ANTIFUNGAL AGENTS, MODE OF ACTION, CHEMICAL COMPOSITION, GENERAL FORMULA AND SIDE EFFECT

Antifungal agents are drugs used to selectively kill or inactivate fungal pathogens from host cells with minimum toxicity. Examples of fungal diseases are Ring worm, Athlete’s foot, Candidasis, Histoplasmosis, crytococosis, Meningitis etc. 

 

Antimycotic agents are classified based on their mode of action.

Classification of antifungal agents

1- POLYENE ANTIFUNGAL AGENT: This is a mycolytic polyene antifungal agent with heavily hydroxylated region on the ring opposite their conjugate systems, examples includes, Amphotericin B, Pimaricin, Nystatin to mention but a few.

 

How it works: Polyene binds to sterol on the cell membrane, ergosterol in fungi cell membrane and cholesterol in mammalian cell membrane. This changes the Transition Temperature of the cell membrane, thereby placing it in a less fluid, more crystalline state. As a result, the cell contents including monovalent ions, K⁺, Na⁺ and CL^- and small organic molecule leaks out of fungal cell and the cell dies.

Chemical composition:  Polyene where originally made From Streptomyces species but it is currently available Cholestyl sulphate complex (ABLC) and as Liposomal formulation (AMB).

General formula: The compound contains double bound in their C₂₇ and C₂₈  for Polyene and Diene, have similar properties, the first contains two or three Nitrogen ring which are the imidazol and triazol respectably.

Side effect: Oral Amphotericin B, are non toxic but intravenous Amphotericin B are toxic. It can cause pore in both fungi and host cell membrane, this destruction in membrane function can have lethal effect.Hypersensitivity reactions includes chill, vomiting, hypotension, Anorexia, trachyponea, dysponea, high fever and general weakness. 

2. AZOLES (Imidazols and triazoles): These includes, Ketaconazol, Voriconazol, Fliconazole, Posaconazol and  Oesaconazol use to treat fungi infections such as itching, athete’s foot, ring worm and certain kinds of dandruff.

It is also used in the treatment of Pityriasis (Tinea versicolor) a skin infection, and also in the treatment of fungi that causes darkening and lightening of skin of arm, neck, chest or legs. Oesaconazol, is used in treatment of mucocontanous candidosis, dermartophytosis and for some systemic fungi infection. Fluconazol, is being used to maintain aids patient with cryptococcosis. Voriconazol is used for treatment of invasive aspergilosis. 

Mode of action: Azole works by inhibiting enzyme Lanosterol 14 a – dimethylase, which is needed to convert Lanosterol to ergosterol in fungi cell membrane Depletion of ergosterol in fungi cell membrane disrupts the structure and many functions in fungi membrane leading to inhibition of fungi growth.

Chemical Composition: Azoles are five membered heterocyclic compounds having nitrogen (N₂) ring made of imidazole and 1,2,3 triazole. It contain at least one other non carbon atom of Nitrogen, Sulphur or oxygen and sometimes fluorine. The parent compounds are aromatic and have two double bounds.

General formula: The general formula of Azole compound is C-H-N-O, e.g. C₂₆H₃₁N₄O_6, for Voriconazole and C₁₃H₁₂+₂N₆O………..

Side effect: Some people react very high to Azole but it’s side effects are uncommon in immunocompetent individual, side effects includes

-          Nausae

-          Vomiting

-          Constipation

-          Dizziness

-          Diarrhea

-          Headache

Certain drugs can react with the compound and make it less effective, others cause problem with the liver, they includes

-          Phenyltoin dilantin, using in treating seizure

-          Sucraphate and antacids uses in treating ulcer

-          Rifampin, use in treatment of tuberculosis.

3 – ALLYMINES

Allymine antifungi agent has been developed by modification of Naftifine, a tropical antimycotic that includes, Amorofine, Butenafine,and Terbinafine, used in treating nail/ finger infection.

Mechanism of action: It inhibits squalence epoxidase, an enzyme required for ergosterol synthesis.

General Formula: The chemical compound has the general formula, C₃H₇N.

Chemical Comosition: It’s a colorless liquid made up of Allylchloride and Ammonia, it is the simplest stable unsaturated amine. 

Side effect:  Allymine side effects includes, stomach upset and fever.

4 – ECHINOCANDINES

Echinocandims are antimycotic used to treat systemic fungi infections in patients with compromised immune system, they are particularly important in treatment of Aspergilosis……… and candidosis. ;;;;;;;;They are fungicidal against some yeast species of Candida and fungistatic against Mould.

Mode of action: This class of antifungal agent is called the penicillin of fungi because of how it works; it targets the cell wall and inhibits the production of glucan. Members include, Caspofungin, Anidulafungi, mica fungin.

General formula: Their general formula is  C₅₂H₈₈N for Caspofungin and C56H_{7 ,} for Micafungin.

Side effect: Echinocandins target cell wall in a unique mechanism, it has no side effect.

 5 - ANTIMETABOLIC ANTIFUNGALS

Antimetabolites are used to treat severe infections caused by susceptible strains of Candida or Cryptococcosis neoforman.

It is also use in treating Chromomycosis. Representatives includes, 5-Flourcytosine(Flucytosine or S.F.C).

Antimetabolic antifungals, should be used in combination with Amphotericin B and azoles because of it relatively weak effect and immediate development of resistance.

Mechanism of action: It’s mechanism of action s by inhibition of DNA or RNA synthesis via intra cytoplasmic conversion of 5 – fluorouracile that undergoes further activation and finally interact as 5 fluororidin triphosphate with RNA biosynthesis and finally disrupt the binding of certain essential proteins.

It also acts by conversion of Fluorodeoxyuryne monophosphate which inhibits fungi DNA synthesis.

Chemical constituents: Antimetabolite, contain 4 – amino – 5 – fluro – 1, 2dihydropyrimidine – 2 – 1.

General formula: C₄H₄FN₃O.

Side effect: The side effects of Antimetabolic antifungal agents includes

-  Anemia

-  Agranulocytosis

-  Pancytopenia

-  Aplastic Anemia

-  Hearing loss

-  Parathesia

F - Griseofulvin: Griseofulvin is produced by Penicillium grisefulvum, it is administered orally and absorbed by growing.

Griseofulvin is active in invitro system against most dermatophytes, and is commonly used to treat chronic fungi infections such as nail infection with (Trychopyton rubrum).

G – Potassium iodide: this Antifungal agent is used to treat cutaneous and lymphocutaneous Sporotrichosis. Potassium iodide is administered orally and act by enhancing transepidermal elimination process in the infected host.