Drug Evaluation

Drugs 39 (2): 308-330, 1990 0012-6667/90/0002-0308/$11. 50/0 © ADIS Press Limited All rights reserved. DREND289

Dopexamine Hydrochloride

A Review of its Pharmacodynamic and Pharmacokinetic

Properties and Therapeutic Potential in Acute Cardiac Insufficiency

Andrew Fitton and Paul Benfield ADIS Drug Information Services, Auckland, New Zealand

Various sections of the manuscript reviewed by: G.P. Biro, Department of Physiology, University of Ottawa, Ottawa, Canada; R.E.S. Bullingham, ,Banbury, England; D.C. Harrison, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; A.O.Moiajo, Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, Northern Ireland; L.M. Opie, Department of Medicine, University of Cape Town, Cape Town, South Africa; D.N. Sharpe, Department of Medicine, Auckland Hospital, Auckland, New Zealand.

Contents

Summary ................................................................................................................................... 309 I. Pharmacodynamic Studies .................................................................................................. 311 1.1 In Vitro Studies ............................................................................................................. 311 1.1.1 Effects on Isolated Cardiac Tissue ...................................................................... 311 1.1.2 Effects on Isolated Vascular Tissue .................................................................... 312 1.2 In Vivo Animal Studies ................................................................................................ 312 1.2.1 Haemodynamic Effects ........................................................................................ 312 1.2.2 Renal Effects ......................................................................................................... 313 1.2.3 Antiarrhythmic Effects ......................................................................................... 314 1.3 Human Studi.es .............................................................................................................. 314 1.3.1 Central Haemodynamic Effects ........................................................................... 314 1.3.2 Peripheral Haemodynamic Effects ...................................................................... 317 1.3.3 Long Term Haemodynamic Effects .................................................................... 318 1.3.4 Renal Effects ......................................................................................................... 319 1.3.5 Effects on Myocardial Metabolism ..................................................................... 321 1.3.6 Catecholamine Effects .......................................................................................... 321 1.3.7 Comparisons with Other Cardiovascular Drugs ................................................ 322 2. Pharmacokinetic Properties ................................................................................................ 322 3. Therapeutic Trials ................................................................................................................ 323 3.1 Studies in Patients with Acute Heart Failure ............................................................. 324 3.2 Studies in Patients with Low Cardiac Output States Following Cardiac Surgery ... 326 4. Adverse Effects ..................................................................................................................... 326 5. Dosage and Administration ................................................................................................ 327 6. Place of Dopexamine Hydrochloride in Therapy ............................................................. 328

Dopexamine Hydrochloride; A Review

309

Summary Synopsis

Dopexamine hydrochloride is a novel synthetic catecholamine, structurally related to dopamine, with marked intrinsic agonist activity at fi2-adrenoceptors, lesser agonist activity at dopamine DA 1- and DA2-receptors and fi/~adrenoceptors, and an inhibitory action on the neuronal catecholamine uptake mechanism. The drug is administered by intravenous infusion, and is characterised by a rapid onset and short duration of action. Short term haemodynamic studies in volunteers and patients with severe chronic heart failure have indicated that dopexamine hydrochloride reduces afterload through pronounced arterial vasodilatation, increases renal perfusion by selective renal vasodilatation and evokes mild cardiac stimulation through direct and indirect positive inotropism. Preliminary smallscale noncomparative studies indicate that dopexamine hydrochloride displays beneficial haemodynamic effects in patients with acute heart failure and those requiring haemodynamic support follOWing cardiac surgery, and that these effects are substantially maintained during longer term administration (~ 24 hours). Dopexamine hydrochloride appears to be generally well tolerated. Nausea and vomiting are the mostjrequently reported adverse effects, and respond to dosage reduction. Occasional reports of chest pain/angina pectoris precipitated by tachycardia indicates the need for caution in the use of dopexamine hydrochloride in patients with ischaemic heart disease. Thus, dopexamine hydrochloride may prove to be a useful alternative to dopamine and dobutamine in the treatment of acute heart failure and the postoperative management. of low cardiac output states, although controlled studies are required to establish its efficacy and tolerability with respect to that of established therapies.

