Drugs to treat inflammation

Question 1

What is the mechanism of action of GCs?

Answer 1

Inhibit AA release and metabolism

Question 2

What is the mechanism of action of NSAIDs?

Answer 2

Inhibit COX1 and 2

Doesn’t inhibit lipoxygenases, lipoxins and LT-R agonists

Question 3

What is the mechanism of action of CysLT1 R Antagonst?

Answer 3

Blocks LTC4/D4 actions

Question 4

Get ready for a revision slide!

Answer 4

Question 5

What are the uses for PGs?

Answer 5

Generally too unstable and expensive

Epoprostenol - PGI2 analogue in pulmonary HTN

Misoprostol - PGE2 analogue; adjuvant to mifepristone as abortifacient

Question 6

What are the functions of NSAIDs and its indications?

Answer 6

• Anti-inflammatory
  
  • RA, gout
• Analgesic
  
  • Headache, menstrual pain, MSK pain
• Anti-pyretic
  
  • fever, but paracetamol prefered
• Anti-aggregatory
  
  • inhibit platelet aggregation

*NSAIDs are pallative, not curatie, they don’t stop the initation of response only blunt it

Question 7

What are the adverse effects of NSAIDs?

Answer 7

• Bleeding time
  
  • Decrease TxA2 syn –> impaired platelet aggregation –> increase bleeding time
• GIT
  
  • PGE2 has protective role in the stomach against gastritis
    
    • Inc mucus secretion
    • Dec acid secretion
    • Promote blood flow
    • Promote angiogenesis
• Renal
  
  • Decreased PGI2 mediation dilation compromises renal blood flow and may increase BP; decrease PHE2 mediated natriuresis (exretion of Na)
• Pulmonary
  
  • Bronchoconstriction seen in 10% asthmatics as AAs generated from PLA2 are shunted down towards the leukotriene pathway

Question 8

What is the mode of action for Aspirin?

Answer 8

Irreversibly acetylate COX –> Incease in PGI2/TxA2 ratio –> vascular protection

Acetylated COX can make ‘aspirin triggered lipoxins’ (ALTs) which are involved in inflammation resolution. Thought to be because ALTs have the same ligand as annexin A1 which is involved in inflammation resolution

Contraindications

• Reye’s syndrome: anyone younger than adolescent age can have hepatotoxic response in bile like molecules risingi n plasma –> CNS complications
• Tinnitis
• Uric acid retention (gout)

Question 9

What is the use of Paracetamol and its MOA?

Answer 9

Analgesic and Antipyretic

Not anti-inflammatory

contraindicated in children <12m due to Reye’s

Hepatotoxicity

Question 10

What is the risk and benefit of selective COX inhibitor?

Answer 10

COX2 active site is bigger. Hence we can exploit this with celecoxib to get decrease GI side effect.

But COX1 has cardioprotective efect as only platelet have COX1

However, COX2 turns out to be cardioprotective on in the heart as it makes most of the PGI2

Question 11

What is the MOA of GCS?

Answer 11

Transactivation - Binding of GCs stimulate gene expression.

Transrepression - GC-R binds to negative GRE in promoter regions of target genes; induces co-repressor transcriription which represses original target genes that are pro-inflammatory

Tethered transrepression - GC-R binds to NFkB, inhibit MKP1, GILZ and neutral endopeptidases

Uses:

• Asthma (beclamethasone)
• Skin,eye (Topical)
• Hypersensitivity (severe allergic rxns)
• RA (prednisiolone)