Antifungal Drugs

Infectious diseases caused by fungi are called

mycoses, and they are often chronic in nature.

Fungal infectious occur due to :

1- Abuse of broad spectrum antibiotics

2- Decrease in the patient immunity

They have rigid cell walls composed

largely of a polymer of N-

acetylglucosamine rather than

peptidoglycan (a characteristic component

of most bacterial cell walls).

The fungal cell membrane contains

ergosterol rather than the cholesterol found

in mammalian membranes.

These chemical characteristics are useful in

targeting chemotherapeutic agents against

fungal infections

Types of fungal infections

1. Superficial : Affect skin – mucous membrane. e.g.

Tinea versicolor

Dermatophytes : Fungi that affectkeratin layer of skin, hair, nail. e.g. tineapedis ,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 : 11% 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 ofseveral days.

Half-life 16 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 modifying 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 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 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.

3- 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 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.

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 oraladministration

Bioavailability is not affected by food orgastric PH

Concentrated in plasma is same by oral or IV route

Has the least effect on hepatic microsomalenzymes

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

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 fattymeal )

Half-life 26 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

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.

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.