Pharmacodynamic Studies

Dopexamine hydrochloride displays dQpaminergic and i32-adrenergic agonist activity in isolated cardiac and vascular preparations, and produces a marked inhibition of neuronal catecholamine uptake. In dogs, dopexamine hydrochloride reduced blood pressure and afterload, increased heart rate and improved indices of myocardial contractility. The positive chronotropic and inotropic actions of the drug resulted from indirect i31-adrenoceptor stimulation, arising from baroreflex activation and inhibition of norepinephrine (noradrenaline) reuptake, and from direct cardiac i32-adrenoceptor stimulation. Dopexamine hydrochloride increased renal, myocardial and skeletal muscle blood flow. The drug displayed activity against ischaemic arrhythmias in the rat. In healthy volunteers, short term (~ 3 hours) intravenous infusion of dopexamine hydrochloride resulted in dose-related increases in cardiac output and heart rate, reductions in renal vascular resistance and minimal changes in blood pressure. In patients with chronic congestive heart failure, dopexamine hydrochloride augmented left ventricular performance, producing a pronounced systemic vasodilatation, positive chronotropy and. mild positive inotropy, and minimal changes in cardiac filling pressures and arterial blood pressure. Dopexamine hydrochloride-mediated improvements in isovolumic phase indices of left ventricular contractility were indicative of a direct positive inotropism. Blood flow to the hepatic-splanchnic and renal vascular beds was selectively increased, and accompanied by marginal increases in natriuresis and diuresis. Myocardial oxygen consumption and metabolic function were unaltered by dopexamine hydrochloride, while myocardial efficiency was slightly improved. Plasma norepinephrine levels were either unaffected or increased. Longer term (~ 72 hours) intravenous infusion of high dose dopexamine hydrochloride was frequently characterised by a rapid and progressive attenuation of the haemodynamic response in patients with chronic congestive heart failure. Direct drug comparisons, performed in patients with chronic congestive heart failure, indicated that the acute haemodynamic effects of dopexamine hydrochloride were similar to those of dobutamine, with both drugs reducing preload and increasing cardiac output through enhanced inotropy and reduced afterload. Dopexamine hydrochloride had a comparable effect to sodium nitroprusside on loading conditions in chronic congestive heart failure, but displayed a more marked inotropic effect coupled with a less pro-

310

Drugs 39 (2) 1990

nounced tachycardic action. In patients with left ventricular dysfunction, dopexamine hydrochloride showed greater chronotropism and preload-reducing properties than dopamine. Pharmacokinetic Studies

There is little published information on the pharmacokinetic properties of dopexamine hydrochloride in animals or humans. Dose titration of dopexamine hydrochloride 1 to 4 ltg/kg/min resulted in proportional increases in plasma drug concentrations in volunteers, with a peak of 124 mg/L after 1 hour. On termination of infusion, plasma drug concentrations declined rapidly and monoexponentially with an elimination halflife of 7 minutes (vs 11 minutes in patients with low cardiac output) and a plasma clearance of 36 mljmin/kg (vs 17 ml/min/kg in patients following cardiac surgery). Tissue distribution of dopexamine hydrochloride was extensive, with the drug acting as a substrate for the extraneuronal catecholamine uptake mechanism (U ptake2). Dopexamine hydrochloride was extensively metabolised by O-methylation and subsequent sulphate conjugation to yield 2 major products which were excreted with the parent drug in the urine and faeces. Urinary excretion was biphasic with a terminal half-life of 4 days; the 2-methoxy, I-sulphate metabolite accounted for more than 90% of the excreted drug recovered from the urine. Over 12 days after administration, the urinary and faecal routes accounted for the elimination of more than 50% and 20%, respectively, of the original dose.

Therapeutic Trials

Noncomparative dose-titration studies indicated that intravenous infusions of dopexamine hydrochloride 0.5 to 6.0 ltg/kg/min produced a beneficial systemic and renal vasodilatation, in conjunction with enhanced diuresis and improvements in indices of myocardial function, in patients with acute heart failure. In contrast to its action in patients with chronic heart failure, dopexamine hydrochloride lacked significant preloadreducing properties in those with acute heart failure. Long term (24 hours) intravenous infusion of dopexamine hydrochloride in patients with acute heart failure following myocardial infarction was associated with sustained haemodynamic improvements, with no evidence of appreciable tolerance to the haemodynamic effects. Noncomparative dose-titration studies in patients with compromised left ventricular function subsequent to cardiac surgery reported that intravenous infusions of dopexamine hydrochloride 1.0 to 10.0 I-'g/kg/min produced dose-related increases in cardiac output and heart rate, reductions in afterload, but no changes in preload. These haemodynamic effects were associated with a tendency towards increased diuresis.

