Methylxanthines
Methylxanthines, also called xanthines, are used to treat respira-tory disorders.
Methylxanthines include anhydrous theophylline and its deriva-tive salt aminophylline.
Theophylline is the most commonly prescribed oral
methylx-anthine. Aminophylline is preferred when an I.V. methylxanthine is
required. Caffeine is also a xanthine derivative.
The pharmacokinetics of methylxanthines vary
according to which drug the patient is receiving, the dosage form, and the
ad-ministration route.
When theophylline is given as an oral solution or a
rapid-release tablet, it’s absorbed rapidly and completely. High-fat meals can
in-crease theophylline concentrations and the risk of toxicity.
Absorption of some of theophylline’s slow-release
forms depends on the gastric pH. Food can alter absorption. When converting the
patient from I.V. aminophylline to oral theophylline, the dosage is decreased
by 20%.
Theophylline is approximately 56% protein-bound in
adults and 36% protein-bound in neonates. It readily crosses the placental barrier
and is secreted in breast milk. Smokers and patients on dialysis may need
higher doses.
Theophylline is metabolized primarily in the liver
by the CYP1A2 enzyme. In adults and children, about 10% of a dose is excreted
unchanged in urine; therefore, no dosage adjustment is required in patients
with renal insufficiency. Elderly patients and those with liver dysfunction may
re-quire a lower dose. Because an infant has an immature liv-er with reduced
metabolic functioning, as much as one-half of a dose may be excreted unchanged
in his urine.
Theophylline levels must be measured to evaluate
efficacy and avoid toxicity. The therapeutic serum concentration is 10 to 20
mcg/ml (SI, 44 to 111 µmol/L). Levels must be assessed when drug therapy is
initiated, when the dosage is changed, and when drugs are added or removed from
the patient’s regimen.
Methylxanthines act in many ways.
Methylxanthines decrease airway reactivity and
relieve bron-chospasm by relaxing bronchial smooth muscle. Theophylline is
believed to inhibit phosphodiesterase, resulting in smooth-muscle relaxation,
bronchodilation, and decreased inflammatory media-tors (namely mast cells, T
cells, and eosinophils). Much of theo-phylline’s toxicity may be due to
increased catecholamine release.
In nonreversible obstructive airway disease
(chronic bronchitis, emphysema, and apnea), methylxanthines appear to increase
the sensitivity of the brain’s respiratory center to carbon dioxide and to
stimulate the respiratory drive.
In chronic bronchitis and emphysema, these drugs
reduce fatigue of the diaphragm, the respiratory muscle that separates the
ab-domen from the thoracic cavity. They also improve ventricular function and,
therefore, the heart’s pumping action.
Theophylline and its salts are used as second- or
third-line therapy for the long-term control and prevention of symptoms related
to:
·
asthma
·
chronic bronchitis
·
emphysema.
Theophylline has been used to treat neonatal apnea
(periods of not breathing in the neonate) and has been effective in reducing
severe bronchospasm in an infant with cystic fibrosis.
Theophylline drug interactions occur with
substances that inhibit or induce the CYP1A2 enzyme. (See Adverse reactions tomethylxanthines.)
·
Inhibitors of the CYP1A2
enzyme (including cimetidine, ciprofloxacin, clarithromycin, erythromycin,
fluvoxamine, hor-monal contraceptives, isoniazid, ketoconazole, ticlopidine,
and zileuton) decrease theophylline metabolism, thus increasing its serum level
as well as the risk of adverse reactions and toxicity. The dosage of
theophylline may need to be reduced.
·
Inducers of the CYP1A2
enzyme (including carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s
wort, and char-broiled meats) increase theophylline metabolism, thus
de-creasing its serum level and possibly its effectiveness. The dosage of
theophylline may need to be increased.
·
Smoking cigarettes or
marijuana increases theophylline elimination, thus decreasing its serum level
and effectiveness.
·
Taking adrenergic
stimulants or drinking beverages that contain caffeine or caffeinelike
substances may result in addi-tive adverse reactions to theophylline or signs
and symptoms of methylxanthine toxicity.
·
Activated charcoal may
decrease theophylline levels.
·
The use of enflurane or
isoflurane with theophylline or theo-phylline derivatives increases the risk of
cardiac toxicity.
·
Theophylline and its
derivatives may reduce the effects of lithi-um by increasing its rate of
excretion.
·
Thyroid hormones may
reduce theophylline levels; antithyroid drugs may increase theophylline levels.
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