9.1 NSAIDS Flashcards
how is arachidonic acid synthesised?
in diet, eat linoleic acid (vegetable oil), from this get arachidonic acid which is incorporated into phosphoplipids
phospholipase A2 will convert it back to arachidonic acid from phospholipids.
what can arachidonic acid be used in the synthesis of?
leukotrienes in the eicosanoid synthesis pathway
can use leukotriene receptor antagnoist medication against them e.g in asthma
what are the structural differences of COX1 and COX2?
cox2 has a larger and more flexible substrate channel than cox1, and a larger space where inhibitors bind
= can use different medications on them
what are the functions of COX1?
COX1
- GI protection
- platelet aggregation
- vascular resistance
- renal blood flow
- chronic inflammation
- chronic pain
- raised blood pressure
what are the functions of COX2?
COX 2
- renal homeostasis
- tissue repair and healing
- reproduction (uterine contractions)
- inhibit platelet aggregation
- chronic inflammation
- chronic pain
- fever
- blood vessel permeability
- tumour cell growth
Name 5 prostanoids (type of prostaglandins)
PGE2
PGF2A
PGD2
(play a role in pyrexia, pain and inflammation)
PGI2 - prostacyclin
TXA2 - thromboxane
what is the action of prostacyclin compared to thromboxane?
Prostacyclin is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
thromboxane however stimulates platelet aggregation and arterial constriction= opposing effects
what enhances the action of prostanoids?
local autocoids e.g bradykinin and histamine
what are COX 1 and COX 2 enzymes in the synthesis of?
in the synthesis of the prostanoids
what is the mode of action of nonsteroidal anti-inflammatory drugs (NSAIDS)?
inhibit COX enzymes and so get subsequent reduction in prostanoid synthesis
they compete with arachidonic acid for hydrophobic site of COX
used for their analgesic and anti-inflammatory effects
why is low dose aspirin not considered to be an NSAIDs?
low dose is an irreversible cox inhibitor
moderate is relegated to use as antiplatelet
high dose to see anti-inflammatory effects as it isnt as effective at lower dosages.
how do NSAIDS have analgesic effects?
local peripheral action at site of pain - greater efficacy if inflamed
central component associated with decreased PGE synthesis in dorsal horn = less neurotransmitter released = decreased excitability of neurones in pain relay after first dose but full analgesia after several days of dosing
how do NSAIDS have an anti-inflammatory effect?
reduction in prostaglandin production during injury esp. PGE and PGD2
how do NSAIDS have anti pyretic effects?
inhibit hypothalamic COX-2 where cytokine induced prostaglandin synthesis elevated
how do NSAIDs differentiate?
as to whether they’re more selective of COX1 or COX2
COX2 selective compounds inhibit COX2 with much greater selectivity than COX1 at therapeutic doses
what drugs are more COX1 selective than COX2?
COX 1 asprin iboprofen naproxen diclofenac (non selective)
COX2 celecoxib parencoxib eteoricoxib (selective)
THE -IBS
Are NSAIDS acidic YES OR NO
yeah they’re weak acids especially COX1 inhibitors
how are NSAIDS absorbed and metabolised?
absorbed in GI tract, some in stomach
usually don’t undergo first past elimination
highly protein bound with small Vd
hepatic metabolism to inactive products
how is aspirin metabolised?
asprin -> salicyclic acid -> conjugated with glycine
saturated at high doses - 1st orer-> 0 order (overdose)
what are the GI ADRs of NSAIDs?
dyspepsia nausea peptic ulceration bleeding perforation makes IBD worse irritation and bleeding from rectal admin
this is because
- less mucus and HCO3 secreted = more acid
- decreased mucous blood flow = enhanced cytotoxicity and hypoxia
- decreased hydrophobicity of mucus layer due to NSAIDS local action
what puts you at risk of the GI ADRs of NSAIDS?
age prolonged use glucocorticoid sterioids (act in a similar way) anticoagulants smoking alcohol history of peptic ulceration Helicobacter pylori
what are the renal ADRs of use of NSAIDS?
get reversible
- decreased GFR
- increased creatinine
- decrease renal medullary blood flow
more likely in underlying CKD and blood flow compromise
- congestive heart failure
- cirrhosis with ascites
otherwise
- increased salt and water retention = hypertension and oedema
- lower renin secretion ->hyperkalaemia
how do ADRs vary between cox1 and cox2 inhibitors?
less GI ADRs, renal ADRs similar to COX1 agents, impair PGI2 potentially leading to unopposed aggregatory effects
what are the cardiovascular ADRs of NSAIDS?
increased salt and water retention = exacerbate heart failure and increase BP
vasoconstriction through reduced ADH secretion by prostaglandins
increased risk of acute MI
what are some DDI of NSAIDs?
NSAIDs and low dose asprin = compete for cox1 = decreased CVS protection
may interact with drugs that rely on protein binding as that is the mechanism of NSAIDs
e. g Sulfonylurea - hypoglycaemia
e. g methotrexate - accumulation and hepatoxicity in RA
e. g warfarin - increased risk of bleeding
why should aspirin not be given to children under 12?
Reye’s syndrome
rapid progressive encephalopathy - febrile viral infections, not for children under 12
how does paracetamol have analgesic effects?
COX2 selective inhibition in CNS (spinal cord) = decreased pain signals to higher centres
what is NAPQI?
a minor oxidation product of paracetamol - highly reactive
normal doses, conjugation with glutathione renders it harmless
hepatic glutathione is limited - balance of conjugation determines build up of NAPQI
what happens in a paracetamol overdose?
FIRST 24 HRS
nausea
vomiting
abdominal pain
24-48 HRS
liver damage
upper quadrant pain
3-4 DAYS
maximal liver damage
what do you treat paracetamol overdose with?
acetylcysteine - a thiol donor for phase 2 metabolism
can get into hepatocytes easier than glutathione itself
