Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Asthma

Adrenomimetic Agents

Adrenergic drugs (Table 39.2) used for the manage-ment of acute and chronic asthma are epinephrine (Primatene), isoproterenol (Isuprel), and a group of adrenoceptor agonists, including albuterol (Proventil, Ventolin, Salbutamol), terbutaline (Brethine, Brethaire), and salmeterol (Serevent), that are relatively selective for β2-adrenoceptors .

Adrenomimetic Agents


Adrenergic drugs (Table 39.2) used for the manage-ment of acute and chronic asthma are epinephrine (Primatene), isoproterenol (Isuprel), and a group of adrenoceptor agonists, including albuterol (Proventil, Ventolin, Salbutamol), terbutaline (Brethine, Brethaire), and salmeterol (Serevent), that are relatively selective for β2-adrenoceptors . This class of agents has become the mainstay of modern bronchodila-tor therapy. These agents are used both as needed to re-verse acute episodes of bronchospasm and prophylacti-cally to maintain airway patency over the long term.


Basic Pharmacology


The principal pharmacological effects that may be observed in hu-mans treated for bronchospasm are bronchodilation, tachycardia, anxiety, and tremor. Stimulating β2-adreno-ceptors produces all of these effects either directly or indirectly.


Epinephrine activates both α - and β-adrenoceptors, whereas isoproterenol is selective for  β-adrenoceptors but does not discriminate between β1- and β2-adreno-ceptors. Much-improved selectivity is offered by agents such as albuterol, terbutaline, and salmeterol. These compounds have a higher affinity for β2-adrenoceptors, the predominant subtype in the airway, than for β1-adrenoceptors. Other β2-selective adrenomimetics used as bronchodilators are bitolterol (Tornalate) and pirbuterol (Maxair). Metaproterenol (Alupent), another - adrenomimetic used as a bronchodilator, is less selec-tive for β2-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 ac-tivity through β-adrenoceptor stimulation, a portion of the therapeutic utility of epinephrine in these acute set-tings may be due to a reduction in pulmonary edema as a result of pulmonary vasoconstriction, the latter effect resulting from α-adrenoceptor stimulation. The effects on pulmonary function are quite rapid, with peak ef-fects occurring within 5 to 15 minutes. Measurable im-provement 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 α - and β-adreno-ceptor stimulation. A decrease in diastolic blood pres-sure and a decrease in systemic vascular resistance are reflections of vasodilation, a β2-adrenoceptor response. The increase in heart rate and systolic pressure is the re-sult of either a direct effect of epinephrine on the myo-cardium, primarily a 1 effect, or a reflex action pro-voked by a decrease in peripheral resistance, mean arterial pressure, or both. Overt α-adrenoceptor effects, such as systemic vasoconstriction, are not obvious un-less large doses are used.


Isoproterenol is administered almost exclusively by inhalation from metered-dose inhalers or from nebuliz-ers. The response to inhaled isoproterenol and other in-haled adrenomimetics is instantaneous. The action of isoproterenol is short-lived, although an objective measurement of pulmonary function has shown an ef-fective duration of up to 3 hours. When it is adminis-tered 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 β2-adrenoceptors and theoretically are capable of producing bronchodilation with minimal cardiac stimu-lation. However, the term 2-selectivity is a pharmaco-logical classification based primarily on the relative po-tency of an individual adrenomimetic to stimulate the pulmonary or the cardiovascular system. Indeed, β2-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 β1-adrenoceptors. In ad-dition, a significant number of β2-adrenoceptors are present in the human heart, and stimulation of these re-ceptors may contribute to the cardiac effects of β2-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 pro-phylactic 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 monophos-phate (cAMP), is thought to mediate the bronchodila-tor effects of the adrenomimetics. Adrenomimetics en-hance the production of cAMP by activating adenylyl cyclase, the enzyme that converts adenosine triphos-phate (ATP) to cAMP. This process is triggered by the interaction of the adrenomimetics with β2-adrenoceptors on airway smooth muscle.


Clinical Uses


Epinephrine is used in a variety of clinical situations, and although concern has been expressed about the use of epinephrine in asthma, it is still used extensively for the management of acute attacks.


Isoproterenol is used principally by inhalation for the management of bronchospasm. It is also used intra-venously for asthma and as a stimulant in cardiac arrest.


Terbutaline, albuterol, salmeterol and other β2-adrenoceptor agonists are used primarily in the man-agement of asthma. Terbutaline and albuterol have very rapid onset of action and are indicated for acute symp-tom relief. Salmeterol, in contrast, has a slow onset of action but a long duration of action. Salmeterol is thus used as prophylactic therapy only, not to reverse acute symptoms.


In addition to its use as a bronchodilator, terbutaline is used extensively to control premature labor, since contractions of uterine smooth muscle are abolished by adrenomimetics .


Adverse Effects


Patients treated with recommended dosages of epi-nephrine will complain of feeling nervous or anxious. Some will have tremor of the hand or upper extremity and many will complain of palpitations. Epinephrine is dangerous if recommended dosages are exceeded or if the drug is used in patients with coronary artery disease, arrhythmias, or hypertension. The inappropriate use of epinephrine has resulted in extreme hypertension and cerebrovascular accidents, pulmonary edema, angina, and ventricular arrhythmias, including ventricular fibril-lation.


At recommended dosages, adverse effects from in-haled isoproterenol are infrequent and not serious. When excessive dosages are used, tachycardia, dizzi-ness, and nervousness may occur, and some patients may have arrhythmias.


The limiting side effect associated with orally ad-ministered β2-adrenoceptor agonists is muscle tremor, which results from a direct stimulation of β2-adreno-ceptors in skeletal muscle. This effect is most notable on the initiation of therapy and gradually improves on con-tinued use. β2-Agonists also cause tachycardia and pal-pitations in some patients. When used by intravenous infusion for premature labor, β2-agonists have been reported to produce tachycardia and pulmonary edema in the mother and hypoglycemia in the baby. When ad-ministered by inhalation, the β2-agonists produce only minor side effects.


A few epidemiological studies suggest that the over-use of β-adrenoceptor agonists is associated with an overall deterioration in disease control and a slight in-crease in asthma mortality. This apparent trend may be caused by several factors, the most likely of which is that patients rely too heavily on bronchodilator therapy to control acute symptoms at the expense of antiinflam-matory therapy to control the underlying disease process.


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