PM 716 Pharmacology I: Chapter 48 Antifungal Drugs PDF

PM 716 Pharmacology I Chapter 48 Antifungal RMRocco, PhD PM716 C48 Antifungals 1  Drug Discovery The history of how a drug or drug class was discovered and introduced into clinical medicine can serve a number of teaching functions: Provide a perspective on tr...

PM 716 Pharmacology I Chapter 48 Antifungal RMRocco, PhD PM716 C48 Antifungals 1  Drug Discovery The history of how a drug or drug class was discovered and introduced into clinical medicine can serve a number of teaching functions: Provide a perspective on treatment modalities before the drug was introduced. Stimulate a wider interest in the history of medicine. Expand the student’s knowledge base beyond the standard requirements of pharmacotherapeutics. PM716 C48 Antifungals 2  Mycoses: No Effective Drug Treatment Before 1954 Dermatomycoses fungus skin infections athlete’s foot ringworm Deep Mycoses histoplasmosis blastomycosis Opportunistic Fungi candidiasis (Candida albacans) PM716 C48 Antifungals 3 Candida albicans Gram stain of vaginal smear (x1000) Treatment was repeated gentian violet applications. Systemic infections had 50-100% mortality rates. Surgery often the only treatment for some local infections. PM716 C48 Antifungals 4 Elizabeth Hazen (1885-1975) Rachel Brown (1898-1980) PM716 C48 Antifungals 5 Elizabeth Hazen (1885-1975) Born in Mississippi, PhD in microbiology from Columbia U. Director of the Microbiology Lab for the NY State Dept of Public Health in the NY City Lab on East 25th St. Challenged by the increasing number of fungal infections for which there was no cure. PM716 C48 Antifungals 6 Good Science Starts With a Good Question. It was Alexander Fleming who discovered a mold in 1929 (Penicillium) that produced a chemical (penicillin) that killed bacteria. Hazen’s Inspiration: Is there a bacterium that produces a chemical that kills mold? PM716 C48 Antifungals 7 Streptomyces noursei In 1948 Hazen began to test hundreds of samples of soil to find a bacterium that would kill fungi. She discovered a Streptomyces in the soil of the garden of her friend Walter B. Nourses and named it Streptomyces noursei. PM716 C48 Antifungals 8  Streptomyces noursei The biggest challenge was to grow the Streptomyces in sufficient quantity and then devise methods to extract out from the media (broth) the active agent. The active agent must then be identified, purified, and tested in animals before it can be tested in humans. This is what took 14 years before penicillin was ready for human use. Fleming and the Oxford Group who worked on penicillin didn’t have.................... PM716 C48 Antifungals 9 Rachel Brown (1898-1980) Born in Springfield, MA. Graduated U Chicago PhD in organic chemistry. Studied under Julius Stieglitz brother of the photographer Alfred Stieglitz. Worked for the NY State Department of Public Health in the Albany Lab. PM716 C48 Antifungals 10 Hazen’s Transport Container Hazen grew up the cultures, harvested the broth and then shipped the broth for the chemical isolation to Rachel Brown in Albany, NY. Hundreds of Mason Jars shipped by USPS, not one broken or lost. Try that today. No 48240 proved to be effective against a wide range of fungi. PM716 C48 Antifungals 11  No. 48240 Number 48240 proved to be relatively safe in animals. The discovery was announced on October 18, 1950 and clinical testing begun. The drug was called nystatin (New York State Division of Laboratories). Hazen and Brown always pronounced the drug “nye-state-in” FDA approved, September 1954 Hazen-Brown US Patent No 2797183, issued June 25, 1957. PM716 C48 Antifungals 12 NYSTATIN PM716 C48 Antifungals 13 Nystatin also called Nystatin A Nystatin binds to ergosterol in the cell wall of fungi (human Nystatin has 6 double bonds cells lack ergosterol but have cholesterol instead). Nystatin-ergosterol complex causes cell walls to leak K+, potassium pours out, cell dies. Amphotericin B used for iv. Differs from nystatin by number of double bonds Amphotericin B has one extra double bond, 7 total PM716 C48 Antifungals 14 Arno Flood Nov 1966 Florence, Italy PM716 C48 Antifungals 15  Royalties From Nystatin Patent licensed to Squibb, sold as Mycostatin© 1955-1976, total revenue $13.4 million. 