14) NSAIDs Flashcards
What are the primary therapeutics effects of NSAIDs?
Analgesia, anti-inflammatory, antipyretic
Give some examples of autocoids:
Bradykinins, histamine, cytokines and leuckotrienes
What are the features of eicosanoids?
Localised release
Short half life
What are eicosanoids derived from?
Arachidonic acid
Give some examples of eicosanoids:
Prostaglandins
Prostacyclins
Thromboxanes
How are prostaglandins synthesised?
Cyclo-oxygenase enzymes
What prostaglandin is most important in mediating the inflammatory response and what is its effect?
PGe
Vasodilation, hyperalgesia, fever, immunomodulation
Describe the features of COX1 (including production):
Constitutively expressed in a wide range of tissues
Short half life
Where is COX1 commonly found?
Gastric mucosa, myocardium, renal parenchyma
Describe the features of COX 2 (including production):
Induced by inflammatory mediators
Constitutively expressed in brain and kidney
How do the structures of COX1 and 2 allow for selective inhibition?
COX1 has a ‘tight’ tunnel for arachidonic acid, whereas COX2 is ‘baggy’
Describe the binding of prostaglandins and their effects at the receptor:
Bind with GPCRs - synthesis of autocoids, potent vasodilators and peripheral nociception
Where does PGE2 bind in the periphery?
C fibres by EP1 receptor
What is the effect of PGE2 binding in C fibres?
Increased C fibre activity by increased sensitivity to bradykinin
What is allodynia?
Triggering of pain from stimuli that don’t usually provoke pain
What is hyperalgesia?
Increased pain from a stimulus that usually provokes pain
Where does PGE2 bind centrally, and what’s its effect?
EP2 receptors - increase sensitivity and discharge rate of secondary interneurones
How do prostaglandins cause pyrexia?
IL-1 release by macrophages causing production of PGE2 in hypothalamus that acts on EP3 to cause increased heat production
Describe the pharmacokinetics of NSAIDs:
First order elimination
Half lives can vary
Heavily plasma protein bound
When are NSAIDs indicated?
MSK disorders for mild-moderate pain
When are renal adverse effects from NSAIDs common?
Heart failure
Renal disease
Hepatic cirrhosis
Hypovolemia
What are some common GI adverse effects of NSAIDs?
Stomach pain, nausea, heartburn, gastric bleeding, ulceration
Why do NSAIDs cause GI side effects?
Gastric prostglandins stimulate mucus production
What are some common renal adverse effects of NSAIDs?
Sodium, potassium, chloride and water retention - hypertension
Why do NSAIDs cause renal side effects?
Decrease renal perfusion, usually maintained by prostaglandins
What are some other adverse effects of NSAIDs (not renal/GI)?
Increased bleeding time
Skin rashes - Stevens Johnson syndorme
Bronchial asthma
Reye’s syndrome
What drugs can NSAIDs displace?
Sulphonylureas
Warfarin
Methotrexate
What is the mechanism of action of aspirin?
Irreversibly inhibits COX enzymes by acetylation
Describe the pharmacokinetics of aspirin:
Half life is short
High doses - zero order elimination
What are some added beneficial effects of aspirin?
Reduces platelet aggregation
May reduce risk of GI and breast cancers
What are the effects of paracetamol?
Mild/moderate analgesia and antipyrexial
What are the potential mechanisms of action of paracetamol?
Weak COX1+2 inhibitor
Metabolite can bind with arachidonic acid
When is paracetamol contraindicated?
Compromised hepatic function
Chronic alcoholics
How is paracetamol usually metabolised?
Phase II conjugation by glucoronide and sulphate
Some phase I oxidation into NAPQI
Describe the metabolism of paracetamol in overdose:
Phase II saturated so build up of NAPQI which can’t be removed due to glutathione depletion
What are the effects of paracetamol overdose?
Necrotic hepatocyte death
Renal failure
What is the treatment plan for someone with paracetamol overdose?
If within 4 hrs: activated charcoal orally
0-36 hrs - N-acteylcysteine IV
Methionine oral if NAC can’t be given promptly
