Heterocyclic Benzofuran

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Chapter: Essential pharmacology : Antifungal Drugs

Griseofulvin : It was one of the early antibiotics extracted from Penicillium griseofulvum. However, because of lack of antibacterial activity, little attention was paid to it: clinical utility in dermatophytosis was demonstrated only around 1960.


HETEROCYCLIC BENZOFURAN

 

Griseofulvin

 

It was one of the early antibiotics extracted from Penicillium griseofulvum. However, because of lack of antibacterial activity, little attention was paid to it: clinical utility in dermatophytosis was demonstrated only around 1960.

 

 

Griseofulvin is active against most dermatophytes, including Epidermophyton, Trichophyton, Microsporum, etc., but not against Candida and other fungi causing deep mycosis. Bacteria are also insensitive. Dermatophytes actively concentrate it: this feature probably accounts for its selective toxicity. Resistance can be induced in vitro and this is associated with loss of concentrating ability. However, emergence of resistance during clinical use is rare.

 

Griseofulvin interferes with mitosis—multinucleated and stunted fungal hyphae result from its action. It also causes abnormal metaphase configurations. However, unlike the typical mitotic inhibitors (colchicine, vinca alkaloids), it does not cause metaphase arrest; rather the daughter nuclei fail to move apart or move only a short distance. It does not inhibit polymerization of tubulin (microtubular protein which pulls the chromosomes apart), but binds to polymerized microtubules and somehow disorients them.

 

Pharmacokinetics

 

The absorption of griseofulvin from g.i.t. is somewhat irregular because of its very low water solubility. Absorption is improved by taking it with fats and by micro-fining the drug particles; now ultra-microfine particle preparations from which absorption is still better are available.

 

Griseofulvin gets deposited in keratin forming cells of skin, hair and nails; it is especially concentrated and retained in tinea infected cells. Because it is fungistatic and not cidal, the newly formed keratin is not invaded by the fungus, but the fungus persists in already infected keratin, till it is shed off. Thus, the duration of treatment is dependent upon the site of infection, thickness of infected keratin and its turnover rate.

 

Griseofulvin is largely metabolized, primarily by methylation, and excreted in urine. Plasma t½ is 24 hrs, but it persists for weeks in skin and keratin.

 

Adverse Effects

 

Toxicity of griseofulvin is low and usually not serious. Headache is the commonest complaint, followed by g.i.t. disturbances. CNS symptoms and peripheral neuritis are occasional.

 

Rashes, photoallergy may warrant discontinuation.

 

Transient leukopenia and albuminuria (without renal damage) are infrequent.

 

Use

 

Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. Systemic azoles and terbinafine are equally or more efficacious; preferred now.

 

Dose: 125–250 mg QID with meals; duration depends on the site of infection (turnover rate of keratin).

 

Body skin: 3 weeks

Palm, soles: 4 to 6 weeks

Finger nails: 4 to 6 months

Toe nails: 8 to 12 months

 

Majority of localized tinea infections are treated with topical agents. Griseofulvin should be reserved for cases with nail, hair or large body surface involvement. It is effective in athletes foot, but not in pityriasis versicolor.

 

GRISOVINFP, WALAVIN, GRISORAL 250 mg tab.

 

Interactions

 

Griseofulvin induces warfarin metabolism and reduces efficacy of oral contraceptives.

 

Phenobarbitone reduces the oral absorption and induces the metabolism of griseofulvin—failure of therapy may occur.

 

Griseofulvin can cause intolerance to alcohol.

 

Flucytosine  (5FC)

 

It is a pyrimidine antimetabolite which is inactive as such. It is taken up by fungal cells and converted into 5fluorouracil and then to 5fluorodeoxyuridylic acid which is an inhibitor of thymidylate synthesis. Thymidylic acid is a component of DNA. The fungal selectivity of 5FC depends on the fact that mammalian cells (except some marrow cells) have low capacity to convert 5FC into 5fluorouracil.

 

It is a narrow spectrum fungistatic, active against Cryptococcus neoformans, Torula, Chromoblastomyces; and a few strains of Candida. Other fungi and bacteria are insensitive.

 

Adverse Effects

 

Toxicity of 5FC is lower than that of AMB; consists of dose-dependent bone marrow depression and gastrointestinal disturbances, particularly enteritis and diarrhoea.

 

Liver dysfunction is mild and reversible.

 

Use

 

Flucytosine is not employed as the sole therapy except occasionally in chromoblastomycosis. Rapid development of resistance limits its utility in deep mycosis. In cryptococcosis (both meningeal and nonmeningeal) its synergistic action with AMB is utilized to reduce the total dose of the more toxic latter drug.

 

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