Chapter: Modern Pharmacology with Clinical Applications: Central Nervous System Stimulants


The compounds known as xanthines, methylxanthines, or xanthine derivatives constitute a particularly inter-esting class of drugs.


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.

Chemistry and Pharmacokinetics

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.

Mechanism of Action

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., acetylcholine).

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.

Clinical Uses

Central Nervous System

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 drunk.

Many over-the-counter 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 humans..

Bronchial Asthma

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 age).

Cardiac Uses

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.

Miscellaneous Uses

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.

Adverse Effects

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 prominent.

The intravenous 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.

Abuse of Xanthines

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.

Drug Interactions

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 anticoagulants.

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