YW - NSAIDs and PG II Flashcards
List some clinical applications of prostaglandin analogs (4)
Gynecological/obstetric:
- Misoprostol (stable PGE analog) for pregnancy termination or labor induction.
- Carboprost (PGF2α analog) to treat postpartum hemorrhage.
Gastrointestinal: Misoprostol to prevent peptic ulcers in patients taking NSAIDs.
Cardiovascular:
- Alprostadil (PGE analog) for presurgical maintenance of arterial ducts in congenital heart disease.
Inhibit platelet aggregation during dialysis. - Used in pulmonary hypertension.
Ophthalmic: Latanoprost (PGF2α analog) eye drops for open-angle glaucoma.
How do prostaglandins contribute to pain and fever?
Prostaglandins sensitize nociceptors to pain-causing stimuli like bradykinin
- They also elevate the body’s temperature set point in the hypothalamus, leading to fever
How do prostaglandins contribute to inflammation?
They directly cause swelling (vasodilation) and indirectly promote edema (fluid buildup) by sensitizing the effects of other pain mediators
What are some potential side effects of NSAIDs? (2)
While NSAIDs effectively reduce inflammation, they can also have side effects:
- Gastrointestinal (GI) issues due to their housekeeping role in stomach lining protection.
- Increased risk of bleeding due to platelet aggregation inhibition (aspirin is an exception)
What are the main therapeutic uses of NSAIDs? (3)
- Analgesic: Reduce pain (headache, backache, post-operative pain). Examples: Aspirin, ibuprofen.
- Anti-inflammatory: Manage chronic conditions like rheumatoid arthritis (higher doses and longer use). Examples: Piroxicam.
- Antipyretic: Reduce fever. Paracetamol is preferred due to fewer side effects
How does chronic NSAID use impact drug selection?
For chronic use, NSAIDs with lower GI side effects are preferred. COX-2 selective drugs (e.g., celecoxib) might be a better option
How do different NSAIDs vary in terms of potency and half-life? (7)
- Aspirin (short half-life, COX-1 selective, good for short-term pain relief but has GI effects).
- Indomethacin (potent but many side effects)
- Ibuprofen (popular choice with low side effects)
- Piroxicam (long half-life, COX-2 selective, but can cause skin reactions, gastric irritation, and tinnitus)
- Celecoxib (COX-2 selective)
- Rofecoxib (highly selective COX-2 inhibitor, withdrawn due to cardiovascular risks)
- Paracetamol (weak COX inhibitor with a different mechanism, preferred for fever due to fewer side effects)
How do COX enzymes work, and how do NSAIDs inhibit them?
COX enzymes metabolise COX into prostaglandins (PGG2 → PGH2 → bioactive PGs).
NSAIDs block the enzyme’s channel, preventing arachidonic acid from entering the active site
What is the structural basis for COX-1 and COX-2 selectivity of certain NSAIDs?
A key amino acid difference (isoleucine in COX-1 vs. valine in COX-2) creates a narrower channel in COX-1
- Bulkier COX-2 selective drugs can fit the wider COX-2 channel but are excluded from the narrower COX-1 channel
How does size matter for COX-2 selective inhibitors? (4)
- COX-2 selective drugs more rigid and fill more space cannot gain access to the COX-1 channel.
- Bulky COX-2 drugs gain access to the drug binding site shared with COX-1
- In addition they bind to a site created by the isoleucine/valine exchange seen in COX-2.
- Unlike non-selective inhibitors COX-2 selective inhibition increase with time.
What is Aspirins mechanism in modifiying COX enzymes?
Aspirin modifies both COX-1 and COX-2 by irreversible covalent modification and kill enzyme activity.
Aspirin acetylates (covalently modifies) serine 530 in the COX-1 and COX-2 enzyme active site.
- Supports its use as conventional NSAID.
- In platelets this inhibits the COX-1 dependent production of thromboxane A2. Thus inhibits aggregation.
- Platelet aggregation central mechanism in clotting and predisposition to cardiovascular disease.
- Platelets anucleate cells thus circulate with the proteins they need-can not make more.
- Small doses of aspirin (relatively non adverse) inhibit platelet aggregation chronically,
it takes 7 days to produce new platelet.
What are 6 important facts about paracetemols action?
Paracetamol (acetaminophen) is a pro-drug for an important analgesic.
Important facts about paracetamol.
- Paracetamol has good analgesic and antipyretic activity.
- Only at higher doses than required for 1 is their a clear anti-inflammatory action.
- High dose lead to a COX inhibition that may produce anti-inflammatory effects.
- It does not block AA delivery like standard NSAIDs.
- Based on the chemical environment, particularly oxidizing potential, it can modify the porphyrin of the Haem group at the catalytic sit of COX.
- COX-2 seems particularly vulnerable.
What are other modes of action for paracetamol as well as a COX inhibitor?
- TRPV-1 (cation channel) that is activated in pain is a target seems to be activated.
- Metabolism of Acetaminophen (AcAP) in cells to para-aminophenol (pAP).
- pAP reacts with AA catalysed by Fatty acid Hydrolase (FAAH) to generate AM404.
- This activates the TRPV1 centrally to contribute analgesia.
- Increases the level of cannabinoid signalling in the central nervous system.
