Dr. Paul Forrest
Royal Prince Alfred Hospital
The drugs that mimic the effects of the sympathetic nervous system stimulation may be divided into catechol- and noncatecholamines.
Adrenaline- the major hormone of the adrenal medulla
Noradrenaline- the transmitter at most sympathetic postganglionic adrenergic nerve terminals
Dopamine- the immediate precursor of noradrenaline
The parent compound of all of the sympathomimetic amines is §-phenylethylamine. This is a benzene ring with an ethylamine side chain (fig. 1). By making substitutions on the aromatic ring and the a- and §-carbons or the terminal amino group, a wide variety of compounds with sympathomimetic activity can be made. As O-dihydroxybenzene is known as catechol, the term 'catecholamine' is applied to sympathomimetic amines that have hydroxyl substitutions in the benzene ring.
There are some generalisations that can be made about the structure- activity relationships of the sympathomimetic amines:
Separation of the Aromatic Ring and Amino Group. By far the greatest sympathomimetic activity occurs when two carbon atoms separate the ring from the amino group.
Substitution on the Amino Group. Increasing the size of the substitution on the amino group generally increases §-receptor activity, except in the case of phenylephrine. Conversely, the less the substitution is on the amino group, the greater is the a- activity.
Substitution on the Benzene Ring. Maximal a- and §- activity depends on the presence of OH groups in the 3 and 4 positions. Hydroxy groups in the 3 and 5 positions confer §2 selectivity on compounds that also have large substituents on the amino group. Phenylethylamines that lack both hydroxyl groups on the ring and in the §- position of the side chain are indirectly acting, that is, they act almost exclusively by causing the release of noradrenaline from adrenergic nerve terminals. Compounds without one or both OH group in the 3 or 4 position are not acted on by catechol-O-methyltransferase in the gut, hence their oral efficacy is improved.
Substitution on the a-Carbon Atom.. This substitution blocks oxidation by monoamine oxidase, greatly prolonging the action of drugs such as ephedrine or amphetamine.
Substitution on the §-Carbon Atom . Substitution of an OH group makes the compound less lipid soluble, hence decreasing central stimulation. However, a- and §- agonist activity are enhanced.
Abscence of a Benzene Ring . Substitution for a different ring generally reduces CNS stimulation without decreasing a- and §- activity, although they tend to have more marked a- effects. Hence they are used mainly as nasal decongestants.
Optical Isomerism. Substitution on either the a or § carbon produces optical isomers. On the a carbon, D-rotation confers greater potency than L-rotation in central stimulant activity. On the §-carbon, L-rotation confers greater peripheral activity, hence naturally occurring l- adrenaline and noradrenaline are ten times as potent as their d isomers.
PHYSIOLOGY OF THE SYMPATHETIC NERVOUS SYSTEM
The preganglionic cholinergic fibers of the sympathetic nervous system arise from the thoracolumbar region of the spinal cord and then synapse in autonomic ganglia. From the autonomic ganglia arise postganglionic adrenergic (neurotransmitter = noradrenaline) or cholinergic fibers (neurotransmitter = acetylcholine). The adrenal medulla is essentially a sympathetic ganglia in which the postganglionic cells have lost their axons and become specialised for secretion directly into the bloodstream, except that the principle catecholamine released is adrenaline (~80%) instead of noradrenaline.
Postganglionic adrenergic neurons act locally on effector cells in a wide variety of tissues, such as vascular smooth muscle, fat, liver, intestines, heart, spleen, brain and spinal cord. The anatomically sympathetic postganglionic cholinergic neurons innervate sweat glands and vasodilate blood vessels in skeletal muscle.
The Adrenergic Receptor
The adrenergic receptors a and § were first described by Ahlquist in 1948, who characterised them according to the order of potency by which they are affected by sympathetic agonists and antagonists. Alpha-receptors are those which are stimulated by catecholamines with an order of potency noradrenaline > adrenaline > isoprenaline, with §-receptors the order is isoprenaline > adrenaline > noradrenaline. Subsequently §-receptors have been further divided into §1 and §2 depending on their relative response to adrenaline and noradrenaline (§1 = I > A > N > D,
§2 = I > A >> N > D).
