Isoproterenol for

Describe the problems with aerosol inhalers (e.g., isoproterenol) for asthma. 

A. Do not use isoproterenol for ventricular fibrillation or ventricular tachycardia (other than torsade de pointes). 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

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). 

The use of selective P-antagonists for treatment of CHF has included the P -blocker metoprolol (Table 1) and results of clinical trials suggest long-term beneficial effects. Selective P -antagonists have also been tested, an example of which is xamoterol [81801 -12-9], C2 H25N20, which is (i)-A/-(2-hydroxy-3-(4-hydroxyphenoxy)propylamino)ethylmorphine-4-carboxamide. Xamoterol exhibits approximately 50% of the activity of isoproterenol, and serves to provide modest inotropic effects (128,129). 

FIGURE 2.18 Inotropic and lusitropic responses of guinea pig left atria to (3-adrenoceptor stimulation. Panels A to C isometric tension waveforms of cardiac contraction (ordinates are mg tension abscissae are msec), (a) Effect of 0.3 nM isoproterenol on the waveform. The wave is shortened due to an increase in the rate of diastolic relaxation, whereas no inotropic response (change in peak tension) is observed at this concentration, (b) A further shortening of waveform duration (lusitropic response) is observed with 3 nM isoproterenol. This is concomitant with positive inotropic response (increase maximal tension), (c) This trend continues with 100 nM isoproterenol, (d) Dose-response curves for ino tropy (filled circles) and lusitropy (open circles) in guinea pig atria for isoproterenol, (e) Dose-response curves for inotropy (filled circles) and lusitropy (open circles) in guinea pig atria for the P-adrenoceptor partial agonist prenalterol. Data redrawn from [6]. 

FIGURE 9.21 Changes in heart rate (ordinates) for agonist-induced changes in cardiac inotropy (changes in rate of ventricular pressure) in anesthetized cats. Responses shown to isoproterenol (filled circles) and dobutamine (open circles), (a) Response in normal cats shows inotropic selectivity (less tachycardia for given changes in inotropy) for dobutamine over isoproterenol, (b) The inotropic selectivity of dobutamine is reduced by previous a-adrenoceptor blockade by phentolamine. From [61],... 

Alternatively, a continuous magnesium infusion may be initiated after the first bolus, at a rate of 0.5 to 1 g/hour. Alternative treatments include transvenous insertion of a temporary pacemaker for overdrive pacing, which shortens the QT interval and may terminate torsades de pointes intravenous isoproterenol 2 to 10 mcg/minute, to increase the heart rate and shorten the QT interval intravenous lidocaine, which may shorten the duration of ventricular repolarization or intravenous phenytoin, which may also shorten the duration of ventricular repolarization, administered at a dose of 10 to 15 mg/kg infused at a rate of 25 to 50 mg/minute. 

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