Noradrenaline/norepinephrine is synthesised and stored in vesicles within adrenergic nerve terminals (Fig. 23.1). The vesicles can be released from these stores by stimulating the nerve or by drugs (ephedrine, amfetamine). The noradrenaline/norepinephrine stores can also be replenished by intravenous infusion of noradrenaline/norepinephrine, and abolished by reserpine or by cutting the sympathetic nerve. Sympathomimetics may be classified on the basis of their sites of action (see Fig. 23.1) as acting:

1. Directly: adrenoceptor agonists, e.g. adrenaline/epinephrine, noradrenaline/norepinephrine, isoprenaline (isoproterenol), methoxamine, xylometazoline, metaraminol (entirely); and dopamine and phenylephrine (mainly).

2. Indirectly: by causing a release of preformed noradrenaline/norepinephrine from stores in nerve endings,³ e.g. amfetamines, tyramine; and ephedrine (largely).

3. By both mechanisms (1 and 2, though one usually predominates): other synthetic agents.

All of the above mechanisms operate in both the central and peripheral nervous systems, but discussion below will focus on agents that influence peripheral adrenergic mechanisms.

Fig. 23.1 Noradrenergic nerve terminal releasing noradrenaline/norepinephrine (NA) to show the sites of action of drugs that impair or mimic adrenergic function. α and β refer to adrenergic receptor subtypes; MAO, monoamine oxidase.

α₁-Adrenoceptor effects^a	β-Adrenoceptor effects
Eye:^b mydriasis
	Heart (β₁, β₂):^c
	increased rate (SA node)
	increased automaticity (AV node and muscle)
	increased velocity in conducting tissue
	increased contractility of myocardium
	increased oxygen consumption; decreased refractory period of all tissues
Arterioles:	Arterioles:
constriction (only slight in coronary and cerebral)	dilatation (β₂)
	Bronchi (β₂): relaxation
	Anti-inflammatory effect:
	inhibition of release of autacoids (histamine, leukotrienes) from mast cells, e.g. asthma in type I allergy
Uterus: contraction (pregnant)	Uterus (β₂): relaxation (pregnant)
	Skeletal muscle: tremor (β₂)
Skin: sweat, pilomotor
Male ejaculation
Blood platelet: aggregation
Metabolic effect:	Metabolic effects:
hyperkalaemia	hypokalaemia (β₂)
	hepatic glycogenolysis (β₂)
	lipolysis (β₁, β₂)
Bladder sphincter: contraction	Bladder detrusor: relaxation
Intestinal smooth muscle relaxation is mediated by α and β adrenoceptors. α₂-adrenoceptor effects:^a α₂ receptors on the nerve ending, i.e. presynaptic autoreceptors, mediate negative feedback which inhibits noradrenaline/norepinephrine release
Use of the term cardioselective to mean β₁-receptor selective only, especially in the case of β-receptor blocking drugs, is no longer appropriate.
Although in most species the β₁ receptor is the only cardiac β receptor, this is not the case in humans. What is not generally appreciated is that the endogenous sympathetic neurotransmitter noradrenaline/norepinephrine has about a 20-fold selectivity for the β₁ receptor – similar to that of the antagonist atenolol – with the consequence that under most circumstances, in most tissues, there is little or no β₂-receptor stimulation to be affected by a non-selective β-blocker. Why asthmatics should be so sensitive to β-blockade is paradoxical: all the bronchial β receptors are β₂, but the bronchi themselves are not innervated by noradrenergic fibres and the circulating adrenaline levels are, if anything, low in asthma.

a For the role of subtypes (α₁ and α₂), see prazosin.

b Effects on intraocular pressure involve both α and β adrenoceptors as well as cholinoceptors.

c Cardiac β₁ receptors mediate effects of sympathetic nerve stimulation. Cardiac β₂ receptors mediate effects of circulating adrenaline, when this is secreted at a sufficient rate, e.g. following myocardial infarction or in heart failure. Both receptors are coupled to the same intracellular signalling pathway (cyclic AMP production) and mediate the same biological effects.

