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NSAIDs, anesthesia, and the kidneys: What they are not telling you (Proceedings)

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Aug 01, 2010

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesic drug class in human and veterinary medicine. NSAIDs are effective due to both peripheral and central mechanisms of analgesia. The widespread use of NSAIDs in human medicine has resulted in a large number of patients experiencing adverse effects including death. It has been estimated that 16,500 human deaths occur annually in the United States due to NSAID use. NSAID – associated deaths would account for the 15th leading cause of death in the U.S. if included separately on the National Vital Statistics report. Only a small number of patients (~19%) with serious gastrointestinal complications reported symptoms prior to presentation for the serious adverse effect. Therefore monitoring patients for adverse effects is a relatively insensitive method of preventing serious adverse effects associated with NSAID use. It is important to realize that severe complications also occur in veterinary medicine, including death, even with short treatment periods.

Mechanisms of Action

The primary mechanism of action associated with NSAIDs is on the arachidonic acid pathway through the inhibition of the cyclooxygenase (COX) enzymes. However inhibition of lipoxygenase (LOX), nuclear factor κ-B (NF-κB), and bradykinin can also contribute to the effects of NSAIDS. At least two isoforms of COX have been identified, COX-1 and COX-2. A variant of COX-1, termed COX-3, has also been identified in the cerebral cortex, but the biologic significance of COX-3 is still debated. COX-1 is often referred to as constitutive as it contributes to routine physiologic processes and homeostasis. COX-1 is also up-regulated in inflammatory conditions and in the cerebral cortex as a component of the ascending pain pathways. COX-1 catalyzes the formation of prostaglandins that result in vasodilation, inflammation and pain, sensitization of nociceptors, fever, gastroprotective effects (increase mucous production, bicarbonate secretion, increase mucosal blood flow, inhibit acid secretion), and regulate renal blood flow in some species. COX-1 products are also converted to thromboxane in platelets that result in platelet aggregation and vasoconstriction.

COX-2 is often referred to as inducible as it is up-regulated in many inflammatory conditions and some neoplastic tissues. Prostaglandins produced by COX-2 result in vasodilation, inflammation and pain, sensitization of nociceptors, and fever. COX-2 is constitutively expressed in the GI tract and renal vasculature of dogs and is primarily responsible for modulation of renal blood flow in dogs. COX-2 is up-regulated in healing GIT ulcers and is necessary for healing in the GIT. COX-2 products are also converted to prostacyclin which is primarily antagonistic to thromboxane. Prostacyclin results in vasodilation and inhibits platelet aggregation. Prostacyclin also sensitizes nociceptors. COX-2 is expressed in the dorsal horn of the spinal cord and is active in the propagation of the ascending pathways. COX-2 is up-regulated in certain neoplastic diseases such as transitional cell carcinoma and osteosarcoma. The mechanisms and reasons for the up-regulation are unclear, but may aid in the growth of blood vessels or be a result of an inflammatory response to the neoplastic growth. Feline neoplasms appear to express COX-2 to less of an extent than canine neoplasms therefore NSAIDs may be less likely to produce desired clinical effects. COX-2 is up-regulated in the uterus during late pregnancy and NSAID use has resulted in prolonged gestation. Maintenance of the patent ductus arteriosis is mediated by COX-2, therefore inhibition results in premature closure and altered fetal hemodynamics.

COX-3 has been identified in the cerebral cortex of dogs and humans. COX-3 is a splice variant of COX-1 with some researchers hypothesizing it has no biologic effect, but in vitro COX-3 catalyzes similar prostaglandins as COX-1. Researchers have shown that acetaminophen and dipyrone are inhibitors of COX-3 with minor effects on COX-1 and COX-2, leading to the hypothesis that the analgesic and antipyretic effects of acetaminophen and dipyrone are due to central effects and not due to peripheral anti-inflammatory effects.

Lipoxygenase catalyzes the formation of leukotrienes as a part of the arachidonic acid pathway. Leukotrienes are antagonistic to prostaglandins in many ways resulting in vasoconstriction and increased gastric acid secretion. Leukotrienes also result in bronchoconstriction and are pro-inflammatory leading to the activation, recruitment, migration, and adhesion of inflammatory cells in addition to increased production of inflammatory cytokines such as TNF-α and IL-1β . Tepoxalin is the only NSAID currently marketed that inhibits LOX, but the duration of inhibition is short; the IC50 is maintained for less the 6 hours. Zileuton (Zyflo) is a specific LOX inhibitor marketed for treatment of asthma in humans. Leukotriene antagonists such as montelukast (Singulair) and zafirlukast (Accolate) are also available for treatment of human asthma. The clinical usefulness of the zileuton and the LT antagonists for the treatment of pain have not been extensively studied in animals, but experimental models have demonstrated antinociceptive (analgesic) effects.

Lipoxins are modulators of inflammation produced from COX-2 products. Lipoxins are inhibitors of leukotrienes, natural killer cells, inhibit leukocyte migration, inhibit TNF-α and NF-κB, and inhibit adhesion molecules and production of interleukins. Aspirin is relatively unique among the NSAIDs as it acetylates COX-2 with lipoxin being preferentially produced, "Aspirin Triggered Lipoxin." COX-2 inhibitors co-administered with aspirin result in increased GIT toxicity than sole administration of either agent.

The simplistic classification of COX-1 is the "good" isoform and COX-2 is the "bad" isoform is an overly simplistic classification system. As described previously both isoforms are constitutively expressed and required for homeostasis and protective responses.