ANTIFUNGALS MMU and associated notes .pptx

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1. PHARMACOLOGY 111 BNSF 3207 DR. JACQUELINE NJERI MUCHIRI. MPS MSCPHAR, PGDME, BPHARM.

2. By the end of this course unit, you should be able to: Describe the pharmacology of antimicrobial agents Manage and treat poisoned patients Interpret and fill prescriptions Describe the main concepts and practices of complimentary and traditional medicines. Identify those complimentary approaches, which might potentially be useful in the practice of nursing .

3. COURSE OUTLINE 1. ANTIMICROBIAL AGENTS 2. TOXICOLOGY 3. THERAPEUTICS 4. TRADITIONAL AND COMPLEMENTARY MEDICINE

4. LECTURE 1 ANTIMICROBIAL AGENTS

5. INTRODUCTION Antimicrobial agents are drugs that are selectively toxic to invading microorganisms These drugs should have minimal effects on the host (Patient) Microbes aka microorganisms are tiny living organisms living all around us They are too small to be seen with the naked eye, hence the term “Micro” These organisms live all around us, in soil, water, air and even our bodies.

6. Normal flora/ microbiota/ resident flora These are microorganisms that reside on or within human tissues and biofluids They are a permanent inhabitant of different body sites in a healthy person Unless interfered with or in immunocompromised people, normal flora is not harmful to the body and more often it is protective

7. Microorganisms are classified as: The term antimicrobial agents therefore, refers to drugs that inhibit all microorganisms in general. The term Chemotherapy was originally used for this but of late, in the public mind, chemotherapy is associated with those types of anti cancer agents that cause vomiting and hair loss. MICROBES PARASITES BACTERIA HELMINTHS FUNGI PROTOZOA VIRUS

8. CLASSIFICATION OF LIVING ORGANISMS PROKARYOTES CELLS WITHOUT NUCLEI BACTERIA EUKARYOTES CELLS WITH NUCLEI PROTOZOA HELMINTHS FUNGI VIRUSES NO BIOCHEMICAL MACINERY VIRUSES CANCER CELLS MORE LIKE HOST CELLS

9. The use of chemotherapeutic agents dates back to the work of Ehrlick et al in the 20 th century. The selectivity of these agents largely relies on the ability to exploit the biochemical differences between the invading organism and the host Unfortunately in the recent past, our efforts to attack these organisms is being counteracted by their ability to develop resistant mechanisms. Although it is also true that AMR to some extent is as a result of patient and healthcare professionals recklessness

10. Molecular basis of chemotherapy Antimicrobial agents are selectively toxic to the pathogenic organism Virtually host and parasites have the same blue print (DNA) except for the RNA virus Most agents will target unique features of the pathogens for example their cell wall, glucose synthesis, folate metabolism

11. Terminologies Empiric treatment- treatment begun on “ educated guess” Antibiotic - agents active against bacterial infections Antifungal -agents active against fungal infections Antiviral -agents active against viral infections Antihelmith - agents active against parasitic infestation Antiprotozoa - agents active against protozoal infections

12. Antibacterial spectrum - range of activity Broad or narrow spectrum Gram positive or gram negative Bacteriostatic- inhibits growth Bactericida l- kills the organism Antibiotic combinations- use of different agents with different mechanisms Antibiotic synergism- combination of two agents have enhanced activity Antibiotic antagonism- combination of two agents in which one interferes with the activity of the other

13. ANTIFUNGAL AGENTS

14. outline Definition of terms Characteristics of fungi Structure of fungi Fungi of medical importance Fungal infections: presentations, treatment Summary

15. INTRODUCTION Fungal infections ( mycoses ) are widespread in the population; they are generally associated with the skin (e.g. 'athlete's foot') or mucous membranes (e.g. 'thrush'). In temperate climates such as the UK, and in otherwise healthy people, they are mainly benign, being more of a nuisance than a threat. However, they become a more serious problem when the immune system is compromised or when they gain access to the systemic circulation. When this occurs, fungal infections can be fatal.

