Antifungal presentation complete 20.pptx

Antifungal presentation complete 20.pptx

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  PHARMACOLOGY &THERAPEUTICS ANTI FUNGAL Dr.Adil Khaliq Pharm-D, MPH MPhil, Ph. D Scholar [email protected] [email protected]
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  Fungal Infections • Infectiousdiseases 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 (e.g. in AIDS)
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  Fungal Cell • Theyhave rigid cell walls composed largely of a chitin (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
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  Cont… • Human fungalinfections have increased dramatically , owing mainly to advances in surgery, cancer treatment, and critical care accompanied by increases in use of broad-spectrum antimicrobials and the HIV epidemic.
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  Types of fungalinfections I. Mucocutaneous (superficial) infections: A. Dermatophytes: • Cause infection of skin, hair, and nails e.g. tinea capitis (scalp), tinea cruris (groin), tinea pedis (foot), onychomycosis (nails).
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  Types of FungalInfections B. Yeasts: • Cause infections of moist skin and mucous membranes e.g. Candida albicans causing oral, pharyngeal, vaginal, & bladder infections 6
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  Types of fungalinfections II. Systemic mycoses: are fungal infections affecting internal organs. It occurs in immunocompromized patients e.g. cryptococcosis (lungs, CNS, prostate), and aspergillosis (lung).
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  Azoles inhibit Polyenes (Disruptmembrane structure & function) Flucytosine inhibits DNA synthesis
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  Caspofungin inhibits cell wallsynthesis
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  Sites of Actionsof Antifungal Drugs
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  Classification of AntifungalAgents Antifungals ERGOSTEROL SYNTHESIS INHIBITORS Voriconazole Itraconazole Posaconazol e Fluconazole Caspofungin
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  Classification of AntifungalDrugs • Classification of Antifungal Drugs based on mechanism of action 1. Fungal cell wall synthesis inhibition: Caspofungin. 2. Bind to fungal cell membrane ergosterol: Amphotericin-B, Nystatin. 3. Inhibition of ergosterol synthesis: Azoles 4. Inhibition of lanosterol synthesis: Terbinafine 5. Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin. 6. Nucleic Acid synthesis inhibitors: Flucytosine
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  Amphotericin B • AmphotericinB is a naturally occurring polyene antifungal produced by Streptomyces nodosus. In spite of its toxic potential, amphotericin B remains the drug of choice for the treatment of several life-threatening mycoses. • It is a macromolecule and consists of both lipophilic and hydrophilic groups i.e., it is amphiphilic in nature • The amphiphilicity of the drug is responsible for its unique mechanism of action
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  Pharmacokinetics • Poorly absorbedorally, is effective for fungal infection of gastrointestinal tract. • For systemic infections given as slow I.V. Infusion. • 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.
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  Cont… • Inflammation favorspenetration into various body fluids, but little of the drug is found in the CSF, vitreous humor, or amniotic fluid. However, amphotericin B does cross the placenta. • Accumulates in renal cells causing nephrotoxicity leading to Azotemia characterized by decreased GFR, Urinary output, Creatinine clearance and increased Serum creatinine and BUN.
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  Mechanism of Action AMPHOTERICINB HYDROPHILIC PART LIPOPHILIC PART Binds with ergosterol and bilipid layer Forms pores in the cell membrane Cell contents such as Na+ and K+ leak trough the spores from the cytoplasm FUNGICIDAL ACTION
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  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 ).
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  Adverse Effects 1- Immediatereactions (Infusion –related toxicity). • Fever, muscle spasm, vomiting, headache, hypotension. Can be avoided by: – Slowing the infusion – Decreasing the daily dose – Premedication with antipyretics, antihistamines or corticosteroids. – A test dose.
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  Adverse Effects 2- Slowertoxicity • Most serious is renal toxicity (nearly in all patients ). • Hypokalemia • Hypomagnesaemia • Impaired liver functions • Thrombocytopenia • Anemia
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  Clinical uses • Hasa broad spectrum of activity & fungicidal action. • The drug of choice for life-threatening mycotic infections. • Also, for chronic therapy & preventive therapy of relapse. • Intestinal candidiasis • Topical candidiasis • Febrile neutropenia • Leishmaniasis – kala Azar (irregular fever, weight loss, swelling of spleen and liver)
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  Liposomal preparations ofAmphotericin B • Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing: • Nephrotoxicity • Infusion toxicity • Also, more effective • More expensive
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  Nystatin • It isa 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
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  Clinical uses • Preventor treat superficial candidiasis of mouth, esophagus, intestinal tract. • Vaginal candidiasis • Can be used in combination with antibacterial agents & corticosteroids.
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  Ergosterol Synthesis Inhibitors(Azoles) • A group of synthetic fungistatic or fungicidal agents with a broad spectrum of activity . • Azoles are made up of two different classes of drugs – Imidazole – Triazoles • Although these drugs have similar mechanisms of action and spectra of activity, their pharmacokinetics and therapeutic uses vary significantly.
