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Anti fungal Agent:- PDF/ PPT

Description

Medicinal Chemistry-III




ANTI-FUNGAL ANTIB




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                      ANTIFUNGAL ANTIBIOTICS
• IMPORTANT GROUP
• TWO CLASSES- POLYENES AND GRISEOFULVIN
• POLYENES- COMPLEX ANTIFUNGAL ANTIBIOTICS ISOLATED FROM SOIL BACTERIA OF THE
 GENUS STREPTOMYCES
• CONTAIN A SYSTEM OF CONJUGATED DOUBLE BONDS IN MACROCYCLIC LACTONE RINGS
• DIFFERENT FROM ERYTHROMYCIN TYPE STRUCTURES (MACROLIDES)
• LARGER AND CONTAIN THE CONJUGATED -ENE SYSTEM OF DOUBLE BONDS- CALLED
 POLYENES
• CLINICALLY USEFUL POLYENES- TWO GROUPS- ON THE BASIS OF SIZE OF MACROLIDE
 RING

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                       ANTIFUNGAL ANTIBIOTICS
• 26-MEMBERED–RING POLYENES, SUCH AS NATAMYCIN (PIMARICIN) FORM ONE GROUP

• 38-MEMBERED MACROCYCLES, SUCH AS AMPHOTERICIN B AND NYSTATIN, FORM OTHER
 GROUP

• NUMBER OF DOUBLE BONDS IN THE MACROCYCLIC RING DIFFERS ALSO

• NATAMYCIN, THE SMALLEST MACROCYCLE, IS A PENTAENE;

• NYSTATIN IS A HEXAENE; AND

• AMPHOTERICIN B IS A HEPTAENE

• POLYENES HAVE NO ACTIVITY AGAINST BACTERIA, RICKETTSIA, OR VIRUSES

• HIGHLY POTENT, BROAD-SPECTRUM ANTIFUNGAL AGENTS

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                      ANTIFUNGAL ANTIBIOTICS
• USE OF THE POLYENES FOR THE TREATMENT OF SYSTEMIC INFECTIONS IS LIMITED

• TOXICITIES OF THE DRUGS,

• LOW WATER SOLUBILITIES, AND

• POOR CHEMICAL STABILITIES

• AMPHOTERICIN B, THE ONLY POLYENE USEFUL FOR THE TREATMENT OF SERIOUS
 SYSTEMIC INFECTIONS, MUST BE SOLUBILIZED WITH A DETERGENT

• OTHER POLYENES ARE INDICATED ONLY AS TOPICAL AGENTS FOR SUPERFICIAL
 FUNGAL INFECTIONS

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                      MECHANISM OF ACTION
• IN THREE-DIMENSIONAL SHAPE,

• A BARREL-LIKE NONPOLAR STRUCTURE CAPPED BY A POLAR GROUP (SUGAR)

• PENETRATE THE FUNGAL CELL MEMBRANE, ACTING AS “FALSE MEMBRANE
 COMPONENTS,”

• BIND CLOSELY WITH ERGOSTEROL,

• CAUSING MEMBRANE DISRUPTION,

• CESSATION OF MEMBRANE ENZYME ACTIVITY, AND

• LOSS OF CELLULAR CONSTITUENTS, ESPECIALLY POTASSIUM IONS

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                           AMPHOTERICIN B
• PURIFIED FROM THE FERMENTATION BEER OF A SOIL CULTURE OF THE ACTINOMYCETE
 STREPTOMYCES NODOSUS, WHICH WAS ISOLATED IN VENEZUELA
• FIRST ISOLATE FROM THE STREPTOMYCETE WAS A SEPARABLE MIXTURE OF TWO
 COMPOUNDS, DESIGNATED AMPHOTERICINS A AND B
• IN TEST CULTURES, COMPOUND B PROVED TO BE MORE ACTIVE, AND THIS IS THE ONE
 USED CLINICALLY
• AMPHOTERICIN B IS BELIEVED TO INTERACT WITH MEMBRANE STEROLS (ERGOSTEROL IN
 FUNGI) TO PRODUCE AN AGGREGATE THAT FORMS A TRANSMEMBRANE CHANNEL
• INTERMOLECULAR HYDROGEN BONDING INTERACTIONS AMONG HYDROXYL, CARBOXYL,
 AND AMINO GROUPS STABILIZE THE CHANNEL IN ITS OPEN FORM


