The toxic effects of theophylline, aminophylline, and other xanthines are additive. Use with other xanthine medications should therefore be avoided if intravenous aminophylline is to be given for acute bronchospasm in patients who have been taking maintenance theophylline therapy, serum-theophylline concentrations should be measured first and the initial dose reduced as appropriate (see Uses and Administration, below).
Theophylline clearance may be reduced by interaction with other drugs including allopurinol, some antiarrhythmics, cimetidine, disulfiram, fluvoxamine, interferon alfa, macrolide antibacterial s and quinolones, oral contraceptives, tiabendazole, and viloxazine, and the dose of theophylline may need to be reduced. Phenytoin and some other antiepileptics, ritonavir, rifampicin, and sulfinpyrazone may increase theophylline clearance, and require an increase in dose or dosing frequency of theophylline.
Xanthines can potentiate hypokalaemia caused by hypoxia or associated with the use of beta2-adrenoceptor stimulants (beta2 agonists), corticosteroids, and diuretics. There is arisk of synergistic toxicity if theophylline is given with halothane or ketamine, and it may antagonise the effects of adenosine and of competitive neuromuscular blockers lithium elimination may be enhanced with a consequent loss of effect. The interaction between theophylline and beta blockers is complex (see below) but use together tends to be avoided on pharmacological grounds since beta blockers produce bronchospasm.
Theophylline is metabolised by several hepatic cytochrome P450 isoenzymes, of which the most important seems to be CYP1A2. Numerous drugs affect the metabolic clearance of theophylline and aminophylline, but the variability in theophylline pharmacokinetics makes the clinical significance of these interactions difficult to predict. Giving theophylline with drugs that inhibit its metabolism should be avoided but, if unavoidable, the dose of theophylline should be halved. There is some evidence to suggest that less of a dose reduction is required in the presence of severe liver dysfunction, aside from that already required by impaired hepatic metabolism, see Administration in Hepatic Impairment, below. Subsequent doses should be adjusted based on serum-theophylline monitoring. Even when introducing medication for which no interaction is suspected, a check on the serum-theophylline concentration within 24 hours of beginning the new drug has been advised.
Theophylline reduces liver plasma flow and may therefore prolong the half-life and increase steady-state levels of hepatically eliminated drugs but it is claimed to have no effect on antipyrine clearance.
An increase in serum-theophylline concentration from 93.2 to 194.2 micromol/litre with symptoms of tachycardia, nervousness, and tremors occurred in a patient 9 days after starting amiodarone therapy. Elevated theophylline concentrations and/or decreased clearance have also been reported following addition of mexiletine to theophylline therapy. Amiodarone and mexiletine probably interact with theophylline through inhibition of its hepatic metabolism. Tocainide has also been found to impair theophylline metabolism resulting in a reduction in theophylline clearance but the effect was substantially smaller than that of mexiletine. In one patient stabilised on theophylline therapy, an increase in the plasma-theophylline concentration with subsequent toxicity was noted after starting treatment with propafenone. See also under Calcium-channel Blockers.
Seizures have been reported in 3 patients receiving theophylline who were given imipenem, although serum concentrations of theophylline were not affected.
Isoniazid inhibits oxidative enzymes in the liver and has been found to impair the elimination of theophylline. Both clearance and volume of distribution of theophylline were reduced with an increase in serum-theophylline concentrations in healthy subjects after 14 days of pretreatment with isoniazid and theophylline toxicity has been reported in a patient one month after adding theophylline to isoniazid therapy.
There are conflicting reports of the effect of erythromycin on the pharmacokinetics of theophylline. Significant decreases in the clearance of theophylline and prolonged elimination half-life have been reported but other studies have found no interaction. It has also been noted that the serum concentrations and bio availability of erythromycin may be reduced by theophylline. The clearance of theophylline is also markedly decreased by troleandomycin but there have been reports that for clinical purposes the pharmacokinetics of theophylline do not seem to be significantly altered by dirithromycin, josamycin, midecamycin rokitamycin, roxithromycin or spiramycin. Clarithromycin also seems unlikely to have a significant effect in most patients, but in a few theophylline dosage may need to be adjusted. In one case report, serum-theophylline concentrations fell over a few days after the withdrawal of azithromycin
The fluoroquinolone antibacterials vary in their propensity to interact with theophylline. Enoxacin shows the most marked interaction and has been reported to cause serious nausea and vomiting, tachycardia, and headaches, associated with unexpectedly high plasma-theophylline concentrations in patients with respiratory-tract infections. Studies, mainly in healthy subjects, have found that enoxacin decreases theophylline clearance by up to 74% with an increase in the elimination half-life and serum-theophylline concentration.
Ciprofloxacin and pefloxacin interact with theophylline to a lesser extent than enoxacin, decreasing theophylline clearance by about 30%. Eight clinically important interactions between ciprofloxacin and theophylline had been reported to the UK CSM including 1 death. A ciprofloxacin-induced seizure has been reported which may have been due to the combined inhibitory effects of the 2 drugs on GABA binding. It has been recommended that ciprofloxacin should not be used in patients treated with theophylline.
Norfloxacin and ofloxacin have been reported to have minor effects on the pharmacokinetics of theophylline. Although their effects were usually considered not to be clinically significant, the US FDA had received 9 reports of theophylline toxicity associated with use with norfloxacin, including 1 death. Fleroxacinflumequine, lomefloxacin moxifloxacin and rufloxacin have been reported to have no significant effect on the pharmacokinetics of theophylline in small studies in healthy subjects.
The mechanism of interaction involves a reduction in the metabolic clearance of theophylline due to inhibition of hepatic microsomal enzymes. However, the exact mechanism is unknown and it is difficult to predict which patients will be at risk. Extreme caution should be used when giving quinolones with theophylline, particularly in the elderly and it may be advisable to use a non-interacting fluoroquinolone, although theophylline concentrations should still be monitored.
Of the non-fluorinated quinolones, nalidixic acid has been reported not to affect theophylline clearance whereas pipemidic acidhas markedly inhibited theophylline clearance.
Rifampicin induces hepatic oxidative enzymes and a dose of 600 mg daily by mouth for 6 to 14 days has been shown to increase mean plasma-theophylline clearance by 25 to 82% due to enhancement of hepatic theophylline metabolism. This increase in clearance is sufficient to require dosage adjustment in some patients, including children.
Tetracycline weakly inhibited theophylline clearance after 5 days of therapy in 5 non-smoking adults with chronic obstructive airways disease and theophylline toxicity has been reported in a patient given a 10-day course of tetracycline during theophylline therapy. Doxycycline has been reported not to have any significant effect on theophylline pharmacokinetics in healthy subjects.
Significantly reduced clearance and increased plasma concentrations of theophylline have been reported when given with viloxazine. The dosage of theophylline should be decreased and its plasma concentrations monitored when viloxazine is also prescribed. The interaction probably involves competition between the two drugs for hepatic microsomal enzymes.
Fluvoxamine has also been associated with a significant reduction in theophylline clearance and theophylline toxicity has been described in patients when fluvoxamine was added to their therapy. This interaction which is due to potent liver enzyme inhibition has been the subject of a warning by the UK CSM in which they issued the standard advice of avoiding the two drugs if at all possible and, where they could not be avoided, of giving half the dose of theophylline and monitoring plasma concentrations. A small study evaluating the effect of liver cirrhosis on the interaction between fluvoxamine and theophylline observed a decrease in fluvoxamine-induced inhibition of theophylline clearance as the severity of liver cirrhosis increased. The authors suggest that theophylline may require less of a dose reduction in the presence of severe liver dysfunction, aside from that already required by impaired hepatic metabolism, see Administration in Hepatic Impairment, below.
St John’s vtwtmay have decreased theophylline concentrations and increased the theophylline dosage requirement in one case report. However, a study in 12 healthy subjects found that 15 days of treatment with St John’s wort did not significantly change theophylline pharmacokinetics.
For a mention of the effect of theophylline on the renal clearance oflithium, see Xanthines, under Interactions of Lithium.
Phenytoin markedly decreases the elimination half-life and increases the clearance of theophylline, probably due to hepatic enzyme induction, at therapeutic serum-phenytoin concentrations, at subtherapeutic phenytoin concentrations, and even in heavy smokers. A preliminary report suggested that the serum concentration of phenytoin may be decreased simultaneously, perhaps due to enzyme induction by theophylline or reduced phenytoin absorption. The interaction has been reported to occur within 5 to 14 days of taking phenytoin and theophylline, and theophylline clearance has increased by up to 350%, and reductions in serum half-life have ranged from 25 to 70% of initial values.’
Carbamazepine has also been seen to increase theophylline elimination. In one patient, theophylline serum half-life was decreased by about 24 to 60%, and clearance was increased by about 35 to 100% when carbamazepine was given. In an 11-year-old girl theophylline-serum half-life was almost halved with loss of asthma control after 3 weeks of concurrent carbamazepine therapy. In turn, theophylline has been reported to reduce serum concentrations of carbamazepine. Although phenobarbital was not found to have a significant effect on the pharmacokinetics of a single dose of theophylline given intravenously, enhanced theophylline clearance has been seen in patients after longer periods of treatment with phenobarbital. The magnitude of the changes in theophylline elimination appears to be smaller with phenobarbital than phenytoin.
Pentobarbital in high doses has also been reported to increase theophylline metabolism. A more recent study has also shown that therapeutic doses of pentobarbital (100 mg daily) increase plasma clearance of theophylline by a mean of 40%, although this was subj ect to marked interindividual variations. Renal clearance was not affected, suggesting hepatic enzyme induction as the probable mechanism.
There have been reports that ketoconazole does not appear significantly to alter the pharmacokinetics of theophylline. The manufacturer offluconazole has, however, stated that plasma clearance of theophylline may be decreased by flu-conazole. A 16% reduction in theophylline clearance has been reported after oral fluconazole but fluconazole was considered to have only a minor inhibitory effect on theophylline metabolism and theophylline disposition was not significantly affected. Theophylline metabolism has been inhibited to a similar degree by terbinafine.
Allopurinol 300 mg by mouth daily for 7 days was found to have no effect on the pharmacokinetics of theophylline after a single intravenous dose of aminophylline or after oral theophylline given to steady state. However, oral allopurinol 600 mg daily for 28 days has been found to inhibit the metabolism of theophylline, increasing the mean half-life by 25% after 14 days and 29% after 28 days and there has been a report of allopurinol increasing peak plasma-fheophylline concentrations by 38% in one patient within 2 days of use together. Probenecid has been reported to have no effect on the hepatic metabolism or total body clearance of theophylline in a single-dose study in healthy subjects.
Sulfinpyrazone 800 mg daily for 7 days increased the total plasma clearance of theophylline by 22% in healthy subjects due to selective induction of certain cytochrome P450 isoenzymes.
There has been a report of increased clearance of theophylline in 3 patients given aminoglutethimide The clearance of theophylline (given as theophylline, aminophylline, or choline theophyllinate) was reported to decrease by an average of 19% in 8 patients with severe corticosteroid-dependent asthma given low-dose weekly intramuscular injections of methotrexate A high degree of interpatient variability was seen. Three patients reported nausea one of whom required a decrease in theophylline dose. The authors reported that the most likely explanation for the change in theophylline clearance was inhibition of microsomal enzyme activity. For reference to a possible interaction between theophylline and lomustine, see Lomustine.
A single injection of recombinant human interferon alfa reduced theophylline clearance by 33 to 81 % in 8 of 9 subjects, resulting in a 1.5 to sixfold increase in the theophylline elimination half-life. Injection of interferon alfa once daily for 3 days in 11 healthy subjects also reduced theophylline clearance and increased elimination half-life, but the magnitude of the changes were of a similar order to normal intra-individual variation and the interaction was considered of minor clinical significance.
