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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