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

is related to the GI and hepatic pathologies associated with this disease.
Aspirin’s kinetics are markedly altered during the febrile phase
of rheumatic fever or Kawasaki vasculitis. The reduction in serum
albumin associated with these conditions causes an elevation of the
free salicylate concentration, which may saturate renal excretion and
result in salicylate accumulation to toxic levels. In addition to dose
reduction, monitoring of the free drug may be warranted in these
situations.
Pharmacokinetics in the Elderly. Physiological changes in absorption,
distribution, and elimination in aging patients can be expected
to affect the pharmacokinetics of most drugs, including NSAIDs.
Coincident diseases may further complicate the prediction of the
response to the drug. The clearance of many NSAIDs is reduced in
the elderly due to changes in hepatic metabolism. Particularly
NSAIDs with a long t 1/2
and primarily oxidative metabolism (i.e.,
piroxicam, tenoxicam, celecoxib) have elevated plasma concentrations
in elderly patients. For example, plasma concentrations after
the same dose of celecoxib may rise up to 2-fold higher in patients
>65 years of age than in patients <50 years of age (U.S. Food and
Drug Administration, 2001), warranting careful dose adjustment.
The capacity of plasma albumin to bind drugs is diminished in older
patients and may result in higher concentrations of unbound
NSAIDs. Free naproxen concentrations, e.g., are markedly increased
in older patients, although total plasma concentrations essentially
are unchanged. The higher susceptibility of older patients to GI complications
may be due to both a reduction in gastric mucosal defense
and to elevated total and/or free NSAID concentrations. Generally, it
is advisable to start most NSAIDs at a low dosage in the elderly and
increase the dosage only if the therapeutic efficacy is insufficient.
SPECIFIC PROPERTIES OF INDIVIDUAL
NSAIDS
General properties shared by tNSAIDs (including
aspirin and acetaminophen) and COX-2–selective
NSAIDs were considered in the preceding section,
“Nonsteroidal Anti-Inflammatory Drugs.” In the following
section, important characteristics of individual
substances are discussed. NSAIDs are grouped by their
chemical similarity (Figure 34–1).
ASPIRIN AND OTHER SALICYLATES
Despite the introduction of many new drugs, aspirin is
still the most widely consumed analgesic, antipyretic,
and anti-inflammatory agent and is the standard for the
comparison and evaluation of the others. Aspirin is the
most common household analgesic; yet, because the drug
is so generally available, the possibility of misuse and
serious toxicity probably is underappreciated, and it
remains a cause of fatal poisoning in children.
Chemistry. Salicylic acid (orthohydroxybenzoic acid) is so irritating
that it can only be used externally; therefore various derivatives
of this acid have been synthesized for systemic use. These comprise
two large classes, namely esters of salicylic acid obtained from substitutions
within the carboxyl group and salicylate esters of organic
acids, in which the carboxyl group is retained and substitution is
made in the hydroxyl group. For example, aspirin is an ester of acetic
acid. In addition, there are sodium, magnesium, and choline salts of
salicylic acid. The chemical relationships can be seen from the structural
formulas shown in Figure 34–3. Substitutions on the carboxyl
or hydroxyl groups change the potency or toxicity of salicylates. The
ortho position of the hydroxyl group is an important feature for
the action of the salicylates. The effects of simple substitutions on
the benzene ring have been studied extensively. A difluorophenyl
derivative, diflunisal, also is available for clinical use.
Mechanism of Action
Salicylates generally act by virtue of their content of salicylic acid.
The effects of aspirin are largely caused by its capacity to acetylate
proteins, as described in “Irreversible Cyclooxygenase Inhibition by
Aspirin,” although high concentrations of aspirin result in therapeutic
plasma concentrations of salicylic acid. In addition to their effect
on PG biosynthesis (see the NSAIDs section and Chapter 33), the
mechanism of action of the salicylates in rheumatic disease also may
involve effects on other cellular and immunological processes in
mesenchymal and connective tissues. Attention has been directed to
the capacity of salicylates to suppress a variety of antigen–antibody
reactions. These include the inhibition of antibody production,
of antigen–antibody aggregation, and of antigen-induced release of
histamine. Salicylates also induce a nonspecific stabilization of
COOH
OH
SALICYLIC ACID
F
N
F
DIFLUNISAL
HOOC
HO
H
O
COOH
COOCH 3
OCOCH 3 OH
COOH
OH
N
N S
N N
O
ASPIRIN
N
OLSALAZINE
SULFASALAZINE
METHYL SALICYLATE
O
COOH
OC
SALSALATE
COOH
OH
OH
COOH
OH
Figure 34–3. Chemical structures of the salicylic acid derivatives.
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT