Review
Antipyretics: mechanisms of action and clinical use in fever suppression

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Abstract

Fever is a complex physiologic response triggered by infectious or aseptic stimuli. Elevations in body temperature occur when concentrations of prostaglandin E2 (PGE2) increase within certain areas of the brain. These elevations alter the firing rate of neurons that control thermoregulation in the hypothalamus. Although fever benefits the nonspecific immune response to invading microorganisms, it is also viewed as a source of discomfort and is commonly suppressed with antipyretic medication. Antipyretics such as aspirin have been widely used since the late 19th century, but the mechanisms by which they relieve fever have only been characterized in the last few decades. It is now clear that most antipyretics work by inhibiting the enzyme cyclooxygenase and reducing the levels of PGE2 within the hypothalamus. Recently, other mechanisms of action for antipyretic drugs have been suggested, including their ability to reduce proinflammatory mediators, enhance anti-inflammatory signals at sites of injury, or boost antipyretic messages within the brain. Although the complex biologic actions of antipyretic agents are better understood, the indications for their clinical use are less clear. They may not be indicated for all febrile conditions because some paradoxically contribute to patient discomfort, interfere with accurately assessing patients receiving antimicrobials, or predispose patients to adverse effects from other medications. The development of more selective fever-relieving agents and their prudent use with attention to possible untoward consequences are important to the future quality of clinical medicine.

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.

References (96)

  • J.G. Filep et al.

    Anti-inflammatory actions of lipoxin A(4) stable analogs are demonstrable in human whole bloodModulation of leukocyte adhesion molecules and inhibition of neutrophil-endothelial interactions

    Blood

    (1999)
  • M. Ouellet et al.

    Mechanism of acetaminophen inhibition of cyclooxygenase isoforms

    Arch Biochem Biophys

    (2001)
  • C. Landolfi et al.

    Inflammatory molecule release by beta-amyloid-treated T98G astrocytoma cellsRole of prostaglandins and modulation by paracetamol

    Eur J Pharmacol

    (1998)
  • M.J. Kluger et al.

    The adaptive value of fever

    Infect Dis Clin North Am

    (1996)
  • A.K. Done

    Treatment of fever in 1982A review

    Am J Med

    (1983)
  • T.F. Doran et al.

    AcetaminophenMore harm than good for chickenpox?

    J Pediatr

    (1989)
  • C.H. Brandts et al.

    Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria

    Lancet

    (1997)
  • E.V. Hersh et al.

    Over-the-counter analgesics and antipyreticsA critical assessment

    Clin Ther

    (2000)
  • M. Whitrow

    Wagner-Jauregg and fever therapy

    Med Hist

    (1990)
  • P.A. Mackowiak et al.

    Benefits and risks of antipyretic therapy

    Ann NY Acad Sci

    (1998)
  • L.J. Bruce-Chwatt

    Cinchona and its alkaloids350 years

    NY State J Med

    (1988)
  • S.M. Aronson

    The miraculous willow tree

    RI Med

    (1994)
  • K.E. Cooper
  • P.A. Mackowiak

    Brief history of antipyretic therapy

    Clin Infect Dis

    (2000)
  • R. Piria

    Sur des nouveaux produits extraits de la salicin

    C R Acad Sci

    (1838)
  • J.B. Spooner et al.

    The history and usage of paracetamol

    J Int Med Res

    (1976)
  • G. Weissmann

    Aspirin

    Sci Am

    (1991)
  • P.A. Mackowiak

    Normal “body” temperature

  • J.A. Boulant

    Thermoregulation

  • C.B. Saper et al.

    The neurologic basis of fever

    N Engl J Med

    (1994)
  • G.N. Luheshi

    Cytokines and feverMechanisms and sites of action

    Ann NY Acad Sci

    (1998)
  • C.A. Dinarello et al.

    FeverLinks with an ancient receptor

    Curr Biol

    (1999)
  • F. Ushikubi et al.

    Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3

    Nature

    (1998)
  • T. Oka et al.

    Relationship of EP(1-4) prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

    J Comp Neurol

    (2000)
  • D. Pajkrt et al.

    Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemiaEffect of timing of recombinant human IL-10 administration

    J Immunol

    (1997)
  • L.R. Leon et al.

    An antipyretic role for interleukin-10 in LPS fever in mice

    Am J Physiol

    (1999)
  • W. Kozak et al.

    Role of cytochrome P-450 in endogenous antipyresis

    Am J Physiol Regul Integr Comp Physiol

    (2000)
  • W. Kozak et al.

    Molecular mechanisms of fever and endogenous antipyresis

    Ann NY Acad Sci

    (2000)
  • Q. Jiang et al.

    Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxin-challenged mice

    Am J Physiol

    (1999)
  • Q. Jiang et al.

    Febrile core temperature is essential for optimal host defense in bacterial peritonitis

    Infect Immun

    (2000)
  • J.I. Schwartz et al.

    Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in humans

    Clin Pharmacol Ther

    (1999)
  • K. Matsumura et al.

    Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced feverLight and electron microscopic immunocytochemical studies

    J Neurosci

    (1998)
  • J.R. Vane

    Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

    Nat New Biol

    (1971)
  • E.H. Awtry et al.

    Aspirin

    Circulation

    (2000)
  • R.J. Flower et al.

    Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol)

    Nature

    (1972)
  • G. Weissmann

    NSAIDsAspirin and aspirin-like drugs

  • D. Riendeau et al.

    Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays

    Can J Physiol Pharmacol

    (1997)
  • X.M. Xu et al.

    Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

    Proc Natl Acad Sci USA

    (1999)
  • Cited by (0)

    Supported in part by Grants GM-15431, DK-46282, and GM-07569 from the National Institutes of Health, and the Tinsley Harrison Society.

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