22 Adrenergic mechanisms and drugs 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. The effect was confirmed in animals and led eventually to the iso- lation and synthesis of adrenaline in the early 1900s. Many related compounds were examined and, in 1910, Barger and Dale invented the word sympatho- mimetic 1 and also pointed out that noradrenaline (norepinephrine) mimicked the action of the sympathetic nervous system more closely than did adrenaline. Adrenaline, noradrenaline and dopamine are formed in the body and are used in therapeutics. The natural synthetic path is: tyrosine —> dopa —> dopamine —> noradrenaline —> adrenaline. Classification of sympathomimetics BY MODE OF ACTION Noradrenaline is synthesised and stored in adrenergic nerve terminals and can be released from these stores by stimulating the nerve or by drugs (ephedrine, amfetamine). These noradrenaline stores may be replenished by i.v. infusion of noradrenaline, and abolished by reserpine or by cutting the sympathetic neuron. Sympathomimetics may be classified as those that act: 1. directly: adrenoceptor agonists, e.g. adrenaline, 1 '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. 447 22 ADRENERGIC MECHANISMSAND DRUGS noradrenaline, isoprenaline (isoproterenol), methoxamine, xylometazoline, oxymetazoline, metaraminol (entirely); and dopamine and phenylephrine (mainly) 2. indirectly: by causing a release of noradrenaline from stores at nerve endings, e.g. amphetamines, tyramine; and ephedrine (largely) 3. by both mechanisms (1 and 2, though often with a preponderance of one or other): other synthetic agents. Tachyphylaxis (rapidly diminishing response to repeated administration) is a particular feature of group 2 drugs. It reflects depletion of the 'releasable' pool of noradrenaline from adrenergic nerve ter- minals that makes these agents less suitable as, for example, pressor agents than drugs of group 1. Longer-term tolerance (see p. 95) to the effects 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 in adre- nergic nerve terminals and potentiate the pressor effects of noradrenaline e.g. cocaine, tricyclic anti- depressants or highly noradrenaline-selective re- uptake inhibitors such as roboxetine. Others de- plete 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: for instance laevo-noradrenaline is at least 50 times as active as the dextro- form. Noradrenaline, adrenaline and phenylephrine are all used clinically as their laevo-isomers. History. Up to 1948 it was known that the peripheral motor (vasoconstriction) effects of adrenaline were preventable and that the peripheral inhibitory (vasodilatation) and the cardiac stimulant actions were not preventable by the then available antag- onists (ergot alkaloids, phenoxybenzamine). That same year, Ahlquist hypothesised that this was due to two different sorts of adrenoceptors (a and (3). For a further 10 years, only antagonists of a-receptor effects (a-adrenoceptor block) were known, but in 1958 the first substance selectively and competitively to prevent p-receptor effects ((3-adrenoceptor block), dichloroisoprenaline, was synthesised. It was, how- ever, 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 (3-adrenoceptor blocker to be used clinically. Unfortunately it had a low therapeutic index and was carcinogenic in mice, and was soon replaced by propranolol (Inderal). 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 indiscriminately from nerve endings, e.g. amfetamine, will have a wider range of effects. Subclassification of adrenoceptors is shown in Table 22.1. 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 amongst adreno- ceptor subtypes. In the case of [3-adrenoceptors, the effector is adenylyl cyclase and hence cyclic AMP is the second messenger molecule. For oc-adrenoceptors, phospholipase C is the commonest effector protein and the second messenger here is IP 3 . It is the cascade of events initiated by the second messenger mole- cules that produces the variety of tissue effects as shown in Table 22.1 It should be clear that specifi- city is provided by the receptor subtype, not the messengers. Complexity of adrenergic mechanisms Drugs may mimic or impair adrenergic mechanisms: • directly, by binding on adrenoceptors: as agonists (adrenaline) or antagonists (propranolol) 448 CLASSIFICATION OF S Y M PAT H O M I M E T I C S 22 449 TABLE 22. 