Kevin M. O'Shaughnessy
Synopsis
Anyone who administers drugs acting on cardiovascular adrenergic mechanisms requires an understanding of how they act in order to use them to the best advantage and with safety.
• Adrenergic mechanisms.
• Classification of sympathomimetics: by mode of action and selectivity for adrenoceptors.
• Individual sympathomimetics.
• Mucosal decongestants.
• Shock.
• Chronic orthostatic hypotension.
Adrenergic mechanisms
The discovery in 1895 of the hypertensive effect of adrenaline/epinephrine was initiated by Dr Oliver, a physician in practice, who conducted a series of experiments on his young son into whom he injected an extract of bovine suprarenal and detected a ‘definite narrowing of the radial artery’.1 The effect was confirmed in animals and led eventually to the isolation and synthesis of adrenaline/epinephrine in the early 1900s. Many related compounds were examined and, in 1910, Barger and Dale invented the word sympathomimetic2 and also pointed out that noradrenaline/norepinephrine mimicked the action of the sympathetic nervous system more closely than did adrenaline/epinephrine.
Adrenaline/epinephrine, noradrenaline/norepinephrine and dopamine are synthesised in the body and are used in therapeutics. The pathway is: tyrosine → dopa → dopamine → noradrenaline/norepinephrine → adrenaline/epinephrine. The final step to adrenaline/epinephrine only occurs in the adrenal medulla.
Classification of sympathomimetics
By mode of action
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.
Tachyphylaxis
(rapidly diminishing response to repeated administration) is a particular feature of group 2 drugs. It reflects depletion of the ‘releasable’ pool of noradrenaline/norepinephrine from adrenergic nerve terminals that makes these agents less suitable as, for example, pressor agents than drugs in group 1. Longer-term tolerance (see p. 78) to the effects of direct sympathomimetics is much less of a clinical problem and reflects an alteration in adrenergic receptor density or coupling to second messenger systems.
Interactions of sympathomimetics
with other vasoactive drugs are complex. Some drugs block the reuptake mechanism for noradrenaline/norepinephrine in adrenergic nerve terminals and potentiate the pressor effects of noradrenaline/norepinephrine, e.g. cocaine, tricyclic antidepressants or highly noradrenaline/norepinephrine-selective reuptake inhibitors (NSRIs) such as reboxetine (see Fig. 23.1). Others deplete or destroy the intracellular stores within adrenergic nerve terminals (e.g. reserpine and guanethidine) and thus block the action of indirect sympathomimetics.
Sympathomimetics are also generally optically active drugs, with only one stereoisomer conferring most of the clinical efficacy of the racemate (a 50:50 mixture of stereoisomers); for instance, L-noradrenaline/norepinephrine is at least 50 times as active as the D-form. Noradrenaline/norepinephrine, adrenaline/epinephrine and phenylephrine are all used clinically as their L-isomers.
History
Up to 1948 it was known that the peripheral motor (vasoconstriction) effects of adrenaline/epinephrine were preventable and that the peripheral inhibitory (vasodilatation) and cardiac stimulant actions were not preventable by the then available antagonists (ergot alkaloids, phenoxybenzamine). That same year, Ahlquist hypothesised that this was due to two different sorts of adrenoceptors (α and β). For a further 10 years, only antagonists of α-receptor effects (α-adrenoceptor block) were known, but in 1958 the first substance selectively and competitively to prevent β-receptor effects (β-adrenoceptor block), dichloroisoprenaline, was synthesised. It was unsuitable for clinical use because it behaved as a partial agonist, and it was not until 1962 that pronethalol (an isoprenaline analogue) became the first β-adrenoceptor blocker to be used clinically. Unfortunately it had a low therapeutic index and was carcinogenic in mice; it was soon replaced by propranolol.
It is evident that the site of action has an important role in selectivity, e.g. drugs that act on end-organ receptors directly and stereospecifically may be highly selective, whereas drugs that act indirectly by discharging noradrenaline/norepinephrine indiscriminately from nerve endings, e.g. amfetamine, will have a wider range of effects.
