Amphotericin-B

August 10, 2020 Rima Pharmacology 0

  • Amphotericin B is an anti-fungal agent used for treating several types of leishmaniasis (parasitic infection) and fungal infections like histoplasmosis and cryptococcosis.
  • It is naturally occurring polyene antibiotic obtained from Streptomyces nodosus which is available as yellowish powder relatively insoluble in water. It is amphiphilic in nature hence the name is amphotericin B. Its amphoteric behavior is because of carboxyl group on the main ring and a primary amino group on mycosamine.
  • Amphotericin B was introduced into medical use in 1958. It is available both as brand and generic medicine. It is included in World Health Organization’s List of Essential Medicines.

Indications of Amphotericin-B

  • Used to treat wide variety of serious, life-threatening fungal infections including:
    • Aspergillus
    • Blastomycosis
    • Candida infections
    • Cryptococcal meningitis
    • Coccidioidomycosis
    • Ocular fungal infections
    • Systemic fungal infections
    • Histoplasmosis
    • Sporotrichosis
  • Also used to treat leishmaniasis.

Mechanism of action of Amphotericin-B

Figure 1- Mechanism of action of amphotericin B by forming pores (Source- Lippincott’s Illustrated reviews)

  • It binds to ergosterol in plasma membrane of sensitive fungal cells and forms pores (channels) in the membrane. These pores disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, causing cell death.
  • It also causes oxidative damage to fungi cells.

Anti-fungal activity of Amphotericin-B

  • It possesses broad spectrum anti-fungal activity. It is either fungicidal or fungistatic depending on the organism and concentration of the drug.
  • Inhibits the growth of H. capsulatum, Cryptococcus neoformans, Blastomycosis dermatitidis, Coccidioides immitis and Sporothrix schenkii and many strains of Aspergillus. Candida responds to a slightly higher concentration.
  • It is also active against Leishmania spp.

Resistance

  • Candida may develop resistance to this antibiotic in vivo.Fungal resistance is infrequent and is associated with decreased ergosterol content of fungal cell membrane.

Pharmacokinetics

  • It is administered by slow IV infusion. GI and topical absorption of Amphotericin B is negligible. The IM administration is painful.
  • It is insoluble in water, so several formulations are devised to improve its intravenous bioavailability. The conventional amphotericin uses sodium deoxycholate to improve solubility.
  • Liposomes prepared by co-formulating amphotericin B with artificial lipids have the advantage of reduced renal and infusion toxicity compared to conventional one. However, due to high cost, liposomal preparations are only used in patients who cannot tolerate conventional Amphotericin B.
  • It is extensively bound to plasma proteins and is distributed throughout the body. Its concentration in the CSF, vitreous humor and amniotic fluid is less. It can cross the placenta.
  • It is concentrated in liver, spleen, kidney and lungs and remain in the body for several weeks. Its metabolic fate is unknown. Low level of the drug and its metabolites appear in the urine and some are also eliminated via bile.
  • Dose adjustment is not required in patients with hepatic dysfunction. In patients with renal dysfunction, dose of conventional amphotericin B is reduced by 50 %.

Adverse Effects

  • It has a low therapeutic index.
  • The major acute reaction due to IV infusion includes fever, chills, phlebitis at the site of injection, nausea, anorexia and vomiting. It can also cause headache, diplopia, convulsions, myalgia and peripheral neuritis.
  • It is nephrotoxic and can cause impairment of renal function, hypokalemia, appearance of urinary cast and microscopic hematuria (rarely). Renal function usually returns with discontinuation of drugs.
  • A shock-like fall in BP may occur accompanied by hypokalemia. So, potassium supplementation may be required.

Drug Interactions

  • Concurrent administration with nephrotoxic drugs exacerbates azotemia. These drugs include aminoglycosides, cyclosporine, vancomycin and pentamidine.
  • Concurrent administration with drugs like diuretics, cisplatin and corticosteroids increase risk of hypokalemia.
  • Hematological side effects are increased when taken with some HIV medicines like tenofovir and adefovir.

Contraindications

  • Contraindicated in patients with known hypersensitivity to Amphotericin B.
  • It belongs to pregnancy category B drugs meaning there is no risk in other studies.

 

References

  1. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013; 73(9): 919-34.
  2. Laborin RL, Vargas MNC. Amphotericin B: side effects and toxicity. Revista Iberoamericana de Micología. 2009; 26 (4): 223-227.
  3. Saravolatz LD, Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: Time for a New “Gold Standard”. Clinical Infectious Diseases. 2003; 37(3): 415–425.
  4. Fanos, L. Cataldi. Amphotericin B-Induced Nephrotoxicity: A Review. Journal of Chemotherapy. 2000; 12(6): 463-470.
  5. https://pharmafactz.com/amphotericin-b-pharmacology/
  6. Pharmacology and Pharmacotherapeutics book. 24th edition.
  7. Goodman and Gillman’s Manual of Pharmacology and Therapeutics.
  8. Lippincott Illustrated Reviews Pharmacology. 6th edition.