1 Clinically relevant aspects of adrenoceptor functions and actions of agonists ctj-adrenoceptor effects' ( -adrenoceptor effects Eye: 2 mydriasis Heart (( , 2 ) 3 increased rate (SA node) increased automaticity (AV node and muscle) increased velocity in conducting tissue increased contractility of myocardium increased O 2 consumption decreased refractory period of all tissues Arterioles: Arterioles: constriction (only slight in coronary and cerebral) dilatation ( 2 ) Bronchi ( 2 ): relaxation Anti-inflammatory effect: inhibition of release of autacoids (histamine, leukotrienses) from mast cells, e.g. asthma in type 1 allergy Uterus: contraction (pregnant) Uterus ( 2 ): relaxation (pregnant) Skeletal muscle: tremor ( 2 ) Skin: sweat, pilomotor Male ejaculation Blood platelet: aggregation Metabolic effect: hyperkalaemia Metabolic effects: hypokalaemia ( 2 ) hepatic glycogenolysis ( 2 ) lipolysis , ) Bladder sphincter: Bladder detrusor: relaxation contraction Intestinal smooth muscle relaxation is mediated by a- and -adrenoceptors. 2 -adrenoceptor effects: 1 2 -receptors on the nerve ending i.e. presynaptic autoreceptors mediate negative feedback which inhibits noradrenaline release. 1 For the role of subtypes ( , and 2 ) see prazosin. 2 Effects on intraocular pressure involve both a- and P-adrenoceptors as well as cholinoceptors. 3 Cardiac -receptors mediate effects of sympathetic nerve stimulation. Cardiac 2 -receptors mediate effects of circulating adrenaline, when this is secreted at a sufficient rate, e.g. following a myocardial infarction or in heart failure. Both receptors are coupled to the same 'ntracellular signalling pathway (cyclic AMP production) and mediate the same biological effects. The use of the term cardioselective to mean , -receptor selective only, especially in the case of -receptor blocking drugs, is no longer appropriate. Although in most species the -receptor is the only cardiac -receptor, this is not the case in humans. What is not generally appreciated is that the endogenous sympathetic neurotransmitter, noradrenaline, has about a 20-fold selectivity for the -receptor — similar to that of the antagonist, atenolol — with the consequence that under most circumstances, in most tissues, there is little or no 2 - receptor stimulation to be affected by a nonselective -blocker.Why asthmatics should be so sensitive to -blockade is paradoxical: all the bronchial -receptors are 2 , and the bronchi themselves are not innervated by adrenergic fibres; the circulating adrenaline levels are, if anything, low in asthma. • indirectly, by discharging noradrenaline stored in • by preventing the destruction of noradrenaline (and nerve endings 2 (amfetamine) dopamine) in the nerve ending (monoamine • by preventing reuptake into the adrenergic nerve oxidase inhibitors) ending of released noradrenaline (and • by depleting the stores of noradrenaline in nerve dopamine) (cocaine, tricyclic antidepressants endings (reserpine) and noradrenaline-selective reuptake inhibitors • by preventing the release of noradrenaline from such as roboxetine) nerve endings in response to a nerve impulse (guanethidine) 2 Fatal hypertension can occur when this class of agent is • fy activation of adrenoceptors on adrenergic taken by a patient treated with monoamine oxidase inhibitor. nerve endings that inhibit release of 22 ADRENERGIC MECHANISMS AND DRUGS noradrenaline ( 2 ~autoreceptors) (clonidine) • by blocking sympathetic autonomic ganglia (trimetaphan). All the above mechanisms operate in both the central and peripheral nervous systems. This dis- cussion is chiefly concerned with agents that influence peripheral adrenergic mechanisms. 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 a- and -receptors, some are partial agonists and, if enough is administered, many will extend their range. The same applies to selective antagonists (receptor blockers), e.g. a 1 - selective adrenoceptor blocker can cause severe exacerbation of asthma (a 2 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. 3 Adrenoceptor agonists (Table 22.1) + effects, nonselective: adrenaline is used as a vasoconstrictor (a) with local anaesthetics, as a mydriatic and in the emergency treatment of anaphylactic shock, for which condition it has the right mix of effects (bronchodilator, positive cardiac inotropic, vasoconstriction at high dose). otj effects: noradrenaline (with slight effect on heart) is selectively released physiologically where it is wanted; as therapeutic agents for hypotensive states (excepting septic shock) dopamine and dobutamine are preferred (for their cardiac inotropic effect). Also having predominantly 1 effects are imidazolines (xylometazoline, oxymeta- 3 While 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, which are dose-dependent. A 10-fold selectivity of an agonist at the 1 -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 to the 2 -subtype. zoline), metaraminol, phenylephrine, phen- ylpropanolamine, ephedrine, pseudoephedrine: some are used solely for topical vasoconstriction (nasal decongestants). 