16. Structure of Fungi

17. Almost all the fungi have a filamentous structure except the yeast cells. They can be either single-celled or multicellular organisms. Fungi consist of long thread-like structures known as hyphae. These hyphae together form a mesh-like structure called mycelium.

18. Fungi possess a cell wall which is made up of chitin and polysaccharides. The cell wall comprises a protoplast, which is differentiated into other cell parts such as cell membrane, cytoplasm, cell organelles and nuclei. The nucleus is dense, clear, with chromatin threads. The nucleus is surrounded by a nuclear membrane.

19. Characteristics of fungi Fungi are: Eukaryotic- membrane bound nucleus Non-vascular – do not have vascular tissue ( roots, stems, leaves, ) Non-motile – do not move Heterotrophic –( they get food and energy from other organisms). Decomposers – live on decaying organism They may be unicellular or filamentous.

20. The fungi have no embryonic stage, they reproduce by means of spores which can be sexual ( meiosis) or asexual (mitosis). Fungi lack chlorophyll and hence cannot perform photosynthesis. Fungi store their food in the form of starch. The nuclei of the fungi are very small. Some fungi are parasitic and can infect the host. Fungi produce a chemical called pheromone which leads to sexual reproduction in fungi. Examples include mushrooms, molds and yeast

21. Classification of fungi Kingdom Fungi are classified based on different modes. The different classification of fungi is as follows: REVIEW THE BINOMIAL NOMENCLATURE OF FUNGI FROM KINGDOM TO SPECEIS

22. Classification on basis of nutrition There are 3  groups. Saprophytic – The fungi obtain their nutrition by feeding on dead organic substances. Examples: Rhizopus ,  Penicillium and Aspergillus . Parasitic – The fungi obtain their nutrition by living on other living organisms (plants or animals) and absorb nutrients from their host. Examples: Taphrina and Puccinia .

23. Symbiotic – These fungi live by having an interdependent relationship with other species in which both are mutually benefited. Examples: Lichens and mycorrhiza .  Lichens are the symbiotic association between algae and fungi. Here fungi provides shelter for algae and in reverse algae synthesis carbohydrates for fungi.  Mycorrhiza is the symbiotic association present between fungi and plants. Fungi improve nutrient uptake by plants, whereas, plants provides organic molecules like sugar to the fungus.

24. Classification based on reproduction Reproduction in fungi is both by sexual ( teleomorph ) and asexual ( anamorph ) means. Asexual reproduction – takes place by either: Spores- formed through mitosis ; are identical to the parent cell Fragmentation- fragments of the hyphae grow into colonies Budding- yeasts form buds via cytokinesis

25. Sexual reproduction Introduces genetic variation into a population of fungi. Homothalic / self fertile- is when both mating types are in the same mycelium Heterothalic - require two different but compatible mycelia Plasmogamy - two haploid cells fuse and both nucleus exist in one cell Karyogamy - the two nuclei fuse and form a diploid cell Meiosis- generates and disseminates spores

26. Based on the formation of spores: Zygomycetes – These are formed by the fusion of two different cells. The sexual spores are known as zygospores , while the asexual spores are known as sporangiospores .. Example – Mucor . Ascomycetes – They are also called sac fungi. They can be coprophilous, decomposers, parasitic or saprophytic. The sexual spores are called ascospores . Asexual reproduction occurs by conidiospores . Example – Saccharomyces. Basidiomycetes – Mushrooms are the most commonly found basidiomycetes and mostly live as parasites. Sexual reproduction occurs by basidiospores . Asexual reproduction occurs by conidia, budding or fragmentation. Example- Agaricus . Deuteromycetes – They are otherwise called imperfect fungi as they do not follow the regular reproduction cycle as the other fungi. They do not reproduce sexually. Asexual reproduction occurs by conidia. Example – Trichoderma .

