Theophylline in broncial asthma. By:Heba Othman Essam El-Din Pharm –D4(2009).

Preperations: 1-Theophylline (anhydrous) is available as oral solution, immediate release and extended release tablets and a premixwd solution in D5% for IV injection. 2- Aminophylline is a water soluble form of theophylline Aminophylline (hydrous) is available as tablets, oral solution and injection. 3- Piperazine theophylline is a salt of theophylline as tablets,oral solution ang injection. 4-Dyphylline and Acefylline. ( are structurally and pharmacologically compounds similar to theophylline ). -Doses are expressed in terms of anhydrous theophylline. Anhydrous theophylline 1 mg is approximately equivalent to 1.17 mg anhydrous aminophylline or 1.27 mg aminophylline hydrate.)

The use in bronchial asthma 1- An additive maintenance therapy in patients whose asthma is not adequately controlled with high doses of inhaled corticosteroids or who have significant side effects of corticosteroids. -Addition of theophylline improves pulmonary function and control symptoms better than increasing the dose of inhaled corticosteroids.

A systematic review of trials that compared addition of theophylline with addition of long acting beta 2 agonists found that they were both effective for control of nocturnal asthma, but that long-acting beta 2 agonists may be more effective in reducing asthma symptoms, and are associated with fewer adverse effects. - Studies compared addition of theophylline with addition of montelukast found that theophylline improves asthma symptoms better than montelukast but with more adverse effects.

2- An initial maintenance therapy in patients who are more likely to adhere to an oral than inhaled regimens. 3- An initial maintenance therapy when administration of inhaled corticosteroids is difficult in some cases as in young children. 4- In acute exacerbation of asthma when the optimum response can not be achieved by other medications.

It is not a prefered alternative in maintenance therapy due to its side effects and the need of theraputic drug monitoring TDM) but it has a low cost over the other long term maintenance medications.

Mechanism of action: - Through the inhibition of phosphodiesterase enzyme, it increases intracellular concentration of cAMP causing a relaxation in the smooth muscles ( bronchodilator effect). -It has an anti inflammatory and immunomodulatory effects. -In patients with allergic asthma it attenuates the late phase increase in airway obstruction and airway responsiveness to histamine and reduces allergen induced migration of activated eosinophils into bronchial mucosa.

Absorption: - The rate and extent of absorption differs between different dosage forms and even between different products of the same dosage forms (unless bioequivalents),so the patient should be stabilized on one preperation. -Oral tablets reach peak conc. In 1-2 hrs. IV in 30 mins. Extended realese tabs in 4 hrs

- For fast oral absorption,oral forms may be administered one hour before or two hrs after meals but if gastrointestinal irrigation occurs, administer with food. -Extended release formulations are useful in patients with continous or frequentlly recurring symptoms, they allow longer dose interval, better compliance and less variation in TDM). - IM administration : irritating and not recommended. -IV administration : by slow IV infusion.

Clearance: -Theophylline is metabolised in the liver, -The elimination of theophylline is dose-dependent and that at high serum concentrations, a small change in dose of a theophylline preparation could cause a disproportionate increase in serum-theophylline concentration (zero order kinetics). -Hepatic metabolism is further affected by factors such as age, smoking, disease and drug interactions. -Total body clearance increases in smokers than non smokers (smokers usually need higher dose). -Total body clearance decreases in patients with hepatic impairment and CHF. (usually need lower dose).

Adverse effects: CNS stimulation: headache, insomnia,irritability and even seizures. CVS: tachycardia,palpitations and hypotension. GIT: abdominal pain,nausea and vomiting. Rapid IV injection may cause palpitations, flushing,bradycardia and hypotension.

Interactions: - Theophylline clearance may be reduced by allopurinol, some antiarrhythmics, cimetidine, disulfiram, fluvoxamine, interferon alfa, macrolide antibacterials and quinolones, oral contraceptives, tiabendazole, and viloxazine, necessitating dosage reduction. -Theophylline clearance may be increased by phenytoin and some other antiepileptics, ritonavir, rifampicin, and sulfinpyrazone, necessitating an increase in dose or dosing frequency. -Theophylline administration with ephedrine or other sympathiomimetics may cause cardiac arrythmias. -Theophylline may increase the excretion of lithium,so lithium dose should be adjusted.

Doses: - Doses are expressed in terms of anhydrous theophylline. - Doses depend on TDM, response and tolerance. -IV doses (in acute exacerbation): Loading: 4.6 mg/kg body weight over 30 mins if the patient is not on theophylline therapy. -If the patient was on theophylline therapy before hospitalization, measure theophylline serum level to calculate the dose. -Maintenance dose range from mg/kg/hr in neonates to 0.4 mg/kg/hr in adults.

- Oral doses (for chronic bronchospasm): -Adult doses: start with 300 mg daily for conventional dosage forms the divided doses are generally given every 6 to 8 hours,increase after 3 days to 400 mg if needed and after another 3 days to 600 mg if needed. -Children: mg/kg given every 6 to 8 hours, increase after 3 days if needed. -For long-term administration, once a maintenance dose has been established, monitoring of serum-theophylline concentrations at 6- to 12-monthly intervals has been recommended.

Therapeutic drug monitoring -The generally accepted optimal serum concentration is between 10 and 20 micrograms/mL -Serum-theophylline concentrations are influenced by various factors including disease states, concurrent medication, diet, smoking, and age. -Serious toxicity is related to serum concentration and may not be preceded by minor symptoms. So it is recommended that theophylline concentrations should be monitored.

Thank You