How do the pharmacodynamics of the NSAIDs differ and are there "resistant" COX phenotypes?

Question

I know that the non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen) affect the enzymes cyclooxygenase (types I and II).Is there any difference in the degree to which these drugs manipulate/inhibit the enzymes (I assume their affinities for COX-1 and COX-2 are at least somewhat different)? Is there any evidence as to whether the the NSAIDs collect in certain areas of the body in a compartmental fashion?Are there differences in fat solubility, etc., between the different drugs?Finally, are there any known phenotypes of COX-1 and COX-2 enzymes that are present in the general population that affect the ability of these drugs to act?

Answer 1

Different NSAID's exhibit different degrees of selectivity for COX-1 and COX-2 enzymes, which is a major factor in defining the side effect profile. For example, aspirin and naproxen have greater COX-1 selectivity while meloxicam and diclofenac have greater COX-2 selectivity. Celecoxib is considered a COX-2 inhibitor because of its very high selectivity for the enzyme.

I'm not sure what you mean by collecting in compartments. If you are referring to a drug's volume of distribution, then you can tell if a drug has low or high volume of distribution by looking at the numbers. A hydrophilic drug has a low volume of distribution, closer to 1 L/kg so it tends to stay in plasma. Lipophilic drugs have higher volumes of distribution, which means it tends to enter extravascular compartments. Each NSAID will have a different volume of distribution. For example, diclofenac has a lower V_d so it tends to stay in plasma vs. meloxicam which has a much higher V_d.

And yes, of course there are mutations of COX-1 and COX-2 but I am not aware of any literature on its pharmacodynamic interactions with NSAIDs