Amphotericin B

Water

Lipid

Lipid

Phospholipid

r

Cholesterol

V

C

0

O

N

0

H

FIGURE 11-10

Proposed partial model for the amphotericin B (AmB)-induced pore in the cell membrane. AmB is an amphipathic molecule: its structure enhances the drug's binding to sterols in the cell membranes and induces formation of aqueous pores that result in weakening of barrier function and loss of protons and cations from the cell. The drug acts as a counterfeit phospholipid, with the C15 hydroxyl, Cjg carboxyl, and Cjg mycosamine groups situated at the membrane-water interface, and the Cj to C14 and C20 to C33 chains aligned in parallel within the membrane. The heptaene chain seeks a hydrophobic environment, and the hydroxyl groups seek a hydrophilic environment. Thus, a cylindrical pore is formed, the inner wall of which consists of the hydroxyl-substituted carbon chains of the AmB molecules and the outer wall of which is formed by the heptaene chains of the molecules and by sterol nuclei [15].

RISK FACTORS IN THE DEVELOPMENT OF AMPHOTERICIN NEPHROTOXICITY

Concurrent use of diuretics Abnormal baseline renal function Larger daily doses Hypokalemia Hypomagnesemia

Other nephrotoxic drugs (aminoglycosides, cyclosporine)

FIGURE 11-11

Risk factors for development of amphotericin B (AmB) nephrotoxic-ity. Nephrotoxicity of AmB is a major problem associated with clinical use of this important drug. Disturbances in both glomerular and tubule function are well described. The nephrotoxic effect of AmB is initially a distal tubule phenomenon, characterized by a loss of urine concentration, distal renal tubule acidosis, and wasting of potassium and magnesium, but it also causes renal vasoconstriction leading to renal ischemia. Initially, the drug binds to membrane sterols in the renal vasculature and epithelial cells, altering its membrane permeability. AmB-induced vasoconstriction and ischemia to very vulnerable sections of the nephron, such as medullary thick ascending limb, enhance the cell death produced by direct toxic action of AmB on those cells. This explains the salutary effect on AmB nephrotoxicity of salt loading, furosemide, theophylline, or calcium channel blockers, all of which improve renal blood flow or inhibit transport in the medullary thick ascending limb.

Indication for amphotericin B therapy

Clinical evaluation:

Correction:

Is patient salt depleted?

yes

Correct salt depletion Avoid diuretics Liberalize dietary sodium

Will salt loading exacerbate underlying disease?

yes

Weigh risk-benefit ratio Seek alternatives

Does patient require concommitant antibiotics?

yes

Select drug with high salt content

Is potassium (K) or magnesium (Mg) depleted?

yes

Correct abnormalities

^NoU

J u

Begin amphotericin B with sodium supplement, 150 mEq/d

Begin amphotericin B therapy

J u

J u

Routine Monitoring:

Clinical evaluation (cardiovascular/respiratory status; body weight; fluid intake and excretion) Laboratory tests (renal function; serum electrolyte levels; 24 -hours urinary electrolyte excretion)

J u

Clinical evaluation: Is patient vomiting? yes y Increase salt load

No

Laboratory evaluation:

Correction:

Is serum creatinine>3mg/dLorisrenal deteriorationrapid?

yes

Interrupt amphotericin B therapy, resume on improvement

Is K level ,3.5 mEq/L or Mg level <1.6 mEq/L?

yes

Use oral or intravenous supplementation

No

Continue amphotericin B therapy and routine monitoring Close follow-up of serum electrolytes

FIGURE 11-12

Proposed approach for management of amphotericin B (AmB) therapy. Several new formulations of amphotericin have been developed either by incorporating ampho-tericin into liposomes or by forming complexes to phospholipid. In early studies, nephrotoxicity was reduced, allowing an increase of the cumulative dose. Few studies have established a therapeutic index between antifungal and nephrotoxic effects of amphotericin. To date, the only clinically proven intervention that reduces the incidence and severity of nephrotoxicity is salt supplementation, which should probably be given prophylactically to all patients who can tolerate it. (From Bernardo JF, et al. [16]; with permission.)

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