Consequences of adrenoceptor activation

All adrenoceptors are members of the G-coupled family of receptor proteins, i.e. the receptor is coupled to its effector protein through special transduction proteins called G-proteins (themselves a large protein family). The effector protein differs among adrenoceptor subtypes. In the case of β-adrenoceptors, the effector is adenylyl cyclase and hence cyclic AMP is the second messenger molecule. For α-adrenoceptors, phospholipase C is the commonest effector protein and the second messenger here is inositol trisphosphate (IP₃). It is the cascade of events initiated by the second messenger molecules that produces the variety of tissue effects shown in Table 23.1. Hence, specificity is provided by the receptor subtype, not the messengers.

Selectivity for adrenoceptors

The following classification of sympathomimetics and antagonists is based on selectivity for receptors and on use. But selectivity is relative, not absolute; some agonists act on both α and β receptors, some are partial agonists and, if sufficient drug is administered, many will extend their range. The same applies to selective antagonists (receptor blockers), e.g. a β₁-selective-adrenoceptor blocker can cause severe exacerbation of asthma (a β₂ effect), even at low dose. It is important to remember this because patients have died in the hands of doctors who have forgotten or been ignorant of it.⁴

Adrenoceptor agonists (see Table 23.1)

α + β effects, non-selective:

adrenaline/epinephrine is used as a vasoconstrictor (α) with local anaesthetics, as a mydriatic (α), and in the emergency treatment of anaphylactic shock (see p. 116).

α₁ effects:

noradrenaline/norepinephrine (with slight β effect on the heart) is selectively released physiologically, but as a therapeutic agent it is used for hypotensive states, excepting septic shock where dopamine and dobutamine are preferred (for their cardiac inotropic effect). Other agents with predominantly α₁ effects are imidazolines (xylometazoline, oxymetazoline), metaraminol, phenylephrine, phenylpropanolamine, ephedrine and pseudoephedrine; some are used solely for topical vasoconstriction (nasal decongestants).

α₂ effects in the central nervous system:

clonidine, moxonidine.

β effects, non-selective (i.e. β₁ + β₂):

isoprenaline (isoproterenol). Used as a bronchodilator (β₂), positive cardiac inotrope and to enhance conduction in heart block (β₁, β₂), it has been largely superseded by more selective agents. Other non-selective β agonists (ephedrine and orciprenaline) are also obsolete.

β₁ effects, with some α effects:

dopamine, used in cardiogenic shock.

β₁ effects:

dobutamine, used for cardiac inotropic effect.

β₂ effects,

used in asthma, or to relax the uterus, include: salbutamol, terbutaline, fenoterol, pirbuterol, reproterol, rimiterol, isoxsuprine, orciprenaline, ritodrine.

Adrenoceptor antagonists (blockers)

See page 402.

Effects of a sympathomimetic

The overall effect of a sympathomimetic depends on the site of action (receptor agonist or indirect action), on receptor specificity and on dose; for instance adrenaline/epinephrine ordinarily dilates muscle blood vessels (β₂; mainly arterioles, but veins also) but in very large doses constricts them (α). The end results are often complex and unpredictable, partly because of the variability of homeostatic reflex responses and partly because what is observed, e.g. a change in blood pressure, is the result of many factors, e.g. vasodilatation (β) in some areas, vasoconstriction (α) in others, and cardiac stimulation (β).

To block all the effects of adrenaline/epinephrine and noradrenaline/norepinephrine, antagonists for both α and β receptors must be used. This can be a matter of practical importance, e.g. in phaeochromocytoma (see p. 419).

Physiological note

The termination of action of noradrenaline/norepinephrine released at nerve endings is by:

• reuptake into nerve endings by the noradrenaline/norepinephrine transporter where it is stored in vesicles or metabolised by monoamine oxidase (MAO) (see Fig. 23.1)

• diffusion away from the area of the nerve ending and the receptor (junctional cleft)

• metabolism (by extraneuronal MAO and catechol-O-methyltransferase, COMT).

These processes are slower than the rapid destruction of acetylcholine at the neuromuscular junction by extracellular acetylcholinesterase seated alongside the receptors. This reflects the differing signalling requirements: almost instantaneous (millisecond) responses for voluntary muscle movement versus the much more leisurely contraction of arteriolar muscle to control vascular resistance.

