DERIPHYLLIN RETARD 300

Indications

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Bronchospasm

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations in paediatric patients, as age and weight considerations are critical in determining appropriate dosages.

Adults: Refer to the BNF for specific dosing recommendations for adults, as dosing may vary based on the formulation and clinical scenario.

Mechanism of action

Etophylline acts primarily as a phosphodiesterase inhibitor, leading to an increase in intracellular cyclic AMP (cAMP) levels. Elevated cAMP results in relaxation of bronchial smooth muscle, bronchodilation, and improved airflow in the lungs. Additionally, etophylline has mild anti-inflammatory effects, which may contribute to its efficacy in treating respiratory conditions.

Pharmacodynamics

The pharmacodynamic profile of etophylline includes its ability to induce bronchodilation through smooth muscle relaxation, as well as its effects on the central nervous system, where it may exert mild stimulant effects. Etophylline has a narrow therapeutic window, and its effects can be influenced by factors such as plasma levels and co-administration with other drugs that affect hepatic metabolism.

Pharmacokinetics

Etophylline is absorbed rapidly following oral administration, with peak plasma concentrations typically reached within one to two hours. It is metabolized in the liver, primarily via cytochrome P450 enzymes, and is excreted mainly in the urine. The half-life of etophylline varies but is generally around 5 to 8 hours. Factors such as age, liver function, and concurrent medications can affect its pharmacokinetic profile.

Contra-indications

• Hypersensitivity to etophylline or any of its components
• Severe cardiac arrhythmias
• Uncontrolled hyperthyroidism
• Acute myocardial infarction

Adverse effects

• Nausea
• Vomiting
• Tachycardia
• Palpitations
• Headache
• Insomnia
• Nervousness
• Dizziness
• Gastrointestinal disturbances

Interactions

• May interact with other xanthine derivatives, leading to increased risk of toxicity
• Caution with concurrent use of medications that affect liver enzymes
• May enhance the effects of other stimulants

Precautions

• Use cautiously in patients with a history of peptic ulcer disease
• Monitor patients with cardiovascular disease closely during treatment
• Adjust doses in elderly patients and those with liver impairment

Pregnancy

Safety in pregnancy has not been established. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Use with caution in breastfeeding mothers. It is unknown whether etophylline is excreted in human milk.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Injectable solution

Indications

• Chronic asthma
• Severe acute asthma
• Chronic obstructive pulmonary disease (COPD)
• Reversible airways obstruction

Dosage

Children: For children aged 2–11 years, the recommended dosage

Adults: For adults, the typical dosage is 200 mg every 12 hours, which can be adjusted according to response, with a maximum of 400 mg every 12 hours for more severe symptoms.

Mechanism of action

Theophylline relaxes smooth muscle in the bronchial airways and pulmonary blood vessels, reducing airway responsiveness to histamine, methacholine, adenosine, and allergens. It inhibits phosphodiesterase types III and IV, leading to increased cyclic AMP levels in smooth muscle cells, promoting bronchodilation. Additionally, theophylline antagonizes adenosine A2B receptors, blocking adenosine-induced bronchoconstriction. It also activates histone deacetylase, reducing the transcription of inflammatory genes, thereby exerting anti-inflammatory effects.

Pharmacodynamics

Theophylline exhibits dual actions in patients with reversible airway obstruction: it promotes smooth muscle relaxation (bronchodilation) and suppresses the airway response to stimuli (non-bronchodilator prophylactic effects). The increase in cyclic AMP levels enhances airway smooth muscle relaxation and decreases inflammation, which are critical in managing asthma and other obstructive airway diseases.

Pharmacokinetics

Theophylline is primarily metabolized in the liver, and its plasma concentrations can be influenced by various factors, including smoking and liver function. The half-life of theophylline is variable, often longer in patients with liver impairment or heart failure. The therapeutic plasma concentration range is typically between 10-20 mg/L, with adverse effects becoming more frequent at levels above this range. Monitoring of plasma theophylline levels is recommended, especially after any dose adjustment.

