Catecholamines: the first messengers

2 Catecholamines: the first messengers N O E L W. L A W S O N

The catecholamines continue to be the pharmacological mainstay of cardiovascular support for the low-flow state. Sustained interest in the catecholamines is related to their predictable pharmacodynamics and favourable pharmacokinetic profiles (Leir and Binkley, 1991). The pharmacodynamic effects of most commonly used catecholamines are linearly related to plasma levels, which are directly and linearly related to rate of infusion. There are few clinical surprises within any dose range and the pharmacokinetics of commercial catecholamines allow rapid titration to effect. The half-life of most is short, ranging from 2 to 3 min. Undesirable side-effects dissipate within minutes of lowering or stopping the infusion. The catecholamines, as a group, produce a wide range of haemodynamic effects. Furthermore, they can be used in any combination to achieve a yet wider spectrum of effects (Lawson, 1990). The last half of the 1980s was particularly productive in cardiovascular pharmacology, as well as in the discovery and function of new adrenoceptors (Prys-Roberts, 1992). The issue is no longer whether there are two or more subtypes of a receptor, but rather how many isoreceptors there are in mammalian tissue (Prys-Roberts, 1991). This chapter reviews some of these discoveries as they relate to the clinical use of the new and old catecholamines. ENDOGENOUS CATECHOLAMINES: SOURCE, FORM AND FUNCTION A catecholamine is composed of a catechol nucleus (a dihydroxyl benzene ring) and an amine-containing side-chain (Figure 1). The ancestral catecholamines in humans are dopamine, noradrenaline and adrenaline (Figure 2). They are important in the homoeostatic response to serious illness or injury, and are also known to be an integral part of many common cardiovascular disorders (Ganguly, 1989). Drugs found useful in the treatment of many cardiovascular diseases modify either the synthesis, release, uptake or storage of catecholamines (Goldstein and Rafjer, 1984). Many are useful because they block or mimic the actions of catecholamines on the adrenergic receptor. All the endogenous catecholamines are stored in presynaptic vesicles and released by the arrival of an autonomic sympathetic action potential Bailli~re's Clinical Anaesthesiology-Vol. 8, No. 1, March 1994 ISBN 0-7020-1824-4

27 Copyright 9 1994, by Bailli~re Tindall All rights of reproduction in any form reserved

28

N.W. LAWSON

Catechol

H

~

HO

B

a

I I

C

I I

C

Catecholamine

.o~ HO

I I I C

C"

N

I

I

I

Non-Catecholamine (Sympathomimetics)

Q

I I I

C

C~N

I

I

I

Neosynephrine HO

~1 f~'

I~h-~ C - - C

I ~ N - -I C I

Methoxamlne

c~ mC

I ~N I I I

I~H 3

Clonldlne Cl

--C

N

II I N~C CI

Figure 1. The chemical configurationsof a catechol and a catecholamine are compared with those of three common non-catecholaminesympathomimetics.

29

CATECHOLAMINES

(Lawson, 1992). They function either as a hormone or a neurotransmitter upon release or when given intravenously. A hormone is a chemical that is secreted by an endocrine gland and is blood-borne to other organs where it produces a physiological action. A neurotransmitter is a chemical that is synthesized, liberated and used locally at a neuroreceptor junction to produce an action (Figure 3). Endogenous dopamine and noradrenaline function primarily as local neurotransmitters at sympathetic postganglionic

ENDOGENOUSCATECHOLAMINES Dopamine HO

HO~

CH2 - CH2 - NH2

Norepinephrlne

HO

Epinephrine

HO

HO

SYNTHETICCATECHOLAMINES Isoproterenol

HO

/c.3 HO

CH3

Dobutamine

HO HO~ Dopexamine

HO~

CH2- - CH2 - NH- - ~H-- CH2--C H 2 ~

HO

CH3

CH2--CH2- - NH(CH2)6--N- - CH2-- CH2~

Figure 2. The chemical configurations of the three endogenous catecholamines are compared with those of three synthetic catecholamines.

30

N. W. LAWSON

Neuron b o d y ~

Synthesis

Storage Neurotransmitter vesicles

o

- -

,

o

~.000 0 0 o00 0 o o0O

I /I

I .-" Mobilization ~ ~ ~ ~ ___ t .~ ~

p2

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Increases NE Release

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~ / ,~ J ( ~ f ,-'-~-;Release ---. \.,.-.."-,._.9 /" "~ ( ,' (~a+*-de endent ~ I ~ ," -.) t ~ ~ ^ 'P-"0 ^ ,t~., 9 - ~ - , . , . ~ C_~%~~" 0 ' " v n ~,," -, oA2,n~ ~'2.NE. Release ..... Inhibits

I

plexus

iI

~

v .nt'c cleft

S,~n-r--I-

Postsynaptic membrane

EFFECTOR CELL Figure 3. Diagram showing the loci of several known adrenergic receptors. The presynaptic a2and DA-receptors serve as a negative feedback mechanism, whereby stimulation of noradrenaline (NA) inhibits its own release. Presynaptic [32 stimulation increases NA uptake, augmenting its availability. Postsynaptic a2- and [32-receptors are extrasynaptic and are considered non-innervated hormonal receptors.

receptors. Adrenaline may stimulate the same receptor sites but reaches that site as a blood-borne hormone from the adrenal medulla, together with medullary noradrenaline. Stress studies have confirmed the concept of the hormonal nature of adrenaline and the local neurotransmitter nature of noradrenaline (Chernow et al, 1982). Dopamine is an important neurotransmitter in the CNS and in some peripheral adrenergic ganglia. It is formed in the cytoplasm of the central neurones and in peripheral adrenergic postganglionic nerves from dihydroxyphenylalanine (Figure 4). Dopamine synthesis stops at this point in the neurones of the CNS and it enters storage vesicles. Dopamine is also stored outside the CNS in vesicles of the peripheral sympathetic postganglionic neurones. The function of these deposits of dopamine was previously regarded simply to serve as the precursor of noradrenaline (Zaritsky and Chernow, 1983). However, these vesicles contain the enzyme, dopamine[~-hydroxylase, which converts dopamine to noradrenaline (Figure 4). Some dopamine is co-released with noradrenaline from these peripheral nerve terminals and there is considerable evidence that the kidney and gut are innervated by some adrenergic nerves that release dopamine exclusively (Murphy and Elliott, 1990).

CATECHOLAMINES

31

H I l ' ~ ] m C-- CH--NH2 "

PHENYLALANINE

l~'~-~ H C O O H COOH

~ C H

I

2--CH-- NH2

HO"~-k~j'

COOHI

HO~CH2-CH--

NH2

HO-k~ HO HO HO

TYROSINE

~ tyrosine hydroxylasi~ DOPA

~ dopa decarboxyias Feedback CH2--CH2--NH 2

DOPAMINE

inhibition /

I dopamine OH

~

CH--CH2-- NH2

NOREPINEPHRINE * "

HO~.-k~/ OH I HO~CH--CH2--1~H H O ~ CH3

13-hydroxylase/

~ phenylethanolamine N-methyltransferase

EPINEPHRINE

Figure 4. Diagram showingthe synthesisof catecholamines.The conversionof tyrosineto

DOPA by tyrosine hydroxylaseis inhibitedby increased noradrenaline(norepinephrine) synthesis.Adrenaline(epinephrine)is shownin these stepsbut is primarilysynthesizedin the adrenal medulla.From Meadowset al (1988),withpermission. Noradrenaline is also synthesized from dopamine in the chromaffin cells of the adrenal medulla, where it serves as the precursor of adrenaline. Adrenaline is stored in chromaffin cell vesicles of the adrenal medulla, where it awaits release as a hormone. Up to 85% of the catecholamine content of the adrenal medulla is adrenaline, with the remainder being noradrenaline. Physiological stimuli causing sympathetic adrenaline release from the adrenal medulla include hypovolaemia, hypotension, hypoxia, hypercarbia and acidosis. Psychogenic stimuli include pain and fright.

