NSAIDs Flashcards
what are eicosanoids made from ?
Arachidonic acid
where does arachidonic acid come from?
what does it go into?
linoleic acid (veg oils) and converted in liver phospholipids
what enzyme releases Arachidonic acid ?
Phospholipase A2
What does PGE2 do ?
GI mucosa protection
what does PGI2 do?
what is it balanced by ?
what can imbalance lead to ?
inhibits platelets , vasodilator
TXA2
Hypertnesion, MI and stroke
what is the difference between COX-1 and 2 ?
constitutively active = 1
Inducable in active/inflamed tissue = 2
where is arachidonic acid most abundant ?
muscle , liver, brain and kidneys
What are the 3 prostanoids for pain , pyrexia and inflammation?
PGE2, PGF2, PGD
What are the pathological functions of COX-1?
chronic inflammation and pain
Raised BP
What are the pathological functions of COX-2?
chronic inflammation and pain
fever , blood vessel permeability
tumour cell growth
what other autacoids enhance action of prostanoids ?
Bradykinin and histamine
why does fish oil reduce CVD incidence ?
EPA and DHA (Omega 3 FAs) convert TXA3 and PGE3 so balance shifted to prostacyclin activity
what is the main difference between aspirin and other NSAIDs?
aspirin irreversibly inhibits COX
compared to competitive inhibitors of arachidonic acid
why do you see reduction in platelets still when aspirin is stopped ?
platelets are non nucleic so new platelets take time to synthesis from megakaryocytes
explain the analgesic action of NSAIDs
local action at site due to increased efficacy at inflammation
Central action = decrease in PGE2 synthesis in dorsal horn - less neurotransmitter released = less excitability of neurones in pain
explain anti-inflammatory effects of NSAIDs
reduction in production of PGs especially PGE2 and PGD2 released during injury
Explain Anti-pyretic effect of NSAIDs
inhibition of hypothalamic COX-2 where cytokine induced PGs synthesis elevated - only lowers temp if raised
list the most Cox-1 selective compound to least (first 4)
Aspirin ibuprofen naproxen diclofenac celecoxib (pare and etori)
how can leukotrienes be affected by NSAIDs?
Inhibition of PGE2 leads to less leukoteienes
which type of NSAIDs are more selective at therapeutic doses ?
COX-2 inhibitors
what are the PKs of NSAIDs?
A, D , M and E?
A= GI
D= Accumulate at site of action, Small Vd so protein bound
M = don’t undergo first pass metabolism
liver converts to inactive form
how does aspirin OD work ?
converted to salicyclic acid then conjugation with glycine which saturates at high doses to go from 1st order to zero order
what are GI ADRs of NSAIDs ?
dyspepsia , nausea , peptic ulceration , bleeding and perforation
exacerbation of IBDs
local irriation and bleeding fro rectum
what can put you at risk for GI ADRs?
age, duration of use, glucocorticoid steroids, anticoagulants, smoking, alcohol, history of peptic ulceration and H Pylori
how does NSAIDs causes GI ADRs?
decrease in :
mucus and bicarb secretion and increase in acid
mucosal blood flow –> hypoxia
hydrophobicity of mucus due to acidic nautre of NSAIDs
what are the renal ADRs of NSAIDs?
decrease ADRs and renal medullary blood flow
increase in creatinine
hyperkalaemia
hypertension and oedema
why does the renal ADRs of NSAIDs occur ?
AA vasodilators are not present leading to decreased renin (hyperkalaemia) and increased salt and water retention due to NaK2Cl upregulation
Name 2 Cox-2 inhibitors
Celecoxib
Etoricoxib
Parecoxib
why are Cox-2 not that selective?
Polymorphisms in Cox-2
patients often take non-selective before
Can Cox-2 inhibitors stop platelet aggregation ?
No, but they impair PGI2 potentially leading to unopposed aggregatory effects
what CVS ADRs are seen in mostly in COX-2 selectives?
salt water rentention = increase in BP
Vasoconstriction - reduced inhibition of ADH by prostaglandins
Efficacy of Antihypertensives reduced
risk of MI with traditional as well
when should you not prescribe NSAIDs ?
pro-thrombotic risk
coronary or cerebrovascular diseases
excluding low dose aspirin
why does combination NSAIDs cause increase risk of ADRs?
competitive displacement due to protein binding - PK and PD affected
Name 4 high protein bound drugs and their increased risk of ADRs with NSAIDs
Sulfonylurea - hypoglycaemia
Methotrexate - Hepatotoxicity and leukopenia
Warfarin
Low dose aspiring - competition for COX-1 = Decrease CVS protection
also look out for diuretics
why cant you give aspiring to children under 12 ?
increased risk of Reye’s syndrome - a rapid progressive encephalopathy
what are the ADRs of NSAIDs in pregnant women ?
Delayed labour
increase blood loss
premature closure of ductus arteriosus
use paracetamol instead
name 4 indication for use of NSAIDs
Inflammatory conditions - joints and soft tissue OA- try topical / paracetamol Post op pain topical on cornea menorrhagia close ductus arteriosus
Where is COX-2 expressed constitutively ?
renal arterioles and cells following inflammation
what is the MOA for paracetamol?
what limits its actions ?
COX-2 inhibition in CNS = decreases pain signals to higher centres
Perioxidases in peripheral inflammation = little inflammatory effect
what must you be careful of when prescribing paracetamol?
OTC medications that already have paracetamol = risk of OD
what is a metabolite of paracetamol? how it is minimised ? how does it cause damage?
NAPQI via Phase 1 (CYP450)
Conjugation with glutathione
Highly nucleophilic = oxidising thiol groups on enzymes leads to cell necrosis / apoptosis
- 150mg/kg for OD
Why don’t you give glutathione in paracetamol OD?
cannot enter the hepatocytes
How would a paracetamol OD present ?
Nausea , vomiting, abdo pain - first 24 hours
liver damage / UQ pain - 24 to 48
what is a good indicator of damage from paracetamol OD?
Prothrombin time
why are Blood tests a sort of red herring in paracetamol OD?
They do not show extent of overdose if multiple doses
what should you give in for paracetamol OD?
Activated charcoal if very early
acetylcystiene
why is alcohol bad with paracetamol ?
induces phase 1 metabolism to make more NAPQI
CVS ADRs are more prone to which type of NSAID?
it is not class specific so neither