§1 receptors predominate in the myocardium, but approximately 15% of myocardial §-receptors are §2. Stimulation of the §-receptor sets in change a sequence of events that results in an increase in the intracellular concentration of cyclic AMP which in turn acts to alter cellular function, usually by phosphorylating an enzyme or protein. This includes the phosphorylation of voltage-sensitive calcium channels in the myocardium, which during membrane depolarisation results in an increased influx of calcium across the sarcolemma, producing an increase in inotropy. Binding of a §1 or a §2-agonist to the §-receptor leads to a structural change in the receptor and activation of guanine nucleotide regulatory proteins (G proteins). There are at least three types of G protein in myocardial tissue, those associated with §-receptors may be either stimulatory (Gs) or inhibitory (Gi). The activated Gs protein in turn activates adenyl cyclase, which converts ATP to cyclic AMP. Cyclic AMP is subsequently inactivated to 5-AMP by phosphodiesterase.
The a-receptors have also been subdivided into two groups, a1 and a2. a1receptors are post-synaptic and stimulation of them by noradrenaline produces smooth muscle vasoconstriction. a1 receptors are also abundant in the myocardium and stimulation of them produces increased contractility. Myocardial a1 receptors do not activate adenylate cyclase (AC), and hence have a different biochemical action than §-receptors. These receptors are coupled to another G protein, Gq, which when activated stimulates phospholipase C. This results in the formation of second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), which increase intracellular calcium levels. a-Adrenergic stimulation develops over time, does not cause an increase in heart rate and is most pronounced at low frequencies of myocardial contraction (eg. hypothermia).
a2 receptors are presynaptic. The release of noradrenaline from the pre-synaptic terminal activates the a2 receptor to inhibit the further release of noradrenaline, in other words, a2 stimulation acts as a negative feedback mechanism. In addition, central postsynaptic adrenergic receptors with a2 characteristics have been identified. Stimulation of these receptors appears to lower sympathetic outflow- this is the postulated mechanism of the hypotensive effect of clonidine.
Dopamine receptors can also recognise catecholamines. The dopaminegic receptor (DA) is found in the central nervous system and in renal and mesenteric blood vessels. There are two receptor subtypes: DA1 and DA2. DA1 receptors are found postsynaptically on the sympathetic nerve; stimulation produces vasodilation of renal, mesenteric, coronary and cerebral vessels, along with an increase in sodium excretion. DA2 receptors are presynaptic and activation of them inhibits the release of noradrenaline, like a2 stimulation. Stimulation of DA2 receptors also produces nausea and vomiting, hence accounting for the action of the DA2 antagonist metaclopramide.
Location of adrenergic and dopaminergic receptors at the sympathetic nerve terminal. Noradrenaline stimulates postsynaptic a1 and a2 receptors to produce vasoconstriction. Dopamine stimulates DA1 and DA2 receptors to produce vasodilation. Noradrenaline stimulates presynaptic a2 receptors to inhibit the release of further noradrenaline. Dopamine activates presynaptic a2 and DA2 receptors to inhibit noradrenaline release. (NE=noradrenaline, E=adrenaline, DA=dopamine)
Physiological effects of the sympathomimetic amines
The important clinical effects of adrenergic receptor stimulation by the sympathomimetic drugs can be summarised as follows:
a-receptor stimulation -
i. vasoconstriction -arterioles of heart, brain, kidneys, lungs, skeletal muscle, skin.
iii. inhibition of insulin release
§ 1- receptor stimulation
i. heart- increased contractility, increased rate (SA node), increased atrioventricular conduction velocity and decreased refractory period.
