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Chapter: Clinical Anesthesiology: Clinical Pharmacology: Analgesic Agents

Analgesic Agents: Cyclooxygenase Inhibitors

Many over-the-counter nonsteroidal antiinflamma-tory agents (NSAIDs) work through inhibition of cyclooxygenase (COX), the key step in prostaglan-din synthesis.


Mechanisms of Action

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 discontinuation.

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.

Structure–Activity Relationships

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.


A. Absorption

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).

B. Distribution

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.

C. Biotransformation

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.

D. Excretion

Nearly all COX inhibitors are excreted in urine after biotransformation.

Eects on Organ Systems

A. Cardiovascular

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.

B. Respiratory

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.

C. Gastrointestinal

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.


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