NSAIDs Flashcards
What are autocoids?
Give some examples of autocoids involved in the inflammatory response
Biological factors “self drugs”- which act like local hormones
They have a brief duration and act near the site of synthesis
e.g. Bradykinins, Histamine, Cytokines, NO, Leukotrines
What are eicosanoids?
Give examples of such
A family of oxygenated derivatives of 20-carbon polyunsaturated fatty acids used as signalling molecules
e.g. prostaglandins, thromboxanes
What are the key features of inflammatory mediators and signalling agents?
Localised release
Short half lives - fine control
Prostaglandins are synthesised from what?
Arachidonic acid
Which enzymes are responsible for the synthesis of prostaglandins?
Cyclo-oxygenase (COX) enzymes
Cell membrane phospholipids are converted to arachidonic acid by which enzyme?
Phospholipase A2
Arachidonic acid is converted (by COX-1/COX2) into which prostaglandin followed by which other prostaglandin before they are converted by specific prostaglandin enzymes?
1) PG ‘G’
2) PG ‘H’
Which is the most important prostaglandin in mediating inflammatory response?
PG ‘E’
What kind of responses are elicited by PG ‘E’?
Vasodilatiomnm
Hyperalgesia
Fever
Immunomodulation
PG synthesis by COX-1 has a major cytoprotective role, in which tissues is this particularly important? Why?
Gastric mucosa
Myocardium
Renal parenchyma
Because they are very metabolically active tissues
What is the approximate half life of PGs?
What does this mean in relation to their production?
10 minutes
They need constant synthesis
COX-1 is constitutively expressed.
In what way does this contribute to the enzymes role in certain ADRs?
Most ADRs that are caused by NSAIDs are due to COX-1 inhibition
COX-2 expression is induced by what?
Injurious stimuli - inflammatory mediators such as bradykinin
Cox-2 appears to be constitutively expressed in which parts of the body?
Brain
Kidney
The main therapeutic effects of NSAIDs occurs via which enzyme?
Cox-2
What is the structural difference between COX-1 and COX-2 enzymes?
COX-1 is narrow mouthed, has a “tight” opening
COX-2 is wide mouthed, has a “baggy” opening
Prostaglandins bind to which receptors?
GPCRs
(G-protein coupled receptors)
What effects do prostaglandins have on local blood vessels?
Vasodilation
Allows access by bradykinin and histamine to the site= increased permeability of the site by these and not PGs directly
Which specific prostaglandin E receptor is responsible for vasodilation or surrounding blood vessels?
Which type of GPCR is this?
EP2
Gs
Which specific Prostaglandin E receptor is responsible for incresed peripheral nociception?
Which kind of GPCR is this?
Where are these receptors found?
EP1
Gq
C fibres
Painful stimuli is carried why which fibres of the nervous system?
C fibres
Binding of prostaglandin E to EP1 receptors on C fibres results in which downstream effects?
What is the overall effect of these?
Increased neuronal sensitivity to Bradykinin
Inhibition of K+ channels (closer to threshold for AP firing)
Increased Na+ channel sensitivity
Overall effect: increase C fibre activity
Explain what is happening at a cellular level when prostaglandin E binds to to EP1 receptors on C fibres
PG E binds EP1 (Gq GPCR)
Increased intracellular calcium
Increased neurotransmitter release
Increased sensitivity via other autocoids
What is allodynia?
How does this differ from hyperalgesia?
The feeling of pain in a tissue given a stimulus that would not normally be painful in that tissue
Hyperalgesia is an increased pain stimulus in a tissue that WOULD normally perceive pain
Which three changes in nociception might a patient experience following injury?
Spontaneous pain
Allodynia
Hyperalgesia
What does increased sustained nociceptive signalling peripherally result in?
Increased cytokine levels in the dorsal horn cell body
Leading to central sensitisation to pain (increased pain perception)
What happens at a cellular level to cause increased central sensitisation to pain?
PG E binds to EP2 receptors (Gs GPCR)
Increased cAMP
Increased PKA
Decreases glycine receptor binding affinity
Increases the discharge rate
In infected/inflammed tissue, bacterial endotoxins stimulte macrophages to release what?
What does this then go on to do?
IL-1
IL-1 within hypothalamus stimulates PGE synthesis
Prostaglandin E interacts with which receptor to cause pyrexia?
EP3 receptor which is a Gi GPCR
It results in increased heat production and reduced heat loss
The main therapeutic effects of NSAIDs are achieved via inhibition of which enzyme?
What kind of inhibition is this?
COX-2 (and 1)
Competitive
NSAIDs display _______ pharmacokinetics within the therapeutic dose range
Linear
What are some of the main ADRs of NSAIDs?
Stomach and GI tract: nausea, heart burn, gastric bleeding, ulceration
Renal ADRs: in HF, renal disease
Vascular risk: Increased risk of bleeding, bruising
Give an example of a serve hypersensitivity reaction to NSAIDs
Stevens Johnson Syndrome
Rash over skin and all mucous membranes within the body
Immune-complex mediated hypersensitvity reaction
Explain the reason for GI ADRs with NSAIDs
COX-1 inhibition leads to reduced binding to receptors and therefore reducted prostaglandin production
The prostaglandins would normally stimulate cytoprotectice mucus secretion through the GI tract, reduce acid secretion and promote mucosal blood flow
What drugs can be combined with NSAIDs to extend their therapeutic range for treating pain?
Low dose opiates
Are NSAIDs heavily or weakly protein bound?
Heavily bound
90-99%
NSAIDs can affect PK and PD of other drugs, give some examples.
Sulphonylurea
Warfarin
Methotrexate
Aspirin is the only NSAID to _________ inhibit COX enzymes by acetylation
Irreversibly
When aspirin is taken orally, what is its half life?
Less than 30 minutes
Aspirin in hydrolysed in the plasma to what?
Which kinetics does this display at varying doses?
Salicylate
Lower: first order kinetics
Higher: zero order
What is the mechanism of action of paracetamol?
Unknown
Possibily weak COX-1/2 inhibitor
Which order of kinetics does paracetamol show in a healthy patient at normal doses?
First order (linear)
(Half life 2-4 hours)
What pharmacokinetics does paracetamol show at high doses?
Zero order kinetics
What is the toxic metabolite produced in the breakdown of paracetamol?
NAPQI
Why do doses over 10g (20 tablets) cause a potentially fatal response in the patient?
NAPQI is produced, glutathione which usually mops it up is saturated due to the excess
Leading to increased production of NAPQI–> unconjugated
Highly reactive- binds with cellular macromolecules and mitochonrdia
Lead to hepatic cell death
How can paracetamol iverdose be treated?
Activated charcoal orally within 0-4 hours
Acetylcysteine within 0-36 hours
or
Methionine orally if this cannot be given in this time
How do we decide whether to treat a patient following paracetamol overdose?
Use a treatment decision graph
Which depends on the time after OD and their current plasma level
