Lecture 11: Anti-inflammatory drugs NSAIDs

Question 1

Main groups of anti-inflammatory drugs

Answer 1

-Drugs that inhibit COX
–> non steroidal anti-inflammatory drugs (NSAIDs) => includes coxibs
- Antirheumatoid drugs (disease-modifying antirheumatic drigs (DMARDs) => together w/ immunosuppressants
- The glucocorticoids
- Anti-cytokines and other biopharmaceutical agents
- Antihistamines
-Drugs that control gout

Question 2

Pharmacological actions of NSAIDs

Answer 2

1. anti-inflammatory effect: modification of the inflammatory reaction.
2. analgesic effect: reduction of certain types of pain.
3. Antipyretic effect: lowering of body temp
   the drugs do not induce hypothermia

Question 3

Mehanism-based effects

Answer 3

• gastric irritation
  -renal blood flow
• inhibition of platelet function
• may increase the likelihood of thrombotic events (myocardial infarction & stroke

Question 4

Compare the main types of COX enzymes and drugs that exhibit preferential action towards the different COX isoforms.

Answer 4

COX 1: constitutively expressed; in tissue; homeostasis; produce prostaglandins; knockout = healthy
COX 2: inducible form; in inflammatory cells; produces mediators; knockout = problems
selectivity: non selective to weakly selective to highly COX 1 or 2 selective
ex. aspirin weakly COX selective.

Question 5

Chemical structures and the main pharmacological actions of NSAIDs
-Antipyretic effects
-Analgesic effects
-Anti-inflammatory effects

Answer 5

-Antipyretic effects: NSAIDs affect prostaglandin in hypothalamus = thermostat
–> prostaglandus synth induced by pyrogens = from fever
- Analgesic effects: lower PG that sensitive receptors to infl. mediators
–> inh. PG = relieve headache: vasodilator effect
-Anti-inflammatory effects: Suppress pain, swelling, ^ blood flow.
-> vasodilation
-> ederna reduced
-> pain reduced

Structures: classic NSAID = carboxylic acids ‘coxibs’ = have bulky group

Question 6

Molecular pharmacology of NSAIDs

Answer 6

• COX-1 & 2 are honodiners in intracellular membranes
  -> dioxygenase step (NSAIDs typically inhibit)
  -> peroxidase step
• NSAID comp. reversible
  -enter hydrophobic channel
• COX-2 is bulky side pocket so some drugs selective for COX-2 if they also bulky
• COX 1 selective, irreversible = aspirin

Question 7

The main side effects of NSAIDs

Answer 7

GI side effects: from inhibit of gastric COX-1; local damage to mucosa symptomatic or asymptomatic
-> gastric discomfort, dyspesia, diarrhea, nausea vomiting, ulceration

Renal side effects: through inhibitions of prostanoids synth: maintain renal flow.
–> abuse = analgesic nephopethy
other: skin rxns, platelet aggregation, CNS, liver disorders, Reye’s syndrome

Question 8

Study of aspirin

Answer 8

• earliest drugs synthesized
• most commonly consumed drugs
• it is approaching the status of a wonder drug that is of benefit not only inflammation, but in other conditions:
• cardiovascular disorders
• colonic, rectal and prostate cancer
• alzheimer’s disease
• Alters balance between TXA2 (promotes aggregation/ synthesis in platelets) and PGI2 (inhibits/ synthesis in endothelium)
• irreversibly inactivates COX-1
• oral administration selective for platelets.

-low doses of aspirin - once every 24-48h
- addictive

pharmacokinetics ——————
- weak acid (not ionized)
- absorption occurs in the iluem
- hydrolised by esterases in plasma/tissues/liver
- excretion higher in alkaline urine
- half-life of aspirin will depend on the doses

Side effects
- general NSAIDs unwated effects
- salicylism
–> ringing in ears
–> vertigo
–> decreased hearing
–> nausea and vomiting
- In CNS coma and respiratory depresssion

Question 9

Study of acetaminophen

Answer 9

• paracetamol
• potent analgesic and antipyretic actions
• weaker anti-inflammatory effects
• not considered as NSAIDs

-given orally + well absorbed
- half-life 3-4h
-toxic doses 4-8h
-Inactivated in the liver (CYP enzymes)

Side effects
@ THERAPEUTIC DOSES
- allergic skin reactions
- kidney damage

• Acetaminophen overdose

TOXIC DOSES
- fatal hepatotoxicity
- liver enzymes catalysing the normal conjugation reactions are saturated.
- nausea and vomiting

Question 10

Current status with coxibs

Answer 10

Vioxx -> causes serious risk of heart attacks so has been pulled out of market.
Diclofenac -> has similar risks of causing heart attacks but hasn’t been pulled from market.