theophylline

Action and Spectrum

Actions and spectrum: 

• Bronchodilation: theophylline works by relaxing the smooth muscles in the airways, particularly in the bronchial tubes. This helps to widen the airways and improve airflow, making it easier for individuals with asthma, chronic obstructive pulmonary disease, and respiratory conditions to breathe. 
• Anti-inflammatory effects: theophylline has been shown to have anti-inflammatory properties, which can help reduce airway inflammation and improve symptoms in conditions such as asthma. 
• Central nervous system stimulation: theophylline acts as a central nervous system stimulant, which can increase alertness and decrease fatigue. 
• Cardiovascular effects: theophylline has mild positive inotropic and chronotropic effects, meaning it can increase the force and rate of heart contractions. However, these effects are less pronounced compared to other medications used specifically for cardiovascular conditions. 

The spectrum of theophylline refers to the wide range of conditions. It is used to treat asthma, chronic bronchitis, and COPD. However, its use is becoming less common due to the availability of newer and more targeted medications with fewer side effects. theophylline may also be used in certain cases of apnea of prematurity, where it helps stimulate breathing in premature infants. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Peak serum concentration above 30 mcg/mL 

• Seizures 
• Acute myocardial infarction 
• Urinary retention 

Peak serum concentration below 20 mcg/mL 

• Diarrhea, vomiting, nausea 
• Exfoliative dermatitis 
• Tachycardia, flutter 
• Difficulty urinating 
• CNS excitement, insomnia, restlessness, headache, irritability, seizure 
• Diuresis 
• Skeletal muscle tremors 
• Hypercalcemia 

Black Box Warning

Black Box Warning: 

theophylline carries a black box warning due to the potential for serious and potentially life-threatening side effects, such as cardiac arrhythmias and seizures.

Close monitoring of blood levels is essential to maintain therapeutic levels while avoiding toxicity. Adverse effects can occur even within the therapeutic range, necessitating careful patient selection and monitoring. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

theophylline is contraindicated in individuals with a known hypersensitivity to the drug or its components. It should be avoided in patients with peptic ulcer disease, uncontrolled cardiac arrhythmias, severe hypotension, or recent myocardial infarction. Additionally, theophylline should not be used in patients with acute porphyria or during acute exacerbations of asthma or COPD.  

Caution: 

• Cardiac disorders: theophylline may cause or worsen cardiac arrhythmias, so caution is needed in patients with heart conditions such as arrhythmias, congestive heart failure, or ischemic heart disease. 
• Liver and kidney impairment: theophylline is primarily metabolized in liver and excreted by kidneys. Impaired liver or kidney function can affect the clearance of the drug, requiring dosage adjustments and careful monitoring. 
• Peptic ulcer disease: theophylline can increase gastric acid secretion, potentially exacerbating peptic ulcer disease. 
• Seizure disorders: theophylline can lower the seizure threshold, so caution is advised in patients with a history of seizures or epilepsy. 
• Thyroid disorders: theophylline may affect thyroid hormone levels, so caution is needed in patients with thyroid disorders, including hyperthyroidism or hypothyroidism. 
• Elderly patients: older adults may be more susceptible to the side effects of theophylline, including cardiac arrhythmias and central nervous system stimulation.

Comorbidities: 

• Cardiovascular disease: theophylline can stimulate the heart and may cause or worsen cardiac arrhythmias. Patients with pre-existing cardiovascular conditions such as arrhythmias, congestive heart failure, or coronary artery disease require careful monitoring. 
• Hypertension: theophylline can increase blood pressure. Patients with hypertension or uncontrolled high blood pressure should be monitored closely during theophylline therapy. 
• Liver disease: theophylline is primarily metabolized in the liver, and liver impairment can affect its clearance. 
• Kidney disease: theophylline is excreted by the kidneys, and impaired kidney function can lead to drug accumulation. Patients with kidney disease may require dosage adjustments and close monitoring of theophylline levels. 
• Peptic ulcer disease: theophylline can increase gastric acid secretion and may aggravate peptic ulcer disease. Caution is needed in patients with peptic ulcers or gastrointestinal bleeding. 
• Seizure disorders: theophylline can lower the seizure threshold and may increase the risk of seizures, especially at high doses. Patients with seizures or epilepsy should be closely monitored. 
• Thyroid disorders: theophylline can affect thyroid hormone levels, and caution is needed in patients with thyroid disorders such as hyperthyroidism or hypothyroidism. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: C 

