NSAIDS Flashcards
Why are NSAIDS so widely used?
Analgesic
- headache, backache
- Postoperative pain (opiate sparing)
- Dysmenorrhea (menstrual pain)
Antipyretic
Anti-inflammatory
How do NSAIDS work?
Inhibition of prostaglandin and thromboxane synthesis
Lipid mediators derived from arachidonic acid
Cyclo-oxygenase enzymes
Widely distributed
Not stored pre-formed
Receptor-mediated
DO more on how they work
Diagram
Describe the prostanoid receptors?
- 10 known receptors
- DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP
- Naming based on agonist potency
- Prostanoids have both G protein-dependent and -independent effects
- Physiological and pro-inflammatory actions
What are the receptors which PGE2 activate?
It is cAMP dependent.
EP1 + EP3 –> Ca2+ mobilization
EP3 + EP2 –> Downregualte cAMP
EP2 + EP4 –> upregulate cAMP
What are the unwanted actions of PGE2?
- Increased pain perception
- Increased body temperature
- Acute inflammatory response
- Immune responses
- Tumorigenesis
- Inhibition of apoptosis
Why does PGE2 increase pain perception?
Stimulation of PG receptors in the periphery sensitizes the nociceptors which cause pain both acutely and chronically.`
cAMP mediated
Activates P2X3 nocioceptors
During inflammation Epac pathway activated and additionally, more PGE2 produced
Greater activation of P2X3 receptors
See slides
EP1receptors and/or EP4 receptors (in periphery and spine)
Endocannabinoids (neuromodulators in thalamus, spine and periphery)
Increasing beta-endorphin in spine
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How does PGE2 cause a rise in body temperature?
It stimulates hypothalamic neurones initiating a rise in body temperature. NSAIDS will lower the temperature of patients (useful in flu)
What are the desirable physiological actions of PGE2?
- Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors)
- Renal salt and water homeostasis
- Gastroprotection
- Vasoregulation (dilation and constriction depending on receptor activated)
In terms of bronchodilation why shouldn’t certain members of the population take NSAIDS?
About 10% of asthma patients experience worsening of symptoms with NSAIDS
Cyclooxygenase inhibition favours production of leukotrienes (bronchoconstrictors)
NSAIDS should not be taken by asthmatics.
Describe PGE2 in the kidney
Production of PGE2 is mediated by COX1 and COX2.
PGE2 increases renal blood flow NSAIDs can cause renal toxicity Constriction of afferent renal arteriole Reduction in renal artery flow Reduced glomerular filtration rate
Role of PGE2 in the stomach?
1) Downregulates the release of HCl
2) Stimulates mucus and bicarbonate secretion
NSAIDS increase the risk of ulcers. To solve this they produces a COX-2 selective drug see slides
However COX2 inhibitors have higher risk of CVS disease
See slides iso forms of cox
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What are the unwanted CVS effects of NSAIDS?
- Vasoconstriction
- Salt and water retention
- Reduced effect of antihypertensives
Draw the diagram for CVS modulation of prostanoids
See diagram
What are the risk of COX 2 and COX selective drugs?
COX 2 increased CVS risk
COX 1 increased GI risk
What are the risk vs benefits of NSAIDS?
Analgesic use
- Usually occasional
- Relatively low risk of side effects
Anti-inflammatory use
- Often sustained
- Higher doses
- Relatively high risk of side effects
What are the strategies other than COX-2 selective NSAIDS for limiting GI side effects?
- Topical application
- Minimise NSAID use in patients with history of GI ulceration
- Treat H pylori if present
- If NSAID essential, administer with omeprazole or other proton pump inhibitor
- Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g.
1) Alcohol consumption
2) Anticoagulant or glucocorticoid steroid use
Describe Aspirin?
- Unique among the NSAIDS
- Selective for COX-1
- Binds IRREVERSIBLY to COX enzymes (acetlylates the active site)
- Has anti-inflammatory, analgesic and anti-pyretic actions
- Reduces platelet aggregation
What are the effects of prostanoids on platelet aggregation?
???? WATCH
Reduced platelet aggregation look at what normally happens
Very high degree of COX-1 inhibition which effectively suppresses TxA2 production by platelets
Covalent binding which permanently inhibits platelet COX-1
Relatively low capacity to inhibit COX-2
Use low dose to allow endothelial resynthesis of COX-2
What are the major side-effects of Aspirin seen at therapeutic doses?
- Gastric irritation and ulceration
- Bronchospasm in sensitive asthmatics
- Prolonged bleeding times
- Nephrotoxicity
Side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1
Describe paracetamol?
- Is a widely used effective analgesic for mild-to-moderate pain which is available over the counter
- Has anti-pyretic action
- Has minimal anti-inflammatory effect
Therefore it is not a NSAID
What is the mechanism of action of paracetamol?
Not understood - probably central and peripheral
What happens during an overdose of paracetamol?
Glutathionine is usually abundant in the liver used to produce an inactive metabolite.
During an overdose glutathione is depleted.
The paracetamol metabolite oxidises thiol groups of key hepatic enzymes and causes cell death
What is the antidote for paracetamol poisoning?
- Add compound with –SH groups
- Usually intravenous Acetylcysteine
- Occasionally oral methionine
- Could be added to the formulation but increased cost
- Acetyl cysteine used in cases of attempted suicide and accidental poisoning
If not administered early enough, liver failure may be unpreventable
