DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

974 warfarin (12-fold), glucocorticoids (4-fold), or selective serotonin
reuptake inhibitors (SSRIs; 3-fold) (Gabriel et al., 1991; Dalton et al.,
2003; García Rodríguez and Barreales Tolosa, 2007).
COX-2–selective NSAIDs were originally designed for a
niche indication, to improve treatment safety for patients at high risk
for GI complications requiring chronic tNSAIDs—a population of
<5% of tNSAID users (Dai et al., 2005). Prescription behavior
changed over time, however, and more than one-third of patients at
the lowest risk for GI events received a COX-2 inhibitor in 2002.
Paradoxically, the incidence of GI adverse events had been falling
sharply in the population prior to the introduction of the coxibs—
which were developed to reduce the risk of serious GI complication,
perhaps reflecting a move away from use of high-dose aspirin as an
anti-inflammatory drug strategy. All selective COX-2 inhibitors are
less prone to induce endoscopically visualized gastric ulcers than
equally efficacious doses of tNSAIDs (Deeks et al., 2002). A more
detailed discussion on this topic can be found in the prior edition of
this textbook.
Gastric damage by NSAIDs can be brought about by at least
two distinct mechanisms (see Chapter 33). Inhibition of COX-1 in
gastric epithelial cells depresses mucosal cytoprotective PGs, especially
PGI 2
and PGE 2
. These eicosanoids inhibit acid secretion by
the stomach, enhance mucosal blood flow, and promote the secretion
of cytoprotective mucus in the intestine. Inhibition of PGI 2
and PGE 2
synthesis may render the stomach more susceptible to
damage and can occur with oral, parenteral, or transdermal administration
of aspirin or NSAIDs. There is some evidence that COX-2
also contributes to constitutive formation of these PGs by human
gastric epithelium; products of COX-2 certainly contribute to ulcer
healing in rodents (Mizuno et al., 1997). This may partly reflect
an impairment of angiogenesis by the inhibitors (Jones et al.,
1999). Indeed, coincidental deletion or inhibition of both COX-1
and COX-2 seems necessary to replicate NSAID-induced gastropathy
in mice, and there is some evidence for gastric pathology in
the face of prolonged inhibition or deletion of COX-2 alone
(Sigthorsson et al., 2002). Another mechanism by which NSAIDs
or aspirin may cause ulceration is by local irritation from contact
of orally administered drug with the gastric mucosa. Local irritation
allows backdiffusion of acid into the gastric mucosa and
induces tissue damage. However, the incidence of GI adverse
events is not significantly reduced by formulations that reduce drug
contact with the gastric mucosa, such as enteric coating or efferent
solutions, suggesting that the contribution of direct irritation to the
overall risk is minor. It also is possible that enhanced generation of
LOX products (e.g., LTs) contributes to ulcerogenicity in patients
treated with NSAIDs.
Co-administration of the PGE 1
analog, misoprostol, or proton
pump inhibitors (PPIs) in conjunction with NSAIDs can be
beneficial in the prevention of duodenal and gastric ulceration
(Rostom et al., 2002).
Several groups have attached NO–donating moieties to
NSAIDs and to aspirin in the hope of reducing the incidence of
adverse events. Benefit might be attained by abrogation of the inhibition
of angiogenesis by tNSAIDs during ulcer healing, as observed
in rodents (Ma et al., 2002); however, the clinical benefit of this strategy
remains to be established. Similarly, LTs may accumulate in the
presence of COX inhibition, and there is some evidence in rodents
that combined LOX-COX inhibition may be a useful strategy.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Cardiovascular. COX-2–selective NSAIDs were developed
to improve the GI safety of anti-inflammatory therapy
in patients at elevated risk for GI complications.
However, placebo-controlled trials with three structurally
distinct compounds—celecoxib, valdecoxib
(withdrawn), and rofecoxib (withdrawn)—revealed an
increase in the incidence of myocardial infarction,
stroke, and thrombosis (Bresalier et al., 2005;
Nussmeier et al., 2005; Solomon et al., 2006). The risk
appears to also extend to those of the older tNSAIDs,
which are quite selective for COX-2, such as diclofenac,
meloxicam, and nimesulide (Grosser et al., 2006).
Regulatory agencies in the U.S, E.U., and Australia have
concluded that all NSAIDs have the potential to increase
the risk of heart attack and stroke.
The cardiovascular hazard is plausibly explained by the
depression of COX-2-dependent prostanoids formed in vasculature
and kidney (Grosser et al., 2006). Vascular PGI 2
constrains the effect
of prothrombotic and atherogenic stimuli, and renal PGI 2
and PGE 2
formed by COX-2 contribute to arterial pressure homeostasis (see
Chapter 33). Genetic deletion of the PGI 2
receptor, IP, in mice augments
the thrombotic response to endothelial injury, accelerates
experimental atherogenesis, increases vascular proliferation, and
adds to the effect of hypertensive stimuli (Cheng et al., 2002; Egan
et al., 2004; Kobayashi et al., 2004; Cheng et al., 2006). Genetic
deletion or inhibition of COX-2 accelerates the response to thrombotic
stimuli and raises blood pressure. Together, these mechanisms
would be expected to alter the cardiovascular risk of humans, as
COX-2 inhibition in humans depresses PGI 2
synthesis (Catella-
Lawson et al., 1999; McAdam et al., 1999). Indeed, a human mutation
of the IP, which disrupts its signaling, is associated with
increased cardiovascular risk (Arehart et al., 2008).
Patients at increased risk of cardiovascular disease or thrombosis
are likely to be particularly prone to cardiovascular adverse
events while on NSAIDs. This includes patients with rheumatoid
arthritis, as the relative risk of myocardial infarction is increased in
these patients compared to patients with osteoarthritis or no arthritis.
The risk appears to be conditioned by factors influencing drug
exposure, such as dose, t 1/2
, degree of COX-2 selectivity, potency,
and treatment duration. Thus, the lowest possible dose should be
prescribed for the shortest possible period. NSAIDs with selectivity
for COX-2 should be reserved for patients at high risk for GI
complications.
Blood Pressure, Renal, and Renovascular Adverse
Events. NSAIDs and COX-2 inhibitors have been associated
with renal and renovascular adverse events.
NSAIDs have little effect on renal function or blood
pressure in normal human subjects. However, in patients
with congestive heart failure, hepatic cirrhosis, chronic
kidney disease, hypovolemia, and other states of activation
of the sympathoadrenal or renin–angiotensin systems,
PG formation becomes crucial in model systems
and in humans. NSAIDs are associated with loss of the