Antifungal DrugsFungal infectious occur due to :1- Abuse of broad spectrum antibiotics2- Decrease in the patient immunity

Types of fungal infections1. Superficial : Affect skin mucous membrane.e.g.Tinea versicolorDermatophytes : Fungi that affect keratin layer of skin, hair, nail.e.g.tinea pedis ,ring worm infectionCandidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.

2- Deep infectionsAffect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis.

Classification of Antifungal Drugs1- Antifungal Antibiotics :GriseofulvinPolyene macrolide : Amphotericin- B & Nystatin2- Synthetic :Azoles :A) Imidazoles : Ketoconazole , MiconazoleB) Triazoles : Fluconazole , Itraconazole

Synthetic Antifungal ( contin)FlucytosineSqualene epoxidase inhibitors : e.g.Terbinafine & Naftifine.

Classification According to Route of AdministrationSystemic :Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine.TopicalIn candidiasis :Imidazoles : Ketoconazole , Miconazole.Triazoles : Terconazole.Polyene macrolides : Nystatin , Amphotericin-BGentian violet : Has antifungal & antibacterial.

In Dermatophytes :Squalene epoxidase inhibitors : Terbinafine &Naftifine. Tolnaftate.White field ointment : 12% Benzoic acid & 6% Salicylic acid .Castellani paint.

Amphotericin BAmphotericin 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 )

PharmacokineticsPoorly 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 BIf ergosterol binding is impaired either by :Decreasing the membrane concentration of ergosterol.Or by modyfing the sterol target molecule.

Adverse Effects1- Immediate reactions ( Infusion related toxicity ).Fever, muscle spasm, vomiting ,headache, hypotension. Can be avoided by :A. Slowing the infusionB. Decreasing the daily dose C. Premedication with antipyretics, antihistamincs or corticosteroids.D. A test dose.

2- Slower toxicityMost serious is renal toxicity (nearly in all patients ).HypokalemiaHypomagnesaemiaImpaired liver functionsThrombocytopeniaAnemia

Clinical usesHas 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 Administration1- 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 BAmphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing :A. NephrotoxicityB. Infusion toxicityAlso, more effectiveMore expensive

NystatinIt 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 usesPrevent or treat superficial candidiasis of mouth, esophagus, intestinal tract.Vaginal candidiasisCan be used in combination with antibacterial agents & corticosteroids.

AzolesA group of synthetic fungistatic agents with a broad spectrum of activity .They have antibacterial , antiprotozoal anthelminthic & antifungal activity .

Mechanism of Action1-Inhibit the fungal cytochrome P450 enzyme, (-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.

AzolesThey are antibacterial , antiprotozoal, anthelminthic & antifungal.They are fungistatic agents.They are classified into :Imidazole group Triazole group

ImidazolesKetoconazoleMiconazoleClotrimazoleThey lack selectivity ,they inhibit human gonadal and steroid synthesis leading to decrease testosterone & cortisol production.Also, inhibit human P-450 hepatic enzyme.

KetoconazoleWell 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 usesUsed topically or systematic (oral route only ) to treat :1- Oral & vaginal candidiasis.2- Dermatophytosis.3- Systemic mycoses & mucocutaneous candidiasis.

Adverse EffectsNausea, vomiting ,anorexiaHepatotoxicInhibits human P 450 enzymesInhibits adrenal & gonadal steroids leading to :Menstrual irregularitiesLoss of libidoImpotenceGynaecomastia in males

Contraindications & Drug interactionsContraindicated in :Prgnancy, lactation ,hepatic dysfunction Interact with enzyme inhibitors , enzyme inducers.H2 blockers & antacids decrease its absorption

TriazolesFluconazoleItraconazoleVoriconazoleThey are :SelectiveResistant to degradationCausing less endocrine disturbance

ItraconazoleLacks endocrine side effectsHas a broad spectrum activityGiven orally & IVFood increases its absorptionMetabolized in liver to active metaboliteHighly lipid soluble ,well distributed to bone, sputum ,adipose tissues.Can not cross BBB

Itraconazole (cont.)Half-life 30-40 hoursUsed orally in dermatophytosis & vulvo-vaginal candidiasis.IV only in serious infections.Effective in AIDS-associated histoplasmosisSide effects :Nausea, vomiting, hypokalemia, hypertension, edema, inhibits the metabolism of many drugs as oral anticoagulants.

FluconazoleWater solubleCompletely absorbed from GITExcellent bioavailability after oral administrationBioavailability is not affected by food or gastric PHConc. in plasma is same by oral or IV routeHas the least effect on hepatic microsomal enzymes

Fluconazole (cont.)Drug interactions are less commonPenetrates 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 kidneyHalf-life 25-30 hours Resistance is not a problem

Clinical usesCandidiasis( is effective in all forms of mucocutaneous candidiasis)Cryptococcus meningitisHistoplasmosis, blastomycosis, , ring worm.Not effective in aspergillosis

Side effectsNausea, vomiting, headache, skin rash , diarrhea, abdominal pain , reversible alopecia.Hepatic failure may lead to deathHighly teratogenic ( as other azoles)Inhibit P450 cytochromeNo endocrine side effects

VoriconazoleA broad spectrum antifungal agent Given orally or IVHigh oral bioavailabilityPenetrates tissues well including CSFInhibit P450Used for the treatment of invasive aspergillosis & serious infections.Reversible visual disturbances

FlucytosineSynthetic pyrimidine antimetabolite (cytotoxic drug ) often given in combination with amphotericin B & itraconazole.Systemic fungistatic

Mechanism of actionConverted within the fungal cell to 5- fluorouracil( Not in human cell ) by cytosine deaminase, that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis.

when 5-FC is given with Amphotericin B or triazoles( itraconazole) they increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic).

PhrmacokineticsRapidly & well absorbed orallyWidely distributed including CSF.Mainly excreted unchanged through kidneyHalf-life 3-6 hours

Clinical usesSevere deep fungal infections as in meningitisGenerally given with amphotericin BFor cryptococcal meningitis in AIDS patients

Adverse EffectsNausea, vomiting , diarrhea, severe enterocolitisReversible neutropenia, thrombocytopenia, bone marrow depressionAlopeciaElevation in hepatic enzymes(some adverse effects related to 5-Fu formed by intestinal organisms from5-FC)

CaspofunginInhibits the synthesis of fungal cell wall by inhibiting the synthesis of (1,3)-D-glucan, leading to lysis & cell death.Given by IV route onlyHighly bound to plasma proteinsHalf-life 9-11 hoursSlowly metabolized by hydrolysis & N-acetylation.Elimination is nearly equal between the urinary & fecal routes.

Clinical usesEffective 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

GriseofulvinFungistatic, has a narrow spectrumGiven orally (Absorption increases with fatty meal )Half-life 24 hoursTaken selectively by newly formed skin & concentrated in the keratin.Induces cytochrome P450 enzymesShould 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 functionUsed 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 Infections1. Topical azole derivatives2. Nystatin& Amphotericin3. Terbinafine4. Tolnaftate5. Naftifine 6. Griseofulvin

Topical Antifungal AgentsUsed 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 useIn the form of vaginal creams, suppositories, tablets for vaginal candidiasis given once daily .

CLOTRIMAZOLEAbsorption 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.

ITRACONAZOLEEffective for treatment of onychomycoses.Should not be given in patients with ventricular dysfunction.Evaluation of hepatic function is recommended.

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

NAFTIFINEBroad 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, decreasesThe 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 onychomycoses6 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 bindingAccumulates 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.