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ANTIFUNGALDRUGS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

CLASSIFICATION

Inhibition Of Fungal Cell Wall Synthesis-ECHINOCANDINS- CASPOFUNGIN, MICAFUNGIN, ANIDULAFUNGIN,

Binds to fungal cell membrane ergosterol and increase membrane permeability-polyene group- AMPHOTERICIN-B, NYSTATIN

Inhibition of Ergosterol+ Lanosterol Synthesis- (Allylamine group)-TERBINAFINE

Inhibition of ergosterol synthesis- (Azole group) KETOCONAZOLE, FLUCONAZOLE, ITRACONAZOLE,

VORICONAZOLE, POSACONAZOLE

CLASSIFICATON

Inhibition of nucleic acid synthesis5-FLUCYTOSINEDisruption of mitotic spindle and inhibition of fungal mitosis-GRISEOFULVINOTHER TOPICAL agents- CICLOPIROX, TOLNAFTATE, CLIOQUINOL, NAFTIFINE, BUTENAFINE, CLOTRIMAZOLE, ECONAZOLE, SULCONAZOLE, SERTACONAZOLE

Fungal infection

SUPERFECIALDermatomycoses affecting skin, hair or nails.

Epidermophyton (skin and nails)Trichophyton (skin,hair & nail)Microsporum (skin and hair)

b) Candidiasis (commonly normal flora of mouth, skin, intestines and vagina) infection caused by genus candida affecting skin, mucous membrane of mouth or G.I.T or female genital tractSYSTEMIC Candidiasis ,cryptococosis, Aspergillosis, Blastomycosis, Histoplasmosis, Coccidioidomycosis, Paracoccidioidomycosis etc

Fungal cell structure

Fungal cell membranes have a unique sterol, ergosterol, which replaces cholesterol found in mammalian cell membranes

Targets of antifungal drugs

ECHINOCANDINS

CASPOFUNGINIt is echinocandin class of antifungal drugs it interferes with the synthesis of fungal cell wall by inhibiting synthesis of 1,3-β-glucan.Mammalian cell wall does not require 1,3-β-glucanSelective toxicity to hostFor aspergillus and candida.Not active orallyHigly bound to serum proteinsHas half life of 9-11 hours

ECHINOCANDINS

slowly metabolized by hydrolysis and N-acetylation. eliminated equally by urinary and fecal route.Adverse effects include Headache, rashes, nausea, vomiting, flushing, abnormal liver function tests very expensiveD/I- Enzyme inducers increase metabolism increase clearance of tacrolimusMicafungin and anidulafungin – more potent

Amphotericin B(polyene group)

It is a natural polyene macrolide (polyene = many double bonds ) (macrolide = containing a large lactone ring )MOA- It is a selective fungicidal drug. Disrupt fungal cell membrane by binding to ergosterol , so alters the permeability of the cell membrane forms poresleading to leakage of intracellular ions & macromolecules.Selective toxicity-mammalian cell membrane-cholesterol

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. NephrotoxicityB. Infusion toxicityAlso, more effectiveMore expensive AMP-B-lipid complex-non liposomal formulation that complexes the drug with two phospholipids

Resistance to amphotericin B

Ergosterol binding is impaired byDecreasing the membrane concentration of ergosterol.Modyfing the sterol target molecule other sterols fungi that lacks ergosterol are not suseptible

Pharmacokinetics

Poorly absorbed orally , is effective for fungal infection of gastrointestinal tract.For systemic infections given as slow I.V.Insoluble in water so prepared as colloidal suspension with sodium desoxycholateHighly bound to plasma protein .Poorly crossing BBB.Metabolized in liver Excreted slowly in urine over a period of several days.Half-life 15 days.

Routes and uses

Slow I.V.infusion for systemic fungal disease.Intrathecal for fungal C.N.S. infections.Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis.Local injection into the joint in fungal arthritis.Bladder irrigation in Candiduria.

Clinical uses

Has a broad spectrum of activity & fungicidal action.The drug of choice for life-threatening mycotic infections in immunocompromised patientsInvasive aspergillosis, mucormycosis, histoplasmosisAlso, for chronic therapy & preventive therapy of relapse.In cancer patients with neutropenia who remain febrile on broad –spectrum antibiotics.Kala azar- reserve drug

Adverse Effects

1- 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.

Adverse effects

Most serious is renal toxicityrenal tubular necrosis, hypokalemia, azotemia, Hypomagnesaemia

Impaired liver functions Thrombocytopenia Anemia-hypochromic normocytic Arachnoiditis, seizures

AZOLES

They are antibacterial, antiprotozoal, anthelminthic and antifungal

These are group of synthetic fungistatic agents They have broad spectrum of activity Inhibit the fungal cytochrome P450 3A enzyme ,

lanosine 14-demethylase which is responsible for converting lanosterol to ergosterol the main sterol in the fungal cell membrane this alters fluidity of the membrane, thus inhibiting the growth of fungi.