Subclassification of adrenoceptors is shown in Table 23.1.
Table 23.1 Clinically relevant aspects of adrenoceptor functions and actions of agonists
|
α1-Adrenoceptor effectsa |
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. |
|
|
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 t½ 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 t½ 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 t½ 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) (t½ 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 (t½ approx. 6 h) is a plant alkaloid6 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.
Choice of drug in shock
On present knowledge the best drug would be one that both stimulates the myocardium and selectively modifies peripheral resistance to increase flow to vital organs.
• Dobutamine is used when cardiac inotropic effect is the primary requirement.
• Adrenaline/epinephrine is used when a more potent inotrope than dobutamine is required, e.g. when the vasodilating action of dobutamine compromises mean arterial pressure.
• Noradrenaline/norepinephrine is used when vasoconstriction is the first priority, plus some cardiac inotropic effect, e.g. septic shock.
Additionally, recombinant activated protein C (APC) drotrecogin α can be given to reverse the procoagulant state of septic shock. Inflammatory conditions such as septic shock inhibit the generation of endogenous APC, which normally inactivates factors Va and VIIIa, with the result that production of these procoagulant factors is unchecked. Recombinant human APC improved survival of patients with septic shock and multi-organ failure in a large randomised controlled trial.8
Monitoring drug use
Modern monitoring by both invasive and non-invasive techniques is complex and is undertaken in units dedicated to, and equipped for, this activity. The present comment is an overview. Monitoring normally requires close attention to heart rate and rhythm, blood pressure, fluid balance and urine flow, pulmonary gas exchange and central venous pressure. The use of drugs in shock is secondary to accurate assessment of cardiovascular state (especially of peripheral flow) and to other essential management, treatment of infection and maintenance of intravascular volume.
Restoration of intravascular volume9
In an emergency, speed of replacement is more important than its nature. Crystalloid solutions, e.g. isotonic saline, Hartmann's, Plasma-Lyte, are immediately effective, but they leave the circulation quickly. (Note that dextrose solutions are completely ineffective because they distribute across both the extracellular and intracellular compartments.) Macromolecules (colloids) remain in the circulation longer. The two classes (crystalloids and colloids) may be used together.
The choice of crystalloid or colloid for fluid resuscitation remains controversial. A Cochrane review of over 56 clinical trials with mortality data concluded that in critically ill patients there was no evidence that colloids offered superior survival over the use of crystalloids in patients following trauma, burns or surgery.10 Colloids are also much more expensive than crystalloids.
Artificial colloidal solutions include dextrans (glucose polymer), gelatin (hydrolysed collagen) and hydroxyethyl starch.
Dextran 70
(mol. wt. 70 000) has a plasma restoring effect lasting for 5–6 h. Dextran 40 is used to decrease blood sludging and so to improve peripheral blood flow.
Gelatin products
(e.g. Haemaccel, Gelofusine) have a plasma restoring effect of 2–3 h (at best).
Etherified starch
Several hydroxyethyl starch solutions are available, with widely differing effects on plasma volume: high molecular weight (450 000) solutions restore volume for 6–12 h, whereas the effect of medium molecular weight (200 000) starches lasts for 4–6 h.
Adverse effects include anaphylactoid reactions; dextran and hydroxyethyl starch can impair haemostatic mechanisms.
Chronic orthostatic hypotension
Chronic orthostatic hypotension occurs most commonly with increasing age, in primary progressive autonomic failure, and secondary to parkinsonism and diabetes. The clinical features can be mimicked by saline depletion. The two conditions are clearly separated by measurement of plasma concentrations of noradrenaline/norepinephrine (supine and erect) and renin, which are raised in saline depletion, but depressed in most causes of hypotension due to autonomic failure.
As blood pressure can be considered a product of ‘volume’ and ‘vasoconstriction’, the logical initial treatment of orthostatic hypotension is to expand blood volume using a sodium-retaining adrenocortical steroid (fludrocortisone11) or desmopressin (see p. 485), plus elastic support stockings to reduce venous pooling of blood when erect.