A D R E N E R G I C VERSUS NON-ADRENERGIC S Y M P A T H O M I M E T I C S

Drugs that stimulate adrenergic receptors or mimic the catecholamines are defined as sympathomimetics. All clinically useful catecholamines are sympathomimetics, but not all sympathomimetics are catecholamines. Likewise, not all sympathomimetic drugs function through adrenoreceptors. Table 1 classifies many commonly used sympathomimetics by configuration

32

N.W. LAWSON Table 1. Sympathomimetic drugs. Catecholamines

Non-catecholamines

Adrenaline Noradrenaline Dopamine* Dobutamine Dopexamine Isoproterenol

Metaraminol? Mephentermine? Ephedrine? Methoxamine Ibopamine Phenylephrine

Non-adrenergics Amrinone

Xanthines Glucagon Digitalis Naloxone Calcium salts

* Direct-acting catecholamine with some indirect action. ? Primarily indirect-acting with some direct action. Adrenergic amines produce sympathomimetic effects via adrenergic

receptors. Non-adrenergic produce sympathomimetic effects exclusive of the adrenergic receptor.

and function. The chemical configurations of three synthetic catecholamines are compared to those of the endogenous catecholamines in Figure 2. They activate adrenergic receptors because of their structural and spatial similarities to the parent compounds. The relative a and DA ~3effect of the catecholamines in current use differ in their cardiovascular effects largely because of substitutions on the amine group. Figure 1 demonstrates the chemical configuration of three commonly used non-catecholamine adrenergic sympathomimetics. The presynaptic et2receptor agonist clonidine does not possess a catechol nucleus and even has two ring systems that are aplanar to each other (Figure 5). However,

//I / /

/

/t

/

/

/

/

/ /

..

,'d II

Clonidine

I

i I

..yJ ~"

Noradrenaline

Figure 5. The spatial similarity of clonidine and noradrenaline allows clonidine to activate presynaptic c~2-receptors, thus inhibiting noradrenaline release.

CATECHOLAMINES

33

clonidine enjoys a remarkable spatial similarity to noradrenaline, which allows it to activate the presynaptic ~-receptor (Hoefke, 1980). Most non-adrenergic sympathomimetic drugs produce sympathomimetic effects indirectly by tying into the adrenergic biochemical process at cellular sites exclusive of the adrenergic receptor, or cause the release of presynaptic noradrenaline to produce an effect. Amrinone is an example of the former, while ephedrine is an example of the latter. Ephedrine is therefore dependent on adequate stores of endogenous noradrenaline to be effective. The phosphodiesterase inhibitor, amrinone, functions independently of either the adrenoreceptor or endogenous noradrenaline. It inhibits breakdown of intracellular cyclic adenosine monophosphate (cAMP), the second adrenergic messenger, emulating the effects of the [3-receptor. Direct-acting sympathomimetics, such as isoproterenol, directly stimulate receptors independently of the presynaptic release of noradrenaline. Dopamine has a mixed direct and indirect mode of action. Dopamine has a direct effect on adrenergic receptors at low doses, but causes a dosedependent release of noradrenaline at higher doses. The haemodynamic pattern produced by an infusion of dopamine at rates greater than 10 ixg kg -1 rain -1 is ahnost indistinguishable from that of noradrenaline. ADRENERGIC RECEPTORS: FUNCTION AND DISTRIBUTION

The actions of catecholamines are mediated through receptors specific for the adrenergic, or sympathetic, division of the autonomic nervous system. Adrenoreceptors are best understood as cellular message decoders of the extracellular first-messenger catecholamines. Von Euler differentiated the physiological effects of adrenaline and noradrenaline in 1946. The dissimilarities of these two drugs led Ahlquist, in 1948, to postulate opposing adrenergic receptors, termed oL and [3. Further studies revealed not only subsets of the o~- and [3-receptors but also another major peripheral adrenergic receptor specific for dopamine, termed the dopaminergic (DA) receptor. The function of dopamine in the CNS had long been known, but the peripheral dopaminergic (DA) receptor has been elucidated only within the past 25 years. The presence of the peripheral DA receptor was obscured because dopamine does not affect the DA receptor exclusively. It also stimulates a- and [3-receptors in a dose-related manner (Goldberg, 1989a). However, DA receptors function independently of a- or [3-blockade, necessitating the addition of the D A receptor and its subsets (DAa and DA2) to the Ahlquist classification. Table 2 is a brief review of the function and location of some of the clinically important receptors now known to exist; additions are expected (see Chapter 1). Receptors have not been identified as anatomical structures, but the anatomical localization and amino-acid structure of these binding sites has been made possible through radioligand studies (Motulsky and Insel, 1984). The distribution of adrenoreceptors in organs and tissues is not uniform and their function differs not only by their location but also in their numbers and/or distribution within an organ system (Vanhoutte and Flavahan, 1985).

34

N.W.

LAWSON

~ ~.o

0

.= o ~ . n . ~ ~ ' = ~ o ~LE

~ ,. ~.~ 0

<

0

0

9 .~

0

~4 0

[.,.

! Or.~ 0

<

o

o

o

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CATECHOLAMINES

>

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>

35

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>

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>

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;~

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2

8

g

N

~

36

N.W. LAWSON

Adrenergic receptors are found at two loci in the sympathetic neuroeffector junction. They are found at both presynaptic (prejunctional) and postsynaptic (postjunctional) sites (Figure 3; Table 2). Prejunctional receptors are considered to be innervated in that they are in the immediate vicinity of the neurotransmitter released by a sympathetic action potential. Postjunctional receptors can be innervated or non-innervated, depending on their proximity to the synaptic cleft (Van Zwieten, 1988). Receptors located directly on postjunctional membranes are considered to be innervated. However, most postsynaptic oL2- and [32-receptors are extrasynaptic and considered non-innervated, even though they are located in the vicinity of the postsynaptic membrane. These receptors are influenced more by hormonal catecholamines than by neurotransmitter. The agonist-receptor interaction of non-innervated receptors is of slower onset and longer duration. Receptors, once thought to be static entities are now thought to be dynamically regulated by a variety of conditions and in a constant state of flux (Prys-Roberts, 1992). Receptors are synthesized in the sarcoplasmic reticulum of the parent cell, where they may remain extrasynaptic, or externalize to the synaptic membranes where they may cluster. Membrane receptors may be removed, or internalized, to intracellular sites for either degradation or recycling (Insel, 1989). Alteration in the number, or density, of receptors is referred to as either upregulation or downregulation. As a rule, an inverse relationship exists between the ambient concentration of the catecholamines and the number of receptors. Extended exposure of receptors to their agonists markedly reduces, but does not ablate, the biological response to catecholamine (Prichard et al, 1991). When inadequate flow or volume results from heart failure, a series of neurohumoral systems is activated, to maintain perfusion. For example, enhanced adrenergic activity occurs in response to acute or chronic myocardial dysfunction and is associated with an increased level of plasma catecholamines. As a result, myocardial postsynaptic [~l-receptors downregulate, which is thought to explain the diminished inotropic and chronotropic response to [~l-agonists and exercise in patients with chronic heart failure. However, calcium-induced inotropism is not impaired because [32-receptor (extrasynaptic) numbers remain intact (Prys-Roberts, 1992). The [32-receptors may account for up to 40% of the inotropism of the failing heart, compared with 20% in the normal. The myocardial eL~-receptor density also remains intact and, in fact, may increase. Tachyphylaxis to infused catecholamines is also thought to be the result of acute downregulation of receptor numbers. Downregulation is the presumptive explanation for the lack of correlation between catecholamine levels and blood pressure in the patient with phaeochromocytoma (Lawson, 1992). Downregulation is reversible upon removal of the agonist. Reduction of blood levels of catecholamines, sympathetic denervation or sympathetic blockade increase the number of receptor sites for both o~- and [~-receptors. Chronic treatment of animals with the non-selective B-blocker, propranolol, produce 100% increase in the number of [3-receptors. This accounts for the propranolol withdrawal syndrome, in which the acute discontinuation of the

