List some of the clinical uses of NSAIDs
- Management of inflammatory disorders
- Management of pain
- Management of endotoxaemia in large animals
- Management of prothrombotic states
- Management of tumours
What physiological pathway do NSAIDs target?
Describe the mechanism of action of NSAIDs
NSAIDs inhibit cyclooxygenase (COX). COX is the enzyme which si responsible for the production of prostaglandins and thromboxanes. Inhibiting COX therefore decreases the production of these inflammatory mediators.
What chemical reaction does COX take part in?
The conversion of arachidonic acid to the prostaglandin precursor PGH2
How many COX isoforms are there?
Two - COX-1 and COX-2
Describe the differences between COX-1 and COX-2
- COX-1 = expressed in most tissues, involved in normal homeostasis, many physiological functions, up-regulated under stress
- COX-2 = expressed in many tissues including kidney, testicular ovarian cells and in the CNS, physiological functions are maintaining renal blood flow, nerve function and bone metabolism, also induced in response to inflammatory stimuli
Describe the difference in the way traditional NSAIDs and those selective for COX-1 or COX-2 work
- A traditional NSAID binds to the channel on both COX-1 and COX-2 and blocks them. Arachidonic acid cannot get in and so cannot be converted into prostaglandins.
- COX-2 has a slightly wider channel and an additional binding site. Specific COX-2 NSAIDs only inhibit COX-2 enzymes as the drug molecule is too big to fit into the COX-1 but fits into COX-2, blocks the normal binding site and the additional binding site.
Most NSAIDS take part in a reversible reaction with COX enzymes, but which NSAID does not?
Aspirin blocks the channel in an irreversible manner and so for the cell to be able to produce prostaglandins again it has to produce new enzymes.
What are the three classes of NSAIDs?
- Non-selective COX inhibitors
- Preferential COX-2 inhibitors
- Specific COX-2 inhibitors
List the useful effects of NSAIDs
- Other uses e.g. cancer treatment
List the adverse effects of NSAIDs
- Renal toxicity
- Injury to articular cartilage
- Precipitate asthma
Describe how the NSAIDs have their analgesic effect
- Peripheral action - NSAIDs decrease prostaglandin production at the site of inflammation, this reduces sensitisation of nociceptive nerve endings to inflammatory mediators
- Central action - NSAIDs block prostaglandin release and neuronal excitation which reduces central sensitisation
- Overall these effects reduce hyperalgesia and pain
Describe how NSAIDs have an anti-pyretic effect
High concentrations of prostaglandins are found in the CSF during infection. Prostaglandins act on the thermoregulatory centre in the hypothalamus to increase body temperature. NSAIDs decrease the production of prostaglandins thus prevent the increase in temperature associated with fever.
Describe how NSAIDs have an anti-inflammatory effect
NSAIDs inhibit COX induction and release of prostanoids at the site of inflammation to decrease vasodilator prostaglandins and reduce the inflammatory response by preventing peripheral sensitisation
Describe how NSAIDs have an anti-thrombotic action
NSAIDs inhibit synthesis of thromboxanes which inhibits platelet aggregation
Describe the effect of a) low dose of NSAIDs b) high dose of NSAIDs on thrombotic action
- a) When a low dose of NSAID is administered this inhibits TXA2 (which normally stimulates aggregation) so it has an anti-thrombotic effect
- b) When a high dose of NSAID is administered this inhibits PGI2 (which normally inhibits aggregation) so it has a pro-thrombotic effect
Describe the effect of NSAIDs on the GIT
NSAIDs inhibit COX-1 which reduces the production of prostaglandins needed to line the gastric mucosa. This leads to ulceration.
Why should NSAIDs be given with food?
The contact area of the tablet results in a high localised concentration of the drug increasing the potential for ulcer formation. By giving NSAIDs with food this reduces the localised area of contract.
Describe the effect of NSAIDs on the kidney
Prostaglandins are synthesised in the kidney. These are involved in renal blood flow and excretion of salt and water via their vasodilatory actions. NSAIDs inhibit the production of prostaglandins which impairs renal blood flow. In healthy well hydrated animals this is of little consequence but it can cause acute renal failure in conditions which depend on protective PGs e.g. if animals have a low circulating volume.
Describe the pharmacokinetics of NSAIDs
- They are most well absorbed following oral administration. Should be given with food. Parenteral formulations are also available.
- They have a relatively small volume of distribution and are highly plasma protein bound, meaning they have good penetration into acute inflammatory exudate.
- They are generally excreted by conjugation and renal elimination of metabolites