NSAIDs. Flashcards
Eicosanoids.
Where is AA primarily derived from in the diet?
What is the rate limiting step?
What is the difference between eicosanoids and prostanoids?
Why can steroids stop the formation of eicosanoids?
What are the unstable endoperoxides?
Lineloic acid
PLA2
Eicosanoids - PGs LTs and TX
Prostanoids - PGs and TX
Cause production of lipocortin which inhibits PLA2
PGG2 -> PGH2
COX ENZYMES.
Where are COX 2 enzymes constitutively active?
Give some homeostatic functions of COX 1 and 2.
Give two pathological functions of booth?
COX2?
COX1?
Renal and CNS tissues.
GI protection Platelet aggregation Vascular resistance Renal blood flow COX2 - inhibition of platelet aggregation, uterine contraction, tissue repair and healing.
Chronic pain and inflammation.
Fever, blood vessel permeability and tumour frowth.
Raised blood pressure.
Prostanoids.
Which two have opposed vascular effects? Describe.
Why can diet rich in fish oils be cardioprotective?
TXA2 and PGI2
PGI2 - vasodialtes and inhibits platelet aggregation
TXA2 - vasoconstriction and stimulates platelet aggregation.
DHA and EPA converted to TXA3 and PGE3 - more prostacyclin activity - lowers incidence of CVD.
NSAIDs.
Peripheral and central analgesia MOA.
Anti inflammatory action.
Anti-pyretic action.
Anti-platelet action?
Name 4 COX-1 selective.
Decrease PG which normally sensitise nociceptors to BK
Decreased PGE2 in dorsal horn decreasing NT release and neuronal excitability.
Decreased prostaglandins ie PGE2 and PGD2 especially decreased vasodilation and swelling.
Inhibition of COX-2 in hypothalamus normally induced by IL-1 to make PGE2.
Decreased TXA2 synthesis.
Aspirin, ibuprofen, naproxen and diclofenac
PK of NSAIDS.
Why are their half lives not representative of their duration of therapeutic effect?
Metabolised mainly by?
Problem with aspirin metabolism?
Because they may accumulate in synovial fluid for example independant of Half life - less fluctuation.
Liver
Goes from first order -> zero order - as glucoronic acid and glycine runs out - level levels in plasma result.
Give some ways in which they cause GI ADRs.
Why are the renal ADRs more likely in those with CKD, congestive heart failure and cirrhosis?
Why salt and water retention? Why can this be bad?
Why hyperkalemia?
What do they CV event do ALL NSAIDS they increase the risk of?
Decrease mucus and bicarbonate production
Increase acid production
Decrease mucosal blood flow
Decreased hydrophobicity of the mucus due to acidic nature of NSAIDs
They are more relevant on prostaglandins for vasodilation.
NKCC2 upregulation
Exacerbate heart failure and increase blood pressure.
Renin secretion decreased.
Acute MI
Name 3 COX-2 selective NSAIDs.
Which ADRs are reduced?
Which action is not shared by these?
Celecoxib
Etoricoxib
Parecoxib
GI
Antiplatelet - instead impaired PGI2 can lead to potentially aggregatory effects.
DDIs.
Give some extensively protein binding drugs which can be potentiated.
What is Reye’s syndrome and when does it occur?
Why is paracetamol a preffered choice in pregnancy?
Methotrexate (leukopenia, hepatotoxicity)
Sulfonylureas (hypoglycaemia)
Warfarin (increased bleeding risk)
Progressive encephalopathy associated with treating viral disease with aspirin in under 12s
Can close the ductus arteriosus
Delayed labour due to fewer prostaglandins to cause the contractions
Increased haemorrhage risk
What should be used in OA?
Why can they be used in cataracts operation?
Give some other uses.
Paracetamol then topical NSAIDs
Due to topical usage on the cornea
PDA
Menorrhagia
Paracetamol.
Proposed MOA?
Why does it not work well in an inflammatory setting?
Presentation in overdose?
What can be used to measure the extent of damage?
Comment on acute and chronic alcohol use in paracetamol overdose.
COX-2 selective inhibition in the CNS leading to decreased pain signals to the higher centres.
Doesnt work well in the presence of peroxidases and there are plenty of peroxidases found in sites of peripheral inflammation.
Asymptomatic for hours - vague abdo pain N/V in 24 hours
RUQ pain and liver damage follows with maximal liver damage occurring 3-4 days later.
Prothrombin time
Acute alcohol - saturation of CYP2E1 - less production of glutathione
Chronic alcohol - leads to induction of CYP2E1 enzymes - increasing potential toxicity of paracetamol.
