The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 13 of 207
Theobromine
PHARMACODYNAMICS
Mechanism of action
The methylxanthines affect many physiological systems of the body through the
mediation of the central nervous system. The probable biochemical basis being the
ability of methylxanthines to inhibit phosphodiesterase breakdown of cAMP leading
to the accumulation of the latter. Theobromine produces central stimulation because
of its effect on the brain cortex. Theobromine has stimulatory effects on the brain,
heart, gastric secretion and urine flow (9).
The action of theobromine on the smooth muscle may depend on the balance between
effects of cAMP and cGMP accumulation rather than cAMP alone. Two adenosine
receptor sites (A1 and A2) are affected by methylxanthines and therefore these
components antagonized the effect of adenosine. Adenosine acts like an inhibitor to
neurotransmitter release and this could explain the mechanism of the methylxanthines
on the CNS. Theobromine, was tested in mice, to determine whether it could function
in vivo as an adenosine receptor antagonist, in keeping with its reported in vitro
effects as a blocker of agonist binding to the adenosine A-1 receptor. Theobromine
doses, which themselves had no direct effects on spontaneous locomotor activity,
completely blocked N6-cyclohexyladenosine (CHA) induced suppression of
locomotor activity but were without effect on ethylcarboxyamido adenosine (NECA)
induced decreases in motor activity. In contrast to the specific antagonism,
theobromine blocked the hypothermia induced by both of these adenosine analogs.
These results demonstrate that theobromine is an active in vivo adenosine receptor
antagonist and that the antagonism of CHA-sensitive systems occurs even though
theobromine does not stimulate spontaneous locomotor activity. Thus, the behavioral
stimulant effects of methylxanthines may be more related to effects on NECAsensitive
systems, which are not blocked by theobromine (17).
Theobromine is also an inhibitor of cholinesterase.
Theobromine protected sensitized guinea pig against anaphylactic shock induced by
aerosolized antigen by inhibition of the release of a slow reacting substance (SRS) of
anaphylaxis and some reduction in histamine release. The methylxanthines have an
active vasodilator action on the coronary vessels and on the vessels of the lungs and
the legs. The protrombin time and plasma coagulation time in humans were
considerably shortened by theobromine. Theobromine also inhibited and reversed
platelet aggregation induced by ADP in vitro. The hepatic drug metabolizing
microsomal enzymes were stimulated in the rat. Theobromine is less effective than
other methylxanthines like caffeine and theophylline on different organs (18).
Pulmonary system
breathing frequency: 1-Substituted theobromine is a respiratory stimulant in
mice and stimulates respiration of the isolated diaphragm of the rat (18).
Tidal volume: No data available.
Lung compliance: No data available.
Airway resistance: Theobromine has a vasodilation effect in the lungs (18) and a
bronchodilatory effect (19). The airway resistance by inhalation of theophylline
aerosol, a theobromine derivate, was investigated. A dose of 15 mg theophylline
aerosol showed significant decrease of the airway resistance after 60 min. of
administration. The airway resistance decrease was not significant immediately or
after 30 min of theophylline administration (20). Theobromine is significantly less
active as a bronchodilator than theophylline. (7, 18)