Antifungal agents

Antifungal Agents

Antifungal Agents

Objective

At the end of this lecture, the student will be able to:

       Classify anti-fungal drugs

       Describe the pharmacology of

      Amphotericin B

      Griseofulvin

Antifungal Agents

       Fungal infections – Mycoses

       Fungi has rigid cell wall composed of Chitin (instead of peptidoglycan)

       Cell membrane which contain ergosterol (rather than cholesterol in mammalian  membrane)

Classes of Fungi

       Yeasts
     –   Produced by budding

      Cryptococcus neoformans (meningitis)

       Yeast– like fungi – grows like yeast & partly as filaments (hyphae)

      Candida albicans (oral/ vaginal thrush, systemic candidiasis)

      Pityrosporom orbiculare (Tinea vesicolor)

       Moulds  – filamentous spores

      Trichophyton species

      Microsporum species

      Epidermophyton species

      Causes infection in skin, nail and hair

       Dimorphic fungi

      Can grow in the form of yeast or filament

      Histoplasma capsulatum

      Blastomyces dermatidis

Classification of Antifungal Agents

Antibiotics

       Polyene antibiotics – Amphotericin B, Nystatin, Hamycin, Natamycin

       Heterocyclic benzofurans – Griseofulvin

Antimetabolites – 5- Flucytosine

Azoles

       Imidazole – Topical – Clotrimazole, Miconazole

       Systemic – Ketoconazole

       Triazoles – systemic – Fluconazole, Itraconazole

Allyl amines – Terbinafine

Miscellaneous (Topical) – Ciclopirox, Tolnaftate, Clioquinol , caspofungin

Mechanism of Action of Antifungal Agents

Mechanism of Action of Antifungal Agents

Amphotericin-B

Amphotericin-B- MOA

       High affinity for ergosterol in fungi

       Binds to ergosterol and forms pores in cell membrane

       Forms pores, fungicidal in nature

       Vital constituents- macromolecules, K+, Na+, Mg2+, H+ leak out

       Pore formation characteristic of the amphoteric nature

       Hydrophobic site complexes with ergosterol outside the pore

       Polar portion makes a lining around the pore

       Great specificity for fungal cells because human cells have cholesterol in the cell membrane, some binding which occurs leading to toxicity

Pharmacokinetics of Amphotericin-B

       Absorbed only in fungal stomach infection

       Not useful in systemic fungal infections by oral route, given by iv infusion

       Wide distribution, except CSF

       Intrathecal treatment of fungal infection in brain

       90% protein bound, t1/2– 15d

       Binds to cholesterol of cell membrane, LDL, sterols in tissues

       Metabolism  liver

       Excretion– biliary and urinary excretion, takes several days

Antifungal Spectrum and Uses of Amphotericin-B

       For Candida albicans infection (systemic & oropharyngeal)

       Mould infection in immuno-compromised patients

       Opportunistic fungal infection like Mucormycosis

       Histoplasmosis infection

       Coccidiodomycoses infection

       Blastomycoses

       Cryptococcal infection

Adverse Effects 

       Serious long term toxicity  – Nephrotoxicity- renal tubular necrosis, hypokalemia, hypomagnesemia secondary to renal 

       Hypochromic normocytic anaemia

       Intrathecal administration may lead to arachnoiditis and seizures

       Rarely hepatic toxicity and jaundice

       Acute adverse effects with infusion

      Fever, chills, difficulty in breathing

      Vomiting

      Moderate hypotension

Remedy – Paracetamol, antihistiminic and hydrocortisone

Griseofulvin

Griseofulvin MOA

Griseofulvin MOA

Pharmacokinetics of Griseofulvin

       Liver – dealkylation

       High affinity for keratin precursor cells, retained in skin, hair and nails

       Plasma half-life 24 h

Therapeutic uses of Griseofulvin

       Systemic treatment of dermatophytose caused by

      Microsporum

      Trichophyton

      Epidermophyton

       Nail infections

       Dose– 500-1000 mg/day in 2 divided doses orally

       Skin and hair infections treated for 2-4 weeks

       Toe nails may need more than a year 

Adverse Effects of Griseofulvin

       Headache, vomiting, nausea

       Photosensitivity, peripheral neuritis

       Hepatotoxicity in patients with porphyria

       CYT inducer – ↓effectiveness of warfarin & oral contraceptives

       Transient albuminuria & leucopenia

       Disulfiram like reaction with alcohol

Azoles

       Synthetic antifungal drug

       Broad spectrum fungistatic and fungicidal activity

       Imidazole group- 2 nitrogen in the azole ring

       Triazole group – 3 nitrogen in azole group

       Imidazole for systemic infections – Ketoconazole

       Other drugs for superficial fungal infection

       Clotrimazole

       Ketoconazole

       Fluconazole

       Itraconazole

       Voriconazole

       Posaconazole

Mechanism of Action of Azoles

Mechanism of Action of Azoles

Ketoconazole

       Metabolism: Ketoconazole inhibits CYP450 enzymes, especially CYP3A4, CYP2C9; CYP2C19

       Raises the blood levels of several drugs including: Phenytoin, Digoxin, Carbamazepine, Omeprazole, Diazepam, Cyclosporine, Haloperidol, Nifedipine and other DHPs Warfarin, HIV protease inhibitors & sulfonylureas, Statins, Cisapride, Terfenidine, Quinidine, Cyclosporine, Tacrolimus

Adverse Effect of Ketoconazole

       Nausea, vomiting, anorexia – minimised by taking drug with food

       Headache, paresthesia, rashes, hair loss

       Reversible elevation in hepatic enzymes

       Inhibits the formation of synthesis of testosterone & estradiol

       Gynacomastia & menstrual irregularities

Uses of Ketoconazole

       For dermatophytes infection – drug accumulates in stratum corneum

       For silent coccididiomycosis

       Oropharyngeal candisiasis in AIDS patients

Summary

       Antifungal agents are classified into antibiotics, azoles, allylamines, antimetabolites and topical agents

       Amphotericin-B is a polyene antibiotic that has affinity to ergosterol of fungal cell membrane

       Amphotericin-B shows fungistatic action

       Griseofulvin is a heterocyclic benzofuran that prevents the movement of daughter chromosomes

       Used in the treatment of dermatophytose and nail infections

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Antifungal Agents: FAQs

How do Antifungal Agents work?

Antifungal Agents work by targeting specific components within fungal cells, disrupting their normal functioning. This targeted approach ensures effective treatment with minimal impact on host cells.

Are there any side effects associated with Antifungal Agents?

While generally safe, Antifungal Agents may cause mild side effects such as nausea or skin irritation. Severe reactions are rare but consult a healthcare professional if any concerns arise.

Can Antifungal Agents be used for preventive purposes?

In certain cases, especially for individuals prone to recurrent fungal infections, prophylactic use of Antifungal Agents may be considered. However, this should be done under medical supervision.

How long does it take for Antifungal Agents to show results?

The timeline for results varies depending on the type of infection and the chosen medication. Improvement is often noticeable within a few days, but complete resolution may take weeks.

Can Antifungal Agents be used during pregnancy?

Pregnant individuals should consult their healthcare provider before using Antifungal Agents, as safety considerations may vary depending on the specific medication and trimester.

Are there any natural alternatives to Antifungal Agents?

While some natural remedies may offer relief for mild fungal infections, they may not be as potent as Antifungal Agents for severe cases. Consultation with a healthcare professional is recommended.

Also, Visit:

B. Pharma Notes | B. Pharma Notes | Study material Bachelor of Pharmacy pdf

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