Methylxanthines

Abstract The closely related alkaloids caffeine (from Coffea arabica, but also present in tea, mate leaves, and cola nuts), theoph ylline (from Thea sinensis), and the less potent theobromine (from the seeds of Theobroma cacao) are widely used centrally acting stimulants. Theophylline is employed therapeutically to relax bronchial smooth muscles in asthma, and caffeine is a component of some migraine medications and drug mixtures used to treat common colds. Methylxanthines are present in popular beverages such as tea, coffee, cola-flavored drinks (to which caffeine is added), cocoa, and chocolate (theobromine). Methylxanthines reduce drowsiness and fatigue, improve mood, and increase work capacity; however, arithmetic skills and delicate muscular coordination can be impaired (2). Caffeine has a MW of 194.19, a MP of 238°C, and can be dissolved in water. Both theophylline and theobromine have a MW of 180.17; their MPs are 270°-274° and 357°C, respectively, and both are preferentially soluble in hot water. Solubility is increased if salts or complex double salts of each of the compounds are formed (21). Methylated xanthines are readily absorbed after parenteral administration or from the gastrointestinal tract. Food intake and sleep slow but do not reduce their absorption. Caffeine is more readily absorbed than theophylline (plasma peaks after 1 and 2 h, respectively). Specific sustained-release preparations of theophylline exist to slow absorption for their use as bronchodilators in pulmonology; this might complicate the clinical profile of an intoxication. The blood concentration of caffeine after two to three cups of coffee (170-250 mg caffeine) reaches 12 mg/1 (20); in comparison a cup of tea contains about 50 mg of caffeine and 1 mg of theophylline. After absorption, methylxanthines are bound to plasma proteins and distributed into all compartments of the body. In comparison, caffeine reaches greater concentrations in the cerebrospinal fluid and in brain than theophylline. Elimination of methylxanthines occurs in the liver, and <15% (5%) of theophylline (caffeine) can be detected in the urine. After caffeine intake, peak serum levels are reached after 30-60 min and its half-life in plasma is 37 h in adults; the half-life of theophylline is 8-9 h. Young children eliminate theophylline at a twofold rate; the elimination rate is much lower in premature infants (21). The half-life of caffeine increases during pregnancy. Genetic factors greatly influence the rate of elimination of methylxanthines. For theophylline, inhibition of hepatic microsomal cytochrome P-450-metabolizing enzymes by other drugs, such as oral contraceptives, histamine receptor antagonists, certain antibiotics, and allopurinol, are factors that increase serum levels and promote neurotoxicity (9). Exogenous factors influence the elimination of caffeine (18); smoking increases elimination.