Synthetic non-catecholamines

in clinical use have a t_½ of hours, e.g. salbutamol 4 h, because they resist enzymatic degradation by MAO and COMT. They may be given orally, although much higher doses are then required versus parenteral routes. They penetrate the central nervous system (CNS) and may have prominent effects, e.g. amfetamine. Substantial amounts appear in the urine.

Pharmacokinetics

Catecholamines

(adrenaline/epinephrine, noradrenaline/norepinephrine, dopamine, dobutamine, isoprenaline) (plasma t_½ approx. 2 min) are metabolised by MAO and COMT. These enzymes are present in large amounts in the liver and kidney, and account for most of the metabolism of injected catecholamines. MAO is also present in the intestinal mucosa (and in peripheral and central nerve endings). COMT is present in the adrenal medulla and tumours arising from chromaffin tissue, but not in sympathetic nerves. This explains the recent discovery that the COMT product, metanephrines, is a more sensitive and specific marker of phaeochromocytoma than measurement of the parent catecholamines. Because of both enzymes catecholamines are ineffective when swallowed (they are not bioavailable), but non-catecholamines, e.g. salbutamol and amfetamine, are effective orally.

Adverse effects

These may be deduced from their actions (Table 23.1, Fig. 23.2). Tissue necrosis due to intense vasoconstriction (α) around injection sites occurs as a result of leakage from intravenous infusions. The effects on the heart (β₁) include tachycardia, palpitations, cardiac arrhythmias including ventricular tachycardia and fibrillation, and muscle tremor (β₂). Sympathomimetic drugs should be used with great caution in patients with heart disease.

Fig. 23.2 Cardiovascular effects of noradrenaline/norepinephrine, adrenaline/epinephrine and isoprenaline (isoproterenol): pulse rate (beats/min), blood pressure in mmHg (dotted line is mean pressure), peripheral resistance in arbitrary units. The differences are due to the differential α- and β-agonist selectivities of these agents (see text). (By permission, after Ginsburg J, Cobbold A F 1960 In: Vane J R, Wolstenholme G E W, O’Connor M O (eds) Adrenergic Mechanisms. Churchill, London, pp. 173–179.)

The effect of the sympathomimetic drugs on the pregnant uterus is variable and difficult to predict, but serious fetal distress can occur, due to reduced placental blood flow as a result both of contraction of the uterine muscle (α) and arterial constriction (α). β₂ agonists are used to relax the uterus in premature labour, but unwanted cardiovascular actions (tachycardia in particular) can be troublesome for the mother. The oxytocin antagonist atosiban does not have these unwanted effects.

Sympathomimetics and plasma potassium

Adrenergic mechanisms have a role in the physiological control of plasma potassium concentration. The Na/K pump that shifts potassium into cells is activated by β₂-adrenoceptor agonists (adrenaline/epinephrine, salbutamol, isoprenaline) and can cause hypokalaemia. β₂-adrenoceptor antagonists block the effect.

The hypokalaemic effect of administered (β₂) sympathomimetics may be clinically important, particularly in patients with pre-existing hypokalaemia, e.g. due to intense adrenergic activity such as occurs in myocardial infarction,⁵ in fright (admission to hospital is accompanied by transient hypokalaemia), or with previous diuretic therapy, and patients taking digoxin. In such subjects the use of a sympathomimetic infusion or of an adrenaline/epinephrine-containing local anaesthetic may precipitate cardiac arrhythmia. Hypokalaemia may occur during treatment of severe asthma, particularly where the β₂-receptor agonist is combined with theophylline.

β-adrenoceptor blockers, as expected, enhance the hyperkalaemia of muscular exercise, and one of their benefits in preventing cardiac arrhythmias after myocardial infarction may be due to block of β₂-receptor-induced hypokalaemia.

Overdose of sympathomimetics

is treated according to rational consideration of mode and site of action (see Adrenaline/epinephrine, below).

