Many over-the-counter nonsteroidal
antiinflamma-tory agents (NSAIDs) work through inhibition of cyclooxygenase
(COX), the key step in prostaglan-din synthesis. COX catalyzes the production
of pros-taglandin H1 from arachidonic acid. The two forms of
the enzyme, COX-1 and COX-2, have differing distribution in tissue. COX-1
receptors are widely distributed throughout the body, including the gut and
platelets. COX-2 is produced in response to inflammation.
COX-1 and COX-2 enzymes differ further
in the size of their binding sites: the COX-2 site can accommodate larger
molecules that are restricted from binding at the COX-1 site. This distinction
is in part responsible for selective COX-2 inhibition. Agents that inhibit COX
nonselectively (eg, aspirin) will control fever, inflammation, pain, and
throm-bosis. COX-2 selective agents (eg, acetaminophen [paracetamol],
celecoxib, etoricoxib) can be used perioperatively without concerns about
platelet inhibition or gastrointestinal upset. Curiously, while COX-1
inhibition decreases thrombosis, selective COX-2 inhibition increases the risk
of heart attack, thrombosis, and stroke.
Aspirin, the first of the so-called
NSAIDs, for-merly was used as an antipyretic and analgesic. Now it is used
almost exclusively for prevention of thrombosis in susceptible individuals or
for treatment of acute myocardial infarction. Aspirin is unique in that it
irreversibly inhibits COX- by acetylating a serine residue in the enzyme. The
irreversible nature of its inhibition underlies the nearly 1-week duration of
its clinical effects (eg, return of platelet aggregation to normal) after drug
The first relatively selective COX-2
agent to be developed was acetaminophen (paracetamol). Curiously, this agent,
while effective for analge-sia, produces almost no effects on inflammation
relative to other COX-2 selective agents. With few exceptions, the COX
inhibitors are oral agents. Acetaminophen and ketorolac are available in an
intravenous form for perioperative use.
Multimodal analgesia typically includes
the use of COX inhibitors, regional or local anesthesia tech-niques, and other
approaches aimed at reducing the requirement for opioids in postoperative
patients. The hope is that reduced exposure to opioids will has-ten and improve
recovery from surgical procedures.
The COX enzyme is inhibited by an
unusually diverse group of compounds that can be grouped into salicylic acids
(eg, aspirin), acetic acid deriva-tives (eg, ketorolac), propionic acid
derivatives (eg, ibuprofen), heterocyclics (eg, celecoxib), and oth-ers. Thus a
conventional discussion of structure to potency (and other factors) is not
useful for these chemicals, other than to note that the heterocyclics tend to
be the compounds with the greatest selectiv-ity for the COX-2 rather than COX-1
form of the enzyme.
All COX inhibitors (save for ketorolac)
are well absorbed after oral administration and all will typi-cally achieve
their peak blood concentrations in less than 3 hours. Some COX inhibitors are
formulated for topical application (eg, as a gel to be applied over joints or
as liquid drops to be instilled on the eye).
After absorption, COX inhibitors are
highly bound by plasma proteins, chiefly albumin. Their lipid sol-ubility
allows them to readily permeate the blood– brain barrier to produce a central
analgesia and antipyresis, and to penetrate joint spaces to produce (with the
exception of acetaminophen) an antiin-flammatory effect.
Most COX inhibitors undergo hepatic
biotransfor-mation. The agent with the most notable metabolite is acetaminophen
which at toxic, increased doses yields sufficiently large concentrations of N-acetyl-p-benzoquinone imine to produce hepatic failure.
Nearly all COX inhibitors are excreted
in urine after biotransformation.
COX inhibitors do not act directly on
the cardio-vascular system. Any cardiovascular effects result from the actions
of these agents on coagulation. Prostaglandins maintain the patency of the
ductus arteriosus, thus prostaglandin inhibitors have been administered to
neonates to promote closure of a persistently patent ductus arteriosus.
At appropriate clinical doses, none of
the COX inhibitors have effects on respiration or lung func-tion. Aspirin
overdosage has complex effects on acid–base balance and respiration.
The classical complication of COX-1
inhibition is gastrointestinal upset. In its most extreme form this can cause
upper gastrointestinal bleeding. Both complications result from direct actions
of the drug, in the former case, on protective effects of prosta-glandins in
the mucosa, and in the latter case, on the combination of mucosal effects and
inhibition of platelet aggregation.
Acetaminophen abuse or overdosage is a
common cause of fulminant hepatic failure result-ing in need for hepatic
transplantation in western societies.