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                             AMPHOTERICIN B
• DESTROYING SYMPORT ACTIVITY AND ALLOWING THE CYTOPLASMIC CONTENTS TO LEAK
 OUT
• THIS EXPLAINS THE TOXICITY IN HUMAN PATIENTS
• IS AN AMPHOTERIC SUBSTANCE, WITH A PRIMARY AMINO GROUP ATTACHED TO THE
 MYCOSAMINE RING AND A CARBOXYL GROUP ON THE MACROCYCLE
• FORMS DEEP YELLOW CRYSTALS THAT ARE SPARINGLY SOLUBLE IN ORGANIC SOLVENTS
 BUT INSOLUBLE IN WATER
• TO CREATE A PARENTERAL DOSAGE FORM, AMPHOTERICIN B IS STABILIZED AS A BUFFERED
 COLLOIDAL DISPERSION IN MICELLES WITH SODIUM DEOXYCHOLATE
• NEARLY 80% OF PATIENTS TREATED WITH AMPHOTERICIN B DEVELOP NEPHROTOXICITY

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                          AMPHOTERICIN B
• FEVER, HEADACHE, ANOREXIA, GASTROINTESTINAL DISTRESS, MALAISE, AND
 MUSCLE AND JOINT PAIN ARE COMMON
• PAIN AT THE SITE OF INJECTION AND THROMBOPHLEBITIS ARE FREQUENT
 COMPLICATIONS OF INTRAVENOUS ADMINISTRATION.
• DRUG MUST NEVER BE ADMINISTERED INTRAMUSCULARLY.
• HEMOLYTIC ACTIVITY OF AMPHOTERICIN B MAY BE A CONSEQUENCE OF ITS
 ABILITY TO LEACH CHOLESTEROL FROM ERYTHROCYTE CELL MEMBRANES
• FOR FUNGAL INFECTIONS OF THE CNS (E.G., CRYPTOCOCCOSIS), AMPHOTERICIN B
 IS MIXED WITH CEREBROSPINAL FLUID (CSF) THAT IS OBTAINED FROM A SPINAL TAP

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                          AMPHOTERICIN B
• DRUG IS SUPPLIED IN VARIOUS TOPICAL FORMS, INCLUDING A 3% CREAM, A 3%
 LOTION, A 3% OINTMENT, AND A 100-MG/ML ORAL SUSPENSION
• NYSTATIN
• FIRST ISOLATED IN 1951 FROM A STRAIN OF THE ACTINOMYCETE STREPTOMYCES
 NOURSEI BY HAZEN AND BROWN
• VERY SLIGHTLY SOLUBLE IN WATER AND SPARINGLY SOLUBLE IN ORGANIC
 SOLVENTS
• UNSTABLE TO MOISTURE, HEAT, AND LIGHT
• AGLYCONE PORTION OF NYSTATIN IS CALLED NYSTATINOLIDE

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                                   NYSTATIN
• IT CONSISTS OF A 38-MEMBERED MACROLIDE LACTONE RING CONTAINING SINGLE
 TETRAENE AND DIENE MOIETIES SEPARATED BY TWO METHYLENE GROUPS

• AGLYCONE ALSO CONTAINS EIGHT HYDROXYL GROUPS, ONE CARBOXYL GROUP, AND
 THE LACTONE ESTER FUNCTIONALITY

• ENTIRE COMPOUND IS CONSTRUCTED BY LINKING THE AGLYCONE TO MYCOSAMINE

• NOT ABSORBED SYSTEMICALLY WHEN ADMINISTERED BY THE ORAL ROUTE

• IT IS NEARLY INSOLUBLE UNDER ALL CONDITIONS

• IT IS ALSO TOO TOXIC TO BE ADMINISTERED PARENTERALLY AND USED ONLY AS A TOPICAL
 AGENT


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                             NYSTATIN
• VALUABLE AGENT FOR THE TREATMENT OF LOCAL AND GASTROINTESTINAL
 MONILIAL INFECTIONS CAUSED BY C. ALBICANS AND OTHER CANDIDA SPECIES

• FOR THE TREATMENT OF CUTANEOUS AND MUCOCUTANEOUS CANDIDIASIS, IT IS
 SUPPLIED AS A CREAM, AN OINTMENT, AND A POWDER

• ORAL TABLETS ARE USED IN THE TREATMENT OF GASTROINTESTINAL AND ORAL
 CANDIDIASIS




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Natamycin


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                              NATAMYCIN
• POLYENE ANTIBIOTIC OBTAINED FROM CULTURES OF STREPTOMYCES NATALENSIS

