Aspirin and other Analgesics

I. Analgesics

A. The anti-inflammatory, analgesic, and antipyretic drugs are a heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and side effects.

B. The prototype is aspirin; hence these compounds are often referred to as aspirin-like drugs.

C. All aspirin-like drugs are antipyretic, analgesic, and anti-inflammatory, but there are important differences in their activities.

1. For example, acetaminophen is antipyretic and analgesic but is only weakly anti-inflammatory.

2. The reason for the differences are not clear; variations in the sensitivity of enzymes in the target tissues may be important.

D. When employed as analgesics, these drugs are usually effective only against pain of low-to-moderate intensity, particularly that associated with inflammation.

E. Aspirin drugs do not change the perception of sensory modalities other than pain.

F. The type of pain is important; chronic postoperative pain or pain arising from inflammation is particularly well controlled by aspirin-like drugs, whereas pain arising from the hollow viscera is usually not relieved.

G. As antipyretics

1. aspirin-like drugs reduce the body temperature in feverish states.

2. Although all such drugs are antipyretics and analgesics, some are not suitable for either routine or prolonged use because of toxicity; phenylbutaxone is an example.

H. This class of drugs finds its chief clinical application as anti inflammatory agents in the treatment of musculoskelatal disorders, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

I. In general, aspirin-like drugs provide only symptomatic relief from the pain and inflammation associated with the disease and do not arrest the progression of pathological injury.

II. Analgesics - Chemistry of Action

A. There has been substantial progress in elucidating the mechanism of action of aspirin-like drugs, and it is now possible to understand why such heterogeneous agents have the same basic therapeutic activities and often the same side effects.

B. Indeed, their therapeutic activity appears to depend to a large extent upon the inhibition of a defined biochemical pathways responsible for the biosynthesis of prostaglandins and related autacoids.

C. Aspirin-like drugs inhibit the conversion of arachidonic acid to the unstable endoperoxide intermediate, PGG2, which is catalyzed by the cyclooxygenase.

D. Individual agents have differing modes of inhibitory activity on the cyclooxygenase. Aspirin itself acetylates a serine at the active site of the enzyme.

E. Platelets are especially susceptible to this action because (unlike most other cells) they are incapable of regenerating the enzyme, presumably because they have little or no capacity for protein biosynthesis.

F. In practical terms this means that a single dose of aspirin will inhibit the platelet cyclooxygenase for the life of the platelet (8 to 10 days); in man a dose as small as 40 mg per day is sufficient to produce this effect.

G. In contrast to aspirin, salicylic acid has no acetylating capacity and is almost inactive against cyclooxygenase in vitro. Nevertheless, it is as active as aspirin in reducing the synthesis of prostaglandins in vivo.

H. Most of the other common aspirin-like drugs are irreversible inhibitors of the cyclooxygenase, although there are some exceptions.

I. For indomethacin, the mode of inhibition is particularly complex and probably involves a site on the enzyme different from that which is acetylated by aspirin.

J. Pain

1. Prostaglandins are associated particularly with the development of pain that accompanies injury or inflammation.

2. Large doses of PGE2 or PGF2a, given to women by injection to induce abortion, cause intense local pain.

3. Prostaglandins can also cause headache and vascular pain when infused intravenously in man.

4. While the doses of prostaglandins required to elicit pain are high in comparison with the concentrations expected in vivo, induction of hyperalgesia occurs when minute amounts of PGE1 are given intradermally to man.

K. Fever

1. The hypothalamus regulates the set point at which body temperature is maintained.

2. In fever, this set point is elevated, and aspirin-like drugs promote its return to normal.

3. These drugs do not influence body temperature when it is elevated by such factors as exercise or increases in the surrounding temperature.

III. Aspirin

A. Also known as acetylsalicylic acid, is one of the most commonly used pain-reducing drugs (analgesics) in the world.

B. It is also used as an antipyretic to reduce fever and is beneficial as an anti-inflammatory drug in the treatment of the symptoms of such diseases of the joints as rheumatoid arthritis, osteoarthritis, and rheumatic fever.

C. In addition, aspirin interferes with blood clotting.

D. Research has suggested that it may also be useful in preventing strokes and other disorders that involve blood clots.

E. Heart attack and stroke patients are generally prescribed one aspirin tablet a day to reduce the risk of recurrence.

F. The usual dosage of aspirin is effective for about three to four hours. Aspirin does not actually cure diseases, but merely relieves symptoms.

G. Aspirin is a relatively safe drug when taken at recommended dosage levels.

H. However, it can irritate the lining of the stomach and cause small amounts of stomach bleeding.

I. Continued use of large doses of aspirin may cause blood clotting defects and liver and kidney disorders.

J. Continued use of aspirin may also lead to anemia, due to blood loss from the digestive tract.

K. Aspirin should not be given to children who have chicken pox or influenza, as the dangerous condition, Reye's syndrome, may result.

L. It should not be taken by pregnant women, and it should be given with caution to infants.

M. Acetaminophen is an effective alternative to aspirin as an analgesic and antipyretic agent.

N. However, its anti-inflammatory effect is minor and not clinically useful.

O. It is commonly felt that acetaminophen may have fewer side effects than aspirin, but it should be noted that an acute overdose may produce severe or even fatal liver damage.

P. Acetaminophen does not inhibit platelet aggregation and therefore is not useful for preventing vascular clotting.

Q. Acetaminophen has been proved to be a reasonable substitute for aspirin when analgesic or antipyretic effectiveness is desired, especially in patients who cannot tolerate aspirin.

R. This might include patients with peptic ulcer disease of gastric distress or those in whom the anticoagulant action of aspirin might

References

Lycos Health with Web MD - Aspirin. http://webmd.lycos.com/content/dmk/dmk_article_14566501996-2001 WebMD Corporation.

Analgesics and Anti-Inflamitory agents. http://www.weber.edu/ewalker/Medicinal_Chemistry/topics/Analgesia_antiinflam/Analgesics_anti-inflamitory.htm. 2001, Weber.edu.