Annals of the Rheumatic Diseases 1993; 52: 241-243 241 HYPOTHESIS Why are non-steroidal anti-inflammatory drugs so variable in their efficacy? A description of ion trapping G A Ellis, D R Blake Hypothesis Non-steroidal anti-inflammatory drugs vary in Our hypothesis is that acidic non-steroidal their aqueous solubility, but most are highly anti-inflammatory drugs (NSAIDs) undergo albumin bound and will be co-distributed with ion trapping in acidotic tissue and that this this protein. Diffusion of an NSAID into the affects not only their gastrotoxicity, which is cell follows Fick's law, as it is dependent on the well known, but also their selectivity for, and concentration gradient across the plasma their efficacy in, inflammatory joint disease. membrane and the lipid/water partition Tissue acidosis may not be a feature of all coefficient of the drug molecule. chronic inflammatory disease states, but it does For weak acids, such as most NSAIDs, the occur in inflammatory joint disease and is effective concentration gradient is that of the highly variable depending on the extent of the non-ionised form, as ionised molecules are not mismatch between synovial perfusion and lipid soluble metabolic demand. This mismatch is influ- HD D- + H+ enced not only by disease activity, but also by Non-ionised Ionised joint movement, which causes transient hypoxic episodes. Interventions, such as rest The position ofthe equilibrium depends on the and drug treatment, would serve to reduce ion intrinsic ionisation constant of the molecule trapping and, therefore, NSAID efficacy (pKa) and on the pH value of the aqueous through their effects on disease activity. The phase. The influence of pH is most profound influence of these factors on pH dependent ion around the pKa value of the molecule (fig 1). trapping may contribute to the variable efficacy For acidic NSAIDs, decreasing the pH of NSAIDs between disease states, between increases the proportion of the non-ionised patients within a disease population, and form, raises the overall lipophilicity, and within a single patient over time. enhances transport across the lipid membrane. Prostaglandins have been found in increased The pKa values for several NSAIDs at 25°C amounts in many chronic inflammatory states, are given in the table. Within tissue, the actual including rheumatoid arthritis' and osteo- values will vary slightly with temperature and arthritis,2 where they contribute to the severity the ionisation potential of the environment. and persistence of inflammation. They are Where pH gradients exist across lipid derived from arachidonic acid by the action of membranes ionisable molecules are subject to cyclo-oxygenase and it is principally through ion trapping. The non-ionised form will tend the inhibition of this enzyme that NSAIDs to equilibrate across the membrane and will exert therapeutic effects.3 Despite their move down its concentration gradient into the mechanism of action NSAIDs are not high pH compartment where it will be ionised. universally effective in all chronic inflamma- tory disease states and this may be due, in part, to the pharmacokinetics of the drugs at the cellular level. 100 [ To reach their active site within inflam- matory cells NSAIDs must be distributed to the extravascular compartment. Passage across E the vascular endothelium can be either via gaps 0 between the endothelial cells or by simple 'a Inflammation them. There ._n0 50 Research Group, diffusion through are, however, . Bone and Joint restrictions and both routes can be altered by Research Unit, disease. 0 25-29 Ashfield Street, z London El 2AD, Normally the gaps between endothelial cells United Kingdom are small, allowing only limited egress of small G A Ellis solutes, but restricting loss of protein. The D R Blake presence of inflammation weakens the Correspondence to: allow Ms Ellis. endothelial barrier, and the wider gaps water and Increasing pH Accepted for publication the extravasation of hydrated 3 November 1992 molecules and proteins, including albumin.4 Figure 1 Ionisation of a weak acid. 242 Ellis, Blake pKa Values ofvarious non-steroidal anti-inflammatory reduction in prostaglandins.'0 Further down drugs (NSAIDs) the intestinal tract pH gradients may occur but, NSAID pKa Value if correctly orientated, are much smaller as the Salicylic acid 3 0 lumenal pH in these regions only varies Diflunisal 3-3 between 7 0 and 8&0. As a class the acidic Acetylsalicylic acid 3-5 Diclofenac 3-9 NSAIDs have considerable gastrotoxicity and Mefenamic acid 4-2 their reduction of endogenous prostaglandins Ibuprofen 4-4 Phenylbutazone 4-5 is a major, but not the only, factor in this Indomethacin 4-5 effect." It is interesting that the pattern of ion Oxyphenbutazone 4.7 6-Methoxy-2-naphthylacetic acid* 5-0 trapping parallels that of the gastrotoxicity Piroxicam 5-1 profile. The incidence of endoscopically *Active metabolite ofnabumetone. proved gastric ulcers in patients treated with NSAIDs is estimated