METHYLXANTHINE DRUGS

The three important methylxanthines are theophylline, theobromine, and caffeine. Their major
source is beverages (tea, cocoa, and
coffee, respectively). The use of theophylline, once a mainstay of asthma treatment, has waned with
demonstration of the greater
efficacy of inhaled adrenoceptor agonists for acute asthma and of inhaled anti-inflammatory agents
for chronic asthma. Accelerating this
decline in theophylline’s use are its toxicities (nausea, vomiting, tremulousness, arrhythmias) and the
requirement for monitoring serum
levels because of the narrowness of its therapeutic index. This monitoring is made all the more
necessary by individual and drugassociated
differences in theopylline metabolism.
Chemistry
As shown below (Figure 20–4), theophylline is 1,3-dimethylxanthine; theobromine is 3,7-
dimethylxanthine; and caffeine is 1,3,7-
trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is
aminophylline, a theophylline-ethylenediamine
complex. The pharmacokinetics of theophylline are discussed below (see Clinical Uses of
Methylxanthines). Its metabolic products,
partially demethylated xanthines (not uric acid), are excreted in the urine.
FIGURE 20–4 Structures of theophylline and other methylxanthines.
Mechanism of Action
Several mechanisms have been proposed for the actions of methylxanthines, but none has been
firmly established. At high
concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase
(PDE) enzyme family thereby increasing
concentrations of intracellular cAMP and, in some tissues, cGMP (Figure 20–2). Cyclic AMP
regulates many cellular functions including,
but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the
immune and inflammatory activity of
specific cells.
Of the various isoforms of PDE identified, inhibition of PDE3 appears to be the most involved in
relaxing airway smooth muscle and
inhibition of PDE4 in inhibiting release of cytokines and chemokines, which in turn results in a
decrease in immune cell migration and
activation. This anti-inflammatory effect is achieved at doses lower than those necessary for
bronchodilation.
In an effort to reduce toxicity while maintaining therapeutic efficacy, selective inhibitors of PDE4
have been developed. Many were
abandoned after clinical trials showed that their toxicities of nausea, headache, and diarrhea restricted
dosing to subtherapeutic levels, but
one, roflumilast, has been approved by the FDA as a treatment for COPD, though not for asthma.
Another proposed mechanism is inhibition of cell surface receptors for adenosine. These receptors
modulate adenylyl cyclase
activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and
histamine release from airway mast
cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg,
enprofylline) can inhibit
bronchoconstriction in asthmatic subjects.
A third mechanism of action may underlie theophylline’s efficacy: enhancement of histone
deacetylation. Acetylation of core histones
is necessary for activation of inflammatory gene transcription. Corticosteroids act, at least in part, by
recruiting histone deacetylases to
the site of inflammatory gene transcription, an action enhanced by low-dose theophylline. This
interaction should predict that low-dose
theophylline treatment would enhance the effectiveness of corticosteroid treatment, and some clinical
trials indeed support the idea that
theophylline treatment is effective as add-on therapy in patients with asthma or COPD uncontrolled
by ICS plus LABA therapy.
Pharmacodynamics
The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal
muscle as well as smooth muscle. Of
the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the
most marked central nervous
system effects.
A. Central Nervous System Effects
All methylxanthines—but especially caffeine—cause mild cortical arousal with increased alertness
and deferral of fatigue. The caffeine
contained in beverages—eg, 100 mg in a cup of coffee—is sufficient to cause nervousness and
insomnia in sensitive individuals and slight
bronchodilation in patients with asthma. The larger doses necessary for more effective
bronchodilation cause nervousness and tremor.
Very high doses, from accidental or suicidal overdose, cause medullary stimulation, convulsions, and
even death.
B. Cardiovascular Effects
Methylxanthines have positive chronotropic and inotropic effects on the heart. At low concentrations,
these effects result from inhibition
of presynaptic adenosine receptors in sympathetic nerves, increasing catecholamine release at nerve
endings. The higher concentrations
(> 10 μmol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may
result in increased influx of calcium.
