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The mechanism of action of theophylline as a broncholytic is unknown. However, some hypotheses are based on its structural similarity to adenosine and 31,51-cyclic adenosinemonophosphate.

Adenosine is an endogenic mediator that, reacting with membrane receptors, can cause bronchial contractions. Theophylline inhibits this reaction, thus preventing substrate-receptor reactions of bronchospasms caused therein.

It is believed that theophylline can inhibit phosphodiesterase, which in turn can lead to elevated levels of cellular cyclic adenosine monophosphate, and subsequently, to the weakening of smooth musculature of the respiratory tract. However, theophylline is not a powerful phosphodiesterase inhibitor, and the necessary concentrations for this cannot be achieved in vivo.

On the other hand, theophylline inhibits reverse uptake catecholamine uptake, which can elevate the level of cyclic adenosine monophosphate, thus causing a broncholytic effect. Finally, theophylline is an adenosine receptor blocker, and this may be responsible for its broncholytic effect.

Despite the fact that the last mechanism may be basic for theophylline, a few xanthines, which in general lack the ability to bind with adenosine receptors, express the same, if not more broncholytic activity than theophylline.

Theophylline and other methylxanthines also display a pharmacological effect on a number of other organ systems. Of course the most pronounced effect is relaxation of smooth musculature in the respiratory tract. However, theophylline is a CNS stimulant, and it lowers arterial blood pressure, increases diuresis, displays cardiotonic activity, and has a specific effect on the gastrointestinal tract. The effects listed are the most frequently encountered side effects upon taking theophylline as a broncholytic.

Action on the CNS depends directly on the dose of administered drug, and can be manifested as fatigue, anxiety, tremors, and even convulsions in relatively high doses. Theophylline acts on the cardiovascular system by displaying positive ionotropic and chronotropic effects on the heart, which, can likely be linked to the elevated influx of calcium ions by modulated cyclic adenosine monophosphate and its action on specific cardiac phosphodiesterases. In the gastrointestinal system, methylxanthines simultaneously stimulate secretion of both gastric juice and digestive enzymes.

Theophylline reduces contractile activity of smooth musculature, widens bronchi and blood vessels, reduces pulmonary vascular resistance, stimulates the respiratory center, and increases the frequency and power of cardiac contractions. It is used for bronchial asthma, preventing attacks, and systematic treatment. Theophylline is also used for symptomatic treatment of bronchospastic syndrome of a different etiology (chronic obstructive pulmonary disease, chronic bronchitis, and pulmonary emphysema). A large number of combined drugs are based on theophylline. Synonyms of theophylline are adophyllin, asthmophyllin, theocin, and many others.

23.3.2 Anticholinergic drugs

Cholinergic drugs, in particular atropine (14.1.4) or scopolamine (14.1.6), have been used for centuries to treat obstructive pulmonary diseases. By inhibiting the action of acetyl-choline on smooth musculature of the respiratory system, anticholinergic drugs prevent bronchospasms resulting from vagus nerve discharge. However, they have an effect on many tissues and systems, and consequently exhibit a wide range of side effects. Currently, they are rarely used to treat coughs that result from certain irritants. However, a quaternary derivative of atropine, ipratropium bromide, is frequently used for chronic bronchitis, pulmonary emphysema, and asthma.

Ipratropium bromide: Ipratropium bromide, 3a-hydroxy-8-isopropyl-1a#,5a#-tropa-nium bromide (23.3.6), is synthesized by reacting N-isopropylnoratropine with methyl bromide [18-20].

This drug exhibits broncholytic action by reducing cholinergic influence on bronchial musculature (m-cholinoblocking action). It relieves bronchial spasms. It is used to treat and prevent minor and moderate bronchial asthma, especially asthma that is accompanied by cardiovascular system diseases. Synonyms of this drug are atrovent, introp, iprafen, and others.

23.3.3 Inhibitors of allergy mediator release

Allergy mediators (histamine, leukotrienes, and others) take part in the formation of bron-chospasms. By blocking allergy mediator release in allergic subjects, a few drugs, in particular cromolyn, are a prototype of drugs of this kind, and they block both early and late phases of reactions in the organism in response to exposure to allergens. These drugs do not have bronchodilating properties; however, they inhibit bronchospasms caused by antigens or for other reasons.

Cromolyn: Cromolyn, 5,5'[(2-hydroxytrimethylen)dioxy] bis 4-oxo-4H-1-benzopiran-2-carboxylic acid (23.3.9), are synthesized by reacting 2,6-dihydroxyacetophenone with epichlorohydrine, during which the chlorine atom in epichlorohydrine is replaced and an opening of the epoxide ring takes place, resulting in a bis-product 23.3.7. Cyclization of this product into a bis-derivative 23.3.8 is accomplished using diethyloxalate, subsequent alkaline hydrolysis of the ester groups of which gives the desired cromolyn (23.3.9) [21-23].

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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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