P-adrenoceptor agonists

Isoproterenol. Isoproterenol hydrochloride is an nonselective P-adrenoceptor agonist that is chemically related to NE. It mimics the effects of stimulation of the sympathetic innervation to the heart which are mediated by NE. It increases heart rate by increasing automaticity of the SA and AV nodes by increasing the rate of phase 4 diastoHc depolarization. It is used in the treatment of acute heart block and supraventricular bradyarrhythmias, although use of atropine is safer for bradyarrhythmias foUowing MI (86). 

FIGURE 2.4 Occupancy-response curves for P-adrenoceptor agonists in transfected CHO cells. Occupancy (abscissae) calculated from binding affinity measured by displacement of [125I]iodocyanopindolol. Response measured as increases in cyclic AMP. Drawn from [3],... 

FIGURE 4.19 Correlation of the GTP shift for P-adrenoceptor agonists in turkey erythocytes (ordinates) and intrinsic activity of the agonists in functional studies (abscissae). Data redrawn from [16]. 

Figure 3.4 Transmembrane topology of a 7-TM domain G-protein receptor such as the P-adrenoceptor. Agonist binding is predicted to be within the transmembrane domains. The extracellular structure is stabilised by the disulphide bond joining the first and second extracellular loop. The third intracellular loop is the main site of G-protein interaction while the third intracellular loop and carboxy tail are targets for phosphorylation by kinases responsible for initiating receptor desensitisation...

FIGURE 7.15 Time-course of the increases in amplitude of the calcium current recorded from bullfrog atrial trabeculae following (A) rapid application of the p-adrenoceptor agonist isoprenaline (3 pM), and (B) rapid intracellular release of cAMP by flash-photolysis of o-nitrobenzyl cAMP. Applications/flashes were made at time zero. (From Nargeot et al., Proc. Natl. Acad. Sci. USA, 80, 2395-2399, 1983. With permission.)... 

Methacholine is used to identify bronchial hyperreactivity in patients without clinically apparent asthma. For this indication, the drug is administered by inhalation, and patients who may be developing asthma usually produce an exaggerated airway contraction. Upon completion of the test, a rapid-acting bronchodilator (e.g., inhaled p-adrenoceptor agonist) can be given to counter the bronchoconstrictor effect of methacholine and relieve the patient s discomfort. 

P-Adrenoceptor agonists Isoproterenol Metaproterenol Isuprel Mistometer Alupent Inhalation Oral Inhalation... 

A few epidemiological studies suggest that the overuse of p-adrenoceptor agonists is associated with an overall deterioration in disease control and a slight increase 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 antiinflammatory therapy to control the underlying disease process. 

Which one of the following p-adrenoceptor agonists has such a slow onset of action that it is not indicated for the relief of acute asthma symptoms ... 

E. Malta, G. A. McPherson, C. Raper (1985). Selective P,-adrenoceptor agonists—fact or fiction Trends Pharmacol. Sci. 6 400403. 

Dobutamine is a directly acting synthetic catecholamine with predominant effects at pi receptors. It has weak 32 and a effects. It is a racemic mixture and both stereoisomers are p-adrenoceptor agonists. The (+) isomer is approximately ten times more potent as a p-receptor agonist than the (-) isomer, which is mainly responsible for the o-adrenoceptor activity. Unlike dopamine, dobutamine does not act by releasing noradrenaline or via dopaminergic receptors. 

Similarly, De Mello [1989] reported on an improvement in intercellular coupling by the P-adrenoceptor agonist isoproterenol in cardiac cell pairs. Thus, stimulation of P-adrenoceptors can be assumed to result in enhancement of intercellular coupling, at least in some preparations. However, on the basis of the hndings of Kwak and Jongsma [1996] on a lack of the effect of PKA to alter gap junction conductance in rat cardiomyocytes, caution seems necessary and species variability or tissue variability seems to play an important role. 

Propranolol P-adrenoceptor agonists, ephedrine, theophylline, thyroxine... 

Down-regulation and the accompanying receptor changes may explain the tolerant or refractory state seen in severe asthmatics who no longer respond to P-adrenoceptor agonists. 

Response to p-adrenoceptor agonists and antagonists appears to be blunted in old age partly, it is believed, through reduction in the number of receptors. 

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. 

Salbutamol, fenoterol, rimiterol, reproterol, pir-buterol, salmeterol, ritodrine and terbutaline are P-adrenoceptor agonists that are relatively selective for p2-receptors, so that cardiac (chiefly p -receptor) effects are less prominent. Tachycardia still occurs because of atrial (sinus node) p -receptor stimulation the P2-adrenoceptors are less numerous in the ventricle and there is probably less risk of serious ventricular arrhythmias than with the use of nonselective catecholamines. The synthetic agonists are also longer-acting than isoprenaline because they are not substrates for catechol-O-methyltransferase, which methylates catecholamines in the liver. They are used principally in asthma, and to reduce uterine contractions in premature labour. 

If there is no response, i.v. injection or infusion of a P-adrenoceptor agonist is used, e.g. isoprenaline (4 micrograms/min, increasing at 1-3-min intervals until the heart rate is... 

Isoprenaline (isoprotenerol), a p-adrenoceptor agonist, can be used to accelerate the heart when there is extreme bradycardia due to heart block, prior to the insertion of an implanted pacemaker this is now rarely needed. Adverse effects are those expected of P-adrenoceptor agonists and include tremor, flushing, sweating, palpitation, headache and diarrhoea. 

The use of permanent pacemakers is beyond the scope of this book. In an emergency, AV conduction may be improved by atropine (antimuscarinic vagal block) (0.6 mg i.v.) or by isoprenaline (p-adrenoceptor agonist) (0.5-10 micrograms/min, i.v.). Temporary pacing wires may be needed prior to referral for pacemaker implantation. 

Hypokalaemia may be aggravated by other drugs, e.g. P -adrenoceptor agonists, theophylline, corticosteroids, eunphoteiicin. 

Some patients develop wheeze that regularly follows within a few minutes of exercise. A similar response occurs following the inhalation of cold air since the common mechanism appears to be airway drying. Inhalation of a p -adrenoceptor agonist, sodium cromoglicate (see below) or one of the newer leukotriene receptor antagonists (see below) prior to either challenge prevents broncho-constriction. 

Give nebulised P -adrenoceptor agonist more frequently, up to every 15-30 minutes... 

Premature labour use of P -adrenoceptor agonists and of dexamethasone (to prevent respiratory distress syndrome in the prematurely newborn) causes hyperglycaemia and increased insulin (and potassium) need. 

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