Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CHONDROPROTECTIVE AGENTS
the blood–brain barrier poorly. Paracetamol (acetaminophen)
does cross this barrier and appears to exert its
main antipyretic and analgesic effects in the CNS. Similarly,
there is evidence to suggest that coxibs also cross
this barrier and may exert a central effect in addition to
their peripheral effects.
It is not always possible to distinguish between the
anti-inflammatory and analgesic effects of NSAIDs.
Clinical analgesic efficacy does not necessarily correlate
with anti-inflammatory effects and the analgesic action
of some compounds such as paracetamol occurs in the
absence of anti-inflammatory activity.
Some NSAIDs inhibit phosphodiesterase, which elevates
the intracellular concentrations of cyclic AMP.
Cyclic AMP has been shown to stabilize membranes,
including lysosomal membranes in polymorphonuclear
neutrophils, thereby reducing the release of enzymes,
such as β-glucuronidase, that play an important role in
the inflammatory process.
Other postulated mechanisms of actions of NSAIDs
include acting as antagonists at prostaglandin-binding
sites and as antioxidants, scavengers of free radicals
and/or inhibitors of the formation of other cytotoxic
chemicals.
General pharmacokinetics and
pharmacodynamics
Chemical structure
Many NSAIDs are chiral molecules and available as
racemates – a balanced combination of optical isomers.
This is particularly true for the 2-aryl propionic acid
group (except naproxen), which includes the profens
carprofen, ketoprofen and vedoprofen. The S-
enantiomers are generally more active than the R-
enantiomers, although studies have demonstrated that
R-enantiomers of some NSAIDs can have activity. The
effectiveness of an individual drug could be dependent
on the differential distribution and elimination of each
enantiomer combined with its intrinsic activity. Several
profens undergo metabolic chiral inversion, which can
take place in several organs but predominantly the liver.
Usually the R-enantiomer is converted to the active S-
enantiomer, although the reverse can occur (e.g. with
carprofen in the horse). However, it has been demonstrated
that there is negligible chiral conversion in the
dog.
A few NSAIDs are nonchiral and remain as the parent
compound or a metabolite. In these cases, depending on
any activity of metabolites, it is easier to estimate potential
exposure to the drug and its effects.
Absorption
Orally administered NSAIDs are well absorbed from the
upper gastrointestinal tract, although the rate and extent
of absorption can be influenced by species, intragastric
pH, presence of food, gastrointestinal motility and
lesions and drug concentration. Most NSAIDs are weak
acids and therefore absorption from the canine and
feline stomach is facilitated by the low pH of gastric
fluid. Efficient absorption also occurs in the small intestine,
despite the less acidic environment, because of the
large surface area and the fact that nonionized forms of
most NSAIDs are lipophilic.
Many NSAIDs are formulated for parenteral administration
and are well absorbed from intramuscular or
subcutaneous sites. NSAIDs have also been formulated
for topical use. Topical administration can result in
measurable drug levels in tissues and synovial fluids
comparable to that observed after oral administration.
Distribution
The NSAIDs are generally distributed extracellularly,
with a small volume of distribution. One reason for this
is that most NSAIDs have an ionic charge. However,
because most are weak acids they readily penetrate
inflamed tissues. As a result, the duration of effect of
NSAIDs may exceed their apparent systemic half-life.
This is thought to be due to the concentration of NSAIDs
in locations where the pH of extracellular fluid is
decreased, such as at sites of inflammation. A few
NSAIDs, including firocoxib, lack ionic moieties and
have an inherently high volume of distribution and
broad tissue penetration.
Protein binding
All NSAIDs are highly protein bound (>90%), with the
exception of salicylate (50% protein bound). This is
believed to be another factor in the accumulation of
drug in protein-rich inflammatory exudate. As a result
of being highly protein bound, NSAIDs can be involved
in drug interactions via protein displacement. They can
sometimes be displaced from protein-binding sites
(resulting in increased biologically active drug) but more
commonly displace other less avidly bound drugs such
as anticoagulants, hydantoins, glucocorticoids and sulfonamides.
This may result in acute potentiation of the
effect of other drugs. However, in general, the clinical
significance of simple protein displacement interactions
is believed to be minimal, as the acute increase in free
drug concentration is immediately available for redistribution,
metabolism and excretion. Most NSAIDs only
bind to albumin and once binding sites are saturated,
the concentration of free drug rapidly increases.
Metabolism and elimination
Metabolism of NSAIDs is usually mediated by hepatic
mixed-function oxidases. A variety of conjugation reactions
is commonly involved in NSAID metabolism and
there are major species differences. Although hepatic
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