NSAIDS: COX-1 and COX-2: What's the difference? (Proceedings)

Inflammation and pain are very common clinical problems in veterinary medicine. Although highly efficacious, use of non-steroidal anti-inflammatory drugs (NSAIDs) is not without risks, especially when used in geriatric or debilitated animals. Practitioners need a basic understanding of the action of these drugs in order to appreciate clinical differences between them.

Physical features

Almost all NSAIDs are weak acids and highly bound to plasma proteins like albumin. Therefore they are well absorbed from the stomach, and most of the drug in the plasma is protein bound. Because of protein binding, most of the drug is distributed in the extracellular fluid and only low levels of NSAIDs are found in normal tissues and joint fluid. In damaged tissues and joints however, NSAID concentrations increase to therapeutic levels because of increased blood flow, vascular permeability, and acute phase protein penetration into sites of inflammation. Most NSAIDs undergo hepatic metabolism either through oxidation or glucuronide conjugation, prior to elimination in urine.

Mechanism of action

Cyclooxygenase inhibition: NSAIDs interrupt formation of thromboxane, prostacyclin and the prostaglandins from arachidonic acid. This results in antipyretic action, mild analgesia, anti-platelet effects, and some anti-inflammatory effects. It has been shown that there are different, distinct forms of cyclooxygenase. The constitutively expressed form (normal for homeostasis) is referred to as COX-1, and the inducible form (in response to injury) is referred to as COX-2. COX-1 is found in platelets, GI mucosal cells, and renal tubule cells. COX-2 has been identified in fibroblasts, chondrocytes, endothelial cells, macrophages, and mesangial cells. COX-2 is induced by exposure to various cytokines, mitogens and endotoxin, and it is up-regulated at inflammation sites. Unfortunately, this classification is now determined to be too simplistic to explain the roles of the different forms of cyclooxygenase. It now appears that COX-2 can be produced constitutively in the brain, spinal cord, kidney, lung, and other tissues. It has even been found near gastric ulcers, and may play a role in ulcer healing. COX-2 is also involved in cellular processes including gene expression, differentiation, mitogenesis, apoptosis, bone modelling, wound healing and neoplasia. A new isoform, COX-3, has also been discovered in the brain. It appears to be a derivative of COX-1, though its function has yet to be elucidated.

The prostaglandins produced in the gastrointestinal tract and the kidney that maintain mucosal integrity in the upper GI tract and renal perfusion appear to be derived from COX-1. Therefore, suppressing COX-1 activity by NSAIDs is believed to be critical to the development of toxicity. It is suggested that COX-2 selective NSAIDs would suppress prostaglandin synthesis at sites of inflammation but would spare constitutive prostaglandin synthesis in the GI tract and kidney. The pharmaceutical companies raced to develop COX-2 selective NSAIDs, but this now appears not be the perfect solution. If COX-2 is primarily responsible for the prostaglandins that mediate pain, inflammation and fever, than COX-2 selective drugs are not more therapeutically effective, because the available NSAIDs are already very effective inhibitors of COX-2.

NSAID classifcations:

→ COX-2 selective: drugs that inhibit COX-2 (but not COX-1) at label dose

→ COX-2 preferential: drugs that inhibit COX-2 at lower drug concentrations than COX-1, but there is some COX-1 inhibition at label dose

→ COX-1 sparing: Same as COX-2 selective

→ COX-2 specific: Same as COX-2 selective

→ COX-nonspecific: Both COX-1 and COX-2 are inhibited at label doses

This classification is based on inhibitory concentration (IC) ratios. For IC50 ratios, the NSAID concentrations needed to cause 50% inhibition of COX-1 and COX-2 are compared. If the IC50 for COX-1 is much higher than for COX-2, then COX-2 is inhibited at a much lower drug concentration. There is some debate about the exact criteria used to classify NSAIDs. Varying COX inhibition ratios, experimental conditions, species differences, and NSAID chirality can alter the

Analgesic effects

NSAIDs act as analgesics by inhibiting COX and preventing the production of prostaglandins that sensitize the afferent nociceptors at peripheral sites of inflammation. However, there is increasing evidence that some NSAIDs have a central mechanism of action for analgesia and act synergistically with opioids. Recent work has shown that the analgesic effect of flunixin in a sheep foot rot model of pain is reversed by the administration of an opiate antagonist, naloxone. To further complicate our understanding of their analgesic action, work with the specific enantiomers of some NSAIDs have shown the "S" enantiomers to have good cyclooxygenase inhibitory effects, while the "R" forms can have weak activity against cyclooxygenase yet still produce analgesia. So the clinical use of NSAIDs of analgesics differs from their use as anti-inflammatory drugs:

• NSAIDs are likely to be more effective as analgesics when inflammation is a part of the pain process.

• NSAIDs are more effective as analgesics when given prior to the onset of the inflammatory processes or insult.

• The time to onset and duration of analgesic properties of NSAIDs does not correlate well with their anti-inflammatory properties. The analgesic effect is likely to have a more rapid onset and shorter duration of action than the anti-inflammatory action.

• Dosage regimens for effective analgesia may need to be different than for anti-inflammatory action.

Adverse Eefects of NSAIDs

The adverse effects of the NSAIDs are related to cyclooxygenase inhibition in tissues where prostaglandins are beneficial and protective. Reduction in protective prostaglandins results in blood vessels constriction and tissue necrosis in the kidney and reduction in blood flow and protective mucus production in the gastrointestinal tract results in ulcers. NSAIDs have a higher incidence of toxicity in neonates because kidney function is not fully developed. When indicated in neonates, they should be administered at the lowest possible doses. NSAIDs should be administered very cautiously to dehydrated animals. As they predominately distribute in extracellular water, plasma concentrations will be greater than normal in the dehydrated animal and more likely to cause toxicity. Many of the NSAIDs are hepatically metabolized by glucuronidation. As the cat is deficient in the glucuronidation enzyme system, drugs like aspirin and acetaminophen that are eliminated by this route have prolonged elimination half-lives and high potential for toxicity. NSAIDs such as ketoprofen that are cleared by alternate pathways can be safely used in cats. Glucuronidation also results in significant enterohepatic recirculation. This tends to be greater in dogs than in other species, such as humans. This is why dogs are more sensitive to the intestinal toxicity of NSAIDs such as naproxen than humans, despite its low COX-2/COX-1 ratio.

GI Toxicity: Gastrointestinal side effects are common to all NSAIDs and are the dose-limiting factor for these drugs. Some NSAIDs, including aspirin, are topically irritating to the gastric mucosa. GI prostaglandins are natural inhibitors of gastric acid secretion and support mucosal blood flow. NSAID inhibition of prostaglandin biosynthesis results in increased acidity and decreases mucosal blood flow and mucous production, leading to ulcer formation. NSAIDs should not be used in conjunction with glucocorticoids as they potentiate gastrointestinal toxicity. Misoprostol, an orally administered synthetic prostaglandin E, may be beneficial in patients at risk for ulceration.

Hematological Toxicity: NSAIDs (especially aspirin, ketoprofen, and tolfenamic acid) should not be used in animals with concurrent hematological disorders or potential bleeding disorders, including thrombocytopenias and von Willebrand's disease. Their use should be avoided during or near surgeries where hemorrhage may be a problem.

Nephrotoxicity: The renal toxicity of NSAIDs is a major concern, particularly in the peri-operative period. NSAIDs typically have little effect on renal function in normal animals. However, they decrease renal blood flow and glomerular filtration rate in patients with congestive heart failure, hypotension, or hypovolemia (especially during anesthesia and surgery), or chronic renal disease. Under these circumstances, acute renal failure may be precipitated as NSAIDs block the ability of renal prostaglandins to mitigate the vasoconstrictive effects of norepinephrine and angiotensin II on the glomerular afferent arterioles. Currently, it is thought that COX-1 is responsible for renal prostaglandin production, so COX-2 selective drugs may avoid this problem. A more severe dose-dependent toxicity associated with NSAIDs is renal papillary necrosis. Although attributed to impaired renal blood flow, other mechanisms such as direct nephrotoxicity of the drug or its metabolites may also be involved.

Hepatotoxicity: NSAIDs are well documented to produce idiosyncratic hepatotoxicity in humans. Recent reports of carprofen-induced hepatotoxicity in dogs may reflect an idiosyncratic reaction with this drug. In dogs and cats overdosed with acetaminophen, hepatic necrosis may occur if they survive the primary hematological toxicity. All NSAIDs have the potential to be hepatotoxic however and should be used with caution in animals with underlying liver disease.

Washout period

The time period between switching drugs to allow for safe administration of the 2nd product. This is very important for anti-inflammatories (both steroids and NSAIDs). An interaction has been demonstrated between prednisolone and ketoprofen or meloxicam (Narita et al), and there are case reports of GI perforations when dericoxib is used concurrently with steroids or other NSAIDs. Although various washout schedules have been published, the exact time required when switching NSAIDs is not definitively known. One rule of thumb is to observe 10 half-lives of the first drug (so that 99.9% will be eliminated), or a minimum of 5 – 7 days, before the second drug is administered. Remember that aspirin has an irreversible effect on platelet function which persists long after the drug is eliminated from the body.

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