ANTIFUNGAL DRUGS   DR SEEMI GULL                   1
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Antifungal Agents        Drugs used to treat infections caused by fungi            – Systemic and topicalFUNGI    – Very l...
STRUCTURE OF FUNGI  They are eukaryotes consists of :-       1.        Cell wall ( chitin) homopolymer of N-              ...
TYPES  i. Yeasts  ii. Moulds  iii. DimorphicI.YEASTS    Single cell fungi, ovoid or spherical    Reproduce by budding & ...
MAGNITUDE OF PROBLEM   Fungi commonly present in environment   Hardly cause any serious disease   Five decades ago most...
FUNGAL INFECTION (MYCOSES)  Three groups cause human disease        I. Yeasts        II. Moulds        III. Dimorphic fung...
Common mycotic infection in human:-  A. Cutaneous       1.Dermatophytes (Ring worm, tinea inf)                 There are t...
Various types of ring worms      Tinea capitus (scalp)      Tinea cruris (Groin)      Tinea corporis (body)      Tinea...
2. Candida albican → candidiasis (moniliasis)     Risk factor              »    Antibiotic therapy              »    Antin...
B. subcutaneous (deep tissue infections):-      1.mycetoma (medura foot)                 Ch. Fungal inf of deep soft tiss...
C. Systemic fungal inf:-      i. Histoplasmosis:- caused by histoplasma capsulatum a diamorphic fungus                Symp...
iii. Coccidiodomycosis:-         Influenza like illness with malaise fever backache cough         arthralgia swelling of k...
Vii. Pneumocystosis:- caused by pneumocystitis cariniiViii. Candidiasis:-   by candida albieans in immunocomproin pts     ...
GEOGRAPHICAL PREVALENCE (INCIDENCE)  UK:-         More incidence of sec inf. Like uryptocococcal    meningitis &  endocard...
CLASSIFICATIONS OF ANTI-FUNGAL DRUGS:-   A. According to MOA     1.Drug affecting synts / Function of cell memb:-        i...
2. Block nucleic acid synth:-        – Flucytosine3. Distrupt microtubular function        – Griseofulvin4. Reduction of f...
B. Acc. To route of admin:-1. Topical   –   Nystatin   –   Clotrimazole   –   Econazole   –   Amphotericin – B2. Oral   – ...
C. Acc. To chemical structure1. Polyenes      • Amphotericin B      • Nystatin2. Pyrimidins:- Flucytosine3. Azoles, ketoco...
D. Therapeutic classification :- 1. Superficial     i. Dermatoplytes (ringworms)        – Griseofulvin        – Terbanafin...
2. Systemic    i. Ketoconazole         – Histoplasm         – Blastomycosis    ii. Ketoconazole         – Coccidiodomy    ...
AMPHOTERICIN B  Chemistry           It is polyene heptanes macrolide           Amphoteri behavior for which the drug is ...
Pharmacokinetics    Poorly absorbed from GIT so oral ampho B is only used for fungi     within lumen of the tract not for...
MOA    selective in fungicidal effect    It binds to ergosterol and form ampho. B associated pores in the     cell membs...
Adverse effects    Immediate reactions by I/V infusion    Slow toxicity  Immediate:- / infusion related toxicity      In...
cumulative toxicity             Renal damage             More common with AMB ,SIGNIFICANTLY LESS with               lipo...
hypochromic, normocytic anemia d/t ↓ production of  erythropoietinThrombocytopenia,LeukopeniaHead ach. Nausea, vomiting...
Antifungal activity        Broad spectrum fungicidal        No antibact activity               i.     Yeast / Candida → ...
Clinical usespectrum   I.   All life threatening mycotic infections d/t blood fungicidal action        It is used initiall...
II.    Systemic fungal disease                → slow I/V infusion at dose of 0.5-1mg /kg/d and usually                   c...
FLUCYTOSINE Chemistry :- discoursed in 1957 accidently while searching for anticancer             drug           Pyrimidi...
Antifungal activity     Candida → Cryptococcus neoformans     Agents of chromomycosisPharmacokinetics          Well abs...
taken up by fungal cells via enzyme deaminase.In fungal cell  converted to 5 FU and then FUTP Which inhibit DNA and RNA s...
Fungal resistance    most common when flucytosine used as mononerapy for     Cryptococcus & Candidiasis    It occur d/t ...
Clinical uses     Oraly 100-15500 µg/kg/d     Used in combination with ampho B to ↑ response and ↓ toxicity     Dose sh...
Azoles     Synthetic comp     Acc to no. of nitrogen atoms in 5 membered azole ring they are       classified in to 2 gr...
Trizole     Metabolize slowly     Less effect on human cytochronic P450 i.e. involved in sterol        synthesis less D/...
Antifungal activity    C. Albican    C. Glabrates    C. Immitis    H. Capsulatern    C. Tropicalis    C. Neoformans ...
