Inflammation DRUGS Flashcards
Azathioprine- What does it do?
What does it treat?
Prodrug of mercaptopurine which affects purine salvage pathway and leads to incorrect DNA activity through false nucleotides being added.
Immunosuppressant
RA, crohns, UC
Azathioprine MOA
Prodrug of mercaptopurine
HPRT converts mercaptopurine to nucleoside monophosphate (TIMP)
TPMT (Thiopurine methyltransferase) converts TIMP to MeTIMP
MeTIMP inhibits new purine biosynthesis
6-thioguanine nucleotides are incorporated into DNA (false purines) causing apoptosis.
Methotrexate- What does it do?
What does it treat?
Competitive inhibitor of dihydrofolate reductase
Folic acid metabolised by dihydrofolate reductase to N5,N10-methylenetetrahydrofolic acid to make DNA bases (pyrimidines)
Decreases N5,N10-methylenetetrahydrofolic acid (which are used to make pyrimidines)
Stronger binding than folic acid (due to NH2)
Metabolised to polyglutamates= increased size and trapped in cell = prolonged action
Treats RA
Psoriasis
Crohn’s
What drug is the rescue therapy for methotrexate toxicity?
Leucovorin
Allopurinol - What does it do?
What does it treat?
Immunosuppresant- antimetabolite
Inhibitor of xanthine Oxidase (stops conversion of thiouric acid)
Higher affinity
Decreases production of uric acid
Allopurinol metabolised to oxypurinol= both active.
For gout.
Name 2 xanthine oxidase inhibitors
Febuxostat and allopurinol
Leflunomide - What does it do?
What does it treat?
For RA
Effects pyrimidine synthesis pathway, usually in lymphocytes.
Reversible inhibitor of dihydroorotate dehydrogenase.
Decreases synthesis of uridine.
therefore less nucleotide production for DNA.
How are prostaglandins made
Cell membrane phospholipids broken down by phospholipase A2 -> aracadonic acid broken down by Cyclooxygenase (COX) -> prostaglandin G2 (PGG2) -> prostaglandin H2 (PGH2) ->PGE2, PGF2a, PGD2
Explain the COX enzyme
Membrane embedded protein
Makes prostaglandins
Hydrophobic channel into active site
HEME Active site
Arachidonic acid is the substrate
Aspirin binds at serine 529
What is the difference between COX1 and COX2
COX1- metabolism, used all time
has isoleucine
COX2 - Inflammation response
has valine
Hydrophilic side pocket in structure
Where is COX3 and what drug works on it?
In the brain, paracetamol
What do all the COX enzymes have in common?
Hydrophobic binding channel
Catalytic site
Acylation site
Arginine for binding carboxylic acids
What do NSAIDS do in short
Inhibit cyclooxygenase from making prostaglandin G2 from arachidonic acid
What type of NSAID is aspirin
A salicylate
What makes aspirin special when it comes to binding to COX compared to other salicylates?
All other salicylates are competitive inhibitors, aspirin binds to serine 529 and acylates it!
Irreversible inhibition-> blocks access of arachidonic acid to active site.
How do competitive Non-selective NSAIDS work?
Affect COX1 and COX2
act competitively against arachidonic acid.
Inhibition is reversible so increasing conc. of arachidonic acid overcomes activity
Name the 3 subclasses of Competitive Non selective NSAIDs
Arylalkanoic acids
N-arylanthranilic acids
Enolic acids
What is the general structure for Competitive Non selective NSAIDs?
Flat surface—1 c spacer—- acidic group
|
|
lipophilic area
What other pathway does diclofenac also inhibit
Lipooxygenase (therefore decreases production of leukotrienes)
What are N-arylanthranilic acids?
Nitrogen bioisosteres of salicylic acid
Give an example of a arylalkanoic acid
profens
Ibuprofen
Naproxen
Give an example of an N-Arylanthranilic Acid
Fenamic acids
Mefanamic acid
What are enolic acids?
oxicams
Non-carboxylic acid NSAIDS
Inhibit COX thru changing conformation to peroxy radical precursor of prostaglandin G2
Give an example of an enolic acid
Piroxicam