Licensed product information for ritonavir states that it substantially increases the clearance of theophylline theophylline dosage may need to be increased to maintain efficacy. There is evidence that aciclovir inhibits theophylline metabolism, resulting in accumulation.
For reference to the antagonism of benzodiazepine sedation by aminophylline, see Xanthines, under Interactions of Diazepam.
Propranolol reduced theophylline clearance by 36% in healthy subjects given aminophylline intravenously. Metoprolol did not reduce clearance in the group as a whole, but a reduction was noted in some smokers whose theophylline clearance was initially high. Propranolol is thought to exert a dose-dependent selective inhibitory effect on the separate cytochrome P450 isoenzymes involved in theophylline demefhylation and 8-hydroxylation. The less lipophilic beta blockers atenolol and nadolol had no significant effect on the pharmacokinetics of theophylline.
In general, however, beta blockers should be avoided in patients taking theophylline as they can dangerously exacerbate bronchospasm in patients with a history of asthma or chronic obstructive pulmonary disease.
Abstention from dietary methylxanthines by healthy subj ects has resulted in faster elimination of theophylline. While the addition of extra caffeine to the diet has been reported not to alter theophylline disposition, some studies in healthy subjects have indicated that the ingestion of moderate amounts of caffeine (120 to 900 mg daily), which could be consumed by drinking several cups of coffee daily, can have a pronounced influence on the pharmacokinetics of theophylline. In these latter studies the mean theophylline clearance was reduced by 23 and 29% with a corresponding increase in the elimination half-lives.
Verapamil has been reported to decrease the clearance of theophylline by a mean of 14% in healthy subjects and although this was not considered to be clinically significant, symptoms of theophylline toxicity, associated with near doubling of the serum-fheophylline concentration have occurred in a 76-year-old woman taking theophylline after 6 days of therapy with verapamil. Studies in healthy subjects and asthmatic patients have produced conflicting results of the effect of nifedipine on the pharmacokinetics of theophylline. Reduced clearance and an increase in the volume of distribution of theophylline have been reported and both decreased and increased serum-fheophylline concentrations theophylline toxicity has been reported. However, most studies have concluded that the effects of nifedipine are unlikely to be of clinical importance.
Serum concentrations of theophylline have been reported to be increased by diltiazem and reduced by felodipine, neither of these effects were considered to be clinically significant.
A search of the literature revealed 2 studies, both published in the 1970s, that showed that marijuana smoking increased the clearance of theophylline.
In 3 patients with acute severe asthma given aminophylline intravenously, serum-fheophylline concentrations rose rapidly from the therapeutic range to between 40 and 50 micrograms/mL when hydrocortisone was given intravenously. In studies in healthy subjects, no significant changes in serum-fheophylline concentrations were noted when hydrocortisone, meihylprednisolone, or prednisone were given, although there was a trend towards increased theophylline clearance during corticosteroid therapy. In preterm neonates, exposure to betamethasone in utero stimulated the hepatic metabolism of theophylline, but did not affect dosage requirements. The possibility that adverse effects such as hypokalaemia may be potentiated by use of theophylline with corticosteroids should be borne in mind.
In a study involving 20 recovering alcoholic patients, disulfiram decreased the plasma clearance and prolonged the elimination half-life of theophylline in a dose-dependent manner. It was concluded that disulfiram exerts a dose-dependent inhibitory effect on the hepatic metabolism of theophylline and that, in order to minimise the risk of toxicity, the dosage of theophylline may need to be reduced by up to 50% if given together.
Although increased mean serum-fheophylline concentrations were noted in 10 patients given continuous intravenous aminophylline infusions after intravenous injection of furosemide, in 8 patients with chronic stable asthma, mean peak serum-theophylline concentrations were reduced from 12.14 micrograms/mL with placebo to 7.16 micrograms/mL when furosemide was given. Reduced concentrations were noted for up to 6 hours after furosemide. Decreased theophylline concentrations were also noted in 4 neonates receiving oral or intravenous theophylline when given furosemide. Serum-theophylline concentrations returned to normal when furosemide and theophylline were given more than 2 hours apart.
