Physiologic responses to intravenously administered theophylline were determined in nine hospitalized asthmatic subjects. In each patient incremental theophylline plasma concentration plateaus were attained at which pulmonary-function changes related to drug administration were examined. Continuous improvement in vital capacity and first-second forced expiratory volume was observed over the plasma range of theophylline concentration of 5 to 20 mg per liter. The improvement varied directly with the logarithm of the plasma concentration. A safe and effective dosage regimen for intravenous theophylline can be based on these observations. After a loading dose of aminophylline, 5.6 mg per kilogram given intravenously, 0.9 mg per kilogram per hour can be given as a maintenance dose. This amount will result in a plasma theophylline concentration of approximately 10 mg per liter for 95 per cent of patients and in recovery from some 30 to 40 per cent of reversible pulmonary-airway obstruction. (N Engl J M...

Rational intravenous doses of theophylline.

On a multiple-dose schedule of oral aminophylline (200 to 300 mg. every 6 hours) “trough” levels of serum theophylline in 83 patients ranged from 2.9 to 32.6 µg per milliliter. Levels usually remained in the same range for each individual. Kinetic studies demonstrate dependence of the mean serum level during multiple dosing on the intravenous theophylline half-life. Theophylline renal clearances are small and constant. Thus, wide variations in metabolism appear to be chiefly responsible. Specific studies are needed to document this and to assess the contribution of absorption variables. Persistent nausea, vomiting, or anorexia were common with trough levels over 20 flg per milliliter but were not seen when trough levels were under 13 µg per milliliter. This suggests that these gastrointestinal side effects usually arise by some mechanism mediated through serum theophylline levels rather than from direct irritation of the gastric mucosa. Serial airway resistances in 7 asthmatic patients following a large single oral dose of aminophylline indicated that the minimum theophylline level required for maximum bronchodilator effect ranged between eight and 20 µg per milliliter. To achieve trough concentrations of 10 to 20 µg per milliliter, final dosage adjustments ranged from 400 to 3,200 mg. of aminophylline per 24 hours, averaging 1,200 mg. General guidelines are offered for aminophylline dose adjustment.

Pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline.

Knowledge acquired of the kinetic disposition and effects of theophylline over the past 8 years has increased the clinical utility of the drug in the treatment of cardiorespiratory disorders. Although the anhydrous theophylline content varies greatly between products, there is similar excellent oral bioavailability. An average 96% (range 75 to 105%) of an uncoated theophylline tablet is absorbed, with peak concentrations occurring from 0.5 to 2.0h. Enteric coated and many sustained release preparations have poor bioavailability. Intravenous preparations of aminophylline contain from 75 to 85% theophylline by weight. Other routes of administration are not to be recommended. In plasma, some 53 to 65% of theophylline is reversibly bound to protein. Premature neonates and adults with hepatic cirrhosis have reduced binding. The apparent volume of distribution in the steady state averages 0.5L/kg body weight regardless of sex, age (1 to 87 years), history of cigarette smoking, asthma, or acute pulmonary oedema. Premature neonates and adults with acidaemia, hepatic cirrhosis or obesity tend to have larger volumes of distribution for theophylline. Theophylline is eliminated by biotransformation in the liver and urinary excretion of its metabolites. Approximately 7 to 13% is excreted unchanged in the urine by a first order process. One of the metabolites, 3-methylxanthine, which is pharmacologically active but less potent than theophylline, is eliminated by Michaelis-Menten kinetics. Removal of dietary methylxanthines can increase the rate of elimination of a single dose of theophylline. Dose dependent elimination kinetics has been suggested but not conclusively demonstrated. The plasma theophylline concentration time curve after intravenous administration fits a 2 compartment open kinetic model with a rapid a distribution phase completed within 30 to 45 minutes after an intravenous dose. The β elimination phase t½β) is quite variable and in healthy adults ranges from 3 to 13h. As the apparent volume of distribution is little altered under most conditions, variations in theophylline elimination half-life reflect alterations in plasma theophylline clearance. The predominant factors which alter theophylline clearance are age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease. The elimination of theophylline is markedly decreased in premature infants and increased in childhood. The rapid clearance in childhood decreases toward adult values in the late teens. Some authors believe old age per se decreases an individual’s capacity to eliminate theophylline. However, this may be a reflection of the inability of hepatic enzymes in the elderly to respond to factors in the diet or environment which usually stimulate theophylline clearance. The elimination half-life of theophylline is prolonged in obese subjects and maintenance doses must be calculated from ideal body weight. Theophylline clearance can be decreased by a high carbohydrate-low protein diet, as well as the ingestion of other methylxanthines such as caffeine. In contrast, a low carbohydrate-high protein diet, especially charcoal broiled meat, may enhance theophylline clearance. Theophylline clearance is markedly increased by tobacco or marihuana smoke. The rate of recovery from the stimulated state on cessation of smoking is unknown. Although there is some evidence that phenobarbitone treatment can slightly induce the hepatic metabolism of theophylline in vitro, the evidence in man for such an effect is inconclusive. The macrolide antibiotics, troleandomycin and erythromycin, are potent inhibitors of theophylline elimination. There is no evidence that uncomplicated asthma or chronic bronchitis alters theophylline clearance but, as chronic obstructive lung disease ensues with complications such as pneumonia or cor pulmonale, theophylline clearance can be markedly impaired. The elimination of theophylline is also reduced by congestive heart failure or acute pulmonary oedema. The mechanism responsible for reduced theophylline clearance in patients with cardiorespiratory disease is unclear. Reduced hepatocellular function is apparently responsible for the most marked decrease in theophylline clearance in patients with hepatic cirrhosis. It is not clear if one or several biochemical tests of liver function will allow prediction of the degree of impairment of theophylline elimination in individual patients. Reduced theophylline clearance has been observed in febrile children with acute viral exanthems. The bronchodilator effect of theophylline is related to plasma theophylline concentrations in the post-distribution period, indicating that the site of its bronchodilator activity is outside of the central kinetic compartment. Continuous improvement in forced expiratory volumes can be observed over the plasma theophylline concentration range of 5 to 20mg/L. These concentrations can reduce the frequency of asthmatic attacks, abolish exercise induced bronchospasm and increase the ventilatory response to hypoxaemia. Plasma theophylline concentrations of 5 to 20mg/L can produce concentration related increases in forearm blood flow and reductions in cerebral blood flow. The mechanism responsible for the reduction in cerebral blood flow is not clear. Peripheral venous distensibility is maximally increased at 10mg/L. Cardiac output and heart rate are variably increased. Although myocardial oxygen consumption increases, there appears to be a greater increase in oxygen delivery by increased coronary blood flow, suggesting a direct reduction of coronary vascular resistance. Pulmonary vascular resistance is reduced with increased ventilation/perfusion abnormalities. Arterial oxygen tension may decrease in asthmatic patients even though airway obstruction is relieved. Serious adverse effects are rare at plasma theophylline concentrations below 20mg/L. The most frequent adverse effects involve the gastrointestinal system (anorexia, nausea, vomiting, abdominal discomfort) and the nervous system (headache, nervousness, anxiety), which usually occur with concentrations over 15mg/L. Between 20 and 40mg/L, sinus tachycardia and atrial or ventricular arrhythmias occur with increasing frequency. Above 40mg/L, focal or generalised seizures, or cardiorespiratory arrest can occur. For rapid attainment of therapeutic plasma theophylline concentrations, a loading dose of aminophylline 5.6mg/kg can be given over 20 minutes via a peripheral vein. Although this dose is relatively safe and almost universally applicable, caution must be exercised if the patient has received theophylline in the previous 12 to 24 hour period. Maintenance doses of theophylline for intravenous or oral use should be calculated based on ideal body weight and modified for the presence of factors which alter theophylline clearance. Dose guidelines are approximations only and the wide variability in theophylline clearance between individuals and with disease makes their indiscriminant application hazardous. It is rational to begin with smaller than recommended doses and increase at intervals as tolerated until the recommended amounts are administered. In adult patients, one may limit theophylline doses to 16mg/kg daily unless a plasma theophylline concentration is obtained as a guide for further adjustment. With the proper resources, interpretive skills, and timing of plasma samples, theophylline concentrations can give the clinician sufficient information to prescribe ideal theophylline doses for an individual patient, provided the clinician searches for and recognises factors which alter theophylline clearance in that patient.

Clinical pharmacokinetics of theophylline.

Eight patients developed grand mal seizures during intravenous theophylline therapy None had a history of neurologic disorder, and all were acutely ill with severe pulmonary or cardiovascular disease, or both Serum theophylline concentrations obtained within 1 hour of the seizure ranged from 25 mug/ml to 70mug/ml, with a mean value (53 plus or minus 48 mug/ml) more than twice the upper limit of the recommended therapeutic concentration This serum theophylline concentration was greater than the concentration found in a group of patients with less severe drug-related symptoms (35 plus or minus 18 mug/ml, P less than 001) A third group of patients without drug-related symptoms had a mean theophylline serum concentration of 19 plus or minus 20 mug/ml, which was less than that found in either group with toxicity symptoms (P less than 005) Factors predisposing to the high serum concentrations in the patients with seizures were both higher drug dosage, compared with the other groups (P less than 001), and hepatic dysfunction, which was more common in both groups with drug-related symptoms

Theophylline-Induced Seizures in Adults: Correlation with Serum Concentrations

Theophylline is a bronchodilator and respiratory stimulant that is effective in the treatment of acute and chronic asthma, Cheyne-Stokes respirations, and apnea/bradycardia episodes in newborns. It is also used as an adjunct in the treatment of congestive heart failure and acute pulmonary edema, but it has no established efficacy in patients with chronic irreversible airways obstruction. Benefits and risks from theophylline relate directly to serum concentration, which is a function of both dose and elimination characteristics of the drug in an individual patient. When used to treat acute symptoms, an initial loading dose based on a mean volume of distribution is required to rapidly obtain maximum bronchodilator effect. Because of large interpatient differences in elimination, constant intravenous infusion rates for continued therapy must be guided by monitoring serum theophylline concentration at intervals until a steady-state serum concentration is reached within the 10-20 micrograms/ml therapeutic range. Intravenous, oral or rectal solutions and plain uncoated tablets are appropriate for acute therapy, while reliably absorbed slow-release formulations offer therapeutic advantages for the management of chronic asthma, particularly in patients with rapid elimination. Dosage for long-term therapy is determined by starting with low doses that allow virtually complete acceptance of the medication followed by gradual increases, if tolerated, at three day intervals until mean age-specific doses are reached. Subsequent adjustment in dosage regimens are then based upon serum concentration measurements. Most clinical laboratories now measure theophylline, and newer systems have been developed to provide emergency results within minutes at a reasonable cost. In cases of theophylline poisoning, the drug must be rapidly removed to prevent life-threatening toxicity. When serum concentrations are in excess of 60 micrograms/ml charcoal hemoperfusion dialysis may be indicated, even in the absence of obvious signs of toxicity.

https://accpjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/j.1875-9114.1983.tb04531.x

Theophylline. A "state of the art" review.

1. A simple, rapid and accurate ultraviolet spectrophotometric method for the determination of theophylline and theobromine in biological fluids has been developed. 2. The method offers satisfactory precision and a sensitivity of 1.0 microgm. per cc. 3. Application of the method to the tissue of rabbits and mice has been shown. 4. Theophylline has been demonstrated to be restricted to the plasma of the circulating blood. 5. Theophylline has been demonstrated to be very loosely bound to the plasma proteins. 6. The tissue level of theophylline following intravenous administration has been found to parallel the blood level in its rate of fall.

An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues

Theophylline and related xanthine derivatives are used extensively, at the present time, in the management of cardiovascular and respiratory diseases. However, there are conflicting opinions among investigators concerning the therapeutic value of these compounds in clinical conditions for which they are prescribed. Schack and Waxler1have shown that theophylline is restricted to the plasma, does not penetrate the red cell membrane and is only slightly bound to the proteins of the blood. Also, the drug appears to be only slightly bound to tissue proteins, since it was readily removed from the liver by simple perfusion with saline solution. It may therefore be suggested that any therapeutic effect of this drug will be closely related to its level in the blood.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=292848&pdfFileName=jama_143_8_010.pdf

Samuel H. Waxler

Papers

An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues

Administration of aminophylline (theophylline ethylenediamine)