1.3 Paracetamol NSAIDs, Gout Medications and DMARDs

WHy we dont what to take greater than 4 g of paracetamol (or long-term use)

risk of the metabolite NAPQI to destroy your liver

Converts into metabolite N-acetyl-p-benzoquinone imine (NAPQI)

(NAPQI)

N-acetyl-p-benzoquinone imine

Acute Alcohol

acutely CYP inhibitor

Chronic Alcohol

Chronically CYP inducer

Paracetamol antidote

N-acetylcysteine

○ Helps restore glutathione stores

○ Very expensive to compound in the hospital

Can we drink alcohol and paracetamol together???

○ There are no clinical data to support or refute this interaction

○ Placebo and hydration is the best treatment for hangovers

● One prevailing theory is that it is very selective in COX it likes to block

● Likes to block COX in the CNS but not in the periphery

Paracetamol MOA

for headaches and fever in the brain can apparently work

● Blocks CNS PG synthesis via COX-1 variant inhibition? COX-2?

Paracetamol

Your body has its own weed

anandamide and 2-acylglycerol that binds to certain cannabinoid receptors

What does paracetamol activate

endocannabinoid system, transient receptor potential vanilloid-1 (TRPV-1) channel

Paracetamol does not itself activate the endocannabinoid system ● Paracetamol gets converted by the enzyme fatty acid amide hydrolase into AM404 which activates the endocannabinoid system that is useful for analgesia

We do know that the endocannabinoid system is useful for pain

Parace

Oral vs IV

Bioavaibility

Onset

ABOUT THE SAME LANG. if thinking it works faster, waste of money sa patient

Efficacy

Accounting for bioavailability and onset, efficacy is also just pretty much the same

Cost

IV is more expensive

Joints are damaged due to exhausted chondrocytes

○ Normally, bones and joints break down. But here, the cells responsible for building back the broken-down bones/joints are tired already and can’t work efficiently anymore

Osteoarthritis

Autoimmune

○ Interleukins and TNFs produced by neutrophils etc., attacking the joints

Rheumatoid arthritis

○ Monosodium urate crystallization in the joints attracts inflammasomes. The crystal formed will then be attacked by your immune cells

○ Monosodium urate + Inflammasome + Immune Cell Recruitment

Gouty arthritis

T/F NSAIDS are the treatment for osteoarthritis beyond reducing inflammation

■ Long-term, it stops the degredation of the joints.

○ We do not have treatment for osteoarthritis beyond reducing inflammation

■ Long-term, there are no disease-modifying: our joints still degrade

NSAIDs, disease modifyiing?

They’re OTC drugs reducing pain and inflammation but not underlying cause/disease-modifying

○ Phospholipids (converted by Phospholipase) ⟶ Arachidonic acid through LOX or COX

○ LOX produces leukotrienes; COX produces prostaglandins and thromboxanes

Competitive COX inhibition EXCEPT Aspirin (Covalent)

. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

In general, all NSAIDs are equivalent almost, except

Aspirin (Non-competitive binding)

blocks COX covalently (mas clingy) which means it is irreversible and can not be displaced anymore

Aspirin

COX major isoforms

COX-1 and COX-2

are always for symptomatic treatment only. They will NOT address underlying pathophysiology.

NSAIDs