Theophylline clearance

Theophylline COCs decrease theophylline clearance by 34% and increase the t1/2 by 33% Increase side effects of theophylline... 

Because of large interpatient variability in theophylline clearance, routine monitoring of serum theophylline concentrations is essential for safe and effective use. A steady-state range of 5 to 15 mcg/mL is effective and safe for most patients. 

Factors that may decrease theophylline clearance and lead to reduced dosage requirements include advanced age, bacterial or viral pneumonia, heart failure, liver dysfunction, hypoxemia from acute decompensation, and use of drugs such as cimetidine, macrolides, and fluoroquinolone antibiotics. 

Factors that may enhance theophylline clearance and result in the need for higher doses include tobacco and marijuana smoking, hyperthyroidism, and use of drugs such as phenytoin, phenobarbital, and rifampin. 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

Drug Interactions According to the product label, interactions between Intron A and other drugs have not been fully evaluated. Caution should be exercised when administering Intron A therapy in combination with other potentially myelo-suppressive agents such as zidovudine. Concomitant use of alfa interferon and theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline levels. 

Grygiel JJ, Birkett DJ. Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther 1981 30 491 196. 

Figure 6.1 Theophylline clearance (ml/min/kg) in controls and in subjects pre-treated with rifampicin...

To follow the analysis, it is particularly important to understand the mechanism implied by the null hypothesis. Figure 6.2 will be used to describe these alleged events. A vertical scale shows theophylline clearances. Each circle (open or solid) represents a member of the population. The data form normal distributions (but these are shown turned at right angles to the usual orientation). 

In most packages, you will enter the data from both samples into a single column of a data sheet and then set up a second column that contains labels indicating which sample each value belongs to. With the theophylline clearance data, you would place... 

Table 6.2 Generic output from a two-sample f-test comparing theophylline clearances in rifampicin treated and control subjects...

Figure 6.4 The 95 per cent confidence interval for the difference in theophylline clearance between control and rifampicin treated subjects...

The key point is that it is pretty obvious that the null hypothesis (with its claim of a difference of zero) is difficult to believe - zero lies well outside the 95 per cent Cl. Since the null hypothesis now looks so shaky, the balance shifts in favour of accepting the alternative hypothesis that rifampicin really does cause a change in theophylline clearance. 

Figure 6.8 shows the effect of the width of the confidence interval. We know that the interval width depends upon the variability (SD) of the data being considered and the number of observations available. Therefore, if the theophylline clearances are fairly consistent and large numbers of subjects have been studied,... 

Whatever package is used, the theophylline clearance data from the previous chapter should produce a P value of 0.001. This can be read as ... 

If rifampicin actually had no effect on theophylline clearance, there would be only a 0.1 per cent (1 in 1000) chance that our samples would suggest an effect as great as (or greater than) the difference we actually observed. 

Figure 8.2 Power curve for the theophylline clearance experiment (assumes the true difference is an increase of 0.3 ml/min/kg and the SD among clearances is 0.21 ml/min/kg)...

Minimum effect to be detectable We talk to some experts and they decide that, if theophylline clearance is changed to an extent of 20 per cent, they want to know about it. (The implication is that, if some smaller difference were present, but our experiment failed to detect it, it would be considered no big deal.) A typical text-book mean clearance for theophylline (under normal circumstances) is 0.67 ml/min/kg. Therefore, a 20 per cent change would equate to an increase or decrease of about 0.13 ml/min/kg. 

Standard deviation among theophylline clearances A review of the literature concerning the clearance of theophylline gave conflicting results, but a guesstimate of SD = 0.25 ml/min/kg was agreed upon. 

Varying the standard deviation among theophylline clearances We can do a similar exercise, varying the assumed standard deviation among the clearances, while holding everything else constant. Figure 8.6 shows the results. 

It does therefore follow that it is very important to reduce the SD as much as possible. Theophylline clearances are intrinsically variable and there is nothing we can do about that. However, random measurement errors maybe inflating the SD and we should certainly be attempting to eradicate all unnecessary sources of variability. 

Figure 13.1 shows that the application of a one-way ANOVA to this data is only a minor extension of what we already did with the rifampicin/theophylline clearances and a two-sample f-test. 

DISULFIRAM BRONCHODILATORS -THEOPHYLLINE t theophylline levels Disulfiram i theophylline clearance by inhibiting hydroxylation and demethylation Monitor theophylline levels before, during and after co-administration... 

Urquhart R, Edwards C. Increased theophylline clearance during hemofiltration. Ann Pharmacother 1995 29 787-8. 

Theophylline neurotoxicity and cardiotoxicity are increased in older patients. Although it is unclear whether decreased theophylline clearance and increased exposure in older patients fully explain this apparent sensitivity, clinical reports are uniform in identifying age as a major contributing risk factor for theophylline toxicity (95,96). This has resulted in much less use of theophylline in older patients. 

Jusko WJ, Gardner MJ, Mangione A, Schentag JJ, Koup JR, Vance JW. Factors affecting theophylline clearances Age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 1979 68 1358-66. 

Absorption of theophylline from the gastrointestinal tract is usually rapid and complete. Some 90% is metabolised by the liver and there is evidence that the process is saturable at therapeutic doses. The tis 8 h, with substantial variation, and it is prolonged in patients with severe cardiopulmonary disease and cirrhosis. Obesity and prematurity are associated with reduced rates of elimination, whereas tobacco smoking enhances theophylline clearance by inducing hepatic P450 enzymes. Because of these pharmacokinetic factors and low therapeutic index, monitoring of the plasma theophylline concentration is necessary to optimise its therapeutic effect and minimise the risk of adverse reactions the optimum concentration range is 10-20 mg/1 (55-110 mmol/1). 

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