MOA   These drugs act by reducing the synthesis of ergosterol by inhibiting      p450 enzymes i.e. 14x dermetlylase thus ...
Resistance:-    Many mech, d/t prolong therapy and emerge slowly    Accumulation of notations in ERGII the gene coding f...
Ketoconazole    Given orally    Cheaper than itraconazole    More hepatotoxic + corticosteroid depression than itracona...
Adverse effects     Dose dependent nausea, anorexia voiting so give dose in divided dose       with food and at bed time ...
ITRACONAZOLE    Synthetic    Given orally and I/V    Dose 100-400mg/dPharmacokinetics    It has equally active metabol...
 Drug absorption is ↑ by food ad low gastric PH    Water solubility is low    Lipid soluble    Drug absorption ↑ after...
Important drug interactions   Rifamycin (Rifampin, rifabutin, rifapeutin)it ↓ bioavailability of   itraconazole   a.   Itr...
c. Other drug ↑            Diazepam            Digoxin            Astemizole            Quinidine                     ...
Therapeutic uses   Drug of choice for systemic infections d/t (non meningeal infection)         Blastomyces I/V         ...
FLUCONAZOLE   Chemistry       Fluocimated bistriazole  Pharmacokinetics       Almost completely absorbed from GIT      ...
Drug interactions     It ↑ Pl. conc. of astemizole, cyclosporine rifampin, sulfonylurea,      theophylline     Adverse e...
Therapeutics uses        Drug of choice in t/m and 2nd prophylaxis        Cryptococcal meningitis i.e. cryptococcal neof...
VORICONAZOLE   Newest triazole   I/V & oral formulations   Dose 400mg/d  Pharmacokinetics      Well absorbed orally wi...
Adverse effects    Rash    Elevated hepatic enzymes    Transient visual disturbances 30%    Include blurring and chang...
Systemic azoles               Water Absop       CSF: serum   t½      Elimination Formulation                              ...
ECHINOCANDINS        Newest class of antifungal to be developed        They are large cyclic peptides linked to a long c...
Mechanism of action:-     It acts at the level of fungal cell wall by inhibiting synthesis of B(1-      3)glucan. This re...
Uses   Salvage therapy in patients with universe aspergillosis who failed to                                             ...
MICAFUNGIN       Undergoing clinical       Effective against aspergillus & Candida speches even in pts who         are i...
SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS  1. Griseofulvin       Chemistry      Isolated from the culture of...
 Potent inducer of p450 so many drug interactions specially warfarin,  phenobenbital so largely replaced by itraconazole ...
 The pediatric dose is 10mg/kg body wt daily in single or divided  dose with meals Oral suspension is also available 50...
Antifungal activity   Fungi static        Various species of dermetophytes i.e. Mycospoum,          epidermophyton and tr...
Mechanism of action     It inhibit mitosis so these is production of multinucleate cells     It causes disruption of mit...
Adverse effects    Serious effects are rare    CNS:- Headache disappears when therapy is continued              Periphera...
Skin :- Cold & worm urticaria         Erythema, photosensitivity         Serum sickness like syndrome angioedema        ...
Precaution:-                If prolong therapy then routine evaluation of                Hepatic                Renal  ...
TERBINAFINE  Chemistry       Synthetic allylanuire, similar to naftifure  Pharmacokinetics:-       Well absorbed       ...
Mechanism of action     Fungicidal     Keratophilic like griseofuluir     Like azoles interfere with ergosterol biosynt...
Uses    More effective than griseofuluin    Itraconazole in treating onychromycosis i.e. cure rate is 90% when       one...
TOPICAL ANTIFUNGAL THERAPY  I. Polyene antifungal antibiotic      a) Nystatin           It is a polyene maesolide produce...
Use:-     Active against candida species i.e orophangeal     Vaginal Candidiasis     Intertrigurious candidal inf     ...
II. Topical azole     Indications are :-              Mucocutauous caudidiasis              T. versicolor              ...
Oral use    Orally indication is orophangeal Candidiasis    There is only local conc. of the drug and no systemic effect...
1. CLOTRIMAZOLE  Kinetics:-     Absorption from intact skin 0.5%                  Absorption from vagina 3-10%           ...
2. MICONAZOLE      Structurally related to econazole           Penetrates readily st. couneum of the skin and therefore m...
Uses:-     Available as cream, lotion, ointment powder vaginal cream +                                                   ...
3. Econazole    Penetrate at. Corneum upto mid dermis reat is same as above     (miconazole)    Terconazole + butoconazo...
