Theophylline is a drug derived from methylxanthine (a purine derivative) and has smooth muscle relaxant, bronchial dilation, diuretic, cardiac and central nervous system (CNS) stimulant activities. Naturally present in tea and cocoa beans in small amounts, it was initially extracted and synthesized in 1895 and used as a diuretic. In 1922, it came out as a clinical treatment for asthma after the identification of its bronchodilator effect. It used in the treatment of various respiratory conditions that obstruct the airways such as asthma and chronic obstructive pulmonary disease (COPD).
Treatment of asthma exacerbation with theophylline is not a recommendation from the current clinical practice guidelines (2018 GINA Report, Global Strategy for Asthma Management and Prevention; National asthma education and prevention program-NAEPP 2007).
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2018, the management of acute COPD with IV theophylline is not recommended by the current clinical practice guidelines due to its significant side effects.
Theophylline relaxes the smooth muscles located in the bronchial airways and pulmonary blood vessels. It also reduces the airway responsiveness to histamine, adenosine, methacholine, and allergens. It exerts these effects mainly through two distinct mechanisms:
Other proposed mechanisms of action of theophylline include:
Theophylline can be used as an oral agent (rapid or slow-release tablets, solution, syrup, or capsule) or in a more soluble form such as aminophylline (an ethylenediamine salt of theophylline) that can be dosed orally or intravenously. Cautiously administer theophylline in a patient who has consumed large amounts of foods or drinks with high caffeine content, as this could potentially increase the risk of side effects of theophylline.
Patients can be administered IV theophylline for acute bronchospasm. Those who are not currently taking theophylline should be given a loading dose of 5 to 7 mg/kg intravenously, followed by a maintenance dose of 0.4 to 0.6 mg/kg per hour intravenously to maintain serum concentrations at 10 to 15 mg/L.
IV aminophylline was previously a frequent therapy used in the management of acute exacerbations of COPD and asthma but now sees much less frequent use, as it is far less effective than nebulized beta2-agonists. The currently recommended loading dose is 6 to 7 mg/kg administered intravenously over 20 to 30 minutes. After this, the patient receives a maintenance dose of 0.5 mg/kg per hour. In patients already taking theophylline, or those who have any factors that decrease its clearance from the body, doses should be cut in half, and its plasma concentration checked more frequently. In patients with cardiac decompensation, cor pulmonale, older patients or those on medications that are known to decrease theophylline clearance, the infusion rate of theophylline should not be increased above 17 mg per hour unless the patient remains symptomatic, their steady-state serum concentrations are consistently below 10 mcg/mL, and their serum concentrations are observable at 24-hour intervals. Administering solutions comprising dextrose concurrently through the same administration route as blood may result in hemolysis or pseudo-agglutination, and should be avoided.
Theophylline tablets are rapidly absorbed, but plasma concentrations show wide fluctuations and are therefore not currently recommended. Several sustained-release preparations that absorb at a relatively constant rate provide steady plasma concentrations of the drug over a 12 to 24-hour period. It should be taken consistently with or without food (as this helps to maintain a more consistent serum drug concentration).
Administering by inhalation is both irritating and ineffective. Administration of theophylline through intramuscular injections is very painful and should never be given.
Theophylline has a very narrow therapeutic window, and its interaction with various other drugs has led to the limitation of its use. The serum theophylline concentrations require monitoring directly to avoid toxicity as the adverse effects of theophylline are related to its plasma concentration and have been observed when plasma concentrations exceed 20 mg/L. Some patients have also experienced adverse effects at low plasma concentrations. The dose gradually increases until achieving therapeutic plasma concentrations. This approach reduces side effects.
The most common side effects are nausea and vomiting, headache, increased stomach acid secretion, and gastroesophageal reflux, which could be due to PDE inhibition. CNS symptoms (irritability, lightheadedness, and dizziness) can also occur in patients. In severe cases, seizures have also occurred. At high serum concentrations, adenosine A1-receptor antagonism could lead to convulsions and cardiac arrhythmias.
Because of the narrow therapeutic window of theophylline and its many side effects, physicians should monitor the following in the patient:
Serum theophylline concentrations should be checked after the initiation of therapy, before increasing dose and if any signs or symptoms of toxicity appear. Worsening of the current illness, an occurrence of a new illness or any change in the patient's treatment protocol that may alter theophylline clearance should also prompt the physician to check serum concentrations of theophylline. Attention should also is necessary for the infusion site.
For patients taking oral treatment, monitor serum concentrations at 6-month intervals for rapidly developing children and at annual intervals for all other patients (if their symptoms are well controlled).
Loading dose: The serum concentration of theophylline should be checked 30 minutes after the completion of an intravenous loading dose in patients with no theophylline use in the last 24 hours to determine if additional loading may be required (if the serum concentration is less than 10 mcg/mL) or to delay initiating the constant IV infusion (if the serum concentration is greater than 20 mcg/mL).
Infusion: Serum concentration of theophylline should be measured to one expected half-life (approximately 4 hours in young children [ages 1 to 9 years], or around 8 hours in otherwise healthy adults, who do not smoke) after administering a continuous infusion, then checked every 12 to 24 hours to establish if any further adjustments are required, and then at 24-hour intervals for the remainder of the infusion.
Therapeutic Concentrations for Theophylline
As with other methylxanthines, theophylline toxicity can lead to gastrointestinal distress, insomnia, and tremor. Reports also exist of severe nausea and vomiting, cardiac arrhythmias, hypotension, and convulsions, more commonly in cases of overdosage. Very large overdoses, such as those during suicide attempts, could potentially be lethal because of the development of arrhythmias and convulsions.
Theophylline is often prescribed by the nurse practitioner, primary care provider, pulmonologist, internist, and emergency department physician. However, all healthcare workers who prescribe this medication should be familiar with its adverse effect profile. The drug has a low therapeutic index and known to cause many unpleasant side effects, including life-threatening arrhythmias. Drug concentrations should be obtained regularly, and close monitoring of the patient is essential. With the availability of better and safer bronchodilators, the use of theophylline should not be routine.
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