Antifungal drugs

Ghanshyam pd. Sah

17th batch ,MBBS
Intern,Dermatology
Antifungal drugs are used for the treatment of fungal

infections (mycoses) that may be superficial or deep

infections.

Fungal infections are susceptible to the immunocompromised

patients due to chemotherapy or antibiotic use.

 Classification of antifungal drugs

1.Antibiotics
polyenes
o Amphotericin B

o Nystatin

o Hamycin

Heterocyclic benzofuran
o Griseofulvin

2.Antimetabolite
flucytosine
3.Azoles
• Imidazoles
Topical
Clotrimazole
Eeconazole
Miconazole
Oxiconazole
Systemic
Ketoconazole
Triazoles(systemic)
Fluconazole
Itraconazole
Voriconazole
4.Allylamine
Terbinafine

5.Other topical agents:

Tolnaftate

Benzoic acid

Undecylenic acid

Butenafine
 Amphotericin B

•Amphotericin A & B are antifungal antibiotics,

Amphotericin A is not used clinically.

Pharmokinetics of Amphotericin
B
•Poorly absorbed orally , is effective for fungal infection of

gastrointestinal tract.

•For systemic infections given as slow I.V.I.

•Metabolized in liver

•Excreted slowly in urine over a period ofseveral days.

•Half-life 16 days.
Mechanism of action of
Amphotericin B

• It is a selective fungicidal drug.

• Disrupt fungal cell membrane by binding to ergosterol , so alters

the permeability of the cell membrane leading to leakage of

intracellular ions & macromolecules (cell death )

Resistance to amphotericin B

• If ergosterol binding is impaired either by :

• Decreasing the membrane concentration of

ergosterol.

• Or by modifying the sterol target molecule.

 Adverse effects OF
AmphotericinB
1- Immediate reactions(Infusion –related toxicity).

Fever, muscle spasm, vomiting, headache, hypotension.

• Can be avoided by:

A. Slowing the infusion

B. Decreasing the daily dose

C.Premedication with antipyretics, antihistamincs orcorticosteroids.

D. A test dose
2- Slower toxicity
• Most serious is renal toxicity (nearly in all patients ).

• Hypokalemia

• Hypomagnesaemia

• Impaired liver functions

• Thrombocytopenia

• Anemia
Clinical use OF Amphotericin B

• Has a broad spectrum of activity & fungicidal action.

• The drug of choice for life-threatening mycotic infections.

• For induction regimen for serious fungal infection.

• Also, for chronic therapy & preventive therapy of relapse.

• In cancer patients with neutropenia who remain febrile on broad –

spectrum antibiotics
Nystatin

• similar in structure & mechanism to amphotericin B.

• Too toxic for systemic use.

• Used only topically.

• It is available as creams, ointments,and other preparations.

• Not significantly absorbed from skin, mucous membrane, GIT .

Clinical use of Nystatin

• Prevent or treat superficial candidiasis of mouth,

esophagus, intestinal tract.

• Vaginal candidiasis

• Can be used in combination with antibacterial

agents & corticosteroids.

Azoles

• A group of synthetic fungistatic agents with a broad

spectrum of activity .

• They have antibacterial , antiprotozoal

anthelminthic & antifungal activity

Mechanism of action of Azoles

1-Inhibit the fungal cytochrome P450 enzyme, (α-demethylase)

which is responsible for converting lanosterol to ergosterol ( the

main sterol in fungal cell membrane ).

2- Inhibition of mitochondrial cytochrome oxidase leading to

accumulation of peroxides that cause autodigestion of the fungus.

3- Imidazoles may alter RNA& DNA metabolism

Azoles

• They are classified into :

• Imidazole group

• Triazole group
Imidazoles

• Ketoconazole

• Miconazole

• Clotrimazole

• They lack selectivity ,they inhibit human gonadal and steroid

synthesis leading todecrease testosterone & cortisol production.

• Also, inhibit human P-450 hepatic enzyme.

Ketoconazoles

• Well absorbed orally .

• Bioavailability is decreased with antacids, H2blockers , proton

pump inhibitors & food .

• Cola drinks improve absorption in patients with achlorhydria.

• Half-life increases with the dose , it is (7-8 hrs)

Clinical uses of ketoconazole

• Used topically or systematic (oral route only ) to treat :

1- Oral & vaginal candidiasis.

2- Dermatophytosis.

3- Systemic mycoses
Adverse effects of ketoconazole
• Nausea, vomiting ,anorexia

• Hepatotoxic

• Inhibits human P 450 enzymes

• Inhibits adrenal & gonadal steroids leading to:

• Menstrual irregularities

• Loss of libido

• Impotence

• Gynaecomastia in males
Contraindication of ketoconazole

•Pregnancy, lactation ,hepatic dysfunction

• Interact with enzyme inhibitors , enzyme inducers.

• H2 blockers & antacids decrease its absorption

Triazoles

• Fluconazole

• Itraconazole

• Voriconazole

• They are :

• Selective

• Resistant to degradation

• Causing less endocrine disturbance

Fluconazole

• Bioavailability is not affected by food or

• gastric PH

• Clinical uses

• Candidiasis ( is effective in all forms of mucocutaneous candidiasis)

• Cryptococcus meningitis

• Histoplasmosis, Blastomycosis, , ring worm

Side effects of fluconazole

• Nausea,Vomiting

• Headache

• skin rash

• Diarrhea, abdominal pain

• Reversible alopecia.

• Hepatic failure may lead to death

• Highly teratogenic ( as other azoles)

Flucytosine

• Synthetic pyrimidine antimetabolite (cytotoxic

drug ) often given in combination with

amphotericin B & itraconazole.

• Systemic fungistatic ,rapid and well absorbed orally

Flucytosine

• Mechanism of action

Converted within the fungal cell to 5-fluorouracil (Not in

human cell ), that inhibits thymidylate synthetase

enzyme that inhibits DNA synthesis

Clinical uses of Flucytosine

• Severe deep fungal infections as in meningitis

• Generally given with amphotericin B

• For cryptococcal meningitis in AIDS patients

Flucytosine
Adverse effects
• Nausea, Vomiting

• Diarrhea

• Severe Enterocolitis

• Reversible Neutropenia

• Thrombocytopenia

• Bone Marrow Depression

• Alopecia
 Griseofulvin

• Fungistatic, has a narrow spectrum

• Given orally (Absorption increases with fatty meal )

• Taken selectively by newly formed skin & concentrated in the

keratin.

• Should be given for 2-6weeks for skin & hair infections to

allow replacement of infected keratin by the resistant
structure
Griseofulvin

Mechanism of action

 Inhibits fungal mitosis by interfering with microtubule function

Uses of griseofulvin

 Dermatophyte infections ( ring worm of skin, hair, nails ).

 Highly effective in athlete foot

Griseofluvin
Adverse effects
Peripheral neuritis

Mental confusion

Fatigue

vertigo

GIT upset

Enzyme inducer

Blurred vision

Increases alcohol intoxication.

Terbinafine

• Drug of choice for treating dermatophytes

(onychomycoses)

• Effective for treatment of onychomycoses

• 6 weeks for finger nail infection & 12 weeks for toe

nail infections .
Terbinafine

side effects

• Severely hepatotoxic,liver failure even death.

• Accumulate in breast milk , should not be given to

nursing mother.

• GIT upset (diarrhea, dyspepsia, nausea )

• Taste & visual disturbance.

References

• Essentials Of Medical Pharmacology Kd Tripathi

Eighth Edition

• Comprehensive Dermatologic Drug Therapy, Third

edition