37

CATECHOLAMINES

[3-antagonists leaves the a-receptors unopposed plus an increased number of [3-receptors. The clonidine withdrawal syndrome can also be explained on this basis. Acute discontinuation of the ~2- inhibitory agonist would permit a resumption of stimulation of adrenoreceptors, which upregulated during the time that noradrenaline release and vascular tone were inhibited.

TRANSLATION OF THE FIRST-MESSAGE CATECHOLAMINES Catecholamine-receptor-effector coupling The net physiological effect of a sympathomimetic is usually defined as the algebraic sum of its relative actions on the e~-, [3- and DA-receptors (Smith and Corbascio, 1970). Most adrenergic drugs activate these receptors to varying degrees. Only methoxamine and phenylephrine are considered pure ~-agonists. Isoproterenol is the only pure [3-agonist. Each catecholamine has a distinctive effect, qualitatively and quantitatively, on the myocardium and peripheral vasculature. Table 3 demonstrates the relative potency of the adrenergic amines on the various myocardial and vascular receptors. This relative potency is also dose related, adding yet another variable. The use of pluses (+) or zeros (0) is the classical method by which the relative sensitivities of cateeholamine-receptor coupling is demonstrated. The use of the (+) is also symbolic of the apparent summation effect of the catecholamines on the receptors. The summation effect further implies a finite number of adrenergic receptor sites to which the adrenergic agonist can couple. This traditional pharmacological statement requires further definition. Receptor pharmacology does not translate easily into clinical parlance because clinical observations are the summated result of the coupling of the receptors to the effectors, which alters physiology. The receptors are the decoders, or 'rules of grammar', by which the first messengers, the catecholamines, are translated into the desired haemodynamic effects.

Haemodynamics Until recently, sympathomimetics were the most common means of treating the hypotension associated with shock. However, elevation of arterial blood pressure alone has repeatedly been demonstrated to be an insufficient goal in the treatment of shock (Shoemaker et al, 1990). The goal, instead, is to re-establish blood flow to vital organs. Although blood pressure has been the historical gold standard for estimating perfusion, there is no correlation between pressure and flow (Reinhart et al, 1990). In physiological as well as constructed systems, flow tends to be least when pressure is highest. Flow, used in the context, refers to cardiac output. Oxygen transport is the product of the arterial oxygen content and cardiac output (CO): DO2 = Ca2 x CO

38

N. W, LAWSON

<

+

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+ +

<

+

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0

+ + + + +

+; ++ 0

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+

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+~.~.~.~

I=

++ +

E 0

++++ ++++ ++++ ++++

+ + ++ ~ +

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*

r,

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*

4.-

39

CATECHOLAMINES

Therefore, there is a close correlation between oxygen transport and cardiac output. Unfortunately, oxygen transport is not identical to cellular oxygen supply, which can be inadequate despite a normal or elevated oxygen transport. Cellular oxygen supply can be inadequate because of maldistribution of blood flow to vital organs or from the inability of the cell to use oxygen. Improving cellular oxygen utilization remains enigmatic but the catecholamines can be of some assistance in the redistribution of flow. The physiological equation that expresses how flow (CO) is generated states that CO is the product of the heart rate (HR) and stroke volume (SV). CO = HR x SV However, SV is determined by three factors: (1) the contractile or inotropic state of the myocardium; (2) preload, or end-diastolic myocardial fibre length; and (3) afterload, or resistance to ejection. The physiological determinants of CO can therefore be expressed as: CO = HR x (inotropism: preload : afterload) Syncheony of atrioventricular contraction is an additional determinant when arrhythmias develop. This equation is graphically illustrated in Figure 6 to

VenousTone VenousReturn

Arterial Resistance HeartRate | Synchrony 9, ardia! u t ( . Contractility Ver

/ AorticImpedance /

/

r

Figure 6. The four principal factors determining cardiac output. Synchrony of atrioventricular contraction is an additional factor, becoming important with the development of cardiac arrhythmias. From Meadows et al (1988), with permission.

emphasize that the biological mechanisms that produce and regulate flow are interdependent. Terms such as inotropism, preload and afterload cannot be defined independently, nor isolated in the clinical setting. We can now measure, calculate and manipulate each of the links in the chain of events that determine flow. Note that blood pressure is not among the determinants of flow. It is the product and not the cause. Most catecholamines affect one or more of these factors via the receptors, and may cause changes in blood pressure by altering flow, vascular tone, or both. A measured blood pressure does not distinguish changes in flow or resistance and, therefore, blood pressure and oxygen transport do not correlate. Preload is clinically synonymous with the volume of venous return to the heart, which establishes cardiac output by the Frank-Starling mechanism.

40

N.W. LAWSON

Preload has repeatedly been demonstrated to be of paramount importance in supporting cardiovascular function. It can be increased by adding volume to the circulation or by acute venoconstriction. The catecholamines can be selected for their effect on preload by either increasing (al-, a2-), or decreasing ([32-, DA1, DA2) venous tone (DeMay and Vanhoutte, 1981). Positive or negative preloading can be a major unrecognized benefit of some sympathomimetic agents (Ramanathan and Grant, 1988). Although venoconstriction produces little increase in total vascular resistance (afterload), minimal venoconstriction is capable of producing large shifts of blood volume into the central circulation because the capacitance vessels contain 60-80% of the total blood volume. The central distributive effect of a catecholamine in improving preload may be as important as its inotropic action in increasing CO in the hypovolaemic patient. Likewise, a central distribution of capacitance blood may be undesirable if the heart is failing, even though that agent may possess positive inotropic properties. Afterload is a measure of impedance to ventricular ejection and is the dominant factor in determining CO when inotropism is impaired. In the absence of outlet obstruction, the clinical correlate of afterload to the left ventricle is the systemic vascular resistance reflected by the mean arterial pressure. Afterload is the only factor of the four major determinants of CO that, if increased, will reduce flow. Figure 6 deliberately emphasizes preload and afterload as balancing forces in producing CO. They are antagonistic and assume differing degrees of dominance depending on whether the myocardium is healthy or ailing.

"5 -i

Normal

0

o

0

o .m

t~

o Afterload

1

2

3 Preload

4

~

5

Preload

1

2

3

4

5

Afterload

Figure 7. The contrastingeffectsof preload and afterload on cardiac output. Increasingpreload increases output in the normal myocardium,but to a lesser degree in the failing myocardium. Increased afterload is usually tolerated by the normal myocardium, but even small increases produce large reductions in output in the failingmyocardium.From Meinertz et al (1989),with permission.

