Xanthines - Clinical Significance of Xanthine Derivatives

Clinical Significance of Xanthine Derivatives

Derivatives of xanthine (known collectively as xanthines) are a group of alkaloids commonly used for their effects as mild stimulants and as bronchodilators, notably in the treatment of asthma symptoms. In contrast to other, more potent stimulants, xanthines mainly act to oppose the actions of the sleepiness-inducing adenosine, making them less effective as stimulants than sympathomimetic amines. Due to widespread effects, the therapeutic range of xanthines is narrow, making them merely a second-line asthma treatment. The therapeutic level is 10-20 micrograms/mL blood; signs of toxicity include tremor, nausea, nervousness, and tachycardia/arrhythmia.

Methylated xanthines (methylxanthines) affect not only the airways but stimulate heart rate, force of contraction, cardiac arrhythmias at high concentrations. In the CNS they increase alertness, stimulate the respiratory centre, and are used for treatment of infantile apnea. In high doses they can lead to convulsions that are resistant to anticonvulsants. Methylxanthines induce acid and pepsin secretions in the GI tract.

Methylxanthines are metabolized by Cytochrome P450 in the liver. They include caffeine, aminophylline, IBMX, paraxanthine, pentoxifylline, theobromine, and theophylline. These drugs act as both

1. competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP, activate PKA, inhibit TNF-alpha and leukotriene synthesis, and reduce inflammation and innate immunity and
2. nonselective adenosine receptor antagonists which inhibit sleepiness-inducing adenosine.

But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthines (some nonmethylated) have been developed searching for compounds with greater selectivity for phosphodiesterase enzyme or adenosine receptor subtypes. Xanthines are also found very rarely as constituents of nucleic acids.