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TABLE 39.2 Adrenomimetics and Anticholinergics Used as Bronchodilators

Class

Agent

Trade name

Route a-, ß-Adrenoceptor agonists ß-Adrenoceptor agonists

Selective ß2-adrenoceptor agonists

Anticholinergics

Epinephrine

Isoproterenol Metaproterenol

Albuterol

Bitolterol Pirbuterol Salmeterol Terbutaline

Ipratropium bromide

Primatene Isuprel Mistometer Alupent

Proventil

Ventolin

Tornalate

Maxair

Serevent

Brethine

Brethine

Brethaire

Atrovent

Subcutaneous Inhalation Inhalation Oral

Inhalation Oral

Inhalation

Inhalation

Inhalation

Subcutaneous

Oral

Inhalation Inhalation buterol (Maxair). Metaproterenol (Alupent), another p-adrenomimetic used as a bronchodilator, is less selective for p2-adrenoceptors than is albuterol or terbu-taline.

Epinephrine administered subcutaneously is used to manage severe acute episodes of bronchospasm and status asthmaticus. In addition to its bronchodilator activity through p-adrenoceptor stimulation, a portion of the therapeutic utility of epinephrine in these acute settings may be due to a reduction in pulmonary edema as a result of pulmonary vasoconstriction, the latter effect resulting from a-adrenoceptor stimulation. The effects on pulmonary function are quite rapid, with peak effects occurring within 5 to 15 minutes. Measurable improvement in pulmonary function is maintained for up to 4 hours. The characteristic cardiovascular effects seen at therapeutic doses of epinephrine include increased heart rate, increased cardiac output, increased stroke volume, an elevation of systolic pressure and decrease in diastolic pressure, and a decrease in systemic vascular resistance. The cardiovascular response to epinephrine represents the algebraic sum of both a- and p-adrenoceptor stimulation. A decrease in diastolic blood pressure and a decrease in systemic vascular resistance are reflections of vasodilation, a p2-adrenoceptor response. The increase in heart rate and systolic pressure is the result of either a direct effect of epinephrine on the myocardium, primarily a pj effect, or a reflex action provoked by a decrease in peripheral resistance, mean arterial pressure, or both. Overt a-adrenoceptor effects, such as systemic vasoconstriction, are not obvious unless large doses are used.

Isoproterenol is administered almost exclusively by inhalation from metered-dose inhalers or from nebulizers. The response to inhaled isoproterenol and other inhaled adrenomimetics is instantaneous. The action of isoproterenol is short-lived, although an objective measurement of pulmonary function has shown an effective duration of up to 3 hours. When it is administered by inhalation, the cardiac effects of isoproterenol are relatively mild, although in some cases a substantial increase in heart rate occurs.

Terbutaline and albuterol are administered either orally or by inhalation, whereas salmeterol is given by inhalation only. All three agents are relatively selective for p2-adrenoceptors and theoretically are capable of producing bronchodilation with minimal cardiac stimulation. However, the term p2-selectivity is a pharmacological classification based primarily on the relative potency of an individual adrenomimetic to stimulate the pulmonary or the cardiovascular system. Indeed, p2-agonists invariably produce a degree of tachycardia at large doses, either by activating sympathetic reflex pathways as a consequence of systemic vasodilation or by directly stimulating cardiac pj-adrenoceptors. In addition, a significant number of p2-adrenoceptors are present in the human heart, and stimulation of these receptors may contribute to the cardiac effects of p2-adrenoceptor agonists.

Inhaled salmeterol has a pharmacological half-life in excess of 12 hours, much longer than either albuterol or terbutaline. The likely basis for this long half-life is that the long lipophilic tail of salmeterol promotes retention of the molecule in the cell membrane. Its long duration of action makes salmeterol particularly suitable for prophylactic use, such as in preventing nocturnal symptoms of asthma. Because of its relatively slow onset of action, salmeterol should not be used to treat acute symptoms.

The second messenger, cyclic adenosine monophosphate (cAMP), is thought to mediate the bronchodila-tor effects of the adrenomimetics. Adrenomimetics enhance the production of cAMP by activating adenylyl cyclase, the enzyme that converts adenosine triphosphate (ATP) to cAMP. This process is triggered by the interaction of the adrenomimetics with ¡2-adrenoceptors on airway smooth muscle.

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