The possibility that adverse effects such as hypokalaemia may be potentiated if theophylline is given with diuretics should be borne in mind.
Oral antacids do not appear to affect the total absorption of theophylline from the gut. However, some studies have shown a reduction in the rate of absorption from both immediate- and modified-release theophylline preparations after antacids. Also an increase in peak serum-theophylline concentrations has been noted with certain modified-release formulations.
Cimetidine inhibits the oxidative metabolism of theophylline reducing its clearance by 20 to 35% and prolonging its serum half-life toxic effects have been reported. It has been recommended that the dose of aminophylline should be reduced by about one-third if given with cimetidine. This inhibition of theophylline metabolism may be enhanced by liver disease, but there is wide interindividual variation.
The reduction in clearance may be greater in smokers. Studies have suggested that ranitidine does not significantly inhibit theophylline metabolism, even at very high doses. However, there have been occasional reports of theophylline toxicity after use with ranitidine. Famotidine has also been reported to not alter theophylline disposition but one small study found a significant decrease in theophylline clearance in some patients with chronic obstructive pulmonary disease.
Omeprazole, lansoprazole, and pantoprazole generally have insignificant or no effect on theophylline clearance. In CYP2C19 poor metabolisers there may be an increase in omeprazole concentrations and subsequent induction of CYP1A, a major enzyme of theophylline metabolism. A pharmacokinetic study of this induction in 5 poor metabolisers given omeprazole did find a trend towards an increase in theophylline clearance.
There have been several reports’ of increased cardiotoxicity when patients taking theophylline were anaesthetised with halothane. There was also an early report of seizures and tachycardia attributed to an interaction between theophylline and ketamine.
Leukotriene inhibitors and antagonists.
Zileuton prolongs the half-life and reduces the clearance of theophylline dosage of theophylline should be reduced to avoid toxicity when both drugs are given together, and plasma-theophylline concentrations should be monitored. Use of zafirlukast with theophylline decreased zafirlukast plasma concentrations but had no effect on theophylline plasma concentrations in clinical trials. However, toxic serum-theophylline concentrations occurred in one patient when zafirlukast was added to therapy, and recurred on rechallenge. A dose of montelukast 10 mg daily did not affect the pharmacokinetics of theophylline, but doses of 200 mg and 600 mg daily reduced the maximum plasma concentration, area under the concentration-time curve, and elimination half-life of theophylline.
In a single-dose pharmacokinetic study in 3 healthy subjects, the rate of elimination of theophylline was decreased after a single oral dose of methoxsalen, while urinary excretion of unchanged theophylline increased. Methoxsalen probably inhibits the metabolism of cytochrome P450 isoenzyme CYP1A2, and it has been suggested that theophylline dose reductions are likely to be required when used with systemic methoxsalen but seem unlikely to be necessary with topical PUVA therapy.
For reference to resistance to neuromuscular block with pancuronium in patients receiving aminophylline, see Xanthines.
Oral contraceptives have been reported to decrease the clearance of theophylline by about 30%, and serum concentrations may be increased, due to the inhibitory effects of oral contraceptives on hepatic P450 isoenzymes.
The effect of beta-adrenoceptor agonists on the pharmacokinetics of theophylline is unclear. Whereas some studies have found that orciprenaline or terbutaline had no effect on theophylline disposition, others have shown an increase in theophylline clearance after isoprenaline or terbutaline.
Use of theophylline with beta-adrenoceptor agonists can potentiate adverse effects including hypokalaemia, hyperglycaemia, tachycardia, hypertension, and tremor. Of 9 patients reported to the UK CSM with hypokalaemia during such combined therapy, 4 had clinical sequelae of cardiorespiratory arrest, intestinal pseudo-obstruction, or confusion. Monitoring of serum-potassium concentrations was recommended in patients with severe asthma given both beta-adrenoceptor agonists and xanthine derivatives.