At much higher concentrations (> 100 μmol/L), sequestration of calcium by the sarcoplasmic
reticulum is impaired.
The clinical expression of these effects on cardiovascular function varies among individuals.
Ordinary consumption of
methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac
output, and an increase in peripheral
resistance, raising blood pressure slightly. In sensitive individuals, consumption of a few cups of
coffee may result in arrhythmias. High
doses of these agents relax vascular smooth muscle except in cerebral blood vessels, where they
cause contraction.
Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The
mechanism of this action is not
well defined, but the effect is exploited in the treatment of intermittent claudication with
pentoxifylline, a dimethylxanthine agent.
C. Effects on Gastrointestinal Tract
The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even
decaffeinated coffee has a potent
stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.
D. Effects on Kidney
The methylxanthines—especially theophylline—are weak diuretics. This effect may involve both
increased glomerular filtration and
reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically
useful.
E. Effects on Smooth Muscle
The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma.
Tolerance does not develop, but adverse
effects, especially in the central nervous system, limit the dose (see below). In addition to their effect
on airway smooth muscle, these
agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue;
their effect on mucociliary transport is
unknown.
F. Effects on Skeletal Muscle
The respiratory actions of methylxanthines are not confined to the airways, for they also improve
contractility of skeletal muscle and
reverse fatigue of the diaphragm in patients with COPD. This effect—rather than an effect on the
respiratory center—may account for
theophylline’s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in
patients with irreversible airflow
obstruction.
Clinical Uses
Of the xanthines, theophylline is the most effective bronchodilator. It relieves airflow obstruction in
acute asthma and reduces the
severity of symptoms in patients with chronic asthma. Theophylline base is only slightly soluble in
water, so it is administered as several
salts containing varying amounts of theophylline base. Most preparations are well absorbed from the
gastrointestinal tract; absorption of
rectal suppositories is unreliable. Numerous sustained-release preparations are available and can
produce therapeutic blood levels for 12
hours or more. These preparations offer the advantages of less frequent drug administration, less
fluctuation of theophylline blood levels,
and more effective treatment of nocturnal bronchospasm.
Theophylline should be used only where methods to measure blood levels are available.
Improvement in pulmonary function is
correlated with plasma concentrations in the range of 5–20 mg/L. Anorexia, nausea, vomiting,
abdominal discomfort, headache, and
anxiety may occur at concentrations of 15 mg/L and become common at concentrations more than 20
mg/L. Higher levels (> 40 mg/L)
may cause seizures or arrhythmias; these may not be preceded by gastrointestinal or neurologic
warning symptoms.
The plasma clearance of theophylline varies widely. It is metabolized by the liver, so usual doses
may lead to toxic concentrations in
patients with liver disease. Conversely, clearance may be increased through the induction of hepatic
enzymes by cigarette smoking or by
changes in diet. In normal adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear
theophylline faster than adults (1–1.5
mL/kg/min). Neonates and young infants have the slowest clearance (see Chapter 60). Even when
maintenance doses are altered to
correct for the above factors, plasma concentrations vary widely.
Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or
when added to inhaled
corticosteroids. It is inexpensive, and it can be taken orally. Its use, however, also requires occasional
measurement of plasma levels; it
often causes unpleasant minor side effects (especially insomnia); and accidental or intentional
overdose can result in severe toxicity or
death. For oral therapy with the prompt-release formulation, the usual dose is 3–4 mg/kg of
theophylline every 6 hours. Changes in
dosage result in a new steady-state concentration of theophylline in 1–2 days, so the dosage may be
increased at intervals of 2–3 days
until therapeutic plasma concentrations are achieved (10–20 mg/L) or until adverse effects develop.
The development of more effective bronchodilators (β2-selective adrenergic agonists) and more
effective anti-inflammatory agents
(ICS) with fewer adverse effects has resulted in the decline in the clinical use of theophylline.
Typically, theophylline is rarely used as
monotherapy and, when prescribed, is most commonly used as add-on therapy when treatment with
other agents, principally ICS, is
inadequate.
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