Pharmacology for Anaesthesia and Intensive Care

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Section IICoredrugs in anaesthetic practice

Membrane phospholipids

Arachidonic acid

Cyclic endoperoxidases

Platelets Widespread

Vascular

endothelium

Leukotrienes

Phospholipase A 2 (inhibited by steroids)

Thromboxane A 2

PGI 2 (prostacyclin)

Prostaglandins (PGE 2 , PGF 2 α, PGD 2 )

Cyclo-oxygenase (inhibited by NSAIDs)

Lipoxygenase

Figure 9.3.Prostaglandin synthesis.

of the platelet. The production of prostacyclin in vascular endothelium is not affected

in this way, so the overall effect is selective inhibition of thromboxane.

The other NSAIDs produce reversible enzyme inhibition, the activity of cyclo-

oxygenase resuming when plasma levels fall. Decreased PGE 2 and PGF 2 αsynthesis

account for their anti-inflammatory effect, while reduced thromboxane synthesis

leads to reduced platelet aggregation and adhesiveness. Their antipyretic actions

are due to inhibition of centrally produced prostaglandins that stimulate pyrexia.

Reduced prostaglandin synthesis in gastric mucosal cells may lead to mucosal ulcer-

ation. Lipoxygenase is not inhibited by NSAIDs and the production of leukotrienes

is unaltered.

Cyclo-oxygenase (COX) exists as two isoenzymes, COX-1 and COX-2. The main

molecular difference between COX-1 and COX-2 lies in the substitution of isoleucine

for valine, which allows access to a hydrophobic side pocket that acts as an alternative

specific binding site for drugs.

COX-1 (the constitutive form) is responsible for the production of prostaglandins

that control renal blood flow and form the protective gastric mucosal barrier. In

addition COX-1 mediates synthesis of thromboxane. (A variant of COX-1, which

has been called COX-3 and exists centrally, is possibly the mechanism by which

paracetamol reduces pain and pyrexia.)

COX-2 (the inducible form) is produced in response to tissue damage and facil-

itates the inflammatory response. COX-2 also mediates production of prostacyclin