100% donated to research by the Brown-Hazen Fund. Brown and Hazen directed large sums to assist colleges and universities to promote the education of woman in the medical sciences. PM716 C48 Antifungals 16  Antifungal Drugs Antifungal Drugs: Systemic Drugs (oral or parenteral) for systemic infections. Oral Drugs for mucocutaneous infections Topical Drugs for mucocutaneous infections. PM716 C48 Antifungals 17  Topical Antifungal Drugs Creams clotrimazole (Lotrimin) miconazole (Monistat-Derm) terbinafine (Lamisil AT) tolnaftate (Tinactin) undecylenic (Desenex) Sprays tolnaftate (Tinactin) miconazole (Monistat) PM716 C48 Antifungals 18  Topical Antifungal Drugs Tinea Pedis Placebo + foot hygiene gave a 30-40% cure rate compared to topical antifungals. (foot hygiene = 2x daily washing) (placebo = cream only however cream may have some antifungal properties) Bedinghaus, J. M. Am Family Physician 64(5):791 (2001) PM716 C48 Antifungals 19  Topical Antifungal Drugs Sprays Often used for prophylaxis After 12 weeks 88% subjects fungus free compared to 69% of subjects who used a placebo (talc spray). PM716 C48 Antifungals 20  Topical Antifungal Drugs Tea Tree Oil Found to be equal to placebo Tong, M. M. Australas J. Dermatol. 33:145 (1992) PM716 C48 Antifungals 21 Topical Antifungal World’s first antifungal, Nystatin. Isolated from Streptomyces noursei, named after the person whose garden the soil sample was obtained, Walter B. Nourses. Drug forms pores in cell walls of fungi. PM716 C48 Antifungals 22 Nystatin E. L Hazen (1885-1975) NYC Health Labs R. F. Brown (1898-1980) NY State Health Labs, Albany. US Patent 2, 797, 183 June 25, 1957. Over $13 million royalties donated to State Health Labs and numerous colleges and university in order to promote women in the sciences. PM716 C48 Antifungals 23  Systemic Antifungal Drugs 1. Structure/Source: Amphotericin B, produced by Streptomyces nodosus, a gram Pos bacterium. Non water soluble amphoteric polyene macrolide. 7 double bonds compared to 6 in Nystatin A. PM716 C48 Antifungals 24  Amphotericin B Cholesterol Ergosterol 2. Mechanism of Action: Binds to Ergosterol found only in fungal cell walls. Cholesterol is major sterol in bacterial and human cells. Drug binds and forms open pore in cell wall. Ions leak out of cell and cause death. PM716 C48 Antifungals 25 Chapter 48 Antifungal Agents PM716 C48 Antifungals 26 © The McGraw-Hill Companies, Inc, Chapter 48 Antifungal Agents PM716 C48 Antifungals 27 © The McGraw-Hill Companies, Inc,  Amphotericin B 3. Pharmacokinetics: iv only, t1/2 is 15 days. Slowly metabolized, no dose adjustment required for hepatic or renal impairment. 4. Antifungal Activity: Broad spectrum, yeasts including Candida albicans, Cryptococcus neoformans, many others. PM716 C48 Antifungals 28  Amphotericin B 5. Clinical Uses: Drug of choice for all life- threatening mycotic infections. 6. Adverse Effects and ADRs: iv Dose Related: fever, chills, muscle spasms. Vomiting, hypertension. Slower Induction: renal damage PM716 C48 Antifungals 29 Amphotericin B Amphotericin B liposome and other lipid bound amphotericin B fomrulations decrease binding of the drug to human cell membranes and this causes less toxicity. PM716 C48 Antifungals 30 PM716 C48 Antifungals 31 PM716 C48 Antifungals 32  Amphotericin B 7. Mechanism of Resistance: Decrease drug binding to ergosterol by decreasing membrane concentration of ergosterol or reduce the binding affinity of ergosterol for the drug. PM716 C48 Antifungals 33 Systemic Antifungal Drugs Flucytosine 1. Structure/ Source: water soluble synthetic pyrimidine analog. Flucytosine 2. Cytosine PM716 C48 Antifungals 34 Chapter 48 Antifungal Agents PM716 C48 Antifungals 35 © The McGraw-Hill Companies, Inc,  Flucytosine 2. Mechanism of Action: Fungal intracellular enzymes convert drug to phosphorylated active compound. Phosphorylated analog inhibits DNA, RNA synthesis. Human cells are unable to phosphorylate flucytosine. PM716 C48 Antifungals 36  Flucytosine 3. Pharmacokinetics: 100 - 150 mg/d/kg po. Dose adjustment required for renal failure. Cp should be monitored to maintain 50 - 100 ug/mL levels to avoid toxicity and ensure efficacy. 4. Antifungal Activity: narrow range. 5. Clinical Uses: Cryptococcus neoformans and some candida species only. Used in combination only to avoid resistance. PM716 C48 Antifungals 37  Flucytosine 6. Adverse Effects and ADRs: Intestinal flora may biotransform drug to toxic antineoplastic drug, fluorouracil. Flucytosine Flurouracil PM716 C48 Antifungals 38  Flucytosine 6. Adverse Effects and ADRs: Bone marrow toxicity especially when combined with amphotericin B. Measure Cp levels to avoid toxicity. 7. Mechanism of Resistance: Altered (reduced) metabolism (phosphorylation) of drug, common in monotherapy. PM716 C48 Antifungals 39 Systemic Antifungal Drugs Azoles 1. Structure/Source: synthetic imidazoles or triazoles. ketoconazole fluconazole PM716 C48 Antifungals 40 Chapter 48 Antifungal Agents PM716 C48 Antifungals 41 © The McGraw-Hill Companies, Inc,  Azoles 2. Mechanism of Action: Reduced fungal synthesis of ergosterol by inhibition of fungal CYP 450 enzymes. Specificity achieved through drug’s greater affinity for fungal CYP450 compared to human CYP 450. Ketoconazole lacks this specificity and is no longer used except as a topical. PM716 C48 Antifungals 42  Azoles 3. Pharmacokinetics: Varies widely between the various azole drugs. PM716 C48 Antifungals 43  Azoles 4. Antifungal Activity: broad range spectrum 5. Clinical Uses: many candida species, endemic mycoses, dermatophytes, and aspergillus (itraconazole and voriconazole). 