27. Types of fungi Clinically important fungi may be classified into four main types: Yeast Mushrooms Molds Truffles

28. Uses of Fungi Fungi are one of the most important groups of organisms on the planet as they have great economic importance on account of both their benefits and harmful effects. Recycling  – They play a major role in recycling the dead and decayed matter. Food  – The mushrooms species Medicines  –are used to produce antibiotics and to control diseases in humans and animals. Penicillin derived from Penicillium . Biocontrol Agents  – Fungi are involved in exploiting insects, other small worms and help in controlling pests. Spores of fungi are used as a spray on crops. Food spoilage – Fungi play a major role in recycling organic material and are also responsible for major spoilage and economic losses of stored food.

29. Fungal infections Can be superficial or systemic Superficial infections Systemic / disseminated infections Dermatomycoses Candidiasis Tinea capitis affects the scalp Oral thrush cryptococcal meningitis Tinea cruris , the groin Vaginal thrush endocarditis Tinea pedis , the feet Skin infectio pulmonary aspergillosis Tinea corporis , the body rhinocerebral mucormycosis

30. Superficial: Outer skin layer - no immune response - caused mostly by yeasts ( Dandruff ) Cutenous : Epidermal layers - evoke immune response - Tinea ( Ringworm , Athlete’s foot , jock itch ) - caused by Dermatophytes Subcutenous : Chronic infection of subdermal tissues may require surgical intervention Systemic : Mostly originating in the lung - caused by virulent dimorphic fungi Opportunistic : In immunocompromised conditions (AIDS; altered mucosal flora due to antibiotics ) - mostly Candidiasis and Aspergillosis ( often cause of epidemic death in birds )

31. Signs and symptoms Rash Patches that ooze clear fluids Pimple like bumps Itching Peeling skin Burning Swelling Pain Whitish or yellow discharge Flaking skin

32. Dermatophytosis (cont….….) - Tinea capitis - Tinea corporis Dr. Glenn Bulmer, http ://www.medicalmycology.net .  

33. Dermatophytosis (cont……) - Tinea pedis (Athlete's Foot) - Tinea manuum Dr. Glenn Bulmer, http ://www.medicalmycology.net .  

34. Dermatophytosis (cont…..) - Tinea barbae - Tinea unguium

35. Dermatophytosis (cont…..) Infected animal (Horse) Infected animal (Sheep)

36. Spread generally from the environment to people ( or animals ) with limited person-to-person spread. - Skin and lungs are prominent entry site for many fungi . - Patients with impaired cell-mediated immunity ( e.g . AIDS, organ transplant ) at heightened risk for severe disease . - Incidence - increasing trend - Slow onset - Difficult to diagnose & eradicate - Long duration of therapy

37. Disease Transmission Disease Transmission By contact with infected persons or animals - By contact with contaminated materials ( Such as Clothes, combs, and others grooming tools )

38. Predisposing factors Healthy skin is natural barrier which prevents invasion by dermatophytes - Infection therefore requires disruption of this healthy barrier - Predisposing factors are : ● Age ● Immunosuppression (stress or treatment), ● Skin integrity or immune status ● Nutritional deficits ● High temperature and humidity ● Poor hygiene and overcrowding

39. Identification of fungi Two approaches: ● Direct microscopy ● Culture method

40. LECTURE 2

41. Antifungal drugs There are sic classes of drugs used to treat fungal infections : Polyene antifungals Imidazole antifungals Triazole antifungals Allylamines Echinocandins Others

42. Drug targets Membrane disrupting agents - AmphoB , Nystatin Ergosterol synthesis inhibitors- azoles, allylamines, morpholine Nucleic acid inhibitors- flucytosine Antimitotic (spindle disruption)- griseofulvin Glucan synthesis inhibitors- echinocandins Chitin synthesis inhibitors- nikkomycin Protein synthesis inhibitors- sordarins , azasordarins

43. Antifungal Agents Polyene antibiotics The polyene antibiotics bind with sterols in the fungal cell membrane, principally ergosterol . This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. Nystatin Amphotericin B Natamycin Rimocidin Filipin Pimaricin

