Decreasing the membrane concentration of ergosterol. • Or by modyfing the sterol target molecule. 10

2 - Nystatin • It is a polyene macrolide , similar in structure & mechanism to amphotericin B. • Too toxic for systemic use(very toxic to kidneys) • Used only topically. • It is available as creams, ointment , suppositories & other preparations. • Not significantly absorbed from skin, mucous membrane, GIT. 11

Clinical uses • Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract. • Vaginal candidiasis • Can be used in combination with antibacterial agents & corticosteroids. 12

3 - Azoles • A group of synthetic fungistatic agents with a broad spectrum of activity • They are antibacterial , antiprotozoal, anthelminthic & antifungal. • They are classified into : • Imidazole group • Triazole group 13

Imidazoles • Ketoconazole • Miconazole • Clotrimazole • They lack selectivity , they inhibit human gonadal and steroid synthesis leading to decrease testosterone & cortisol production.

Agents inhibiting nucleic acids Flucytosine • Synthetic pyrimidine antimetabolite (cytotoxic drug ) often given in combination with amphotericin B & itraconazole. • Systemic fungistatic • 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 • bone marrow depression • Elevation in hepatic enzymes

Agents affecting fungal cell walls 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

Clinical uses • Effective in aspergillus & candida infections. • Second line for those who have failed or cannot tolerate amphotericin B or itraconazole. • Adverse effects : • Nausea, vomiting • Flushing( release of histamine from mast cells) • Very expensive

Griseofulvin • Inhibits fungal mitosis • Used to treat dermatophyte infections ( ring worm of skin, hair, nails ). • Ineffective topically. • Not effective in subcutaneous or deep mycosis. 18

Antiprotozoan Drugs • Protozoa are eukaryotic cells • Many drugs are experimental and their mode of action is unknown

Antiprotozoan drugs • Quinine still used to control malaria • Chloroquinone- has largely replaced Quinine • Mefloquinone- used in areas where resistance to chloroquinone has developed • Quinacrine- drug of choice for treating protozoan disease, giardiasis

Antihelminthic Drugs • Helminths are macroscopic multicellular eukaryotic organisms: as tapeworms, pinworms, hook worms & roundworms

Antihelminthic Drugs • • Prevent ATP generation (Tapeworms) Alters membrane permeability (Flatworms) Inhibits nutrient absorption(Intestinal roundworms) Paralyzes worm (Intestinal roundworms) • Praziquantel- used in treatment of tapeworms and other trematoda; kills worms by altering permeability of plasma membranes