Inhibits respiration under aerobic conditions

Imidazoles.

Ketoconazole, miconazole, clotrimazole, isoconazole , Tioconazole

Triazoles-Fluconazole, itraconazole, voriconazoleThey are selective Penetrate to CNSResistant to degradationCause less endocrine disturbance

KETOCONAZOLE

First azole that could be given orally to treat systemic fungal infections.Well absorbed orally as acidic environment favors its dissolution.Bioavailability is decreased with H-2 blocking drugs, proton pump inhibitors and antacids and is impaired with food.After oral administration of 200,400 and 800 mg, Half life increases with dose and it is 7-8 hrs with 800 mg

KETOCONAZOLE

Metabolized extensively in liver and inactive products appear in the feces.84 % is bound to plasma proteins.It does not enter CSF.Moderate hepatic dysfunction has no effect on drug concentration. Induction of microsomal enzymes by other drugs reduces the concentration.Warfarin ,Rifampin increase its metabolismH2 blockers ,antacids decrease its absorption.

Side effects

Dose dependent nausea, anorexia ,vomitingLiver toxicity is rare but may prove fatal.Hair lossAs it inhibits steroid biosynthesis, several endocrinological abnormalities may be evident as menstrual abnormalities, gynecomastia, decreased libido and impotency.Fluid retention and hypertension.

ITRACONAZOLEIt is a synthetic triazoleIt lacks endocrine side effects of ketoconazole. It has broad spectrum activityFood increases its absorptionMetabolized in liver extensively by cytochrome CYP3A4 It is highly lipid soluble, it is well distributed to bone, sputum and adipose tissue. Highly bound to plasma proteinDo not penetrate CSF adequately, therefore its concentration is less to treat meningeal fungal infection

Itraconazole

Half life is 30-40 hoursSteady state reaches in 4 days, so loading doses are recommended in deep mycosis.Dose 100 mg twice daily with food, initially 300 mg thrice daily as a loading dose.Intravenously reserved only in serious infections.

Adverse effects: Nausea, vomiting, hypertriglyceridemia, Hypokalemia, increased aminotransferase, hepatotoxicity

Fluconazole

It is fluorinated bistriazole.Completely absorbed from GITExcellent bioavailability by oral route.

Concentration in plasma is same by oral or I/v route.Bioavailability not altered by food or gastric acidityIt has least effect on hepatic microsomal enzymes.

It easily penetrate CSF and is a drug of choice in cryptococcal meningitis and coccido mycosis. It can safely be administered prophylactically in patients receiving bone marrow transplants.

Fluconazole-P/K and uses

Resistance not a problem except in patients with HIV100mg repetitive dose.Renal excretion 90%t1/2 -25-30 hours.Diffuse in all body fluids including CSF concentration 50-90 %.Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.Cryptococcosis: 400 mg daily for 8 weeks in meningitis.In AIDS 200 mg for life.Coccidial meningitis it is drug of choice

Fluconazole-uses and adverse effects

It has also activity against histoplasmosis, blastomycosis, spirotrichosis ,and ring wormNot effective in aspergillosis.

Adverse effectsNausea, vomiting, headache, skin rash, abdominal pain, diarrhea, reversible alopecia No endocrine adverse effects.Hepatic failure may lead to death It is highly teratogenic

Voriconazole

Second generation triazoleHigh oral bioavailability-96%Low plasma protein binding -55%Good CSF penetrationT1/2- 6hrsTherapeutic uses- invasive aspergillosisUseful I esophagial candidiasisCandida resistant to fluconazole are sensitive to voriconazoleDose- 200mg 12th hourly

Voriconazole-adverse effects

Blurred vision, photophobia-30%Rashes, nausea, raised hepatic enzyme levels

Drug interactionsInhibitors or inducers of CYP may increase or decrease voriconazole plasma concentrationsRifampicin, Rifabutin, Phenytoin and Ritonavir accelerate metabolismand reduce efficacy voriconazole retards metabolism of sirolimus, tacrolimus, cyclosporine and Warfarin

Flucytosine (5-fluorocytosine; 5fc)

It is a fluorinated analogue of cytosine Structurally related to antineoplastic agent 5-FlurouracilTaken up into the fungal cell by means of permease converted to 5-fluorouracil (5-FU) by cytosine deaminase5-FU eventually inhibits thymidylate synthetase blocks formation of thymidylate mono phosphate fungal DNA formation is inhibited

Mechanism of action

Flucytosine

Has useful activity against Candida and Cryptococcus.

