Salicylates
Aspirin is a weak organic
acid and is one of the oldest known drugs for the relief of fever and pain.
Aspirin re-mains the standard to which most NSAIDs are com-pared for efficacy.
Aspirin itself is an acid
with a pKa of 3.5 and is rela-tively insoluble in water, while its sodium or
calcium salts have enhanced solubility. Aspirin and related sali-cylates are
rapidly absorbed upon oral administration, with most absorption occurring in
the small intestine. The pH of the stomach, a secondary site of drug
ab-sorption, along with the gastric emptying time of the stomach, determines
the rate of absorption of the drug. Thus, food, which alters gastric emptying
time and pos-sibly the pH of the stomach, will alter absorption of the drug.
Buffering of the drug decreases irritation in the stomach, increases drug
solubility, and therefore may increase the rapidity of absorption.
Enteric-coated as-pirin tablets have a variable rate of dissolution depend-ing
on the preparation but are somewhat useful for pre-vention of stomach
ulceration and gastric distress. Absorption of aspirin from rectal
suppositories is slower and more variable than from oral administra-tion. The
peak plasma concentration of aspirin occurs 1 to 2 hours following oral
administration. Aspirin is im-mediately hydrolyzed by various esterases in the
stom-ach and in the liver to acetate and salicylic acid. Salicylic acid is
glucuronidated, conjugated to glycine to form salicyluric acid (the major
metabolic pathway), oxidized to gentisic acid (a minor metabolic pathway), or
re-mains free as salicylic acid, which is secreted in the proximal tubule of
the kidney. Diflunisal (Dolobid)
dif-fers from other salicylates in that it is not metabolized to salicylic acid
but is rapidly glucuronidated. The con-jugated metabolites of salicylates are
inactive.
Salicylic acid is highly
plasma protein bound, an effect that alters the pharmacokinetics of other drugs
taken in combination with aspirin. Salicylates passively diffuse to all
tissues, including breast milk, fetal tissues, and the CNS.They tend to
accumulate, since increases in dose de-crease renal clearance and prolong the
half-life of the drug. Clearance at high doses (>2–4 g/day) is via zero or-der
kinetics, and the half-life can approach 15 hours. At lower doses (600–1000
mg/day), clearance depends on the concentration of glucuronide or glycine
available for conjugation and is a first-order process (half-life of
ap-proximately 3–6 hours). However, renal clearance is highly dependent on the
pH of the urine; the higher the pH of the urine, the greater the clearance
of the drug. Alkalinization of the urine is used to increase clearance of
the salicylates in the case of toxicity or overdose.
Aspirin and related salicylates produce their pharmaco-logical
effects predominantly by inhibiting the synthesis of prostaglandins and to a lesser extent
synthesis of the thromboxanes
(implicated in platelet aggregation). The prostanoids are mediators of
inflammatory responses in many cell types. Aspirin is unique among NSAIDs in
that it irreversibly acetylates COX-1 and COX-2, which are required for the
synthesis of prostanoids from arachidonic acid. COX-2 is induced during
inflamma-tion and is therefore considered to mediate most in-flammatory
responses. Aspirin acetylation of COX-1 permanently inactivates the enzyme,
while acetylated COX-2 is capable of producing 15-HETE. New enzyme must be
synthesized to overcome the effects of aspirin, which in the case of
platelets can take as long as 11 days. The metabolite of aspirin, salicylic
acid, is a reversible inhibitor of COX. Other NSAIDs have reversible ef-fects
at different sites on COX-1 and on COX-2. In ad-dition, aspirin interferes with
kinin-induced modulation of the inflammatory response.
Aspirin and related
salicylates are the primary treat-ment for mild to moderate pain, such as that
associated with headache, joint and muscle pain, and dysmenor-rhea. At higher
doses aspirin is an effective analgesic in rheumatoid arthritis . The analgesic
ef-fects of salicylates are thought to be due to the inhibi-tion of
prostaglandin synthesis in the periphery and to a less well documented
mechanism at cortical areas.
The salicylates are also
potent antipyretic agents, with the exception of diflunisal, which is only
weakly ac-tive. Aspirin acts at two distinct but related sites. It de-creases
prostaglandin-induced fever in response to py-rogens and induces a decrease in
interleukin-1 modulation of the hypothalamic control of body tem-perature.
