Anti-inflammatory drugs

Difference between the two drug classes?

• Anti-inflammatory drugs reduce inflammation

• Immunosuppressive drugs reduce the amount/action of T and B cells

What’s special about glucocorticoids?

They act as both anti-inflammatory and immunosuppressive drugs

COX-1 vs COX-2

	COX-1 (constitutive)	COX-2 (inducible)
Where	Stomach, intestine, endothelium, kidney, platelets, is "always on"	Induced at inflammation sites (macrophages, synoviocytes)
Produces	PGE2 (gastric protection), TXA2 (platelet aggregation), PGI2 (renal blood flow)	Inflammatory prostaglandins
Physiological role	Housekeeping/protective	Drives inflammation

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

General mechanism: inhibits cyclooxygenase (COX) → block conversion of arachidonic acid into prostaglandins/thromboxane, resulting in anti-inflammatory, antipyretic, analgesic effects.

ASA & Ibuprofen are both NAISDs, but how are they different?

The general mechanism is the same and they are both npn-selective, but reversibility is different between the two.

Differences	ASA (aspirin)	Ibuprofen
Reversibility	Irreversible; acetylates and permanently inactivates COX	Reversible competitive inhibition
Selectivity	Non-selective (COX-1 + COX-2)	Non-selective (COX-1 + COX-2)

Why does aspirin have such a long-lasting antiplatelet effect?

Platelets have no nucleus, so they can't synthesise new COX once ASA has acetylated it. The inhibition therefore lasts the entire lifespan of that platelet (~7–10 days).

What conclusions can be drawn from the selectivity plot?

• Drug X: above the diagonal → lower IC50 for COX-1 → COX-1 selective

• Drug Z: below the diagonal → lower IC50 for COX-2 → COX-2 selective

• Drug Y: on the diagonal → non-selective

Why have selective COX-2 inhibitors been developed?

COX-2 has a larger, more flexible binding pocket than COX-1, so drugs (e.g. celecoxib) can be shaped to fit COX-2 only, sparing COX-1. This protects stomach and platelets while still treating inflammation.

Adverse Effects of NSAIDs

Non-selective NSAIDs:

• Inhibition of TXA2 reduces platelet aggregation, leading to bleeding risks

• Inhibition of gastric prostaglandins (which normally protect the mucosa) can lead to GI damage

Selective COX-2 inhibitors:

• Inhibition of PGI2 (antiplatelet, vasodilator) from endothelium without inhibiting platelet TXA2 shifts balance toward clotting

• Increased risk of heart attack and stroke (black box warning for cardiac patients)

• Advantage: less GI irritation than aspirin

Prednisolone - Glucocorticoid (transcriptional modulator)

• Mechanism: Binds to intracellular (cytoplasmic) glucocorticoid receptor (GR) → receptor-ligand complex translocates to the nucleus and binds DNA → alters gene transcription to alter protein synthesis → altered cell function

• Transcriptional effects

  • Trans-repression: ↓ inflammatory genes (cytokines, chemokines, adhesion molecules, COX-2)

  • Trans-expression: ↑ anti-inflammatory proteins, notably annexin 1, which inhibits phospholipase A2 → less arachidonic acid substrate available in the first place

How do glucocorticoids differ from NSAIDs?

• NSAIDs directly inhibit the COX enzyme itself, and is therefore used for acute pain

• Glucocorticoids inhibit transcription of the COX-2 gene, which is a step further upstream, and genomic/slow rather than direct/fast; this is why GCs aren't useful for acute relief

Adverse Effects of glucocorticoids

• During treatment (supraphysiological doses): hyperglycemia, osteoporosis, myopathy, growth arrest, Cushing's features (moon face, buffalo hump, striae, hypertension, bruising, insomnia)

• On withdrawal: flare of underlying disease, and acute adrenal insufficiency, because exogenous GC suppresses the HPA axis via negative feedback, so the adrenal cortex stops producing endogenous cortisol; abrupt stopping leaves the body without adequate cortisol.

  • This is why glucocorticoids must gradually be stopped rather than abruptly