Adverse Effects

Dopexamine hydrochloride was well tolerated during short and extended term (~ 72 hours) intravenous infusion at doses of 0.5 to 10.0 ltg/kg/min. Nausea, vomiting, tachycardia, chest pain/angina pectoris, ventricular ectopy and tremor (which occurred in 2% to 5% of patients) accounted for the majority of reported adverse effects and responded rapidly to dose reduction or infusion termination. However, chest pain/angina pectoris precipitated by tachycardia have been chiefly encountered in patients with pre-existing ischaemic heart disease. In most patients, the dopexamine hydrochloride-induced tachycardia is within limits of clinical acceptability and there is no evidence of significant arrhythmogenic potential. Reversible reductions in neutrophil and platelet counts have been recorded in healthy subjects receiving short term intravenous infusions of dopexamine hydrochloride I to 4 ltg/kg/min. There have been no reports of biochemical abnormalities following administration of the drug to normoglycaemic patients.

Dosage and Administration

For the treatment of acute heart failure and haemodynamic support in patients following cardiac surgery, dopexamine hydrochloride should be infused intravenously at an initial dose of 0.5 ltg/kg/min and then titrated upwards in dosage increments of 1.0 Itg/ kg/min, in accordance with haemodynamic response, to a maximum of 6.0 ltg/kg/min. The use of dopexamine hydrochloride is contraindicated in patients with thrombocytopenia. Caution is advised in the case of patients with hyperglycaemia and hypokalaemia in view of the drug's ~-adrenergic action.

Dopexamine Hydrochloride: A Review

311

1. Pharmacodynamic Studies

ventricular myocardium (B6hm et al. 1988). In the spontaneously beating guinea-pig atrium incubated in the presence of cocaine, dopexamine hydrochloride (0.1 ~mol/L to 0.1 mmoljL) [0.043 mg/L to 42.9 mg/L] displayed weak {11-agonistactivity (intrinsic activity 0.16 relative to dopamine), producing a slight increase in atrial rate which was susceptible to propranolol blockade (Brown et al. 1985a). Dopexamine hydrochloride had similarly weak effects at {1t-adrenoceptors mediating inotropy in the electrically paced guinea-pig atrium (Mitchell et al. 1987; Smith & O'Connor 1988). This latter effect was unmodified by cocaine or reserpine pretreatment, thereby indicating that dopexamine hydrochloride, unlike dopamine, is free of significant 'tyramine-like' indirect sympathomimetic activity (Mitchell et al. 1987). In contrast to the above effects, dopexamine hydrochloride (0.01 ~moljL to 0.1 mmoljL) showed a marked positive inotropic effect on the isolated field-stimulated guinea-pig atrium (Mitchell et al. 1987). This response was susceptible to attenuation by propranolol and abolition by reserpine pretreatment, implying that dopexamine hydrochloride has an indirect sympathomimetic action which is mediated by inhibition of neuronal catecholamine uptake (Uptakel). Confirmation of this action was provided by the report of a potent concentrationdependent inhibitory effect of dopexamine hydrochloride (0.01 ~moljL to 1.0 ~moljL) on 3H-norepinephrine (noradrenaline) uptake into rabbit cerebral cortex synaptosomes, a phenomenon which was more pronounced with dopexamine hydrochloride [concentration producing 50% inhibition of response (ICSO) = 26 ~mol/L] than with dopamine (ICso = 270 nmol/L) and cocaine (ICso= 108 nmol/L) [Mitchell et al. 1987]. Dopexamine hydrochloride (3 nmol/L to 10 ~mol/L) has similarly been. shown to be a potent inhibitor of the uptake mechanism in the isolated rabbit aorta (Nedergaard 1989). Studies employing isolated electrically driven cardiac tissue derived from patients with mild-tosevere heart failure [New York Heart Association (NYHA) class II to IV] or coronary heart disease indicated that the positive inotropic effect of do-

