Pharmacology for Anaesthesia and Intensive Care

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Section IICoredrugs in anaesthetic practice


Halothane


Cocaine


Lidocaine and prilocaine (bupivacaine safe)


Clonidine


Metoclopramide


Hyoscine


Diclofenac


Ranitidine

Protein bound (80% )

Free (20%)

Ionized (8%)

Unionized (12%)

Figure 8.5.Thiopental in plasma. Only 12% is immediately available as non-protein bound

and unionized drug.

Kinetics

Thiopental has a pKa of 7.6, so that 60% is unionized at pH 7.4. However, as only

20% of administered thiopental is unbound, only 12% isimmediatelyavailable in

the unbound and unionized form (Figure8.5). Its pKa of 7.6 means that 60% of free

drug is unionized. Despite this it has a rapid onset due to its high lipid solubility and

the large cardiac output that the brain receives. In addition, a dynamic equilibrium

exists between protein bound and free drug. Critically ill patients tend to be acidotic

and have reduced plasma protein-binding, resulting in a greater fraction of drug

in the unionized form and fewer plasma protein-binding sites, so that significantly

less thiopental is required to induce anaesthesia. Non-steroidal anti-inflammatory

drugs may also reduce available protein-binding sites and increase the fraction of

free drug.

Rapid emergence from a single bolus dose is due to rapid initial distribution into

tissues, not metabolism. A tri-exponential decline is seen representing distribution

to well-perfused regions (brain, liver) followed by muscle and skin. The final decline

is due to hepatic oxidation mainly to inactive metabolites (although pentobarbitone

is also a metabolite). When given as an infusion its metabolism may become linear

(zero-order, cf. p. 78) due to saturation of hepatic enzymes. The hepatic mixed-

function oxidase system (cytochrome P450) is induced after a single dose.