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

ingestion of anti-inflammatory doses of 4-5 g of
aspirin produces plasma salicylate levels in the range
of 120-350 μg/mL. Optimal anti-inflammatory effects
for patients with rheumatic diseases require plasma
salicylate concentrations of 150-300 μg/mL.
Significant adverse effects can be seen at levels of
>300 μg/mL. At lower concentrations, the drug clearance
is nearly constant (despite the fact that saturation
of metabolic capacity is approached) because the fraction
of drug that is free, and thus available for metabolism
or excretion, increases as binding sites on plasma
proteins are saturated. The total concentration of salicylate
in plasma is therefore a relatively linear function
of dose at lower concentrations. At higher
concentrations, however, as metabolic pathways of disposition
become saturated, small increments in dose
can disproportionately increase plasma salicylate concentration.
Failure to anticipate this phenomenon can
lead to toxicity.
Therapeutic Uses
Systemic Uses. The dose of salicylate depends on the
condition being treated.
The analgesic–antipyretic dose of aspirin for adults is 324-
1000 mg orally every 4-6 hours. The anti-inflammatory doses of
aspirin recommended for arthritis, spondyloarthropathies, and systemic
lupus erythematosus (SLE) range from 3-4 g/day in divided
doses. Salicylates are contraindicated for fever associated with viral
infection in children (see “Reye’s Syndrome”); for nonviral etiologies,
40-60 mg/kg/day given in six divided doses every 4 hours is
recommended. The maximum recommended daily dose of aspirin
for adults and children >12 years or older is 4 g. The rectal administration
of aspirin suppositories may be preferred in infants or when
the oral route is unavailable. Although aspirin is regarded as the standard
against which other drugs should be compared for the treatment
of rheumatoid arthritis, many clinicians favor the use of other
NSAIDs perceived to have better GI tolerability, even though this
perception remains untested by randomized clinical trials. Salicylates
suppress clinical signs and improve tissue inflammation in acute
rheumatic fever. Much of the possible subsequent tissue damage,
such as cardiac lesions and other visceral involvement, however, is
unaffected by salicylate therapy.
Other salicylates available for systemic use include salsalate
(salicylsalicylic acid), which is hydrolyzed to salicylic acid
during and after absorption, and magnesium salicylate (tablets;
DOAN’S, MOMEMTUM, others). A combination of choline salicylate
and magnesium salicylate (choline magnesium–trisalicylate) also
is available.
Diflunisal is a difluorophenyl derivative of salicylic acid that
is not converted to salicylic acid in vivo. Diflunisal is more potent
than aspirin in anti-inflammatory tests in animals and appears to be
a competitive inhibitor of COX. However, it is largely devoid of
antipyretic effects, perhaps because of poor penetration into the
CNS. The drug has been used primarily as an analgesic in the
treatment of osteoarthritis and musculoskeletal strains or sprains; in
these circumstances, it is about three to four times more potent than
aspirin. The usual initial dose is 1000 mg, followed by 500 mg every
8-12 hours. For rheumatoid arthritis or osteoarthritis, 250-1000 mg/day
is administered in two divided doses; maintenance dosage should
not exceed 1.5 g/day. Diflunisal produces fewer auditory side effects
(see “Ototoxic Effects”) and appears to cause fewer and less intense
GI and antiplatelet effects than does aspirin.
Local Uses. Mesalamine (5-aminosalicylic acid) is a salicylate that
is used for its local effects in the treatment of inflammatory bowel
disease (see Chapter 47, especially Figure 47–4). The drug as an
immediate-release formulation would not be effective orally because
it is poorly absorbed and is inactivated before reaching the lower
intestine. However, oral formulations that deliver drug to the lower
intestine—mesalamine formulated in a pH-sensitive, polymercoated,
delayed-release tablet (ASACOL, LIALDA); an extended-release
mesalamine capsule (APRISO); and olsalazine (sodium azodisalicylate,
a dimer of 5-aminosalicylate linked by an azo bond; DIPEN-
TUM)—are efficacious in the treatment of inflammatory bowel
disease (in particular, ulcerative colitis). Mesalamine is available as
a rectal enema (ROWASA, others) for treatment of mild to moderate
ulcerative colitis, proctitis, and proctosigmoiditis and as a rectal suppository
(CANASA) for the treatment of active ulcerative proctitis.
Sulfasalazine (salicylazosulfapyridine; AZULFIDINE, others) contains
mesalamine linked covalently to sulfapyridine, and balsalazide
(COLAZAL, others) contains mesalamine linked to the inert carrier
molecule 4-aminobenzoyl-β-alanine. Both drugs are absorbed poorly
after oral administration and cleaved to the active moiety by bacteria
in the colon. Sulfasalazine and olsalazine have been used in the
treatment of rheumatoid arthritis and ankylosing spondylitis. Some
over-the-counter medications to relieve indigestion and diarrhea
agents contain bismuth subsalicylate (PEPTO-BISMOL, others) and have
the potential to cause salicylate intoxication, particularly in children.
The keratolytic action of free salicylic acid is employed for
the local treatment of warts, corns, fungal infections, and certain
types of eczematous dermatitis. After treatment with salicylic acid,
tissue cells swell, soften, and desquamate. Methyl salicylate (oil of
wintergreen) is a common ingredient of ointments and deep-heating
liniments used in the management of musculoskeletal pain; it also is
available in herbal medicines and as a flavoring agent. The cutaneous
application of methyl salicylate can result in pharmacologically
active, and even toxic, systemic salicylate concentrations and has
been reported to increase prothrombin time in patients receiving
warfarin.
Adverse Effects
Respiration. Salicylates increase O 2
consumption and CO 2
production
(especially in skeletal muscle) at anti-inflammatory doses; these
effects are a result of uncoupling oxidative phosphorylation. The
increased production of CO 2
stimulates respiration (mainly by an
increase in depth of respiration with only a slight increase in rate).
The increased alveolar ventilation balances the increased CO 2
production,
and thus plasma CO 2
tension (PCO 2
) does not change or
may decrease slightly. Salicylates also stimulate the respiratory center
directly in the medulla. Respiratory rate and depth increases, the
Pco 2
falls, and primary respiratory alkalosis ensues. Both mechanisms
can occur in parallel, although the stimulation of ventilation
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT