week 5: NSAIDS & steroids

Question 1

What is the main mechanism of action of NSAIDs?

Answer 1

NSAIDs inhibit cyclooxygenase (COX) enzymes—COX-1 and/or COX-2—thereby blocking the conversion of arachidonic acid into prostaglandins and thromboxane, reducing inflammation, pain, fever, and platelet aggregation.

Question 2

What are the four main types of anti-inflammatory drugs and their targets?

Answer 2

Glucocorticoids → inhibit arachidonic acid release/metabolism (direct)

NSAIDs → inhibit COX1/COX2 enzymes (direct)

CysLT1 antagonists → inhibit LTC₄/D₄ actions at CysLT1 receptor (direct)

Biologics → inhibit TNFα (indirect)

Question 3

What are the four main clinical effects of NSAIDs?

Answer 3

Anti-inflammatory

Analgesic (pain relief)

Antipyretic (fever reduction)

Anti-aggregatory (prevents platelet clumping)

Question 4

How do prostaglandins contribute to pain?

Answer 4

Enhance pain receptor sensitivity

Increase bradykinin and Bk-1 receptor activation

Promote COX-2 and PLA2 expression → ↑ PGE₂

Question 5

How do prostaglandins contribute to fever?

Answer 5

Cytokines from macrophages cross the BBB

Bind to PGE₂ → stimulate cAMP release

cAMP raises the hypothalamic set-point → ↑ temperature
(NSAIDs reduce fever by blocking this process)

Question 6

Which NSAID is best for antipyretic use?

Answer 6

Paracetamol (effective in the CNS with minimal anti-inflammatory effects)

Question 7

Which NSAIDs are best for inflammatory conditions like rheumatoid arthritis?

Answer 7

Non-selective or COX-2 selective NSAIDs for acute and chronic inflammation

Question 8

Which NSAIDs are best for pain relief?

Answer 8

Analgesics such as aspirin or paracetamol for headaches, menstrual pain, etc.

Question 9

What are the gastrointestinal (GIT) adverse effects of NSAIDs?

Answer 9

Inhibit protective prostaglandins in the stomach

Can cause irritation, ulcers, or pain

Question 10

Why do NSAIDs increase the risk of bleeding?

Answer 10

NSAIDs block thromboxane A₂ (TXA₂), impairing platelet aggregation and increasing bleeding risk

Question 11

How do NSAIDs cause renal (kidney) adverse effects?

Answer 11

↓ renal prostaglandins → ↓ Na⁺/water balance

Leads to Na⁺ retention → fluid overload → hypertension

Question 12

How do NSAIDs cause pulmonary side effects?

Answer 12

Inhibit COX → shunts arachidonic acid to leukotriene pathway

↑ Leukotrienes (LTC₄, LTD₄, LTE₄) → bronchoconstriction → asthma symptoms

Question 13

What is the gastroprotective role of PGE₂ in the stomach?

Answer 13

Increases mucus secretion

Decreases acid secretion

Promotes repair via increased blood flow and angiogenesis

Question 14

What are the cardiovascular side effects of NSAIDs?

Answer 14

↓ TXA₂ synthesis → impaired platelet aggregation

↑ bleeding time → risk of hemorrhage (e.g. stroke)

Question 15

What is the mechanism of action of aspirin?

Answer 15

Irreversibly inhibits COX-1 and COX-2 via acetylation

↓ Prostaglandins → ↓ pain, inflammation, fever

↓ TXA₂ → ↓ platelet aggregation

Question 16

What are aspirin-triggered lipoxins (ATLs)?

Answer 16

Anti-inflammatory molecules produced when aspirin acetylates COX-2

Pro-resolving → help end inflammation

Question 17

What roles do COX-1 and COX-2 play in the body?

Answer 17

COX-1: Cytoprotective (e.g. gastric mucus production)

COX-2: Inducible during inflammation

Question 18

Why were COX-2 inhibitors developed?

Answer 18

To reduce inflammation without affecting COX-1-mediated gastric protection, minimizing ulcer risk

Question 19

What is a modern COX-2 selective NSAID and what are its risks?

Answer 19

Celecoxib: COX-2 selective NSAID

↓ gastric side effects, but carries cardiovascular risks

Question 20

What happened with the COX-2 inhibitor rofecoxib

Answer 20

It was withdrawn due to increased risk of myocardial infarction and stroke

Question 21

What is the mechanism of action of paracetamol?

Answer 21

Inhibits COX (mainly COX-2) in the brain

↓ CNS prostaglandins → ↓ pain and fever

Minimal anti-inflammatory effects

Question 22

When is inflammation treated pharmacologically?

Answer 22

When symptoms are disproportionate to injury/infection

When immune response is maladaptive

Question 23

What enzyme converts membrane phospholipids into arachidonic acid?

Answer 23

Phospholipase A2 (PLA2)

Question 24

What does the 5-lipoxygenase pathway produce from arachidonic acid?

Answer 24

Leukotrienes (LTA₄ → LTB₄, LTC₄, LTD₄, LTE₄)

Question 25

What is the role of prostaglandins in the body?

Answer 25

Induce pain and fever Regulate inflammation Control blood flow and gastric protection

Question 26

What are leukotrienes most associated with?

