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Acta Med Scand 1985; 217: 149-53

REVIEW ARTICLE

On the Mechanism of Action of Theophylline and Caffeine

BERTIL B. FREDHOLM
From the Department of Pharmacology, Karolinska Institute, Stockholm. Sweden

ABSTRACT. Fredholm BB. (Department of Pharmacology, Karolinska Institute, Stock-


holm, Sweden.) On the mechanism of action of theophylline and caffeine. Acta Med Scand
1985; 217: 14!9-53.
Important developments in our understanding of the mechanism of action of methylxan-
thines have taken place in the last 10 years. A brief overview of these developments is
provided below and the author concludes that the common view that theophylline (and
caffeine) acts by raising the levels of cyclic AMP is generally untenable. Instead, many of
the actions of the methylxanthines can be explained on the basis of their being antagonists
of endogenous adenosine. However the mechanism behind the antiasthmatic effects of
xanthines still remains unknown and further research is necessary. Key words: theophyl-
line, cafleine, cyclic AMP, adenosine, adenosine receptors.

Caffeine is one of the most widely consumed drugs in the world. The Scandinavian
countries come very high on the list of coffee consumption per capita. Chemically caffeine
is 1,3,7-trimethyIxanthine.Two other naturally occurring xanthine derivatives are closely
related-theophylline is I ,3-dimethylxanthine and theobromine is 3,7-dimethylxanthine.
All three compounds are central nervous stimulants and at least caffeine and theophylline
are also effective bronchodilators useful in the treatment of asthma. Caffeine and theo-
phylline stimulate diuresis and cause some metabolic effects-the most prominent being
stimulation of lipolysis. The aim of this commentary is to highlight some recent develop-
ments regarding the mechanism of action of these and related drugs.
Sutherland and his coworkers employed theophylline and caffeine in their studies on the
regulation of glycogen metabolism. After the discovery of the central role of cyclic
adenosine monophosphate (AMP) in regulating these processes it was noted that theophyl-
line and caffeine prevented the enzymatic degradation cyclic AMP via the enzyme
phosphodiesterase (PDE) (1). This finding provided a plausible mechanism of action of
methylxanthines-accumulation of cyclic AMP and potentiation of the effects of cyclic
AMP stimulating drugs such as catecholamines (Fig. 1 a).
A second possible mechanism of action was discovered in the course of work on skeletal
muscle. It was found that caffeine caused marked contractures, presumably because it
releases calcium from stores in the sarcoplasmatic reticulum (Fig. l b ) . Other types of
interactions with calcium metabolism in cells have also been found (2).
A third mechanism of action was first noted by Sattin and Rail (3). They made the
surprising discovery that in several instances theophylline actually reduces the accumula-
tion of cyclic AMP in brain slices instead of increasing it as would have been expected
from a PDE inhibitor. They proposed that theophylline antagonized the actions of endog-
enous adenosine that acts as a stimulator of cyclic AMP accumulation.
These three putative mechanisms of action are schematically presented in Fig. 1. Other
mechanisms of action have also been proposed but they lack the experimental support of
the first three and are left out of this discussion (4).

Abbreviations: AMP = adenosine monophosphate, PDE = phosphodiesterase.


150 B . B . Fredholm Acta Med Scand 1985; 217

( a ) Inhibition of cyclic AMP phosphodiesterase. Drugs such


as isoprenaline interact with specific cell surface receptors to
activate a GTP-binding N-protein, which in turn stimulates
the adenylate cyclase to form cyclic AMP from magnesium
ATP. Intracellular cyclic AMP can then activate cyclic AMP-
Caffeine dependent protein kinase which phosphorylates various key
enzymes to produce the biological actions. However, cyclic
protein kinase AMP may also be metabolized by phosphodiesterase to form
5'-AMP 5'-AMP, which is unable to stimulate protein kinase. This
inactivation is blocked by methylxanthines, which therefore
raises the levels of cyclic AMP and potenties the actions of
Biological action drugs that stimulate cyclic AMP formation.

