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Antifungals drugs classification,mechanism of action uses and adverse effects
Antifungal drugs are used to treat fungal infections by preventing fungal growth and reproduction. The document discusses several classes of antifungal drugs including polyenes like amphotericin B and nystatin, azoles like ketoconazole and fluconazole, and others. It describes the mechanisms of action, spectra of activity, clinical uses, and side effects of some common antifungal drugs used in veterinary medicine to treat superficial and systemic fungal infections.
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Introduces antifungal drugs and their function. Highlights challenges of treating fungal infections due to cell similarities.
Describes eukaryotic fungi, their structure, reproduction, and pathogenic forms affecting humans and animals.
Categorizes fungal infections (mycoses) into superficial and systemic, emphasizing severity and complications.
Details introduction and categories of antifungal medications, including historical context and classification.
Focuses on Amphotericin B, its origin, action mechanism, spectrum, and resistance details.
Details Nystatin's antifungal properties, uses for skin and GI infections, and combination therapies.
Discusses Griseofulvin's origin, mechanism of action, spectrum, and clinical uses in dermatophyte infections.
Explains Flucytosine's mechanism as an antifungal agent, its effect on RNA and DNA synthesis.
Introduces Imidazoles, detailing their action on fungal cell membranes and ergosterol synthesis inhibition.
Covers Ketoconazole’s antifungal spectrum, clinical uses, and efficacy against various fungal species.
Describes Fluconazole’s mechanism, efficacy against specific fungi, and uses in systemic and superficial infections.
Outlines other antifungal treatments like sodium/potassium iodide, benzoic acid, and their uses.
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Antifungals drugs classification,mechanism of action uses and adverse effects
- 1.
- 4. • Antifungal (Antimycotic)drugs are agents which are used to prevent growth and multiplication of fungi. • Unlike bacteria, the pathogenic fungi those affect animals are eukaryotes possessing nuclei, mitochondria and cell membranes containing sterols. • The similarities between fungal and mammalian cells therefore, work against the selective toxicity and the fungal infections are generally resistant to antibiotics used in the treatment of bacterial diseases.
- 5. • In general,fungal infections are more difficult to treat, are slowly eradicated, and the antifungal drugs are more toxic to host than antibacterial drugs.
- 6. Fungi • Fungi area large group of eukaryotic organisms which include microorganisms such as yeasts and moulds, as well as the mushrooms.
- 7. • The fungalcell is surrounded by a rigid cell wall containing chitin and polysaccharides and a cell membrane containing a lipid bilayer composed mainly of ergosterol. • The cell wall provides structural support to the fungal cell. • Fungi generally reproduce asexually via budding, sporulation or hyphal fragmentation.
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- 12. • The pathogenicfungi, which cause diseases in humans and animals generally consist of two main groups of organisms- moulds and yeasts. • The moulds exist in multicellular filamentous forms (hyphal form) whereas yeasts have unicellular oval are spherical appearance. Many other fungi produce biologically active compounds, several of which are toxic to animals or plants. • Fig. 66.1 page 1011
- 13. Types of fungalinfection • Fungal infections, usually called mycoses, have been divided into two distinct classes: • superficial and systemic.
- 14. 1.Superficial fungal infection •The superficial fungal infections generally affect the keratinised layers of skin and its appendages (hair, feathers, horns and nails ) or mucous membranes (buccal, gastrointestinal ,ruminal or vaginal). • The superficial fungal infections are generally irritating with manifestations of alopecia, erythema, scale formation, exudation, etc. The lesions are frequently ring shaped hence the disease is commonly called ringworm.
- 16. 2.Systemic fungal infections •The systemic fungal infections (systemic mycoses) affect deeper tissues and organs. • Depending on the types of causative agent, the fungal diseases have been named as histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioiodomycosis, candidiasis, cryptococcosis, aspergillosis, etc. • Some fungi affect dermis and subcutaneous tissues and are generally called subcutaneous mycoses.
- 17. • The systemicfungal diseases are often serious and life- threatening and are generally difficult to treat. • Immuno–suppression, prolonged use of broad-spectrum antibacterial or cytotoxic drugs, moist environment and necrotic tissue predispose the patient to fungal infection.
- 18. Anti-fungal drugs: • Dependingon the requirement , initially two important antibiotics-amphotericin B and griseofulvin were introduced around 1960 for systemic mycoses and dermatophytosis, respectively. • This was followed by flucytosine and imidazoles in 1970s and triazoles in 1980s • Some newer compounds such as terbinafine have been introduced recently.
- 19. Selection and useof antifungal drugs: • The therapeutic use of antifungal agents should be initiated only after clear identification of the organisms because some infections are of mixed type where a suitable antibacterial agent must accompany antifungal agent.
- 20. Classification: • I. Antifungalantibiotics • 1. Polyenes: amphotericin B, nystatin • 2. Heterocyclic benzofurans: griseofulvin • II. Antimetabolites: flucytosine
- 21. • III. Azoles: •1. Imidazoles: ketoconazole, miconazole • 2. Triazoles: fluconazole , itraconazole • IV. Alkylamines: terbinafine, butenafine
- 22. • V. Echinocandins: caspofungin, micafungin • VI. Iodides: sodium iodides, potassium iodide • VII. Miscellaneous agents: • 1. Organic acids: benzoic acid, salicylic acid
- 23. • 2. Fattyacids and salts: propionates and undecylenate • 3. Dyes: gentian violate • 4. Phenols and phenolic ether: phenol, thymol • 5. Hydroxyquinolines: clioquinol
- 24. • 6. Thiocarbamate:tolnaftate • 7. Sulphur and Sulphur preparations: sulfur and sulfiram • 8. Copper preparations: copper sulfate • 9. Other antifungal agents: selenium sulphide, dichlorophen, sodium thiosulphate, nitrofuroxine
- 25. AMPHOTERICIN B: • Amphotericin(AMB) is an amphoteric polyene antibiotic obtained from Streptomyces nodusus. • Two amphotericins, Amphotericin A and Amphotericin B are known, but only B is used clinically because it is significantly more active in-vivo. • Amphotericin A is almost identical to Amphotericin B, but has little antifungal activity. Amphotericin B is often used intravenously for systemic fungal infections.
- 26. Mechanism of action: •The amphotericin B and other polyene antibiotics have high affinity for sterols, particularly ergosterol, present in fungal cell membranes. • The interaction of AMB and other polyene antibiotics with membrane ergosterol results in formation of channels or pores in the cell membrane with altered membrane permeability and leakage of cellular contents.
- 27. • The alteredK+/H+ exchange results in the efflux of potassium and influx of hydrogen ions, producing a state of acidosis that halts some important enzymatic processes. • Loss of important organic molecules such as amino acids and sugars from the fungal cells results in irreversible damage.
- 28. • High concentrationof amphotericin B directly disrupts the fungal cell membrane permeability. • Amphotericin B, like some other antifungal agents, also has some immunomodulatory action by potentiating both humoral and cell-mediated immunity. This enhances the host’s ability to fight fungal infection.
- 29. • Amphotericin Bis a fungistatic at normal dosages, but it can become fungicidal at higher concentrations.
- 30. Antimicrobial spectrum: • AmphotericinB and other polyene antibiotics have broad –spectrum antifungal activity, although the sensitivity of various species and strains of fungi to these antibiotics vary widely. • Amphotericin B is useful against several systemic fungi including Candida, Histoplasma, Cryptococcus, Blastomyces, Coccidiodies, Aspergillus etc. • It has a greater activity against Candida and Aspergillus spp. and Coccidiodal meningitis.
- 31. • Fungal resistance: •Ressistance to Amphotericin B is infrequent and is rarely noted during therapy. • Side effects/Adverse effects: • Amphotericin B is a toxic drug with side effects/adverse effects especially renal function impairment, occurring in many patients. • The nephrotoxicity generally occurs via two mechanisms- intense renal vasoconstriction and binding of drug to membrane cholesterol in the renal tubular cell membrane.
- 32. NYSTATIN • Nystatin isa polyene antifungal antibiotic produced by Streptomyces noursei. • It is structurally similar to Ampohotericin B and has the same mechanism of action. • Nystatin has activity against a variety of fungi, but its use is restricted to fungal infections of the skin and GI tract mainly caused by Candida spp. • It is not absorbed from skin or GI tracts, so its topical application or GI administration is safe.
- 33. • Nystatin isprimarily used for skin, mouth, intestinal or vaginal candidiasis in dogs, cats and birds. • The lesion of thrush (oral candidiasis) and vaginitis usually respond well to nystatin. • Combination of nystatin with antibacterial agents and corticosteroids are also available to enhance efficacy and to reduce Candida superinfection.