It is synthetic pyrimidine antimetabolite that is often used in combination with amphotericin B

It is fungistatic, effective in combination with itraconazole for treating chromoblastomycosis and with Amphotericin for treating cryptococosis

Given orally, penetrates into CNS Excreted in urine-80% unchanged t 1/2 3-6 hours, but in renal failures it may be 200

hours

Flucytosine-Uses

Systemic fungi, mainly candida, and cryptococcus. Effective in combination with itraconazole for treating chromoblastomycosis and with Amphotericin-B for treating cryptococosis (cryptococcal meningitis)

Adverse effects-Nausea, vomiting, colitis, Bone marrow suppressionThrombocytopenia, alopecia, decreased liver function

Topical antifungal agents

In superficial fungal infections those drugs are preferred which get confined to stratum corneum, squamous mucosa or corneadermatophytosis (ring worm), candidiasis tinea and fungal keratitis.

Topical administration of antifungal agents is usually not successful in mycoses of the nails and hair and has no place in the treatment of subcutaneous mycoses.

Topical antifungal agents

The efficacy of topical agents in the superficial mycosis depends on 1. Type of lesion 2. Mechanism of the drug action3. Viscosity, 4. Hydrophobicity and acidity of the formulation.

The preferred formulation for cutaneous application usually is a cream or solution.

Antifungals for topical infections

Topical anti fungal preparationsTopical azole derivatives Ciclopirox olamine Naftifine Terbinafine Butenafine tolnaftate Nystatin and Amphotericin

Oral anti fungal agents used for topical infections

Griseofulvinoral azoles

Terbinafine

Azoles- Clotrimazole, Miconazole

These are synthetic and used both topically and systemicallyVaginal creams, suppositories and tablets for vaginal candidiasis used once a day preferably at bed timeErythema, edema, vesication, pruritus, urticaria mild vaginal burning sensation may occur.Clotrimazole is effective in 60-100%.Cutaneous candidiasis is 80-100% Vulvovaginal candidiasis is 80%.

Griseofulvin

Isolated from Pencillium griseofulvumIt has largely been replaced by terbinafine for treatment of dermatophytic infections of the nails. Much insoluble in waterIt is useful for dermatophytes (fungistatic) It has narrow spectrum.It interacts with microtubules and interferes with mitosis.

Griseofulvin-Pharmacokinetics

Absorption increases with fatty mealIt is ineffective topically.Extensively metabolized in liver. Induce CYP450. t 1/2 -1dayDrug is deposited in keratin, nail and hair5-15 mg /kg for children and 0.5 -1 gram for adults.Uses-Treatment required is 1 month for scalp and hair (T. capitis) 6-9 months for finger nails, and at least 1 year for toe nailsIt is also highly effective in athlete's foot

Griseofulvin-adverse effects and drug interactions

Adverse effects Headache Peripheral neuritis , lethargy , mental confusion,

impairment in performance of routine task, fatigue, vertigo ,syncope, blurred vision.

D/I-Barbiturates decreases the absorption from GIT.

Allylamines- Terbinafine

It is synthetic allylamineIt is a drug of choice for treating dermatophytesIt is better tolerated , requires shorter duration of therapy

MOA-It inhibits fungal sequalene epoxidase, decreases synthesis of ergosterol affects cell membrane integrity and functionAlso accumulation of toxic amounts of squalene causes cell death.It is fungicidal but activity is limited to C. albicans and dermatophytes.

Terbinafine

Oral bioavailability is 50-70%Highly lipophilic and keratophilic – resulting in high concentrations in corneum, hair and nailsEffective for the treatment of onychomycosis 250 mg daily for 6 weeks for finger nail infection and for 12 weeks in toe nail infection

Protein binding more than 99% in plasma.Drug accumulates in skin, nails and fat.Rarely hepatotoxic , liver failure even death. Rifampicin decreases its serum concentration and cimetidine increases

Nystatin

It is polyene macrolide,similar in structure to amphotericin and with same mechanism of action

Too toxic for systemic use Not absorbed from GIT, skin or vagina, therefore

administered orally for candidial infection of the mucosatablets 500,000 U are used to decrease GIT colonization with Candida

Prevent or treat superficial candidiasis of mouth, esophagus or intestinal tract, oral suspension of 100,000 U/ml 4 times a day

Nystatin

For vaginal candidiasis in form of pessaries used for 2 weeks

In Cutaneous infection available in cream, ointment or powder form and applied 2-3 times a day

Can be used in combination with antibacterial agents and corticosteroids

Tolnaftate

Synthetic antifungal drugDistorts hyphae and mycelial growth of yeast-like fungi and mouldsEffective in most cutaneous mycosis.It is ineffective against Candida.In tinea pedis cure rate is around 80%.Available in 1% con.as cream, powder and topical solution.Applied locally twice a day.

Naftifine

It is broad spectrum, fungicidal.Available as 1% cream or gel Effective for tropical treatment of tinea cruris.

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