ii. increased liver glycogenolysis and adipose tissue lipolysis
§2 -receptor stimulation
i. vasodilation- skeletal muscle
ii. bronchial relaxation
iii. uterine relaxation (if pregnant)
iv. hypokalaemia due to stimulation of the sodium-potassium pump
Metabolism of the Sympathomimetic Amines
All drugs containing the 3,4-dihydroxybenzene structure (ie. the catecholamines) are rapidly inactivated by the enzymes monoamine oxidase (MAO) and/or catechol-O-methyltransferase (COMT). MAO is found in large amounts in the mitachondria of the sympathetic neurons as well as in the liver and intestine. COMT appears to be localised exclusively outside the sympathetic neuron but in close proximity, and also in large amounts in the liver and kidneys. The final major metabolic product of noradrenaline in man is 3-methoxy-4-hydroxymandelic acid (VMA) which is excreted in the urine.
Despite the importance of enzymatic degradation of catecholamines, their biological actions are terminated principally by uptake into the postganglionic terminal.
Both adrenaline and dopamine are unaltered by passage through the lungs while noradrenaline is removed to a large extent.
The prototypical sympathomimetic amine, adrenaline is the key hormone involved in the body's "fight of flight" response to stress.
Adrenaline causes direct stimulation of a- and §- adrenergic receptors. Stimulation of cardiac §-receptors causes an increase in heart rate and contractility. Cardiac work and MVO2 are markedly increased. When adrenaline increases heart rate within the physiological range it shortens systole more than diastole, so that the duration of diastolic perfusion is increased. It reduces the refractory period of the atrium and improves conduction through the AV node, large doses may provoke arrhythmias. Ventricular arrhythmias are more common when the blood pressure is elevated. When infused at low doses (1-2µg/min.) in an adult, primarily §-stimulation occurs, producing vasodilation. At 2-10µg/min., the effect is mixed a- and §- stimulation, larger doses result in mainly a stimulation which tend to mask the §1 cardiac effects due to the intense vasoconstriction produced. The §- effects outlast the a- effects so secondary hypotension may occur after a bolus or upon termination of an infusion of adrenaline.
CENTRAL NEVOUS SYSTEM EFFECTS
Tremor, anxiety, restlessness and headache may result from large doses.
Respiratory stimulation occurs due to an increase in central respiratory drive. It also has a powerful bronchodilator action due to its §2 agonism.
Produces a reduction in splanchnic blood flow and a reduction in gut tone and motility.
Decreases renal blood flow, GFR (a). Detrusor muscle relaxation and increased vesical sphincter tone.
Adrenaline raises blood glucose and free fatty acids. The lipolytic action is mediated by §1 receptors . These effects are more pronounced in diabetic patients with (but not in those without) autonomic neuropathy. Adrenaline also produces hypokalaemia due to a §2 mediated increase in potassium influx into cells.
Adrenaline is useful in the management of cardiac arrest, peripheral vascular collapse (such as anaphylaxis), acute heart failure and in cardiac surgery. Its usefulness in cardiac arrest is due primarily to the increase in coronary perfusion pressure resulting from a -stimulation. Following CPB, adrenaline at 0.04µg/kg/min. when compared to dopamine and dobutamine at 5-15µg/kg/min. has been shown to produce the largest increase in CI and MAP, without producing a significant increase in heart rate.
Adrenaline used to be the mainstay of therapy for sever bronchospasm before the advent of selective §2 agonists.
Adrenaline is commonly added to local anaesthetic solutions to prolong their duration of action.
DOSAGE AND PRECAUTIONS
To increase myocardial contractility adrenaline is given by infusion in the range of 0.01-0.1µg/kg/min. For cardiovascular emergencies 0.2-1.0mg. intravenous boluses may be repeated every 2-5minutes.
The volatile agents (particularly halothane) sensitise the myocardium to adrenaline, increasing the risk of ventricular arrhythmias. During halothane anaesthesia, it is recommended that the total dose of 1:100,000 solution should not exceed more than 10ml in 10 minutes or 30ml. in one hour.
Noradrenaline, like adrenaline is a naturally occurring catecholamine. It is the chemical neurotransmitter liberated by postganglionic adrenergic neurons.
