Volume of distribution of theophylline in acute exacerbations of reversible airway disease. Effect of body weight

The literature is unclear as to whether theophylline loading doses should be based on total body weight (TBW) or ideal body weight (IBW). The objective of this study was to determine the most appropriate body weight for estimation of volume of distribution (Vd) in calculating theophylline loading dose in patients with acute bronchospasm. Fifty-four adult patients with acute bronchospasm requiring intravenous (IV) theophylline therapy were entered into the study. Patients were randomized into three theophylline loading dose groups based on (1) TBW, (2) IBW, and (3) adjusted body weight (ABW). Initial serum theophylline concentrations were used to determine an IV loading dose to reach a plasma concentration of 12 to 15 micrograms/ml. Percent prediction error was used to determine the appropriateness of each dosing group. Volumes of distribution were also determined for each group. There was a statistically significant difference at p less than 0.01 in the percent prediction error when patients in the TBW group were compared to the IBW and ABW groups. A statistically significant difference in the Vd was observed between the TBW and IBW group (p less than 0.01). We conclude that IBW is more appropriate than TBW or ABW for determining theophylline loading dose in patients with acute bronchospasm.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW^0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW 0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

Comparison of intravenous and oral routes of theophylline loading in acute asthma

In a prospective, randomized clinical trial, 19 patients with an acute exacerbation of asthma were given a loading dose of aminophylline by the IV (n = 10) or oral route (n = 9) of administration following treatment with epinephrine. Plasma concentrations of theophylline were measured prior to giving the loading dose, and one, two, three, and 24 to 48 hours later. Therapeutic effectiveness was evaluated by analyzing spirometric measurements prior to giving the loading dose, and one, three, and 24 to 48 hours later. Side effects also were recorded. In the IV group, the mean peak plasma theophylline concentration was 15.1 micrograms/mL one hour after loading, and in the oral group the mean peak serum theophylline concentration was 14.2 micrograms/mL three hours after loading. There was no correlation between theophylline concentrations and normalized change in spirometric values. There was no significant difference in spirometric values between the IV and oral groups. Nausea was slightly more common in the IV group. We conclude that there is no therapeutic advantage to giving a loading dose of aminophylline by the IV route rather than orally in patients with mild-to-moderate exacerbation of asthma initially treated with epinephrine.     

Bronchodilator effects of caffeine in coffee. A dose-response study of asthmatic subjects

Although caffeine is a universal drug and has multiple pharmacologic and physiologic actions in man, there are surprisingly few objective data about its effect on pulmonary function. We conducted a short-term, double-blind, randomized crossover study in nine asthmatic adults who ingested decaffeinated coffee containing varying amounts of added caffeine (mean of 0.2,2.5,5.6, and 7.2 mg/kg of body weight) on different days. The subjects also ingested decaffeinated coffee and aminophylline (200 mg) on a separate day of study. Baseline and post-drug determinations of serum levels of caffeine and theophylline, forced expired volume and flow, specific airway conductance (Gaw/VL), vital signs, and reported symptoms were obtained. Peak increases in serum caffeine concentrations (mean, 12.4 micrograms/ml +/- 1.5 micrograms/ml) occurred 45 minutes following the highest dose of caffeine (7.2 mg/kg), whereas the peak theophylline level (mean 3.8 micrograms/ml +/- 0.4 micrograms/ml) occurred 90 minutes following oral administration of aminophylline (mean theophylline, 2.6 mg/kg). Comparable peak increases in the forced expiratory volume in one second (FEV1), the forced expiratory flow during the middle half of the forced vital capacity (FEF25-75%), and Gaw/VL occurred at 120 minutes following aminophylline and the highest dose of caffeine, indicating that caffeine is an effective bronchodilator but is only 40 percent as active as an equivalent molar dose of theophylline. Regression analysis revealed statistically significant dose-response relationships between peak increases in serum caffeine concentrations and increases in FEV1, FEF25-75%, and Gaw/VL from baseline values. These findings have diagnostic and therapeutic implications regarding the use of caffeine prior to tests of pulmonary function and as a dietary agent, alone or in combination with theophylline.     

Single-dose oral phenytoin loading

A single 18 mg/kg dose of oral phenytoin capsules or suspension (mean dose, 1.3 g) was given to 44 patients with recent seizures and no detectable serum phenytoin level. Mean serum phenytoin levels after loading for patients receiving capsules were 6.8 micrograms/mL at two hours, 9.7 micrograms/mL at three to five hours, 12.3 micrograms/mL at six to ten hours, and 15.1 micrograms/mL at 16 to 24 hours. Mean levels for patients receiving suspension were slightly, but not significantly, lower than for patients receiving capsules. No seizures occurred during an eight-hour observation period after loading. Drug toxicity was minimal. Single-dose, 18 mg/kg oral phenytoin loading provides rapid therapeutic levels and is well tolerated.     