CATECHOLAMINES

41

Preload is the dominant regulator of CO in the normal cardiovascular system. Afterload dominates flow regulation when the myocardium is failing. Figure 7 compares the contrasting effects of preload and afterload on the CO of both the healthy and ailing myocardium. Acute increases in afterload in a healthy patient are tolerated up to a fourfold increase. In contrast, even small increases in afterload produce large reductions in CO when the myocardium is depressed by disease or anaesthesia (Schwinn and Reves, 1989). The use of vasodilators for afterload reduction in the patient with a failing myocardium is based on this concept. THERAPEUTIC CATECHOLAMINES The selection of vasoactive drugs requires a knowledge of both the haemodynamic disturbance and pharmacology of the available drugs. Shock research of the 1970s pinpointed hypovolaemia, either relative or absolute, as the most common source of the shock syndrome. Even a major percentage of patients with cardiogenic shock were found to improve with volume therapy. Persuasive evidence revealed that a major pathophysiological component of shock involved sympathetic hyperactivity. This compensatory neurohumoral response, essential to the survival of patients with shock in the early stages, was shown to become malignant with time, particularly when augmented by exogenous catecholamines. Recognition of the value of volume therapy ended the age of the vasopressor with its mindless chart cosmetology. The goal for managing the critically ill is to establish and maintain adequate tissue perfusion. Aggressive fluid therapy will suffice in most instances. Vasopressors are not a substitute for volume. However, once intravascular volume is optimized, a vasoactive drug may be required if perfusion remains inadequate. The term 'inodilator' has entered our lexicon within the past 5 years to supplant the more archaic term vasopressor. This neologism reflects a change of philosophy in managing low-flow states, particularly those characterized by heart failure. The new synthetic catecholamines have been chemically engineered to obtain inotropism and vasodilatation rather than for pressor effects. Ironically, the catecholamines were once the pre-eminent vasopressors. The potential for benefit, or harm, of these new drugs can best be understood in terms of receptor characteristics. For example, activation of the inotropic myocardial [31- and [~2-receptors results in positive inotropism and chronotropism. Selective stimulation of the vascular [32-receptors causes vasodilatation. Left ventricular outflow may improve as a function of increased inotropism and afterload reduction, two of the factors that determine cardiac output. However, chronotropism may not be a desirable feature of some of these drugs, for example in patients with mitral stenosis. Noradrenaline

Noradrenaline (NA) is the standard by which all other catecholamines are

42

N.W.

LAWSON

compared. It produces non-selective, direct activation of the a- and [3receptors in a dose-related manner when given by infusion. It is a potent oL-adrenergic, and a moderate [31-adrenergic, agonist with almost no [32 effect. NA is often considered a pure a-agonist. However, an increase in cardiac output and blood pressure is seen when N A is given in low doses, primarily as a result of its predominant [3i inotropic action. Vasoconstriction, both arterial and venous, occurs with increasing doses and supersedes the [31effect at standard infusion rates (Table 4). This increase in afterload may reduce cardiac output and produce marked increases in systolic and diastolic blood pressure. Any benefit from increased preload is offset by the dominant effect of afterloading on cardiac output in the failing myocardium. Reflex slowing of the heart usually occurs despite intense [31 activity. Although increased diastolic pressure and filling time may improve Table 4. Vasoactive drug dosage guide.

Explanation Constant 0xg/min) = mg/ml x ml/h x 1 h/60 min • 1000 mg/1 mg C = mg/ml x 1000/60

Formulae: 1.

~xgk g - i rain-1 = constant • rate (ml/h)

2.

Rate (ml/h)

weight = weight x p,g k g - ~m i n constant

Example: Wanted dopamine 5 Ixg kg- 1m i n - 1 _ weight 50 kg - constant 26.7 Rate = weight x I~g kg -x min -~ = 50 x 5 = 9.36 ml/h constant

26.7 Concentration

Standard rates of infusion

(mg per 250 ml)

Constant

i.v. loading dose 200 200

13.3 16.7

400 800 1

26.7 53.3 0.07

Nitroprusside

0.75 ixg kg- 1 5.0 p~gk g - a m i n - 1 5 t~g kg -1 min -1 (2-30 ~g kg - i rain - i) 5 I~gkg i min-1 (0.5-104 pogkg i min-~) 0.3 ~xgkg 1 m i n - i (0.01-0.301xgkg a min-1) 0.025 p~gkg l m i n - 1 0.1 p~gkg - i rain - 1 0.05txgkg a min -1 l m g k g 1rain - i

Nitroglycerine Phenylephrine

1 p,g k g - 1min-1 0.1 p.g k g - i m i n - ~

1 4 2 50 100 50 t0

0.07 0.27 0.13 3.3 6.7 3,3 0.67

Amrinone Dobutamine* Dopamine* Epinephrine

Isoproterenol Noradrenaline

Titrate to desired effect beginning with standard rate. * Rule of 6. Dopamine and dobutamine use the same dosages. The dosage of either may quickly be calculated by multiplying the patient's weight (kg) • 6, to obtain mg added to 100 ml D 5% W (5% dextrose in water). The number of drops delivered through a calibrated infusor (60 drops = 1 ml) willbe the p~gkg i m i n - 1infusedinto the patient. Example: 70 kg • 6 = 420 mg per 100 ml = 4200 Ixg/ml 1 or 70 ixg per drop; 5 txg kg -1 min 1 = 5 drops per min.

CATECHOLAMINES

43

coronary perfusion, this may be offset by increased workload and oxygen consumption as a result of increases in preload, afterload and contractility. NE is probably best used as a supplement to other [32-agonists to improve perfusion, and should be considered a short-term catecholamine. Depleted cardiac stores of NA may rapidly respond to intravenous NA infusion in patients with chronic congestive heart failure (Chernow et al, 1984). However, objections to the use of NA for cardiogenic shock are based on two considerations: (1) vasoconstriction increases the pressure work of the left ventricle, with an adverse effect on the oxygen economy of an already ischemic pump; and (2) it causes further vasoconstriction and organ ischaemia in a syndrome in which intense constriction is already present (Boudarius et al, 1983). Prolonged therapy may produce a reduction in plasma volume as a result of fluid transudation at the capillary level. Use of the minimal effective dose of NA requires invasive haemodynamic monitoring and attention to fluid management if iatrogenic disaster is to be avoided. Complications such as renal failure and tissue necrosis can be expected when NA is not used in this manner. In general, NA is used to treat hypotensive states in which myocardial failure and decreased peripheral vascular resistance coexist. Sepsis is an example, but the results of NA in this state appear to be better when it is used in combination with other drugs, rather than alone (see Combination therapy). Intravenous NA has received an unseemly reputation over the years that is perhaps unjustified. Current studies indicate that NA was being used in doses that are many orders of magnitude greater than that necessary to obtain the best response. Many traditional published infusion rates have been based on blood pressure titration rather than measured flow. Personal experience, and the published experience of others, also indicafes that, if NA is used simply to titrate pressure, the amount infused can be five to ten times more than that necessary to obtain best oxygen delivery and consumption. This is not surprising when you consider that NA normally functions as a direct neurotransmitter but is being used therapeutically as a diffusing hormone. Although NA is less commonly used in the critically ill than other catecholamines, a resurgence of interest in NA is noted in the literature, particularly in the management of sepsis, in combination with other sympathomimetics (Meadows et al, 1988; Desjars et al, 1987, 1989; Stuart-Taylor and Crosse, 1989). Adrenaline

Adrenaline is the most widely used catecholamine in medicine. It is used for a variety of conditions such as asthma, anaphylaxis, haemostasis, prolonging regional anaesthesia, as well as cardiac arrest. The cardiovascular effects result from its direct activation of both ~- and [3-receptors (see Tables 2 and 3). The effect of adrenaline on the peripheral vasculature is mixed. It has predominantly al stimulating properties in some vascular beds (skin, mucosa and kidney) and f3a stimulating actions in others (skeletal muscle). These effects are dose dependent and related to the predominant receptor

44

N.W.