The major difference between noradrenaline and adrenaline is that the a- stimulating effects of noradrenaline are clinically apparent at lower doses of the drug, producing pronounced arteriolar vasoconstriction and an increase in SVR. Renal, hepatic and cerebral blood flow are all reduced. Normally this results in a reflex bradycardia and CO may be reduced. However, in the patient with severe hypotension, noradrenaline does not normally produce reflex bradycardia and the CO is well maintained. Noradrenaline is indicated where severe hypotension due to a marked reduction in SVR (such as in septic shock or anaphylaxis) and in situations where it is essential to maintain an adequate coronary perfusion pressure, eg. cardiogenic shock due to acute MI or after cardiac surgery.
There is little bronchdilator effect. Respiratory minute volume is slightly increased.
DOSAGE AND PRECAUTIONS
The usual dose range in an adult is 2-4µg/min.
Extravasation can produce necrosis at the site of injection, hence it should be administered centrally. Prolonged infusion of noradrenaline will result in reduced blood flow to organ beds and may also produce peripheral ischaemia.
Isopenaline is a synthetic catecholamine with pure §-adrenergic receptor activity.
Stimulation of cardiac §1-receptors results in an increase in heart rate, contractility and automaticity. The resulting net increase in CO may be limited by impairment of cardiac filling due to rate and rhthym changes along with a reduction in preload due to venodilation. Stimulation of §2-receptors results in dilation of all vascular smooth muscle, producing a marked reduction in SVR and an increase in venous capacitance. Isoprenaline should be used with caution in the presence of coronary artery disease as it produces an increase in MVO2 while reducing the CPP, leading to a mismatch in myocardial oxygen supply and demand. Following CPB, isoprenaline produces more tachycardia and a smaller increase in CI than dobutamine, and it frequently produces arrrythmias. It has also been shown to produce an intracoronary steal in dogs with experimental acute coronary occlusion. However, it is occasionally useful in patients with CAD who have profound §-blockade as it is the most potent of the §-adrenergic stimulating drugs.
Isoprenaline remains the drug of choice in the treatment of acute bradyarrythmias or AV block. It reduces the refractory period of pacemaker cells and increases automaticity. The resulting tachycardia is both the result of direct effects on the SA and AV node and reflex effects due to peripheral vasodilation.
Isoprenaline is also useful in patients with right ventricular failure due to the combination of its inotropic action and its pulmonary vasodilator action.
Marked bronchodilation occurs from §2-stimulation.
DOSAGE AND SIDE EFFECTS
Isoprenaline is titrated by infusion to patient response, the usual range is 0.01-0.1µg/kg/min. The side effectsthat can occur are tachycardia, ventricular arrythmias and hypotension.
Dopamine differs from the other naturally occurring catecholamines in lacking a hydroxyl group on the §-carbon atom . It is the immediate precursor of noradrenaline. Dopamine is an agonist at both the DA1 and DA2 receptors along with the a1 and a2 receptors. Dopamine is a §1 agonist but with minimal effect at the §2 receptor.
At low infusion rates (0.1-3µg/kg/min.) stimulation of postjunctional DA1 dopaminergic receptors occurs, stimulating diuresis due to a rise in renal blood flow, glomerular filtration rate and sodium excetion, along with vasodilation in mesenteric, coronary and cerebral vascular beds. These changes are accompanied by little or no change in cardiac output or heart rate. Some vasodilation may result from stimulation of pre-junctional DA2 receptors and inhibition of noradrenaline release. Low dose dopamine infusion is useful in improving renal blood flow in the oliguric patient, these effects are maximal at 2-3µg/kg/min. Infusion of dopamine at medium rates (2-6µg/kg/min.) produces §1 stimulation resulting in an increase in myocardial contractility, stroke volume and cardiac output, with an increase in cardiac output and a further increase in renal blood flow. Beginning at doses as low as 5µg/kg/min., a-receptor stimulation occurs and overrides the DA2 receptor effects, producing vasoconstriction. Medium infusion rates are useful in providing inotropic support. Higher doses of dopamine (over 30µg/kg/min.) produce marked a-stimulation, with an increase in SVR, a decrease in RBF, and an increased potential for arrythmias. In addition, reflex bradycardia may occur.
