NSAIDs Flashcards
What signals the inflammatory response?
Autacoids - diverse range of local molecular mediators and signalling agents
- bradykinins
- cytokines
- nitric oxide
- histamine
- leukotrienes
- neuropeptides
- eicosanoids
What are features of autacoids? What does this allow?
Localised release
Short half-life
Allows fine control of the signalling response
What are eicosanoids derived from?
Arachidonic acid
Which class of eicosanoids do prostaglandins belong to? Name another part of the class
Prostaglandins
Leukotrienes
Name the types of prostaglandins
Prostacyclins
Thromboxanes
List the steps of how prostaglandins are synthesised
Cell membrane phospholipids converted to arachidonic acid by phospholipase A2
Arachidonic acid converted to PG’G’ by COX1/2
PG’G’ converted to PG’H’ by COX 1/2
PG’H’ converted to PGs D, E, F, I by specific PG enzymes
Which is the most important prostaglandin for mediating the inflammatory response and what effects does it have?
PG ‘E’
- vasodilation
- hyperalgesia
- fever
- immunomodulation
When is COX 1 expressed and where?
All the time - constitutively - has a short half life of around 10 mins
In a wide range of tissue types
What is the role of prostaglandins synthesised by COX-1?
Major cytoprotective role in tissues such as
- gastric mucosa
- myocardium
- renal parenchyma
Ensures optimised local perfusion and reduces ischaemia
When and where is COX 2 expressed?
Induced by injurious stimuli and inflammatory mediators such as bradykinin
Constitutively expressed in parts of the brain and kidney
Via which COX are the main therapeutic effects of NSAIDs done via?
COX 2
COX 1 inhibition by NSAIDs is the reason for ADRs
What is the difference in active sites of COX1 and 2?
COX-1 has a narrow ‘mouth’ so can only fit small, sharp, aspirin-like objects
COX-2 has a wide mouth so fit small and big, blunt drugs
What do prostaglandins interact with?
Bind with specific GPCRs
-for PG ‘E’, the main receptors are EP1-4
Where are autacoids released from?
Blood vessels and local tissues
What do prostaglandins do?
Synergise action of other autacoids including bradykinin and histamine
Act as potent vasodilators (do not increase permeability, just synergises effect of the above two)
What do EP1 and EP2 receptors do?
EP1 is Gq - increases peripheral nociception
EP2 is Gs - increases vasodilation
What happens when PGE2 is released following trauma/injury?
PGE2 binds to EP1 GPCR receptor on C fibre
Activation of this receptor causes
-increased neuronal sensitivity to bradykinin
-inhibition of K+ channels
-increased Na+ channel sensitivity
Acts to increase c fibre activity
Activates previously silent C fibres
How does peripheral sensitisation occur via PGE2?
Binds to EP1 which is a Gq GPCR
Leads to an increase in intracellular calcium concentration
Increased neurotransmitter release
Increased sensitivity due to other autacoids
How does central sensitisation to pain occurs?
Increased sustained nociceptive signalling peripherally results in increased cytokine levels in the dorsal horn cell body
This increases COX-2 and PGE2 synthesis
PGE2 acts via local GPCR EP2 receptors (Gs)
-increase in cAMP and PKA
-decrease in glycine receptor binding affinity
-increase in sensitivity and discharge rate of secondary interneurones
-increase in pain perception
How does pyrexia occur?
Infected/inflammatory states and bacterial endotoxins causes macrophage release of IL-1
In the hypothalamus, IL-1 (possibly by induction of COX-2) stimulates PGE2 synthesis
PGE2 binds with EP3 receptors - Gi type GPCR
What can NSAIDs be used as?
Analgesics
Anti-inflammatories
Antipyretics
What type of pharmacokinetics do NSAIDs show?
Linear
What is the half life of NSAIDs?
Two groups
- less than 6 hours
- more than 10 hours
What is protein binding like with NSAIDs?
Heavily bound - 90-99%
What are some GI ADRs of NSAIDs?
Stomach pain Nausea Heart burn Gastric bleeding Ulceration
How do NSAIDs cause a lot of their GI ADRs?
Inhibit gastric COX-1 PGE2
- decrease in cytoprotective mucus secretion
- increased acid secretion
- reduced mucosal blood flow
How can GI ADRs be reduced with NSAIDs?
PPIs
Misoprostol (a synthetic of PGE)
How do NSAIDs cause renal ADRs?
More common in neonates and elderly due to reduced renal perfusion blood flow
- PGE2 and PGI2 are inhibited, leading to less dilation of afferent arteriole
- Na/K/Cl and H2O retention occurs due to decreased GFR, so increased likelihood of hypertension
What are some vascular ADRs?
Increased risk of bleeding time, bruising and haemorrhage
Why are some hypersensitivity ADRs with NSAIDs?
Skin rash
Stevens-Johnson syndrome - rare but serious - rash of skin and mucous membranes and can compromise hepatic function
Can affect bronchial asthma, care in asthmatics
What is a paediatric ADR that can happen with NSAIDs?
Reye’s syndrome - serious brain/liver injury
-don’t give aspirin to children
Name some COX-2 inhibitors
Rofecoxib
Celecoxib
What is the theoretical benefit of specific COX-2 inhibitors?
Overcome ADRs due to lack COX-1 inhibition with equal efficacy to standard NSAIDs
What are some problems with COX-2 specific inhibitors?
Not completely free of GI ADRs
Increased risk of CVS ADRs with long term use
-only approved for short term
What is the benefit of combining NSAIDs with low dose opioids?
Can extend their therapeutic range for treating pain as they act by different mechanisms
Reduce ADRs seen with opioids when opioids are used by themselves
How can combining NSAIDs increase risk of ADRs?
Can affect eachother’s PK/PDs due to competition for plasma protein binding sites
NSAIDs and low-dose aspirin compete for COX-1 binding sites, which may interfere with the cardio-protective action of aspirin
What are some DDIs of NSAIDs?
Affect highly protein-bound drugs such as
- sulphonylurea - increases to cause hypoglycaemia
- warfarin - increases to cause increased bleeding
- methotrexate - increases to cause many ADRs
What is different about aspirin compared to other NSAIDs?
It is the only NSAIDs to irreversibly inhibit COX enzymes by acetylation
Why does aspirin have a unique PK profile?
Half-life is less than 30 minutes
Rapidly hydrolyse in the plasma to salicylate
What order kinetics does salicylate have?
Lower doses - linear, half-life is four hours Higher doses (12x300mg aspirin/day) - zero order kinetics
What are the current and possible uses of aspirin?
Cardioprotective (75mg/day)
Reduces platelet aggregation
Prophylactic for GI, breast and other cancers
How does aspirin reduce platelet aggregation?
Irreversibly inhibits COX-1 activity that normally drives pro-aggregate activity in both platelets and the vessel wall
-reduces the likelihood of thrombotic formation
How is aspirin thought to prevent against tumour growth?
Cancers synthesise PGE2 which promotes tumour growth
What is paracetamol used for?
Mild-moderate analgesia and fever
Why is paracetamol better than NSAIDs?
Better ADR profile
How is paracetamol thought to work?
Weak COX1/2 inhibitor
Primarily acts on CNS, possibly on COX-3 isoform
Metabolite in CNS may combine with arachidonic acid to block binding with COX-1/2
Order of pharmacokinetics of paracetamol?
First order
High dose - zero order
Half-life of paracetamol?
2-4 hours
Who do you need to be careful prescribing paracetamol for?
Those with compromised hepatic function or alcoholics
What is the normal metabolism of paracetamol?
Phase II conjugation with glucuronide (60%) and sulphate (30%) via CYP450 enzymes
Some phase I oxidation to produce NAPQI (reactive and toxic). Detoxified and conjugated with glutathione
How is NAPQI so toxic?
Highly reactive and nucleophilic
Binds with cellular macromolecules and mitochondria
Leads to loss of function and hepatic cell death
Can cause renal failure
How is paracetamol overdose treated?
Within 4 hours - give activated charcoal to reduce uptake
0-36 hours - start IV N-acetylcysteine
Give methionine PO if NAC cannot be given promptly
