ReviewAntipyretics: mechanisms of action and clinical use in fever suppression☆
Section snippets
Normal thermoregulation
Normal body temperature is circadian and varies from an approximate low of 36.4°C (97.6°F) in the morning to a high of 36.9°C (98.5°F) in the late afternoon (10). At the heart of thermoregulation is an integrated network of neural connections involving the hypothalamus, limbic system, lower brainstem, the reticular formation, spinal cord, and the sympathetic ganglia (11). An area in and near the rostral hypothalamus is also important in orchestrating thermoregulation. This region, the “preoptic
The pathogenesis of fever
Many of the mediators underlying pyrexia have been described in recent years (Figure 1). The critical “endogenous pyrogens” involved in producing a highly regulated inflammatory response to tissue injury and infection are polypeptide cytokines. Pyrogenic cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor (TNF), and interleukin-6 (IL-6), are those that act directly on the hypothalamus to effect a fever response (13). Exogenous pyrogens, such as microbial surface components, evoke
The role of prostaglandin E2
PGE2 is synthesized from arachidonic acid, which is released from cell membrane lipid by phospholipase. Arachidonic acid is metabolized by two isoforms of the COX enzyme, COX-1 and COX-2. COX-1 usually is expressed constitutively and generates prostanoids important to housekeeping functions supporting homeostasis (24). COX-2, on the other hand, is inducible by inflammatory signals such as the pyrogenic cytokines, IL-1β, TNF, and IL-6, and bacterial lipopolysaccharide (24). Genetically
The cyclooxygenase hypothesis
The antipyretic drug aspirin was in wide clinical use for more than 70 years (9) before Vane (29) demonstrated in 1971 that it exerted its physiologic action by inhibiting the production of prostaglandins. Further work suggests a current model of how aspirin and similar NSAIDs act as antipyretics.
Aspirin interferes with the biosynthesis of cyclic prostanoids derived from arachidonic acid, such as thromboxane A2 and prostaglandins (30). As a nonselective COX inhibitor, aspirin has been widely
Noncyclooxygenase targets for antipyretics
Interestingly, clinically useful actions of antipyretics may also be COX independent (45), and relevant anti-inflammatory effects of aspirin, sodium salicylate, and other NSAIDs are seen only with doses much higher than those required to suppress COX activity (46). Thus, a variety of noncyclooxygenase-dependent functions have been proposed to explain the full effects of salicylates on the pyrogenic cascade (Table 2). For example, salicylates and other antipyretics also suppress tissue
Effects on leukocytes and endothelial cells
Fever frequently begins with inflammation in peripheral tissues (Figure 1). Infectious and noninfectious diseases stimulate regional inflammatory reactions involving activated leukocytes and endothelial cells. Leukocyte adhesion to, and migration through, activated vascular endothelium can be inhibited by aspirin and other NSAIDs 32, 39, 46, 49. Aspirin and sodium salicylate, for example, inhibit leukocyte accumulation at sites of tissue injury (50).
Effects on endogenous antipyretics
Enhancing the production of the body’s own antipyretic mediators would appear to be a useful method for reducing fever. As noted, hormones such as hypothalamic AVP (5), α-melanocyte stimulating hormone, and glucocorticoids are capable of buffering the magnitude of the febrile response. AVP participates in the antipyretic mechanisms of salicylates and related NSAIDs, but not acetaminophen 48, 66, 67. The antipyretic effect of sodium salicylate and indomethacin is blocked by administration of an
The use of antipyretics
Although the complex biochemistry of antipyretics is increasingly understood, their indications for use are not. Despite the pervasive application of antipyretics by physicians, nurses, pharmacists, and parents, it remains unclear whether reducing the core temperature benefits febrile patients (2). Animal models of infection demonstrate that fever plays an important role in host defense 23, 76, and the potential salutary role of pyrexia in disease has been reviewed elsewhere 76, 77.
There are
Recommendations for the use of antipyretics
If antipyretic effects were truly limited to reducing fever, their use might be appropriate in few circumstances. For example, treating fever in patients with underlying cardiopulmonary disease might be reasonable, as discussed above, assuming these patients cannot tolerate the dilatory effects of pyrexia 2, 82. Patients suffering from noninfectious febrile diseases (such as malignancy or autoimmune phenomena) might also be given antipyretics in an effort to reduce their catabolic rates.
Summary
The antipyretic effects of acetaminophen, aspirin, and other NSAIDs are complex and repress inflammatory signals at many levels. Although COX enzyme inhibition plays a central role in the antipyretic actions of these drugs, other immunomodulatory actions appear to contribute. As our understanding of these medications deepens, indications for their use in treating febrile patients may also change.
Acknowledgements
We thank Drs. Allen Kaiser, Nancy Brown, and John Oates for their careful reading of an earlier version of this manuscript.
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Supported in part by Grants GM-15431, DK-46282, and GM-07569 from the National Institutes of Health, and the Tinsley Harrison Society.