44. Amphotericin B Polyene macrolide antibiotic . Drug of choice for the treatment of life-threatening , systemic mycoses . MOA It binds to ergosterol in the plasma membranes of sensitive fungal cell , form pores ( channels ). The pores disrupt membrane function , allowing electrolytes (K + ) and small molecules to leak from the cell , resulting in cell death . It produces free radicles that increase membrane permiability It also has stimulatory effect of phagocytic cells K + Amphotericin B Fungal cell

45. Amphotericin B PK P poorly absorbed when given orally Given in a slow IV infusion Highly p ro t ein bo u nd Can cross the BBB Has low affinity to colesterol which leads to weak cell membrane of the mammalian cell This effect occurs mostly on the renal epitelial cells hence the nephrotoxicity

46. Antifungal spectrum : Candida albicans , Histoplasma capsulatum , Cryptococcus neoformans , Coccidiodes immitis , Blastomyces dermatitidis , Strains of aspergillus, Protozoal infections (leishmaniasis).

47. Uses: Systemic fungal infections : Intestinal candidiasis, severe invasive candidiasis, invasive aspergillosis , criptococcal meningitis, disseminated cryptococcosis in HIV patients , severe hystoplasmosis , visceral leishmaniasis . ADR: Fever , chills , renal impairment , hypotension , anemia, neurologic problems ( intrathecal ), thromboflebitis . hypokalemia ( The liposomal preparation of Amphotericin B reduces the risk of nephrotoxicity ).

48. Monitor BUN, creatinine, urine output Potassium supplements Premeds antipyretics, antiemetics

49. Nystatin. The first antibiotic against fungi Its use is restricted to topical treatment of Candida infections (oral agent ) It is more toxic tan AmphoB

50. Azoles MOA The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. This enzyme is present in humans also The drug often inhibits cytochrome P450 hence the many drug-drug interactions of azoles including disruption gonadal and adrenal synthesis

51. Imidazoles : (local treatment of vaginal candidiasis, and for dermatophyte infections ) Miconazole Bifonazole Ketoconazole Butoconazole Clotrimazole Econazole Mebendazole Fenticonazole Isoconazole Oxiconazole Sertaconazole Sulconazole Thiabendazole Tiaconazole

52. Ketoconazole Azoles are predominantly fungistatic . Inhibit C-14  - demethylase (a cytochrome P450 enzyme ), thus blocking the conversion of lanosterol to ergosterol Ergosterol is the principal sterol of the fungal cell membranas This leads to weak membrane structure and function and thereby inhibits fungal cell growth . Lanosterol Ergosterol Inhibition of ergosterol synthesis Disrupts membrane function and Increases permeability. P450 Ketoconazole -

53. Ketoconazole Was the first azole that could be given orally It is less toxic than clotrimazole and miconazole P K It is well absorbed from the gastrointestinal tract It is distributed widely throughout the tissues and tissue fluids It does not reach therapeutic concentrations in the central nervous system unless in very high doses It is metabolized in the liver It is excreted in bile and in urine. Its half-life in the plasma is 8 hours Uses Histoplasma , Blastomyces , Candida , Coccidiosis .

54. Interactions Increase levels of cyclosporin, warfarin, phenytoin, Side effects: Decreased libido, gynecomastia, menstrual irregularities GI upset- Nausea, anorexia, diarrea Abnormal liver enzymes

55. Miconazole and other topical agents. Miconazole , clotrimazole , butoconazole and terconazole are topically active drugs . Severe toxicity parenterally . Antifungal spectrum and mechanism of action are the same of ketoconazole . Topical use is associated with contact dermatitis, vulvar irritation and edema. Miconazole is used for dermatophyes and toical candidiasis locally for oral infections .

56. Fl u conazole Drug of choice in Cryptococcus neoformans ( fungal meningitis), for candidemia and coccidioidomycosis , Administered orally or IV. Azole family , Mechanism of action = ketoconazole . It lacks of the endocrine side effects of ketoconazole . It has excellent penetrability into the CSF. It is employed prophylactically for reducing fungal infections ( bone marrow transplants ). what are he advantages of fluconazole over keoconazole ?