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  1. 1. ANTIFUNGAL DRUGS DR SEEMI GULL 1
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  14. 14. Antifungal Agents Drugs used to treat infections caused by fungi – Systemic and topicalFUNGI – Very large and diverse group of microorganisms 14
  15. 15. STRUCTURE OF FUNGI They are eukaryotes consists of :- 1. Cell wall ( chitin) homopolymer of N- acetylglucogamine 2. Cell memb:- Contains ergosterol & zymiosterol in contrast to human which contain cholesterol cell memb also contain lipids glycoprotein & sterols 3. Inside the cell → golgi app. Ribosome’s bond to ER & cytoskeleton with microtubules, microfilaments & intermediate filament 4. Nucleus enclosed by nuclear memb. 15
  16. 16. TYPES i. Yeasts ii. Moulds iii. DimorphicI.YEASTS  Single cell fungi, ovoid or spherical  Reproduce by budding & devision  Some are useful organisms  Baking  Alcoholic beveragesII. Molds  Multicellular characterized by ong, branching filaments called hyphae → form myceliumIII. Dimorphic  Have growth characteristics of both  At body temp glow as yiest in host tissue  At ambient temp. glow as mold in saprophytic, free living state 16
  17. 17. MAGNITUDE OF PROBLEM  Fungi commonly present in environment  Hardly cause any serious disease  Five decades ago most common inf. Were – Athlete foot – 1- oral & vaginal through  Incidence of serious fungal inf. increased after 1970  Mostly secondary inf. → caused by opportunistic organismFACTORS WHICH INCREASE RISK:-  Use of broader spectrum antibiotics which destroy normal florc which compete fungi  Immouno compromised pts  Immunosuppressant  Anti-cancer drugs  Increased international travelling  Pregnancy  Diabetes  Oral contraceptives
  18. 18. FUNGAL INFECTION (MYCOSES) Three groups cause human disease I. Yeasts II. Moulds III. Dimorphic fungi 18
  19. 19. Common mycotic infection in human:- A. Cutaneous 1.Dermatophytes (Ring worm, tinea inf) There are three main genera Trichophyton → skin, hair & nail Microsporum → skin & hair Epidermophyton → skin & nail Dermatophytes only invade karatin & zoophilic fungi cause more severe but short lived inf then anthropophilic fungi 19
  20. 20. Various types of ring worms Tinea capitus (scalp) Tinea cruris (Groin) Tinea corporis (body) Tinea pedia (Feet) → Athlete footManaged by :- White field ointment Griseofilum Turbenafine 20
  21. 21. 2. Candida albican → candidiasis (moniliasis) Risk factor » Antibiotic therapy » Antineoplastics » Immunosuppressants » Prolong neutropenia » Recent surgery » Catheterization » I/V catheter » Cellular immune deff  May result in overgrowth and systemic infections  Oral candidiasis or thrush  Newborn infants and immune compromised patients  Vaginal candidacies → preg, diabetes, oral contraceptives 3. Pit versicolor → pityrosporium orbiculare 21
  22. 22. B. subcutaneous (deep tissue infections):- 1.mycetoma (medura foot)  Ch. Fungal inf of deep soft tissue & bones  Most commonly introduced by thoru. & common in foot 2. other soft tissue inf:- i. Zygomycosis • Face, limbs & syst in immunocompromized pts presented by S/C swelling ii. ch. Ronoblastomycosis:-on feet presented as nurossy foot iii. Rhinosporodidiosis:- on nose & cheeks presented by nasal polysps & S/c mudule iv. sporothrichosis:- on limbs rarely syst as S/C swelling ulcer, lymphatic spread → common informers 22
  23. 23. C. Systemic fungal inf:- i. Histoplasmosis:- caused by histoplasma capsulatum a diamorphic fungus Symptomatic & resp illness is most common hepatomegaly & lymphadenopathy rare Common in AIDS Mode of inf. Is inhalation of conidia → conversion in small budding in lungs → engulfation by phagocytes → prolif of organism → carried to for hematology spread ii. Aspergillosis:- Caused by aspergillus fumigates involves lungs → pulmonary aspergillosis leading cause of death in recipients of bone marrow transplant in pts of asthma & cysticfibrosis Colonization of lungs with aspergillus’ cause allergic bronchopulmonary aspergillosis 23
  24. 24. iii. Coccidiodomycosis:- Influenza like illness with malaise fever backache cough arthralgia swelling of knees & ankles caused byconidia of coccidiodes immitisiv. Paracoccidiodomycosis:- Caused By Paracoccidiodies Brasilienensis Mucocut. Lesions with involvement of lymph nodes & lungsv. Blastomycosis:- Mostly in men infected during occupational or eroatianal activities mostly in south central begins in lungs & mediestimal lymph nodes canidia resemble pulm T.Bvi. Cryptococcasis by C. Neoformans local grannlomatons lesions of lungs bones brain & meanings 24
