NSAIDs Flashcards
Examples of prostanoids + their actions
- Prostaglandins: vasodilators
- Prostacyclin (PGI2): vasodilator | prevent platelet aggregation
- Thromboxane: platelet granule > initiation of platelet aggregation | vasoconstrictor
- PGE2: good for stomach > regulation of a stomach acid
How are prostanoids produced?
Produced locally on demand from arachnoid acid
Role of prostanoids in the GI system
- PGE2: regulation of acid secretion in parietal cells
- prostacyclin: maintenance of blood flow + mucosal repair
How do prostanoids signal?
Act locally via many GPCRs
What is a consequence of imbalance of prostanoids?
Hypertension
MI
Stroke
Why is the Mediterranean diet suggested to lower incidence of CVD?
- diet is rich is fish oil
- proposed to lead to conversion of thromboxane + PGI3 (better prostanoids)
What are the two functional isoforms of cyclooxygenase enzymes?
COX-1
COX-2
Compare the haemostatic function of COX-1 + COX-2
COX-1:
- GI protection
- platelet aggregation
- vascular resistance
.
COX-2:
- renal homeostasis
- tissue repair + healing
- uterine contractions
- inhibition of platelet aggregation
Compare the pathological functions of COX-1 + COX-2
COX-1:
- chronic inflammation
- chronic pain
- hypertension
.
COX-2:
- chronic inflammation
- chronic pain
- fever
- blood vessel permeability
Compare the active sites in COX-1 + COX-2
COX-2 has a larger + more flexible binding site
What is the common mode of action of NSAIDs?
Inhibition of COX
- decrease prostaglandin, prostacyclin + thromboxane synthesis
- compete with arachidonic acid for site of COX enzymes
What are three general actions of NSAIDs?
Analgesia
Anti-inflammatory
Antipyretic
How do NSAIDs work as analgesics?
- COX inhibition
- decreases PGE2 synthesis in dorsal horn
- decrease neurotransmitter release > decrease excitability of neurone in pain relay pathway
- inhibition reduces peripheral pain fibre sensitivity
How do NSAIDs work as anti inflammatories?
- COX inhibition
- reduce production of prostaglandins released at site of injury
- reduces vasodilation + swelling
How do NSAIDs work as antipyretics?
Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated > reduced temperature
Outline NSAID COX selectivity
COX1 selectivity
- aspirin
- ibuprofen
- naproxen
- diclofenac
- celecoxib
- etoricoxib
COX2 selectivity
What are GI adverse drug reactions of NSAIDs?
What is this due to?
- dyspepsia
- nausea
- peptic ulceration
- bleeding + perforation
- exacerbation of IBD
. - decreased prostaglandins
- reduction in mucosal blood flow > hypoxia
- reduction in mucous + bicarb secretion > increased acid secretion
What are important drug drug interactions of NSAIDs in relation to GI ARDs?
- aspirin
- Glucocortioid steroids
- anticoagulants
(PPI should be considered as additional drug)
What are renal adverse drug reactions of NSAIDs?
What is this due to?
- reversible decreases in renal blood flow + GFR
. - reduction in prostaglandins
- reduced vasodilation of afferent arteriole
- reduced blood supply
What are important drug drug interactions of NSAIDs in relation to renal ARDs?
ACEi
ARBs
Diuretics
Examples of selective COX-2 inhibitors
Celecoxib
Etoricoxib
Difference in selective COX2 inhibitors + non selective ADRs
- less GI ADRs
- renal ADRs similar
Effect of thromboxane + prostacyclin on CVS
Thromboxane is generally bad
Prostacyclin is generally good
How does NSAID use effect MI risk?
- All NSAIDs (but baby aspirin) increase risk of MI
- possibly due to decrease in prostacyclin
What are considerations/possible contraindications of NSAIDs?
- CVD
- renal function
- GI disease
- DDIs
- level of pain, pyrexia + inflammation
- 3rd trimester of pregnancy
What are indications for NSAID use?
- inflammatory conditions
- osteoarthritis
- post op pain
- Menorrhagia
- low dose aspirin for platelet aggregation inhibition
- topical use on cornea
What is the mechanism of action of paracetamol?
COX-2 selective inhibition in CNS
How can NSAIDs increase free plasma conc. of other drugs?
Competitively displaced other bound drugs > increase free drug conc.
What builds up in paracetamol overdose?
NAPQI
What is used to treat paracetamol overdose?
How does it work?
N-acteylcysteine
- replaces glutathione which is protective agaisnt NAPQI
Difference in action of COX-1 + COX-2 inhibition in relation to platelet aggregation
- COX-1inhibitors decrease thromboxane > decrease platelet aggregation
- COX-2 selective inhibitor’s decrease PGI > unopposed aggregatory effects
Why can NSAIDs exacerbated CKD?
Why do ACEi/ARB compound this?
- NSAID use > reduction in prostaglandins > reduction in vasodilation > reduced GFR + renal blood flow
- in CKD, there is a greater reliance on PG for vasodilation + renal perfusion
. - ACEi/ARBs cause vasodilation > increase renal blood flow
Describe how NSAIDs should be prescribed
Lowest effective dose for shortest time necessary
Presentation + consequences of paracetamol overdose
- asymptomatic at first
- N+V + abdo pain in first 24 hours
- maximal liver damage occurs at 3-4 days
What NSAID is most selective for COX2?
Etoricoxib
What are mechanisms by which NSAIDs can cause GI ADRs?
- Decreased mucous secretion
- Decreased bicarbonate secretion
- Reduced mucosal blood flow
- Inhibtion of PGE2 + PGI2 cause them