( b )Effects on calcium. There is


good evidence that methylxanthines
may facilitate the release of calcium
from endoplasmatic reticulum in
skeletal and cardiac muscle. At still
higher concentrations these xan-
thines may per se release calcium.
Finally, there is some evidence that
methylxanthines may affect the
transport of calcium across the cell
membrane. In view of the critical
role of calcium in muscular contrac-
tion and release processes these ac-
tions on calcium may explain cer-
release tain actions of the methylxanthines.
c

STlM INHlB BLOCK


CYCLASE CYCLASE C&+ENTRY ( c ) Adenosine receptor antagonism. Most cells appear
to be equipped with cell surface receptors for adeno-

I
lnhibition
I
Inhibition
I
Inhibition
sine. These receptors may be linked to adenylate cy-
clase mediating either inhibition (Ri-receptors) or
stimulation (Ra-receptors) of adenylate cyclaie. Aden-
osine receptors may also affect calcium influx. Theo-
platelets
lymphocytes
Lipolysis transmitter
release
_ _
ohvlline and other methvlxanthines act at these adeno-
sine receptors as competitive inhibitors.

Fig. 1 . Schematic presentation of three proposed mechan-


isms of action of methylxanthines.
Acta Med Scand 1985; 217 Xanthines as adenosine antagonists 151

How can we decide which of these three mechanisms, if any, is the most important in
producing a given biological effect? Two approaches seem particularly promising. First,
one may compare the dose-effect relationship for the xanthines in producing the biological
effect in question with the dose-effect relationship for producing the biochemical effect.
Second, one may compare the relative order of potency of a series of xanthines with
regard to their activity in a biological system with their activity to cause PDE inhibition,
adenosine receptor antagonism and to cause changes in calcium metabolism. Table I gives
some approximate potencies of a series of xanthines with regard to the three mechanisms
of action. The results clearly indicate that caffeine and theophylline are considerably more
potent as inhibitors of adenosine actions than as inhibitors of cyclic AMP breakdown and
that very high concentrations are required to produce contraction of skeletal muscle. Table
I also shows that there are xanthine derivatives (such as 8-phenyl-theophylline) that are
much more potent than theophylline as adenosine antagonists, but actually less potent as
PDE inhibitors-thus producing more selective agents than the prototypes caffeine and
theophylline. Conversely, there are compounds, such as enprofylline, which are more
potent than theophylline as a PDE inhibitor but less potent as an adenosine antagonist.
The plasma concentration of theophylline following therapeutic doses of theophylline is
in the order of 30 pM (5). Concentrations exceeding 100 yM lead to toxic effects including
tachycardia, restlessness and eventually seizures ( 6 ) . Toxic effects of caffeine are ob-
served at concentrations above 200 pM and fatal poisoning is associated with concentra-
tions above 500 pM.The concentration of caffeine in plasma after ingestion of caffeine-
containing beverages is usually below 100 pM. Thus, the mechanisms responsible for the
therapeutic effects of caffeine and theophylline must be sought among those that are
responsive to concentrations below 100 yM.Conversely, such biochemical effects of these
methylxanthines that require concentrations in the mM range are probably of mere
toxicological interest. Based on such comparisons of potency and therapeutic concentra-
tion, inhibition of adenosine effects is the mechanism, of those three mentioned above,
that is most likely to be of therapeutic importance.
Essentially the same conclusion can be drawn from studies of several analogs of caffeine
and theophylline. Some of the findings are summarized in Table 11. Several of the effects
of theophylline and caffeine are likely to be due to adenosine antagonism, viz. central
excitation, metabolic stimulation, catecholamine release, renal effects. However, there is
one notable exception: the results obtained in the lung and trachea do not suggest that
antagonism of the actions of endogenous adenosine is the major mechanism underlying the

Table I. Potency of some xanthine derivatives as adenosine receptor antagonists, phos-


phodiesterase (PDE) inhibitors and stimulators of skeletal muscle contraction (approxi-
mate figures)
For details and references, see ref. 4

ECSO (pM)
~~ ~

Adenosine receptor PDE inhibition Contraction

Caffeine 40 loo0 3000


Theophylline 10 300 5000
Enprofylline 100 100 ND
8-phenyl-theophylline 0.5 >300 ND
1,3-diethyl-8-phenyl-theophylline 0.2 > 100 ND