  25. 25. Vii. Pneumocystosis:- caused by pneumocystitis cariniiViii. Candidiasis:- by candida albieans in immunocomproin pts GIT, mucosal dis resopligitis & catheter associated fungenia in hospilized ptsIx. Candidal endocarditic:- Caused by non albicans like candida prapsilarus, cond. Tropicals Risk factor:- bypass surgeryX. Penicillins marneffie inf:- Diamorphic organism in south east asia syst inf in both normal & immunocompr. PersonsXI. sporotrichosis Caused by sporo thrix schenchiiXII. Chromoblastomycosis:- Ch. Cut inf caused by phialo 25
  26. 26. GEOGRAPHICAL PREVALENCE (INCIDENCE) UK:- More incidence of sec inf. Like uryptocococcal meningitis & endocarditic & aspergillosis. Other parts of world:- More common are primary inf. Like blostomycosis histoplasmosis CoccidiodomycosisANTI FUNGAL AGENTS Systemic Examples:- Amphotericin B, fluconazole, ketoconazole, itraconazole Topical Examples:- Clotrimazole, miconazole, nystatin 26
  27. 27. CLASSIFICATIONS OF ANTI-FUNGAL DRUGS:- A. According to MOA 1.Drug affecting synts / Function of cell memb:- i. Synthesis (inhibit synth of ergosterol) – Ketoconazole – Fluconazole – Itraconazole – Voviconazole – Miconazole – Turbenafine (inhibit enzy squaline epoxidase so interfere ergosterol synth) ii.Function • Polyene antibiotics – Amphotericin B 27 – Nystatin
  28. 28. 2. Block nucleic acid synth:- – Flucytosine3. Distrupt microtubular function – Griseofulvin4. Reduction of fungal cell wall viability – Pradimicin – Nikkomycin5. Fungal protein synth inhib:- – Jordanians 28
  29. 29. B. Acc. To route of admin:-1. Topical – Nystatin – Clotrimazole – Econazole – Amphotericin – B2. Oral – Miconazole – Ketoconazole – Fluconazole – Itraconazole – Flucytosine – Grisofulvin – Terbenafine3. I/V – Amphotercin – Miconazole – Flucytozine – Fluconazole 29
  30. 30. C. Acc. To chemical structure1. Polyenes • Amphotericin B • Nystatin2. Pyrimidins:- Flucytosine3. Azoles, ketoconazole, miconazole, Clotrimazole, fluconazole, voriconazole, podaconazole4. Benzofurans:- Griseofulvin5. Misc. drugs • Undecylenic acid • Benzoic acid • Salicylic acid • Propionic acid • Caprylic acid • Pot iodide • Vaccines 30
  31. 31. D. Therapeutic classification :- 1. Superficial i. Dermatoplytes (ringworms) – Griseofulvin – Terbanafine – Ketoconazole – Nystatin ii. Candidacies – Fluconazole – Miconazole 31
  32. 32. 2. Systemic i. Ketoconazole – Histoplasm – Blastomycosis ii. Ketoconazole – Coccidiodomy – Para iii. Amphotericin B cocdidiodo – Cryptococcus – Candidacies – 2ygomycosis iv. Fluconazole – Candidiasis v. Flucytosine – Candidiasis – Cryptococcus 32
  33. 33. AMPHOTERICIN B Chemistry  It is polyene heptanes macrolide  Amphoteri behavior for which the drug is named is presence of a ‘’ on the main ring & primary ammi group on mycosamine  Prepared as colloidal susp with Na deoxycholate for I/V inf. Is called fungizone 33
  34. 34. Pharmacokinetics  Poorly absorbed from GIT so oral ampho B is only used for fungi within lumen of the tract not for systemic disease  I/V inj , topical  90% bound to PP  Liposomal prep(active drug in lipid delivery vehicles)  Widely distributed in most tissue ,poorly penetrates BBB  Some of it excreted in urine slowly over period of several days  Severe t ½ = 15days  Hepatic dis, renal disease and dialysis has little effect on drug conc. And dose adjustment is not required 34
  35. 35. MOA  selective in fungicidal effect  It binds to ergosterol and form ampho. B associated pores in the cell membs and alters its permeability  Its double bond rich side combines with ergosterol and OH rich side binds to water.  This pore allows leakage of intercellular ions & macromolecules and results in cell death  Some drug may bind to human cells and may lead to prominent toxicity  Oxidative damage to fungal cells at least in sites.Resistance  If ergosterol binding is impaired either by  ↓ conc. Of ergosterol reduced affinity of drug d/t modifications of sterol into precursor sterol d/t mutation 35
  36. 36. Adverse effects  Immediate reactions by I/V infusion  Slow toxicity Immediate:- / infusion related toxicity Include  Fever, chills ,Muscle spasms  Vomiting, headache, hypotension  can be lessen by  slowing infusion rate or ↓ daily dose  Premedication by Antipyretics Antihistaminic Meperidine or corticosteroid ( test dose of 1mg and should be kept under observation for 2 hours ) 36
  37. 37. cumulative toxicity Renal damage More common with AMB ,SIGNIFICANTLY LESS with liposomal prep Reversible,prerenal renal failure  occur in almost all patients 80% dose dependantd/t ↓ renal perfusion can be reduce by giving inf of N. saline with daily dose irreversible renal tubular acidosis severe K+ and Mg wasting creatinine Cl- drops and K+ lost with potentiated by hypo natremia K= loss can be reversed by KCl 37
