ANTIFUNGAL DRUGS (Drugs used in treatment of fungal infections) Dr. Yasodha Krishna Janapati

Introduction Fungi are Eukaryotic cells. They possess mitochondria, nuclei & cell membranes. While bacterial cells are prokaryotic. So, antibacterial agents can exhibit Selectivity. The treatment of fungal infection id difficult b/s both mammals and fungi are eukaryotes. Thus, Antifungal drugs are in general more toxic than antibacterial agents. They have rigid cell walls containing chitin as well as polysaccharides, and a cell membrane composed of ergosterol instead of cholesterol in humans

Ergosterol(C28) and cholesterol (C27) The extra methyl on C24 and Extra double bond on C7 and C22 will help to bind effectively to the polyene antibiotics

Factors aiding the spread of fungal disease Action of immunosuppressant drugs Acquired immunodeficiency syndrome (AIDS) Cancer patients Broad-spectrum antibiotics People under steroid treatment Poor hygiene Weakened Immune system Poorly controlled DM Low WBC Very old or very young groups (Although all are at risk of developing fungal infections, the likelihood is higher in these groups.)

Clinical classification of Mycoses(fungal infection): Cutaneous mycoses- These are superficial fungal infections of the skin, hair or nails. Subcutaneous mycoses-It involve the dermis, subcutaneous tissues, muscle. These infections are difficult to treat and may require surgical interventions such as debridement ( is the medical removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue.). III Systemic mycoses due to opportunistic pathogens-Systemic mycoses due to opportunistic pathogens such as Candidiasis, Asergillosis, Cryptoccosis, Zygomycosis. (HIV, Cancer, Poorly controlled DM, Very old or very young, Low WBC, ) IV Systemic mycoses due to primary pathogens- originate primarily in the lungs and may spread to many organ systems 4/29/2017

Classification of drugs Anti fungal Antibiotics: Polyenes: Amphotericin B (Fungizone), Nystatin (Mycostatin) Others: Griseofulvin Azole Derivatives: a) Imidazoles Clotrimazole Econazole Fenticonazole, Ketoconazole, Luliconazole, Miconazole,Omoconazole b)Triazoles Albaconazole, Efinaconazole, Epoxiconazole, Fluconazole,Isavuconazole, Itraconazole, Posaconazole, c) Thiazoles Abafungin

Allylamine Drugs: Terbinafine (Lamisil) Naftifine (Naftin) Butnafine Nucleoside antifungal: Flucytosine Echinocandin Drugs: Caspofungin (Cancidas) Micafungin (Mycamine) Other Antifungals: Ciclopirox (Loprox) Benzoic acid Undeclenic Acid Crystal violet Salicylic acid

Anti fungal Antibiotics: Polyene anti fungals A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. Amphotercin B

The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol and remove ergosterol. In ordinary circumstances membrane sterols increase the packing of the phospholipid bilayer making the plasma membrane more dense and stiff. As a result, the cell's contents including monovalent ions (K+, Na+, H+, and Cl−), small organic molecules leak and this is regarded one of the primary ways cell dies. 

Ergosterol(C28) and cholesterol (C27) The extra methyl on C24 and Extra double bond on C7 and C22 will help to bind effectively to the polyene antibiotics

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Antifungal spectrum & Therapeutic uses: -To treat superficial candidiasis -Treatment of invasive aspergillosis -Mucormycosis (an opportunistic fungal infection in lungs) -Rapidly progressive blastomycosis , Histoplasmosis. - Non-AIDS cryptococcal meningitis (used with fluconazole or with flucytosine) Adverse effects : Acute toxicity- chills, fever, vomiting and modest hypotension - Long term toxicity- anaemia, nephrotoxicity - Intrathecal administration may lead to seizures - Hepatic impairment with jaundice

Azole Antifungal Agents The azoles represent a class of synthetic antifungal agents that possess a unique mechanism of action. They are broad spectrum antifungal drugs With these drugs, one can achieve selectivity for the infecting fungus over the host. Depending on the azole drug used, one can treat infections ranging from simple dermatophytoses to life-threatening, deep systemic fungal infections. The first members of the class were highly substituted imidazoles, such as clotrimazole and Miconazole.

Fungistatic or fungicidal properties depending upon drug concentration Azoles can be divided into two groups: the imidazole group (2 nitrogen in the azole ring) & triazole group(3 nitrogens in the azole ring). M/A These bind to the fungal cytochrome P-450 dependent 14-α demethylase enzyme that is responsible for the demethylation of lanosterol to ergosterol synthesis. The ergosterol synthesis is therefore hindered. which results in damaged leaky fungal cell membrane.

Allylamine drugs Azoles Squalene epoxidase 14-a-demethylase Acetyl CoA Squalene epoxide Squalene epoxidase Squalene-2,3 oxide Squalene Lanosterol Lanosterol Lanosterol rol Azoles 14-a-demethylase (ergosterol)

14 desmethyl lanosterol

The most potent antifungal azoles possess two or three aromatic rings, STRUCTURE–ACTIVITY RELATIONSHIPS The basic structural requirement for members of the azole class is a weakly basic imidazole or 1,2,4-triazole ring (pKa of 6.5–6.8). At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of molecular oxygen and prevent oxidation of 14 α-CH3. The most potent antifungal azoles possess two or three aromatic rings, at least one of which is halogen substituted.

The halogen atom that yields the most potent compounds is fluorine, although functional groups such as sulfonic acids have been shown to do the same. Substitution at other positions of the ring yields inactive compounds (Most of these compounds have Subs. At C2 & C4). Presumably, the large nonpolar portion of these molecules mimics the nonpolar steroidal part of the substrate for lanosterol 14-demethylase, lanosterol, in shape and size. The nonpolar functionality confers high lipophilicity to the antifungal azoles. The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. Fluconazole, which possesses two polar triazole moieties, is an exception, in that it is sufficiently water soluble to be injected intravenously as a solution of the free base.

Triazoles

Imidazoles

Synthesis of Clotrimazole

Terbinafine(fungicidal) Allylamine: Terbinafine(fungicidal) M/A -squalene epoxidase converts squalene to lanosterol -Terbinafine inhibits fungal enzyme squalene epoxidase - Leads to reduction in lanosterol production that decreases ergosterol production which affects fungal cell membrane integrity and function. Pharmacokinetics: - highly lipophilic and keratophilic resulting in high concentrations in stratum corneum,sebum, hair and nails. -A prolonged terminal half-life of about 15 days because of the very slow release of the drug from skin, nails and adipose tissue. 4/29/2017

-It can be used systemically as well as topically. Therapeutic Uses: -It can be used systemically as well as topically. - Orally it is specifically used to treat onychomycosis - Unlabeled use includes topical treatment of cutaneous candidiasis Adverse Effects: -Headache - GIT upset - Liver enzymes elevation -Hepatobiliary dysfunction (but rarely) 4/29/2017