8.2.1 NSAIDs I Flashcards
What are prostanoids?
Active lipid mediators that regular inflammatory response
What are some examples of prostanoids?
PGE2
PGF2 alpha
PGD2
TXA2
PG-prostaglandin
How are prostanoids synthesised?
Arachadonic acid incorporated into phospholipids
Arachadonic phospholipid complex catalysed by COX1 and COX2 to form prostanoids
Produced on demand
How do prostanoids have fine local control?
Due to short half-lives
What do PGE2 and PGI2 do?
PGE2
Contributes to regulation of acid secretion in parietal cells
PGI2
PRostacyclin-contributes to maintenance of blood flow and mucosal repair
How do prostanoids act?
Act locally at GPCRs, action depends on receptor type and location
How are actions of prostanoids enhanced?
Enhanced by local autacoids e.g. bradykinin and histamine
Which prostanoids must have a fine balance between them?
TXA2 and PGI2 as they have opposing vascular effects
Important for haemodynamic and thrombogenic control
TXA2- vasoconstriction and platelet aggregation
PGI2- vasodilation and inhibition of platelet aggregation
What does an imbalance in prostanoids lead to?
Significant role in hypertension, MI and stroke risk
What diet cause higher levels of TXa3 and PGI3?
Diet rich in fish oils “Mediterranean diet”
Better prostanoids, lower incidence of CVD
What are the two functional isoforms of cyclooxygenase enzymes?
COX-1-active across most tissues
COX-2-mostly in chronic inflammation, constitutively in brain, kidney and bone
Complete the table
What are the structural difference between COX-1 and COX-2?
COX-2 has a larger and more flexible substrate channel than COX-1
COX-2 has a large space at the site where inhibitors bind
What are NSAIDs used for mainly?
Analgesic and anti-inflammatory effects
What is the single common mode of action of NSAIDs ?
Inhibition of COX
Reduces synthesis of:
- Prostaglandin
- Prostacyclin
- Thromboxane
Competes with arachidonic acid for hydrophobic site of COX enzymes
What is the mechanism of NSAIDs for analgesia?
Inhibition of COX reduces peripheral pain fibre sensitivity due to blocking of PGE2
Reduction of PGE2 in dorsal horn
Reduction of neurotransmitter release
Decreased excitability of neurones in pathway to brain
When is the full analgesic effect of NSAIDs acheived?
Efficacious after first dose
Full analgesia after several days dosing
What is the mechanism of action of NSAIDs for reducing inflammation?
NSAIDs reduce production of prostaglands released at site of injury
PGs normally released causing vasodilation(post-capillary venules), increasing permeability leading to vasodilation and oedema
What is the effect of NSAIDs on underlying chronic conditions?
Little effect
Give symptomatic relief with COX inhibition
What is the mechanism of NSAIDs reducing pyrexia?
PGE2 critical component in the preoptic area of the hypothalamus
Can still be stimulated by cytokines
Inhibition of hypothalamic COX2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature
How are NSAIDs differentiated?
By their selectivity
High prevalnce of ADRs attributed to COX1 selective inhibitiors
COX2 selective inhibitors inhibitor COX2 with much greater selectivity than COX1
Give some examples of NSAIDs and their COX selectivity
Aspirin
Ibuprofen
Naproxen
Diclofenac
Celecoxib
Etoricoxib
CoxiB
B is 2nd in the alphabet so if it ends in coxib its more selective for COX2
What are the GI considerations of NSAIDs?
Dyspepsia
Nausea
Peptic ulceration
Bleeding
Perforation
Exacerbation of IBD
Relative risk of GI bleed increases by 1-10x depending on NSAID
Why do NSAIDs cause GI issues?
Inhibiton of COX enzymes leads to reduced prostaglandin synthesis causing:
- Decreased mucus and bicarbonate secretion
- Increased acid secretion
- Decreased mucosal blood flow causing enhanced cytotoxicity and hypoxia
When should you not use NSAIDs?(GI)
Elderly
Prolonged use
Smoker
Alchol
History of peptic ulceration
Helicobacter pyrloi
What are some important drug to drug interactions with NSAIDs? (GI)
Aspirin
Glucocorticoid steroids
Anticoagulants (PPI should be considered)
What are some adverse drug reactions of NSAIDs? (Renal)
- Reversible decrease in GFR, decreased renal blood flow
Therapeutic dose in healthy person- less issues - Prostaglandins inhibit sodium absorption in the collecting duct, NSAIDs inhibit this causing increase in Na+, H2O, BP
When should you not use NSAIDs? (Renal)
CKD
Heart failure
More likely to have low GFR and rely on prostaglandins for vasodilation of the afferent arteriole to maintain GFR pressure and renal perfusion
What are some important drug to drug interactions with NSAIDs? (Renal)
ACEi
ARBs
Diuretics