  38. 38. hypochromic, normocytic anemia d/t ↓ production of erythropoietinThrombocytopenia,LeukopeniaHead ach. Nausea, vomiting, malaise after Intrathecal therapy → seizures and chemicalHepatic toxicityAnaphylaxis 38
  39. 39. Antifungal activity Broad spectrum fungicidal No antibact activity i. Yeast / Candida → Candida albicans Cryptococcus neofromans ii. Endemic mycoses → histoplasma capsultive blastomycoses dermatitides ,coccidioides immitis iii. Molds → aspergillus furnigatus 39
  40. 40. Clinical usespectrum I. All life threatening mycotic infections d/t blood fungicidal action It is used initially for serious infections and then replace by azoles for chronic or preventive therapy Fungal pneumonia status Empiric therapy systemic fungal inf e.g. cancer patient with neutropenia who remain febrile on brad spectrum antibiotics 40
  41. 41. II. Systemic fungal disease → slow I/V infusion at dose of 0.5-1mg /kg/d and usually continued to the total dose of 1-2 mg → in AIDS given once daily to prevent replace of cryptococcosis + histoplasmosisIII. Intrathecal therapy  For cryptococcal meningitis not responding to other drugs.IV. Local use  Mycotic corneal ulcer + keratitis in form of drops and direct sub conj. Inj  Fungal cystitis – bladder irrigation with Amphotericin B 41
  42. 42. FLUCYTOSINE Chemistry :- discoursed in 1957 accidently while searching for anticancer drug  Pyrimidine derivative related to 5 fluorouracil  Water soluble  Spectrum of action less than Amphotericin B  Synthetic compd. 42
  43. 43. Antifungal activity  Candida → Cryptococcus neoformans  Agents of chromomycosisPharmacokinetics  Well absorbed from GIT ,crosses BBB  Min pl. protein binding  80% excreted unchanged in urine  can. be removed by haemodialysis MOA Pyrimidine analog , blocks fungal DNA SYNTHESIS 43
  44. 44. taken up by fungal cells via enzyme deaminase.In fungal cell converted to 5 FU and then FUTP Which inhibit DNA and RNA synthatase respectively Drug selective for fungi bcoz human cells are unable to convert drug to active metabolite. Amphotericin B enhances its effect by↑ its entry through damaged fugal cells membranes Action synergistic with azole 44
  45. 45. Fungal resistance  most common when flucytosine used as mononerapy for Cryptococcus & Candidiasis  It occur d/t altered metabolism of flucytosineAdverse effectsd/t conversion of flucytosine to 5FU by microbial flora in intestinal traction hosts  Bone marrow depression leading to leucopenia and thrombocytopenia.  Rash, nausea, vomiting, diarrhea and severe enterocolitis  Reversible elevated hepatic enzy in 5% of patients  Toxicity is more with AIDS and azotemia taking Amphotericin B and 45
  46. 46. Clinical uses  Oraly 100-15500 µg/kg/d  Used in combination with ampho B to ↑ response and ↓ toxicity  Dose should be adjusted in renal disease  Cryptococcus neofurmans / meningitis  Chromoblastomycosis itraconazole + flucytosine 46
  47. 47. Azoles  Synthetic comp  Acc to no. of nitrogen atoms in 5 membered azole ring they are classified in to 2 groups 1. Imidazoles 2. TriazolesImidazole  Metabolize rapidly  More effect in human sterol → so more drug interactions e.g. ketoconazole miconazole Clotrimazole Econazole Butoconazole 47
  48. 48. Trizole  Metabolize slowly  Less effect on human cytochronic P450 i.e. involved in sterol synthesis less D/F E.g. Itraconazole Terconazole Fluconazole New azoles 48
  49. 49. Antifungal activity  C. Albican  C. Glabrates  C. Immitis  H. Capsulatern  C. Tropicalis  C. Neoformans Don’t have antibacterial or parasitic effect except antiprotozoal effect against 49
  50. 50. MOA  These drugs act by reducing the synthesis of ergosterol by inhibiting p450 enzymes i.e. 14x dermetlylase thus acumlating 14x metlylsterol  These methyl sterols disrupts the cell membrane and impair function of membrane bound enz e.g. atpase and thus inhibiting growth of fungi  Some azoles such as Clotrimazole may directly ↑ the cell membrane permeability but only in topical use 50
  51. 51. Resistance:-  Many mech, d/t prolong therapy and emerge slowly  Accumulation of notations in ERGII the gene coding for 14x sterol dermetylase  Cross resistance in all sterols  ↑ azole efflux by ATP binding casseltc and transporter can add to fluconazole resistance in C. albicans C. glabruta  ↑ Production of c 14 x dermatolyse is another cause  ↑ in no of resistant strains b/c of tis ↑ use in prophylaxis 51