Answer 26

Inflammation in asthma and allergies (bronchoconstriction)

Question 27

What happens if NSAIDs block the COX pathway?

Answer 27

Arachidonic acid is shunted into the 5-lipoxygenase pathway → overproduction of leukotrienes → bronchoconstriction and asthma symptoms

Question 28

Why is COX-1 considered “constitutive” and COX-2 “inducible”?

Answer 28

COX-1 is always active (housekeeping roles, e.g. stomach protection) COX-2 is induced during inflammation (produces inflammatory prostaglandins)

Question 29

What is the clinical rationale for selective COX-2 inhibition?

Answer 29

To reduce inflammation (via COX-2 inhibition) while preserving stomach lining protection (via COX-1 activity), thereby reducing GIT side effects

Question 30

What ADRs are shared by all NSAIDs regardless of COX selectivity?

Answer 30

GIT ulcers (less so with COX-2 inhibitors) Increased bleeding risk Renal impairment Hypertension Potential for bronchoconstriction in sensitive individuals

Question 31

Why is paracetamol not classified as a true NSAID?

Answer 31

Weak anti-inflammatory effect Primarily acts in the CNS Lacks peripheral COX inhibition

Question 32

What is cortisone and how is it activated?

Answer 32

Cortisone is a prodrug, meaning it is inactive until converted to the active form (cortisol) by the enzyme 11β-HSD1, which is found in the liver, adipose tissue, lungs, and macrophages.

Question 33

Where and how can cortisone be inactivated?

Answer 33

Cortisone is inactivated by 11β-dehydrogenase, primarily in the kidney, salivary glands, and colon, preventing overactivation of mineralocorticoid effects.

Question 34

How do anti-inflammatory steroids exert their effects?

Answer 34

They bind to the glucocorticoid receptor (GR), leading to: Anti-inflammatory effects Immunosuppressive effects Antiproliferative effects The GR is part of the nuclear receptor superfamily, acting as a ligand-activated transcription factor.

Question 35

What type of receptor is the glucocorticoid receptor (GR)?

Answer 35

It is a type III nuclear receptor in the ligand-activated transcription factor family, linking signalling molecules to transcriptional responses.

Question 36

Where is the GR found and how widespread are its effects?

Answer 36

GRs are found in nearly all human cells and modulate transcription of 10–20% of the human genome, producing cell-specific outcomes like apoptosis (e.g., thymocytes) or survival (e.g., hepatocytes).

Question 37

Outline the stress response pathway leading to glucocorticoid release.

Answer 37

Stress → Hippocampus → Hypothalamus → Pituitary → Adrenal Cortex → Cortisol release

Question 38

What receptors are targeted by cortisol and what are their functions?

Answer 38

Glucocorticoid Receptor (GR): anti-inflammatory and immunosuppressive Mineralocorticoid Receptor (MR): electrolyte balance, water retention, and blood pressure regulation

Question 39

Why is it important that cortisol binds both GR and MR?

Answer 39

to avoid MR-related side effects (e.g., hypertension, fluid retention), drug design aims to create selective GR agonists that do not activate MR.

Question 40

How does the drug’s formulation affect its use and side effects?

Answer 40

Formulations (oral, inhaled, topical, IV) affect onset, bioavailability, and systemic exposure, which is crucial for minimizing systemic side effects.

Question 41

What are 3 common systemic side effects of glucocorticoids (GCs)?

Answer 41

Hypertension Immunosuppression Osteoporosis

Question 42

How can local corticosteroid use help reduce side effects?

Answer 42

Using local corticosteroids at the site of inflammation increases targeted bioavailability and avoids widespread systemic side effects.

Question 43

How does the GR mediate anti-inflammatory effects at the molecular level?

Answer 43

Blocks NF-κB → ↓ prostaglandins Blocks Jun/Fos (AP-1) → ↓ pro-inflammatory cytokines → Overall ↓ cytokines, inflammatory cells, vasodilation, and vascular permeability

Question 44

What are the two major signalling mechanisms of GR?

Answer 44

Transactivation – turns on anti-inflammatory genes Transrepression – turns off pro-inflammatory genes

Question 45

Describe GR transactivation in detail.

Answer 45

GR + corticosteroid form a complex Complex translocates to the nucleus and forms a heterodimer Binds to GREs → recruits HAT → activates anti-inflammatory genes

Question 46

Describe GR transrepression in detail.

Answer 46

GR acts as a monomer Binds to NF-κB and AP-1 Recruits HDACs → suppresses pro-inflammatory gene expression

Question 47

What are steroidal anti-inflammatory drugs and how do they work?

Answer 47

Drugs like cortisone, prednisolone, fluticasone propionate that bind to GR and modulate gene transcription to suppress inflammation and immunity.

Question 48

What are SEGRAs or SEGRMs, and why are they being developed?

Answer 48

Selective GR Agonists/Modulators, designed to preserve anti-inflammatory benefits while reducing side effects, by selectively activating beneficial GR pathways.

Question 49

What are steroid-sparing agents and what is their limitation?

Answer 49

They reduce the required steroid dose and associated side effects, but adherence to therapy can be problematic.