Dopexamine hydrochloride [4-(2-[(6-[(2-phenylethyl) amino] hexyl) amino] ethyl)-1 ,2 benzenediol dihydrochloride] is a novel synthetic catecholamine designed to enhance the desirable cardiovascular actions of its structural analogue dopamine in the short term treatment of low cardiac output states (fig. I). While retaining agonist activity at peripheral dopamine DAt-receptors, dopexamine hydrochloride differs from dopamine in, producing potent stimulation of {12-adrenoceptors and minimal direct stimulation of {1t-adrenoceptors and dopamine DA2-recept9rs, and is devoid of activity at a-adrenoceptors. Thus, in addition to its selective renal vasodilator effect, dopexamine hydrochloride shows pronounced afterload-reducing and mild cardiostimulant properties, and is free of the unwanted arrhythmogenic and vasoconstrictor actions of dopamine. This pharmacological profile, in conjunction with the drug's rapid onset and short duration of action following intravenous administration, may be of value in the short term management of acute heart failure and other low cardiac output states. 1.1 In Vitro Studies 1.1.1 Effects on Isolated Cardiac Tissue Weak positive inotropic and chronotropic responses to dopexamine hydrochloride have been described in the isolated guinea-pig atrium, perfused, isolated guinea-pig heart (Brown et al. 1984, 1985a) and isolated human atrial trabeculae and

Dopamine ·2HCI

Dopexamine hydrochloride

Fig. 1. Structural formulae of dopamine and its analogue dopexamine hydrochloride.

Dr ugs 39 (2) 1990

312

pexamine hydrochloride was-roore pronounced on right atrial trabeculae (30% of the maximal response elicited by calcium) than on left ventricular papillary muscle taken from patients with failing hearts (~ 8% of the maximal response to calcium). The response, which was inversely related to the severity of heart failure, was selectively blocked by the .82-adrenoceptor antagonist ICI 118 551 and enhanced by the phosphodiesterase inhibitor milrinone (B6hm et at. 1988). 1.1.2 Effects on Isolated Vascular Tissue On the isolated rabbit ear artery incubated in the presence of cocaine, dopexamine hydrochloride (0.3 JLmoljL to to JLmoljL) produced a concentration-dependent reduction in neurogenic vasoconstriction which was partially blocked by the dopamine DA2-receptor antagonist metoclopramide. In producing this inhibitory effect, which is presumably mediated by presynaptic dopamine DA2-receptor agonist activity, dopexamine hydrochloride was approximately 6 times less potent than dopamine (Brown et al. 1985a). In the presence of propranolol and cocaine, dopexamine hydrochloride, in contrast to dopamine, failed to contract the isolated canine saphenous vein at concentrations as high as 0.1 mmoljL, thereby demonstrating that it is devoid of intrinsic a-adrenoceptor agonist activity (Brown et at. 1985a). Dopexamine hydrochloride was approximately 60 times more potent than dopamine in depressing spontaneous tone in isolated guinea-pig trachea during neuronal and extraneuronal uptake inhibition and a- and fJladrenoceptor blockade; dopexamine hydrochloride"induced tracheal relaxation was blocked by the selective fJ2-adrenoceptor antagonist ICI 118 551 (Brown et at. 1985a). A summary of the comparative agonist activities and actions of dopexamine hydrochloride is presented in table I.

1.2 In Vivo Animal Studies 1.2.1 Haemodynamic Effects Haemodynamic studies in the anaesthetised and conscious dog have indicated that parenterally administered dopexamine hydrochloride is a se\ec-

Table I. Summary of the pharmacological properties of dopexamine hydrochloride (after Smith & O'Connor 1988) Pharmacological property

Relative potency of dopexamine hydrochloride (dopamine = 1)