2 effects in the central nervous system: clonidine. effects, nonselective (i.e. 1 + 1 ): isoprenaline (isoproterenol). Its uses as bronchodilator ( 2 ), for positive cardiac inotropic effect and to enhance conduction in heart block ( 1 , 2 ) have been largely superseded by agents with a more appropriately selective profile of effects. Other agents with non- selective effects, ephedrine, orciprenaline, are also obsolete for asthma. 1 effects, with some a effects: dopamine, used in cardiogenic shock. 1 effects: dobutamine, used for cardiac inotropic effect. 2 effects, used in asthma, or to relax the uterus, include: salbutamol, terbutaline, fenoterol, pirbuterol, reproterol, rimiterol, isoxsuprine, orciprenaline, rit- odrine. Adrenoceptor antagonists (blockers) See page 474. 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 adre- naline ordinarily dilates muscle blood vessels ( 2 ; mainly arterioles, but veins also) but in very large doses constricts them (a). 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 ( ) in some areas, vasoconstriction (a) in others, and cardiac stimulation ( ). To block all the effects of adrenaline and nor- adrenaline, antagonists for both a- and -receptors must be used. This can be a matter of practical importance, e.g. in phaeochromocytoma (see p. 495). 450 CLASSIFICATION OF S Y M P AT H O M I M E T I C S 22 Physiological note. The termination of action of noradrenaline released at nerve endings is by: • reuptake into nerve endings where it is stored and also subject to MAO degradation • diffusion away from the area of the nerve ending and the receptor (junctional cleft) • metabolism (by extraneuronal MAO and COMT). These processes are slower than the very swift destruction of acetylcholine at the neuromuscular junction by extracellular acetylcholinesterase seated alongside the receptors. This difference reflects the differing signalling requirements: almost instan- taneous (millisecond) responses for voluntary muscle movement versus the much more leisurely con- traction of arteriolar muscle to control vascular resistance. Synthetic noncatecholamines in clinical use have t// of hours, e.g. salbutamol 4h, because they are more resistant to enzymatic degradation and conjugation. They may be given orally although much higher doses are required. They penetrate the central nervous system and may have prominent effects, e.g. amphetamine. Substantial amounts appear in the urine. Pharmacokinetics Catecholamines (adrenaline, noradrenaline, dopa- mine, dobutamine, isoprenaline) (plasma t 1 / 2 approx. 2 min) are metabolised by two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (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 nerve endings, peripheral and central). Because of these enzymes catecholamines are ineffective when swallowed, but noncatecholamines, e.g. salbutamol, amphetamine, are effective orally. a result of leakage from i.v. infusions. The effects on the heart ( 1 ) include tachycardia, palpitations, cardiac arrhythmias including ventricular tachy- cardia and fibrillation, and muscle tremor (( 2 ). Sym- pathomimetic drugs should be used with great caution in patients with heart disease. 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 (a) and arterial constriction (a). 2 -agonists are used to relax the uterus in pre- mature labour, but unwanted cardiovascular actions can be troublesome. Sympathomimetics were parti- cularly likely to cause cardiac arrhythmias ( 1 effect) in patients who received halothane anaesthesia (now much less used). Sympathomimetics and plasma potassium. Adrenergic mechanisms have a role in the physio- logical control of plasma potassium concentration. The biochemical pump that shifts potassium into cells is activated by the ( 2 -adrenoceptor agonists (adrenaline, salbutamol, isoprenaline) and can cause hypokalaemia. 2 -adrenoceptor antagonists block the effect. The hypokalaemia effects of administered ( 2 ) Sympathomimetics may be clinically important, particularly in patients having pre-existing hypo- kalaemia, e.g. due to intense adrenergic activity such as occurs in myocardial infarction, 4 in fright (admission to hospital is accompanied by transient hypokalaemia), or with previous diuretic therapy, and taking digoxin. In such subjects the use of a sympathomimetic infusion or of an adrenaline- containing local anaesthetic may precipitate a cardiac arrhythmia. Hypokalaemia may occur during treatment of severe asthma, particularly where the 2 -receptor agonist is combined with theophylline. -adrenoceptor blockers, as expected, enhance the hyperkalaemia of muscular exercise; and one of their benefits in preventing cardiac arrhythmias Adverse effects These may be deduced from their actions (Table 22.1, Fig. 22.1). Tissue necrosis due to intense vasoconstriction (a) around injection sites occurs as 4 Normal subjects, infused i.v. with adrenaline in amounts that approximate to those found in the plasma after severe myocardial infarction, show a fall in plasma K of about 0.8 mmol/1 (Brown M J 1983 New England Journal of Medicine 309:1414). 451 22 ADRENERGIC M E C H A N I S M S A N D DRUGS Fig. 22.1 Cardiovascular effects of noradrenaline (norepinephrine), adrenaline (epinephrine) and isoprenaline (isoproterenol): pulse rate/min, blood pressure in mmHg (dotted line is mean pressure), peripheral resistance in arbitrary units.The differences are due to the differential a and agonist selectivities of these agents (see text). (By permission,after GinsburgJ,Cobbold A F I960 InrVane J R et al (eds) Adrenergic mechanism. Churchill, London) after myocardial infarction may be due to block of 2 -receptor-inducedhypokalaemia. Overdose of sympathomimetics is treated according to rational consideration of mode and site of action (see Adrenaline, below). Individual sympathomimetics The actions are summarised in Table 22.1. 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 5 For pharmacokinetics, see above. Adrenaline (epinephrine) Adrenaline ( - and -adrenoceptor effects) is used: • as a vasoconstrictor with local anaesthetics (1:80 000 or weaker) to prolong their effects (about 2-fold) • as a topical mydriatic (sparing accommodation; it also lowers intraocular pressure) • for severe allergic reactions, i.m., i.v. (or s.c.). The route must be chosen with care. For adults, adrenaline 500 micrograms (i.e. 0.5 ml of the 1 in 1000 solution) may be given i.m. and repeated 5 Traditionally catecholamines have had a dual nomenclature (as a consequence of a company patenting the name Adrenalin), broadly European and N. American. The latter has been chosen by the World Health Organization as International Nonproprietary Names (INN) (see Ch. 6), and the European Union has directed member states to use INN. Because uniformity has not yet been achieved and because of the scientific literature, we use both. For pharmacokinetics, see above. 452 22 at 5-min intervals according to the response (see Ch. 8, p. 143). If the circulation is compromised to a degree that is immediately life-threatening, adrenaline 500 micrograms may be given by slow i.v. injection at a rate of 100 micrograms/min (i.e. 1 ml/min of the dilute 1 in 10 000 solution) with continuous monitoring of the ECG. This course requires extreme caution and use of a further x 10 dilution (i.e. a 1 in 100 000 solution) may be preferred as providing finer control and greater safety. The s.c. route is generally not recommended as there is intense vasoconstriction, which slows absorption. Adrenaline is used in anaphylactic shock because its mix of actions, cardiovascular and bronchial, provide the best compromise for speed and sim- plicity of use in an emergency; it may also stabilise mast cell membranes and reduce release of vaso- active autacoids (see p. 280). Patients who are taking nonselective -blockers may not respond to adrenaline (use salbutamol i.v.) and indeed may develop severe hypertension (see below). Adrenaline (topical) decreases intraocular pressure in chronic open-angle glaucoma, as does dipivefrine, an adrenaline ester prodrug. They are contra- indicated in closed-angle glaucoma because they are mydriatics. Hyperthyroid patients are intolerant of adrenaline. Accidental overdose with adrenaline occurs occasionally. It is rationally treated by propranolol to block the cardiac effects (cardiac arrhythmia) and phentolamine or chlorpromazine to control the a effects