• CONSISTS OF A 26-MEMBERED LACTONE RING CONTAINING A TETRAENE CHROMOPHORE,

• AN Α,Β-UNSATURATED LACTONE CARBONYL GROUP, THREE HYDROXYL GROUPS, A
 CARBOXYL GROUP, A TRANS EPOXIDE, AND A GLYCOSIDICALLY JOINED MYCOSAMINE

• NATAMYCIN IS AMPHOTERIC

• MECHANISM- 26-MEMBERED–RING POLYENES CAUSE BOTH POTASSIUM ION LEAKAGE AND
 CELL LYSIS AT THE SAME CONCENTRATION

• WHEREAS THE 38-MEMBERED–RING POLYENES CAUSE POTASSIUM LEAKAGE AT LOW,
 FUNGISTATIC CONCENTRATIONS AND CELL LYSIS AT HIGH, FUNGICIDAL CONCENTRATIONS


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                                     NATAMYCIN
• SMALLER POLYENES ARE FUNGISTATIC AND FUNGICIDAL WITHIN THE SAME CONCENTRATION
  RANGE
• SUPPLIED AS A 5% OPHTHALMIC SUSPENSION INTENDED FOR THE TREATMENT OF FUNGAL
  CONJUNCTIVITIS, BLEPHARITIS, AND KERATITIS
• GRISEOFULVIN
• ANTIBIOTIC OBTAINED FROM THE FUNGUS PENICILLIUM GRISEOFULVUM
• IT WAS ISOLATED ORIGINALLY AS A “CURLING FACTOR” IN PLANTS
• DRUG HAS BEEN USED FOR MANY YEARS FOR ITS ANTIFUNGAL ACTION IN PLANTS AND ANIMALS
• IN 1959, GRISEOFULVIN WAS INTRODUCED INTO HUMAN MEDICINE FOR THE TREATMENT OF TINEA
  INFECTIONS BY THE SYSTEMIC ROUTE


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GRISEOFULVIN




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                                 GRISEOFULVIN
• EXAMPLE OF A RARE STRUCTURE IN NATURE, A SPIRO COMPOUND
• COMPOUND IS A WHITE, BITTER, HEAT-STABLE POWDER OR CRYSTALLINE SOLID
• SPARINGLY SOLUBLE IN WATER BUT SOLUBLE IN ALCOHOL AND OTHER NONPOLAR
 SOLVENTS
• USED FOR A LONG TIME FOR THE SYSTEMICALLY DELIVERED TREATMENT OF REFRACTORY
 RINGWORM INFECTIONS OF THE BODY, HAIR, NAILS, AND FEET
• CAUSED    BY   SPECIES   OF   DERMATOPHYTIC   FUNGI   INCLUDING     TRICHOPHYTON,
 MICROSPORUM AND EPIDERMOPHYTON
• GRISEOFULVIN NEITHER POSSESSES ANTIBACTERIAL ACTIVITY NOR IS EFFECTIVE AGAINST P.
 OBICULARE, THE ORGANISM THAT CAUSES TINEA VERSICOLOR

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                            GRISEOFULVIN
• MOST COMMON ONES ARE ALLERGIC REACTIONS SUCH AS RASH AND URTICARIA,
 GASTROINTESTINAL UPSET, HEADACHE, DIZZINESS, AND INSOMNIA

• ORAL BIOAVAILABILITY OF GRISEOFULVIN IS VERY POOR

• COMPOUND IS HIGHLY LIPOPHILIC WITH LOW WATER SOLUBILITY

• SEVERAL STRUCTURAL DERIVATIVES HAVE BEEN SYNTHESIZED, BUT THEY HAVE FAILED
 TO IMPROVE ABSORPTION

• BEST ADVICE THAT THE PHARMACIST CAN GIVE A PATIENT WHO IS ABOUT TO USE
 GRISEOFULVIN IS TO TAKE THE DRUG WITH A FATTY MEAL