The possibility of an interaction with phenylpropanolamine should also be borne in mind, as it has been shown to reduce the clearance of theophylline significantly.
Results of a study in healthy subjects indicated that tacrine reduced theophylline clearance by about 50% and increased plasma-theophylline concentrations. Competitive inhibition by tacrine of theophylline metabolism was proposed.
Tiabendazole has been reported’ to increase serum-theophylline concentrations and to decrease theophylline clearance. It has been recommended that theophylline dosage should be reduced by 50% when tiabendazole therapy is started.
Theophylline elimination half-life was increased and plasma clearance was decreased in 10 healthy subjects after the use of ticlopidine 500 mg daily by mouth for 10 days.
Transient inhibition of the hepatic metabolism of theophylline, possibly secondary to interferon production, resulting in increased theophylline serum half-life and concentration has been reported after BCG vaccination and influenza vaccination. Other studies have not been able to confirm the interaction with influenza vaccine. The differing findings are probably due to differences in vaccine modern purified subvirion vaccines which do not induce interferon production do not appear to alter theophylline metabolism.
Theophylline is rapidly and completely absorbed from liquid preparations, capsules, and uncoated tablets the rate, but not the extent, of absorption is decreased by food, and food may also affect theophylline clearance. Peak serum-theophylline concentrations occur 1 to 2 hours after ingestion of liquid preparations, capsules, and uncoated tablets. Modified-release preparations exhibit considerable variability in their absorption characteristics and in the effect of food. They are generally not considered to be interchangeable if a patient needs to be transferred from one such preparation to another then the dose should be retitrated.
Rectal absorption is rapid from enemas, but may be slow and erratic from suppositories. Absorption after intramuscular injection is slow and incomplete. Theophylline is about 40 to 60% bound to plasma proteins, but in neonates, or adults with liver disease, binding is reduced. Optimum therapeutic serum concentrations for bronchodilatation are generally considered to range from 10 to 20 micrograms/mL (55 to 110 micromol/litre) although some consider a lower range appropriate (see Therapeutic Drug Monitoring, below).
Theophylline is metabolised in the liver to 1,3-dimeth-yluric acid, 1-methyluric acid (via the intermediate 1-methylxanthine), and 3-methylxanthine. Demethyla-tion to 3-methylxanthine (and possibly to 1-methylx-anthine) is catalysed by the cytochrome P450 isoen-zyme CYP1A2 hydroxylation to 1, 3-dimethyluric acid is catalysed by CYP2E1 and CYP3A3. Both the demethylation and hydroxylation pathways of theophylline metabolism are capacity-limited, resulting in non-linear elimination. The metabolites are excreted in the urine.
In adults, about 10% of a dose of theophylline is excreted unchanged in the urine, but in neonates around 50% is excreted unchanged, and a large proportion is excreted as caffeine. Considerable interindivid-ual differences in the rate of hepatic metabolism of theophylline result in large variations in clearance, serum concentrations, and half-lives. Hepatic metabolism is further affected by factors such as age, smoking, disease, diet, and drug interactions. The serum half-life of theophylline in an otherwise healthy, non-smoking asthmatic adult is 7 to 9 hours, in children 3 to 5 hours, in cigarette smokers 4 to 5 hours, in neonates and premature infants 20 to 30 hours, and in elderly non-smokers 10 hours. The serum half-life of theophylline may be increased in patients with heart failure or liver disease. Steady state is usually achieved within 48 hours with a consistent dosing schedule. Theophylline crosses the placenta it is also distributed into breast milk.
Food has substantial but variable effects on the absorption of theophylline from modified-release formulations but it is difficult to predict whether a particular formulation will be affected. Some formulations are not affected by the presence of food but for others increases or decreases in the rate and/or extent of absorption have been reported. The composition and fluid content of the food appears to be important and a rapid release of theophylline (‘dose-dumping’) has occurred with some formulations after a meal, especially one with a high fat content. A diet high in protein and low in carbohydrate has been reported to increase theophylline clearance, and a low-protein, high-carbohydrate diet to decrease theophylline clearance. The consumption of methylxanthines, particularly caffeine, in the diet may decrease theophylline clearance (see Caffeine, under Interactions, above).
