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Antifungal drugs

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undergraduate prescription of antifungals

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Antifungal drugs

  1. 1. Antifungal Drugs  Infectious diseases caused by fungi are called mycoses, and they are often chronic in nature.  Fungal infectious occur due to :  1- Abuse of broad spectrum antibiotics  2- Decrease in the patient immunity
  2. 2.  They have rigid cell walls composed largely of a polymer of N- acetylglucosamine rather than peptidoglycan (a characteristic component of most bacterial cell walls).  The fungal cell membrane contains ergosterol rather than the cholesterol found in mammalian membranes.  These chemical characteristics are useful in targeting chemotherapeutic agents against fungal infections
  3. 3. Types of fungal infections  1. Superficial : Affect skin – mucous membrane. e.g.  Tinea versicolor  Dermatophytes : Fungi that affect keratin layer of skin, hair, nail. e.g. tinea pedis ,ring worm infection  Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.
  4. 4. 2- Deep infections  Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis.
  5. 5. Classification of Antifungal Drugs 1- Antifungal Antibiotics :  Griseofulvin  Polyene macrolide : Amphotericin- B & Nystatin 2- Synthetic :  Azoles : A) Imidazoles : Ketoconazole , Miconazole B) Triazoles : Fluconazole , Itraconazole
  6. 6. Synthetic Antifungal ( contin…)  Flucytosine  Squalene epoxidase inhibitors : e.g.Terbinafine & Naftifine.
  7. 7. Classification According to Route of Administration  Systemic : Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine.  Topical In candidiasis :  Imidazoles : Ketoconazole , Miconazole.  Triazoles : Terconazole.  Polyene macrolides : Nystatin , Amphotericin-B  Gentian violet : Has antifungal & antibacterial.
  8. 8. In Dermatophytes :  Squalene epoxidase inhibitors : Terbinafine & Naftifine.  Tolnaftate.  White field ointment : 11% Benzoic acid & 6% Salicylic acid .  Castellani paint.
  9. 9. Amphotericin B  Amphotericin 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 )
  10. 10. Pharmacokinetics  Poorly 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 16 days.
  11. 11. 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 ).
  12. 12. Resistance to amphotericin B If ergosterol binding is impaired either by :  Decreasing the membrane concentration of ergosterol.  Or by modifying the sterol target molecule.
  13. 13. Adverse Effects 1- Immediate reactions (Infusion –related toxicity).  Fever, muscle spasm, vomiting, headache, hypotension. Can be avoided by: A. Slowing the infusion B. Decreasing the daily dose C.Premedication with antipyretics, antihistamincs or corticosteroids. D. A test dose.
  14. 14. 2- Slower toxicity  Most serious is renal toxicity (nearly in all patients ).  Hypokalemia  Hypomagnesaemia  Impaired liver functions  Thrombocytopenia  Anemia
  15. 15. Clinical uses  Has 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.
  16. 16. Routes of Administration 1- Slow I.V.I. For systemic fungal disease. 2- Intrathecal for fungal C.N.S. infections. 3- Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis. 3- Local injection into the joint in fungal arthritis. 4- Bladder irrigation in Candiduria.
  17. 17. 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. Nephrotoxicity B. Infusion toxicity  Also, more effective  More expensive
  18. 18. Nystatin  It 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 .
  19. 19. Clinical uses  Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract.  Vaginal candidiasis  Can be used in combination with antibacterial agents & corticosteroids.
  20. 20. Azoles  A group of synthetic fungistatic agents with a broad spectrum of activity .  They have antibacterial , antiprotozoal anthelminthic & antifungal activity .
  21. 21. Mechanism of Action 1-Inhibit the fungal cytochrome P450 enzyme, (α- 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.
  22. 22. Azoles They are classified into :  Imidazole group  Triazole group
  23. 23. Imidazoles  Ketoconazole  Miconazole  Clotrimazole  They lack selectivity ,they inhibit human gonadal and steroid synthesis leading to decrease testosterone & cortisol production.  Also, inhibit human P-450 hepatic enzyme.
  24. 24. Ketoconazole  Well 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).
  25. 25. Ketoconazole (cont.)  Inactivated in liver & excreted in bile (feces ) & urine.  Does not cross BBB.
  26. 26. Clinical uses  Used topically or systematic (oral route only ) to treat : 1- Oral & vaginal candidiasis. 2- Dermatophytosis. 3- Systemic mycoses.
  27. 27. Adverse Effects  Nausea, vomiting ,anorexia  Hepatotoxic  Inhibits human P 450 enzymes  Inhibits adrenal & gonadal steroids leading to: Menstrual irregularities Loss of libido Impotence Gynaecomastia in males
