The newer sympathomimetic amines, dopamine and dobutamine, are now being

investigated for treatment ofcongestive heart failure .

Dopamine

Dopamine, the precursor in the endogenous synthesis of noradrenaline, acts directly

on ß.-adrenergic receptors of the myocardium and indirectly by releasing

noradrenaline from sympathetic nerve endings. Dopamine also acts on a-adrenergic

receptors in arteries and veins. lts effects on ß2-adrenergic receptors are minimal.

Dopamine-induced vasodilation of the renal, mesenteric, coronary, and cerebral

vascular beds is attributed to activation of dopamine vascular receptors (Goldberg,

1972). Because of the multiple actions of dopamine, variable haemodynamic

responses are observed with different concentrations of dopamine. At low infusion

rates, cardiac contractility, cardiac output, and renal blood flow increase with little

change in heart rate and either reduction or no change in total peripheral vascular

resistance (McDonald, Goldberg, McNay & Tuttle, 1964; Goldberg, 1974). The

relati ve lack of incrcase in heart rate appears to be due to an inhibition of

sympathetic nerve ac tivity, possibly by the action of dopamine on presynaptic

dopamine receptors (Langer & Dubocovich, 1979). At higher doses (usually greatcr

th an 10 IJg kg-i min-J

) peripheral resistance increases, heart rate may increase, and

renal blood flow decreases (Goldberg, Hsieh & Resnekov, 1977). Therefore, careful

adjustment ofthe dose is necessary to prevent an excessive increase in heart rate and

vascular resistance. Left ventricular filling pressure generally remains unchanged or

is increased with higher doses (Beregovich, Bianchi, Rubler, Lomnitz, Cagin &

Levitt, 1974; Leier, Heban, Hu ss, Bush & Lewis, 1978).

Dopamine increases sodium cxcrction in both normal subjects and patients with

heart failure (McDonald et al., 1964). The diurcsis appears to be secondary to the

incrcase in renal blood flow but other mechanisms ma yaiso be responsible .

184 L. I. GOLDBERG & S. I. RAJFER

The use of a vasodilator drug with dopamine can lead to additive beneficial

haemodynamic effects (Miller, Awan, Joye, Maxwell, DeMaria, Amsterdam &

Mason, 1977; Stemple, Kleiman & Harrison, 1978). This combination can be a very

effective pharmacological measure for restoring cardiac output to adequate levels in

the setting ofsevere pump failure. This is usually accomplished with a simultaneous

reduction in ventricular filling pressure.

Dopamine is inactive orally. It is metabolized rapidly and must be given as a continuous intravenous infusion. This should be initiated at low rates (0.5-1 lJg kg-1

min-1

) and increased gradually as needed. This dose should be reduced ifthe patient

has been recently treated with monoamine oxidase inhibitors (Goldberg et al., 1972).

Arrhythmias and angina pectoris have been reported in patients treated with dopamine (Goldberg, 1977). Gangrene has been described in patients in shock treated with

this agent (Alexander, Sako & Mikulic, 1975). Nausea and vomiting may be observed

and are more common with high doses (Goldberg, 1972).

Two orally active forms of dopamine have been reported in human studies. The

anti-Parkinson drug, levodopa, is decarboxylated to dopamine. When administered

orally in-doses of 1.0 and 1.5 g, a significant shortening of systolic time intervals

occurs for a duration of30 to 90 min (Whitsett & Goldberg, 1972). The same doses of

levodopa have been shown to increase inulin c1earance, PAH c1earance and sodium

excretion (Finlay, Whitsett, Cucinell & Goldberg, 1971). After three months of continuous administration tolerance develops to the cardiac effects, The mechanism for

th is tolerance is not known since the cardiac responses to dopamine were unchanged.

It is possible that continuous therapy with levodopa results in decreased activity of

the enzyme required to convert levodopa to dopamine. More recently, a potent orally

active analogue of dopamine, SB 7505 (the diisobutyric ester of N-methyIdopamine), was reported to cause a prolonged shortening of systolic time intervals

and sodium diuresis (DeiCas, Manca, Vansini, Mansour, Bernardini & Visioli, 1980).

The effects ofchronic treatment ofpatients with congestive heart failure by SB 7505

have not yet been reported.

Dobutamine

Dobutamine is a synthetic catecholamine that acts directly on ßi-adrenergic

receptors to increase cardiac contractility and heart rate . It does not stimulate the

heart indirectly by releasing noradrenaline. It has relatively weak ß2- and aadrenergic receptor activity (Goldberg et al., 1977). Dobutamine does not act on

dopamine receptors (Robie & Goldberg, 1975). At equivalent cardiac inotropic

effects dobutamine exerts a much weaker ß2-adrenergic action than isoprenaline

and a much weaker a receptor activity than noradrenaline. With moderate

infusion rates , augmentation of myocardial contractility is the most prominent

action of dobutamine without major changes in arterial pressure or heart rate

(Sonnenblick, Frishman & LeJemtel, 1979). A decrease in left ventricular filling

pressure usually accompanies the increase in cardiac output (Leier et al., 1978;Jewitt,

Jennings & Jackson, 1978). At very high doses tachycardia and a decrease in vascular

resistance may occur.