  52. 52. Ketoconazole  Given orally  Cheaper than itraconazole  More hepatotoxic + corticosteroid depression than itraconazolePharmacokinetics  Oral absorption varies in individuals  Acidic environment is required for dissolution  So antacids, proton pump inhibitor etc reduces bioavailability  t ½ = 7-8 hours  metabolize extensile in liver and excreted via faces  84% bound to Albion  45% of erythrocytes  1% is free  Duly 1% penetration to CSF  Enzyme induces e.g. IND, rifampicin ↑ metabolism  Water solubility is low  It was the first oral azole but not used b/c of less selectively for p450 52
  53. 53. Adverse effects  Dose dependent nausea, anorexia voiting so give dose in divided dose with food and at bed time  Skin rash, purities  Hair loss  As it inhibit cytoch p450 → inhibit steroid synthesis so endocrinological effects 53
  54. 54. ITRACONAZOLE  Synthetic  Given orally and I/V  Dose 100-400mg/dPharmacokinetics  It has equally active metabolite i.e. hydroxyl itraconazole  99% bound to Pl. protests  Neither appear in urine, CSF  t ½ = 24-42 hours  metabolized in liver extensively first pass state level achieved in 4 days  I/V is 80-90% excreted in urine  Teratogenic 54
  55. 55.  Drug absorption is ↑ by food ad low gastric PH  Water solubility is low  Lipid soluble  Drug absorption ↑ after food and gastricAdverse effects  GIT disturbances  Headache, dizziness  Rare are hepatitis, hypocalcemia impotence  Allergic reactions  Drug interactions b/c interact with hepatic microtonal enz 55
  56. 56. Important drug interactions Rifamycin (Rifampin, rifabutin, rifapeutin)it ↓ bioavailability of itraconazole a. Itraconazole conc. ↓ with Rifamycin, Phenytoin, Pherobalbetone Drugs that ↓ gastric acidity b. Itraconazole conc. ↑ with  Claisthromycin  Indinavir  Ritonavil 56
  57. 57. c. Other drug ↑  Diazepam  Digoxin  Astemizole  Quinidine 57
  58. 58. Therapeutic uses Drug of choice for systemic infections d/t (non meningeal infection)  Blastomyces I/V  Sporotheix  S/C Chromoblastomycosis Alternative T/M for infections caused by  Aspergillus (outside CNS) I/V  Coccidioides  Cryptococcus  Histoplasma  In HIV patients with disseminated histoplasmosis → for maintenance  Bronchopul aspergillosis Active against some strains of esophageal Candidiasis resistant to fluconazole (in form of itraconazole solution) Used in dermatophytoses 58
  59. 59. FLUCONAZOLE Chemistry  Fluocimated bistriazole Pharmacokinetics  Almost completely absorbed from GIT  Plasma conc. almost same after oral or I/V  Bioavailability not effected by food or gastric acidity  Half life 25-30hours  Excretion of 90% renal and 10% faces  CSF conc. in 50-90%  Can also penetrate body fluids e.g. sputum or saliva  11-12% protein bound  100-200mg given after haemodialysis  Water soluble  Least effect on cytochrome p 450 so less drug interactions  Dose is 100-800mg/day oral or I/V  Widest therapeutic index b/c better GIT tolerance and less effect on p450 59
  60. 60. Drug interactions  It ↑ Pl. conc. of astemizole, cyclosporine rifampin, sulfonylurea, theophylline  Adverse effects  Nausea & vomiting above 200mg and above 800mg require antiemetic  Headaches, skin rash, vomiting, abd pain, diarrhea after 7days of therapy  Reversible alopecia  Hepatic failure  Steven syndrome 60
  61. 61. Therapeutics uses  Drug of choice in t/m and 2nd prophylaxis  Cryptococcal meningitis i.e. cryptococcal neofurmans of AIDS 400mg PL 8 wks  Esophageal & oropharyngeal Candidiasis  Dose is 200mg on first day twice 100mg -150mg Pl 2 wks 61
  62. 62. VORICONAZOLE  Newest triazole  I/V & oral formulations  Dose 400mg/d Pharmacokinetics Well absorbed orally with Bioavailability < 90% Less protein binding than itraconazole Hepatic metabolism Propensity for inhibition of p450 is low 62
  63. 63. Adverse effects Rash Elevated hepatic enzymes Transient visual disturbances 30% Include blurring and changes in color Vision or brightness these changes occur immediately after dose of voriconazole and resolve with 30minUses Similar to itraconazole Excellent activity against Candida (including fluconazole – resistant species such as & dimorphic fungi Less toxic and more effective in invasive as 63
  64. 64. Systemic azoles Water Absop CSF: serum t½ Elimination Formulation conc ratioKetoconazole Low Variable <0.1 7-10 Hepatic OralItraconazole Low Variable <0.01 24-42 Hepatic Oral, I/VFluconazole High High >0.7 22-31 Renal Oral, I/VVoriconazole High High >0.7 6 Hepatic Oral, I/V 64