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                   SYNTHETIC ANTI-FUNGAL AGENTS
• CLOTRIMAZOLE, ECONAZOLE, BUTOCONAZOLE, OXICONAZOLE TIOCONOZOLE KETOCONAZOLE,
  TERCONAZOLE, ITRACONAZOLE, FLUCONAZOLE, NAFTIFINE HYDROCHLORIDE
• SYNTHESIS- MICONAZOLE, TOLNAFTATE
• AZOLE ANTIFUNGAL AGENTS
• POSSESS A UNIQUE MECHANISM OF ACTION
• CAN ACHIEVE SELECTIVITY FOR THE INFECTING FUNGUS OVER THE HOST
• CAN TREAT INFECTIONS RANGING FROM SIMPLE DERMATOPHYTOSES TO LIFE-THREATENING, DEEP
  SYSTEMIC FUNGAL INFECTIONS
• FIRST MEMBERS OF THE CLASS WERE HIGHLY SUBSTITUTED IMIDAZOLES, SUCH AS CLOTRIMAZOLE
  AND MICONAZOLE



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                     AZOLE ANTIFUNGAL AGENTS
• STRUCTURE–ACTIVITY STUDIES REVEALED THAT THE IMIDAZOLE RING COULD BE REPLACED
 WITH A BIOISOSTERIC 1,2,4-TRIAZOLE RING WITHOUT ADVERSELY AFFECTING THE
 ANTIFUNGAL PROPERTIES OF THE MOLECULE
• SPECTRUM OF ACTIVITY
• AZOLES TEND TO BE EFFECTIVE AGAINST MOST FUNGI THAT CAUSE SUPERFICIAL
 INFECTIONS OF THE SKIN AND MUCOUS MEMBRANES, INCLUDING THE DERMATOPHYTES
 SUCH AS TRICHOPHYTON, EPIDERMOPHYTON, AND MICROSPORUM SPP. AND YEASTS
 SUCH AS C. ALBICANS
• ON THE OTHER HAND, THEY ALSO EXHIBIT ACTIVITY AGAINST YEASTS THAT CAUSE
 SYSTEMIC INFECTIONS, INCLUDING C. IMMITIS, C. NEOFORMANS, PARACOCCIDIOIDES
 BRASILIENSIS, PETRIELLIDIUM BOYDII, B. DERMATITIDIS, AND H. CAPSULATUM

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       AZOLE ANTIFUNGAL AGENTS- MECHANISM OF ACTION

• AT MICROMOLAR, THE AZOLES ARE FUNGICIDAL
• AT NANOMOLAR, THE AZOLES ARE FUNGISTATIC
• FUNGICIDAL EFFECT IS CLEARLY ASSOCIATED WITH DAMAGE TO THE CELL MEMBRANE,
 WITH THE LOSS OF ESSENTIAL CELLULAR COMPONENTS SUCH AS POTASSIUM IONS AND
 AMINO ACIDS
• FUNGISTATIC EFFECT IS ASSOCIATED WITH INHIBITION OF MEMBRANE-BOUND ENZYMES
• A CYTOCHROME P450-CLASS ENZYME, LANOSTEROL 14Α-DEMETHYLASE, IS THE LIKELY
 TARGET FOR THE AZOLES
• FUNCTION OF LANOSTEROL 14Α-DEMETHYLASE IS TO OXIDATIVELY REMOVE A METHYL
 GROUP FROM LANOSTEROL DURING ERGOSTEROL BIOSYNTHESIS

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AZOLE ANTIFUNGAL AGENTS- MECHANISM OF ACTION




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       AZOLE ANTIFUNGAL AGENTS- MECHANISM OF ACTION

• LANOSTEROL 14Α-DEMETHYLASE IS ALSO REQUIRED FOR MAMMALIAN BIOSYNTHESIS OF
 CHOLESTEROL, AND THE AZOLES ARE KNOWN TO INHIBIT CHOLESTEROL BIOSYNTHESIS

• HIGHER CONCENTRATIONS OF THE AZOLES ARE NEEDED TO INHIBIT THE MAMMALIAN
 ENZYME

• PROVIDES SELECTIVITY FOR ANTIFUNGAL ACTION

• 1,2,4-TRIAZOLES APPEAR TO CAUSE A LOWER INCIDENCE OF ENDOCRINE EFFECTS AND
 HEPATOTOXICITY THAN THE CORRESPONDING IMIDAZOLES