6. Adverse Effects and ADRs: relatively non-toxic, minor GI disturbances, all may induce abnormal liver function. All inhibit human CYP450 to some extent and cause drug-drug interactions. PM716 C48 Antifungals 44  Azoles 7. Mechanism of Resistance: Multiple mechanisms with ever increasing frequency. Imidazoles: ketoconazole, miconazole, clotrimazole Triazoles: itraconazole, fluconazole, voriconazole, posaconazole PM716 C48 Antifungals 45 Systemic Antifungal Drugs Echinocandins 1. Structure/Source: Synthetic cyclic peptides. Caspofungin (Cancidas®) also micafungin anidulsfungin PM716 C48 Antifungals 46  Caspofungin 6. Adverse Effects and ADRs: minor GI, 7. Mechanism of Resistance: none reported so far. PM716 C48 Antifungals 47 Systemic for Mucocutaneous Infections Griseofulvin Derived from penicillium mold used to treat dematophytosis Discovered 1939 binds to new keratin in skin and blocks new infection through inhibition of fungal mitosis by blocking microtubles. Long term usage required (months) to allow new protected skin to replace old infected skin. PM716 C48 Antifungals 48 Systemic for Mucocutaneous Infections Terbinafine (Lamisil®) Synthetic that inhibits the fungal enzyme squalene epoxidase (not the CYP450). Squalene accumulation is toxic to fungi. Once daily po dose for 12 weeks. PM716 C48 Antifungals 49 Terbinafine (Lamisil®) Antifungal (dermatophytoses) po and topical. Drug inhibits the fungal enzyme squalene epoxidase, which results in cell wall disruption and cell death. PM716 C48 Antifungals 50  Terbinafine Product Insert PDR 2001 PM716 C48 Antifungals 51  FDA Classification of Potential Teratogens A Studied in pregnant woman, no harm to the fetus. B Studied in pregnant animals, no harm to the fetus OR harm in animals but not in pregnant humans. C Harm in pregnant animals but not studied in humans. PM716 C48 Antifungals 52 D Studied in pregnant woman and found to cause fetal harm but risk benefit analysis may allow drug to be used. X Causes harm to fetus, should never be used in pregnant women or women who may become pregnant. PM716 C48 Antifungals 53  FDA Pregnancy Category Drug US FDA Acetaminophen B Amoxicillin B Phenytoin D Thalidomide X Theophylline C PM716 C48 Antifungals 54  Topical Antifungals Nystatin (world’s first antifungal) Topical azoles: clotrimazole, miconazole Topical Allylamines: terbinafine, naftifine PM716 C48 Antifungals 55  Summary of Drug Mechanisms (1) Polyenes (amphotericin B) binds to ergosterol in cell wall cell wall develops pores, leaks, cell lysis (2) Azoles (ketoconazole, fluconazole etc) inhibits CYP450 (14 alpha demethylase) decrease in ergosterol production PM716 C48 Antifungals 56 weak cell walls, leaks, cell lysis  Summary of Drug Mechanisms (3) Echinocandins (caspofungin) inhibits D-glucan synthesis cell wall becomes weak, leaks, cell lysis (4) DNA or Protein Synthesis (flucytosine) flucytosine metabolized to 5- flucytosine 5-flucytosine incorporated into fungal PM716 C48 Antifungals 57 RNA and protein synthesis stopped  Summary of Drug Mechanisms (5) Squalene epoxidase inhibitor (terbinafine) inhibits squalene epoxidase enzyme squalene accumulates which is toxic to the fungal cell (6) Mitotic Inhibitor (griseofulvin) binds to new keratin in skin blocks new infection through inhibition of fungal mitosis by microtubule disruption. PM716 C48 Antifungals 58  Summary I (1) Antifungals Topicals clotrimazole miconazole nystatin ketoconazole PM716 C48 Antifungals 59  Summary II (2) Antifungals Systemics amphotericin B and lipsome forms flucytosine Azoles (synthetics) fluconazole itraconazole voriconazole PM716 C48 Antifungals 60  Summary III (3) Antifungals Systemics echinocandins caspofungin (synthetic) For Mucocutaneous Infections griseofuvin terbinafine PM716 C48 Antifungals 61  Case Study 56 year-old man, expanding ulcer in lower left leg. Treated with deferoxamine for hepatic iron overload. Was given dicloxacillin thinking it was an insect bite. Left leg has 6x12 cm black ulcer with surrounding swelling and erythema that is tender. Biopsy reveals fungi. PM716 C48 Antifungals 62  Case Study Biopsy shows Rhizopus, an agent of mucormycosis. Treat with amphoteracin B and caspofungin and subsequent chronic suppressive therapy with posaconazole. PM716 C48 Antifungals 63