to be about 20%,/12 whereas in the intestine the adverse effects of More non-ionised drug is then pulled across NSAIDs are generally limited to subclinical the membrane and this dynamic process inflammation, and radiologically demonstrable continues until equilibrium is achieved (fig 2). ulceration and strictures occur only Ion trapping of NSAIDs within cells occasionally. '3 therefore occurs in situations where the pH of McCormack and Brune" considered the the extracellular fluid (pHe) is lower than that physicochemical characteristics of a few acidic of the intracellular fluid (pHi), such as in the NSAIDs with a lower than average gastrotoxic gastric mucosa and in acidotic diseased tissue. potential. They noted that these drugs did not Normally the pHi of a cell is about 7 1 whereas reach high concentrations in the gastric the pHe is 7 5. In vitro studies have shown, mucosa. For flufenamic acid, fenclofenac, and however, that the orientation of this pH diflunisal this was suggested to be owing to gradient is reversed when the pHe decreases their enhanced lipophilicity, whereas for below approximately 7X 1 in cells that have the azapropazone it was thought to be because it mechanisms to cope with acidification.56 is a cation at low pH values. In most situations the magnitude of the Ion trapping also occurs in tissues made measurable pHe-pHi gradient will be small, acidotic by pathophysiological mechanisms but nevertheless it can have a considerable such as in tumours and in inflammation. effect on the drug concentration at the active Research with ionisable 5-fluorouracil in rat site. In human erythrocytes in vitro, decreasing fibrosarcomas in vivo, using nuclear magnetic the pHe ofthe phosphate buffer from 7X4 to 6 8 resonance spectroscopy techniques, has shown approximately doubled the concentration of that a localised pHe reduction from 7-3 to 6-9 phenylbutazone in the intracellular compart- enhanced the cellular uptake of the drug, ment, without affecting that of the basic causing a 2-5-fold increase in the elimination compound, antipyrine.7 Physical effects can half life.'5 Such direct studies have not been enhance the pH gradient. The electrostatic conducted in inflammation. Acidic NSAIDs interaction between negatively charged groups have been shown to accumulate in inflamed in the plasma membrane reduces the pHe at tissue in several animal models, however.'6 1' the external surface of the cell. For example, In patients with joint inflammation, total with a bulk pHe of 7 0 the surface pHe is NSAID concentrations increase in the synovial calculated to be only about 6.2.8 In addition, fluid and tissue as inflammation becomes more good buffering in the unstirred layer at the severe and, therefore, more acidotic.'8 '9 surface amplifies the ion trapping effect. Although increased extravasation of albumin Replacing sodium chloride in a buffer solution bound NSAIDs will contribute to the higher with sodium citrate produced a 43-fold NSAID concentrations, ion trapping could increase in the ion trapping of salicylate.9 also have a role. The gastric mucosa has the largest pH If ion trapping does occur with NSAIDs, it gradients in the body and is the prime site for would explain why acidic NSAIDs are more NSAID trapping. These drugs accumulate in effective in vivo than NSAIDs such as the cells of this tissue and produce a prolonged proquazone and indoxole, which, although fairly potent cyclo-oxygenase inhibitors in vitro, are not acidic.20 It might also explain why more than 90% of patients with gout, with its severe synovitis, respond to NSAID treatment Low pHe Hig pH within one day, with complete resolution of / (relative) \ symptoms in five to eight days2' and why the patients with rheumatoid arthritis most likely HA HA to respond well to NSAID treatment are those with more aggressive disease.22 The acidosis of osteoarthritis is less severe and probably less persistent than in rheumatoid arthritis.23 Given H+ +±A- H+ +A- this, NSAIDs would be expected to be most effective during inflammatory and acidotic episodes and less so in the intervening periods. Differences in NSAID ion trapping may Figure 2 Ion trapping ofweak acids. pHe=pH ofthe account for some ofthe variation in therapeutic extracellularfluid; pHi=pH ofthe intracellularfluid. response within a disease group,24 as acidosis NSAIDs anid ion trapping 243 3 Vane J R. Inhibition of prostaglandin synthesis as a is a dynamic variable and is under the influence mechanism of action for aspirin-like drugs. Natirc 197 1; of diverse factors. In rheumatoid arthritis the 231: 232-5. extent of acidosis differs considerably between 4 Simkin P A, Pizzorno J E. Svnovial permeabilitv and rheumatoid arthritis. Arthritis Rlicioiii 1979; 22: 689-96. patients and seems to be compounded by 5 Nuccitelli R, Heiple J M. Summary of the evidence and movement.'9 2 2' Flexion of an inflamed joint discussion concerning the involvement of pHi in the control of cellular functions.