• POSSIBLY BECAUSE OF A LOWER AFFINITY FOR THE MAMMALIAN CYTOCHROME P450
 ENZYMES INVOLVED


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                           CLOTRIMAZOLE
• BROAD-SPECTRUM ANTIFUNGAL DRUG THAT IS USED TOPICALLY FOR THE
 TREATMENT OF TINEA INFECTIONS AND CANDIDIASIS
• IT OCCURS AS A WHITE CRYSTALLINE SOLID THAT IS SPARINGLY SOLUBLE IN WATER
 BUT SOLUBLE IN ALCOHOL AND MOST ORGANIC SOLVENTS
• IT IS A WEAK BASE THAT CAN BE SOLUBILIZED BY DILUTE MINERAL ACIDS
• EXTREMELY STABLE, WITH A SHELF LIFE OF MORE THAN 5 YEARS
• EFFECTIVE AGAINST VARIOUS PATHOGENIC YEASTS AND
• REASONABLY WELL ABSORBED ORALLY, EXTENSIVELY PROTEIN BOUND
• NOT CONSIDERED SUITABLE FOR THE TREATMENT OF SYSTEMIC INFECTIONS
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                           ECONAZOLE
• IT IS ONLY SLIGHTLY SOLUBLE IN WATER AND MOST ORGANIC SOLVENTS

• USED AS A 1% CREAM FOR THE TOPICAL TREATMENT OF LOCAL TINEA INFECTIONS
 AND CUTANEOUS CANDIDIASIS




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                        BUTOCONAZOLE
• EXTREMELY BROAD-SPECTRUM ANTIFUNGAL DRUG THAT IS SPECIFICALLY EFFECTIVE
 AGAINST C. ALBICANS

• IT IS INTENDED FOR THE TREATMENT OF VAGINAL CANDIDIASIS- 2% OF
 BUTOCONAZOLE NITRATE IN THE FORM OF CREAM




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                           OXICONAZOLE
• IT IS USED IN CREAM AND LOTION DOSAGE FORMS IN 1% CONCENTRATION FOR
 THE TREATMENT OF TINEA PEDIS, TINEA CORPORIS, AND TINEA CAPITIS




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                          TIOCONAZOLE
• USED FOR THE TREATMENT OF VULVOVAGINAL CANDIDIASIS

• A VAGINAL OINTMENT CONTAINING 6.5% OF THE FREE BASE IS AVAILABLE

• MORE EFFECTIVE AGAINST TORULOPSIS GLABRATA THAN ARE OTHER AZOLES




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                          MICONAZOLE
• OCCURS AS WHITE CRYSTALS THAT ARE SPARINGLY SOLUBLE IN WATER AND MOST
 ORGANIC SOLVENTS
• THE FREE BASE IS AVAILABLE IN AN INJECTABLE FORM, SOLUBILIZED WITH
 POLYETHYLENE GLYCOL AND CASTOR OIL, AND INTENDED FOR THE TREATMENT OF
 SERIOUS SYSTEMIC FUNGAL INFECTIONS
• LIKE CANDIDIASIS, COCCIDIOIDOMYCOSIS, CRYPTOCOCCOSIS, PETRIELLIDIOSIS,
 AND PARACOCCIDIOIDOMYCOSIS
• THROMBOPHLEBITIS, PRURITUS, FEVER, AND GASTROINTESTINAL UPSET ARE
 RELATIVELY COMMON SIDE EFFECTS


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                         KETOCONAZOLE
• BROAD-SPECTRUM IMIDAZOLE ANTIFUNGAL AGENT THAT IS ADMINISTERED ORALLY
 FOR THE TREATMENT OF SYSTEMIC FUNGAL INFECTIONS

• IT IS A WEAKLY BASIC COMPOUND THAT OCCURS AS A WHITE CRYSTALLINE SOLID
 THAT IS VERY SLIGHTLY SOLUBLE IN WATER




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                         KETOCONAZOLE
• PRIMARY ROUTE OF EXCRETION IS ENTEROHEPATIC
• IT IS ESTIMATED TO BE 95% TO 99% BOUND TO PROTEIN IN THE PLASMA
• HEPATOTOXICITY- MOST SERIOUS ADVERSE EFFECT
• KNOWN TO INHIBIT CHOLESTEROL BIOSYNTHESIS IN BOTH MAMMALS AND FUNGI
• HIGH DOSES HAVE ALSO BEEN REPORTED TO LOWER TESTOSTERONE AND
 CORTICOSTERONE LEVELS
• KETOCONAZOLE IS A RACEMIC COMPOUND, CONSISTING OF THE CIS-2S,4R AND
 CIS-2R,4S ISOMERS
• TRANS-ISOMERS, 2S,4S AND 2R,4R, ARE MUCH LESS ACTIVE
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                             KETOCONAZOLE
• RECOMMENDED FOR THE TREATMENT OF THE FOLLOWING SYSTEMIC FUNGAL
 INFECTIONS:   CANDIDIASIS   (INCLUDING   ORAL   THRUSH   AND     THE    CHRONIC
 MUCOCUTANEOUS FORM), COCCIDIOIDOMYCOSIS, BLASTOMYCOSIS, HISTOPLASMOSIS,
 CHROMOMYCOSIS, AND PARACOCCIDIOIDOMYCOSIS
• IT IS ALSO USED ORALLY TO TREAT SEVERE REFRACTORY CUTANEOUS DERMATOPHYTIC
 INFECTIONS NOT RESPONSIVE TO TOPICAL THERAPY OR ORAL GRISEOFULVIN
• ANTIFUNGAL ACTIONS OF KETOCONAZOLE AND THE POLYENE ANTIBIOTIC AMPHOTERICIN
 B ARE REPORTED TO ANTAGONIZE EACH OTHER
• USED TOPICALLY IN A 2% CONCENTRATION IN A CREAM AND IN A SHAMPOO FOR THE
 MANAGEMENT OF CUTANEOUS CANDIDIASIS AND TINEA INFECTIONS

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                         TERCONAZOLE
• TRIAZOLE DERIVATIVE THAT IS USED EXCLUSIVELY FOR THE CONTROL OF
 VULVOVAGINAL MONILIASIS CAUSED BY C. ALBICANS AND OTHER CANDIDA
 SPECIES

• IT IS AVAILABLE IN CREAMS CONTAINING 0.4% AND 0.8% OF THE FREE BASE
 INTENDED FOR 7-DAY AND 3-DAY TREATMENT PERIODS, RESPECTIVELY




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                          ITRACONAZOLE
• UNIQUE MEMBER OF THE AZOLE CLASS THAT CONTAINS TWO TRIAZOLE MOIETIES
 IN ITS STRUCTURE

• A WEAKLY BASIC 1,2,4-TRIAZOLE AND A NON-BASIC 1,2,4-TRIAZOL-3-ONE

• ORALLY ACTIVE, BROAD-SPECTRUM ANTIFUNGAL AGENT AND IMPORTANT
 ALTERNATIVE TO KETOCONAZOLE




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                           ITRACONAZOLE
• AN ACIDIC ENVIRONMENT IS REQUIRED FOR OPTIMUM SOLUBILIZATION AND ORAL
 ABSORPTION

• FOOD GREATLY ENHANCES THE ABSORPTION OF ITRACONAZOLE, NEARLY DOUBLING ITS
 ORAL BIOAVAILABILITY

• DRUG IS AVIDLY BOUND TO PLASMA PROTEINS (NEARLY 99% AT CLINICALLY EFFECTIVE
 CONCENTRATIONS) AND EXTENSIVELY METABOLIZED IN THE LIVER

• ONLY ONE OF THE NUMEROUS METABOLITES, NAMELY 1-HYDROXYITRACONAZOLE, HAS
 SIGNIFICANT ANTIFUNGAL ACTIVITY

• TERMINAL ELIMINATION HALF-LIFE OF ITRACONAZOLE RANGES FROM 24 TO 40 HOURS

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                          ITRACONAZOLE
• USED FOR THE TREATMENT OF SYSTEMIC FUNGAL INFECTIONS INCLUDING
 BLASTOMYCOSIS, HISTOPLASMOSIS (INCLUDING PATIENTS INFECTED WITH [HIV]),

• NONMENINGEAL     COCCIDIOIDOMYCOSIS,     PARACOCCIDIOIDOMYCOSIS,        AND
 SPOROTRICHOSIS

• IT MAY ALSO BE EFFECTIVE IN THE TREATMENT OF PERGELLOSIS, DISSEMINATED AND
 DEEP ORGAN CANDIDIASIS, COCCIDIOIDAL MENINGITIS, AND CRYPTOCOCCOSIS

• UNLIKE KETOCONAZOLE, IT IS NOT HEPATOTOXIC AND DOES NOT CAUSE ADRENAL
 OR TESTICULAR SUPPRESSION IN RECOMMENDED THERAPEUTIC DOSES