on the peripheral circulation that will be prominent when the (3 effects are abolished. Labetalol ( + block) would be an alternative. p-adrenoceptor block alone is hazardous as the then unopposed ot- receptor vasoconstriction causes (severe) hyper- tension (see Phaeochromocytoma, p. 494). Use of antihypertensives of most other kinds is irrational and some may also potentiate the adrenaline. Noradrenaline (norepinephrine) (chiefly OL and , effects) The main effect of administered noradrenaline is to raise the blood pressure by constricting the arterioles INDIVIDUAL SYM PATHOM I M ETI CS and so raising the total peripheral resistance, with reduced blood flow (except in coronary arteries which have few 1 -receptors). Though it does have some cardiac stimulant ( a ) effect, the tachycardia of this is masked by the profound reflex bradycardia caused by the hypertension. Noradrenaline is given by i.v. infusion to obtain a gradual sustained response; the effect of a single i.v. injection would last only a minute or so. It is used where peripheral vaso- constriction is specifically desired, e.g. vasodilation of septic shock. Adverse effects include peripheral gangrene and local necrosis; tachyphylaxis occurs and withdrawal must be gradual. Isoprenaline (isoproterenol) Isoprenaline (isopropylnoradrenaline) is a non- selective (3-receptor agonist, i.e. it activates both Pj- and P 2 -receptors. It relaxes smooth muscle, including that of the blood vessels, has negligible metabolic or vasoconstrictor effects, but a vigorous stimulant effect on the heart. This latter is its main dis- advantage in the treatment of bronchial asthma. Its principal uses are in complete heart block and occasionally in cardiogenic shock (hypotension). Dopamine Dopamine activates different receptors depending on the dose used. At the lowest effective dose it stimulates specific dopamine (D a ) receptors in the CNS and the renal and other vascular beds (dilator); it also activates presynaptic autoreceptors (D 2 ) which suppress release of noradrenaline. As dose is raised, dopamine acts as an agonist on P^adrenoceptors in the heart (increasing contractility and rate); at high doses it activates a-adrenoceptors (vasoconstrictor). It is given by continuous i.v. infusion because, like all catecholamines, its i l / 2 is short (2 min). An i.v. in- fusion (2-5 micrograms/kg/min) increases renal blood flow (partly through an effect on cardiac out- put). As the dose rises the heart is stimulated, resulting in tachycardia and increased cardiac out- put. 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 and should be treated by local injection of an a-adrenoceptor blocking agent (phentolamine 5 mg, diluted). 453 22 ADRENERGIC MECHANISMSAND DRUGS It may be mixed with dobutamine. For CNS aspects of dopamine, agonists and antagonists: see Neuroleptics, Parkinsonism. Dobutamine Dobutamine is a racernic mixture of d- and 1- dobutamine. The racemate behaves primarily a 1 adrenoceptor agonist with greater inotropic than chronotropic effects on the heart; it has some - 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 2 - adrenoceptors (positive inotropic effect). It is also a weak dopamine agonist (thus causing renal vasodilatation) and inhibitor of noradrenaline uptake thereby enhancing stimulation of cardiac 1 - receptors by noradrenaline. It is used occasionally to optimise the cardiac output, particularly perioperatively. NONCATECHOLAMINES Salbutamol, fenoterol, rimiterol, reproterol, pir- buterol, salmeterol, ritodrine and terbutaline are fi- adrenoceptor agonists that are relatively selective for 2 -receptors, so that cardiac (chiefly 1 -receptor) effects are less prominent. Tachycardia still occurs because of atrial (sinus node) 2 -receptor stimulation; the 2 -adrenoceptors are less numerous in the ventricle and there is probably less risk of serious ventricular arrhythmias than with the use of nonselective catecholamines. The synthetic agonists are also longer-acting than isoprenaline because they are not substrates for catechol-O-methyltransferase, 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 1/2 4h) is taken orally, 2-4 mg up to 4 times/day; it also acts quickly by inhalation and the effect can last as long as 4h, which makes it suitable for both prevention and treatment of asthma. Of an inhaled dose < 20% is absorbed and can cause cardiovascular effects. It can also be given by injection, e.g. in asthma, premature labour 2 -receptor) and for cardiac inotropic ( 1 ) effect in heart failure (where the ( 2 vasodilator action is also useful). Clinically imp- ortant 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 additional binding property to a site adjacent to the 2 -adrenoceptor, which results in slow onset and long duration of action (about 12 h) (see p. 560). Ephedrine Ephedrine (t l / 2 approx. 