Chemical Properties

Three xanthines are pharmacologically important: caffeine, theophylline, and theobromine. All three alkaloids, which occur naturally in certain plants, are widely consumed in the form of beverages (infusions or decoctions) derived from these plants. Coffee primarily contains 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 predominantly due to the caffeine.
The xanthines are readily absorbed by the oral and rectal routes. Although these agents can be administered by injection (aminophylline is a soluble salt of theophylline), intravascular administration is indicated only in status asthmaticus and apnea in premature infants. Intramuscular injection generally produces considerable pain at the injection site.
The compounds are extensively metabolized, primarily to uric acid derivatives. There is, however, no indication that methylxanthines aggravate gout.

Biological Functions

The compounds known as xanthines, methylxanthines, or xanthine derivatives constitute a particularly interesting class of drugs. Since they possess diverse pharmacological pharmacological properties, there is always a question of where most appropriately to discuss them in a pharmacology 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 xanthinecontaining 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.

Mechanism of action

The mechanism of action of methylxanthine-induced stimulation of the CNS has been the subject of much investigation, 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 compound adenosine, a substance that can inhibit both neuronal 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 actions of adenosine. Thus, as an equilibrium-competitive antagonist of adenosine, the methylxanthines may produce 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 chloride channel is intimately associated with neuronal inhibition, 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 chloride channel activation.

Clinical Use

Central Nervous System
Xanthines, primarily as the intramuscularly administered combination of caffeine and sodium benzoate, have been used in the treatment of CNS depressant overdosage. Black coffee has been used to physiologically 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 compounds 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.
Diuresis
All the xanthines, but especially theophylline, are capable 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 paroxysmal 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 vascular congestion. Theophylline increases myocardial contractile force and has occasionally been used in the treatment of refractory forms of congestive heart failure failure. 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 combination 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.

Side 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 administration. Subsequently the patient may show signs of excessive CNS stimulation, shock, and even death. Children appear to be especially prone to this toxicity.

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 expected to antagonize the effectiveness of oral anticoagulants. However, the usual therapeutic doses of xanthines cause no significant effect on the patient’s response to oral anticoagulants.

Raw materials

Preparation Products