Theophylline

Mechanism of Action

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:

• It acts as a competitive nonselective phosphodiesterase inhibitor (inhibiting type III and type IV phosphodiesterase), which increases the concentration of intracellular cAMP, activates protein kinase A, inhibits TNF-alpha, and leukotriene synthesis, and also decreases inflammation and innate immunity.
• It is also a nonselective adenosine receptor antagonist. It acts on A1, A2, and A3 receptors with almost the same affinity, which possibly explains theophylline's cardiac effects. Adenosine-mediated channels also increase the contraction force of diaphragmatic muscles by enhancing their calcium uptake.[2][3][4]

  Other proposed mechanisms of action of theophylline include:

• It inhibits nuclear factor-kappaB, preventing the translocation of the pro-inflammatory transcription factor (NF-kappaB) to the nucleus, reducing the expression of known inflammatory genes in COPD and asthma. 
• Increases interleukin-10 secretion; interleukin-10 has broad anti-inflammatory effects
• Increases histone deacetylase 2 through inhibiting phosphoinositide 3-kinase-delta.
• Decreases poly (ADP-ribose) polymerase-1 (PARP-1)
• Increases apoptosis of inflammatory cells (T cells, neutrophils)

Administration

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, which could increase the risk of side effects of theophylline.

Intravenous (IV)

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 to manage 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 with any factors that decrease its clearance from the body, doses should be cut in half, and its plasma concentration is 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.  

Oral

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 maintain a more consistent serum drug concentration).

• The 12-hour formulation: Dosing can be once every 24-hours in patients who are non-smokers (who have appropriate total body clearance of theophylline) and in patients who have low dosage requirements. Only after theophylline has titrated to therapeutic concentrations in the patient can the 12-hour formulation be considered. The once-daily dosing should be based on the twice-daily dosing and initiated at the end of every 12-hour dosing interval. Do not give the once-daily dosing to the patient at night (after the evening meal).

• The 24-hour formulation: Take each morning around the same time and avoid taking it at night (after the evening meal). In patients whom a higher dose is required (13 mg/kg or greater than or equal to 900 mg, whichever one is less) should take the medication less than 60 minutes before a high-fat meal (as a significant increase in the peak serum concentrations and absorption could occur). Patients should consistently take theophylline either in a fasting state or with food (as this helps maintain a more consistent serum drug concentration). The twice-daily dosing could be a consideration for those who metabolize theophylline quickly (for example, smokers, younger patients, and some nonsmoking adults) and those who still have symptoms at the end of the dosing interval. The first dose should be in the morning and the second one around 10 to 12 hours after the first dose (but before eating the evening meal). Administration at night should be avoided.

Other Routes

Administering by inhalation is both irritating and ineffective. Administration of theophylline through intramuscular injections is very painful and should never be given.

Dosing Considerations

• If administering aminophylline, the dose should increase by 25% (as aminophylline is 79% to 86% theophylline).
• Dose calculations should use the ideal body weight.
• Aminophylline or immediate-release theophylline should be used for per-oral loading.[5][6][7]

Adverse Effects

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.[8][9][10]

Contraindications

Contraindications

• Theophylline is contraindicated if the patient previously developed a hypersensitivity reaction to the drug or any component of its formulation (such as an allergy to corn-related products (in injection use only).
• Other contraindications include hypersensitivity to xanthine derivatives and patients with coronary artery disease (where the cardiac stimulation effect of theophylline might prove harmful).

Precautions

• Patients with cardiovascular disease: Use cautiously in patients who have cardiac arrhythmias (excluding bradyarrhythmias), at it may exacerbate arrhythmias.
• Patients with cystic fibrosis: Use cautiously in patients with cystic fibrosis, as increased theophylline clearance may occur in these patients.  
• Patients with hepatic impairment: Use cautiously in patients with a hepatic impairment such as cirrhosis, cholestasis, acute hepatitis because there is an increased risk of severe and potentially fatal complications. This risk exists because clearance decreases by 50% or more in these patients. Frequent monitoring and dose reduction of theophylline are necessary for these patients.
• Patients with hyperthyroidism: Use cautiously in patients with hyperthyroidism, as increased theophylline clearance may occur.  
• Patients with peptic ulcer disease: Use cautiously in patients who have active peptic ulcer disease, as the use of theophylline may exacerbate peptic ulcers.
• Patients with seizure disorders: Use theophylline cautiously in patients with seizure disorders, as its use may exacerbate the seizure disorder.

Special Populations 

• Elderly patients: Theophylline use requires extreme caution in elderly patients as these patients are at an increased risk of serious theophylline toxicity.  

• Pediatric patients: Dose selection requires caution, and regular monitoring of concentrations is necessary (especially if the child is younger than 1 year of age) as the rate of clearance varies significantly in these patients.

Pregnancy

• Theophylline is a pregnancy category C drug. It should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.[9][10][11]

Monitoring

Because of the narrow therapeutic window of theophylline and its many side effects, physicians should monitor the following in the patient:

• The heart rate of the patient
• CNS effects (headache, insomnia, irritability)
• The respiratory rate
• Patient's arterial or capillary blood gases
• The patient's electrolyte concentrations, fluid balance, and acid-base balance require monitoring during prolonged IV therapy.

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.

Oral Theophylline

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).

IV Theophylline

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

• For children: 5 to 15 mcg/mL
• For adults: 10 to 20 mcg/mL  
• Toxic serum concentration: greater than 20 mcg/mL.[12][13][14][15][16]

Toxicity

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.

• Activated charcoal may prevent absorption by adsorbing the drug in the intestine.
• Beta-blockers could potentially help in reversing the severe cardiovascular toxicity caused by theophylline. 
• Intravenous benzodiazepines may abort seizures.[9][10][11]

Enhancing Healthcare Team Outcomes

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 is 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. When necessary, the entire interprofessional healthcare team should be aware that the patient is taking the drug and being alert for potential adverse effects. Pharmacists can verify dosing and perform medication reconciliation, and nurses can counsel on dosing and adverse effects. This interprofessional approach will improve patient outcomes with this medication. [Level 5]