It is more difficult to reproduce the actions of the endogenous vasoconstrictors, and especially their selective release on standing, in order to achieve erect normotension without supine hypertension. Because of the risk of hypertension when the patient is supine, only a modest increase in erect blood pressure should be sought; fortunately a systolic blood pressure of 85–90 mmHg is usually adequate to maintain cerebral perfusion in these patients. Few drugs have been formally tested or can be recommended with confidence.
Clonidine and pindolol are partial agonists at, respectively, α and β receptors, and may therefore be more effective agonists in the absence of the endogenous agonist, noradrenaline/norepinephrine, than in normal subjects. Midodrine, an α-adrenoceptor agonist, is the only vasoconstrictor drug to receive UK regulatory approval for the treatment of postural hypotension. It is given at doses of 5–15 mg three times daily.
Postprandial fall in blood pressure (probably due to redistribution of blood to the splanchnic area) is characteristic of this condition; it occurs especially after breakfast (blood volume is lower in the morning). Substantial doses of caffeine (two large cups of coffee) can mitigate this, but they need to be taken before or early in the meal. The action may be due to block of splanchnic vasodilator adenosine receptors. Administration of the somatostatin analogue octreotide also prevents postprandial hypotension, but twice-daily subcutaneous injections are often not attractive; long-acting formulations of somatostatin (and its relative lanreotide) are available, which can be given as subcutaneous or intramuscular depots monthly – this may be more tolerable.
Some of the variation reported in drug therapy may be due to differences in adrenergic function dependent on whether the degeneration is central, peripheral, preganglionic, postganglionic or due to age-related changes in the adrenoceptors on end-organs. In central autonomic degeneration – ‘multi-system atrophy’ – noradrenaline/norepinephrine is still present in peripheral sympathetic nerve endings. In these patients, an indirect-acting amine may be successful, and one patient titrated the amount of Bovril (a tyramine-rich meat extract drink) she required in order to stand up.12
Erythropoietin has also been used with success (it increases haematocrit and blood viscosity), but a cautionary note: increasing the haematocrit in this way is known to cause an excess of cardiovascular deaths in chronic renal failure patients and a significant thrombosis risk in cancer patients given erythropoietin.13
Summary
• The adrenergic arm of the autonomic system uses noradrenaline/norepinephrine as its neurotransmitter.
• Adrenaline/epinephrine, unlike noradrenaline/norepinephrine, is a circulating hormone.
• These two catecholamines act on the same adrenoceptors: α1 and α2, which are blocked by phenoxybenzamine but not by propranolol, and β1 and β2, which are blocked by propranolol but not phenoxybenzamine. Noradrenaline/norepinephrine is a 20-fold weaker agonist at β2 receptors than is adrenaline/epinephrine.
• Distinction between receptor classes is made initially by defining the differing ability of two agonists (or antagonists) to mimic (or block) the effects of catecholamines.
• Often these differences correlate with a difference in receptor type on two different tissues: e.g. stimulation of cardiac contractility by β1 receptors, and bronchodilatation by β2 receptors.
• The distinction between α1 and α2 receptors corresponds to their principal location on blood vessels (causing vasoconstriction) and neurones, respectively.
• Catecholamines themselves can be used in therapy when rapid onset and offset are desired. Selective mimetics at each of the four main receptor subtypes are used for individual locations, e.g. α1 for nasal decongestion, α2 for systemic hypotension, α1 for septic shock, β2 for bronchoconstriction.
• Both α- and β-blockade are used in hypertension; selective β-blockade is used in angina and heart failure.
Guide to further reading
Ahlquist R.P. A study of adrenotropic receptors. Am. J. Physiol.. 1948;153:586–600.
Brown M.J. To β-block or better block? Br. Med. J.. 1995;311:701–702.
Brown S.G. Cardiovascular aspects of anaphylaxis: implications for treatment and diagnosis. Curr. Opin. Allergy Clin. Immunol.. 2005;5(4):359–364.