Individual sympathomimetics

The actions are summarised in Table 23.1. The classic, mainly endogenous, substances will be described first despite their limited role in therapeutics, and then the more selective analogues that have largely replaced them.

Catecholamines

Traditionally catecholamines have had a dual nomenclature (as a consequence of a company patenting the name Adrenalin), broadly European and North American. The North American naming system has been chosen by the World Health Organization as recommended international non-proprietary names (rINNs) (see Ch. 7), and the European Union has directed member states to use rINNs. By exception, adrenaline and noradrenaline are the terms used in the titles of monographs in the European Pharmacopoeia and are thus the official names in the member states. Because uniformity has not yet been achieved, and because of the scientific literature, we use both names. For pharmacokinetics, see above.

Adrenaline/epinephrine

Adrenaline/epinephrine (α- and β-adrenoceptor effects) is used:

• as a vasoconstrictor with local anaesthetics (1 in 80 000 or weaker) to prolong their effects (about two-fold)

• as a topical mydriatic (sparing accommodation; it also lowers intraocular pressure)

• for severe allergic reactions, i.e. anaphylactic shock, intramuscularly or intravenously. The route must be chosen with care (for details, see p. 116). The subcutaneous route is not recommended as the intense vasoconstriction slows absorption.

Adrenaline/epinephrine is used in anaphylactic shock

because of its mix of actions, cardiovascular and bronchial; it may also stabilise mast cell membranes and reduce release of vasoactive autacoids. Patients who are taking non-selective β-blockers may not respond to adrenaline/epinephrine (use intravenous salbutamol) and indeed may develop severe hypertension (see below).

Adrenaline/epinephrine (topical) decreases intraocular pressure in chronic open-angle glaucoma, as does dipivefrine, an adrenaline/epinephrine ester prodrug. These drugs are contraindicated in closed-angle glaucoma because they are mydriatics. Hyperthyroid patients are intolerant of adrenaline/epinephrine.

Accidental overdose

with adrenaline/epinephrine occurs occasionally. It is rationally treated with propranolol to block the cardiac β effects (cardiac arrhythmia) and phentolamine or chlorpromazine to control the α effects on the peripheral circulation that will be prominent when the β effects are abolished. Labetalol (α + β blockade) is a good alternative. β-adrenoceptor block alone is hazardous as the then unopposed α-receptor vasoconstriction causes (severe) hypertension (see Phaeochromocytoma, p. 419). Use of other classes of antihypertensives is irrational and may even cause adrenaline/epinephrine release.

Noradrenaline/norepinephrine (chiefly α and β₁ effects)

The main effect of administered noradrenaline/norepinephrine is to raise the blood pressure by constricting the arterioles and so increasing the total peripheral resistance, with reduced blood flow (except in coronary arteries which have few α₁ receptors). Though it does have some cardiac stimulant (β₁) effect, the resulting tachycardia is masked by the profound reflex bradycardia caused by the hypertension. Noradrenaline/norepinephrine is given by intravenous infusion to obtain a controlled and sustained response; the effect of a single intravenous injection is unpredictable and would last only a minute or so. It is used where peripheral vasoconstriction is specifically required, e.g. vasodilatation of septic shock. Adverse effects include peripheral gangrene and local necrosis following accidental extravasation from a vein; tachyphylaxis occurs and withdrawal must be gradual.

Isoprenaline (isoproterenol)

Isoprenaline (isopropylnoradrenaline) is a non-selective β-receptor agonist, i.e. it activates both β₁ and β₂ receptors. It relaxes smooth muscle, including that of the blood vessels and airways, and has negligible metabolic or vasoconstrictor effects. It causes a marked tachycardia, which is its main disadvantage in the treatment of bronchial asthma. It is still occasionally used in complete heart block, massive overdose of a β-blocker, and in cardiogenic shock (for hypotension).

