Vasopressors

Dr. Paul Forrest

Royal Prince Alfred Hospital

Vasopressors are any agents which produce an increase in vascular smooth muscle tone. In anaesthesia, vasopressors are administered to produce an increase in systemic blood pressure, this handout will also cover other specialised applications such as their use in haemodynamic support following cardiopulmonary bypass, septic shock and cardiopulmonary resuscitation.

The vasopressors that are in common clinical use all produce an increase in the level of intracellular calcium in vascular smooth muscle. This is mediated either through a-receptor stimulation or can be brought about by raising the extracellular ionised calcium concentration. Hence vasopressors are either drugs that mimic the effects of sympathetic nervous system stimulation (the sympathomimetic amines) or they are drugs that raise the concentration of extracellular ionised calcium (eg. calciumchloride).

The Sympathomimetic Amines

The sympathomimetic amines may be divided into catechol- and noncatecholamines. Their efficacy as vasopressors depends on their relative potency as a-receptor agonists.

The chatecholamines with prominent a- agonist activity are:

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 noncatecholamines commonly used as vasopressors are:

Ephedrine

Phenylephrine

Metaraminol

Methoxamine

Chemistry of the Sympathomimetic Amines

The parent compound of all of the sympathomimetic amines is ß-phenylethylamine. This is a benzene ring with an ethylamine side chain (fig. 1). By making substitutions on the aromatic ring and the a- and ß-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.

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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 ß-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 ß- activity depends on the presence of OH groups in the 3 and 4 positions. Hydroxy groups in the 3 and 5 positions confer ß2 selectivity on compounds that also have large substituents on the amino group. Phenylethylamines that lack both hydroxyl groups on the ring and in the ß- 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 ß-Carbon Atom . Substitution of an OH group makes the compound less lipid soluble, hence decreasing central stimulation. However, a- and ß- agonist activity are enhanced.

Abscence of a Benzene Ring . Substitution for a different ring generally reduces CNS stimulation without decreasing a- and ß- 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 ß carbon produces optical isomers. On the a carbon, D-rotation confers greater potency than L-rotation in central stimulant activity. On the ß-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 actions of all of the sympathomimetic amines are quite predictable once you understand the physiology of the sympathetic nervous system and the relative potency that individual agents have at different sympathetic receptors. For the sake of completeness I have included a description of the ß and dopamine receptors, this is because the differring actions of the sympathomimetic vasopressors on these receptors is of clinical relevence..

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 ß 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 ß-receptors the order is isoprenaline > adrenaline > noradrenaline. Subsequently ß-receptors have been further divided into ß1 and ß2 depending on their relative response to adrenaline and noradrenaline (ß1 = I > A > N > D,

ß2 = I > A >> N > D).

ALPHA RECEPTORS

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 ß-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). These second messengers in turn bring about release of Ca2+ from the sarcoplasmic reticulum and may also increase the Ca2+ sensitivity of contractile protein. The net effect is an increase in the force of contraction of the contractile proteins.

a1-receptors are involved in the adrenergic control of vascular resistance in both arteriolar and capacitance vessels, along with a variety of other tissues. The existence of a-receptors in the coronary arteries of humans has yet to be established, however it has recently been recognised that a1-receptor stimulation also produces an inotropic response. This inotropic response is not mediated by cAMP, it develops over time, it does not cause an increase in heart rate and it is most pronounced at low frequencies of myocardial contraction (eg. hypothermia).

a2 receptors are both presynaptic and postsynaptic. 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. Postjunctional a2- receptors are also located on resistance and capacitance vessels which mediate vasoconstriction. The effects of activation of these receptors differ from those of a1-receptor activation in that they are slower in onset, longer lasting, more sensitive to pH and temperature changes and may be mediated by angiotensin II. 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.

BETA RECEPTORS

ß1 receptors predominate in the myocardium, but approximately 15% of myocardial ß-receptors are ß2. Stimulation of the ß-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 ß1 or a ß2-agonist to the ß-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 ß-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.

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DOPAMINE RECEPTORS

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.

ii. mydriasis

iii. inhibition of insulin release

ß 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

ß2 -receptor stimulation

i. vasodilation- skeletal muscle

ii. bronchial relaxation

iii. uterine relaxation (if pregnant)

iv. hypokalaemia-due to stimulation of the sodium-potassium pump

CATECHOLAMINE VASOPRESSORS

Adrenaline

The prototypical sympathomimetic amine, adrenaline is the key hormone involved in the body's "fight of flight" response to stress.