Evans T.W., Smithies M. ABC of intensive care. Organ dysfunction. Br. Med. J.. 1999;318:1606–1609.
Insel P.A. Adrenergic receptors – evolving concepts and clinical implications. N. Engl. J. Med.. 1996;334:580–585.
Moore F.A., McKinley B.A., Moore E.E., et al. The next generation in shock resuscitation. Lancet. 2004;363:1988–1996.
Rice T.W., Bernard G.R. Therapeutic intervention and targets for sepsis. Annu. Rev. Med.. 2005;56:225–248.
Russell J.A. Management of sepsis. N. Engl. J. Med.. 2006;355:1699–1713.
Small K.M., McGraw D.W., Liggett S.B. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu. Rev. Pharmacol. Toxicol.. 2003;43:381–411.
1 Dale H 1938 Edinburgh Medical Journal 45:461.
2 ‘Compounds which … simulate the effects of sympathetic nerves not only with varying intensity but with varying precision … a term … seems needed to indicate the types of action common to these bases. We propose to call it “sympathomimetic”. A term which indicates the relation of the action to innervation by the sympathetic system, without involving any theoretical preconception as to the meaning of that relation or the precise mechanism of the action’ (Barger G, Dale H H 1910 Journal of Physiology XLI:19–50).
3 Fatal hypertension can occur when this class of agent is taken by a patient treated with a monoamine oxidase inhibitor. In addition, remember that large amounts of tyramine are contained in certain food items (cheese, red wine and marmite), forming the basis of the pressor ‘cheese reaction’ in these patients (see p. 403).
4 Although it is simplest to regard the selectivity of a drug as relative, being lost at higher doses, strictly speaking it is the benefits of the receptor selectivity of an agonist or antagonist that are dose-dependent. A 10-fold selectivity of an agonist at the β1 receptor, for instance, is a property of the agonist that is independent of dose, and means simply that 10 times less of the agonist is required to activate this receptor compared with the β2 subtype.
5 Normal subjects, infused with intravenous adrenaline/epinephrine in amounts that approximate to those found in the plasma after severe myocardial infarction, show a fall in plasma potassium concentration of about 0.8 mmol/L (Brown M J, Brown D C, Murphy M B 1983 Hypokalemia from beta2-receptor stimulation by circulating epinephrine. New England Journal of Medicine 309:1414–1419).
6 Ephedra alkaloids are found in Chinese herbal remedies (ma huang) and in guarana-derived caffeine products which are widely consumed as appetite suppressants or for energy enhancement. These have been associated with stroke and seizures only rarely. The relationship of phenylpropanolamine consumption and haemorrhagic stroke seems clearer and has led to the suspension of its sale in the USA (Fleming G A 2000 The FDA, regulation, and the risk of stroke. New England Journal of Medicine 243:1886–1887).
7 In fact, a cocktail of substances (autacoids) – kinins, prostaglandins, leukotrienes, histamine, endorphins, serotonin, vasopressin – has been implicated. In endotoxic shock, the toxin also induces synthesis of nitric oxide, the endogenous vasodilator, in several types of cell other than the endothelial cells that are normally its main source.
8 Bernard G D, Vincent J L, Laterre P F et al 2001 Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 344:699–709.
9 Nolan J 2001 Fluid resuscitation for the trauma patient. Resuscitation 48:57–69.
10 Perel P, Roberts I, Pearson M 2007 Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD000567. DOI: 10.1002/14651858.CD000567.pub3. Available online at: http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000567/frame.html (accessed 2 August 2010)
11 Effective doses may not restore blood volume and may work by sensitising vascular adrenoceptors.
12 Karet F E, Dickerson J E C, Brown J et al 1994 Bovril and moclobemide: a novel therapeutic strategy for central autonomic failure. Lancet 344:1263–1265.
13 Drüeke TB, Locatelli F, Clyne N et al 2006 Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New England Journal of Medicine 355(20): 2071–2084. And FDA advisory: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126485.htm (accessed 2 August 2010)