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Chapter: Clinical Pharmacology: Respiratory drugs


Methylxanthines, also called xanthines, are used to treat respira-tory disorders.


Methylxanthines, also called xanthines, are used to treat respira-tory disorders.


Types of methylxanthines


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.


Gastric measures


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.

Metabolism and excretion


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.

Blood levels matter

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.

Relax and breathe deeply


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.


A stimulating conversation


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.


Pumping you up


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.


Useful for neonates?


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.

Drug interactions


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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