DA, agonism

0.34

DA2 agonism Q{ agonism

0.17

/3,

Uptake-1 block

0.16 60 10

'Tyramine-like ' activity

Inactive

Arrhythmogenic potential

None

agonism

(32 agonism

Inactive

tive regional vasodilator and a potent afterload-reducing agent with mild cardiostimulant properties. The principal cardiovascular effects of intravenous dopexamine hydrochloride (I to 43 JLg/kg/min) in this species consist of dose-related falls in blood pressure, systemic vascular resistance and left ventricular end-diastolic pressure, and increases in heart rate, indices of myocardial contractility (left ventricular dP/dt max and dP/dt.p-l) and cardiac output (Bass et al. 1987; Biro et at. 1988; Brown et at. 1985b; Smith & Naya 1987; Smith et al. 1987). These effects were rapid in onset, with the peak haemodynamic response occurring after 6 minutes, and were rapidly reversed on termination of dopexamine hydrochloride infusion (Bass et al. 1987). Dopexamine hydrochloride-induced falls in systemic vascular resistance and blood pressure have been shown to be mediated by stimulation of vascular dopamine DAI- and DA2-receptors and .82adrenoceptors, with the fJ2-adrenoceptor apparently making a predominant contribution (Bass et al. 1987; Smith et al. 1987). Indirect cardiac fJladrenoceptor stimulation, resulting from reflex baroreceptor activation secondary to the fall in systemic blood pressure, has been implicated in mediating, to a varying degree, the cardiostimulant effects of dopexamine hydrochloride. In the anaesthetised dog the positive inotropic and chronotropic effects of dopexamine hydrochloride (1 to 43 JLg/kg/min intravenous infusion; 4 and 16 JLg/kg bolus injection) were significantly reduced following autonomic ganglion blockade with hex-

Dopexamine Hydrochloride:

A

Review

amethonium + atropine (Bass et al. 1987) and, to a lesser extent, with chlorisondamine + methylatropine (Smith et al. 1987). The residual responses were greatly attenuated by the selective Ih-adrenoceptor antagonist ICI 118 551, thereby indicating that direct stimulation of myocardial i32-adrenoceptors also contributes to the cardiostimulant effects of dopexamine hydrochloride. The observation that dopexamine hydrochloride (16 JLg/kg intravenous bolus) had a greater cardiostimulant action than an equipotent hypotensive dose of the i32-adrenoceptor agonist salbutamol (albuterol) in the anaesthetised dog, and that the effects of both drugs were severely attenuated following ganglion blockade (Bass et al. 1987; Goldberg & Bass 1988), suggests that a third mechanism is involved in mediating the cardiostimulant action of dopexamine hydrochloride - viz. potentiation of the effect of neurally released norepinephrine at the cardiac i3tadrenoceptor as the result of dopexamine hydrochloride-induced inhibition ofUptaket. Additional support for this hypothesis is provided by reports that dopexamine hydrochloride (I to 13 JLg/kg/min) potentiated the positive inotropic effect of exogenous norepinephrine (Bass et al. 1987, 1989; Smith & Naya 1987) and the chronotropic effect of cardioaccelerator nerve stimulation (Bass et al. 1989; Smith & Naya 1987), and attenuated the cardiovascular effects of tyramine (Bass et al. 1987; Smith & Naya 1987) in the anaesthetised dog. Using the radionuclide-Iabelled microsphere method, Biro et al. (1988) established that dopexamine hydrochloride (I to 13 JLg/kg/min) increased myocardial, gastrointestinal and, in particular, skeletal muscle (l40 to 330%) blood flow in the anaesthetised dog, while decreasing bronchial and hepatic artery blood flow. The cardiovascular effects of dopexamine hydrochloride (4 to 13 JLg/kg/min) in anaesthetised dogs with mild heart failure induced by regional myocardial ischaemia were reported to be similar to those seen in the normal heart; arterial blood pressure and peripheral vascular resistance were reduced, heart rate and cardiac output were increased, and indices of left ventricular contractility