The effects of esmolol on the hemodynamics of acute theophylline toxicity

The effects of esmolol, a beta 1-selective adrenergic receptor antagonist with a short duration of action, were studied in a canine model of the hemodynamics of theophylline toxicity. Animals were anesthetized, then given 50 mg/kg aminophylline IV over 20 minutes followed by a continuous infusion of 1.75 mg/kg/hr. Hemodynamic parameters, including heart rate, cardiac output, systemic blood pressure, pulmonary arterial pressure, and pulmonary artery wedge pressure, were measured every 30 minutes along with plasma catecholamines and theophylline levels. Marked tachycardia was seen in the intoxicated state, with heart rate rising from a baseline of 128.0 +/- 8.3 beats per minute (BPM) to 179.0 +/- 7.4 BPM (P = .012). This was associated with increases in catecholamines (baseline norepinephrine .04 +/- .04 ng/mL plasma rose to .42 +/- .21 ng/mL plasma after intoxication, P = .048). The average serum theophylline level during the experiment was 44.0 +/- 1.1 micrograms/mL serum. Esmolol then was given by IV infusion in these animals in doses of 25, 50, and 100 micrograms/kg/min. It returned the heart rate to the preintoxication baseline in a dose-related manner. Esmolol did not decrease cardiac output or lower blood pressure.     

Enhancement of theophylline clearance by oral albuterol.

The possible effect of albuterol on theophylline clearance was studied in ten adult volunteers. Subjects received intravenous aminophylline loading dose (5.6 mg/kg), with oral albuterol (4 mg every 6 h), or inhaled albuterol (200 micrograms every 6 h), or alone (control). Theophylline levels were determined for 12-h periods. Theophylline clearance and elimination t 1/2 were calculated. Theophylline clearance was significantly higher when given with oral albuterol, in comparison with control (0.83 +/- 0.05 vs 0.73 +/- 0.06 ml/kg/min, p less than 0.02). Theophylline elimination t 1/2 was shorter with the coadministration of oral albuterol, compared with control (7.1 +/- 0.3 vs. 8.1 +/- 0.6 h, p less than 0.02). These alterations in theophylline clearance and elimination were greater in subjects who had lower control theophylline clearance. Theophylline clearance and elimination t 1/2 recorded with inhaled albuterol were not significantly different from control values. Coadministration of oral albuterol and theophylline resulted in enhancement of theophylline clearance, particularly in subjects with initially slow theophylline elimination. Such patients may require theophylline dosage adjustment as a result of this interaction.     

Theophylline Pharmacokinetics After Intramuscular Administration

This study was aimed at assessing the pharmacokinetics of a single dose of theophylline solution (aminophylline 480 mg) administered by intramuscular (j.m.) route to 16 subjects (age 28-61 years, body weight 52-75 kg). The same dose was given a week apart by oral route in fasting conditions. The intraindividual comparison shows that by i.m. route the rate, but not the extent, of absorption may be somewhat lower. From the first hour on, until hour 3-4 after i.m. dosing, all subjects achieved a safe and effective serum theophylline concentration (9-17 mg/liter). This suggests that, although usually not recommended, self-administration of a single dose of aminophylline by i.m. route may temporarily help theophylline-responsive patients in distress, when other routes of administration are not available and facilities for intensive conventional treatment are lacking.     

Effect of antiasthma drugs on microvascular leakage in guinea pig airways

We have studied the effect of intravenous epinephrine, albuterol, verapamil, and aminophylline on airway microvascular leakage in guinea pigs. Microvascular leakage was induced by platelet-activating factor (PAF; 50 ng/kg intravenously), which acts directly on venular endothelial cells, and measured by quantifying extravasation of Evans blue (EB) dye. Epinephrine (20 micrograms/kg) inhibited PAF-induced changes in dye leakage in larynx and main bronchi; at 80 and 160 micrograms/kg, significant inhibition was observed in all airways studied. This effect was reversed by phentolamine (2.5 mg/kg) or prazosin (100 micrograms/kg). By contrast, albuterol (20 to 320 micrograms/kg) and aminophylline (12.5 to 50 mg/kg) failed to inhibit dye leakage at any dose studied. Verapamil inhibited PAF-increased leakage in larynx, main bronchi, and intrapulmonary airways at the lowest dose tested (125 micrograms/kg), although inhibition was not dose dependent. These results suggest that the antiedema effect of epinephrine may be due to vasoconstriction rather than to a direct effect on endothelial cell contractility and that neither beta-agonists nor theophylline have an inhibitory effect. The inhibitory effect of epinephrine on airway microvascular leakage may have therapeutic implications for asthma.     

Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease

Often chronic obstructive pulmonary disease (COPD) patients treated for acute exacerbations receive intravenous (IV) aminophylline in addition to inhaled bronchodilators that may raise serum levels of theophylline into the toxic range. A double-blind, randomized study of 52 men with COPD who came to the emergency department for treatment of exacerbations was initiated to establish the efficacy and safety of this common practice. After history and physical examination, patients were treated with 28% oxygen by Venturi mask and 0.3 cc metaproterenol sulfate in 2.5 cc saline by nebulizer; an IV line was started and patients received either aminophylline or D5W. Measurements included baseline and two-hour serum theophylline levels, pulmonary function tests, and symptom questionnaires. Mean values from the entire group showed decreases in respiratory rate, cardiac rate, and pulsus paradoxus, and increases in forced expiratory volume in one second (FEV1) and vital capacity (VC) over a two-hour treatment period (P less than .01). Despite the increase in serum theophylline in the treatment group, the demographic, clinical, pulmonary function, and outcome data were found to have no statistically significant differences when compared to control patients. The data were then analyzed according to serum theophylline levels. Theophylline level greater than 20 micrograms/mL occurred in 15 patients with no untoward effects; premature ventricular contractions (PVCs) were no more frequent in this group than in those with lower serum theophylline levels. A theophylline level greater than 10 micrograms/mL after two hours of treatment resulted in the following differences, which were not statistically significant: mean FEV1 response less than or equal to 10 micrograms/mL vs greater than 10 micrograms/mL, 20% vs 28%; mean VC change, 17% vs 30%; or mean emergency department returns in one week, 0.1 vs 0.26. In our experience, oxygen and inhaled metaproterenol are effective treatment for exacerbations of COPD.     

Cardiac arrhythmias during the combined use of intravenous aminophylline and terbutaline in status asthmaticus

The purpose of this study was to evaluate prospectively the occurrence of cardiac arrhythmias during the combined therapy with intravenous aminophylline and terbutaline in 29 consecutive patients with status asthmaticus. The 24-hour Holter recordings were performed during continuous intravenous infusions of aminophylline (0.56 +/- 0.20 mg/kg/h) and terbutaline (0.034 +/- 0.014 microgram/kg/min). Serum theophylline concentration was 12.1 +/- 3.8 micrograms/ml and never reached the toxic level (greater than 20 micrograms/ml). Premature ventricular contractions (PVCs) were absent in 35 percent of patients and 48 percent had rare unifocal PVCs (less than 10/h). Only 17 percent of patients (five of 29) exhibited severe ventricular arrhythmias: PVCs greater than 10/h (n = 3), multifocal PVCs (n = 1); and a short run of ventricular tachycardia (n = 1). Serious supraventricular arrhythmias occurred in only 7 percent of patients (two of 29) who developed sustained runs of atrial tachycardia. These arrhythmias were always clinically well tolerated and spontaneously resolved without any antiarrhythmic treatment. We conclude that severe arrhythmias are rarely observed during combined therapy with aminophylline and terbutaline in status asthmaticus.     

Aspirin dosing using 15 grain enteric coated tablets

A high unit dose (15 grain/975 mg) enteric coated aspirin preparation was studied in normal individuals and patients with arthritis to determine how readily well tolerated, therapeutic (150-300 micrograms/ml) salicylate (SA) levels could be achieved using a twice daily dosing regimen. Of 36 participants enrolled, 33 (92%) achieved this goal (mean SA = 224 micrograms/ml), while in the remaining 3 an initially toxic level fell below the therapeutic range after reducing the dose by one tablet/day. Although the relationship between dose (mg/kg) and steady state SA levels was roughly linear (r = 0.74), in some subjects there was a striking incremental change in the SA level when the dose was adjusted. Over 90% of subjects taking a starting dose between 45-60 mg/kg/day achieved a therapeutic level. Thus, antiinflammatory therapy using 15 grain/975 mg enteric coated aspirin given twice daily appears to be feasible.     

