Amphotericin B

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Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Amphotericin B.jpg

[edit] MECHANISM OF ACTION

Amphotericin B is an agent capable of binding ergosterol. By so doing, it forms pores in the membrane that allows the exit of essential ions and elements required for the fungus. This also results in an oxidative damage that participates to the fungicidal action of Amphotericin B.

Resistance to Amp B is due to modification of the amount of ergosterol present in the cell membrane and replacements of ergosterol with different sterols that can no longer bind Amphotericin B.

Amphotericin B is an amphoteric molecule that is soluble only at extreme levels of pH. It is insoluble in water. Thus, its more common preparation is the colloidal suspension called C-AMB. C-AMB is used by IV administration. In this C-AMB, amphotericin is combined with deoxycholate.

Amphotericin B is very toxic to the kidney, therefore, a number of formulations have been designed in order to improve the fungal penetration and reduce systemic toxicity. These lipid formulations include: Abelcet ABLL (Ribbon-like particles), Amphotec ABCD (Disk-like particles)and Ambisome L-AMB.

The Ambisome is a formulation of Amphotericin B in liposome. It is the most expensive of the formulations.

The Amphotericin B liposomal formulation shows an increased ability to bind the fungus. They are rapidly phagocytised within the endothelial reticular system, liver, spleen and lungs (where fungi are generally concentrated). This property reduces toxicity especially in the kidney compared to the highly nephrotoxic non-liposomal formulation.

[edit] INDICATIONS

  • Serious mycotic systemic infection.
  • Cryptococcal meningitis, when administered intrathecally.
  • Histoplasmosis, blastomycosis, coccidioidomycosis, candidiasis.
  • Invasive Aspergillus is less responsive to Amp B; used for the initial treatment and then continued with oral azoles.
  • In cancer patients with neutropenia that doesn’t respond to antibiotic therapy. A patient that does not respond to antibiotic therapy after 3 days is suspected to have fungal infection.
  • Can be used locally in the joints to treat fungal arthritis.
  • Bladder cystitis caused by Candida in patients with catheters.

[edit] DOSAGE

[edit] CONTRAINDICATIONS

[edit] PRECAUTIONS

[edit] INTERACTIONS

[edit] PHARMACOKINETICS

  • Amphotericin B has a low bioavailability; it cannot be used by oral administration to treat a systemic infection
  • Amphotericin B can’t cross BBB; when used to treat meningitis, it is given intrathecally
  • Amphotericin B highly bound to plasma proteins (approx. 90%)
  • Amphotericin B has a long half-life (approx. 15 days)
  • Amphotericin B is eliminated through the bile and urine
  • Amphotericin B cannot be administered orally; can only be given intrathecally, IV or topically.

[edit] PREGNANCY AND LACTATION

[edit] SIDE EFFECTS

Toxicity: The side effects of Amphotericin B are of two types:

  • Quick onset: The quick onset is characterized by a flu-like syndrome with chills and fever. This is due to the release of cytokines (IL-1 and TNF) by monocytes and macrophages, thus: nausea, vomiting, hypotension and headache. The treatment with Amp B therefore, frequently requires premedication with antipyretic agents (like Paracetamol). Also, a premedication with hydrocortisone can reduce this infusion-related reaction.
  • Slow onset: The slow onset toxicity is the nephrotoxicity that is observed in 80% of patients. It is characterised by a reduction in the filtration rate that is often associated with hypokalemia and hypomagnesaemia. Since the kidney is the site of erythropoietin synthesis, these patients usually manifest hypochromic anaemia (due to reduced production of erythropoietin). This anaemia shouldn’t be confused with myelotoxicity.

[edit] RELATED LINKS

[edit] BIBLIOGRAPHY

[edit] REFERENCES

Antifungals
Ergosterol target : Cell membrane target Azoles (lanosterol 14 alpha-demethylase inhibitors) : Ergosterol inhibitors Imidazoles Topical: Bifonazole   Clotrimazole   Econazole   Fenticonazole   Ketoconazole   Isoconazole   Miconazole   Sertaconazole   Tioconazole
Triazoles Topical: Fluconazole   Terconazole
Systemic: Fluconazole   Itraconazole   Posaconazole   Voriconazole
Polyene antimycotics (ergosterol binding; they form pores in the membrane) Topical: Nystatin
Systemic: Amphotericin B
Allylamines (squalene epoxidase inhibitors) : Ergosterol inhibitors Topical: Amorolfine   Naftifine   Terbinafine
Systemic: Terbinafine
Echinocandins (β-glucan synthase inhibitors) : Cell wall target Anidulafungin   Caspofungin   Micafungin
Pyrimidine analogues / Thymidylate synthase inhibitors : Nucleic acid inhibitors Flucytosine
Mitotic inhibitors Griseofulvin
Others Ciclopirox