Methylxanthines
Methylxanthines
Methylxanthines, also called xanthines, are used to treat respiratory disorders.
Types of methylxanthines
Methylxanthines include anhydrous theophylline and its derivative salt aminophylline.
Theophylline is the most commonly prescribed oral methylxanthine. Aminophylline is preferred when an I.V. methylxanthine is required. Caffeine is also a xanthine derivative.
Pharmacokinetics
The pharmacokinetics of methylxanthines vary according to which drug the patient is receiving, the dosage form, and the administration route.
Absorption
When theophylline is given as an oral solution or a rapid-release tablet, it’s absorbed rapidly and completely. High-fat meals can increase 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%.
Distribution
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 require a lower dose. Because an infant has an immature liver 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.
Pharmacodynamics
Methylxanthines act in many ways.
Relax and breathe deeply
Methylxanthines decrease airway reactivity and relieve bronchospasm by relaxing bronchial smooth muscle. Theophylline is believed to inhibit phosphodiesterase, resulting in smooth-muscle relaxation, bronchodilation, and decreased inflammatory mediators (namely mast cells, T cells, and eosinophils). Much of theophylline’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 abdomen from the thoracic cavity. They also improve ventricular function and, therefore, the heart’s pumping action.
Pharmacotherapeutics
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.
Memory jogger
How can you remember what theophylline and its salts are used to treat? Simple: Just remember that you really need to “ACE” this one! It’s used for long-term control and prevention of symptoms related to:
A— asthma
C—chronic bronchitis
E—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.
Warning!
Adverse reactions to methylxanthines
Gut reactions
Adverse GI system reactions include:
- nausea and vomiting
- abdominal cramping
- epigastric pain
- anorexia
- diarrhea.
Nerve racking
Adverse central nervous system reactions include:
- headache
- irritability
- restlessness
- anxiety
- insomnia
- dizziness.
Heart of the matter
Adverse cardiovascular reactions include:
- tachycardia
- palpitations
- arrhythmias.
Drug interactions
Theophylline drug interactions occur with substances that inhibit or induce the CYP1A2 enzyme.
- Inhibitors of the CYP1A2 enzyme (including cimetidine, ciprofloxacin, clarithromycin, erythromycin, fluvoxamine, hormonal 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 charbroiled meats) increase theophylline metabolism, thus decreasing 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 additive 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 theophylline derivatives increases the risk of cardiac toxicity.
- Theophylline and its derivatives may reduce the effects of lithium by increasing its rate of excretion.
- Thyroid hormones may reduce theophylline levels; antithyroid drugs may increase theophylline levels.
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