Enprofylline in chronic asthma

A double-blind crossover study has been performed in 14 patients with moderately severe chronic asthma to compare the bronchodilator efficacy of two dosage regimens of intravenous enprofylline (high dose = 2 mg/kg bolus and 1 mg/kg/hour infusion; low dose = 1 mg/kg bolus and 500 micrograms/kg/hour infusion) with aminophylline (5 mg/kg/bolus and 500 micrograms/kg/hour infusion) and placebo. The bolus injections were given over 20 minutes and infusion over 160 minutes. Twelve subjects completed the study. High dose enprofylline was more effective than aminophylline in increasing PEF (P = 0.008) and FEV1 (P = 0.004). Low dose enprofylline and aminophylline were of similar efficacy. Side-effects, notably headaches and nausea, were more common with enprofylline; three out of 14 subjects receiving the high dose regimen developed severe nausea. The plasma enprofylline levels achieved with the high dose regimen were greater than anticipated. Further studies are required in acute severe asthma to clarify the therapeutic role of intravenous enprofylline and the most appropriate dosage regimen.     

Once-daily dosing of a new ultrasustained-release theophylline preparation

Theophylline plasma levels and profiles were evaluated in patients with chronic obstructive pulmonary disease during once-daily dosing of an ultrasustained-release theophylline preparation (Theo-1; capsules filled with microgranules containing 400 mg anhydrous theophylline). In a first study, 6 patients received a single morning dose of 800 mg (a) in the fasting state, and (b) with a protein-fat-rich breakfast in a random order, and the systemic theophylline availability was evaluated for 48 h. No significant differences were found either in Cmax (a: 7.0 +/- 3.2 micrograms/ml; b: 7.6 +/- 2.6 micrograms/ml), or in Tmax (a: 11.7 +/- 6.1 h; b: 10.2 +/- 3.6 h). Elimination half-life was in a 11.4 +/- 4.4 h and in b 12.9 +/- 4.8 h (p less than 0.05). In a second study, the steady-state theophylline levels were measured during a 24-hour dosage interval on day 8 after intake of 800 mg at 8 a.m. in 16 patients and at 8 p.m. in 11 patients. Plateau-shaped plasma concentration-time curves were obtained, with small fluctuations between the peak (Cmax) and trough (Cmin) levels: [100(Cmax-Cmin)/Cmin] was 83 +/- 40% after morning dose, and 54 +/- 26% after evening dose (p less than 0.05). Cmax was 12 +/- 5 and 11 +/- 4 micrograms/ml, respectively (NS). Tmax was 9 +/- 3 and 11 +/- 3 h, respectively (NS). The FDA fluctuation for the 37 patients was 48 +/- 20%. In a third study, the dose-plasma concentration relationship was evaluated in steady state in 6 patients receiving 400, 800 and 1,200 mg for 3 days each. The trough plasma concentrations were 2.6 +/- 0.9, 6.2 +/- 2.1 and 10.2 +/- 3.1 micrograms/ml, respectively. Six hours after drug intake the plasma levels were 5.0 +/- 1.6, 10.6 +/- 2.5 and 15.4 +/- 4.2 micrograms/ml, respectively; and 12 h after drug intake, 4.9 +/- 1.4, 11.6 +/- 2.4 and 14.5 +/- 3.7 micrograms/ml, respectively. In conclusion, we found in these studies that with once-daily dosing of the ultrasustained-release preparation Theo-1, plateau-shaped 24-hour theophylline plasma levels could be achieved. The relationship between daily dosage and theophylline plasma levels was linear intraindividually but showed an important interindividual variation. No consistent interference by food intake was found and no serious side effects occurred within therapeutic plasma levels.     

Cardiovascular effects of toxic concentrations of theophylline in the dog

A canine model of theophylline toxicity was used to study the cardiovascular effects seen in severe theophylline poisoning. Eight mongrel dogs were divided equally into two groups. The dogs were anesthetized with pentobarbital and paralyzed with pancuronium bromide. They were ventilated with 100% oxygen and underwent the placement of pulmonary arterial, central venous, femoral arterial, and peripheral venous lines. Group 1 animals received 5.6 mL/kg D5W intravenously (IV) over 20 minutes. Group 2 animals received 140 mg/kg (5.6 mL/kg) of aminophylline IV over the same period. Peak theophylline levels in Group 2 animals averaged 208.9 micrograms/mL. Group 2 animals suffered a marked fall in mean arterial pressure (MAP) and an increase in heart rate. In spite of the fall in MAP (P less than .01), cardiac index actually was increased almost two-fold over Group 1 animals, due mainly to a fall in systemic vascular resistance index (P less than .01). There were no physiologically significant differences in ventricular filling pressures or stroke index between the two groups.     

