Pharmacology for Anaesthesia and Intensive Care

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22 Antimicrobials

Kinetics

These drugs are all absorbed well via the oral route with the exception of miconazole,

which is available in a parenteral form (prepared in cremophor EL).

Fluconazole is minimally protein bound (12%) and penetrates CSF well. It is not

metabolized in man and excreted unchanged in the urine. Itraconazole, ketocona-

zole and miconazole are all highly protein bound (99%) and do not penetrate CSF.

They are not therapeutically active in urine but tissue levels are high. Ketoconazole

and miconazole are metabolized by the liver and inactive metabolites excreted in

bile. Itraconazole is degraded before inactive metabolites are excreted in bile. No

dose adjustment for renal failure or CVVHDF is required with these antifungals.

Side effects

Drug interaction


Cisapride metabolism is inhibited and high plasma concentrations increase the

risk of prolonged QT syndrome and fatal arrhythmias.


Warfarin effect is enhanced.

Ketoconazole


Gastrointestinal symptoms (20%), rash and pruritus


Hepatitis (rare)


Steroid synthesis inhibition (subclinical adrenocortical deficiency)

Miconazole


Thrombophlebitis


Cardiac arrhythmias with rapid i.v. administration

Antiviral drugs

Viruses utilize the biochemical components of their host cell and it is, therefore,

difficult to prevent viral replication without causing damage to the host cell.

Acyclovir

Acyclovir is used to treat infection due toHerpes simplex(type I and II) andVaricella

zoster.

Mechanism of action

Acyclovir inhibits nucleic acid synthesis. Cells infected withH. simplexorV.zoster

contain a virally encoded thymidine kinase that converts acyclovir to acyclovir

monophosphate. This is then converted to an active triphosphate that inhibits viral

DNA polymerase and acts as a chain terminator. The thymidine kinase present in

uninfected cells has a low affinity for acyclovir and therefore only very small amounts

of acyclovir triphosphate are produced. This variable affinity forms the basis of its

selectivity. Whilst useful againstH. simplexandV.zosterit does not eradicate them

and is only effective if given at the start of an infection.