LAWSON

population in these areas. At low therapeutic doses (0.05-0.2 txg kg -1 min-1), 131and 132inotropic and 132vasodilating effects predominate. The summated effect of low-dose adrenaline is an increase in cardiac output (131,132), heart rate (131) and systolic blood pressure, but with a decreased diastolic perfusion pressure (132). Systolic blood pressure will be increased as a result of increased cardiac output. The fall in diastolic pressure is the result of vasodilatation. These effects can be attenuated by B-blockers, allowing al effects to predominate (DiSesa, 1991; Tarnow and Muller, 1991). Even with low doses of adrenaline, vasoconstriction is seen in renal, mucosal and cutaneous vascular beds because of their predominant population of alreceptors. The addition of infused adrenaline causes marked vasoconstriction with elevation of the diastolic blood pressure in a stressed patient, because of pre-existing high plasma levels of adrenaline before infusion. The increased cardiac output from an adrenaline infusion may therefore be accompanied by a marked decrease of blood flow to vital organs, plus a redistribution of flow to non-vital muscle vascular beds. Overall, afterload is reduced because 132-receptors are stimulated at much lower concentrations of adrenaline than are aa-receptors. Doses of adrenaline exceeding 0.3 p~gkg -1 min -~ begin to exhibit its predominant eLeffects. This produces arterial and venous constriction with a marked increase in afterload and preload. The strong chronotropic and vasoconstrictive effects of adrenaline have limited its use. However, adrenaline is frequently used for cardiac failure following cardiac surgery where greater than usual infusion rates may be required to obtain a response related in part to downregulation of myocardial 131-receptors. Adrenaline can also increase pulmonary blood flow, especially in hypertensive patients (Guazzi et al, 1986). It may cause significant changes in systemic and pulmonary haemodynamics, especially in patients with altered vascular reactivity, as is the case of many patients undergoing cardiac surgery (DiSesa, 1991). Adverse haemodynamic effects of adrenaline include cardiac arrhythmias. It shortens systole more than diastole by increasing conduction through the AV node and Purkinje system. It has a direct accelerating effect on the SA node and ectopic loci. Adrenaline decreases the refractory period of the ventricles, increasing the possibility of dangerous re-entry arrhythmias.

Dopamine dopaminergic agonists and pro-drugs

Dopamine Dopamine (DA) offers distinct advantages over many sympathomimetics in treating the low-output syndrome (Goldberg, 1989a,b). It is a dose-related agonist to all three types of adrenoceptors and the desired action can be effected by changing the infusion rate. The DA receptors are most sensitive, followed by the 13-, and then oL-receptors. However, DA possesses a unique property not found with other catecholamines: it dilates renal and mesenteric vascular beds as a direct effect of its DA receptor effect. The [3-receptors present in the renal vascular are not involved in DA-induced vasodilatation.

CATECHOLAMINES

45

Dopamine dosage regimens have been traditionally, and arbitrarily, divided into low, medium and high doses according to its dose-receptor sensitivity. Renal and mesenteric vascular dilatation, and tubular cell natriuresis, are mediated through the DA receptors at low-dose infusion rates of 0.5-2.0 p,g k g - l m i n -1. This is often referred to as 'renal dose dopamine' because of the enhanced renal blood flow and diuresis. The diuresis may also be attributed, in part, to the inhibition of aldosterone secretion seen with low-dose DA administration (Noth et al, 1979). A general improvement in cardiac output from afterload reduction also contributes to improvements in renal blood flow. These effects have been well demonstrated in patients with heart failure. However, the protective effects of DA on the development of renal failure in the critically ill or injured patient, although an attractive principle, is much less certain. Prevention of renal failure by prophylactic renal-dose DA (with or without furosemide) in the critically ill or traumatized patient has not been conclusively demonstrated, even when used early (Vincent, 1990). This may be related to the adrenergic milieu into which the DA is given. The vasoconstrictive effects of DA are expected to occur only at relatively high doses. However, even relatively low doses can cause renal vasoconstriction when added to the pre-existing high plasma levels of endogenous catecholamines commonly seen in the acutely injured patient. This phenomenon is akin to that seen with the infusion of low-dose adrenaline in shocked patients. The haemodynamic effects of low-dose DA are primarily related to vasodilatation by activation of the DA1 and DA2-receptors. Activation of presynaptic DA2-adrenoceptors adds to the vasodilating effect of the DA1receptors by inhibiting presynaptic noradrenaline release in the renal and mesenteric vessels. The reduction of total systemic vascular resistance would be significant when one considers that 25% of the cardiac output goes to the kidneys alone. A reduced diastolic blood pressure is often noted, with a slight reflex increase in heart rate. Increasing the infusion rate of DA to from 2 to 5 txg kg-1 min-1 begins to activate [3-receptors, increasing the cardiac output by increased chronotropism and contractility with early venoconstriction (preload) and systemic vasodilatation (afterload reduction). Blood pressure may not increase despite significant increases in cardiac output. This dose range would appear to be optimal for managing congestive heart and lung failure because it combines inotropism and afterload reduction with diuresis. Further increases in dosage activate a-receptors, which increases vascular resistance and blood pressure, but further improvements in cardiac output may be attenuated. Infusion rates greater than 10 txg kg -1 min -1 produce intense a activity, which may override any beneficial DA or [3vasodilatation effect on total flow. High-dose DA behaves very much like noradrenaline and, in fact, causes noradrenaline release at this dose range (Murphy, 1990). Despite the apparent dose-response divisions of DA, a wide variability of individual responses has been noted. For example, the a-adrenergic effects can be seen in some individuals at doses as low as 5 Ixg kg -1 min -1, whereas doses as high as 20 txg kg -a min -a may be required to obtain this effect in shocked patients (Murphy and Elliott, 1990). This wide variation in doseresponse has led to a re-examination of DA as a primary adrenergic for

46

N.W. LAWSON

patients in cardiogenic shock or failure. Increased venous return may not be desirable in this situation, but the haemodynamic versatility of DA continues to be useful in cardiogenic shock, when combined with other complementary catecholamines such as dobutamine (see Combination therapy). The venoconstriction, or distributive effects, of D A are useful in surgical patients in whom third-space oedema and sepsis are the most common abnormalities. D A increases mean pulmonary arterial pressure and is not recommended as sole support in patients with right heart failure, adult respiratory distress syndrome or pulmonary hypertension.