Contra-indications

• Allergy to theophylline or any of its excipients
• Severe hepatic impairment
• Acute myocardial infarction
• Peptic ulcer disease

Adverse effects

• Nausea
• Vomiting
• Agitation
• Restlessness
• Dilated pupils
• Sinus tachycardia
• Hyperglycaemia
• Haematemesis
• Convulsions
• Supraventricular and ventricular arrhythmias
• Severe hypokalaemia

Interactions

• Stiripentol - Severe (increases exposure)
• Beta-blockers (selective) - Severe (increases risk of bronchospasm)
• Deferasirox - Severe (increases exposure)
• Roflumilast - Severe (increases exposure)
• Phosphodiesterase type inhibitors - Severe (increases exposure)
• Aciclovir - Moderate (increases exposure)
• Ritonavir - Moderate (decreases exposure)
• Leflunomide - Moderate (decreases exposure)
• Lithium - Moderate (decreases concentration)
• Mexiletine - Moderate (increases exposure)

Precautions

• Caution in patients with hepatic impairment due to risk of increased exposure
• Monitor plasma theophylline concentration regularly, especially after dose adjustments or in cases of smoking cessation or initiation
• Be aware of potential interactions with other medications

Pregnancy

Theophylline can be taken as normal during pregnancy, as it is important to maintain controlled asthma. However, neonatal irritability and apnoea have been reported.

Breast-feeding

Theophylline is present in breast milk and has been associated with irritability in infants; modified-release preparations are preferable. It can be taken as normal during breastfeeding.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Modified-release tablets
• Solution for injection
• Infusion solution
• Suppository

Mechanism of action

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. Theophylline is an old drug experiencing a renaissance owing to its beneficial antiinflammatory effects in chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Multiple modes of antiinflammatory action have been reported, including inhibition of the enzymes that degrade cAMP-phosphodiesterase (PDE). Using primary cultures of airway smooth muscle (ASM) cells, we recently revealed that PDE4 inhibitors can potentiate the antiinflammatory action of beta2-agonists by augmenting cAMP-dependent expression of the phosphatase that deactivates mitogen-activated protein kinase (MAPK)-MAPK phosphatase (MKP)-1. Therefore, the aim of this study was to address whether theophylline repressed cytokine production in a similar, PDE-dependent, MKP-1-mediated manner. Notably, theophylline did not potentiate cAMP release from ASM cells treated with the long-acting beta2-agonist formoterol. Moreover, theophylline (0.1-10 uM) did not increase formoterol-induced MKP-1 messenger RNA expression nor protein up-regulation, consistent with the lack of cAMP generation. However, theophylline (at 10 uM) was antiinflammatory and repressed secretion of the neutrophil chemoattractant cytokine IL-8, which is produced in response to TNF-a. Because theophylline's effects were independent of PDE4 inhibition or antiinflammatory MKP-1, we then wished to elucidate the novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase (PP) 2A, a master controller of multiple inflammatory signaling pathways, and show that theophylline increases TNF-a-induced PP2A activity in ASM cells. Confirmatory results were obtained in A549 lung epithelial cells. PP2A activators have beneficial effects in ex vivo and in vivo models of respiratory disease. Thus, our study is the first to link theophylline with PP2A activation as a novel mechanism to control respiratory inflammation. Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel. Lung deflation and inflation during cardiac surgery with cardiopulmonary bypass contributes to pulmonary dysfunction postoperatively. Theophylline treatment for lung diseases has traditionally been thought to act by phosphodiesterase inhibition; however, increasing evidence has suggested other plausible mechanism

Pharmacodynamics

Theophylline, an xanthine derivative chemically similar to caffeine and theobromine, is used to treat asthma and bronchospasm. Theophylline has two distinct actions in the airways of patients with reversible (asthmatic) obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects).