Chemical formula: C₇H₈N₄O₂ Molecular mass: 180.164 g/mol PubChem compound: 2153
Theophylline is a bronchodilator. In addition it affects the function of a number of cells involved in the inflammatory processes associated with asthma and chronic obstructive airways disease. Of most importance may be enhanced suppressor T-lymphocyte activity and reduction of eosinophil and neutrophil function. These actions may contribute to an anti-inflammatory prophylactic activity in asthma and chronic obstructive airways disease.
Theophylline stimulates the myocardium and produces a diminution of venous pressure in congestive heart failure leading to marked increase in cardiac output.
Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).
Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.
Bronchodilation occurs over the serum theophylline concentration range of 5–20 mcg/mL. Clinically important improvement in symptom control and pulmonary function has been found in most studies to require serum theophylline concentrations greater than 10 mcg/mL. At serum theophylline concentrations greater than 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining average serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.
Following oral administration, theophylline is efficiently absorbed and is associated with an absolute bioavailability approximating 100%. Following oral administration, the delivery of theophylline is controlled and, at steady state, peak concentrations are typically seen after approximately 5 hours.
An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.
Theophylline is distributed through all body compartments; approximately 60% is bound to plasma proteins.
An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.
Theophylline is metabolised in the liver to 1, 3-dimethyl uric acid and 3-methylxanthine.
Theophylline and its metabolites are excreted mainly in the urine. Approximately 10% is excreted unchanged. The mean elimination half life associated with theophylline tablets is approximately 7 hours.
The predominant factors which alter theophylline clearance are: age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease. Clearance is increased in children compared to values observed in adult subjects. Clearance decreases towards adult values in late teens.
Studies involving prolonged-release theophylline tablets have demonstrated approximately dose-proportional pharmacokinetics across the 200-600 mg dose range.
The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients receiving intravenous theophylline (e.g., at 24-hr intervals). More frequent measurements should be made during the initiation of therapy and in the presence of any condition that may significantly alter theophylline clearance.
Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states*:
| Population characteristics | Total body clearance† mean (range)‡ (mL/kg/min) | Half-life mean (range)‡ (hr) | |
|---|---|---|---|
| Age | |||
| Premature neonates | |||
| postnatal age 3–15 days | 0.29 (0.09–0.49) | 30 (17–43) | |
| postnatal age 25–57 days | 0.64 (0.04–1.2) | 20 (9.4–30.6) | |
| Term infants | |||
| postnatal age 1–2 days | NR§ | 25.7 (25–26.5) | |
| postnatal age 3–30 weeks | NR§ | 11 (6–29) | |
| Children | |||
| 1–4 years | 1.7 (0.5–2.9) | 3.4 (1.2–5.6) | |
| 4–12 years | 1.6 (0.8–2.4) | NR§ | |
| 13–15 years | 0.9 (0.48–1.3) | NR§ | |
| 6–17 years | 1.4 (0.2–2.6) | 3.7 (1.5–5.9) | |
| Adults (16–60 years) | |||
| otherwise healthy non-smoking asthmatics | 0.65 (0.27–1.03) | 8.7 (6.1–12.8) | |
| Elderly (greater than 60 years) | |||
| non-smokers with normal cardiac, liver, and renal function | 0.41 (0.21–0.61) | 9.8 (1.6–18) | |
| Concurrent illness or altered physiological state | |||
| Acute pulmonary edema | 0.33¶ (0.07–2.45) | 19¶ (3.1–82) | |
| OPD-greater than 60 years, stable | |||
| non-smoker greater than 1 year | 0.54 (0.44–0.64) | 11 (9.4–12.6) | |
| COPD with cor pulmonale | 0.48 (0.08–0.88) | NR§ | |
| Cystic fibrosis (14–28 years) | 1.25 (0.31–2.2) | 6.0 (1.8–10.2) | |
| Fever associated with-acute viral respiratory illness (children 9–15 years) | NR§ | 7.0 (1.0–13) | |
| Liver disease | – cirrhosis | 0.31¶ (0.1–0.7) | 32¶ (10–56) |
| acute hepatitis | 0.35 (0.25–0.45) | 19.2 (16.6–21.8) | |
| cholestasis | 0.65 (0.25–1.45) | 14.4 (5.7–31.8) | |
| Pregnancy – | 1st trimester | NR§ | 8.5 (3.1–13.9) |
| 2nd trimester | NR§ | 8.8 (3.8–13.8) | |
| 3rd trimester | NR§ | 13.0 (8.4–17.6) | |
| Sepsis with multi-organ failure | 0.47 (0.19–1.9) | 18.8 (6.3–24.1) | |
| Thyroid disease – | hypothyroid | 0.38 (0.13–0.57) | 11.6 (8.2–25) |
| hyperthyroid | 0.8 (0.68–0.97) | 4.5 (3.7–5.6) | |
* For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.
† Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations less than 20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.
‡ Reported range or estimated range (mean ± 2 SD) where actual range not reported.
§ NR = not reported or not reported in a comparable format.
¶ Median
Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.
Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3–0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of theophylline in the therapeutic range (10–20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6–12 mcg/mL.
In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.
Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are less than 1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.
Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations less than 10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see Table VI). Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.
In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35–40%), 1-methyluric acid (20–25%) and 3-methylxanthine (15–20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children greater than 3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function.
In a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6–16 mcg/mL. In non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7–26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/kg/hr.
(see Table I for mean clearance and half-life values)
The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (greater than 60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients.
The clearance of theophylline is very low in neonates. Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients.
Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.
Pharmacokinetic differences in theophylline clearance due to race have not been studied.
Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children greater than 3 months of age. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function.
Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function.
Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF.
Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on theophylline clearance.
Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever.
Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions. Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
In vitro and in vivo assays have shown both positive and negative genotoxic results for theophylline. However, oral theophylline administered daily to rats and mice for 2 years did not show carcinogenicity. Therefore, it is unlikely that theophylline poses a carcinogenic risk in humans.
Theophylline has been shown to have effects upon the male reproductive system in rodents, but at doses considered in excess of the maximum human dose indicating little relevance to clinical use.
Several embryofetal developmental studies in rats, mice and rabbits have demonstrated developmental effects independent from maternal toxicity at high doses of theophylline. Therefore, theophylline should be considered to have the potential for developmental toxicity in humans.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
