Antagonists of adenosine - Theophylline and caffeine
The stimulation of A1 adenosine receptors inhibits adenylcyclase and decreases intracellular cyclic AMP. The inhibition of these receptors leads to the opposite effect, i.e. an increase in adenylcyclase activity. The antagonists used are xanthine derivatives.
The xanthine bases, caffeine, theophylline and theobromine which is not used any more in therapeutics, are antagonists of the A11 receptors and certain A22 receptors of adenosine but have also other mechanisms of action.
Theophylline and caffeine produce their effects by several mechanisms, in particular inhibition of A1 adenosine receptors and inhibition of phosphodiesterases:
Inhibition of the A1 receptors of adenosine induces:
heart rate acceleration with possibility of palpitations
stimulation of the central nervous system with increase of vigilance and sometimes of anxiety
bronchodilation, or more precisely decrease of bronchoconstrition in asthmatic patients where adenosine appears to play a dominant role
respiratory stimulation by central action, which explains why theophylline and caffeine can be used for the prevention of apnea of the new-born baby.
Inhibition of phosphodiesterases: at concentrations higher than those which are necessary to inhibit adenosine receptors, theophylline and caffeine inhibit phosphodiesterases, among which phosphodiesterases of type 4, responsible of cAMP inactivation whose concentration rises.
By reducing adenylcyclase inhibition, they increase cAMP production, and by inhibiting phosphodiesterases, they limit its destruction. Other drugs such as beta-2 mimetics also increase the formation of cAMP.
Increase of intracellular calcium: caffeine and theophylline increase, probably by activating ryanodine receptors, the concentration of Ca2+ in the cytoplasm of the skeletal muscles and the cardiac muscle and increase their force of contraction.
Inhibition of autacoid release: theophylline and caffeine decrease the release of autacoids (histamine and bradykinin) by the mast cells by a cromolyn like effect. They could also modify the release of neurotransmitters.
By complex mechanisms, caffeine could potentiate the activity of certain analgesics.
