Pharmacodynamics and pharmacokinetics of nonsteroidal anti‐inflammatory drugs in species of veterinary interest

Abstract

This review summarises selected aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not intended to be comprehensive, in that it covers neither minor species nor several important aspects of NSAID PD. The limited objective of the review is to summarise those aspects of NSAID PK and PD, which are important to an understanding of PK-PD integration and PK-PD modelling (the subject of the next review in this issue). The general features of NSAID PK are: usually good bioavailability from oral, intramuscular and subcutaneous administration routes (but with delayed absorption in horses and ruminants after oral dosing), a high degree of binding to plasma protein, low volumes of distribution, limited excretion of administered dose as parent drug in urine, marked inter-species differences in clearance and elimination half-life and ready penetration into and slow clearance from acute inflammatory exudate. The therapeutic effects of NSAIDs are exerted both locally (at peripheral inflammatory sites) and centrally. There is widespread acceptance that the principal mechanism of action (both PD and toxicodynamics) of NSAIDs at the molecular level comprises inhibition of cyclooxygenase (COX), an enzyme in the arachidonic acid cascade, which generates inflammatory mediators of the prostaglandin group. However, NSAIDs possess also many other actions at the molecular level. Two isoforms of COX have been identified. Inhibition of COX-1 is likely to account for most of the side-effects of NSAIDs (gastrointestinal irritation, renotoxicity and inhibition of blood clotting) but a minor contribution also to some of the therapeutic effects (analgesic and anti-inflammatory actions) cannot be excluded. Inhibition of COX-2 accounts for most and possibly all of the therapeutic effects of NSAIDs. Consequently, there has been an intensive search to identify and develop drugs with selectivity for inhibition of COX-2. Whole blood in vitro assays are used to investigate quantitatively the three key PD parameters (efficacy, potency and sensitivity) for NSAID inhibition of COX isoforms, providing data on COX-1:COX-2 inhibition ratios. Limited published data point to species differences in NSAID-induced COX inhibition, for both potency and potency ratios. Members of the 2-arylpropionate sub-groups of NSAIDs exist in two enantiomeric forms [R-(-) and S-(+)] and are licensed as racemic mixtures. For these drugs there are marked enantiomeric differences in PK and PD properties of individual drugs in a given species, as well as important species differences in both PK and PD properties.

ISFM and AAFP Consensus Guidelines: Long-Term use of NSAIDs in Cats

“…They exert these effects mostly through inhibiting the production of prostaglandins (PGs) and leukotrienes (LTs) by the cyclo-oxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, respectively. [33][34][35] Most NSAIDs primarily inhibit the activity of COX enzymes. Although some also inhibit LOX enzymes, for currently licensed feline drugs this is generally short-lived in comparison with COX inhibition, and evidence of additional clinical efficacy from this is lacking.…”

Association Between Nonsteroidal Anti-Inflammatory Drugs and Gastric Ulceration in Horses and Ponies

“…As mentioned previously, the majority of NSAIDs are poorly selective, inhibiting COX-1 and COX-2 equally (Fitzpatrick et al, 2004;Vicente, 2004). Drugs that inhibit COX-1 are considered the main causative of stomach lesions, because this enzyme is generally -but not exclusively -responsible for the above mentioned adverse effects on the gastrointestinal tract (Jones & Blikslager, 2001;Lees et al, 2004;Videla & Andrews, 2009). Although the ulcer-causing potential may vary among NSAIDs, a study of rat stomachs with normal mucosa after acid challenge showed that inhibition of both cyclooxygenases causes gastrointestinal injury; however, inhibition of only one of these enzymes did not have this effect (Gretzer et al, 2001).…”

“…Furthermore, administering NSAIDs on an empty stomach may result in local gastric irritation. Therefore, these drugs should be administered with food when given orally (Mathews, 2002;Lees et al, 2004;Monreal et al, 2004). The site of NSAID-induced ulcers in the stomach of horses remains controversial.…”

Laboratory and Farm Animal Law. Opportunities for Ending Animal Use

“…The cancer drug 6-azauridine can be used in humans for long periods; but in dogs small doses produce potentially lethal results in a few days (Weatherall 1982). Phenylbutazone works through the body slowly in humans; but in dogs it disappears in hours (Lees et al 2004). The list of substances and their effects in different species is immeasurable.…”