Thus, the hypothalamic control of body tem-perature returns, vasodilation
occurs, heat dissipates, and fever decreases. Other uses of aspirin include
inhi-bition of platelet aggregation via inhibition of throm-boxanes, which has
been shown to decrease the inci-dence of blood clots, myocardial infarction,
and transient ischemic attacks.
The major consequence of
aspirin overdose, which of-ten occurs in children, results from actions on
respira-tory centers in the medulla. Salicylate-induced stimula-tion of
respiration leads to hyperventilation. In addi-tion, salicylates uncouple
oxidative processes leading to increased carbon dioxide production and
metabolic aci-dosis. The onset of acidosis, if not treated less than 1 hour
after ingestion of aspirin, will lead to loss of rhyth-micity of respiration
and eventually loss of breathing. Treatments include alkalinization of the
urine, fluid re-placement, gastric lavage with activated charcoal, dialy-sis,
and artificial ventilation.
Some patients exhibit
hypersensitivity to aspirin in the form of salicylism,
which is accompanied by ringing in the ears (tinnitus), vertigo, and
bronchospasm (espe-cially in asthmatics). The use of salicylate-containing
preparations is not the only source of this drug. Those sensitive to
salicylates should be aware of salicylates in a number of foods, such as curry
powder, licorice, prunes, raisins, and paprika.
The use of aspirin in
children and teenagers with ei-ther chickenpox or influenza is contraindicated,
since there is evidence linking the use of the salicylates in such diseases to
Reye’s syndrome, a potentially fatal disease accompanied by liver damage and
encephalopa-thy. The mechanism by which the use of salicylates in-creases the
chances for development of Reye’s syn-drome is not known.
Other potential adverse
effects of the drugs include the use of aspirin by patients who anticipate
surgery or dental procedures. Such patients should be closely mon-itored and
the salicylate stopped at least 1 week prior to surgery because of the
possibility of increased clotting time and excessive bleeding. Similarly, the
use of salicy-lates in pregnant women may increase bleeding upon delivery and
prolong delivery. In addition, adverse fetal effects have been documented, such
as low birth weight, fetal intracranial bleeding, and possible teratogenic
ef-fects. Due to the ulcerogenic effects of the drugs, pa-tients with a history
of ulcers or other GI disturbances should be carefully monitored for increased
blood in the feces while taking salicylates.
The salicylates displace a number of drugs from plasma protein
binding sites, thereby leading to potential adverse effects by these agents. Since aspirin is an
over-the-counter medication, patients may fail to inform the doctor of their
aspirin consumption. Anticoagulants are potentiated by aspirin by (1)
displacement of the antico-agulants from plasma proteins and (2) the intrinsic
anti-coagulant effect of aspirin. Thus, the dosage of drugs such as coumarin
and heparin should be reduced in patients taking aspirin. A similar effect is
observed in patients taking oral sulfonylureas (Orinase, DiaBeta) for non–insulin-dependent diabetes or phenytoin (Dilantin) for seizures. Displacement of
the sulfonylureas or phenytoin from plasma binding necessitates a de-crease in
dosage to prevent an acute hypoglycemic event or sedation, respectively.
Aspirin enhances the effects of insulin (leading to hypoglycemia), penicillins
and sulfon-amides (increasing acute toxicity), and corticosteroids. Aspirin
increases the hypotensive effects of the cardiac drug nitroglycerin but
decreases the effectiveness of the loop diuretics. In patients taking
methotrexate for can-cer chemotherapy, aspirin may increase retention of the
drug, and severe toxicity may result.
Conversely, certain drugs
modify the effectiveness or side effects of aspirin. Phenobarbital,
occasionally used for seizures, induces liver enzymes that increase the
metabolism and excretion of aspirin, β-adrenoceptor– blocking drugs, such as
propranolol, and decrease the an-tiinflammatory effects of aspirin, whereas
reserpine de-creases its analgesic effects. Antacids decrease the ab-sorption
of aspirin. Alcohol consumption in combination with aspirin increases the
latter’s ulcerogenic effects
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