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                                  FLUCONAZOLE
• WATER SOLUBLE BIS-TRIAZOLE WITH BROAD-SPECTRUM ANTIFUNGAL PROPERTIES
• SUITABLE FOR BOTH ORAL AND INTRAVENOUS ADMINISTRATION AS THE FREE BASE
• EXCELLENT BIOAVAILABILITY IN BOTH TABLET AND SUSPENSION DOSAGE FORMS
• PRESENCE OF TWO WEAKLY BASIC TRIAZOLE RINGS IN THE MOLECULE CONFERS SUFFICIENT
  AQUEOUS SOLUBILITY TO BALANCE THE LIPOPHILICITY OF THE 2,4-DIFLUOROPHENYL GROUP
• HAS A RELATIVELY LONG ELIMINATION HALF-LIFE, RANGING FROM 27 TO 34 HOURS
• IT PENETRATES WELL INTO ALL BODY CAVITIES, INCLUDING THE CSF
• LITTLE OR NO HEPATIC METABOLISM AND IS EXCRETED SUBSTANTIALLY UNCHANGED IN THE URINE
• PLASMA PROTEIN BINDING OF FLUCONAZOLE IS LESS THAN 10%




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                           FLUCONAZOLE
• INHIBITION OF CYTOCHROME P450 OXIDASES BY FLUCONAZOLE CAN GIVE RISE
 TO CLINICALLY SIGNIFICANT INTERACTIONS INVOLVING INCREASED PLASMA
 LEVELS OF CYCLOSPORINE, PHENYTOIN, AND THE ORAL HYPOGLYCEMIC DRUGS

• RECOMMENDED FOR THE TREATMENT AND PROPHYLAXIS OF DISSEMINATED AND
 DEEP ORGAN CANDIDIASIS

• IT IS ALSO USED TO CONTROL ESOPHAGEAL AND OROPHARYNGEAL CANDIDIASIS

• AGENT OF CHOICE FOR THE TREATMENT OF CRYPTOCOCCAL MENINGITIS AND

FOR PROPHYLAXIS AGAINST CRYPTOCOCCOSIS IN AIDS PATIENTS



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                   NAFTIFINE HYDROCHLORIDE
• WHITE CRYSTALLINE POWDER THAT IS SOLUBLE IN POLAR SOLVENTS SUCH AS
 ETHANOL AND METHYLENE CHLORIDE

• IT IS SUPPLIED IN A 1% CONCENTRATION IN A CREAM AND IN A GEL FOR THE
 TOPICAL TREATMENT OF RINGWORM, ATHLETE’S FOOT, AND JOCK ITCH

• ALTHOUGH UNAPPROVED FOR THESE USES, NAFTIFINE HAS
                                                             Cl
SHOWN EFFICACY FOR TREATMENT OF RINGWORM OF THE

BEARD, RINGWORM OF THE SCALP, AND TINEA VERSICOLOR



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                                TOLNAFTATE
• WHITE CRYSTALLINE SOLID THAT IS INSOLUBLE IN WATER, SPARINGLY SOLUBLE IN
 ALCOHOL, AND SOLUBLE IN MOST ORGANIC SOLVENTS

• COMPOUND, A THIOESTER OF Β-NAPHTHOL, IS FUNGICIDAL AGAINST DERMATOPHYTES,
 SUCH AS TRICHOPHYTON, MICROSPORUM, AND EPIDERMOPHYTON SPP., THAT CAUSE
 SUPERFICIAL TINEA INFECTIONS

• AVAILABLE IN A CONCENTRATION OF 1% IN CREAMS, POWDERS, AEROSOLS, GELS, AND
 SOLUTIONS FOR THE TREATMENT OF RINGWORM, JOCK ITCH, AND ATHLETE’S FOOT

• SHOWN TO ACT AS AN INHIBITOR OF SQUALENE EPOXIDASE

• IN SUSCEPTIBLE FUNGI



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                              MICONAZOLE- SYNTHESIS

                                             -HBr

                                                                                           Reduction of
                                                                                            ketone to
                                                                                             alcohol
2,4-dichlorophenacylbromide     imidazole


                                                   2,4-dichlorobenzylbromide




                                            -HBr


                                                                                Miconazole
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                         TOLNAFTATE- SYNTHESIS




2-naphthol and thiophosgene to make a monosubstituted product of thiophosgene,
which is then reacted with N-methyl-3-toluidine to give the desired tolnaftate




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