Dopamine

Dopamine activates different receptors depending on the dose used. At the lowest effective dose it stimulates specific dopamine (D₁) receptors in the CNS and the renal and other vascular beds (dilator); it also activates presynaptic autoreceptors (D₂) which suppress release of noradrenaline/norepinephrine. As the dose is increased, dopamine acts as an agonist on β₁-adrenoceptors in the heart (increasing contractility and rate); at high doses it activates α-adrenoceptors (vasoconstrictor). It is given by continuous intravenous infusion because, like all catecholamines, its t_½ is short (2 min). An intravenous infusion (2–5 micrograms/kg/min) increases renal blood flow (partly through an effect on cardiac output). As the dose rises the heart is stimulated, resulting in tachycardia and increased cardiac output. At these higher doses, dopamine is referred to as an ‘inoconstrictor’.

Dopamine is stable for about 24 h in sodium chloride or dextrose. Subcutaneous leakage causes vasoconstriction and necrosis (compare with noradrenaline/norepinephrine), and should be treated by local injection of an α-adrenoceptor-blocking agent (phentolamine 5 mg, diluted).

It may be mixed with dobutamine.

For CNS aspects of dopamine, agonists and antagonists, see Neuroleptics (p. 290) and Parkinsonism (p. 359).

Dobutamine

Dobutamine is a racemic mixture of D– and l-dobutamine. The racemate behaves primarily as a β₁-adrenoceptor agonist with greater inotropic than chronotropic effects on the heart; it has some α-agonist effect, but less than dopamine. It is useful in shock (with dopamine) and in low-output heart failure (in the absence of severe hypertension).

Dopexamine

Dopexamine is a synthetic catecholamine whose principal action is as an agonist for the cardiac β₂-adrenoceptors (positive inotropic effect). It is also a weak dopamine agonist (thus causing renal vasodilatation) and inhibitor of noradrenaline/norepinephrine uptake, thereby enhancing stimulation of cardiac β₁ receptors by noradrenaline/norepinephrine. It is used occasionally to optimise the cardiac output, particularly perioperatively.

Non-catecholamines

Salbutamol, fenoterol, rimiterol, reproterol, pirbuterol, salmeterol, ritodrine and terbutaline are β-adrenoceptor agonists that are relatively selective for β₂ receptors, so that cardiac (chiefly β₁-receptor) effects are less prominent. Tachycardia still occurs because of atrial (sinus node) β₂-receptor stimulation; the β₂-adrenoceptors are less numerous in the ventricle and there is probably less risk of serious ventricular arrhythmias than with the use of non-selective catecholamines. The synthetic agonists are also longer acting than isoprenaline because they are not substrates for COMT, which methylates catecholamines in the liver. They are used principally in asthma, and to reduce uterine contractions in premature labour.

Salbutamol (see also Asthma)

Salbutamol (Ventolin) (t_½ 4 h) is taken orally, 2–4 mg up to four times per day; it also acts quickly by inhalation and the effect can last for 4–6 h, which makes it suitable for both prevention and treatment of asthma. Of an inhaled dose less than 20% is absorbed and can cause cardiovascular effects. It can also be given by injection, e.g. in asthma, premature labour (β₂ receptor) and for cardiac inotropic (β₁) effect in heart failure (where the β₂-vasodilator action is also useful). Clinically important hypokalaemia can also occur (the shift of potassium into cells). The other drugs above are similar.

Salmeterol

(Serevent) is a variant of salbutamol that has an additional binding site adjacent to the β₂-adrenoceptor; this results in slow onset (15–30 min) and long duration of action (12–18 h) (see p. 474). This behaviour is distinct from the other widely used long-acting β₂-agonist, formoterol, which has a rapid bronchodilator effect like salbutamol (within a few minutes).

Ephedrine

Ephedrine (t_½ approx. 6 h) is a plant alkaloid ⁶ with indirect sympathomimetic actions that resemble those of adrenaline/epinephrine peripherally and amfetamine centrally. Hence, (in adults) it produces increased alertness, anxiety, insomnia, tremor and nausea; children may be sleepy when taking it. In practice, central effects limit its use as a sympathomimetic in asthma.

