Pj-Adrenoceptor agonists

Terbutaline and albuterol are relatively selective Pj-adrenoceptor agonists. Both have a longer duration of action than isoproterenol because they are not metabolized by COMT. Like isoproterenol, they are not metabolized by MAO and are not transported into adrenergic neurons. Terbutaline and albuterol are effectively administered either orally or subcutaneously. Because of their selectivity for Pj-adrenoceptors, they produce less cardiac stimulation than does isoproterenol but are not completely without effects on the heart. 

Terbutaline, albuterol, salmeterol and other Pj-adrenoceptor agonists are used primarily in the management of asthma. Terbutaline and albuterol have very rapid onset of action and are indicated for acute symptom rehef 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. 

Dobutamine is a racemic mixture of d- and 1-dobutamine. The racemate behaves primarily a pj-adrenoceptor agonist with greater inotropic than chronotropic effects on the heart it has some a-agonist effect, but less than dopamine. It is useful in shock (with dopamine) and in low output heart failure (in the absence of severe h5 ertension). 

Pj-adrenoceptor agonists. The predominant adrenoceptors in bronchi are of the type and their stimulation causes bronchial muscle to relax. adrenoceptor activation also stabilises mast cells. Agonists in widespread use include salbutamol, terbutaline, fenoterol, eformoterol and salmeterol, and are discussed in Chapter 22. Salmeterol is longer-... 

Pj-adrenoceptor agonists relax the uterus and are given by i.v. infusion by obstetricians to inhibit premature labour, e.g. isoxsuprine, terbutaline, ritodrine, salbutamol. Their use is complicated by the expected cardiovascular effects, including tachycardia, hypotension. Less easy to explain, but more devastating on occasion to the patient, is severe left ventricular failure. Possibly the combination of fluid overload (due to the vehicle) and increased oxygen demand by the heart are factors. 

Epinephrine activates all adrenoceptors, whereas norepinephrine has minimal agonist activity at [J -adrenoceptors. This difference is important in anaphylaxis because adrenoceptor activation is needed to provide a bronchodilatory effect that will oppose the anaphylaxis-induced airway obstruction. The aj-adrenoceptor agonist effect of epinephrine opposes the anaphylaxis-induced vasodilation and, to some extent, the vascular leak (administration of fluid is also a cornerstone of the treatment of anaphylaxis), while the Pj-adrenoceptor agonist effect helps maintain cardiac output. 

Ipratropium has greater effectiveness than P2-adreno-ceptor agonists in two settings in psychogenic asthma and in patients taking Pj-adrenoceptor antagonists. A fixed combination of ipratropium and albuterol (Combivent) is approved for use in chronic obstructive pulmonary disease. 

Terbutaline (Brethine, Bricanyl) is a relatively specific P2-adrenoceptor agonist (see Chapters 10 and 39). Terbutaline can prevent premature labor, especially in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate Pj-adrenoceptors. While it appears to be especially selective for P2-receptor activation, terbutaUne does have some Pi activity as well. 

Bond, R.A., Leff, P., Johnson, T.D., Milano, C.A., Rockman, H.A., McMinn, T.R., Apparsundaram, S., Hyek, M.F., Kenakin, T.P., and Allen, L.F. 1995. Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the Pj-adrenoceptor. Nature 374 272-276. 

Adrenergic mechanisms have a role in the physiological control of plasma potassium concentration. The biochemical pump that shifts potassium into cells is activated by the P -adrenoceptor agonists (adrenaline, salbutamol, isoprenaline) and can cause hypokalaemia. Pj-adrenoceptor antagonists block the effect. 

Pj-selective agonists are used for the relief of acute bronchoconstriction and as a prophylaxis in exercise-induced asthma. Longer-acting p-adrenoceptor agonists can be used prophylactically to decrease nighttime attacks. The mechanisms responsible for their effects are shown in Figure Vl-8-1, which illustrates the action of antiasthmatic drugs. 

It was confirmed experimentally on a1B-adrenoceptor and Gn that GPCRs are able to bind Ga and G independently and interactions with G contribute considerably to the ability of agonists to activate alpha subunit of G protein. Studies on leukotriene B4 BLT1 receptor and a G protein consisted of ai2, Pj and y2 subunits also provided evidence for a pentameric complex involving two GPCRs and a trimeric G protein.23... 

Dopexamine is a synthetic catecholamine whose principal action is as an agonist for the cardiac P -adrenoceptors (positive inotropic effect). It is also a weak dopamine agonist (thus causing renal vasodilatation) and inhibitor of noradrenaline uptake thereby enhancing stimulation of cardiac Pj-receptors by noradrenaline. It is used occasionally to optimise the cardiac output, particularly perioperatively. 

Quick relief can be obtained with a p-adrenoceptor blocking drug (judge dose by heart rate) though these do not block all the metabolic effects of the hormone, e.g. on the myocardium, and the basal metabolic rate is unchanged. For this reason they should not be used as sole therapy except in mild thyrotoxicosis in preparation for radioiodine treatment, and should be continued in these patients until the radioiodine has taken effect. They do not alter the course of the disease, nor biochemical tests of thyroid function. Any effect on thyroid hormonal action on peripheral tissues is clinically unimportant. It is desirable to choose a drug that is nonselective for pj and p2 receptors and lacks partial agonist effect (e.g. propranolol 20-80 mg 6-8-hourly, or timolol 5 mg once daily). Usual contraindications to P-blockade (see p. 478) should be observed, especially asthma. 

Norepinephrine is a naturally occurring adrenergic agonist, with a, pj and weak P2 adrenoceptor activity. Its primary action is to cause vasoconstriction and administration of norepinephrine (noradrenaline) has, therefore, been advocated for the treatment of cardiogenic shock in human patients that do not respond to dopamine or dobutamine (Anon. 1999). Cardiac contractility increases as a result of the Pi adrenoceptor action. Initial concerns about the effects of norepinephrine (noradrenaline) on renal blood flow prevented its acceptance in the human critical care setting. Renal blood flow is reduced in normal dogs after the administration of norepinephrine (noradrenaline)... 

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