Dopamine is useful where a combination of inotropy and vasoconstriction is required. It is a less powerful inotrope than adrenaline or isoprenaline, with many properties similar to low dose adrenaline. When compared to dobutamine, dopamine produces a greater increase in SVR as it stimulates a1-receptors but not vascular §2 receptors. Hence in contrast to dobutamine, it does not change or may increase ventricular filling pressures. Dopamine is useful in cardiogenic shock (particularly in combintion with a vasodilator), septic shock and other patients in need of haemodynamic support.
There is evidence emerging that low-dose dopamine infusions are of no value in producing Ôrenal sparingÕ in the critically ill patient. It has been shown to have no beneficial effect on renal function postoperatively in major vascular cases nor to prevent postoperative renal failure following liver translantation. Moreover, because of the wide individual variability in response to low-dose dopamine and the considerable overlap of its effects, this therapy carries significant risks. Tachycardia, arrhythmias, myocardial ischaemia and infarction can occur. Low-dose dopamine blunts hypoxic ventilatory drive, it may increase the shunt fraction in critically ill patients and it can cause digital necrosis. In a porcine shock model, it has been shown to hasten the development of gut ischaemia, presumably through precapillary vasoconstriction with diversion of blood flow away from the gut mucosa. Mucosal ischaemia and the subsequent translocation of bacteria or bacterial toxins plays a part in the development of multiple organ dysfunction syndrome, low-dose dopamine may in fact exacerbate this process.
Nausea, vomiting, headache, arrhythmias, hypertension and dyspnoea may occur. Extravasation may produce sloughing and necrosis due to local a-effects.
Comparison of the cardiovascular effects of iv. infusion of adrenaline, noradrenaline, isoprenaline and dopamine
Dobutamine is a synthetic derivative of isoprenaline that is primarily a §1 -agonist. It is a powerful inotrope that augments ventricular contractility, SV and CO. Some of its positive inotropic effects may also be mediated through stimulation of myocardial a1 receptors. DobutamineÕs peripheral a1 -agonist effects are offset by its §2-agonism, producing an overall mild vasodilatory effect. Although dobutamine increases SA node automaticity and intraventricular conduction, it produces greater inotropy than chronotropy. In contrast to dopamine, it does not stimulate dopamine receptors nor does it cause release of noradrenaline.
Dobutamine exists as two stereoisomers, the (+) and (-) forms have differing potencies at different receptors, the commercial preparation is a racemic mixture of the two.
Dobutamine is useful in treating low CO states associated with chronic CHF, MI and cardiac surgery. Dobutamine reduces preload more than dopamine in patients with CHF, and produces a greater increase in cardiac index. Following CPB, dobutamine produces less tachycardia and a greater increase in CI than isoprenaline. Dobutamine probably produces less tachycardia than dopamine after CPB, with a greater reduction in preload. When compared to adrenaline, however, dobutamine produces significantly more tachycardia.
The usual dose range is 2-10µg/kg/min.
Dopexamine is a new synthetic catecholamine that has marked intrinsic §2- agonist activity along with less pronounced agonism at DA1 and DA2 receptors. Dopexamine has no a-activity and weak §1 agonism. Dopexamine produces some indirect §1 stimulation by inhibiting the reuptake of noradrenaline.
Dopexamine has mild inotrope and marked vasodilator properties. When compared with dobutamine, it produces a greater increase in blood flow to the kidneys, gut and skeletal muscle. Dopexamine produces less renal vasodilation and sodium excretion than equivalent doses of dopamine.
Dopexamine has been used in the management of CHF. Its beneficial effects of an increase in CI and a decrease in filling pressures are mainly due to vasodilation and mild inotropy, whereas dopamine produces more inotropy and a smaller increase in heart rate. The usual dose range of dopexamine in CHF is 0.25-1.0µg/kg/min., higher doses may result in an increase in ventricular arrhythmias and tachycardia.