Lactation: theophylline gets excreted into the human milk  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

theophylline is a methylxanthine derivative with multiple pharmacological effects. It acts as a nonselective phosphodiesterase inhibitor, leading to increased intracellular levels of cyclic adenosine monophosphate (cAMP). This results in bronchodilation, relaxation of smooth muscles, and anti-inflammatory effects in the respiratory system. 

theophylline also antagonizes adenosine receptors, which can lead to bronchodilation and increased cardiac contractility. It stimulates the central nervous system, promoting respiratory drive and reducing fatigue of the diaphragm. 

The pharmacological effects of theophylline include bronchodilation, increased mucociliary clearance, anti-inflammatory actions, and improved respiratory muscle strength.  

Pharmacodynamics: 

theophylline exerts its pharmacodynamic effects through multiple mechanisms of action. It acts as a nonselective phosphodiesterase inhibitor, preventing the breakdown of cyclic adenosine monophosphate (cAMP). This results in bronchial smooth muscle relaxation and bronchodilation, improving airflow in the lungs. 

theophylline also has central nervous system stimulant effects. It stimulates the medullary respiratory center, promoting increased respiratory drive and reducing fatigue of the diaphragm. It inhibits the release of inflammatory mediators, such as histamine and leukotrienes, and reduces the recruitment and activation of inflammatory cells, leading to decreased airway inflammation.  

Pharmacokinetics: 

Absorption 

theophylline is well-absorbed after oral administration, with peak plasma concentrations achieved within 1-2 hours. The absorption rate can be influenced by various factors, such as the formulation, food intake, and individual patient characteristics. 

Distribution 

Theophylline has a large volume of distribution, indicating its extensive distribution throughout body tissues. 

Metabolism 

theophylline undergoes hepatic metabolism primarily by the cytochrome P450 enzyme system, specifically the CYP1A2 isoenzyme. It is metabolized into several active metabolites, including 1,3-dimethyluric acid, 3-methylxanthine, and 1-methylxanthine. Genetic variations in CYP1A2 activity can affect theophylline metabolism. 

Elimination and excretion 

theophylline and its metabolites are primarily excreted in the urine. Renal clearance is an important factor in determining theophylline levels in the body. The elimination half-life of theophylline is influenced by factors such as age, liver function, and co-administration of other medications. 

Adminstartion

Administration: 

• Oral tablets or capsules: theophylline is commonly taken orally with water. It is important to follow dose instructions and take the medication with or after a meal to minimize stomach upset. 
• Intravenous (IV) infusion: In certain situations, such as in critical care settings or when oral administration is not possible, theophylline can be administered intravenously. This requires a healthcare professional to administer the medication directly into a vein. 
• Extended-release formulations: Extended-release formulations of theophylline are available, which provide a sustained release of the medication over a longer period. These formulations are typically taken once or twice daily, and it is important not to crush or chew these tablets as it may affect their release characteristics. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: theophylline 

Pronounced: [ thee-OFF-i-lin ]  

Why do we use theophylline? 

• Asthma: theophylline is used as a bronchodilator to relieve and prevent symptoms of asthma, such as wheezing, shortness of breath, and coughing. 
• Chronic obstructive pulmonary disease (COPD): theophylline can help improve breathing in individuals with COPD, including chronic bronchitis and emphysema. 
• Apnea of prematurity: theophylline may be used in premature infants to stimulate breathing and prevent apnea (pauses in breathing). 
• Chronic lung diseases: theophylline may be prescribed for other chronic lung conditions, such as bronchiectasis and interstitial lung diseases. 
• Exercise-induced bronchoconstriction: theophylline can be used to prevent exercise-induced bronchoconstriction in individuals who experience asthma symptoms during physical activity. 
• Pulmonary hypertension: theophylline may be used as an adjunct therapy for certain types of pulmonary hypertension.