Pharmacology

Theophylline and related products (T§ble..,167:l) have a complex mechanism of action that has not been entirely elucidated.4 Although traditional teaching is that theophylline acts by inhibiting the action of phosphodiesterase, the concentration required for effective in vivo inhibition far exceeds the concentration usually produced by clinical dosages. Others have suggested that theophylline may act by affecting the binding of cyclic adenosine monophosphate, cyclic glucose monophosphate phosphodiesterase inhibition, prostaglandin antagonism, modification of intracellular calcium, stimulation of catecholamine release, or adenosine antagonism. In addition to its bronchodilatory effect, theophylline affects both the immune and inflammatory mechanisms.5

Theophylline is readily absorbed after oral administration, with peak levels occurring 90 to 120 min after ingestion. Oral absorption is enhanced by fasting or ingestion of large volumes of fluid and is decreased following ingestion of certain foods. Enteric-coated tablets and sustained-released preparations reach peak plasma levels between 6 and 8 h. The newer, once-daily preparations have an erratic absorption rate, particularly after eating, which may lead to drug "dumping" (rapid absorption) and elevated theophylline levels. Peak levels are reached within 30 min after intravenous administration of aminophylline. The absorption of intramuscularly and rectally administered drug is erratic and unpredictable. Consequently, these routes should not be used.

Theophylline is approximately 60 percent protein bound, with less binding in neonates and patients with cirrhosis. The volume of distribution ranges from 0.3 to 0.7 L/kg, with an average of 0.5 L/kg. Theophylline is primarily (85 to 90 percent) eliminated by the hepatic P450 cytochrome system, and the remaining 10 to 15 percent is eliminated by urinary excretion. Metabolism generally follows first-order elimination. The half-life is 4 to 8 h in young, healthy, nonsmoking adults and shorter in children and smokers. Some authors have recommended a lowering of the target serum concentration from 20 to 15 pg/mL, since most bronchodilation occurs by that level.

A number of factors affect theophylline's half-life, including cigarette use, diet, cardiac and liver disease, and medications that interfere with the cytochrome P450

pathway (Table 167:2). Theophylline acts as an adenosine antagonist. It markedly inhibits the coronary vasodilating effects of adenosine and may interfere with the usefulness of pharmacologic stress tests. Theophylline has been reported to reverse adenosine-induced bronchoconstriction. Few studies have examined the effects of theophylline on the therapeutic use of adenosine to reverse supraventricular tachycardia. One study reported on the successful conversion from supraventricular tachycardia in two patients with therapeutic theophylline levels. A few case reports describe the use of adenosine in theophylline-induced arrythmias, but experience on which to base recommendations is inadequate.

Caffeine is probably the most commonly used drug in the world. It is readily absorbed after oral administration, with an onset of action of 30 min and peak effect at 60 to 120 min (T§b.!e,..167i3). Caffeine is also metabolized by demethylation in the liver, forming L-methyluric acid and L-methyl xanthine, the active agents. As with theophylline, about 10 percent of the drug is eliminated by urinary excretion. Many of the factors that affect the half-life of theophylline, such as severe liver disease, also affect that of caffeine.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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