NSAIDs Flashcards
What are the 3 primary therapeutic effects of NSAIDs?
Analgesia
Anti-inflammatory
Antipyretic
What is the key action of NSAIDs?
Prostaglandin synthesis enzyme inhibition
What are autacoids?
A diverse range of local molecular mediators and signalling agents
Give some examples of autocoids.
Bradykinins Histamine Cytokines Leukotrienes Nitric oxide Neuropeptides Prostaglandins
When are autocoids released?
In response to local injury to tigger a local response
What are prostaglandins synthesised from?
Arachidonic acid
What enzymes are used in prostaglandin synthesis?
COX Enzymes (Cyclo-oxygenase)
Describe the pathway of prostaglandin synthesis.
Cell membrane phospholipids -> arachidonic acid (Phospholipase A2)
Arachidonic acid -> PG “G” (COX-1/COX-2)
PG “G” -> PG “H” (COX-1/COX-2)
PG “H” to D, E, F, and I via further specific enzymes
Which PG is the most important in mediating the inflammatory response?
E
What effects for PGs have, especially E?
Vasodilation
Hyperalgesia
Fever
Immunomodulation
Where is COX-1 expressed?
Throughout a wide range of tissues
Where and for what is PG synthesis by COX-1 very important?
Cytoprotective role in the:
- Stomach mucosa
- Myocardium
- Renal parenchyma
What is the half life of PG?
Short, so need constant synthesis
What are most NSAID ADRs caused by?
The effect of NSAIDs on COX-1
Where is COX-2 expressed?
Induced by injury and inflammatory mediators such as bradykinin.
Also in part of the brain and kidney constitutively.
Via which of the COX enzymes do NSAIDs exert their main therapeutic effect?
COX-2
Do COX 1 and 2 work independantly or together?
Independantly
Why do different NSAIDs work differently on COX 1 and 2?
COX-1 and 2 have different tunnel for catalysing arachidonic acid, so different shaped drugs fit the different enzymes.
What kind of receptor do PGs have?
GPCRs
How do PGs act on blood vessels?
As potent vasodilators
Which PG receptor increases afferent nociception?
EP-1
Which PG receptor causes vasodilation?
EP-2
What happens when a PG binds to its receptor?
GPCR is activated -> increased neuronal sensitivity to bradykinin, K+ channel inhibition, and increased sensitivit of Na2+ channels.
This all causes increased C fibre activity, including previously silent C fibres.
How is pyrexia caused by PGs?
Infection/inflammation -> IL-1 release from macrophages which stimulates PGE2 synthesis in the hypothalamus. PGE2 acts on EP3 receptor which causes heat production and decreased heat loss.
How do NSAIDs generally inhibit COX1 and 2?
As competative inhibitors - occupy the hydrophobic channel
How many NSAIDs are there roughly?
50
Tell me about the pharmacokinetics of NSAIDs.
Can be given orally (typical) but also topically for soft tissue injury.
Linear pharmacokinetics
2 groups of half lives - under 6 hours, or over 10 hours.
90-99% bound to plasma proteins.
When are NSAIDs used?
In inflammatory disorders such as RA or OA
Analgesia for mild to moderate pain
NSAIDs vs Opioids
NSAIDs are less effective but have a better ADR profile
What are the ADRs associated with NSAIDs?
Many many…
Stomach and GI tract major side effects
Renal ADRs in pts with Heart, hepatic, or renal impairment, or hypovolaemia.
What GI side effects can NSAIDs have?
Varying degrees of stomach pain, nausea, heart burn, gastric bleeding, ulceration.
How can we offset some of the GI ADRs of NSAIDs?
Give a PPI alongside, or misoprostol if using long term
What % of pts on NSAIDs get GI side effects?
35%, and some may be asymptomatic
What renal/renovascular ADRs can pt on NSAIDs get?
Decreased renal perfusion -> decreased eGFR, Na2+, K+, Cl- and water retention -> hypertension.
Which renal vascular element do NSAIDs act on and how?
Prevent vasodilation of the afferent arterioles by inhibiting COX-1/2 so PG synthesis prevented.
Can people be allergic to NSAIDs?
Some people can have a hypersensitivity rxn to NSAIDs. Some NSAIDs have skin rash rate of 15%, usually mild. Can get Steven Johnson syndrome (vvv rare).
What is Steven Johnson syndrome?
Immune complex mediated hypersensitivity rxn, with compromised hepatic function, and rash of skin and mucous membranes.
What can happen to children who take NSAIDs?
They can have paediatric Reyes syndrome - rare serious brain/liver injury, usually comes about due to viral infection treated with aspirin.
What have clinical trials shown to be the problem of specific COX-2 inhibitors?
Long term use leads to increased risk of CVS ADRs
What can NSAIDs be used alongside?
Low dose opiates to extend therapeutic range and reduce opiate ADR profile.
What can happen between NSAIDs and aspirin?
NSAIDs can interfere with aspirins cardioprotective action, and compete for plasma protein binding sites.
What drugs require dose adjustments when taken with NSAIDs, and why?
Sulphonylurea
Warfrain
Methotrexate
Competative displacement by NSAIDs, so have to avoid PK and PD changes.
What is the risk of NSAID + sulphonylurea?
Increases BA of sulphonylurea -> hypoglycaemia
What is the risk of NSAID + warfarin?
Increases warfarin BA -> bleeding
What is the risk of NSAID + methotrexate?
Wide range of ADRs associated with methotrexate
How does aspirin work?
Irreversibly inhibits COX enzymes by acetylation. Unique in its MoA.
What is unusual about aspirins pharmacokinetics?
T1/2 is less than 30 minutes.
Hydrolysed in plasma to salicylate.
First order kinestics at lower doses. Zero order at higher doses.
What is paracetamol?
A unique non-NSAID non-opiate analgesic
What actions does paracetamol have?
Virtually no anti-inflammatory action.
Mild/moderate analgesic and antipyrexic
What kind of therapeutic index does paracetamol have?
A low one - even 10 tablets in an hour is potentially fatal.
What is the MoA of paracetamol?
Weak COX-1 and 2 inhibitor, with potential action on CNS COX-3 isoform (unable to isolate yet).
Also metabolite combines with arachidonic acid to block bidning of COX-1 and 2 in the CNS.
What is the t1/2 in healthy patients for paracetamol?
2-4 hours
Who needs to careful around paracetamol?
Pts with impaired hepatic function or alcoholics
How is NAPQI toxic?
V reactive - binds to cellular macromolecules and mitochondria -> loss of function -> necrotic hepatocyte death.
When is the peak for hepatotoxic effects of a paracetamol overdose?
72-96 hours post ingestion
How much can activated charcoal reduce paracetamol uptake by?
50-90% if given within an hour of ingestion
What is the management of paracetamol overdose?
IV N-acetylcysteine according to blood levels of paracetamol 4 hours post ingestion.
Psychiatric assessment, and supportive treatment.
What can we give if N-acetlycysteine can’t be given promptly for a paracetamol overdose?
Methionine
