Antifungal Drugs Fungal infectious occur due to : 1- Abuse of broad spectrum antibiotics 2- Decrease in the patient immunity

Types of fungal infections 1. Superficial : Affect skin – mucous

membrane.e.g. Tinea versicolor Dermatophytes : Fungi that affect

keratin layer of skin, hair, nail.e.g.tinea pedis ,ring worm infection

Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.

2- Deep infections Affect internal organs as : lung ,heart ,

brain leading to pneumonia , endocarditis , meningitis.

Classification of Antifungal Drugs 1- Antifungal Antibiotics : Griseofulvin Polyene macrolide : Amphotericin- B &

Nystatin 2- Synthetic : Azoles : A) Imidazoles : Ketoconazole , Miconazole B) Triazoles : Fluconazole , Itraconazole

Synthetic Antifungal ( contin…)

Flucytosine Squalene epoxidase inhibitors : e.g. Terbinafine & Naftifine.

Classification According to Route of Administration Systemic : Griseofulvin , Amphotericin- B , Ketoconazole ,

Fluconazole , Terbinafine. Topical In candidiasis : Imidazoles : Ketoconazole , Miconazole. Triazoles : Terconazole. Polyene macrolides : Nystatin , Amphotericin-B Gentian violet : Has antifungal & antibacterial.

In Dermatophytes :

Squalene epoxidase inhibitors : Terbinafine & Naftifine. Tolnaftate. White field ointment : 12% Benzoic acid &

6% Salicylic acid . Castellani paint.

Amphotericin B Amphotericin A & B are antifungal

antibiotics. Amphotericin A is not used clinically. It is a natural polyene macrolide (polyene = many double bonds ) (macrolide = containing a large lactone ring )

Pharmacokinetics Poorly absorbed orally , is effective for fungal

infection of gastrointestinal tract. For systemic infections given as slow I.V.I. Highly bound to plasma protein . Poorly crossing BBB. Metabolized in liver Excreted slowly in urine over a period of

several days. Half-life 15 days.

Mechanism of action 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 modyfing the sterol target molecule.

Adverse Effects 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 or

corticosteroids. D. A test dose.

2- Slower toxicity Most serious is renal toxicity (nearly in all

patients ). Hypokalemia Hypomagnesaemia Impaired liver functions Thrombocytopenia Anemia

Clinical uses 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.

Routes of Administration 1- Slow I.V.I. For systemic fungal disease. 2- Intrathecal for fungal C.N.S. infections. Topical drops & direct subconjunctival

injection for Mycotic corneal ulcers & keratitis.

3- Local injection into the joint in fungal arthritis.

4- Bladder irrigation in Candiduria.

Liposomal preparations of amphotericin B Amphotericin B is packaged in a lipid-

associated delivery system to reduce binding to human cell membrane , so reducing :

A. Nephrotoxicity B. Infusion toxicity Also, more effective More expensive

Nystatin It is a polyene macrolide ,similar in structure

& mechanism to amphotericin B. Too toxic for systemic use. Used only topically. It is available as creams, ointment ,

suppositories & other preparations. Not significantly absorbed from skin, mucous

membrane, GIT .

Clinical uses 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 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 antibacterial , antiprotozoal,

anthelminthic & antifungal. They are fungistatic agents. They are classified into : Imidazole group Triazole group

Imidazoles

Ketoconazole Miconazole Clotrimazole They lack selectivity ,they inhibit human

gonadal and steroid synthesis leading to decrease testosterone & cortisol production.

Also, inhibit human P-450 hepatic enzyme.

Ketoconazole Well absorbed orally . Bioavailability is decreased with antacids, H2

blockers , proton pump inhibitors & food . Cola drinks improve absorption in patients

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

Ketoconazole (cont.) Inactivated in liver & excreted in bile (feces )

& urine. Does not cross BBB.

Clinical uses Used topically or systematic (oral route only )

to treat : 1- Oral & vaginal candidiasis. 2- Dermatophytosis. 3- Systemic mycoses & mucocutaneous

candidiasis.

Adverse Effects Nausea, vomiting ,anorexia Hepatotoxic Inhibits human P 450 enzymes Inhibits adrenal & gonadal steroids leading

to : Menstrual irregularities Loss of libido Impotence Gynaecomastia in males

Contraindications & Drug interactions

Contraindicated in : Prgnancy, 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

Itraconazole Lacks endocrine side effects Has a broad spectrum activity Given orally & IV Food increases its absorption Metabolized in liver to active metabolite Highly lipid soluble ,well distributed to bone,

sputum ,adipose tissues. Can not cross BBB

Itraconazole (cont.) Half-life 30-40 hours Used orally in dermatophytosis & vulvo-

vaginal candidiasis. IV only in serious infections. Effective in AIDS-associated histoplasmosis Side effects : Nausea, vomiting, hypokalemia, hypertension,

edema, inhibits the metabolism of many drugs as oral anticoagulants.

Fluconazole Water soluble Completely absorbed from GIT Excellent bioavailability after oral

administration Bioavailability is not affected by food or

gastric PH Conc. in plasma is same by oral or IV route Has the least effect on hepatic microsomal

enzymes

Fluconazole (cont.) Drug interactions are less common Penetrates well BBB so, it is the drug of choice

of cryptococcal meningitis Safely given in patients receiving bone marrow

transplants (reducing fungal infections) Excreted mainly through kidney Half-life 25-30 hours Resistance is not a problem

Clinical uses Candidiasis ( is effective in all forms of mucocutaneous

candidiasis) Cryptococcus meningitis Histoplasmosis, blastomycosis, , ring worm. Not effective in aspergillosis

Side effects Nausea, vomiting, headache, skin rash ,

diarrhea, abdominal pain , reversible alopecia. Hepatic failure may lead to death Highly teratogenic ( as other azoles) Inhibit P450 cytochrome No endocrine side effects

Voriconazole A broad spectrum antifungal agent Given orally or IV High oral bioavailability Penetrates tissues well including CSF Inhibit P450 Used for the treatment of invasive aspergillosis

& serious infections. Reversible visual disturbances

Flucytosine Synthetic pyrimidine antimetabolite (cytotoxic

drug ) often given in combination with amphotericin B & itraconazole.

Systemic fungistatic

Mechanism of action Converted within the fungal cell to 5-

fluorouracil( Not in human cell ), that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis.

( Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic).

Phrmacokinetics Rapidly & well absorbed orally Widely distributed including CSF. Mainly excreted unchanged through kidney Half-life 3-6 hours

Clinical uses Severe deep fungal infections as in meningitis Generally given with amphotericin B For cryptococcal meningitis in AIDS patients

Adverse Effects Nausea, vomiting , diarrhea, severe

enterocolitis Reversible neutropenia, thrombocytopenia,

bone marrow depression Alopecia Elevation in hepatic enzymes (some adverse effects related to 5-Fu formed

by intestinal organisms from5-FC)

Caspofungin Inhibits the synthesis of fungal cell wall by

inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis & cell death.

Given by IV route only Highly bound to plasma proteins Half-life 9-11 hours Slowly metabolized by hydrolysis & N-acetylation. Elimination is nearly equal between the urinary &

fecal routes.

Clinical uses Effective in aspergillus & candida infections. Second line for those who have failed or

cannot tolerate amphotericin B or itraconazole.

Adverse effects : Nausea, vomiting Flushing( release of histamine from mast cells) Very expensive

Griseofulvin Fungistatic, has a narrow spectrum Given orally (Absorption increases with fatty

meal ) Half-life 24 hours Taken selectively by newly formed skin &

concentrated in the keratin. Induces cytochrome P450 enzymes Should be given for 2-6weeks for skin & hair

infections to allow replacement of infected keratin by the resistant structure

Griseofulvin(cont.) Inhibits fungal mitosis by interfering with microtubule

function Used to treat dermatophyte infections ( ring worm of

skin, hair, nails ). Highly effective in athlete,s foot. Ineffective topically. Not effective in subcutaneous or deep mycosis. Adverse effects ; Peripheral neuritis, mental confusion, fatigue,

vertigo,GIT upset,enzyme inducer, blurred vision. Increases alcohol intoxication.

Antifungal Drugs Used For Topical Fungal Infections 1. Topical azole derivatives 2. Nystatin& Amphotericin 3. Terbinafine 4. Tolnaftate 5. Naftifine 6. Griseofulvin

Topical Antifungal Agents Used in superficial fungal infections , such as : Dermatophytosis ( ring worm), candidiasis,

fungal keratitis. They are not effective in mycoses of the nails &

hair or subcutaneous mycoses. The preferred formulation for cutaneous

application is cream or solution.

Azoles for topical use In the form of vaginal creams,

suppositories, tablets for vaginal candidiasis given once daily .

CLOTRIMAZOLE

Absorption is less than 0.5% from intact skin, 3-10% from vagina (its activity remains for 3 days ).

Used in dermatophytes , cutaneous candidiasis & vulvovaginal candidiasis.

Causes : Erythema, edema, , urticaria & mild vaginal burning sensation.

ITRACONAZOLE Effective for treatment of onychomycoses. Should not be given in patients with

ventricular dysfunction. Evaluation of hepatic function is

recommended.

TOLNAFTATE Effective in most cutaneous mycosis. Ineffective against Candida. Used in tinea pedis ( cure rate 80% ). Used as cream, gel, powder, topical solution. Applied twice daily.

NAFTIFINE Broad spectrum fungicidal . Available as cream or gel. Effective for treatment of tinea cruris.

TERBINAFINE

Drug of choice for treating dermatophytes (onychomycoses).

Better tolerated ,needs shorter duration of therapy.

Inhibits fungal squalene epoxidase, decreases The synthesis of ergosterol .(Accumulation of

squalene ,which is toxic to the organism causing death of fungal cell).

Fungicidal ,its activity is limited to candida albicans & dermatophytes.

Effective for treatment of onychomycoses 6 weeks for finger nail infection & 12 weeks

for toe nail infections . Well absorbed orally , bioavailability

decreases due to first pass metabolism in liver.

Highly protein binding Accumulates in skin , nails, fat. 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.