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  Azoles Triazoles Voriconazole Itraconazole Posaconazole Fluconazole Imidazoles Systemic Ketoconazole Topical Clotrimazole Oxiconazole Moconazole Econazole Butoconazole
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  Azole Mechanism ofAction • Inhibit the fungal cytochrome P450 enzyme, (α- demethylase) which is responsible for converting lanosterol to ergosterol Lanosterol Lanosterol 14 demethylase (CYP 450 enzyme) Azoles Ergosterol
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  Imidazoles • Imidazoles includes: –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.
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  Ketoconazole • Well absorbedorally • Bioavailability is decreased with antacids, H2 blockers, proton pump inhibitors & food . • Cola drinks improve absorption in patients with achlorhydria. • Half-life: 7-8 hrs. • Inactivated in liver & excreted in bile (feces) & urine. • Does not cross BBB
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  Ketoconazole Clinical Uses •Used topically or systematic (oral route only ) to treat : 1. Oral & vaginal candidiasis 2. Dermatophytosis. 3. Systemic mycoses.
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  Ketoconazole 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
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  Triazoles • Triazoles includes: –Fluconazole – Itraconazole – Voriconazole • They are : – Selective – Resistant to degradation – Causing less endocrine disturbance
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  Itraconazole • Lacks endocrineside effects • Has a broad spectrum activity • Given orally & IV • Food increases its absorption (also by low PH) • Metabolized in liver to active metabolite • Highly lipid soluble, well distributed to bone, sputum, adipose tissues. • Can not cross BBB
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  Itraconazole (cont.) • Half-life30-40 hours Clinical uses: • 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
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  Fluconazole • Completely absorbedfrom 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 enzymes
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  Fluconazole (cont.) • Druginteractions 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
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  Clinical uses • Candidiasis(is effective in all forms of cutaneous candidiasis) • Cryptococcus meningitis • Histoplasmosis, blastomycosis, ring worm
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  Side effects • Nausea,vomiting, headache, skin rash, diarrhea, abdominal pain, reversible alopecia. • Hepatic failure may lead to death • Highly Teratogenic ( as other azoles) • Inhibit cytochrome P450 • No endocrine side effects
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  Inhibition of LanosterolSynthesis: Terbinafine • Mechanism of action: • It inhibits squalene epoxidase thus blocking the biosynthesis of ergosterol, an essential component of fungal cell membranes. • This inhibition also results in an accumulation of squalene, result in the death of the fungal cell.
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  Terbinafine • Fungicidal ,itsactivity 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.
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  Therapeutic uses • Itis fungicidal and drug of choice for treating dermatophytosis and, especially, onychomycoses (fungal infections of nails). • It is better tolerated, requires shorter duration of therapy, and is more effective than either itraconazole or griseofulvin
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  Adverse effects • Thedrug is well tolerated, with a low incidence of gastrointestinal distress headache, or rash • Contraindicated in pregnancy
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  Nucleic Acid synthesisinhibitors Flucytosine • Flucytosine (5-FC) is a synthetic pyrimidine analog that is often used in combination with amphotericin B. • This combination of drugs is administered for the treatment of systemic mycoses and for meningitis caused by Cryptococcus neoformans and Candida albicans.
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  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).
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  Pharmacokinetics • Rapidly &well absorbed orally • Widely distributed including CSF. • Mainly excreted unchanged through kidney • Half-life 3-6 hours
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  Clinical Uses • Severedeep fungal infections as in meningitis • Generally given with amphotericin B • For cryptococcal meningitis in AIDS patients
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  Adverse Effects • Nausea,vomiting, diarrhea, severe enterocolitis • Reversible neutropenia, thrombocytopenia, bone marrow depression • Alopecia • Elevation in hepatic enzymes
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  Fungal Cell WallSynthesis Inhibitors Caspofungin • Inhibits the synthesis of fungal cell wall, leading to lysis & cell death. • Given by IV route only • Highly bound to plasma proteins • Half-life 9-11 hours • Slowly metabolized by hydrolysis • Elimination is nearly equal between the urinary & fecal routes.
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  Caspofungin Mechanism ofAction • Inhibit synthesis of glucan in the cell wall via noncompetitive inhibition of enzyme 1,3-β glucan synthase • Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components .
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  Clinical Uses • Effectivein 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)
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  Anti- Mitotic (Griseofulvin) •Fungistatic, has a narrow spectrum of activity. • Given orally (Absorption increases with fatty meal) • Half-life 26 hours • Taken selectively by newly formed skin & concentrated in the keratin. • Should be given for 2-6weeks for skin & hair infections to allow replacement of infected keratin by the resistant structure.
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  Griseofulvin(cont.) • MOA: Inhibitsfungal mitosis by interfering with microtubule function • Clinical uses: – Used to treat dermatophyte infections ( ring worm of skin, hair, nails ). – Highly effective in athlete's foot. • Adverse effects: – Peripheral neuritis, mental confusion, fatigue, vertigo, – GIT upset, enzyme inducer, blurred vision.