Theophylline side effects

Herbs that may T risk of theophylline side-effects ... 

Similar to the clinical efficacy of theophylline, side effects are also closely related to sernm concentrations. No critical side effects have been observed at sernm theophylline levels np to 20 pg/ml. However, transient comparatively slight side effects similar to those of caffeine, including nausea, vomiting, headache, diarrhea, and insomnia, occnr in some patients at theophylline sernm concentrations below 20 pg/ml. These side effects may be present in np to 50% of patients when serum concentrations of 10 to 20 pg/ml are rapidly achieved, bnt they are usually much less frequent when the initial dose is low and the hnal drng concentration is gradually achieved by increasing doses in intervals of at least 3 days. 

Common side effects of theophylline therapy include headache, dyspepsia, and nausea. More serious side effects such as lethal seizures or cardiac arrythmias can occur if blood levels are too high. Many derivatives of theophylline have been prepared in an effort to discover an analogue without these limitations (60,61). However, the most universal solution has resulted from the development of reHable sustained release formulations. This technology limits the peaks and valleys in semm blood levels that occur with frequent dosing of immediate release formulations. ControUed release addresses the problems inherent in a dmg which is rapidly metabolized but which is toxic at levels ( >20 7g/mL) that are only slightly higher than the therapeutically efficacious ones (10—20 p.g/mL). Furthermore, such once-a-day formulations taken just before bedtime have proven especially beneficial in the control of nocturnal asthma (27,50,62). 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

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

Tremor is a frequent side effect of caffeine or theophylline consumption and tremulousness is often attributed to caffeine by the public. 

Guarana contains tetra methylxanthine, a compound almost identical to caffeine and other stimulants such as theophylline (which has been isolated and sold as a drug and which can be toxic when consumed in high doses), theobromine, and saponins. Although not well documented, the side effects of guarana are similar to those of other stimulants. 

Whenever side effects occur, dosage should be reduced to a previously tolerated lower dose. (SRT, sustained-release theophylline.)... 

The most common side effects of theophylline include dyspepsia, nausea, vomiting, diarrhea, headache, dizziness, and tachycardia. Arrhythmias and seizures may occur, especially at toxic concentrations. 

The quinolones have been found to cause erosion of cartilage in the joints of immature animals [56]. This observation, which has been seen in several studies, has resulted in the contraindication of quinolones for the treatment of children. A study analyzing the risk-benefit situation for the use of pefloxacin in children (clinically, several adverse athralgic effects have been attributed to this agent) has appeared [57]. The underlying mechanism responsible for these effects has yet to be established, and the development of an agent which is safe for paediatric use would be a major advance in quinolone therapy. Some of the quinolones, such as enoxacin, have been shown to interfere with theophylline metabolism [58], and side-effects associated with this agent may be related to this property. 

Theophylline (Fig. 20) is structurally very similar to caffeine and present at a low concentration in tea. It is also known as dimethyl xanthine. It is used for the treatments of asthma and COPD, for more than 50 years despite its many side effects. The mechanism of beneficial effect of theophylline is through HD AC activation. 

Theophylline is one of the mainstays of therapy for acute and chronic obstructive airways disease. Until recently little was known about its pharmacokinetics and their clinical application, but there is now good evidence (J4) that both the therapeutic response and toxic side effects are related to the concentration of theophylline in plasma, rather than to its dosage. 

Side effects include unpleasant gastrointestinal symptoms, nausea, and vomiting and are very common in patients with a steady-state plasma theophylline level above 20 /xg/ml. They are not observed at plasma theophylline levels under 13 U,g/ml, regardless of the daily dose. It seems unlikely, therefore, that these troublesome toxic side effects are due to local tissue damage produced by theophylline in the gut, but rather that they are a systemic response to a high plasma theophylline level and, therefore, preventable by proper monitoring. 

Theophylline and other methylxanthines also display a pharmacological effect on a number of other organ systems. Of course the most pronounced effect is relaxation of smooth musculature in the respiratory tract. However, theophylline is a CNS stimulant, and it lowers arterial blood pressure, increases diuresis, displays cardiotonic activity, and has a specific effect on the gastrointestinal tract. The effects listed are the most frequently encountered side effects upon taking theophylline as a broncholytic. 

This xanthine derivative is an only a modest bron-chodilator in COPD, and because of its narrow therapeutic range, frequently seen adverse effect and drug interactions, it is becoming less frequently used, some patients experience side effects even within the therapeutic range. The non-bronchodilator effects of theophylline such as systemic and pulmonary vascular dilatation, central nervous system stimulation, improvement of the strength and effectiveness of respiratory muscles and possibly anti-inflammatory effects are of disputed clinical significance at usual therapeutic levels. 

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. 

Theophylline has a narrow therapeutic index and produces side effects that can be severe, even life threatening. Importantly, the plasma concentration of theophylline cannot be predicted reliably from the dose. In one study, the oral dosage of theophylline required to produce therapeutic plasma levels (i.e., between 10 and 20 pg/mL) varied between 400 and 3,200 mg/day. Heterogeneity among individuals in the rate at which they metabolize theophylline appears to be the principal factor responsible for the variability in plasma levels. Such conditions as heart failure, liver disease, and severe respiratory obstruction will slow the metabolism of theophylline. 

