Pharmacology for Anaesthesia and Intensive Care

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Section IVOther important drugs

been reported after prolonged treatment, especially from heart valve vegetations,

and fungal endocarditis normally requires surgical intervention to cure.

Mechanism of action

Amphotericin reacts withergosterol in the fungal cell membrane, creating pores

through which cell contents are lost. It reacts less withcholesterol and is not as toxic

to human cells. As the dose is increased, the pore size created increases and cell

damage occurs at a faster rate.

Kinetics

Amphotericin is only administered parenterally and is highly plasma protein bound.

Tissue penetration is poor and negligible levels are found in CSF or urine. It appears

to be metabolized by the liver and plasma levels do not rise in renal failure. However,

due to its potential for nephrotoxicity, dose reduction is still considered in renally

impaired patients. Liposomal preparations are available that allow higher doses to

be given with less renal toxicity – they are considerably more expensive.

Side effects


Renal – renal impairment is only reversible if treatment is stopped early. Renal

toxicity can be limited if the dose is gradually increased over the first 48 hours.


Miscellaneous – it may cause any of the following: gastrointestinal upsets, blood

dyscrasias, febrile reactions, muscle pains, visual and hearing disturbances, con-

vulsions, anaphylaxis and altered liver function tests. Some of these effects can be

ameliorated by reducing the rate of administration or by the co-administration of

steroids or antihistamines.

Azoles

This category can be further subdivided into triazoles (fluconazole and itraconazole)

and imidazoles (ketoconazole and miconazole). They are active against a wide range

of fungi and yeasts includingCandidaspp.,Coccidioidesspp.,Cryptococcusspp. and

Histoplasmaspp. Itraconazole and miconazole also coverAspergillusspp. infection.

Resistance is rarely problematic but isolates are known to demonstrate resistance to

more than one agent.

Mechanism of action

These agents all work by disrupting ergosterol synthesis. The blockade of 14-α

demethylation during ergosterol manufacture leads to an alteration in membrane

function. Higher concentrations of azoles also damage ergosterol directly leading to

loss of membrane integrity, cell leakage and death.