Metabolism and excretion.
From about 1 year of age until adolescence, children have a rapid theophylline clearance. Premature infants and those under 1 year of age have a slower clearance due to immature metabolic pathways. In neonates the capacity of hepatic cytochrome P450 enzymes is much reduced compared with older children and adults, and N-demethylation and oxidation reactions play a minor role in the metabolism of theophylline. Neonates are, however, capable of methylating theophylline at the N7 position to form caffeine, which is present at about one-third the concentration of theophylline at steady state. The proportion of theophylline excreted unchanged is also increased in premature neonates and decreases with age as hepatic enzyme systems develop. More rapid clearance on the first day of life in premature neonates has been reported. Some studies have found a progressive decline in clearance throughout adult years whereas others have not. Similarly, some studies have noted a decreased clearance in the elderly’ but others have found no significant change.
There is evidence that the elimination of theophylline is dose-dependent and that at high serum concentrations, a small change in dose of a theophylline preparation could cause a disproportionate increase in serum-theophylline concentration, due to a reduction in clearance. However, it is not clear that this effect is clinically significant when serum-theophylline concentrations are within the therapeutic range. It has also been suggested that repeated oral dosing of theophylline might result in a decrease of clearance compared with pre-treatment values.
A higher theophylline clearance and shorter elimination half-life has been reported in healthy premenopausal women than in healthy men, probably due to sex-related differences in hepatic metabolism. Changes in the pharmacokinetics of theophylline in women have also been reported according to the stage of the menstrual cycle another study found no changes.
Pregnancy and breast feeding.
For mention of the pharmacokinetics of theophylline during pregnancy and breast feeding, see under Precautions, above.
Albumin is the major plasma binding protein for theophylline, binding is pH-dependent, and the percentage of theophylline bound at physiological pH is reported to range from about 35 to 45%. Some studies have found the plasma protein binding of theophylline to be concentration dependent, but others have not confirmed this. Protein binding has been reported to be slightly but significantly higher in patients with bronchial asthma than in healthy controls. Reduced protein binding occurs in patients with hypoalbuminaemia it has also been found in obese subjects (possibly due to elevated concentrations of free fatty acids, which can displace theophylline from binding sites).
Therapeutic drug monitoring.
Dosage requirements of theophylline preparations vary widely between subjects and even vary with time in individuals, since serum-theophylline concentrations are influenced by factors including disease states, other drugs, diet, smoking, and age. Serious toxicity is related to serum concentration and may not be preceded by minor symptoms. For these reasons it is recommended that serum-theophylline concentrations should be monitored.
The generally accepted optimal serum concentration is between 10 and 20 micrograms/mL, but this should be regarded as a guide and not a rigid barrier and clinical decisions should never be based solely on the serum concentration. The therapeutic range in the treatment of neonatal apnoea is usually considered to be 5 to 15 micrograms/mL although some babies may respond at lower concentrations. Some now consider that this is a more appropriate range in asthma (except perhaps acute severe asthma).
It has been suggested that pulmonary function tests provide a better guide in long-term therapy with theophylline. Serum-theophylline concentrations were originally measured by spectrophotometry but this is subject to considerable interference from other drugs. High performance liquid chromatography is now the method of choice when extreme accuracy is important and the enzyme multiplied immunoassay technique (EMIT) has become popular because of its rapidity and adaptability to processing large batches. Devices are also available that provide serum-theophylline measurements within several minutes using monoclonal antibody technology.
The use of salivary concentrations for monitoring theophylline dosage requirements has been tried, because it is noninvasive, but poor correlations between salivary- and serum-theophylline concentrations mean it has not gained general usage.
Theophylline. Uses. Preparations
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