Dopexamine Dopexamine is a 'designer' catecholamine, developed in an attempt to overcome some of the disadvantages of DA in managing cardiogenic low-flow states (Leir et al, 1988). Afterload reduction and renal vasodilatation were desirable, but a drug was needed that did not increase myocardial oxygen consumption or provoke arrhythmias, and whose actions could be sustained for long periods. Dopexamine is a short-acting (tl/2 b = 7 rain) intravenous analogue of DA with predominantly [32- and DAl-receptor agonist activity. It also inhibits the direct neuronal reuptake of noradrenaline (Smith and Naya, 1987). Dopexamine provides mild positive inotropism with systemic and renal vasodilatation through its predominant receptor agonism. It has no direct [3a or oq agonist activity like that possessed by DA (Lokhandwala and Hedge, 1991). It is considered an 'inodilator', although its inotropic actions are weak, lacking any [31 activity except that produced by reduced noradrenaline uptake. The predominant inotropic activity is from its [32 effect. The summated effects of dopexamine are due to afterload reduction via renal and mesenteric vasodilatation (DAaand [32-receptor activation), positive inotropism (myocardial [32 activation and reduced noradrenaline uptake) and natriuresis (DA1 tubular receptors) (Jaski and Peters, 1988). The relative potency of dopexamine on the DA1- and DA2-receptors is only 0.3 and 0.17, respectively, that of DA. It is 60 times more potent on [32-receptors than DA. Downregulation of myocardial [31-receptors occurs with chronic heart failure but the [32subpopulation is preserved. This profile has the potential to be useful as an adjunct in increasing cardiac output in patients with chronic heart failure because the myocardial [32subpopulation is preserved while the [31-receptors are downregulated. However, adjunct inotropic agents will likely be required to realize the full benefits of its vasodilating DA1 and [32 properties (Boudarius et al, 1983). Doses of ~xgkg- 1 min- 1 will augment inotropism while significantly increasing visceral blood flow (Leir et al, 1988; Poelaert et al, 1989; Gollub et al, 1991). Dopexamine has been reported to improve renal function to a greater extent than could be attributed to an increased cardiac output alone (Lokhandwala, 1990). Animal studies indicate that it is effective in restoring renal function to control levels following acute renal failure. However, the efficacy of dopexamine in preventing renal failure in humans, as in the case of dopamine, is less conclusive. Dopexamine is a less potent direct renal

CATECHOLAMINES

47

vasodilator than DA. The relative contributions of dopaminergic versus [3z-receptor activation in improving renal and mesenteric blood flow has been questioned. Stephan et al (1990) could not demonstrate DA~ activity of dopexamine in patients undergoing elective coronary artery bypass. Gray and colleagues (1991) found dopexamine to be at least as effective as DA for renal protection in patients undergoing liver transplantation, while Jamison et al (1989) were unable to demonstrate any increase in renal blood flow in patients in chronic congestive heart failure. The infusion rate for effective doses of dopexamine range from 0.5 ~g kg -1 min -1 to 5 p.g kg -a min -1, depending on the pathology. Dopex~ amine should be infused intravenously at an initial dose of 0.5 ~xgkg- ~min- 1 in the treatment of acute heart failure after cardiac surgery (Ghosh et al, 1991). It can be titrated upward in dosage increments of 1.0 p~gkg -a min -1, according to haemodynamic response, to a maximum of 6.0 ~g kg -1 min -1 (Fitton and Benfield, 1990). Infusion rates greater than 6 ~g kg -1 min -1 can cause intolerable tachycardia and angina in patients with pre-existing ischaemic heart disease (Meinertz et al, 1989). Dopexamine inhibits hypoxic pulmonary vasoconstriction by activation of [3z-receptors. This profile has proven beneficial in both short- and long-term management of pulmonary hypertension (Hunter et al, 1989). Dopexamine appears to be a promising catecholamine, but there has been only limited experience with its use in the critically ill. Its ultimate value for prolonged administration remains to be established.

Fenoldapam The effectiveness of DA in heart failure has led to development of orally active dopaminergic drugs which lack the ~x-adrenergic actions of the parent, DA. some are selective DA1- or DAz-agonists. Others are pro-drugs that are converted into active metabolites which activate DA receptors. Most are of little value to the anaesthesiologist in the acute situation. Fenoldapam, a benzazepine derivative, is a selective DAl-agonist. It has no c~-or [3-receptor activity. Oral bioavailability is poor but it is an effective antihypertensive when given intravenously. Intravenous fenoldapam promotes natriuresis, diuresis and an increase in creatinine clearance. It may offer some advantages in the acute resolution of severe hypertension, particularly if the patient has pre-existing renal impairment (Murphy and Elliott, 1990).

Bromocriptine This compound is a selective DAz-agonist. DAz-agonists reduce neuronal release of noradrenaline. The magnitude of the response is directly proportional to the background of sympathetic activity. Bromocriptine was originally found to be effective in humans in the treatment of Parkinson's disease and acromegaly, which can be attributed to DAz-receptors. It also lowers blood pressure in normotensive and hypertensive individuals.

48

N.W. LAWSON

Ibopamine This compound is an orally active pro-drug that is rapidly converted into its active metabolite, epinine (n-methyldopamine). The pharmacological properties of ibopamine are qualitatively similar to those of DA. It is a non-selective agonist of DA1- and DA2-receptors. Ibopamine is an effective natriuretic and diuretic in patients with congestive heart failure.

Levodopa Levodopa has been one of the most widely used prodrug of DA. It is the immediate precursor of DA and has been used for many years in the treatment of Parkinson's disease. It is decarboxylated, after absorption, into DA (Chatterjee et al, 1985). Dose restrictions are necessary when levodopa is given alone because ot-adrenergic activity can occur in higher oral doses. For this reason, it is most often combined with carbidopa, which inhibits peripheral carboxylase activity, allowing therapeutic CNS levels of DA to be achieved without the peripheral vascular side-effects. Oral levodopa has been used effectivelyin treating patients with advanced heart failure (Rafjer et al, 1987). The effects noted are an increase in stroke volume and a decrease in vascular resistance, with little change in heart rate or blood pressure. The effects are similar to those noted in patients receiving lowdose DA. Decreased noradrenaline release may be a factor in producing vasodilatation.

Dobutamine

Dobutamine is a synthetic catecholamine, modified from the classic inodilator isoproterenol. Isoproterenol was, in turn, synthesized from dopamine. Variations and similarities in structure can be seen in Figure 2. Isoproterenol, the parent drug of dobutamine, is a potent non-selective [31and [32-agonist which increases heart rate and contractility while reducing vascular resistance and diastolic pressure. Deleterious side-effects include serious cardiac arrhythmias, tachycardia and reduced coronary artery perfusion. Increased myocardial oxygen demand, 'with only a modest improvement in cardiac output, make isoproterenol an unattractive drug in many situations, especially ischaemic heart failure. It does remain useful in the temporary management of third-degree heart block, asthma and some forms of cor pulmonale and heart transplantation. Dobutamine has clear advantages over isoproterenol and dopamine in many clinical situations. It acts directly on [31-receptors but exerts much weaker [32-stimulation than isoproterenol. It does not cause NA release or stimulate DA receptors. Dobutamine, unlike isoproterenol or dopexamine, possesses weak oq-agonism, which can be unmasked by B-blockade as a prompt and dramatic increase in blood pressure (Tarnow and Komar, 1988). Ordinarily, changes in arterial blood pressure do not occur because the mild oq activity is countered by the [32 activity. Dobutamine produces strong inotropism, but with weak chronotropic or vascular effects. Increases in

CATECHOLAMINES

49

cardiac output are primarily through increased inotropism and, secondarily, by reduced afterload. Dobutamine increases automaticity of the SA node and increases conduction through the AV nodes and ventricles. Dobutamine produces a lesser increase in heart rate per unit gain in cardiac output than dopamine, but is not devoid of chronotropic activity. Troublesome tachycardia can occur in sensitive individuals, and caution should be exercised in patients with established atrial fibrillation or recurrent tachycardia. Early studies found dobutamine preferable to dopamine, adrenaline and isoproterenol because of its lack of chronotropic effects (Steen et al, 1978; Maekawa et al, 1983). A more recent study indicates that dobutamine increases heart rate more than adrenaline for a given increase in cardiac output (Butterworth et al, 1992). Dobutamine may decrease diastolic coronary filling pressure because of its vasodilator properties. However, many animal and human studies show improvement of ischaemia and augmentation of myocardial blood flow with dobutamine (Royster, 1990). It appears to produce coronary vasodilatation in contrast to the constriction produced by dopamine. These studies suggest that dobutamine produces an overall favourable metabolic climate in the ischaemic myocardium, despite an increase in inotropism. This improvement is rate limited. Dobutamine has been used effectively to improve coronary flow to differentiate, by echocardiography, responsive or unresponsive areas of dyskinesia in patients following myocardial infarction (Pierard et al, 1990). Dobutamine is highly controllable, with a half-life of 2 min. Tachyphylaxis is rare but may be noted if given over 72 h. The net haemodynamic effects of dobutamine include: (1) an increase in cardiac output; (2) a decrease in left ventricular filling pressure; and (3) a decrease in systemic vascular resistance without a significant increase in chronotropism at lower doses (Teich and Chernow, 1985; McGhie and Goldstein, 1992). It has been proved to be as effective as combined dopamine and nitroprusside in treating heart failure with infarction. It is even more effective when summated with the dopaminergic properties of DA. In contrast to dopamine, dobutamine seems to inhibit hypoxic pulmonary vasoconstriction. Like its piarent compound, isoproterenol, dobutamine may prove to be useful in managing right ventricular failure as well. C O M P A R A T I V E E X T R A C A R D I A C EFFECTS OF D O P A M I N E VERSUS D O B U T A M I N E

