Pharmacology for Anaesthesia and Intensive Care

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Section IICoredrugs in anaesthetic practice

high doses, its duration of action is significantly prolonged as tissues become sat-

urated. Its clearance is similar to and its elimination half-life is longer than that

of morphine, reflecting its higher lipid solubility and volume of distribution. Fen-

tanyl may become trapped in the acidic environment of the stomach where more

than 99.9% is ionized. As it passes into the alkaline environment of the small bowel

it becomes unionized and, therefore, available for systemic absorption. However,

this is unlikely to raise systemic levels significantly due to a rapid hepatic first-

pass metabolism, where it is N-demethylated to norfentanyl, which along with

fentanyl is further hydroxylated. These inactive metabolites are excreted in the

urine.

Alfentanil

Alfentanil is a synthetic phenylpiperidine derivative. It is aμ-receptor agonist but

with some significant differences from fentanyl.

Presentation and uses

Alfentanil is presented as a colourless solution containing 500μgor5mg.ml−^1 .For

short-term analgesia it is used in boluses of 5–25μg.kg−^1 .Itisalso used by infusion

for sedation where its duration of action is significantly prolonged.

Kinetics

Alfentanil has a pKa=6.5; at a pH of 7.4, 89% is present in the unionized form and

is, therefore, available to cross lipid membranes. Fentanyl has a pKa=8.4, so only

9% is unionized at a pH of 7.4. So despite a significantly lower lipid solubility than

fentanyl, it has a faster onset of action (when given in equipotent doses). Alfentanil

has a much smaller initial volume of distribution so that despite a smaller clearance

its elimination half-life is also shorter.

Metabolism occurs in the liver by N-demethylation to noralfentanil. This and

other metabolites are conjugated and excreted in the urine. Midazolam is metabo-

lized by the same hepatic enzymes (CYP3A3/4) so when administered concurrently

both elimination half-lives are significantly increased. Erythromycin may prolong

alfentanil’s activity by inhibiting hepatic CYP450.

Remifentanil

The pureμ-receptor agonist remifentanil is a synthetic phenylpiperidine derivative

of fentanyl with a similar potency. While it shares many of the effects associated with

the opioids its metabolism makes it unique in this class of drug. It is not a controlled

drug.