Lecture 34: NSAIDS Analgesic 2 Flashcards
What type of pain do NSAIDS treat? How does this manifest and what are the 5 main symptoms
Inflammatory pain caused by:
1) damage to cells
2) release of inflammatory mediators: kinin histamine and other chemicals
3a) stimulate Pain receptors
b) leaky capillaries: Edema
c) Vasodilatation: heat + redness
d) fever due to prostaglandins (acting on the thalamus)
What are the 4 administration routes for NSAIDs
- Oral (mostly)
- Parenteral (after surgery)
- Topical
- Suppositories
What is the mechanism of action of NSAIDS
Traditional NSAIDS inhibit both the cyclo-oxyenase (COX1 and COX2) leading to suppression of prostanoids production in the cells.
This inhibition is reversible and incomplete except for Aspirin
Newer agents selectively inhibit COX2 only. eg. Celecoxib. They can still get gastric side effects, increased incidence of heart attacks and stroke.
What are the 4 main effects of NSAIDS
By reducing prostaglandins
- Decrease inflammation
- Relieve mild pain
- Anti pyretic by acting on PGE2 in the thalamus
- Anticoagulation inhibiting platelet aggregation by reducing TXA2
What are Prostaglandins: made of, half life, where
Lipid compounds made from fatty acids.
Short half life.
Highly potent, produced, released, act and inactivated locally by the same tissues in all cells of the body (sans RBC).
What is Arachidonic Acid (AA), what is its sources and possible routes of action
- Substrate for elcosanoid synthesis, made from FA linoleate or ingested in diet.
Usually esterified to cell membrane phospholipids, Specific stimuli (Autacoids) activate phospholipase-A2 to release AA from the membrane of the cell.
a) AA goes on through COX1 & 2 to become prostanoids: 1. Prostaglandins
2. Prostacycline (in bv endothelium for vasodilation,
3. Thromboxane (in the platelet for clotting)
b) 5-Lipooxygenases pathway to make leukotrienes:
Mediators of inflammatory response to allergy (chemotactic effect, vaso +bronchoconstriction, vaso permeability).
What is the COX1 pathway for AA: desirability, inhibitors, effect
COX1 is present all the time in all cells (constitutive enzyme) with homeostatic functions.
Inhibiting this with NSAIDS can get
- lack of coagulation, - GIT ulcers,
- Renal failure
- less macrophages making it an undesirable target for NSAIDS
What is the COX2 pathway from AA: desirability, inhibitors, effect
COX2 is inducible enzyme with a stimulus
eg. Cytokines, IL1, TNF growth factor.
Produces inflammatory prostaglandins for pain and inflammation.
Desirable to suppress and inhibit this enzyme via NSAIDs and Glucocorticoids.
What is the bioavailability, volume of distribution, rate of absorption and protein binding of NSAIDS
- High bioavailability due to v low first pass metabolism
- Rapid and complete absorption after oral administration due to highly lipophilic
- High protein binding so small VD
What is the onset of action, half life, metabolism and excretion of NSAIDS
- Slow onset of action- peak conc 3-4 hrs
- Clearance determines the variability in half life of these drugs.
- Metabolised in liver into mostly inactive products
- Excreted in urine as phase 2 Glucuronides, , sulphate conjugates, small % excreted unchanged
What are 4 drug interactions of the NSAIDS
- Can displace other highly protein bound medications, leading to more of the free drug in the plasma= toxicity/ overdose.
eg. Oral anticoagulants, Anticancer methotrexate,
Oral anti-diabetic agents,
thyroid hormones,
Digoxin
- Compete for renal tubular secretion against other organic acids
eg. uric acid. Therefore can trigger gout. - NSAID metabolism reduced by enzyme inhibitors: cimetidine/valproate
- Increase metabolism of NSAID by inducers: carbmazepine
Why is aspirin an exception to most NSAIDS - including notable effects
It selectively acetylates a single serine residue of the both COX1 and COX2 to inactivate them irreversibly.
For platelet COX1: inhibits Thromboxane A2, reducing platelet adhesion therefore reduce risk of heart attach and stroke.
What is aspirin absorbed as compared to its active form and where does this happen
- Absorbed in stomach and upper intestine through passive diffusion as acetylsalicyclic acid.
- It is hydrolized (deacetylated) in the liver into salicylate which is responsible for the anti inflammatory and analgesic effects.
Why would you use a a small dose of Aspirin compared to a high dose for CVS patients
Small dose doesn’t completely inhibit COX1 prostanoid production, just mostly the TXa2
Therefore still have endothelial Prostacyclin PGI2= Vasodilator.
Higher doses have more side effects including toxicity to the kidney and gastric mucosa
What is Aspirin induced asthma and what causes it
Severe asthma triggered within 1-3 hrs of ingestion of Aspirin/NSAIDS. Mostly in 30yr+.
Inhibition of COX1 + 2 leads to
1. Reduced PGE2 (bronchodilator)
- Activation of the lipo-oxygenase pathway which increases inflammatory mediators -> leukotrienes which precipitate bronchospasm/constrictionn.
