Antifungal Chemotherapy PDF

POD-2 Module Antifungal Drugs (Antimicrobial Chemotherapy) Pre- LBL Questions • What does mycosis mean? • Mention the main types of fungi of medical importance • What is the difference between human & fungi cells? • How does Azoles act? • What are the main side effects of antifungal agents • Doe...

POD-2 Module Antifungal Drugs (Antimicrobial Chemotherapy) Pre- LBL Questions • What does mycosis mean? • Mention the main types of fungi of medical importance • What is the difference between human & fungi cells? • How does Azoles act? • What are the main side effects of antifungal agents • Does Amphoterocin-B can be given orally? • How anti-metabolite act as antifungal agent? • What is the difference between imidazoles & Triazoles? 2 Lecture objectives By the end of the lecture, you should be able to: • Identify the fungi of medical importance and their relevant Mycosis infections to determine the drug targets. • Discuss the various Anti-fungal drugs classes with their main pharmacological features. 3 Lecture contents • • A. Introduction: • Mycosis infections. • Classification of fungi of medical importance & their relevant disorders. B. Anti-fungal agents Pharmacology: • Anti-fungal general info. • 1- Antibiotics • 2-Anti-metabolites • 3-Azoles • 4- Allylamines • C. References • Basic & Clinical Pharmacology (Katzung). 4 Introduction • Fungal infections (Mycoses): • It may be superficial (foot) or systemic (in immunocompromised patients such as; (AIDS, corticosteroids, anticancer and immunosuppressive drugs). • Are often life-threatening and require intensive therapy. • Pathogenic fungi do not produce toxins, but in the host, they often produce hypersensitivity reactions. • In systemic mycoses the typical tissue reaction is chronic granuloma formation with varying degrees of necrosis and abscess formation. • Invasive mycoses in immunocompromised patients have a high mortality rate (30–60% in C. albicans’ infections). 5 Classification of fungi of medical importance Group Superficial Systemic mycosis Yeast Oral and vaginal thrush, Meningitis candidaemia, empyema Rare systemic infection. Yeast-like - - Dimorphic fungi Deep subcutaneous infection following trauma Deep systemic organ involvement Moulds Neutropenic patients diabetic ketoacidosis, keratitis Invasive pulmonary or central nervous system, Deep infection (transplant patients) Dermatophytes Various skin (ringworm), hair and nail infections Dematiaceous Deep tissue infection with granulomas Chromomycosis, mycetomas 6 Fungal infections 7 8 1 0 11 • Clinical uses • Oral, skin and vaginal candidiasis (polyenes, azoles). • Dermatophyte infections (terbinafine, griseofulvin). • Histoplasmosis (azoles, polyenes). • Aspergillosis infections (polyenes, azoles). • Cryptococcal meningitis (polyenes, azoles). • SE: • Anorexia and GI disturbance • Muscle and joint pain • Rash and pruritus • Headache • Hepatotoxicity (azole antifungals), why? 12 • Drug interactions • Itraconazole can precipitate heart failure if given in high doses and for long periods to elderly patients or individuals with IHD/prescribed negative inotropes (e.g. CCBs). • Amphotericin can result in renal impairment when administered with other nephrotoxic drugs. • The dose of terbinafine may need to be adjusted with co-administration of drugs metabolized via Cytochrome P450. 13 1-Antibiotics (Amphotericin-B, Nystatin & Griseofulvin) • A- Amphotericin-B: Is the first-line drug in severe and potentially fatal systemic mycoses for many years. • Effective, but highly toxic drug. • MOA: Amphotericin is a polyene antibiotic that binds to ergosterol (E) in the fungal cell membrane and forms channels through which essential fungal cell constituents (e.g. Potassium) are lost. • The drug has a relatively selective action on fungal cells because, in human cells, the major sterol is cholesterol rather than ergosterol. • Amphotericin is not absorbed orally and is given by intravenous infusion to treat systemic fungal infections. • Lipid formulations are much less toxic and allow higher doses to be administered. 1 4 • B-Nystatin: has a similar structure to amphotericin. • Not absorbed from mucous membranes and its use is limited to C. albicans infections of the skin and mucous membranes. • C-Griseofulvin: Fungistatic • MOA: Binds to tubulin and interferes with microtubule formation, (Mitosis +cell wall synthesis). • Used for some dermatophyte infections, particularly scalp ringworm. • It is rarely used now, having been replaced by more effective drugs. 1 5 2-Antimetabolite (Flucytosine) • Flucytosine: is much less toxic than amphotericin • Its use is limited because it has a narrow spectrum and resistance can develop rapidly during therapy. • MOA: Converted in fungal cells, but not in human cells, into fluorouracil that inhibits fungal DNA synthesis. • Used with amphotericin to produce a synergistic action. 1 6 3-Azoles (Imidazoles & Triazoles) • A- Imidazoles: are broad-spectrum antifungal drugs that are widely used topically and systemically. • MOA: They inhibit cytochrome lanosterol-αdemethylase, an enzyme that converts lanosterol to ergosterol. • This causes lanosterol to accumulate and leads to perturbation of the fungal cell membrane and fungistasis. • B-Triazoles: are structurally like the imidazoles with a wider range of antifungal activity. • They have a lower incidence of adverse effects, because they are much more specific inhibitors of lanosterol –α-demethylase. 1 7 4-Allaylamines (Terbinafine) • Terbinafine: Inhibits squalene epoxide and leads to toxic levels of squalene accumulating in the fungal cells. • Used for confirmed dermatophyte infections of the nails or skin. • SE: Peeling or itching skin , Muscle or joint pain, Losing your sense of taste & Malaize • SSE: Inflammation of the blood vessels (vasculitis), inflamed pancreas (acute pancreatitis). • Side effects usually go away when you stop using the medicine. 1 8 Important Mnemonics to Remember Pharmacology (Funny & Easy) Amphotericin –B SE 1 9 ‫&&&&&&&&&‬ ‫■ كتبت‪ ،‬ومامن كاتب االسيفنى **ويبقى الدهر ماكتبت يـداه‬ ‫■ فـالتـكتب بيـدك غـير شــــئ ** يسرك فى القيــامة ان تراه‬ ‫‪■$$$‬‬ ‫‪■Al-Baha, 18. 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