NSAIDs Flashcards
Name some autacoids released in response to local injury
Eicosanoids (prostaglandins)
Bradykinin
Histamine
Cytokines
Leukotrines
Nitric oxide
Neuro peptides
Outline the synthesis of prostaglandins
Eicosanoids are phospholipid derivatives that can form prostanoids (prostaglandins including prostacyclins and thromboxanes)
Cell membrane phospholipid is converted to arachidonic acid by phospholipase A2
Arachidonic acid is converted to PGG by COX-1/COX-2
PGG is converted to PGH by COX-1/COX-2
PGH is then converted to PGD/E/F/I by specific PG enzymes
Which is the most important PG and what are its main actions?
PGE - vasodilation, hyperalgesia, fever, immunomodulation
Works with other autacoids in the inflammatory response
In addition to assisting in the local inflammatory response, what else do autacoids do?
Upregulate COX-2
Describe the differences between COX-1 and COX-2
COX-1 - present all the time, PGs produced have protective effect in GI mucosa, myocardium, renal parenchyma, optimises perfusion, reason for ADRs, narrow tunnel structure (big drugs can not fit)
COX-2 - induced by injury, reason for therapeutic effects, wide tunnel structure
How is peripheral sensitisation achieved through prostaglandins?
PGE2 binds to EP1 which is a GPCR receptor (q) in afferent C fibres. This results in increased sensitivity to bradykinin, inhibition of K+ channels, increased Na+ sensitivity (increased C fibre activity) and increases intracellular Ca2+ (more neurotransmitter released)
What can increased sensitivity of C fibres lead to?
Hyperalgesia - increased response to a painful stimulus
Allodynia - painful response to a normally innocuous stimuli
How is central sensitisation achieved by prostaglandins?
Increased nociceptive signalling peripherally results in increased cytokine levels in the dorsal horn. This causes increased COX-2 synthesis and increased PGE2. PGE2 acts on EP2 GPCRs (Gs) and cAMP and PKA phosphorylates the glycine receptor affecting its binding activity, reducing glycinergic inhibition
How do prostaglandins cause pyrexia?
Infection or inflammation stimulates macrophages which release IL-1. In the hypothalamus IL-1 stimulates PGE2 synthesis which acts on EP3 receptors which are GPCRs (Gi) which resets the body’s temperature higher by increasing heat production and reducing heat loss
What are the 3 main therapeutic effects of NSAIDs?
Analgesia - less ADRs than opiates
Anti-inflammatory
Antipyretic
Describe the pharmacokinetics of NSAIDs
Oral/topical
Linear pharmacokinetics in therapeutic range
T1/2 either < 6 hours e.g. Ibuprofen 2 hours or >10 hours e.g. Naproxen 14 hours
Highly protein bound
What is the mechanism for NSAIDs?
The main therapeutic effect is through COX-2 inhibition and they compete with arachidonic acid for the occupation of the channel in COX-1 and COX-2
What are the main ADRs of NSAIDSs?
GI - pain, nausea, heartburn, bleeding, ulceration (give PPI/synthetic prostaglandins) as PE2 usually stimulates mucus production and promotes blood flow
Renal - in patients with HRH problems they can lead to reduced perfusion and GFR leading to water retention (hypertension) as PE2 usually maintains renal blood flow
Increased bleeding time (anti-platelet action)
Hypersensitivity - skin rash, Steven Johnson syndrome, asthma
Reye’s syndrome - paediatric swelling of the liver and brain
Why are selective COX-2 inhibitors not as effective as expected?
Significant cardiovascular ADRs
What are the DDIs concerning opiates, other NSAIDs, aspirin and ACE inhibitors?
Opiates - extends therapeutic range and reduces opiate ADRs
Other NSAIDs - increases risk of ADRs (protein binding)
Aspirin - competes for COX-1 sites and may interfere with cardioprotection
ACE inhibitors - reduces the effect of stimulating vasodilation