  28. 28. Contraindications & Drug interactions Contraindicated in :  Prgnancy, lactation ,hepatic dysfunction  Interact with enzyme inhibitors , enzyme inducers.  H2 blockers & antacids decrease its absorption
  29. 29. Triazoles  Fluconazole  Itraconazole  Voriconazole  They are :  Selective  Resistant to degradation  Causing less endocrine disturbance
  30. 30. Itraconazole  Lacks endocrine side effects  Has a broad spectrum activity  Given orally & IV  Food increases its absorption  Metabolized in liver to active metabolite  Highly lipid soluble ,well distributed to bone, sputum ,adipose tissues.  Can not cross BBB
  31. 31. Itraconazole (cont.)  Half-life 30-40 hours  Used orally in dermatophytosis & vulvo- vaginal candidiasis.  IV only in serious infections.  Effective in AIDS-associated histoplasmosis  Side effects :  Nausea, vomiting, hypokalemia, hypertension, edema, inhibits the metabolism of many drugs as oral anticoagulants.
  32. 32. Fluconazole  Water soluble  Completely absorbed from GIT  Excellent bioavailability after oral administration  Bioavailability is not affected by food or gastric PH  Concentrated in plasma is same by oral or IV route  Has the least effect on hepatic microsomal enzymes
  33. 33. Fluconazole (cont.)  Drug interactions are less common  Penetrates 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 kidney  Half-life 25-30 hours  Resistance is not a problem
  34. 34. Clinical uses  Candidiasis  ( is effective in all forms of mucocutaneous candidiasis)  Cryptococcus meningitis  Histoplasmosis, blastomycosis, , ring worm.  Not effective in aspergillosis
  35. 35. Side effects  Nausea, vomiting, headache, skin rash , diarrhea, abdominal pain , reversible alopecia.  Hepatic failure may lead to death  Highly teratogenic ( as other azoles)  Inhibit P450 cytochrome  No endocrine side effects
  36. 36. Voriconazole  A broad spectrum antifungal agent  Given orally or IV  High oral bioavailability  Penetrates tissues well including CSF  Inhibit P450  Used for the treatment of invasive aspergillosis & serious infections.  Reversible visual disturbances
  37. 37. Flucytosine  Synthetic pyrimidine antimetabolite (cytotoxic drug ) often given in combination with amphotericin B & itraconazole.  Systemic fungistatic
  38. 38. Mechanism of action  Converted within the fungal cell to 5- fluorouracil (Not in human cell ), that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis.  (Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic).
  39. 39. Phrmacokinetics  Rapidly & well absorbed orally  Widely distributed including CSF.  Mainly excreted unchanged through kidney  Half-life 3-6 hours
  40. 40. Clinical uses  Severe deep fungal infections as in meningitis  Generally given with amphotericin B  For cryptococcal meningitis in AIDS patients
  41. 41. Adverse Effects  Nausea, vomiting , diarrhea, severe enterocolitis  Reversible neutropenia, thrombocytopenia, bone marrow depression  Alopecia  Elevation in hepatic enzymes
  42. 42. Caspofungin  Inhibits the synthesis of fungal cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis & cell death.  Given by IV route only  Highly bound to plasma proteins  Half-life 9-11 hours  Slowly metabolized by hydrolysis & N- acetylation.  Elimination is nearly equal between the urinary & fecal routes.
  43. 43. Clinical uses  Effective 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
  44. 44. Griseofulvin  Fungistatic, has a narrow spectrum  Given orally (Absorption increases with fatty meal )  Half-life 26 hours  Taken selectively by newly formed skin & concentrated in the keratin.  Induces cytochrome P450 enzymes  Should be given for 2-6weeks for skin & hair infections to allow replacement of infected keratin by the resistant structure
  45. 45. Griseofulvin(cont.)  Inhibits fungal mitosis by interfering with microtubule function  Used 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.
  46. 46. TOLNAFTATE  Effective in most cutaneous mycosis.  Ineffective against Candida.  Used in tinea pedis ( cure rate 80% ).  Used as cream, gel, powder, topical solution.  Applied twice daily.
  47. 47. NAFTIFINE  Broad spectrum fungicidal .  Available as cream or gel.  Effective for treatment of tinea cruris.
  48. 48. TERBINAFINE  Drug of choice for treating dermatophytes (onychomycoses).  Better tolerated ,needs shorter duration of therapy.  Inhibits fungal squalene epoxidase, decreases  The synthesis of ergosterol .(Accumulation of squalene ,which is toxic to the organism causing death of fungal cell).
  49. 49.  Fungicidal ,its activity is limited to candida albicans & dermatophytes.  Effective for treatment of onychomycoses  6 weeks for finger nail infection & 12 weeks for toe nail infections .  Well absorbed orally , bioavailability decreases due to first pass metabolism in liver.
  50. 50.  Highly protein binding  Accumulates 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.

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