Ephedrine is well absorbed when given orally and, unlike most other sympathomimetics, undergoes relatively little first-pass metabolism in the liver (it is not a substrate for MAO or COMT); it is excreted largely unchanged by the kidney. It differs from adrenaline/epinephrine principally in that its effects come on more slowly and last longer. Tachyphylaxis occurs on repeated dosing. It can be given by mouth for reversible airways obstruction, topically as a mydriatic and mucosal vasoconstrictor or by slow intravenous injection to reverse hypotension from spinal or epidural anaesthesia. Newer drugs that are better suited for these purposes have largely replaced it. It is sometimes useful in myasthenia gravis (adrenergic agents enhance cholinergic neuromuscular transmission). Pseudoephedrine is similar to ephedrine but much less active.

Phenylpropanolamine (norephedrine) is similar but with fewer CNS effects. Prolonged administration of phenylpropanolamine to women as an anorectic has been associated with pulmonary valve abnormalities and stroke, leading to its withdrawal in some countries.⁶

Amfetamine (Benzedrine) and dexamfetamine (Dexedrine) act indirectly. They are seldom used for their peripheral effects, which are similar to those of ephedrine, but usually for their effects on the CNS (narcolepsy, attention deficit in children). (For a general account of amfetamine, see p. 343).

Phenylephrine

has actions qualitatively similar to those of noradrenaline/norepinephrine but of longer duration, up to several hours. It can be used as a nasal decongestant (0.25–0.5% solution), but sometimes irritates. In the doses usually given, the CNS effects are minimal, as are the direct effects on the heart. It is also used as a mydriatic and briefly lowers intraocular pressure.

Mucosal decongestants

Nasal and bronchial decongestants (vasoconstrictors) are widely used in allergic rhinitis, colds, coughs and sinusitis, and to prevent otic barotrauma, as nasal sprays or taken orally. All of the sympathomimetic vasoconstrictors, i.e. with α effects, have been used for the purpose, with or without an antihistamine (H₁ receptor), and there is little to choose between them. Ischaemic damage to the mucosa is possible if they are used excessively (more often than 3-hourly) or for prolonged periods (more than 3 weeks), and is a common problem for regular users of cocaine. The occurrence of rebound congestion is also liable to lead to overuse.

The least objectionable drugs are ephedrine 0.5% and phenylephrine 0.5%. Xylometazoline 0.1% (Otrivine) should be used, if at all, for only a few days because longer application reduces the ciliary activity and leads to rebound congestion. Oily drops and sprays, used frequently and long term, may also enter the lungs and eventually cause lipoid pneumonia. They interact with antihypertensives and can be a cause of unexplained failure of therapy unless enquiry into patient self-medication is made. Fatal hypertensive crises have occurred when patients treated for depression with a monoamine oxidase inhibitor have taken these preparations.

Shock

Definition

Shock is a state of inadequate organ perfusion (oxygen deficiency) sufficient adversely to affect cellular metabolism, causing the release of enzymes and vasoactive substances,⁷ i.e. it is a low flow or hypoperfusion state.

Typically the blood pressure is low, reflecting reduced cardiac output. The exception is septic shock, where the cardiac output is typically high, but it is maldistributed (due to constriction, dilatation, shunting), leading to poor oxygen utilisation and tissue injury (warm shock).

The essential element, hypoperfusion of vital organs, is present whatever the cause, whether pump failure (myocardial infarction), maldistribution of blood (septic shock) or loss of intravascular volume (bleeding or increased permeability of vessels damaged by bacterial cell products, burns or anoxia). Functions of vital organs, such as the brain (consciousness), lungs (gas exchange) and kidney (urine formation) are clinical indicators of adequacy of perfusion of these organs.

Treatment

may be summarised as follows:

• Treatment of the cause: bleeding, infection, adrenocortical deficiency.

• Replacement of any fluid lost from the circulation.

• Perfusion of vital organs (brain, heart, kidneys) and maintenance of the mean blood pressure.

Blood flow (oxygen delivery) rather than blood pressure is of the greatest immediate importance for the function of vital organs. A reasonable blood pressure is needed to ensure organ perfusion, but peripheral vasoconstriction may maintain a normal mean arterial pressure despite a very low cardiac output. Under these circumstances, blood flow to vital organs will be inadequate and multiple organ failure will ensue unless the patient is resuscitated adequately.