Dobutamine requires continuous intravenous administration. Its serum half-life is

2 min . The drug is metabolized in the liver, and most of its metabolites are excreted

in the urine. The drug is infused at a rate of2.5-1O g lJg kg-1min-1

, but doses as high as

40 lJg kg-1 mirr" have been used . The most serious adverse effect is the precipitation

ofarrhythmias. Angina has also been reported (Sonnenblick el al., 1979).

An orally active derivative of dobutamine is not available, but other orally active

sympathomimetic amines with predominant ßi-adrenergic activity are under

investigation (Johnsson, Jordö, Lundborg, Rönn, Welin-Fogelberg & Wikstrand,

1978).

INOTR OPIC AGEN TS

Other positive inotropic drugs

185

Po sitive inotropic agents with mechanism s of action d iffer ent from those of cardiac

glyco sides and sym pa thomimetic amines a lso ha ve promise in th e treatment of

congestive heart failure. Phosphodiesterase in hibitors increase cardi ac contractile

force and decrease peripheral vascular resistance. The co mmonly used in hibitor,

aminophylline , has limited oral utility and a narrow th erapeutic range when given

intravenously. However, new inhibitors wh ich ma y have greater application are now

under in vestigation (Je nnings, Jackson , Mon aghan & Jewitt, 1978).

The pancreat ic hormon e, glucagon, a lso ex hibits a positi ve inotropic effect by an

unusual mechanism . Unfortunately thi s drug has a relatively poor ratio betwe en its

effect ive dose and the dose producin g nausea and vomiting (Glick, Pa rmley,

We chs ler & Sonnenblick, 1969; Will iams, 1969; Siman is & Goldberg, 1971).

Amrinone, a rece ntly syn thesized bipyridine derivative, causes a do se-related

increase in cardiac contrac tile force . Its ino tropic effect is not diminished by pr etreatment with reserpine or blo cked by propranolol. Nei ther cycl ic AM P levels nor

phosphodiesterase activity ar e altered by a mrinone. Na+, K+-ATPase ac tivi ty is not

inhibited (Alousi, Farah, Lesher & Opalka, 1979).

In animal studies amrinone has proven to be a potent, long-act ing po sitive

inotropic agent with a wide therap eutic index . The augmentation in contractile force

occurs without development of arrhyt hmias. Large doses are associated with a

reduction in blood pressure (Alousi et al., 1979).

In pat ients with congest ive heart failure, the haemod ynamic effects of amrinone

are characterized by an inc rease in ca rdiac output accom panied by substantial

reduction s in left ventric ula r filling pressu re and syste m ic vasc ular resistan ce. Left

ventricular ejection fraction increases, wh ile arter ial pr essure is un ch anged or

minimally reduced. Heart rate is not a ltered (Benott i, Grossman, Braunwold,

Davolds & Alousi, 1978 ; LeJ emtel, Keung, Sonnenblick, Ribner, Matsumoto, Da vis,

Schwartz, Alousi & Davolos, 1979; LeJemtel, Keung, Ribner, Davis, We xler,

Blaufox & Sonnenblick , 1980). Thus, the improvement in ventricular performance

appear s to result from increased myocardial contractil ity, possibl y associated with

direct arteria l vasodilation.

The beneficial effects of amrinone occur after oral or intravenous administration.

Aft er an intravenous dose the onse t of ac tio n was noted within 2 min and persi sted

for 60-90 min. With oral ad ministration, haemodynamic effects were first ob served

at 30-120 min and persisted for 4-7 h.

The safety of long-terrn admi nis tratio n of am rino ne remains to be estab lished.

Fo ur cases ofthrombocy topenia have now been rep orted after 4-9 wee ks of trea tme nt

(LcJe mtel et al.. 1980 ; Wynn e, Malacoff, Benotti, C urfma n, Grossm an , Holman,

Smith & Braunwald, 1980). Defin itive Iong-terrn studie s have not been co mpleted.

Arrh ythmias ha ve not been documented .

Conclusions

It is appa rent fro m th is review that th e ino tropic agents pr esently available po ssess

man y deficiencies. The only clinic all y useful oral ino tropic age nts a re the digital is

glycosides, despite th eir narrow th erap eutic ran ge and high inci de nce of toxicity.

Sympathomimetic amines are poten t card iot onic agents but these drugs a lso have th e

po tential to ind uce tac hycardia and arrhythmias . A large number of inot ro pic agents

of different classes have been eva lua ted but have not found clin ical a pplication for

the treatment of heart failure. A recen tly synthesize d co m pound, amrinone, has been

shown in preliminary studies to be effective both ora lly and intrave nously, but its

long-term efficac y rem ains to be established.

186 L. I. GOLDBERG & S. I. RAJFER

An orally effective inotropi c agent, with a wi de therapeutic index, is urgen tl y

n eed ed . The de ve!opment of suc h an agent rem a ins a major cha lle nge in the treatment ofco ngestive hea rt fa ilure.

Acknowledgements

This work was sup ported b y NIH grants PHS G M-222 20 a nd G M-07019.

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