A third proposed mechanism of action for theophylline’s efficacy is enhancement of histone deacetylation. Acetylation of core histones is necessary for activation of inflammatory gene transcription. Corticosteroids act, at least in part, by recruiting histone deacetylactylases to the site of inflammatory gene transcription, an action enhanced by low-dose theophylline. This interaction should predict that low-dose theophylline treatment would enhance the effectiveness of corticosteroid treatment, but this approach to treating patients with asthma or COPD uncontrolled by ICS plus LABA therapy has not been widely adopted. Of the various isoforms of PDE identified, inhibition of PDE3 appears to be the most involved in relaxing airway smooth muscle and inhibition of PDE4 in inhibiting release of cytokines and chemokines, thus decreasing immune cell migration and activation. This anti-inflammatory effect is achieved at doses lower than those necessary for bronchodilation.
In an effort to reduce toxicity while maintaining therapeutic efficacy, selective inhibitors of PDE4 have been developed. Many were abandoned after clinical trials showed that they induced unacceptably frequent side effects of nausea, headache, and diarrhea. However, one, roflumilast, has been shown to be effective for reducing the frequency of exacerbations of COPD and is approved by the US Food and Drug Administration (FDA) as a treatment for COPD, although not for asthma.
The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects.
A. Central Nervous System Effects
All methylxanthines, particularly caffeine, cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages, approximately 100 mg in a cup of coffee, is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma.
The larger doses necessary for more effective bronchodilation cause nervousness and tremor. Very high doses, from accidental or suicidal overdose, can cause medullary stimulation, convulsions, and even death.
B. Cardiovascular Effects
Methylxanthines have positive chronotropic and inotropic effects on the heart. At low concentrations, these effects result from inhibition of presynaptic adenosine receptors in sympathetic nerves, increasing catecholamine release at nerve endings. The higher concentrations (>10 μmol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (>100 μmol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired.
The clinical expression of these effects on cardiovascular function varies among individuals. Ordinary consumption of methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, potentially raising blood pressure slightly. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. High doses of these agents relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction.
Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent.
C. Effects on Gastrointestinal Tract
The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.
D. Effects on Kidney