Dyspepsia is the most common side effect of zileuton. Liver transaminase levels are elevated in a small percentage of patients taking zileuton. Serum Uver transaminase levels should be monitored and treatment halted if significant elevations occur. Zileuton inhibits the metabolism of theophylline. Thus, when these agents are used concomitantly, the dose of theophylline should be reduced by approximately one-half, and plasma concentrations of theophylline should be monitored closely. Caution should also be exercised when using zileuton concomitantly with warfarin, terfenadine, or propranolol, as zileuton inhibits the metabolism of these agents. Zileuton is contraindicated in patients with acute liver disease and should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. 

Touted to produce less GI side effects if dosed equipotent ly based on theophylline equivalents (oxtriphylline = 64% theophylline), no difference compare costs as well as other characteristics... 

Geriatric Considerations - Summary Increased risk of side effects in patients with CVD and hepatic dysfunction. Theophylline has a narrow therapeutic index and is associated with numerous drug interactions. Target serum concentrations are 5-20 mg/L, with adverse effects increasing between 15-20 mg/L. Hepatic metabolism and renal excretion declines with age and the half-life of theophylline increases by 3 to 9 hours in older adults. Smoking induces theophylline metabolism therefore, if a pa-tienf sfops smoking, empiric dosage reduction may be indicated and follow serum concenfrafions closely. 

Side effects are usually associated with the increasing serum concentration of theophylline and includes nausea, vomiting, headache, insomnia, tachypnea, epigastric pain, palpitation, hypotension, irritability. Higher doses can cause persistent vomiting, cardiac arrhythmias, intractable seizures, tachycardia. Other side effects include alopecia, hyperglycemia, inappropriate ADH syndrome, rash. 

Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. It is inexpensive, and it can be taken orally. Its use, however, also requires occasional measurement of plasma levels it often causes unpleasant minor side effects (especially insomnia) and accidental or intentional overdose can result in severe toxicity or death. For oral therapy with the prompt-release formulation, the typical dose is 3-4 mg/kg of theophylline every 6 hours. Changes in dosage result in a new steady-state concentration of theophylline in 1-2 days, so the dosage may be increased at intervals of 2-3 days until therapeutic plasma concentrations are achieved (10-20 mg/L) or until adverse effects develop. 

Treatment with a leukotriene-receptor antagonist, particularly montelukast, is widely prescribed, especially by primary care providers. Taken orally, leukotriene-receptor antagonists are easy to use and appear to be used more regularly than inhaled corticosteroids. They are rarely associated with troublesome side effects. Maintenance therapy with a leukotriene antagonist or with cromolyn or nedocromil appears to be roughly as effective as maintenance therapy with theophylline. Because of concerns over the possible long-term toxicity of systemic absorption of inhaled corticosteroids, this maintenance therapy is widely used for treating children in the USA. 

An example of a potentially important drug interaction is that which occurs when fluvoxamine is given along with theophyllin (Figure 6—13). In that case, the theo-phyllin dose must be lowered or else the blood levels of theophyllin will rise and possibly cause side effects, even toxic side effects such as seizures. The same may occur with caffeine. Fluvoxamine also affects the metabolism of atypical anti-psychotics. 

FIGURE 6-13. Theophyllin is a substrate for CYP450 1A2. Thus, in the presence of the 1A2 inhibitor fluvoxamine, theophyllin levels rise. The theophyllin dose must be lowered when it is given with fluvoxamine in order to avoid side effects. 

Xanthine derivatives are a group of chemically similar compounds that exert a variety of pharmacologic effects. Common xanthine derivatives include theophylline, caffeine, and theobromine (Fig. 26-2) these compounds are frequently found in various foods and beverages (tea, coffee, soft drinks). Theophylline and several theophylline derivatives are also administered therapeutically to produce bronchodilation in asthma and other forms of reversible airway obstruction (bronchitis, emphysema).65,79 Theophylline and caffeine are also potent CNS stimulants, and some of the more common side effects of these drugs are related to this CNS excitation (see Adverse Side Effects, later in this chapter). 

Caffeine is used medicinally as a CNS stimulant, usually combined with another therapeutic agent, as in compound analgesic preparations. Theobromine is of value as a diuretic and smooth muscle relaxant, but is not now routinely used. Theophylline is an important smooth muscle relaxant for relief of bronchospasm, and is frequently dispensed in slow-release formulations to reduce side-effects. It is also available as aminophylline (a more soluble preparation containing theophylline with ethylenediamine) and choline theophyllinate (theophylline and choline). The alkaloids may be isolated from natural sources, or obtained by total or partial synthesis. 

In low and moderate doses, the methylxanthines—especially caffeine—cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages—eg, 100 mg in a cup of coffee—is sufficient to cause nervousness and insomnia in unusually sensitive individuals and slight bronchodilation in patients with asthma. At very high doses, medullary stimulation and convulsions may occur and can lead to death theophylline has been used successfully in suicide attempts. Nervousness and tremor are primary side effects in patients taking large doses of aminophylline for asthma. 

In 1987 the xanthine derivative theophylline was the most commonly used medication in the treatment of asthma, followed by / 2-agonists, such as albuterol or ter-butaline, and inhaled corticosteroids, for example budesonide or flunisolide. Today, the most frequently used medication is inhaled / 2-agonists and it is expected that these therapy patterns have shifted toward greater use of inhaled corticosteroids [4, 5], Nevertheless, whether used alone or in combination with other therapies, corticosteroids do not consistently abrogate airway inflammation in patients with asthma common side effects associated with this type of drug are increased heart rate, nervousness, tremors, nasal irritation, nausea, and headaches [8, 10, 11],... 

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