Anti-inflammatory drugs and their effects on cartilage synthesis and renal function.
Growing evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs), while able to alleviate inflammation, may damage articular cartilage, though both chondrodestructive and chondroprotective activities have been observed with different NSAIDs. Experiments conducted on explants of normal and osteoarthritic human cartilage have shown that certain NSAIDs at pharmacologic concentrations achievable in man consistently inhibit glycosaminoglycan (GAG) synthesis. The addition of the prostaglandin E1 analogue misoprostol consistently reversed these inhibitory effects in a dose-related manner. Paradoxically, with some NSAIDs, such as diclofenac and aspirin, misoprostol was also able to enhance GAG synthesis above control levels, especially in osteoarthritic cartilage. This supports findings from other work that NSAIDs exert effects other than through inhibition of cyclooxygenase, direct action on cell membranes being one of these alternative mechanisms of action. Additionally it is interesting to note and may be of clinical relevance that misoprostol on its own also stimulates GAG synthesis in explants of human osteoarthritic cartilage whilst exerting no apparent effect on healthy cartilage with a normal GAG turnover. With regard to renal aspects, the effects of NSAIDs are readily explicable in terms of interference with prostanoid synthesis. The consequent inhibition exerted on vasodilatory prostaglandins (PGs), which oppose vasoconstrictor action induced by substances such as thromboxane or leukotrienes, upsets the balance that maintains renal function. In situations in which there is reduced renal reserve, reduction of renal PG synthesis by NSAIDs will adversely affect maintenance of renal blood flow and glomerular filtration rate and excretion of sodium, potassium, and water. Patients with alcoholic cirrhosis manifest this type of compromised renal function and in them misoprostol reverses the adverse effects of indomethacin on renal hemodynamics and partially reverses indomethacin-induced renal sodium retention. Although the clinical significance of these data is not yet established, exogenous administration of specific PGs may be able to minimize the deleterious actions of NSAIDs.
Shield
M J
MJ
Department of Medical and Clinical Research, Searle, Bucks, United Kingdom.
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D011453:Prostaglandins / Q000378:metabolism / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006025:Glycosaminoglycans; D011453:Prostaglandins