  65. 65. ECHINOCANDINS  Newest class of antifungal to be developed  They are large cyclic peptides linked to a long chain fatly acid (Lipophilic) CASPOFUNGIN:- is only licensed agent, others are under investigation  Water soluble semi-synthetic lipopeptide derivative Pharmacokinetics  Water soluble  Only available in I/V form  Administered as a single loading dose of 70mg followed by 50mg/d  Highly protein bound  t ½ 9-11hours  Metabolites are executed by kidneys and GIT  Dosage adjustment required only in severe hepatic in sufficiency 65
  66. 66. Mechanism of action:-  It acts at the level of fungal cell wall by inhibiting synthesis of B(1- 3)glucan. This results in disruption of cell wal and cell death  Resistance occur d/t mutationsAdverse effects:-  Usually well tolerated with mino GIT side effects and flushing reported infrequently  Elevated liver enzymes specially in patients taking cospafungis cyclosporine in combination so avoid it 66
  67. 67. Uses  Salvage therapy in patients with universe aspergillosis who failed to respond to Amphotericin B  Active against Candida i.e. mucocutaneous Candidiasis and blood stream Candida inf  H. capsulation  C. albises 67
  68. 68. MICAFUNGIN  Undergoing clinical  Effective against aspergillus & Candida speches even in pts who are immunocompromised with AIDSAMOROLFINE  Morphemic derivative that interferes with fungal sterol synthesis  Given locally effective against infections of nails 68
  69. 69. SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS 1. Griseofulvin Chemistry  Isolated from the culture of penicillin Griseofulvin  Narrow spectrum antifungal agent Pharmacokinetics  Given orally, absorption ↑ with fatly finds  Poorly soluble in water and absorption varies with type of preparation specially size of the particle  Peak Pl. conc. reaches in 5hour  It is taken up by the newly formed skin and concentrated in the lceratin drug can be detected in St. corneuna after 4-8 hour of oral adm. 69  t ½ is 24hour but retained for with higher conc. in upper layer
  70. 70.  Potent inducer of p450 so many drug interactions specially warfarin, phenobenbital so largely replaced by itraconazole and terburafine Reductive in particle size greatly ↑ the absorption Formulation that contain the smallest particle size are labeled “ULTRAMICRONISED” it adueues bioequivalent PL> levels with half the dose of micronized drug In addition solubilizing Griseofulvin in polyethylene glycol enhances absorption even further Micronized grisesfuliun is available as 250mg, 500mg tab Ultra micronized as 125mg, 165mg, 250mg and 330mg tab and 250mg capsule Adult done of micronized is 500mg/day in single or divided doses with meals & occasionally 1g/d in t/m of recalcitrant infections 70
  71. 71.  The pediatric dose is 10mg/kg body wt daily in single or divided dose with meals Oral suspension is also available 50% of oral dose can be detected in urine within 5days mostly in the form of metabolites mainly 6 methlgaseofulvin Barbiturate ↓ its absorption The drug is deposited in keratin precursor cell The antibiotic present in cells when they differentiate is tightly bound to and persist in keratin & makes this substance resistant to fungal infection → so new growth of hair & nail is first to become free of disease, as the fungus containing keratin is shed it is replaced by normal tissue. 71
  72. 72. Antifungal activity Fungi static  Various species of dermetophytes i.e. Mycospoum, epidermophyton and trichophyton  Most effective in twice inf of scalp and glabrous skin  In scalp response in 4-6 weeks glabrous skin 3-4 weeks  dermatophyte inf of nail need prolong therapy – finger nail 6 weeks towards 8-18 month  No effect on bacteria & other fungi i.e. Candida & p. Orbicular 72
  73. 73. Mechanism of action  It inhibit mitosis so these is production of multinucleate cells  It causes disruption of mitotic spindle by interacting with polymerized microtubules of spindle and cytoplasmix microtubules result in the impaired processing of newly synthesized cell wall at the growing tips oc hyphare  antifungal activity is  Inhibiting of hyphal cell wall synthesis  Nuc acid synthesis  Inhibition of mitosis 73
  74. 74. Adverse effects Serious effects are rare CNS:- Headache disappears when therapy is continued  Peripheral neuritis  Lethargy  Mental confusion  Impairment of performance of routine tasks, fatigue, syncope, vertigo  Blurred vision transient macular edema  Augmentation of the effects of alcohol GIT:- Nausea, vomiting, diarrhea, flatulence, dry mouth, angular stomatitis, hepatotoxicity  Haematological leucopenia  Neutropenia  Punctarte basoplilia  Monocytosis 74
  75. 75. Skin :- Cold & worm urticaria  Erythema, photosensitivity  Serum sickness like syndrome angioedema  Estrogen like effects in children  Induces hepatic p450 → cry inducer ↑ metabolism of warfarin + oral contraceptives  Cross sensitivity with penicillin may occurC/I:-  Prophria  Hepatic failure  Hypersensitivity to guisofuloxia in post 75
