ZATHIN TABLETS

Indications

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

Dosage

Children: For children, the dosage varies based on age and weight, typically ranging from 5-10 mg/kg/day. For specific dosing, please refer to the BNF for Children.

Adults: The usual maintenance dose for adults is 200-600 mg daily, adjusted based on serum theophylline levels and clinical response.

Mechanism of action

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels while reducing airway responsiveness to histamine, methacholine, adenosine, and allergens. It competitively inhibits type III and type IV phosphodiesterase (PDE), which breaks down cyclic AMP in smooth muscle cells, leading to bronchodilation. Theophylline also binds to the adenosine A2B receptor, blocking adenosine-mediated bronchoconstriction. Additionally, it activates histone deacetylase to prevent the transcription of inflammatory genes, enhancing its anti-inflammatory properties in chronic respiratory diseases.

Pharmacodynamics

Theophylline has dual actions in patients with reversible airway obstruction: it promotes smooth muscle relaxation (bronchodilation) and suppresses airway responses to various stimuli (non-bronchodilator effects). As an xanthine derivative, it shares structural similarities with caffeine and theobromine, contributing to its pharmacological profile.

Pharmacokinetics

Theophylline is absorbed quickly from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1-2 hours after oral administration. It is metabolized primarily in the liver, and its elimination half-life can vary widely based on factors such as age, liver function, and the presence of other medications. Theophylline is excreted mainly in urine as metabolites, with a small fraction excreted unchanged.

Contra-indications

• Hypersensitivity to theophylline or any ingredient in the formulation
• Severe peptic ulcer disease
• Uncontrolled seizure disorders
• Acute myocardial infarction

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Tachycardia
• Palpitations
• Headache
• Insomnia
• Nervousness
• Restlessness
• Seizures

Interactions

• Other xanthine derivatives may increase the risk of toxicity
• Certain antibiotics (e.g., erythromycin, ciprofloxacin) may increase theophylline levels
• Cimetidine may increase theophylline concentrations
• Phenobarbital and phenytoin may decrease theophylline effectiveness
• Smoking may reduce the effectiveness of theophylline

Precautions

• Use with caution in patients with cardiovascular disease
• Monitor for signs of theophylline toxicity, especially in the elderly
• Adjust dose in patients with liver impairment
• Consider renal function when dosing

Pregnancy

Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution is advised.

Breast-feeding

Theophylline is excreted in breast milk. Caution should be exercised when administering to breastfeeding women.

Storage

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

Formulations

• Tablets
• Extended-release tablets
• Oral solution
• Injectable solution

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).