Antifungal Drugs 3

5/28/2018 Antifungal Drugs 3

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Antifungal Drugs Fungal infectious occur due to :

1- Abuse of broad spectrum antibiotics

2- Decrease in the patient immunity


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Types of fungal infections 1. Superficial : Affect skinmucous

membrane.e.g.

Tinea versicolor

Dermatophytes : Fungi that affectkeratin layer of skin, hair, nail.e.g.tinea

pedis ,ring worm infection Candidiasis : Yeast-like, oral thrush,

vulvo-vaginitis , nail infections.


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

brain leading to pneumonia ,

endocarditis , meningitis.


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Classification of Antifungal Drugs

1- Antifungal Antibiotics :

Griseofulvin

Polyene macrolide : Amphotericin- B &

Nystatin

2- Synthetic :

Azoles :

A) Imidazoles : Ketoconazole , Miconazole

B) Triazoles : Fluconazole , Itraconazole


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Synthetic Antifungal ( contin)

Flucytosine

Squalene epoxidase inhibitors : e.g.

Terbinafine & Naftifine.


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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.


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In Dermatophytes :

Squalene epoxidase inhibitors : Terbinafine &

Naftifine.

Tolnaftate.

White field ointment : 12% Benzoic acid &

6% Salicylic acid .

Castellani paint.


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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 )


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Pharmacokinetics

Poorly absorbed orally , is effective for fungalinfection 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 ofseveral days.

Half-life 15 days.


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Mechanism of action

It is a selective fungicidal drug.

Disrupt fungal cell membrane by binding to

ergosterol , so alters the permeability of thecell membrane leading to leakage of

intracellular ions & macromolecules ( cell

death ).


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Resistance to amphotericin B

If ergosterol binding is impaired either by :

Decreasing the membrane concentration of

ergosterol.

Or by modyfing the sterol target molecule.


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Adverse Effects

1- Immediate reactions( Infusionrelatedtoxicity ).

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.


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2- Slower toxicity

Most serious is renal toxicity (nearly in all

patients ).

Hypokalemia

Hypomagnesaemia

Impaired liver functions

Thrombocytopenia

Anemia


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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 remainfebrile on broadspectrum antibiotics.


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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 fungalarthritis.

4- Bladder irrigation in Candiduria.


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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


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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 .


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Clinical uses

Prevent or treat superficial candidiasis of

mouth, esophagus, intestinal tract.

Vaginal candidiasis

Can be used in combination with antibacterial

agents & corticosteroids.


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Azoles

A group of synthetic fungistatic agents with a

broad spectrum of activity .

They have antibacterial , antiprotozoalanthelminthic & antifungal activity .


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Mechanism of Action

1-Inhibit the fungal cytochrome P450 enzyme,

(-demethylase) which is responsible for

converting lanosterol to ergosterol ( the mainsterol 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.


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Azoles They are antibacterial , antiprotozoal,

anthelminthic & antifungal.

They are fungistatic agents.

They are classified into :

Imidazole group

Triazole group


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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.


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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).


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

& urine.

Does not cross BBB.


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Clinical uses

Used topically or systematic (oral route only )

to treat :

1- Oral & vaginal candidiasis.

2- Dermatophytosis.

3- Systemic mycoses & mucocutaneous

candidiasis.


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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


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Contraindications & Drug interactions

Contraindicated in :

Prgnancy, lactation ,hepatic dysfunction

Interact with enzyme inhibitors , enzyme

inducers.

H2blockers & antacids decrease its absorption


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Triazoles

Fluconazole

Itraconazole

Voriconazole

They are :

Selective Resistant to degradation

Causing less endocrine disturbance


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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


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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 drugsas oral anticoagulants.


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Fluconazole Water soluble

Completely absorbed from GIT

Excellent bioavailability after oraladministration

Bioavailability is not affected by food orgastric PH

Conc. in plasma is same by oral or IV route

Has the least effect on hepatic microsomalenzymes


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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


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Clinical uses

Candidiasis

( is effective in all forms of mucocutaneous

candidiasis)

Cryptococcus meningitis

Histoplasmosis, blastomycosis, , ring worm.

Not effective in aspergillosis


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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


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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


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Flucytosine Synthetic pyrimidine antimetabolite (cytotoxic

drug ) often given in combination with

amphotericin B & itraconazole. Systemic fungistatic


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Mechanism of action Converted within the fungal cell to 5-

fluorouracil( Not in human cell ), that inhibits

thymidylate synthetase enzyme that inhibitsDNA synthesis.

( Amphotericin B increases cell permeability ,

allowing more 5-FC to penetrate the cell, they

are synergistic).


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Phrmacokinetics Rapidly & well absorbed orally

Widely distributed including CSF.

Mainly excreted unchanged through kidney

Half-life 3-6 hours


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Clinical uses Severe deep fungal infections as in meningitis

Generally given with amphotericin B

For cryptococcal meningitis in AIDS patients


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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)


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Caspofungin Inhibits the synthesis of fungal cell wall by

inhibiting the synthesis of (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.


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Clinical uses Effective in aspergillus & candida infections.

Second line for those who have failed or

cannot tolerate amphotericin B oritraconazole.

Adverse effects:

Nausea, vomiting Flushing( release of histamine from mast cells)

Very expensive


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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 & hairinfections to allow replacement of infectedkeratin by the resistant structure


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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.


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Antifungal Drugs Used For Topical

Fungal Infections 1. Topical azole derivatives

2. Nystatin& Amphotericin

3. Terbinafine

4. Tolnaftate

5. Naftifine

6. Griseofulvin


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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 cutaneousapplication is cream or solution.


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Azoles for topical use

In the form of vaginal creams,

suppositories, tablets for vaginal

candidiasis given once daily .


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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.


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ITRACONAZOLE Effective for treatment of onychomycoses.

Should not be given in patients with

ventricular dysfunction. Evaluation of hepatic function is

recommended.


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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.


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NAFTIFINE Broad spectrumfungicidal .

Available as cream or gel.

Effective for treatment of tinea cruris.


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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 ofsqualene ,which is toxic to the organismcausing death of fungal cell).


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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 , bioavailabilitydecreases due to first pass metabolism in liver.


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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.

Antifungal Drugs 3

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