- 35. Griseofulvin: • Griseofulvin isa systemic antifungal antibiotic obtained from Pencillium griseofulvin. • Although it was isolated in 1939, its antifungal activity was demonstrated only around 1960.
- 36. Mechanism of action: •Griseofulvin is a fungistatic drug that enters into the susceptible fungi through energy-dependent transport system. • It then acts by interfering with the polymerization of the microtubular protein with microtubules. • Interaction with the microtubules interferes with the spindle formation in dividing cells thereby arresting the metaphase of cell division.
- 37. • Impairment ofmicrotubule function may also interfere with the transport of essential material through cytoplasm to periphery, which accounts for inhibition of hyphal cell wall synthesis. • Griseofulvin also probably binds to RNA and inhibits nucleic acid synthesis. • It also binds to keratin precursor cells and makes them resistant to fungal infections.
- 38. Antimicrobial spectrum: • Griseofulvinis a narrow-spectrum antifungal agent active only against dermatophytes i.e.: Microsporum, Trichophyton and Epidermophyton. • Griseofulvin is unique among antifungal antibiotics which on oral administration accumulates into keratin (proteins) and produces action against superficial fungi.
- 39. • It isineffective against deep mycoses, Candida species and bacteria. • Griseofulvin is a fungistatic against older and dormant fungi, but may kill (fungicidal) growing young cell.
- 40. Clinical uses • Griseofulvinis primarily recommended for treatment of dermatophytic fungal infections of skin, hair and claws in dogs, cats, calves, horses and some other species. • It is available for oral use as either a microsize or ultramicrosize tablet.
- 41. Antimetabolites • Flucytosine • Flucytosineis a fluorinated pyrimidine antifungal agent. • It was originally synthesized as an antineoplastic drug, but later on it was found to have good antifungal activity.
- 42. Mechanism of action: •Flucytosine, an analogue of cytosine, is inactive as such and requires conversion into active metabolite inside the fungal cells. • On administration, flucytosine enters fungal cell via a cytosine specific permease, an enzyme not found in mammalian cells. • Inside the fungal cell, it is rapidly converted into 5-flurouracil by cytosine deaminase enzyme.
- 43. • The 5-flurouracilact as an anti-metabolite by competing with uracil. • It initially forms 5-flurouracil monophosphate and then 5-flurouracil triphosphate, which interferes with pyrimidine metabolism and eventually RNA and protein synthesis.
- 44. • The 5-flurouracilmonophosphate by an alternate pathway is also metabolized to 5- Flurourodeoxyuracil monophosphate, an inhibitor of thymidylate synthetase. • Inhibition of thymidylate synthetase deprives the organisms of thymidylic acid, an essential DNA component, which eventually disrupts DNA synthesis and cell division.
- 45. • The combinationof flucytosine and amphotericin B is synergistic because amphotericin affects fungal cell permeability, allowing more of flucytosine to penetrate the cell
- 46. Imidazoles • Imidazoles area group of organic compounds in which the aromatic heterocyclic is a diazole. • The imidazoles include a large number of predominantly synthetic drugs. • They are active against many microoraganisms and parasites including fungi, bacteria, helminths and protozoa.
- 47. Mechanism of action: •The imidazoles and triazoles act on the fungal cell membrane and alter the membrane permeability of susceptible fungi by inhibition of ergosterol synthesis. • They inhibit 14 alpha- demethylase, a fungal microsomal cytochrome 450 dependent enzyme. • This enzyme normally participates in the sterol biosynthesis pathway and catalyses demethylation lanosterol to ergosterol, the major cell membrane component.
- 48. • The reducedsynthesis of ergosterol content in the cell membrane in response to azole antifungals in turn decreases the fluidity of membrane and increases the permeability with effects similar to amphotericin B. • Inhibition of ergosterol synthesis also results in accumulation of 14 alpha-methyl sterol, which impairs membrane functions leading to alterations in energy metabolism and growth inhibition. High concentrations of azole derivatives also inhibit fatty acid and glyceride synthesis.
- 49. Ketoconazole: • Ketoconazole issynthetic imidazole antifungal drug for systemic use. • It was the first azole that could be given orally to treat systemic fungal infection and is still considered the prototype drug.