The decision on how to treat shock depends on assessment of the pathophysiology:

• whether cardiac output, and thus peripheral blood flow, is inadequate (low pulse volume, cold-constricted periphery)

• whether cardiac output is normal or high and peripheral blood flow is adequate (good pulse volume and warm dilated periphery), but there is maldistribution of blood

• whether the patient is hypovolaemic or not, or needs a cardiac inotropic agent, a vasoconstrictor or a vasodilator.

Types of shock

In poisoning by a cerebral depressant

or after spinal cord trauma, the principal cause of hypotension is low peripheral resistance due to reduced vascular tone. The cardiac output can be restored by infusing fluid and/or giving vasoactive drugs (e.g. noradrenaline/norepinephrine, metaraminol).

In central circulatory failure

(cardiogenic shock, e.g. after myocardial infarction) the cardiac output and blood pressure are low because of pump failure; myocardial perfusion is dependent on aortic pressure. Venous return (central venous pressure) is normal or high. The low blood pressure may trigger the sympathoadrenal mechanisms of peripheral circulatory failure summarised below.

Not surprisingly, the use of drugs in low-output failure caused by acute myocardial damage is disappointing. Vasoconstriction (by an α-adrenoceptor agonist) may raise the blood pressure by increasing peripheral resistance, but the additional burden on the damaged heart can further reduce the cardiac output. Cardiac stimulation with a β₁-adrenoceptor agonist may fail; it increases myocardial oxygen consumption and may cause an arrhythmia. Dobutamine or dopamine offers a reasonable choice if a drug is judged necessary; dobutamine is preferred as it tends to vasodilate, i.e. it is an ‘inodilator’. If there is bradycardia (as sometimes complicates myocardial infarction), cardiac output can be increased by accelerating the heart rate by vagal block with atropine.

Septic shock

is severe sepsis with hypotension that is not corrected by adequate intravascular volume replacement. It is caused by lipopolysaccharide (LPS) endotoxins from Gram-negative organisms and other cell products from Gram-positive organisms; these initiate host inflammatory and procoagulant responses through the release of cytokines, e.g. interleukins, and the resulting diffuse endothelial damage is responsible for many of the adverse manifestations of shock. The procoagulant state, in particular, predisposes to the development of microvascular thrombosis that leads to tissue ischaemia and organ hypoperfusion. Activation of nitric oxide production by LPS and cytokines worsens the hypoperfusion by decreasing arterial pressure. This initiates a vigorous sympathetic discharge that causes constriction of arterioles and venules; the cardiac output may be high or low according to the balance of these influences.

There is a progressive peripheral anoxia of vital organs and acidosis. The veins (venules) dilate and venous pooling occurs so that blood is sequestered in the periphery; effective circulatory volume decreases because of this and fluid is lost into the extravascular space from endothelial damage caused by bacterial products.

When septic shock is recognised, appropriate antimicrobials should be given in high dose immediately after taking blood for culture (see p. 174). Beyond that, the primary aim of treatment is to restore cardiac output and vital organ perfusion by increasing venous return to the heart, and to reverse the maldistribution of blood. Increasing intravascular volume will achieve this, guided by the central venous pressure to avoid overloading the heart. Oxygen is essential as there is often uneven pulmonary perfusion.

After adequate fluid resuscitation has been established, inotropic support is usually required. Noradrenaline/norepinephrine is the vasoactive drug of choice for septic shock: its potent α-adrenergic effect increases the mean arterial pressure and its modest β₁ effect may raise cardiac output, or at least maintain it as the peripheral vascular resistance increases. Dobutamine may be added to augment cardiac output further. Some clinicians use adrenaline/epinephrine, in preference to noradrenaline/norepinephrine plus dobutamine, on the basis that its powerful α and β effects are appropriate in the setting of septic shock; it may exacerbate splanchnic ischaemia and lactic acidosis.

Hypotension in (atherosclerotic) occlusive vascular disease is particularly serious, for these patients are dependent on pressure to provide the necessary blood flow in vital organs whose supplying vessels are less able to dilate. It is important to maintain an adequate mean arterial pressure, whichever inotrope is selected.