CARDIOVASCULAR EFFECTS

Adrenaline causes direct stimulation of a- and ß- adrenergic receptors. Its effects on the peripheral vasculature are mixed. It has mainly a1 stimulating properties in some vascular beds (skin, mucosa and kidney) and ß2. stimulating properties in others (skeletal muscle). These effects are dose-dependent. When infused at low doses (0.05-0.2µg/kg/min.) in an adult, primarily ß-stimulation occurs, producing inotropy and vasodilation. Above 0.3µg/kg/min., the effect is mixed a- and ß- stimulation with a effects predominating, these tend to mask the ß1 cardiac effects due to the intense vasoconstriction produced. The ß- effects outlast the a- effects so secondary hypotension may occur after a bolus or upon termination of an infusion of adrenaline.

Stimulation of cardiac ß-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.

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, greater infusion rates than usual may be required to produce a response due to down-regulation of myocardial ß1-receptors. Adrenaline at 0.04µg/kg/min. when compared to dopamine and dobutamine at 5-15µg/kg/min. following CPB has been shown to produce the largest increase in CI and MAP, without producing a significant increase in heart rate.

CENTRAL NEVOUS SYSTEM EFFECTS

Tremor, anxiety, restlessness and headache may result from large doses.

RESPIRATORY EFFECTS

Respiratory stimulation occurs due to an increase in central respiratory drive. It also has a powerful bronchodilator action due to its ß2 agonism.

METABOLIC EFFECTS

Adrenaline raises blood glucose and free fatty acids. The lipolytic action is mediated by ß1 receptors . These effects are more pronounced in diabetic patients with (but not in those without) autonomic neuropathy. Adrenaline also produces hypokalaemia due to a ß2 mediated increase in potassium influx into cells.

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) sensitize 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 30ml. in one hour.

Noradrenaline

Noradrenaline, like adrenaline is a naturally occurring catecholamine. It is the chemical neurotransmitter liberated by postganglionic adrenergic neurons. It produces direct activation of both a and ß receptors in a dose-dependent manner. It is a potent a- adrenergic and a moderate ß1-adrenergic agonist with almost no ß2 effect.

CARDIOVASCULAR EFFECTS

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. Although increased diastolic pressure and filling time may improve coronary perfusion, this may be offset by the increased workload and oxygen consumption resuling from the increased preload, afterload and contractility that is produced.

INDICATIONS

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.

Noradrenaline can effectively restore vascular tone in high-output septic shock, with less tacharrythmia than dopamine. It may have undesirable effects in reducing organ perfusion, particularly to the gut, which may facilitate bacterial translocation and endotoxin resorption.

DOSAGE AND PRECAUTIONS

The usual dose range is 0.05-0.1µg/kg/min. Use of the minimal effective dose requires invasive haemodynamic monitoring and close attention to fluid management to minimise the potential for complications.

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 renal failure and peripheral necrosis.

Dopamine

Dopamine differs from the other naturally occurring catecholamines in lacking a hydroxyl group on the ß-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 ß1 agonist but with minimal effect at the ß2 receptor.

CARDIOVASCULAR EFFECTS

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 ß1 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.

INDICATIONS

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 ß2 receptors. Hence in contrast to dobutamine, it does not change or may increase ventricular filling pressures.

Dopamine may be useful in cardiogenic shock or left ventricular failure (particularly in combintion with a vasodilator). However, there is a wide individual variation in the dose required to produce a- effects in the shocked patient (up to 20µg/kg/min) hence the use of dopamine as a primary adrenergic agent is being re-examined. Dopamine (along with adrenaline and noradrenaline) increases mean pulmonary artery pressures and is therefore not recommended as a sole support in patients with right ventricular failure, ARDS or pulmonary hypertension.

There is evidence emerging that low-dose dopamine infusions are of no value in producing ‘renal sparing’ in the critically ill patient. Dopamine 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.

SIDE EFFECTS

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

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.

NONCATECHOLAMINE VASOPRESSORS

Ephedrine

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 ß-receptors and acts both directly and indirectly. Cardiac output and heart rate are increased, vasoconstriction is almost balanced by vasodilatation and overall vascular resistance is usually only mildy increased or unchanged. Larger doses produce more vasoconstriction. Its effects are similar to those of adrenaline, although they persist longer.

Ephedrine is used as a vasopressor for hypotension due to vasodilation occurring during general or neuraxial anaesthesia. It is the vasopressor of choice for use during pregnancy, because of its mixed a- and ß- effects it does not produce significant reductions in uterine blood flow, as do pure a- agonists.