- 50. Antimicrobial spectrum: • Ketoconazolehas a broad spectrum of antifungal activity which include Candida, Cryptococcus, Coccidioides, Blastomyces and Hisptoplama spp. • It is also effective against Candida and dermatophytes like Microsporum and Trichophyton. • High concentrations of ketoconazole are required to treat most strains of Aspergillus and Sporothrix.
- 51. • It alsopossess in vitro activity against some bacteria (e.g. Staph. aureus, Nocardia and enterococci) and viruses (Herpes simplex virus 1 and 2), but clinical implications of this have not been determined. • It has no anti parasitic activity, with possible exception of antiprotozoal effects against Leishmania major.
- 52. Clinical uses: • Ketoconazolehas been used to treat systemic mycoses in dogs, cats, horses, birds and some other species. • It is also used to treat superficial infections those have not responded to griseofulvin or topical antifungal therapy.
- 53. Fluconazole: • Fluconazole isa synthetic triazole antifungal drug commonly used in the treatment and prevention of superficial and systemic fungal infections.
- 54. Mechanism of action: •Similar to imidazoles, fluconazole inhibits the fungal cytochrome P450 enzyme 14 alpha- demethylase that converts lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane. • Mammalian demethylases activity is much less sensitive to fluconazole than fungal demethylase.
- 55. Antimicrobial spectrum: • Fluconazolehas fungistatic action against a wide range of pathogenic fungi. • It is effective against local and systemic Candida spp. and systemic Cryptococcus, Hisptoplasma, Sporothrix and Blastomyces spp. • It is also effective against dermatophytes. • In general, it appears to have a wider range of antifungal activity than ketoconazole.
- 56. Clinical uses: • Fluconazoleis a drug indicated for the treatment and prophylaxis of fungal infection where other antifungals have failed or are not tolerated. • It is used against dermatophytes, yeast and a variety of systemic fungi. • These include treatment of systemic mycoses including cryptococal meningitis and treatment of superficial candidiasis and dermatophytes.
- 57. • It isalso used for the prophylaxis of candidiasis in immunocompromised individuals. • It is mostly used by oral administration. • Intravenous route may be used for severe infections.
- 58. Sodium iodide • Sodiumiodide is occasionally used in the treatment of fungal infections. • The mechanism of antifungal infection of iodides is not well understood. • After oral administration, sodium iodide is rapidly and completely absorbed from the GI tract and freely distributed into extracellular fluid and glandular secretions. • It accumulates in the thyroid gland and to lesser extent in salivary, lachrymal and tracheobronchial glands.
- 59. Potassium iodide • Potassiumiodide possesses antifungal actions similar to those of sodium iodide. However, it is less commonly used than the sodium iodide. • Similar to sodium iodide, it is used as a 20% solution for oral or IV administration.
- 60. Benzoic acid: • Benzoicacid has both bacteriostatic and fungistatic actions. • For funagal infections, it is mostly combined with salicyclic acid to make Whitfield ointment. It is considered useful against superficial dermatophyte infections, particularly Trichophyton infection, in cattle and man. • Benzoic acid and its salts are used as a food preservative and inhibit the growth of mould, yeast and some bacteria.
- 61. Propionic acid: • Propionicacid is a naturally occurring carboxylic acid. It inhibits the growth of mould and some bacteria at levels between 0.1-1% weight. • Propionate salts (sodium and calcium propionate) are used as mould inhibitors and preservatives for both animal feed and food for human consumption and as a topical antifungal agent. • Sodium propionate is useful in the treatment of dermatophytosis in concentration of 1%-5%.
- 62. Gentian violet • Gentianviolet (crystal violet) is a dye. • The dye is used as a histological stain and in Gram’s Method of classifying bacteria. • It has antibacterial, antifungal and anthelminthic properties and is occasionally used as a topical antiseptic.
- 63. Sulphur • Sulphur isa multi-valent non–metal with multiple uses including as a drug. • Sulphur is externally used as an ointment, powder or lotion for various skin diseases such as ringworm and eczema. • It is also used externally as parasiticide, insecticide and disinfectant.
- 64. Copper sulphate: • Coppersulphate, also known as cupric sulphate, is the chemical compound. • Copper sulphate applied topically is considered useful against ringworm infection. • The fungicidal action is produced partly by the virtue of its astringent and caustic nature and partly by the antifungal action of copper ion. • It is used as ointment or paste in strengths of up to 5% or as aqueous solutions of 1-2%.