57. Voriconazole Is approved for the treatment of invasive aspergillosis ( lungs ) and serious infections caused by Scedosporium apiospermum ( lungs and brain ) and fusarium species ( onychomycosis ( nail ) & keratitis (cornea)). Is orally active and penetrate tissue very well including CNS. ADR: Visual disturbance .

58. Itraconazole (dermatophytes) Itraconazole has a broader spectrum of activity than Fluconazole ( but not as broad as Voriconazole or Posaconazole ). Drug of choice for the treatment of blastomycosis , aspergillosis , sporotrichosis , and histoplasmosis. Unlike ketoconazole , it is effective in AIDS- associated histoplasmosis. Is well absorbed orally but requires acid for dissolution . I s over 99% protein bound and has virtually no penetration into CSF. s over 99% protein bound and has virtually no penetration into Food increases its bioavailability .

59. Allylamines MOA Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis. Terbinafine Amorolfine Naftifine Butenafine

60. Terbinafine Drug of choice for treating dermatophytoses and especially onychomycoses . It is well tolerated , requires shorter duration of therapy and is more effective than either itraconazole or griseofulvin . Inhibits fungal squalene epoxidase , decreasing the synthesis of ergosterol, accumulation of toxic amounts of squalene result in the death of the fungal cell . Fungicidal

61. Terbinafine Antifungal spectrum: Dermatophytes and Candida albicans. Therapy is prolonged (3 months) Orally active. Has first-pass metabolism. It is deposited in the skin, nails, fat and breast milk. ADR: Diarrhea, nausea, headache, rash, taste and visual disturbances, elevations in serum liver enzyme levels.

62. Echinocandins MOA Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase. Caspofungin Micafungin

63. Caspofungin. Is the first approved member of the echinocandinds class of antifungal drugs. It interferes with the synthesis of the fungal cell wall by inhibiting the synthesis of B(1,3)-D-glucan, leading to lysis and cell death. This drug is limited to aspergillus and Candida species. It is a second-line antifungal for those who have failed or cannot tolerate amphotericin B or itraconazole. ADR: Nausea, fever, rash, flebitis. candidiasis

64. Others: Flucytosine is an antimetabolite. Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis; It is derived from the mold Penicillium griseofulvum . Fluocinonide

65. Flucytosine Is used in combination with amphotericin B to treat systemic mycoses and for meningitis caused by Cryptococcus neoformans or Candida albicans , and in combination with itraconazole for treating chromoblastomycosis .

66. Flucytosine. ADR: Reversible neutropenia, thrombocytopenia , bone marrow depression , enterocolitis, elevation of serum transaminases and alkaline phosphatase . Mechanism of action Flucytosine is converted to the antimetabolite 5-fluorouracil in fungal but not human cells. 5-Fluorouracil inhibits thymidylate synthetase and thus DNA synthesis . Resistant mutants may emerge rapidly, so this drug should not be used alone.

67. Griseofulvin. Largely replaced by terbinafine for the treatment of dermatophytic infections of the nails . Requires treatment of six to twelve months in duration . It is only fungistatic . Accumulates in newly synthesized keratin-containing tissue , where it causes disruption of the mitotic spindle and inhibition of fungal mitosis. Induces hepatic cytochrome P450 activity .

68. Antifungals Mechanism of actions- Summary

69. Antifungal drug resistance mechanisms Resistance to antifungals is rare but can occur due to: Increased efflux Alteration of target enzyme- prevent binding Known resistance: fluconazole

70. Must knows Differences between fungal cell and mammalian cell Fungal cell structure, its components Fungal cell enzymes and synthesis Antifungal drug classes and their examples MOA of drugs Side effects of antifungals Drug interactions

71. Reading assignment Draw the structure of a fungal cell wall and understand how the MOA of antifungal agents are derived.