Figure 8 demonstrates the cascade of events following the loss of ventricular contractility. This condition can worsen in a cyclic manner and will serve as the basis for the remaining discussion of the catecholamines. These are the circumstances for which 'inodilators' are most commonly used and encountered during coronary artery bypass surgery. The cascade could be drawn, beginning with dysfunction of any of the five physiological determinants of cardiac output, which includes arrhythmias (see Figure 6).

50

N.W. LAWSON

/

-' ~

~U

'

] ~ I LVEDP I' CONTRACTILITY/~... ~' "~k~lsehemia /

' t VENRT2~CUAL2 R

~ Wall Tension

~'%%%%IuATC

/ VENTRICULAR t OUTFLOW IMPEDANCE ~.

\

I 02 Demand j ~-.~.. T02 2mand

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/ SYMPATHETIC.____. v t HeartRate l NERVOUS )CT,V,TY

ARTERIAL J / CONSTRICTION/ I coVETNOUTSoNp Figure 8. Low cardiac output may be precipitated by a reduction in myocardial contractility. This diagram depicts the cascade of events following decreased contractility secondary to a myocardial infarction. The primary insult produces a reduction in cardiac output, increased left ventricular end-diastolic pressure (LVEDP) and a host of reflex responses. Dysfunction of any of the five determinants of cardiac output could be entered in this same cascade. As depicted, the failure worsens in a cyclical manner. From Meinertz et al (1989), with permission.

The ideal drug for reversal of cardiac failure is depicted in Table 5. This drug would improve inotropism and reduce afterload, without increasing chronotropism or myocardial oxygen consumption. Table 6 presents one approach to the management of cardiogenic failure, listed in order of relative importance. It puts the role of pharmacological intervention into perspective (Perret, 1990). Dopamine and dobutamine are the two most popular primaryinodilators in use today. A comparison of these two drugs will underscore the importance of the extracardiac side-effects in selecting a drug either for use alone or in combination. This comparison is particularly appropriate because dopamine and dobutamine are considered equipotent inotropic agents, and are effective in the same dose range of 2-15 p.g kg-1 min-a. Their differences can be compared at low (0.5-4 Ixg kg -1 min-1), medium (5-9 Ixg kg -1 min -1) and high (10-151xgkg-lmin -1) doses. This comparison will illustrate the divergent effects of two drugs on preload and afterload while sharing the property of inotropism. Although they share several clinical indications, these drugs are pharmacologically distinct and are not interchangeable. Their divergent properties, however, make them particularly valuable when used in combination. Dobutamine is a direct-acting catecholamine that produces a positive inotropic 131 effect but with minimal changes in 132 heart rate or vascular resistance ([32-, al-counteraction). Thus, dobutamine may not alter blood pressure even though cardiac output is markedly improved. Dopamine may do both. Low-dose dopamine can produce haemodynamic changes similar to those of dobutamine (inotropism and mesenteric vasodilatation).

CATECHOLAMINES

51

Table 5. Characteristics of the ideal positive inotropic agent. Enhances contractile state by increased velocity and force of myocardial fibre shortening Lacks tolerance Does not produce vasoconstriction No cardiac dysrhythmias Does not affect heart rate Controllability: immediate onset and termination of action Elevates perfusion pressure by raising cardiac output rather than systemic vascular resistance Redistributes blood flow to vital organs Direct acting: not dependent on release of endogenous amines Compatible with other vasoactive drugs Effective orally or parenteratly

Table 6. Management of low-output syndrome due to myocardial dysfunction. 1. Assure adequate ventilation and oxygenation 2. Relieve pain and symptoms of recurrent ischaemia 3. Haemodynamic monitoring (PA, PCW, arterial pressures; urine output, cardiac output) 4. Optimize LV filling pressure 5. Correct metabolic abnormalities 6. Control dysrhythmias (give priority no. 2 if life threatening) 7. Pharmacological support Diuretics Inotropic drugs Vasodilators 8. Rule out 'correctable' causes of shock (septal or LV rupture, mitral regurgitation, acute aneurysm) 9. Mechanical support of circulation 10. Surgical correction if possible Haemodynamic monitoring is essential in confirming a diagnosis, optimizing filling pressure and cardiac output; selecting pharmacological support and avoiding complications. Adjustment of LV filling pressure may require additional volume or a relative volume reduction with vasodilators. The diagnostic criteria for cardiogenic shock are not met until step 4 has been accomplished. LV, left ventricular. PA, pulmonary artery; PCW, pulmonary capillary wedge.

Dopamine produces an increase in blood pressure at higher doses, related to its direct and indirect al activation. This increased afterload with dopamine may attenuate any further increase in cardiac output comparable to that of an equal dose of dobutamine (Figure 9). Dobutamine does not have any clinically important venoconstrictor activity, in contrast to dopamine for which an increase in ventricular filling pressure can be noted at low doses. This contrasting effect on preload is seen in Figure 10. The cardiac response to all vasodilators is dependent on the pre-existing preload status. Patients who have acute failure with normal or only slightly elevated end-diastolic volumes may not respond to afterload reduction with an increase in cardiac output. Balanced vasodilators such as nitroprusside, or venodilators such as the nitrates, may actually reduce cardiac output in these patients. Patients with dilated left ventricles and elevated filling pressures usually have an impressive improvement in cardiac output with afterload reduction. This underscores the importance of

52

N . W . LAWSON

Cardiac Output(CO)

150 O O =J

E z

/

/ f

J f

f -

dobutamine

dopamine

f

100 LOW

MEDIUM

HIGH

DOSE

Figure 9. Equal rates of infusion of dopamine and dobutamine do not produce an equal increase in cardiac output (CO). Increrasing afterload with higher doses of dopamine inhibits full achievement of CO, comparable to that of dobutamine in the intact human. Courtesy of Eli Lilly.

monitored volume loading before proceeding apace with vasoactive drugs (Table 6). It is possible, and indeed likely, that a portion of the reduced effectiveness of long-term vasodilator therapy results from inadequate preload, which in some circumstances can actually be a consequence of successful drug therapy (Braunwald and Colucci, 1984). Clinical studies suggest that dobutamine is less likely to increase heart rate than dopamine for a given dose which is a major concern in the patient with coronary artery disease. Dobutamine is a coronary artery dilator whereas dopamine is not. A dopamine-induced tachycardia, however, may be of less concern in the septic patient who commonly has a maldistribution of volume, low vascular resistance, pre-existing refractory tachycardia, but a previously healthy heart. The empiric preference of dopamine in surgical units and of dobutamine in coronary units has been observed, and is perhaps well founded. The surgical patient is more likely to have distributive defects and fluid shifts from major trauma and surgery. The haemodynamics of the septic patient are characterized by low vascular resistance, hypotension, high cardiac output and some degree of myocardial depression. The renal, distributive, inotropic and pressor effects of dopamine seem ideal for this condition. However, a shift of blood volume to the central circulation, tachycardia or an unpredictable increase in afterload may not be appropriate for the patient in congestive heart failure or with an acute infarct (see

53

CATECHOLAMINES

Pulmonary Capillary Wedge Pressure (PCWP)

160 140 a.

o. ,_1

120

_< Z

100

J

J

J

dopamine

f

n

o~ dobutamine

8060

LOW

MEDIUM

HIGH

DOSE Figure 10. A decrease in venous capacitance has been demonstrated as an early effect of dopamine. An increase in pulmonary capillary wedge pressure (PCWP) may be noted. Dobutamine may decrease PCWP by increased inotropism as well as vasodilatation, with minimal effect on venous capacitance. Courtesy of Eli Lilly.