313

(dP/dt max and dP/dt· p-t) were essentially unaltered (parratt et al. 1988). 1.2.2 Renal Effects Oopexamine hydrochloride (l to 43 JLg/kg/min intravenously or intra-arterially) decreased renal vascular resistance and increased renal blood flow in the anaesthetised and conscious dog (Bass et al. 1987; Biro et al. 1988; Brown et al. 1984, I 985a,b; Smith et al. 1987). The renal vascular effects of dopexamine hydrochloride (I to 43 JLg/kg/min) were variously reported to be unaltered by propranolol and haloperidol pretreatment, to be slightly reduced by the selective i32-adrenoceptor antagonist ICI 118 551 and markedly attenuated by the selective dopamine OAt-antagonists SCH 23390 and bulbocapnine (Bass et al. 1987; Brown et al. 1985a,b; Smith et al. 1987). The dopexamine hydrochloride-induced increase in renal blood flow occurred despite a reduction in systemic blood pressure and an essentially unaltered cardiac output (Brown et al. 1985b), thereby implying that the degree of vasodilatation in the renal bed exceeded that in the systemic circulation. In anaesthetised dogs pretreated with propranolol and the selective dopamine DA2-antagonist domperidone Brown et al. (1985a) found intra-arterially administered bolus doses of dopexamine hydrochloride (4 to 13 JLg/kg) to be approximately 3 times less potent than dopamine (0.6 to 1.9 JLg/kg) in stimulating the vascular dopamine OAt-receptor. Oopexamine hydrochloride thus differs from dopamine, which is slightly more potent as a dopamine OAt-agonist but does not display i32-adrenoceptor-mediated renal vasodilatation. Employing the radionuclide-Iabelled microsphere method to determine the effects of dopexamine hydrochloride (l to 13 JLg/kg/min) on renal blood flow in the anaesthetised dog, Biro et al. (1988) recorded an increase in blood flow to the renal cortex, whereas estimated medullary blood flow (which in this instance represents blood flow bypassing the glomerular capillaries rather than total renal medullary blood flow) was unaltered. Despite an increase in glomerular filtration rate, urinary water and electrolyte excretion were unaltered by dopexamine hydrochloride (2 JLg/kg/min)

314

in the anaesthetised dog (Bass 1989). However, in the presence of selective dopamine DAI-receptor and JJ2-adrenoceptor blockade (with SCH 23390 and ICI 1I8 55 I ,respectively), dual actions of dopexamine hydrochloride at the tubular level were revealed: while drug-mediated stimulation of renal dopamine DAI-receptors enhanced diuresis, natriuresis and kaliuresis in the absence of changes in glomerular filtration rate, ·stimulation of renal JJ2adrenoceptors decreased diuresis and kaliuresis. 1.2.3 Antiarrhythmic Effects Dopexamine hydrochloride counteracts early ischaemic arrhythmias in anaesthetised rats (parratt et al. 1988). Intravenous infusion of dopexamine hydrochloride (0.25 JLg/kg/min) initiated 15 minutes prior to, and maintained for the duration of, coronary artery ligation significantly reduced the incidence of ventricular ectopic beats (by 70%) and the duration of episodes of ventricular tachycardia (by 73%) and ventricular fibrillation (by 81 %) during the early phase of arrhythmias (0 to 30 minutes after coronary artery ligation). In addition, this dose significantly reduced the mortality rate from ventricular fibrillation during coronary artery ligation in comparison with untreated controls (lO%vs 40%). The maximum haemodynamically tolerated dose of dopexamine hydrochloride (l3 JLg/kg/min) fonowing coronary artery ligation was associated with a lower incidence and severity of ventricular ectopic activity than that observed with haemodynamically equivalent doses of dopamine, norepinephrine and dobutamine (Parratt et al. 1988). The lower arrhythmogenicity of dopexamine hydrochloride may be related to its relative lack of JJI-adrenoceptor agonist activity, which has been implicated in dopamine"induced arrhythmias (Katz et al. 1967). 1.3 Human Studies 1.3.1 Central Haemodynamic Effects The haemodynamic responses to short term (~ 3 hours) intravenous infusions of dopexamine hydrochloride have been evaluated in healthy volunteers, patients with mild-to-moderate hypertension

