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

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

Binds to fungal cell membrane ergosterol andincrease 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

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

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 candidaaffecting skin, mucous membrane of mouth or G.I.T or femalegenital tractSYSTEMIC

Candidiasis ,cryptococosis, Aspergillosis,Blastomycosis, Histoplasmosis,Coccidioidomycosis, Paracoccidioidomycosis etc.

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

CASPOFUNGINIt is echinocandin class of antifungal drugsit 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 orallyHighly bound to serum proteinsHas half life of 9-11 hours

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

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

Amphotericin B colloidal dispersion contains roughlyequimolar amounts of amphotericin B and cholesterylsulfate formulated for injection.Like C-AMB, ABCD forms a colloidal solution whendispersed in aqueous solution.Resistance to amphotericin BErgosterol binding is impaired by Decreasing themembrane concentration of ergosterol. Modifying thesterol target molecule other sterols fungi that lacksergosterol are not susceptible

Amphotericin B is packaged in alipid- associated delivery system,that complexes the drug with twophospholipids to reduce binding tohuman cell membrane,so reducing :A. NephrotoxicityB. Infusion toxicityAlso, more effectiveMore expensive

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

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

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

Immediate reactions ( Infusion –related toxicity ).Fever, muscle spasm, vomiting ,headache,hypotension.Can be avoided by :

Slowing the infusionDecreasing the daily dosePremedication with antipyretics, antihistamincsor corticosteroids.A test dose.

Most serious is renal toxicityrenal tubular necrosis,hypokalemia, azotemia, HypomagnesaemiaImpaired liver functionsThrombocytopeniaAnemia-hypochromic normocyticArachnoiditis, seizures

They are antibacterial, antiprotozoal, anthelminthicand antifungal

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

lanosine 14-demethylasewhich is responsible forconverting lanosterol to ergosterol the main sterolin the fungal cell membrane this alters fluidity ofthe membrane, thus inhibiting the growth of fungi.

Inhibits respiration under aerobic conditions

Ketoconazole, Miconazole, Clotrimazole,isoconazole , Tioconazole

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

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

Metabolized extensively in liver and inactive productsappear in the feces.84 % is bound to plasma proteins.It does not enter CSF.Moderate hepatic dysfunction has no effect on drugconcentration.Induction of microsomal enzymesby other drugs reducesthe concentration.Warfarin, Rifampin increaseits metabolismH2 blockers, antacids decreaseits absorption.

Dose dependent nausea, anorexia ,vomitingLiver toxicity is rare but may prove fatal.As it inhibits steroid biosynthesis, severalEndocrinological abnormalities may be evident asmenstrual abnormalities, gynecomastia, decreasedlibido, Hair loss and impotency.Fluid retention and hypertension.

It is a synthetic triazoleIt lacks endocrine side effects of ketoconazole.It has broad spectrum activity

Food increases its absorptionMetabolized in liver extensively by cytochrome CYP3A4It is highly lipid soluble, it is well distributed to bone,sputum and adipose tissue.Highly bound to plasma proteinDo not penetrate CSF adequately, therefore itsconcentration is less to treat meningeal fungal infection

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

Adverse effects: Nausea, vomiting,hypertriglyceridemia, Hypokalemia, increasedaminotransferase, hepatotoxicity

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 incryptococcal meningitis and coccido mycosis.It can safely be administered prophylactically in

patients receiving bone marrow transplants.

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 concentration50-90 %.Candidiasis: 200 mg on 1st day then 100 mg daily for 2weeks.Cryptococcosis: 400 mg daily for 8 weeks in meningitis.In AIDS 200 mg for life.Coccidial meningitis it is drug of choice

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

Adverse effectsNausea, vomiting, headache, skin rash, abdominalpain, diarrhea, reversible alopeciaNo endocrine adverse effects.

Hepatic failure may lead to deathIt is highly teratogenic

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

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

Drug interactionsInhibitors or inducers of CYP may increase or decreaseVoriconazole plasma concentrationsRifampicin, Rifabutin, Phenytoin and Ritonaviraccelerate metabolism and reduce efficacyVoriconazole retards metabolism of Sirolimus,

Tacrolimus, cyclosporine and Warfarin

It is a fluorinated analogue of cytosine. Structurallyrelated to antineoplastic agent 5-FlurouracilTaken up into the fungal cell by means of permeaseconverted to 5-fluorouracil (5-FU) by cytosinedeaminase5-FU eventually inhibits thymidylate synthetaseblocks formation of thymidylate mono phosphatefungal DNA formation is inhibited

Selective action of flucytosine is due to the lack ofcytosine deaminase in mammalian cells, whichprevents metabolism to fluorouracil

Mechanismof action

Has useful activity against Candida and Cryptococcus.It is synthetic pyrimidine antimetabolite that is oftenused in combination with amphotericin BIt is fungistatic, effective in combination withitraconazole for treating chromoblastomycosis andwith Amphotericin for treating cryptococosisGiven orally, penetrates into CNSExcreted in urine-80% unchangedt 1/2 3-6 hours, but in renal failures it may be 200 hours

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

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

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

Topical administration of antifungal agents is usuallynot successful in mycoses of the nails and hair andhas no place in the treatment of subcutaneousmycoses.

The efficacy of topical agents in the superficial mycosisdepends on1. Type of lesion2. Mechanism of the drug action3. Viscosity,4. Hydrophobicity and acidity of the formulation.

The preferred formulation for cutaneous applicationusually is a cream or solution.

Topical anti fungalpreparationsTopical azole derivativesCiclopirox olamineNaftifineTerbinafineButenafinetolnaftateNystatin and

Amphotericin

Oral anti fungal agentsused for topicalinfections

Griseofulvinoral azolesTerbinafine

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

Isolated from Pencillium griseofulvumIt has largely been replaced by terbinafine fortreatment of dermatophytic infections of the nails.Much insoluble in water

It is useful for dermatophytes (fungistatic)It has narrow spectrum.It interacts with microtubules and interferes withmitosis.

Absorption increases with fatty mealIt is ineffective topically.Extensively metabolized in liver.Induce CYP450. t 1/2 -1day

Drug is deposited in keratin, nail and hair5-15 mg /kg for children and0.5 -1 gram for adults.Uses-Treatment required is1 month for scalp and hair (T. capitis)6-9 months for finger nails, and at least1 year for toe nailsIt is also highly effective in athlete's foot

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.

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

MOA-It inhibits fungal sequalene epoxidase, decreasessynthesis of ergosterolaffects cell membraneintegrity and functionAlso accumulation of toxic amounts of squalenecauses cell death.It is fungicidal but activity is limited to C. albicans anddermatophytes.

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

It is polyene macrolide, similar in structure toamphotericin 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 themucosatablets 500,000 U are used to decreaseGIT colonization with Candida

Prevent or treat superficial candidiasis of mouth,esophagus or intestinal tract, oral suspension of100,000 U/ml 4 times a day

For vaginal candidiasis in form of pessaries used for2 weeks

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

Can be used in combination with antibacterialagents and corticosteroids

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

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

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