ND = not determined.
152 B . B . Fredholm Acta Med Scand 1985; 217

actions of the xanthines in asthma. One factor in the mechanism of action of theophyllinel
caffeine in asthma that could be mediated by adenosine antagonism appears to be inhibi-
tion of the release of anaphylactic mediator substances (7).
The bulk of the evidence would suggest that adenosine antagonism is the mechanism
underlying the majority of the actions of theophylline, except the antiasthmatic effects.
There are two important corollaries to this conclusion. First, the fact that the antiasthma-
tic effect of theophylline is probably unrelated to many of the other effects, which in
therapy are side-effects, could make it possible to design antiasthmatic xanthine deriva-
tives with fewer side-effects and enprofylline may be a prototype for such a compound (8).
It should be pointed out, however, that compounds with few adenosine-related side-effects
may be accompanied by other equally debilitating side-effects. For example, caffeine and
theophylline possess, if anything, the ability to diminish headaches (especially those
resulting from caffeine withdrawal), whereas enprofylline may actually cause headaches.
The second corollary is that we must still search for the mechanism underlying the
tracheo-bronchial actions of theophylline-like compounds: antagonism of endogenous
adenosine is probably not involved, PDE inhibition occurs at concentrations higher than
therapeutic and xanthine derivatives do not potentiate the actions of drugs such as
isoprenaline as would be expected from a drug that prevents cyclic AMP breakdown.
Relaxation of smooth muscle is also difficult to explain on the basis of calcium release
from the sarcoplasmic reticulum. The mechanism responsible for relaxation of respiratory
smooth muscle remains unknown. However, it is tempting to speculate that an effect
involving an alteration in the intracellular disposition of calcium may be involved.
In conclusion, recent research regarding the mechanism of action of xanthine drugs such
as caffeine and theopylline has provided some important answers and posed some interest-
ing questions. The finding that many of the actions of the methylxanthines are in all
probability due to inhibition of the actions of endogenous adenosine obviously implies that
adenosine is in fact an important regulator of several physiological processes including
many in the central nervous system. Much independent research supports this conclusion.
Furthermore, the failure to account for the effects of xanthines in bronchial smooth muscle
by any of the proposed mechanisms of action not only implies that theophylline and
caffeine are “dirtier” as pharmacological agents than hitherto appreciated but also indi-

Table 11. Effects of adenosine, enprofylline (Enpr., a weak adenosine antagonist), 8-


phenyl-theophylline (8-pt., a potent adenosine antagonist) and theophyllinelcaffeine (theol
cuff.) in selected organs

Adenosine Theokaff. Enpr. 8-pt.

Bronchodilatation + 0
Anaphylactic mediator release - (-)
Respiratory stimulation 0 +
Central nervous stimulation 0 +
Lipolysis 0 +
Diuresis 0 +
Cardiac stimulation (+) +
NA release 0 +
Renin release 0 ?

a Adenosine may cause a weak relaxation of the resting trachea and a marked relaxation of the
contracted trachea. Furthermore the extent of the contractile response depends on the type of
tracheal preparation.
Acta Med Scand 1985: 217 Xanthines as adenosine antagonists 153

cates that there are important physiological regulatory processes in smooth muscle that are
insufficiently outlined and understood.

REFERENCES
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mechanical properties of isolated mammatian heart muscle. Circ Res 1972; 30: 367-92.
3. Sattin A, Rall TW. The effect of adenosine and adenine nucleotides on the adenosine 3’,5’-
phosphate content of Guinea-pig cerebral cortex slices. Molec Pharmacol 1970; 6: 13-23.
4. Fredholm BB. Cardiovascular and renal actions of the methylxanthines. In: Spiller AG, ed.
Methylxanthine beverages and foods. Chemical, biochemical, physiological and epidemiological
aspects. 1984; in press.
5 . Webb-Johnson DC, Andrews JL Jr. Bronchodilator therapy Parts 1 and 11. N Engl J Med 1977;
297: 476 and 758.
6. Rall TW. Central nervous stimulants. The xanthines. In: Goodman AG, Gilman LS, Goodman A,
eds. The pharmacological basis of therapeutics. New York: MacMillan, 1980; 592-605.
7. Sydbom A, Fredholm BB. On the mechanism by which theophylline inhibits histamine release
from rat mast cells. Acta Physiol Scand 1982; 114: 243-51.
8. Lunell E, Svedmyr N, Anderson K-E, Persson CGA. Effects of enprofylline, a xanthine deriva-
tive lacking adenosine receptor antagonism, in patients with chronic obstructive lung disease. Eur
J Clin Pharmacol 1982; 22: 395402.

Received May 21, 1984.

Correspondence: B. B. Fredholm. MD, Department of Pharmacology, Karolinska Institute, Box


60400, S-10401 Stockholm, Sweden.