13. NSAIDs Flashcards
What are the three primary therapeutic effects of NSAIDs?
Analgesia, anti-inflammatory, antipyretic.
Name some autacoids.
Bradykinins, histamine, cytokines, leukotrienes, nitric oxide, neuropeptides, eicosanoids - includes prostaglandins.
What are eicosanoids?
20 C phospholipid derivatives used as signalling molecules.
What are the different classes of eicosanoids?
Prostaglandins, prostacyclins, thromboxanes, leukotrienes.
What are eicosanoid classes derived from?
Arachidonic acid, cleaved from cell membrane phospholipids.
What synthesises prostaglandins?
Cyclo-oxygenase enzymes (COX enzymes).
Outline the mechanism of PG ‘G’ and PG ‘H’ formation.
Cell membrane phospholipids -> arachidonic acid (phospholipase A2) -> PG ‘G’ (COX-1/COX-2) -> PG ‘H’ (COX-1/COX-2).
Which prostaglandin is most important in mediating inflammatory response?
PG ‘E’.
What are the effects of PG ‘E’?
Vasodilaton, hyperalgesia, fever, immunomodulation.
Where is COX-1 expressed?
Across a wide range of tissue types.
What is the role of PG synthesised by COX-1?
Cytoprotective role in gastric mucosa, myocardium, renal parenchyma, ensures optimised local perfusion (reduces ischaemia).
What is the half life of COX-1 synthesised PG?
Short, around 10 mins so it needs to be synthesised constantly.
What is the result of NSAIDs acting to inhibit COX-1?
ADRs.
Where is COX-2 expressed?
Only in injured tissues, induced by inflammatory mediators, or constitutively in brain and kidney.
What is the result of NSAIDs acting to inhibit COX-2?
Therapeutic effects.
What is the difference in structure of COX-1 and COX-2?
COX-1 is tight, COX-2 is baggy.
How is selective inhibition by different NSAIDs achieved with COX-1 and COX-2 enzymes?
COX-1 can only fit smaller drugs, COX-2 can fit larger drugs.
What is the action of prostaglandins?
Bind GPCRs (action depends on PG receptor type) then has synergising effects of other autacoids.
How do prostaglandins respond to inflammation?
Autacoids and prostaglandins released post injury from local tissues and blood vessels. Autacoid release induces expression of COX-2 and synergises with other autacoids. PGs act as potent vasodilators and synergise permeating effects of bradykinin and histamine.
What is the result of PG ‘E’ acting on EP2 receptors?
Increased vasodilation.
What is the result of PG ‘E’ acting on EP1 receptors?
Increased peripheral nociception. Increases neuronal sensitivity to bradykinin, inhibits K+ channels (prevents hyperpolarisation), increases Na+ channel sensitivity.
How is pain felt via EP1 receptors?
Painful stimuli carried by afferent C fibres, PGE2 synthesised by surrounding tissue to trauma/injury, other atuacoids are released. PGE2 binds with C fibre neuronal EP1 via Gq GPCR and activates it to have more C fibre activity.
What is meant be peripheral sensitisation of EP1 binding?
EP1 binding increases C fibre activity, it also increases intracellular Ca2+ via Gq GPCR so there is more neurotransmitter release which gets more autacoids involved -> increased sensitivity.
What happens with increased sustained nociceptive signalling peripherally?
Increased cytokine levels in dorsal horn cell body so more COX-2 synthesis and PGE2 synthesis. PGE2 acts via local GPCR EP2 receptors to increase sensitivity and discharge rate of secondary interneurones via glycinergic inhibition.
What is meant by central sensitisation by PGE2?
PGE2 binds EP2 Gs type and activates it so increased cAMP and PKA, decreased glycine receptor binding affinity and increased pain perception.
What is the overall effect of activation of EP3 receptors?
Pyrexia.
How do EP3 receptors cause pain?
Endotoxins stimulate macrophages to release IL-1 which acts in hypothalamus to increase PGE2 synthesis. This acts on EP3 Gi GPCRs causing increased heat production and decreased heat loss.
What are the general therapeutic effects of NSAIDs?
Competitive inhibition of COX-2 (+ COX-1) to cause analgesia, anti-inflammation, and anti-pyrexia.
What determines the physician’s choice of NSAID for a patient?
The dominant disesae state and the individual patient response.
What is the typical route of administration of NSAIDs?
Orally, may be topical for soft tissue injury.
What are the half lives of NSAIDs?
<6hrs or >10hrs.
What is the main therapeutic use of anti-inflammatory NSAIDs?
Musculoskeletal disorders, such as rheumatoid/osteoarthritis.
What are the main therapeutic uses of analgesic NSAIDs?
Mild to moderate pain (less effective than opiates), moderate pain.
What are the ADRs of NSAIDs due to?
Inhibition of COX-1 enzymes.
What are the ADRs of NSAIDs?
Iatrogenic morbidity and mortality with long term use in elderly, stomach/GI tract symptoms, renal ADRs if HRH or hypovolaemia.
What are the GI ADRs of NSAIDs?
Stomach pain, nausea, heartburn, gastric bleeding, ulceration.
What causes the GI ADRs of NSAIDs?
COX-1 PGE2 stimulates cytoprotective mucus secretion throughout the GI tract so reduces acid secretion and promotes mucosal blood flow.
What are the rates of GI ADRs with NSAID use?
35% of users, if long term 10-30%.
How can GI ADRs form NSAIDs be offset?
Use PPIs or misoprostol (synthetic PG).
Which patients suffer from renal ADRs with NSAID use?
HRH compromised - heart failure, renal disease, hepatic cirrhosis - due to compromised renal blood flow.
What causes renal ADRs with NSAID use?
PGE2 and PGI2 maintain renal blood flow so if decreased then GFR is reduced. Na+/K+/Cl- and H2O retention leads to increased likelihood of hypertension.
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