What is the pathophysiology of caffeine toxicity?

Updated: Oct 24, 2020
  • Author: David Yew, MD; Chief Editor: Michael A Miller, MD  more...
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Caffeine, a methylxanthine, is closely related to theophylline. Caffeine is rapidly and completely absorbed from the GI tract; it is detectable in the plasma 5 minutes after ingestion, with peak plasma levels occurring in 30-60 minutes. The volume of distribution in adults is approximately 0.5 L/kg.

Caffeine is primarily metabolized by the cytochrome P450 (CYP) oxidase system in the liver. The plasma half-life of caffeine varies considerably from person to person, with an average half-life of 5-8 hours in healthy, nonsmoking adults. Caffeine clearance is accelerated in smokers; clearance is slowed in pregnancy, in liver disease, and in the presence of some CYP inhibitors (eg, cimetidine, quinolones, erythromycin). In addition, the hepatic enzyme system responsible for caffeine metabolism can become saturated at high levels, resulting in a marked increase in serum concentration with small additional doses.

Various mechanisms mediate the effects of caffeine in the human body. Caffeine directly stimulates respiratory and vasomotor centers of the brain and acts as an adenosine antagonist, resulting in peripheral vasodilatation and CNS stimulation. Caffeine is a potent releaser of catecholamines (norepinephrine and, to a lesser extent, epinephrine) that increases cardiac chronotropic and inotropic activity, bronchodilation, and peripheral vasodilatation. Caffeine is also a phosphodiesterase inhibitor. However, because extremely high concentrations of caffeine are required to inhibit this enzyme, whether this effect contributes to the clinical effects of caffeine in vivo is unknown.

In addition to its cardiovascular effects, caffeine induces a number of metabolic changes, including hyperglycemia (by stimulating gluconeogenesis and glycogenolysis), increased renal filtration, ketosis, and hypokalemia. Caffeine is a potent stimulator of gastric acid secretion and GI motility.

Death from caffeine toxicity is rare, but it has been reported due to dysrhythmias, seizures, and aspiration of emesis. Oral doses of caffeine greater than 10 g can be fatal in adults. [10] A daily intake of 400 mg—about four or five cups of coffee—is considered safe for adults, while 200 mg is considered safe for pregnant women. [7, 11]

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