MedicalConspiracies- NSAIDs therapeutic and toxic effects

NSAIDs therapeutic and toxic effects

https://sites.google.com/site/biophysisicsbiomembranes/highligths/nsaids-therapeutic-and-toxic-effects

The principal targets of NSAIDs in the control of pain and inflammation are the membrane-associated enzymes COX. To bind with their targets, NSAIDs have to pass through the membranes, and thus, the interactions of these drugs with the lipids of the biomembranes are expected to play a major role in guiding their COX inhibition. Evidence has accumulated during the past decade to support the view that the capacity of NSAIDs to interact with lipid membranes contributes not only decisively to their therapeutic effects but also to the type and incidence of their toxic side effects. In fact, it has been shown that NSAIDs reach particularly high concentrations in compartments in which they cause therapeutic and side effects, and the accumulation within gastric mucosal cells is a principal factor associated with the intervention of intracellular biochemical events and resultant gastric mucosal damage. However, it has also been shown that prostaglandins, synthesized locally by COX-1 in the gastric mucosa, play a physiologically important role in protecting the tissue against damaging agents, such as acid.

Therefore, it can be said that there is not only one mechanism responsible for the NSAIDs toxicity, but there are two important mechanisms that may condition the resultant gastric toxicity of these drugs, which are the inhibition of COX-1 with the consequent inhibition of the gastroprotective prostaglandins and the local action of NSAIDs in the lipid gel layer that protects gastricmucosa.

Additionally, the degree of water solubility and ionization, as well as liposolubility, of the NSAIDs is believed to play a role in both their absorption and gastro intestinal side effects. Therefore, the rational development of safer NSAIDs will depend upon the determination of the various effects of these drugs on membranes and vice versa, as this is a precondition to understanding how these drugs act. In this context and from the obtained results, it can be concluded that the NSAIDs are able to interact with the membranes at both pH values. However, while at pH 7.4 the ionized forms of NSAIDs prevailed and the drug location at the membrane level is shallower, at pH 5 (the pH of inflamed tissues) the neutral forms of NSAIDs have stronger interactions with the membrane, which also correlate well with their efficacy as inflammation inhibitors.