Figure 8). Dobutamine, with its dose-related inotropism, afterload reduction and relative lack of chronotropism seems more appropriate in these circumstances. Dobutamine does not cause noradrenaline release or stimulate DA receptors. DA does both, but the effect is dose related. The dopaminergic effects of increased renal perfusion is seen at low doses of DA, whereas noradrenaline is stimulated only at higher doses. DA offers distinctive advantages over many sympathomimetics in managing the low-output syndrome with oliguria. This effect is ablated at higher doses. Dobutamine does not selectively increase renal blood flow but, like dopexamine, does improve renal blood flow secondarily, with improved cardiac output and weak [32 vasodilatation. Much of the reduced afterload observed with the use of dobutamine may be related more to a reduced sympathetic tone with improved flow than to active vasodilatation. Dobutamine belongs on the opposite end of the spectrum from amrinone. It is a potent inotropic agent but a weak vasodilator, whereas amrinone is a potent vasodilator but a weak inotrope. Dopamine and dobutamine also have contrasting effects on the pulmonary vasculature. Dopamine has been noted to increase pulmonary artery pressure and does not inhibit the pulmonary hypoxic response. It is not recommended for patients in right heart failure. Dobutamine does vasodilate the pulmonary

54

N.W. LAWSON

vasculature and is helpful in treating right heart failure and cor pulmonale (Chernow et al, 1984). COMBINATION THERAPY

The adrenergic effects of combined sympathomimetics, like the solo drugs, appear to be additive and competitive for receptor sites. Many combinations of adrenergic drugs have been described as having a synergistic effect. Synergism is the joint action of agents such that their combined effect is greater than the algebraic sum of their individual effects. This synergism may be a clinical interpretation of a summated receptor effect that appears synergistic. For example, infusions of the combination of dopamine and dobutamine have been noted to produce a greater improvement in cardiac output, at lower doses, than can be achieved by either drug alone. Each drug, although an equipotent inotropic agent, dilates different vascular beds. Therefore, the summation of afterload reduction by both drugs could produce a greater improvement in cardiac output than could be achieved by either drug alone, even at the same level of inotropism. Summation is more consistent with current receptor pharmacology and can be used to advantage in selectively avoiding the unwanted side-effects of one drug while supplementing its desired attributes with another. The summation principle obviates the necessity of knowing a large number of drugs. One need become familiar with only a few agents to manage most clinical situations. Because of summation, many combinations of vasoactive drugs have been found useful in making fine haemodynamic adjustments in the critically ill (Lawson, 1990). The available sympathomimetic agents provide a wide range of haemodynamic effects, particularly when combined with vasodilators. For example, if a larger positive inotropic action and less vasoconstriction are desired, dobutamine could be added to dopamine. Also, nitroprusside could be added to dopamine or combined with any other appropriate inodilator. Combinations are also useful in redistributing the cardiac output to vital organs. This is why the combination of dobutamine and dopamine has been helpful. Dopamine could distribute the cardiac output to the renal and mesenteric vascular bed, while dobutamine could provide additional afterload reduction by opening up the vascular beds of skin and muscle (Richard et al, 1983; Allaf et al, 1984). Noradrenaline has been used successfully in combination with dopamine to increase vascular resistance in septic patients while distributing a greater portion of the cardiac output to the renal and mesenteric bed. The studied use of adrenergic combinations in patients with cardiac failure has been proposed because pathophysiology cannot be approached with the attitude that [3-agonism is all good and ~-agonism all bad. The objective is to increase coronary perfusion and cardiac output while decreasing afterload. This is the effect achieved by the intra-aortic balloon pump. No single vasoactive agent can achieve this, but these conditions can be approached with combination therapy. Because of receptor summation during combination therapy, standard rates of infusion as outlined in

CATECHOLAMINES

55

Table 4 no longer apply. Invasive h a e m o d y n a m i c monitoring is mandatory for success; otherwise iatrogenic disasters can be expected. Other conditions necessary for success with vasoactive drugs also require that: (1) the failing m y o c a r d i u m or vasculature must have functional reserve; (2) the reserve can be stimulated; and (3) perfusion can be maintained.

SUMMARY The catecholamines continue to be the pharmacological mainstay of cardiovascular support in the low-flow state. Sustained interest is related to their predictable profiles and controllability. As a group, the catecholamines produce a wide range of h a e m o d y n a m i c effects and can be used in any combination to achieve a yet wider spectrum of action. T h e net physiological effect of a catecholamine or sympathomimetic is usually defined as the algebraic sum of its relative actions on the o~-, [3- and DA-receptors. Most catecholamines activate these receptors to varying degrees. Each catecholamine has a distinct effect on haemodynamics, related to its relative potency on cardiovascular adrenoceptors. This potency is also dose related, adding yet another variable. Just as the net effect of a single drug is the algebraic sum of its receptor action, the combined effects of sympathomimetics also appear to be additive. Many adrenergic combinations have been described as synergistic, but this m a y be a clinical interpretation of a s u m m a t e d receptor effect that is simply m o r e physiologically efficient. Summation is m o r e consistent with current receptor pharmacology. This concept can be used to advantage in selectively avoiding unwanted side-effects of one drug while supplementing its desired attributes with another. The second half of the 1980s was particularly productive in terms of receptor pharmacology. The issue is no longer whether there are two or m o r e subtypes of a receptor, but rather how m a n y isoreceptors there are in m a m m a l i a n tissue. This treatise reviews these discoveries as they relate to our understanding of the clinical use of the new and old catecholamines. These discoveries point the way to the development of new drugs.

REFERENCES Allaf DE, Cremers S, D'Orio V & Carlier J (1984) Combined haemodynamic effects of low doses of dopamine and dobutamine in patients with acute infarction and cardiac failure. Archives Internationales de Physiologie et de Biochimie 92(4): $49-$55. Boudarius JP, Dubourg O, Gueret P e t al (1983) Inotropic agents in the treatment of cardiogenic shock. Pharmacology and Therapeutics 22: 53-79. Braunwald E & Colucci WS (1984) Vasodilator therapy of heart failure: has the promissory note been paid? New England Journal of Medicine 310(7): 459-461. Butterworth JF, Prielipp RC, Royster RL et al (1992) Dobutamine increases heart rate more than epinephrine in patients recovering from aortocoronary bypass surgery. Journal of Cardiothoracic and Vascular Anesthesia 6(5): 535-541. Chatterjee K, Viquerat CE & Daly P (1985) Neurohumoral abnormalities in heart failure. Heart Failure March-April 1: 69-83.

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