Where is arachidonic acid from?
Where converts it?
Where is it found?
What does it turn into?
vegetable oils (linoleic acid)
the liver converts this to arachidonic acid and its incorporated to phosphlipids
all over the body but especially in MUSCLE BRAIN LIVER KIDNEY
it is converted by COX into prostanoids
What does PGE do?
What does does PGF do?
What does PGD2 do?
What does PGI2 do?
What does TX2 do?
these are all prostanoids btw
good for stomach (GI mucosal protection) - Gi to inhibit acid secretion by parietal cells, uterine contraction
pain, pyrexia, inflammation, uterine contraction, bronchoconstrictor
pain pyrexia inflammation, inhibits platelets aggregation, bronchoconstrictor
inhibits platelet aggregation (cytoprotective in CVS), mucosal repair to GI + blood flow
platelet aggregation (bad for CNS), vasoconstriction
What receptors do prostanoids act on.
What can enhance their action?
Which prostanoids have opposing effects?
GPCRs
autacoids e.g. bradykinin and histamine
TXA2 and PGI2 have opposing vascular effects (platelet aggregation and inhibition of this)
imbalance in these plays roles in hypertension, MI and stroke risk!!
Why does the Mediterranean diet lower CVD chances?
the diet is rich in fish oil (omega 3 fatty acids)
this is thought to lead to the conversion to TXA3 and PGI3 = better protsanoids = lower CVD
what does cyclooxygenase do?
What 2 enzymes are there?
catalyse the reaction to make prostanoids
COX-1
COX-2
also COX-3 but not sure what it does
What are COX-1 homeostatic functions?
Pathological functions?
What are COX-2 homeostatic functions?
Pathological functions?
What is different about the structure of COX 1 and 2?
Why are NSAIDs so important?
What do they inhibit?
What do they compete with?
they have multiple uses, 10% of uk population prescribed in any year
inhibit COX = less postanoids (prostaglandins, prostacyclin and thromboxane)
they compete with arachidonic acid for hydrophobic site on COX enzymes
what are the 3 main used of NASIDs?
- analgesia
- anti inflammatory
- antipyretic
How do NSAIDs cause analgesia ?
When is there greater efficacy?
reduces peripheral pain fibre sensitivity by blocking PGE2
less PGE2 synthesis in the Doral horn of the spinal cord
less neurotransmitter release and reduces excitability of neurones in pain pathway
several days of dosing and if the area is also inflamed
how do NSAIDs cause anti inflammatory effects?
What other benefit can happen due to the anti inflammatory effect?
Does the NSAID solve the problem?
reduced COX action = less postanoids = less vasodilation and oedema
inhibits post capillary venule dilation = less permeability and swelling
reduction in other anti inflammatory mediators = ROS lower = reduction in some cancers
How do NSAIDs have an antipyretic effect?
PGE2 is inhibited - this is crucial on acting on the hypothalamus to increase the set point of temperature in the thermoregulatory centre only with pyrogens and cytokines
why were COX -2 inhibitors created?
Why are they better?
Examples of COX 2 selective inhibitors?
Non COX2?
because COX-1 had a high amount of ARDs
more selective at therapeutic doses
celecoxib, etoricoxib
aspirin
side effects of NSAIDS?
contraindications?
Interactions?
dyspepsia, nausea, peptic ulcer, bleeding and perforation, exacerbation of IBD, lower GFR due to lower renal blood flow, higher BP as protagalndins usually cause naturesis
CKD and heart failure (larger reliance n prostaglandins for vasodilation/renal perfusion), elderly, prolonged use, smoking, alcohol, history of peptic ulcer or H. pylori
aspirin, glucocorticoid steroids, anticoagulants, ACEi, ARB, diuretics
Why are you more at risk of GI bleed when using NSAIDs?
Why is using NSAIDs bad fro the kidney?
What other drug can effect the kidney especially when used with NSAIDS?
acid secretion is increased
lower mucosal blood flow = enhanced hypoxia and cytotoxicity
lower mucus and bicarbonate
lower PGI2 and PGE2
cannot dilate the afferent arteriole via prostaglandins = lower GFR!!
ACEi and ARB prevent vasoconstriction of efferent = lower GFR!
does COX - 2 cause an increase in GI ADRs?
Renal?
What does it do to platelets?
When is this drug used?
less GI ARDs!!
similar renal effect
ads to unopposed aggregator effects due to PGI2 inhibits
less analgesic effect - useful for sever osteo and RA
What drugs can NSAIDs displace from protein in plasma and therefore what effect is had?
What steps should you take when mixing these?
sulfonylureas = hypoglycaemia
methotrexate = accumulation and hepatotoxicity
warfarin - increased bleed risk
dose adjustment and monitoring
When should you use NSAIDS?
What should you consider when using NSAIDs / potentially not prescribe?
What is paracetamol?
Why can they be seen as better than NSAIDS?
What is the half life.
Where are they inactivated and how?
a non NSAID, non opiate analgesic and antipyretic for mild and moderate analgesia and fever
fewer ARDs and no effect on platelet or GI !!
2.5 hours
conjugation in the liver
What is a toxic metabolite of paracetamol at high doses?
What substance normal renders this harmless?
What does the toxic substance do?
How many mg/kg is enough for irreversible damage.
NAPQI
glutathione
very nucleophilic = oxidises key metabolic enzymes = cell death and necrosis and apoptosis
150mg/kg
In paracetamol overdose what is seen in the first 24 hours?
3-4 days?
What 2 drugs can be used to treat a paracetamol overdose?
asymptomatic or nausea, vomiting and abdo pain
maximal liver damage !!
activated charcoal if the overdose is very recent !!
acetylcysteine (glutathione thiol replacement) if later presentation
blood should e taken after 4 hours in order to see extent of OD