MSK 03 Flashcards
Abbreviate NSAIDS?
Non-steroidal Anti-Inflammatory drugs (so it is not a steroid).
Does paracetamol is NSAIDS?
Paracetamol is not a true NSAIDS however as it has no place, so we still put it in this class.
What are the 2 enzymes we target with NSAIDS in our body?
These are COX-1 & COX2
What are the usages of NSAIDS?
Analgesic, Inflammatory, antipyretics effects.
Indications are: Headache, dysmenorrhea, AR, GOUT, surgical pain etc.
What is the General structure of NSAID?
An “acidic moity” attached with aromatic group.
Some also contain an additional lipophilic group attached via linker.
What are the Characteristics of NSAIDS?
Strong acids pKa 3-5
Most are carboxylic acid.
Acidic group is essential for its target Cyclooxygenase
Acidic group is highly protein bound through electrostatic (ionic) interaction.
The acidic functional group is the major part for metabolism (through conjugation- Glucuronidation)
Different drugs within NSAIDS differs based on?
Their aromatic structure and other lipophilic moieties.
What is the General Mechanism of NSAIDs?
Reversible inhibitors of the enzyme Cyclooxygenase (COX). Cyclooxygenase catalyses the conversion of Arachidonic Acid (AA) to Prostaglandin H2. (So, By Ibuprofen are inhibiting “cyclooxygenase” So we can stop the production of prostaglandin (which control process i.e. inflammation))
What is Prostaglandin?
Mediators of Inflammation
How Aspirin inhibits COX enzyme?
Irreversibly acylates.
Acidic group of NSAIDs interacts with Cyclooxygenase enzyme by which interaction?
By Ionic interaction
Why paracetamol does not have anti-inflammatory activity?
Paracetamol structure not made of acidic functional group as a result it is very weak acid. And its pKa is 9.5. This is the reason why it does not attach with cyclooxygenase enzyme in our body, so it does not have inflammatory ACTIVITY, however it has analgesic and antipyretic effect.
What is the good thing about paracetamol compared with NSAIDS?
NSAIDs has side effects i.e GI bleeding, but Paracetamol does not.
Why Ibuprofen and paracetamol can be given together as a combined dose?
Because they have different mechanism of Action. Ibuprofen and Paracetamol can be given as a combined dose because their MOA is different than each other and they work in a separate way. Ibuprofen NSAIDS inhibit COX enzyme but paracetamol Not. Ex: Maxegisic: para+Ibupro
What is the Mechanism of Paracetamol?
Paracetamol is not a true NSAIDS, as it does not have an acidic group attached so it does not bind with cyclooxygenase or inhibit COX enzymes outside the CNS. (in our body) so it is not useful as an anti-inflammatory.
But it selectively inhibits “COX activities” in our brain, which may contribute of its ability to treat fever and pain. But this inhibition of Cox activity is NOT through direct inhibition, so it reduces the Active Cox making it catalytically deficient.
It is well understood that Some of these analgesic activities occurs via the endogenous cannabinoid system(receptor) in our CNS. So, Paracetamol get conjugate with (Arachidonic acid AM404) which is very similar like endogenous cannabinoid Anandamide. Which is weak agonist(activates) CB1 and CB2 receptor. And Inhibit anandamide membrane transporter reduce pain and fever.
How Metabolism of Paracetamol happen?
Glucuronidation with OH group, it also become Sulfation with OH group and excreted out. In addition, we metabolise paracetamol in our liver by CYP450 (which is a minor route). So, this can be a problem if we are taking too much paracetamol leading to overdose. So, we get the conversion of paracetamol to this toxic metabolite NAPQI, which in small amounts is ok but over production create problems.
What happen when a person takes too much paracetamol leading to toxicity?
so normally we can have normal levels of glutathione will interact with NAPQI and help with renal excretion. so, we get nontoxic conjugates. but we only have a certain amount of glutathione being produced in our system so if someone takes too much paracetamol, we have a depletion of glutathione ending up with an overdose of paracetamol. which gives us too much NAPQI which cannot be excreted renally. This then form/bind with protein adducts which leads to hepatic necrosis and renal failure.
So, what we can do for paracetamol Toxicity?
One option is given N-acetylcysteine (treatment for overdose) which is SIMILER to “glutathione” we will use as replacement therapy or substitute therapy in this case for treatment of overdose. This also increases the production of glutathione. if we caught in time.
