Pharmacology Of Theophylline

Indication	For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis.
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).
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.
Absorption	Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.
Volume of distribution	0.3 to 0.7 L/kg
Protein binding	40%, primarily to albumin.
Metabolism	Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity.
Route of elimination	Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.
Half life	8 hours
Clearance	0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days] 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days] 1.7 mL/kg/min [Children 1-4 years] 1.6 mL/kg/min [Children 4-12 years] 0.9 mL/kg/min [Children 13-15 years] 1.4 mL/kg/min [Children 16-17 years] 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease cirrhosis] 0.35 mL/kg/min [acute hepatitis] 0.65 mL/kg/min [cholestasis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid]
Toxicity	Symptoms of overdose include seizures, arrhythmias, and GI effects.