These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs such as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:

Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)
Blockage of acid-sensing ion channels (ASICs)
Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)The action of one single dose is much longer (6 to 8 h) than the very short 1.2–2 h half-life of the drug would indicate. This could be partly because it persists for over 11 hours in synovial fluids. As a veterinary drug
Diclofenac is widely approved as a veterinary drug. It is used in the treatment of companion animals and livestock. In sheep, pigs, cattle and goats, it is used in the management of several bacterial diseases, including diarrhoea, enteritis, dysentery, foot rot and septicaemia.
If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other NSAIDs. As of December 2009, Endo, Novartis, and the US FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium. Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 week after initiating treatment with diclofenac. Kidney
NSAIDs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins" in sensitive persons or animal species, and potentially during long-term use in nonsensitive persons if resistance to side effects decreases with age. However, this side effect cannot be avoided merely by using a COX-2 selective inhibitor because, "Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney... Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered." However, diclofenac appears to have a different mechanism of renal toxicity.