HUF 2-83 Pharmacology of autacoids and anti-inflammatory drugs IV

Question 1

Classification of COX

Answer 1

1. COX-1
   - constitutively expressed in ER of most cell types
   - regulation of homeostasis
   e. g. renal and gastric blood flow, gastric lining protection, platelet aggregation
2. COX-2
   - found in many cells (endothelial cells, macrophages, ..)
   - induced by cytokines and inflammatory stimuli
   - NO clear separation between functions of COX-1 and COX-2 in kidney, CNS, CVS and reproductive system
3. COX-3
   - splice variant of COX-1 in CNS (lesser extent in heart, endothelial cells and monocytes)
   - pain perception
   - precise function uncertain

Question 2

Actions of COX inhibitors

Answer 2

1. Anti-inflammatory
   - ↓ prostanoids (e.g. PGE2)
   - ↓ vasodilation and edema
2. Analgesic
3. Antipyteric
   * Traditional NSAIDs are reversible COX inhibitors (e.g. ibuprofen)

Question 3

Anti-inflammatory action of COX inhibitors

Answer 3

• inhibit COX2 and subsequent PG production
• acetylate Ser529 in COX1 at active site
  => irreversibly inhibit the enzyme (Aspirin)

Question 4

Analgesic action of COX inhibitors

Answer 4

• block PG synthesis near nociceptors
• nociceptors sensitised by bradykinin (e.g. from endothelial cells) and SP (e.g. from local tissues)
• further intensified by peripheral nociceptor sensitisation with prostanoids

Question 5

Antipyretic action of COX inhibitors

Answer 5

• bacterial endotoxin (pyrogen)
  => IL-1 from macrophage
  => ↑ PG production in CNS (PGE2 in hypothalamus)
  => ↑ set point for temperature control in hypothalamus
  => fever
• COX inhibitors suppress PG production in CNS
  => reset body temperature

Question 6

Low dose aspirin selectively inhibit COX-1 (anti-platelet action)

Answer 6

• aspirin inhibits platelet aggregation more than endothelial anti-thrombic activity
• ↓ risk of developing colorectal cancer
• may not be applicable to other NSAIDs

Question 7

Aspirin (acetylsalicylic acid)

Answer 7

• Anti-inflammatory (treating rheumatoid arthritis)
• Analgesic
• Anti-pyretic
• ↓ risks of CVS problems and CRC

Question 8

PK profile of aspirin

Answer 8

• oral
• rapidly absorbed in stomach (weak acid + ion trapping effect)
• hydrolysed to salicylate, conjugated to glucuronic acid in liver
• excreted rapidly in urine

Question 9

Undesirable effects of aspirin (therapeutic doses)

Answer 9

• gastric irritation
• gastric and duodenal ulcers

Reye’s syndrome in children

• liver disorder and encephalopathy => CNS distubrances
• acute viral illness (flu, chickenpox…)

Question 10

Undesirable effects of aspirin (repeated intake of fairly high doses)

Answer 10

Salicylism

• tinnitus
• vertigo
• decreased hearing
• nausea and vomiting

Question 11

Undesirable effects of aspirin (toxic doses)

Answer 11

Respiratory alkalosis (↑ respiratory centre => hyperventilation)
→ Metabolic acidosis (uncoupling of oxidative phosphorylation; lactic acid; compensation to respiratory alkalosis)
→ Severe hyperthermia (uncoupling of oxidative phosphorylation)

Question 12

Aspirin-induced asthma

Answer 12

• asthmatic patients more prone to asthma attack
• overexpression of CysLTR or LTC4 synthase
• COX pathway inhibited by aspirin
  => AA shunted to LT pathway
  => ↑ CysLT production (potent spasmogens)

Question 13

Ibuprofen

Answer 13

• short term analgesia
• less gastric irritation
• reversible COX inhibitor
• anti-inflammatory
• analgesic
• anti-pyretic

Question 14

Examples of non-selective NSAIDs

Answer 14

1. Acetic acid derivatives (-ac)
   e. g. Diclofenac
2. ‘Profen’ class
   e. g. Naproxen, ibuprofen
3. Enolic acid derivatives (oxicam)
   e. g. Piroxicam
4. Anthranilic acid derivatives (fenemates)
   e. g. Mefenamic acid

Question 15

PK profile of non-selective NSAIDs

Answer 15

• oral
• well absorbed
• plasma protein-bound
• metabolised by liver and excreted by kidney

Question 16

Undesirable side effects of non-selective NSAIDs

Answer 16

1. Gastric upset upon long-term use
   - reduced with proton pump inhibitors e.g. omeprazole / protective effect of misoprostol (PGE1)
2. Renal insufficiency (reversible) or nephropathy (irreversible)
   - inhibit sysnthesis of PGE2 and PGI2 in renal blood dynamics
3. Cardiovascular risk
   - hypertension
   - all NSAIDs, except aspirin, may increase CSV events when used at high dose for prolonged periods
4. Skin rashes (drug allergy) and phototoxic

Question 17

Selectivity of COX-2 selective NSAIDs

Answer 17

1. COX-2 side pocket (Val523) allows specific binding of COX-2 selective NSAID’s bulky rigid side group
2. Bulkier COX-2 selective NSAID will not fit into narrower COX-1 entrance channel
   => uninhibited access of AA into COX-1

Question 18

COX-2 selective NSAIDs (coxib)

Answer 18

e.g. Celecoxib, Etoricoxib
- less inhibitory action on COX-1
=> fewer or no gastric irritation
- anti-inflammatory, analgesic
- long-term treatment for patients who cannot tolerate undesirable effects of non-selective NSAIDs

• possible risks of CVS ecents
  e.g. rofecoxib => ↑ risk of MI in people with known ischaemic heart disease or at high risk of CSV event
  ∴ active monitoring

Question 19

Paracetamol

Answer 19

• antipyretic
• analgesic
• very weak anti-inflammatory
  ∵ inactivated by peroxidases by cells of inflamed tissues
• little effect on COX-1 or COX-2
• more specific in inhibiting COX-3 in CNS
• NOT regarded as NSAID (∵ weak anti-inflammatory)
• NO GI side effects
• NO anti-platelet effects

Question 20

Danger of paracetamol

Answer 20

Long-term regular use or overdose
=> hepatic necrosis

Rare adverse effectsL epidermal necrolysis

e. g. Stevens-Johnson Syndrome
- severe hypersensitivity towards drugs
- ibuprofen, carbamazepine
- 40% of people do not survive