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Fungal infection
Divided into 2 types:
A-Superficial mycosis:
1-Dermatophyte infections (ringworm, tinea);
Tinea capitis (ring worm of scalp).
Tinea corporis(ringworm of trunk).
Tinea ungum (tinea of the nail)
2-candida infections: e.x. oral thrush and vaginal candidiasis.
3- tinea versicolor(hypo pigmented, hyper pigmented and fawn color).
B- Systemic mycosis: e.x. aspergilosis, histoplasmosis,blastomycosis.
Classifications of antifungal drugs:
1-drugs that distrupt the fungal cell membrane:
a- polyenes e. g. amphotericin
b-Azoles e. g.ketoconazole, fluconazole
c-allylamine: terbenafine .
2-drugs that inhibit mitosis: grisofulvin
3- drugs that inhibit DNA synthesis: flucytosine
1-drugs that distrupt the fungal cell membrane:
a-Polyene antibiotics:
1-Amphotericin: In spite of its toxic potential, amphotericin B is the
drug of choice for the treatment of life-threatening, systemic mycoses.
The drug is also sometimes used in combination with flucytosine so that
lower (less toxic) levels of amphotericin B are possible.
Mechanism of action: Several amphotericin B molecules bind to
ergosterol in the plasma membranes of sensitive fungal cells, There, they
form pores (channels) The pores disrupt membrane function, allowing
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electrolytes (particularly potassium) and small molecules to leak from the
cell, resulting in cell death.
Pharmacokinetics:
Amphotericin
B
is
administered
by
slow,
intravenous infusion.
Adverse effects:
1-Fever and chills: Premedication with a corticosteroid or an antipyretic
helps to prevent this problem..
2-Renal impairment:
3-Hypotension:
4-Anemia:
5-Thrombophlebitis: Adding heparin to the infusion can alleviate this
problem.
2-Nystatin
Nystatin is a polyene antibiotic, and its structure, chemistry, mechanism
of action, and resistance resemble those of amphotericin B. Its use is
restricted to topical treatment of candida albican because of its systemic
toxicity. The drug is negligibly absorbed from the gastrointestinal tract,
and it is never used parenterally.
Indications:
1-oral thrush .candidiasis of esophagus and intestinal tract.
2- Vaginal candidiasis.
3- Cutaneous infections.
-B-Azoles:
1-Ketoconazole: superseded by fluconazole and itraconazole because of
adverse effects.
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Adverse effects:
1-Endocrine effects, such as gynecomastia, decreased libido, impotence,
and menstrual irregularities, result from the blocking of androgen and
adrenal steroid synthesis by ketoconazole.
2- impairment of liver functions.(monitoring the patient by liver function
test every 6 weeks).
2- Fluconazole
Fluconazole is clinically important because of its lack of the endocrine
side effects of ketoconazole and its excellent penetrability into the CSF of
both normal and inflamed meninges.
3-Itraconazole:
Itraconazole
is an azole antifungal agent with a broad antifungal
spectrum. Like fluconazole also lacks the endocrinological side effects of
ketoconazole.
Mechanism of action:
Azoles are predominantly fungistatic. They inhibit C-14 αdemethylase (a
cytochrome P450 enzyme), thus blocking the demethylation of lanosterol
to ergosterol, the principal sterol of fungal membranes . This inhibition
disrupts membrane structure and function and, thereby, inhibits fungal
cell.
CLINICAL INDICATIONS:
1-Fluconazole and itraconazole is employed prophylactically, for
reducing fungal infections in recipients of bone marrow transplants.
2-Systemic mycosis ketocnazole can be used but it has been superseded
by fluconazole and itraconazole.
3- Fluconazole is used for treatment of fungal meningitis (because of
good penetrations to CSF).
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4- Mucocutaneous candidiasis.
Ketoconazole
fluconazole
itraconazole
expanded
spectrum
narorow
expanded
routs
oral
oral,i.v.
CSF
no
yes
oral
no
Penetrations
Excretion
hepatic
Interaction
frequent
inhibition of
yes
renal
hepatic
occasional
occasional
no
no
gonadal and steroid synthesis
exercise -1Select the best answer:
1-All these are the side effects of ketoconazole except:
a- impotence.
b- gynaecomastia.
c- chill and fever.
d-liver impairment.
e-menstural irregularities.
2- all these drugs are used in treatment of systemic mycosis except:
a-fluconazole.
b- itraconazole.
c- amphotricine B.
d- nystatin.
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e- ketoconazole
3-All the following statements correctly describe the ketoconazole
except:
a-It inhibits conversion o f lanosterol to ergosterol.
b-It may produce gastrointestinal upset.
c-it can cause gynecomastia in male.
d-It penetrates into cerebrospinal fluid.
e-Fluconazole is moreeffective than ketoconazole in systemic mycosis.
4- All the following statements correctly describe the fluconazole
except:
a-It can be used in treatment of fungal meningitis.
b-it is a drug of first choice in treatment of systemic candidiasis.
c-the drug dose should be reduced in patient with renal failure.
d-it has frequent drug interactions.
e-it dose not inhibit steroid synthesis in the body.
5-ALL these are indications of nystatine except:
a-vaginal candidiasis
b-oral thrush
c-dermatophyte infections.
d- intestinal candidiasis.
e-cutaneous candidiasis
.
c- allylamine (Terbinafine)
Terbinafine is the drug of choice for treating dermatophytoses and,
especially, onychomycoses (fungal infections of nails) and tenia capitis. It
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is better tolerated, requires shorter duration of therapy, and is more
effective than either itraconazole or griseofulvin.
CLINICAL INDICATIONS:
1-used topically for dermatophyte infections.
2- used orally for nail and hair infections ,treatment takes weeks .
2- Drugs that inhibit mitosis:
Gresiofulvin:(inhibit mitotic spindles).
Mechanism of action:
It is a fungstatic drug ,it dose not kill the fungus already established, it
prevent the infection of new keratin so that the duration of treatment is
governed by time that it take for infected keratin to be shed(4-6wks for
hair and skin 6 months for finger nail and I year for toenail infections).
Clinical indications:
Dermatophyte infections but is ineffective against p. v. ,superficial
candidiasis and all systemic mycosis.
Side effect: GITdisturbances, photosensitivity.
3- drugs that inhibit DNA synthesis:
Flucytosine:
Flucytosine is metabolized in the fungal cell membrane to 5-fluorouracil
which inhibits nucleic acid synthesis. Dose should be reduced in patients
with renal impairment. Resistant to flucytosine is frequent , so it is
combined with amphotericin.
Exercise-2-: (case study)
Case -1-: patient presented with tenia capitis (scalp fungal infection),
doctor prescribed gresofulvin for 6-8 weeks. During the treatment skin
eruption was appeared on exposed parts of the body. What was the cause
of this eruption?
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Do you have an alternative drug?
Case -2-:60 old age patient presented with severe mucocutaneous
candidiasis with renal impairment. What are preferred antifungal drugs
given for this patient?
Case -3-: patient presented with severe systemic histoplasmosis.
Doctor prescribed a combination therapy (fluconazole plus amphotericin)
As part of synergism. do you expect that this combination is true? Why?
Exercise-3-(home work)
Q1:Describe the interaction of ketoconazole in the liver.
Q2:The side effecs of itraconazole.
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