Drugs 39 (2) 1990

and, predominantly, in patients with stable, chronic, moderate-to-severe (NYHA class II to IV) heart failure maintained on conventional digitalis, diuretic and vasodilator therapy. The majority of these studies employed a combination of standard non-invasive and invasive techniques to monitor cardiac performance. In healthy volunteers, intravenous infusion of dopexamine hydrochloride 1 to 8 JLg/kg/min was associated with marked, dose-related increases in heart rate (~ 54%) and cardiac output (~ 100%), increases in pulse pressure, but minimal changes in mean arterial blood pressure (Foulds 1988; Mousdale et al. 1988). The tachycardic response to dopexamine hydrochloride was more pronounced in volunteers than in patients with heart failure (see table II), a phenomenon which is presumably related to the reduced baroreceptor reflex sensitivity associated with heart failure (Cohn & Franciosa 1977). In patients with mild-to-moderate hypertension, dopexamine hydrochloride I to 3 JLg/kg/min produced dose-related increases in cardiac output and heart rate and, in the absence of significant changes in systemic vascular resistance, increased systolic and mean arterial blood pressures (Magrini et al. 1988). Intravenous infusion of dopexamine hydrochloride has been shown to augment left ventricular performance at rest in patients with chronic moderate to severe (NYHA class II to IV) heart failure. Dopexamine hydrochloride 0.25 to 6.0 JLg/kg/min consistently produced a marked peripheral vasodilatation and positive chronotropic and mild inotropic effects, as indicated by dose-related reductions in systemic vascular resistance (~ 50%) and increases in heart rate (~ 33%), cardiac index (~ 110%), stroke volume index (~ 82%) and left ventricular dP/dt max (~ 31 %). Changes in arterial blood pressure were minimal at doses of 2 JLg/kg/min or less, whereas a maximal fall in mean arterial blood pressure of 15% was manifest at a dose of 4 JLg/kg/ min (see table II). While dopexamine hydrochloride had a· pronounced effect on systemic vascular resistance, particularly at doses greater than 2 JLg/kg/min, in patients with chronic heart failure (Bonnier & Read 1988; Colardyn & Vandenbogaerde 1988; Dawson

Dopexamine Hydrochloride: A Review

et al. 1985), the accompanying reductions in right and left ventricular filling pressures (right atrial pressure and pulmonary capillary wedge pressure) and left ventricular end-diastolic pressure were generally smaller or minimal (Dawson et al. 1985; De Marco et al. 1988; Jaski & Peters 1988; Murphy & Hampton 1988; Svensson et al. 1986). This suggests that dopexamine hydrochloride has relatively little effect on systemic capacitance vessels or on the pulmonary circulation, and that its major site of vasodilator action is the systemic arterial system. The dopexamine hydrochloride-induced increase in cardiac output appeared to be mediated partially through an increase in stroke volume, particularly at low doses (~ 2 J,tg/kg/min) and through an increase in heart rate, this latter effect being particularly evident at higher doses (> 2 J,tg/ kg/min) [Bayliss et al. 1987; Dawson et al. 1985; Jackson et al. 1988; Jamison et al. 1989]. The mechanism underlying the positive chronotropic effect of dopexamine hydrochloride is unclear. A reflex tachycardia secondary to systemic vasodilatation and baroreceptor activation, while supported by a reported increase in plasma norepinephrine levels following dopexamine hydrochloride infusion (l to 4 J,tg/kg/min) [Bayliss et al. 1987; Jaski & Peters 1988], is unlikely in view of the diminished baroreceptor responsiveness characteristic of chronic heart failure (Cohn & Franciosa 1977; Goldstein et al. 1975). Moreover, low dose dopamine (2.5 J,tg/kg/min) showed a more potent vasodilator effect than an equipotent (with respect to the cardiac output response) dose of dopexamine hydrochloride (0.5 J,tg/kg/min) in patients with left ventricular dysfunction (NYHA class II to III), yet failed to produce a greater increase in heart rate (Jackson et al. 1988). De Marco et al. (1988) have suggested that direct stimulation of myocardial i32-adrenoceptors is the most likely mechanism of the tachycardic response to dopexamine hydrochloride in congestive heart failure" since they found that blood pressure and plasma norepinephrine levels were unaltered by dopexamine hydrochloride (I to 6 J,tg/kg/min). Myocardial i32-adrenoceptors, which are reported to play a

