The compounds known as
xanthines, methylxanthines, or xanthine derivatives constitute a particularly
inter-esting class of drugs. Since they possess diverse phar- macological
properties, there is always a question of where most appropriately to discuss
them in a pharma-cology text. The xanthines are clearly CNS stimulants,
although not all have this characteristic equally. While the xanthines have
legitimate therapeutic uses, by far the greatest public exposure to them is in
xanthine-containing beverages, including coffee, tea, cocoa, and cola drinks.
The popularity of xanthine-containing drinks appears to be related to its
subtle CNS stimulant effect. It is primarily for this reason that xanthines are
listed as CNS stimulants in this text.
Three xanthines are
pharmacologically important: caf-feine,
theophylline, and theobromine. All
three alka-loids, which occur naturally in certain plants, are widely consumed
in the form of beverages (infusions or decoc-tions) derived from these plants.
Coffee primarily con-tains caffeine (about 100–150 mg per average cup); tea
contains caffeine (30–40 mg per cup) and theophylline; and cocoa contains
caffeine (15–18 mg per cup) and theobromine. Cola drinks also contain
significant amounts of caffeine (about 40 mg/12 oz). The CNS stimulation
associated with these beverages is predomi-nantly due to the caffeine.
The xanthines are readily
absorbed by the oral and rectal routes. Although these agents can be
adminis-tered by injection (aminophylline
is a soluble salt of theophylline), intravascular
administration is indicated only in
status asthmaticus and apnea in premature in-fants. Intramuscular injection
generally produces con-siderable pain at the injection site.
The compounds are extensively
metabolized, prima-rily to uric acid derivatives. There is, however, no
indi-cation that methylxanthines aggravate gout.
The mechanism of action of
methylxanthine-induced stimulation of the CNS has been the subject of much
in-vestigation, and at least two other possible mechanisms of action of the methylxanthines
have been suggested. The first derives from the ability of the methylxanthines
to act as antagonists of the naturally occurring com-pound adenosine, a
substance that can inhibit both neu-ronal activity and behavior through direct
postsynaptic action on neurons and through indirect action involving
presynaptic inhibition of neurotransmitter release. The A1 subtype of the
purine receptors mediates these ac-tions of adenosine. Thus, as an
equilibrium-competitive antagonist of adenosine, the methylxanthines may
pro-duce excitation either by direct blockade of inhibitory effects of
adenosine at the neuron or by an antagonism of the presynaptic inhibitory
effect of adenosine on the release of an excitatory substance (e.g.,
Another suggested mechanism
of action involves the chloride channel. As discussed previously, the chlo-ride
channel is intimately associated with neuronal inhi-bition, and its activity
appears to be modulated at many different sites. Caffeine can compete for
binding at the benzodiazepine site and would therefore be expected to reduce
chloride conductance. Thus, caffeine may act functionally like the analeptic
stimulants that limit chlo-ride channel activation.
Xanthines, primarily as the
intramuscularly adminis-tered combination of caffeine and sodium benzoate,
have been used in the treatment of CNS depressant overdosage. Black coffee has
been used to physiologi-cally antagonize alcohol intoxication, although many
physicians believe that this ineffective therapy simply produces a wide-awake
preparations are aimed at relieving fatigue through CNS stimulation. Such
com-pounds are often referred to as wake-up tablets, but these
methylxanthine-containing products do little to offset physical fatigue, so
they place individuals using them at risk for accidental injuries.
All the xanthines, but
especially theophylline, are capa-ble of producing some degree of diuresis in
Theophylline is frequently
used as a bronchodilator in the treatment of asthma. Caffeine as the citrate
salt (Cafcit) is used for the
short-term management of apnea in premature infants (28–33 weeks of gestational
Theophylline, given as the soluble
ethylenediamine salt aminophylline, offers some help in relieving the
parox-ysmal dyspnea that is often associated with left heart failure. A major
portion of its efficacy may be due to the relief of bronchospasm secondary to
pulmonary vascu-lar congestion. Theophylline increases myocardial con-tractile
force and has occasionally been used in the treatment of refractory forms of
congestive heart fail- ure. Theophylline also has shown some benefit in the
treatment of neonatal apnea syndrome.
Xanthines (usually caffeine)
are frequently combined with aspirin in the treatment of headaches. In
combina-tion with an ergot derivative, methylxanthines have been used to treat
migraine. These effects are likely due to their ability to produce
vasoconstriction of cerebral blood vessels. Aminophylline is useful in the
relief of pain due to acute biliary colic.
Toxicity associated with the
methylxanthines usually takes the form of nervousness, insomnia, and in severe
cases, delirium. Cardiovascular stimulation is seen as tachycardia and
extrasystoles. Excessive respiratory stimulation may occur, and diuresis may be
administration of aminophylline (or theophylline) may present some problems if
the drug is given too rapidly. In such cases, severe headache, hypotension, and
palpitation accompany drug adminis-tration. Subsequently the patient may show
signs of ex-cessive CNS stimulation, shock, and even death. Children appear to
be especially prone to this toxicity.
The use of some
xanthine-containing beverages is cus-tomary in most cultures, and moderate use
of such bev-erages does not appear to cause problems in most peo-ple. There is
little question, however, that such use is habituating. For example, it has
been observed that chronic coffee drinkers who suddenly abstain fre-quently
have headaches and a general feeling of fatigue that may last for several days.
Although it has not been established that these symptoms constitute any kind of
abstinence syndrome, it remains a possibility. There is no good evidence for
the development of tolerance to the CNS stimulant effects of caffeine.
An interaction of potential
clinical significance involves the xanthines and the coumarin anticoagulants.
Xanthines by themselves shorten clotting time by increasing tissue prothrombin
and factor V and in this regard may be ex-pected to antagonize the
effectiveness of oral anticoagu-lants. However, the usual therapeutic doses of
xanthines cause no significant effect on the patient’s response to oral