Theophylline disease

The development of easy-to-use assays for determining theophylline blood levels afforded a handle on maintenance of effective but nontoxic levels. The relatively good availabihty of such assays in the United States probably contributed to the historical preference for theophylline treatment by U.S. physicians. Careful titration of the dose must be done on a patient-by-patient basis because individual rates of metaboHsm vary widely. Most ( 85%) of an oral dose of theophylline is metabolized by Hver microsomal enzymes. As a result many dmgs, eg, cimetidine [51481-61-9], anticonvulsants, or conditions, eg, fever, cigarette smoking, Hver disease, which affect Hver function alter theophylline blood levels. 

Jubran A, Gross N, Ramsdell J, et al. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study. Chest 1993 103 678-84. 

Dose adjustments should generally be made based on trough serum concentration results. A conservative therapeutic range of 8 to 15 mcg/mL is often targeted, especially in elderly patients, to minimize the likelihood of toxicity. Once a dose is established, concentrations should be monitored once or twice a year unless the disease worsens, medications that interfere with theophylline metabolism are added, or toxicity is suspected. 

Theophylline is one of the mainstays of therapy for acute and chronic obstructive airways disease. Until recently little was known about its pharmacokinetics and their clinical application, but there is now good evidence (J4) that both the therapeutic response and toxic side effects are related to the concentration of theophylline in plasma, rather than to its dosage. 

Theophylline reduces contractile activity of smooth musculature, widens bronchi and blood vessels, reduces pulmonary vascular resistance, stimulates the respiratory center, and increases the frequency and power of cardiac contractions. It is used for bronchial asthma, preventing attacks, and systematic treatment. Theophylline is also used for symptomatic treatment of bronchospastic syndrome of a different etiology (chronic obstructive pulmonary disease, chronic bronchitis, and pulmonary emphysema). A large number of combined drags are based on theophylline. Synonyms of theophylline are adophyllin, asthmophyllin, theocin, and many others. 

Pharmacology The methyixanthines (theophylline, its soluble salts and derivatives) directly relax the smooth muscle of the bronchi and pulmonary blood vessels, stimulate the CNS, induce diuresis, increase gastric acid secretion, reduce lower esophageal sphincter pressure, and inhibit uterine contractions. Theophylline is also a central respiratory stimulant. Aminophylline has a potent effect on diaphragmatic contractility in healthy people and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airways disease. Pharmacokinetics ... 

Theophylline, a dimethylxanthine, causes broncho-dilation, possibly by inhibiting the enzyme phosphodiesterase in smooth muscle of the bronchioli. An other proposed mechanism of action is that of adenosine receptor antagonism. It has positive chronotropic and inotropic, CNS stimulant and weak diuretic properties. In obstructive lung disease sustained release tablets are to be preferred. Theophy-line has a narrow therapeutic index. Therapeutic plasma concentrations are between 7-15 mg/1. Theophylline undergoes N-demethylation via CYPl A2 in the liver and is eliminated in the urine as metabolites... 

Cazzola M, Donner CF, Matera MG. Long acting beta2-agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 1999 54 730-6. 

The principal use of theophylline is in the management of asthma. It is also used to treat the reversible component of airway obstruction associated with chronic obstructive pulmonary disease and to relieve dyspnea associated with pulmonary edema that develops from congestive heart failure. 

Theophylline has a narrow therapeutic index and produces side effects that can be severe, even life threatening. Importantly, the plasma concentration of theophylline cannot be predicted reliably from the dose. In one study, the oral dosage of theophylline required to produce therapeutic plasma levels (i.e., between 10 and 20 pg/mL) varied between 400 and 3,200 mg/day. Heterogeneity among individuals in the rate at which they metabolize theophylline appears to be the principal factor responsible for the variability in plasma levels. Such conditions as heart failure, liver disease, and severe respiratory obstruction will slow the metabolism of theophylline. 

Theophylline should be used with caution in patients with myocardial disease, liver disease, and acute myocardial infarction. The half-life of theophylline is prolonged in patients with congestive heart failure. Because of its narrow margin of safety, extreme caution is warranted when coadministering drugs, such as cime-tidine or zUeuton, that may interfere with the metabolism of theophylline. Indeed, coadministration of zileu-ton with theophylline is contraindicated. It is also prudent to be careful when using theophylline in patients with a history of seizures. 

Dyspepsia is the most common side effect of zileuton. Liver transaminase levels are elevated in a small percentage of patients taking zileuton. Serum Uver transaminase levels should be monitored and treatment halted if significant elevations occur. Zileuton inhibits the metabolism of theophylline. Thus, when these agents are used concomitantly, the dose of theophylline should be reduced by approximately one-half, and plasma concentrations of theophylline should be monitored closely. Caution should also be exercised when using zileuton concomitantly with warfarin, terfenadine, or propranolol, as zileuton inhibits the metabolism of these agents. Zileuton is contraindicated in patients with acute liver disease and should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. 

Based on the concept that asthma is an inflammatory disease that leads to airway obstruction, inhaled glucocorticoids are the first-line treatment for moderate to severe asthma. Inhaled preparations are particularly effective when used to prevent recurrent attacks. This therapy is often combined with an inhaled bron-chodUator such as a p-adrenergic agonist. The use of p-adrenergic agonists or theophylline enables use of a lower dose of glucocorticoid, especially in patients relatively resistant to therapy (see Chapter 39). 

Patients with cardiovascular disease (including hypertension), diabetes (risk of hyperglycemia), pregnancy (uterine contractions), prostatism, and anxiety disorders are among those who should not take ma huang at any dose. Drug-herb interactions occur with MAOIs (hypertensive crisis), phenoth-iazines (tachycardia, hypotension), (3-blockers (hypertension) and theophylline (increased CNS effects). Of course, caffeine and other stimulants have an additive effect. 

Theophylline is widely used as a bronchodilator for the treatment of asthma or obstructive pulmonary disease [1]. Significant relief of bronchospasm is usually achieved with 7-20 mg/1 of theophylline in serum and toxic manifestations occur above 20-30 mg/1. The available literature... 

The plasma clearance of theophylline varies widely. Theophylline is metabolized by the liver, so typical doses may lead to toxic concentrations of the drug 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 59). Even when maintenance doses are altered to correct for the above factors, plasma concentrations vary widely. 

Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson s disease dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol. 

Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline levels and increased methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias. 

Barnes PJ. Theophylline in chronic obstructive pulmonary disease new horizons. Proc Am Thorac Soc. 2005 2 334-341. 

Culpitt SV, de Matos C, Russell RE, et al. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002 165 1371-1376. 

Hansel TT, Tennant RC, Tan AJ, et al. Theophylline mechanism of action and use in asthma and chronic obstructive pulmonary disease. Drugs Today. 2004 40 55-69. 

Ram FS, Jardin JR, Atallah A, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease a systematic review and meta-analysis. RespirMed. 2005 99 135-144. 

Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. Quinine, theophylline, penicillin G, morphine, paclitaxel, digoxin, vincristine, doxorubicin, cyclosporin, and vitamin A all share two important characteristics they are cornerstones of modem pharmaceutical care, and they are all natural products. The use of natural substances, particularly plants, to control diseases is a centuries-old practice that has led to the discovery of more than half of all modem pharmaceuticals. 

The mode of action of theophylline is different from that of Beta2-adrenergic agonists and anticholinergic agents, so it is still used in the treatment of selected patients with asthma or chronic obstructive pulmonary disease. 

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