Theophylline gastrointestinal effects

In a double-blind, crossover study, 13 healthy subjects were given 200 mg of theophylline Slo-Phyllin) four times daily for 5 days and either zileuton 800 mg twice daily or a placebo. Zileuton caused a 73% rise in the mean steady-state peak serum levels of theophylline (from 12 to 21 mg/L), a 92% increase in its AUC, and halved its apparent plasma clearance. During the use of zileuton the incidence of adverse effects increased (headache, gastrointestinal effects), which was attributed to theophylline toxicity, and this caused 3 of the original 16 subjects to withdraw from the study. ... 

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. 

Action on the CNS depends directly on the dose of administered drug, and can be manifested as fatigue, anxiety, tremors, and even convulsions in relatively high doses. Theophylline acts on the cardiovascular system by displaying positive ionotropic and chronotropic effects on the heart, which, can likely be linked to the elevated influx of calcium ions by modulated cyclic adenosine monophosphate and its action on specific cardiac phosphodiesterases. In the gastrointestinal system, methylxanthines simultaneously stimulate secretion of both gastric juice and digestive enzymes. 

Of the xanthines, theophylline is the most effective bronchodilator, and it has been shown repeatedly both to relieve airflow obstruction in acute asthma and to reduce the severity of symptoms and time lost from work or school in patients with chronic asthma. Theophylline base is only slightly soluble in water, so it has been administered as several salts containing varying amounts of theophylline base. Most preparations are well absorbed from the gastrointestinal tract, but absorption of rectal suppositories is unreliable. 

Theophylline should be used only where methods to measure theophylline blood levels are available because it has a narrow therapeutic window, and its therapeutic and toxic effects are related to its blood level. Improvement in pulmonary function is correlated with plasma concentrations in the range of 5-20 mg/L. Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety occur at concentrations of 15 mg/L in some patients and become common at concentrations greater than 20 mg/L. Higher levels (more than 40 mg/L) may cause seizures or arrhythmias these may not be preceded by gastrointestinal or neurologic warning symptoms. 

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). 

The commonest gastrointestinal adverse effects of aminophylline in adults are nausea and gastrointestinal irritation, which are primarily a function of serum theophylline concentrations, although some additional local irritation may be produced by oral administration. Nausea was reported in six of 20 asthmatic patients with serum theophylline concentrations of 20 pg/ml (SED-9, 4). In a survey of 2766 theophylline-treated patients with cardiac or pulmonary diseases, 11% had adverse effects, most of which were gastrointestinal disturbances (7.8%) (SED-9, 4). 

Once a dose is established, serum concentrations should be monitored once or twice a year unless the patient s disease worsens, medications that interfere with theophylline metabolism are added to therapy, or toxicity is suspected. The most common side effects of theophylline therapy are related to the gastrointestinal system, the cardiovascular system, and the central nervous system. Side effects are dose-related however, there is overlap in side effects between the therapeutic and toxic ranges. Minor side effects include... 

E. Toxicity The common adverse effects include gastrointestinal distress, tremor, and insomnia. Severe nausea and vomiting, hypotension, cardiac arrhythmias, and convulsions may result from overdosage. Very large overdoses (eg, in suicide attempts) are potentially lethal because of the arrhythmias and convulsions. Beta-blockers are useful antidotes for severe cardiovascular toxicity from theophylline. 

D. Enhancement of Elimination Enhancement of elimination is possible for a number of toxins, including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity due to fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidiflcation may be useful in toxicity due to weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to avoid acidosis and renal failure in rhabdomyolysis. Hemodialysis or hemoperfusion enhances the elimination of many toxic compounds, including acetaminophen, ethylene glycol, formaldehyde, lithium, methanol, procainamide, quinidine, salicylates, and theophylline. Cathartics such as sorbitol (70%) may decrease absorption and hasten removal of toxins from the gastrointestinal tract. 

Activated charcoal is effective in decreasing theophylline absorption from the gastrointestinal tract, and whole bowel irrigation is especially useful for decontamination of orally administered sustained-release formulations of the drug. Hypotension is often managed by saline infusion, though vasopressors may be required. The blood levels of theophylline are decreased by charcoal hemoperfusion or by hemodialysis. Ipecac fluid extract contains cardiotoxic alkaloids and should never be used as an emetic. The answer is (D). 

Caffeine and theophylline are methylxanthine derivatives that are widely distributed in plant products and beverages. Theophylline and caffeine have been widely used for the treatment of asthmatic manifestations, neonatal apnea and bronchial spasms. However, these compounds produce the biological effect of dieresis, and excessive intake leads to many undesired side effects, with symptoms including tremors, excessively fast heartbeat and gastrointestinal difficulties [35]. Therefore, it is very important to determine accurately the content of these alkaloids in foods and pharmaceutical preparations. 

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