315

role in the chronotropic control of the human heart (Brown et al. 1986), are present in a high proportion in the failing human ventricle as a consequence of the selective down-regulation of myocardial i31-adrenoceptors (Bristow et al. 1986) and might assume particular importance in maintaining myocardial function under these circumstances. While isovolumic phase indices [left ventricular dP/dt max , the elastic stiffness-contractile shortening velocity product (KV max)] and ejection phase indices [peak aortic blood velocity, maximum blood acceleration during ejection and the maximum rate of change of power (dPower/dt)] of myocardial contractility were increased by dopexamine hydrochloride 1 to 6 J,tg/kg/min (Dawson et al. 1985), this apparent increase in inotropic state may have arisen indirectly from drug-induced changes in preload, heart rate or afterload. Jaski et al. (.1986) compared the haemodynamic effects of dopexamine hydrochloride (2 J,tg/kg/min) with those obtained at a matched heart rate (via atrial pacing) in patients undergoing diagnostic cardiac catheterisation for presumed coronary artery disease. While it was demonstrated that the positive inotropic response and the accompanying improvement in left ventricular relaxation [a reduction in the exponential time constant of the first 40 msec ofisovolumic pressure decline (Tl) and an increase in the peak negative rate of change of pressure (-dP/dt max )] resulting from dopexamine hydrochloride infusion could be partially attributed to the increase in heart rate, the presence of additional heart rate-independent improvements in cardiac index, left ventricular isovolumic phase indices [increases in dP/dt max , the peak velocity of the contractile element at zero load (V max)] and left ventricular relaxation (a reduction in T d implied that the myocardial stimulant action was direct and independent of heart rate and preload. However, the possibility of an indirect improvement in left ventricular function secondary to afterload reduction could not be discounted. Leier et al. (1988) reported that the magnitude of the changes in left ventricular function elicited by dopexamine hydrochloride (0.25 to 4 J,tg/kg/min) [increases in left ventricular dP/dt, fractional

...,

Table II. Acute haemodynamic effects of intravenous dopexamine hydrochloride in resting patients with chronic heart failure

0-

Reference

Baumann et al.

No. of patients

NYHA class

Dose (I'g/kg/ min)

12

III

4.0

33

III-IV

1.0 2.0 3.0 4.0

Results (mean % change from baseline) HR

SBP

~

10

DBP

~

20

MBP

~

15

PAP

~

35

PCWP RAP

Baumann et al.

Bayliss et al.

15 a ~ loa ~ 12 a ~

8

III-IV

1.0

119

19

12

II-III

0.5 1.0 2.0

t5

P 111

11 3

~ 13a 123a 131 a 1 39 3

PVR

47

160

r r

poa i 93 a 93 a

r

1293 1473 1543 157 a

1243 ~ 42 a ~ 48 3 ~ 53 a

1 57

1 15

117

SVI

r 80

HO

166

1183 131 a 1443 152 3

21 a i 36a Hoa P6 a 155 a 105a 114a 161 a

(1988) (1990)

SVR

CI

~

~

i 39a

LVdP/ dt m3x

LVeDP

t 28 a t 31

t 15 a

113 126 122

i 14

125

(1987) Bonnier & Read

(1988) Colardyn & Vandenbogaerde

9

III-IV

(1988) Dawson et al.

10

III

1.0 3.0 6.0

10

III-IV

12

II-III

(1985) De Marco et al.

0.5 1.0 2.0 4.0

~

19

P P

i 13 t 20 t 23

P

r8

5

P ~

14

13 120 ~

112 115

18 ~ 17 133 125

Mean 5.2b

t 20a t 33 t 17

1 18

0.5 1.0 2.0

t 13 t 24

15 15

126

j 25

18 i 14 t 25

~ 6

t 13

i 26 i 39 t 56

t 13 i 21 t 32

14 27 139

t 43a t 71 a t 121 t 45

t 38a t 503 t 63

130a H2 a 1 49

115a ~ 12 a 123

t 31

H4

j 34

t9

19 121 129

P 1 12 ~ ~

(1988) Jackson et al.

- (1988) Jamison et al.

9

III-IV

(1989) Jaski & Peters

10

III

t5

1 17 119 ~ 17

1.0 2.0 Mean 7.2c

t 18

4.0

t 27

i 12 i 24

t 37

i6

i 32

~

t 37

110 115

j 13

122

i 65

~

t 29

19 32

148

139

(1988) Lang et al. (1988)

...tl

:;::

~

8

III-IV

1.0 2.0 4.0

i 11 I 12 I 14

129 149 I 110

t 32 t 82

116 125 150

..... '0

N '-" 134

...... '0 '0



Dopexamine Hydrochloride: A Review

E :J

E Ox 01

E

o C\I C\I(')

Cl

ll)C\lCO ~C\IC\I

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