Dopexamine is also useful in higher doses (1-4µg/kg/min.) following CPB where similar haemodynamic changes occur. At doses above 4µg/kg/min., tachycardia and hypotension may be a problem.
There has been considerable interest in the use of dopexamine in the septic or shocked patient. It is hypothesised that the improvement in organ blood flow from dopexamine might reverse or prevent the reduction that occurs due to endotoxaemia. There are animal studies that both support and oppose this hypothesis. Several animal tudies have shown that a variety of sympathomimetics (including noradrenaline) do not produce their usual redistribution of blood flow away from the small intestine and liver during the septic state. This is presumably due to depressed vascular reactivity occuring during sepsis, hence dopexamine may not possess any clinical advantages over agents such as dobutamine. In man, dopexamine has been shown to to induce gastric mucosal acidosis (indicating inadequate mucosal blood flow) despite an increase in splanchnic blood flow. However,when dopexamine was infused perioperatively to increase oxygen delivery in a prospective study of 107 high-risk surgical cases, it significantly decreased mortality and morbidity compared to the control group. This study was not blinded, however. If confirmed, this result might conceivably be solely due to the improvement in oxygen delivery andnot to any specific effects of dopexamine on regional blood flow.
Ephedrine is a synthetic sympathomimetic amine that does not possess the catechol nucleus and is therefore not metabolised by COMT. It is the active ingredient of the plant Ma Huang and it has been used for centuries in China.
Ephedrine stimulates both a- and §-receptors and acts both directly and indirectly. Its effects are similar to those of adrenaline, although they persist longer. Ephedrine can be given orally as it resistant to MAO, the dose is 15-50mg. The dose is 10-15mg. iv. or im.
Phenylephrine is a directly acting sympathomimetic with strong a-stimulating and weak §-receptor activity.
It produces a marked increase in SVR, with a reflex decrease in heart rate. Cardiac output is either unchanged or decreased, filling pressures are increased. The blood flow to the viscera, kidneys and skin are all reduced.
Phenylephrine may be given as a bolus (50-100µg.iv.) or by infusion at at a rate of 0.15-0.7µg/kg/min.
Metaraminol has both direct and indirect actions. It acts predominantly at a-receptors but it has weak §- activity as well. It produces similar haemodynamic effects to phenylephrine. The iv. bolus dose is 50-100µg., the usual rate of infusion in the adult is 40-500µg/min.
Methoxamine is a potent, directly acting vasopressor with almost pure a-activity and with a long duration of action (1-2 hours). The usual dose is 10-20mg. im. or 2-10mg. given slowly iv.
Selective §2 -receptor agonists
Increasing the size of the substitution on the amino group of isoprenaline increases the §2 activity of the resultant compounds. Examples of these compounds include salbutamol, terbutaline, ritodrine, metaproterenol, fenoterol and orciprenaline. Higher doses of all of these agents produces §1 effects. They are used primarily as bronchodilators and to inhibit uterine activity in premature labour.
Salbutamol will produce a prompt reduction in airway resistance for up to 4-6 hours when administered by aerosol (100µg per inhalation). Cardiac effects are unlikely if the aerosol dose ia kept below 400µg. Salbutamol and isoprenaline are equipotent as bronchodilators but approximately ten times the dose of salbutamol is required to produce cardiac effects. When given intravenously, cardiac effects are more prominent and hypokalaemia may develop.
Other Sympathomimetic Amines
Included are amphetamine, methamphetamine, mephenteramine and some newer agents such as:
i). Prenalterol- a relatively selective §1 agonist that has been used in the management of CHF. It is also useful orally, with a bioavailability of about 33%.
ii). Pirbuterol- a §2 agonist which has ben used both as a bronchodilator and as as inotrope.
iii). Xamaterol- an orally active partial §1 agonist used for chronic CHF
iv). Dopamine analogs- aside from dopexamine a number of other dopamine analogs have been employed in the treatment of CHF and hypertension. These include l-dopa, ibopamine, propylbutyl dopamine and fenoldopam.
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