  76. 76. Precaution:-  If prolong therapy then routine evaluation of  Hepatic  Renal  Haemopoitic systemUses:-  Recommended daily dose  5-15mg/kg --- children  500mg – 1g/d –adults  1.5-2g fore severe infection  Best results if repeated 6 hourly but mostly given twice daily  Not effective for S/C or deep mycosis  T/M should be gives until diseased portro is replaced by wound twice skin of nails,  Normal hair, skin, nails → I µ for scalp & hair ring worm  6-9µ for finger nails 76
  77. 77. TERBINAFINE Chemistry  Synthetic allylanuire, similar to naftifure Pharmacokinetics:-  Well absorbed  Bioavailability is 40% d/t first pass effect  Protein bound 99%  Drug accumulates in skin walls and fat  Initial half life is 12hour but extends to 200-400hour at steady state  Drug can be found in plasma for 4-8weeks after prolong therapy  Hepatic metabolism P450, excreted by urine  If given topically then can penetrate the skin & M. memb 77
  78. 78. Mechanism of action  Fungicidal  Keratophilic like griseofuluir  Like azoles interfere with ergosterol biosynthesis  Inhibits fungal enz squalene epoxidase instead of P450  This leads to accumulative of sterol squalene which is toxic to the organismAdverse effects  Rare & self limiting  GIT upset  Headache, dizziness  Rashes, purities  Rarely hepatitis 78  Don’t effect p450, so no drug restrictions
  79. 79. Uses  More effective than griseofuluin  Itraconazole in treating onychromycosis i.e. cure rate is 90% when one 250mg tabled given for 12 weeks  Ringworm else where in body  No pediatric formulation is available 79
  80. 80. TOPICAL ANTIFUNGAL THERAPY I. Polyene antifungal antibiotic a) Nystatin  It is a polyene maesolide produced by streptomyces noursei  Same structure and mechanism as Amphotericin B Pharmacokinetics  it is not absorbed from GIT skin or vagina  A liposomal preparation is in clinical trial for candidemia  Too toxic for parental administration only used topically  It has little toxicity as absorption is poor  Oral use is limited by unpleasant taste and may cause nausea 80
  81. 81. Use:-  Active against candida species i.e orophangeal  Vaginal Candidiasis  Intertrigurious candidal inf  Powder form twice daily for wet lesions  Vaginal tablets once daily for 2 weeks for vaginal Candidiasis  Zoles are more effective  Oral suspensions 4 times /day  Premature babies 1ml  Children 2ml  Adults 4 -6ml per doseB) Amphotericin B  In the form of ointment, lotion, cream all contain 3% ampho B applied 2-4twice daily for cretaceous and mucocutaneous lesions 81
  82. 82. II. Topical azole Indications are :-  Mucocutauous caudidiasis  T. versicolor  Ring worm Vaginal application  Creams, suppositories, ballets for vaginal Candidiasis  3 preparations are available  Clotomazole tablets  Miconazole supporitory  Terconazole cream 82
  83. 83. Oral use  Orally indication is orophangeal Candidiasis  There is only local conc. of the drug and no systemic effect 83
  84. 84. 1. CLOTRIMAZOLE Kinetics:- Absorption from intact skin 0.5%  Absorption from vagina 3-10%  Metabolized in liver & excreted in bile Adverse effect:- Skin:- Stinging, Erythema, edema, vesication, desquamation, pruitis, urtecaria Vagina:- Burning, ↑frequency of urine, skin rash Oral :- GIT inhibition Uses:- Available as OTC (Cream) dermatophyte infections 60-100% cure rate Coetaneous Candidiasis 80-100% 84
  85. 85. 2. MICONAZOLE Structurally related to econazole  Penetrates readily st. couneum of the skin and therefore more than 4 days  Less than 10% is absorbed in to blood  Absorption is 1.3% from vagina Adverse effects  Burning, itching, irritation. Pelvic cramps, headache, hives, skin rash safe in pregnancy but avoid is 1st trimester 85
  86. 86. Uses:- Available as cream, lotion, ointment powder vaginal cream + suppository In t/m of T. curis pedis, versiolor 90% Vulmoraginal Candidiasis 80-95% 86
  87. 87. 3. Econazole  Penetrate at. Corneum upto mid dermis reat is same as above (miconazole)  Terconazole + butoconazole + tioconazole – Terconazole resemble ketoconazole used → in vaginal Candidiasis – Butoconazole → comparable to clotimazole in vaginal Candidiasis  Oxiconazole + sulconazole – For deratophytes  Ciclopirox olamine – Blood spectrum – Cutaneous Candidiasis – T. coxposis, cursis, pedis & versicolor  Haloprogin fungicidal – T. pedis 80% T. crunis corpsis cersicotor  Tolnaftate – Cutaneous mycosis – T. Pedis  Allylamines i. Naftifuie » Allyeamine » Fungicidal, inhibit swualene 2,3 epoxidese 87

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