Kinetics of theophylline; variability and effect of arterial pH in chronic obstructive lung disease.

The pharmacokinetic behavior of theophylline was determined in 12 patients during an acute exacerbation of their chronic obstructive pulmonary disease. A 5.6 mg/kg loading dose of aminophylilne was administered, followed three hours later by a 0.9 mg/kg/hr continuous infusion. The loading dose increased the serum theophylline level an average of only 5.77 microgram/ml. After the loading dose, only five patients had levels greater than 10 microgram/ml. Mean initial drug clearance was 0.77 L/kg/hr, half-life 9.1 hr, and apparent volume of drug distribution .887 L/kg. Wide inter- and intrapatient pharmacokinetic variability was observed. The variability of drug distribution was inversely correlated with the arterial pH. These patients with chronic obstructive pulmonary disease appeared to require more theophylline when acidemic than when alkalemic to achieve similar serum theophylline concentrations.     

Dosage of antituberculous drugs in obese patients

There are no published data defining efficacious drug therapy for obese patients with active tuberculosis. Current dosage recommendations are based on total body weight (TBW); drug toxicity might result in obese patients receiving TBW doses. Peak and trough serum levels were measured for rifampin, streptomycin, ethambutol, and pyrazinamide in an obese patient (166 kg TBW, 87 kg ideal body weight (IBW] with miliary and meningeal tuberculosis. The observed drug levels and the calculated serum half-lives of these drugs were compared with the expected serum levels and serum half-lives in lean patients treated with literature-recommended doses. The observed serum levels in our obese patients were within the expected range for lean patients when dosage was based on IBW rather than on TBW. The observed cerebrospinal fluid penetrations of the drugs studied in our obese patient were similar to those reported in lean patients.     

Conversion of COPD patients from multiple to single dose theophylline. Serum levels and symptom comparison

The objective of the present study was to determine if patients with COPD who were taking Theo-Dur bid or tid (total dose 400 to 900 mg per day) could be safely switched to Uni-Dur, 800 mg given qd at bedtime. Twenty-eight patients were enrolled in the study, and 23 completed the study. The mean daily dose of theophylline prior to the study was 828 mg, while the mean dose after three weeks of Uni-Dur therapy was 783 mg. The mean serum theophylline level 10.5 +/- 3.6h after the last Theo-Dur dose was 10.5 mg/L. After three weeks of Uni-Dur therapy, the mean theophylline level at 8:00 AM was 14.6 mg/L, while the mean theophylline level at 8:00 PM was 9.9 mg/L. This latter level did not differ significantly from that obtained at the start of the study 10.5 +/- 3.6 h after the last dose of Theo-Dur. After three weeks of Uni-Dur therapy, the peak expiratory flow rate, the FEV1, and the FVC were not significantly changed from those at the initial evaluation. Twenty-one of the 23 patients ended up receiving 800 mg Uni-Dur qd. From this study, we conclude that once daily theophylline dosing with Uni-Dur compared with bid or tid dosing with Theo-Dur produces similar theophylline levels and pulmonary function, and most COPD patients who are taking 400 to 900 mg Theo-Dur daily can be managed with 800 mg Uni-Dur once daily at bedtime.     

Clinical predictors of theophylline blood levels in asthmatic patients

To determine the usefulness of clinical information in predicting theophylline levels, 21 parameters were studied in 204 asthmatic patients. The best single parameter for predicting theophylline levels was the last outpatient level (r = 0.484), which was within +/- 5 micrograms/mL of the presenting theophylline level in 62.5% of cases. However, there was considerable variability in theophylline levels in the other 37.5% of cases. The best combination of predictors was the last outpatient level and time since the last dose in patients taking a short-acting preparation. Even with this combination, however, 20.8% of predicted levels fell outside a range of +/- 5 micrograms/mL of the presenting theophylline levels. The only patients in whom a theophylline level could be predicted reliably were those who reported taking a sustained-release or short-acting preparation more than 15 or 8 hours prior to evaluation, respectively. In these patients, all presenting theophylline levels were in the subtherapeutic range (ie, less than 10 micrograms/mL), with 92% of the levels less than 5 micrograms/mL. Except for these patients, readily available theophylline determinations are necessary in order to optimize theophylline therapy with minimal risk of toxicity.