The dose is 5-15mg. iv. or im.

Ephedrine is excreted unchanged in the urine within 24 hours. It is not metabolised by MAO, therefore it is active when given orally.

Phenylephrine

Phenylephrine is a potent, directly acting sympathomimetic with strong a-stimulating and weak ß-receptor activity.

It produces a marked increase in SVR, with a reflex decrease in heart rate. It has less effect on heart rate than noradrenaline due to its weaker ß- effects. 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 used to correct hypotension during spinal anaesthesia, 5-10mg. im. will produce a prolonged effect. It is also a useful agent to treat myocardial ischaemia by raising the coronary perfusion pressure, when it is usually combined with a nitrate. During cardiopulmonary bypass, phenylephrine can be used to raise the mean perfusion pressure.

If given iv. , phenylephrine may be given as a bolus (50-100µg) or by infusion at at a rate of 0.15-0.7µg/kg/min.

Metaraminol

Metaraminol has both direct and indirect actions. It acts predominantly at a-receptors but it has weak ß- activity as well. It produces similar haemodynamic effects to phenylephrine.

Metaraminol is most commonly administered to treat hypotension occurring during general anaesthesia or during epidural or spinal anaesthesia. It is also commonly given during CPB to raise the mean perfusion pressure.

The iv. bolus dose is 50-100µg., the usual rate of infusion in the adult is 40-500µg/min. A bolus iv. dose acts within 1-3minutes and lasts for about 25 minutes. The usual im. dose is 2-10mg, this acts within 5-10 minutes and will last for an hour or more.

Methoxamine

Methoxamine is a potent, directly acting vasopressor with almost pure a-activity and a long duration of action (1-2 hours). It has similar actions and indications to phenylephrine. The usual dose is 10-20mg. im. or 2-10mg. given slowly iv. , iv. doses act within 2 minutes and may last about an hour.

VASOPRESSOR -DRUG INTERACTIONS

Halothane

Halothane sensitises the myocardium to catecholamines, the maximum doses of adrenaline recommended are no more than 10ml of 1:100 000 solution in 10 minutes and a maximum of 0.3mg in 1 hour.

MAOIs

Indirectly acting vasopressors such as ephedrine and metaraminol can produce dangerous hypertension in patients taking monoamine oxidase inhibitors.

TCAs, Cocaine, Reserpine

TCAs inhibit the reuptake of noradrenaline. The pressor response to direct -acting vasopressors such as adrenaline, noradrenaline and phenylephrine in patients taking TCAs will be greatly increased- by up to 10 fold. This response will also be seen will also be seen with cocaine and reserpine.

Oxytocin, Ergometrine

Severe hypertension may occur when any of the vasopressors are combined with oxytocics or with the ergot alkaloids. Hence they should be avoided if possible or used with caution.

The Role of Calcium as a Vasopressor

PHYSIOLOGY

Raising either extracellular or intracellular Ca2+ increases cardiac and vascular contractility. Increasing the level of extracellular Ca2+ results in diffusion of calcium into the cell , this process in turn stimulates the release of additional calcium from the sarcoplasmic reticulum (‘calcium-dependent calcium release), which further augments smooth muscle contraction.

CARDIOVASCULAR EFFECTS

Most studies indicate that CaCl2 (in doses of 5mg/kg or more) will effectively raise the mean arterial pressure. This occurs mainly due to an increase in SVR, although the effect is transient (around 20 minutes). Calcium does not reliably increase cardiac output or oxygen delivery in normocalcaemic or mildly hypocalcaemic patients following CPB or in critically ill patients. There is also evidence that the use of calcium (at least in larger doses ) reduces the efficacy of ß-adrenergic agents such as adrenaline and dobutamine.

ADVERSE EFFECTS

A high Ca2+ level may produce heart block due to AV node depression. Vasoconstriction produced by calcium may contribute to organ failure. High intracellular calcium levels worsen the cellular damage that occurs during ischaemia or shock, conversely, the use of calcium channel blockers may be useful in limiting this damage. Large doses of CaCl2 given on weaning from CPB have beenimplicated as causes of both pancreatic damage and of spasm of the internal mammary artery graft, resulting in myocardial ischaemia.

INDICATIONS

In view of their limited efficacy and potential for toxicity, the use of calcium salts as vasopressors/inotropes should be limited to the treatment of severe hypocalcaemia (ie. ionised calcium

<0.8mmol/l), hyperkalaemia and calcium-channel blocker overdose.

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