4 h) is a plant alkaloid with indirect sympathomimetic actions that resemble adrenaline peripherally. Centrally (in adults) it pro- duces increased alertness, anxiety, insomnia, tremor and nausea; children may be sleepy when taking it. In practice central effects limit its use as a sym- pathomimetic in asthma. Ephedrine is well absorbed when given orally and, unlike most other sympathomimetics, under- goes relatively little first-pass metabolism in the liver; it is largely excreted unchanged by the kidney. It is usually given by mouth but can be injected. It differs from adrenaline principally in that its effects come on more slowly and last longer. Tachyphylaxis occurs on repeated dosing. Ephedrine can be used as a bronchodilator, in heart block, as a mydriatic and as a mucosal vasoconstrictor, but newer drugs, which are often better for these purposes, are dis- placing it. It is sometimes useful in myasthenia gravis (adrenergic agents enhance cholinergic neuro- muscular transmission). Pseudoephedrine is similar. Phenylpropanolamine (norephedrine) is similar but with less CNS effect. Prolonged administration of phenylpropanolamine to women as an anorectic has been associated with pulmonary valve abnor- malities and led to its withdrawal in some countries. Amfetamine (Benzedrine) and dexamphetamine (Dexedrine) act indirectly. They are seldom used for their peripheral effects, which are similar to those of 454 SHOCK 22 ephedrine, but usually for their effects on the central nervous system (narcolepsy, attention deficit in children). (For a general account of amphetamine, see p. 193) Phenylephrine has actions qualitatively similar to noradrenaline but a longer duration of action, up to an hour or so. It can be used as a nasal decongestant (0.25-0.5% solution), but sometimes irritates. In the doses usually given, the central nervous 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 otitic barotrauma, as nasal drops or nasal sprays. All the sympathomimetic vasoconstrictors, i.e. with a effects, have been used for the purpose, with or without an antihistamine (Hj-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 (> 3 weeks). The occurrence of rebound congestion is also liable to lead to over- use. 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 since longer application reduces the ciliary activity and will lead to rebound congestion. Naphazoline and adrenaline should not be used, and nor should blunderbuss mixtures of vaso- constrictor antihistamine, adrenal steroid and anti- biotics. Oily drops and sprays, used frequently and long-term, may enter the lungs and eventually cause lipoid pneumonia. It may sometimes be better to give the drugs orally rather than up the nose. 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 capillary perfusion (oxygen deficiency) of vital tissues to an extent that adversely affects cellular metabolism (capillary endothelium and organs) causing mal- function, including release of enzymes and vasoactive substances, 6 i.e. it is a low flow or hypo- perfusion state. The cardiac output and blood pressure are low in fully developed cases. But a maldistribution of blood (due to constriction, dilatation, shunting) can be sufficient to produce tissue injury even in the presence of high cardiac output and arterial blood pressure (warm shock), e.g. some cases of septic 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 total intravascular volume (bleeding or increased permeability of vessels damaged by bacterial cell products, burns or anoxia). Function of vital organs, brain (consciousness, respiration) and kidney (urine formation) are clinical indicators of adequacy of perfusion of these organs. Treatment may be summarised: • 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 6 In fact, a medley 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 cells other than the endothelial cells which are normally its main source. 455 22 ADRENERGIC M E C H A N I S M S A N D DRUGS failure will ensue unless the patient is resuscitated adequately. The decision how to treat shock depends on assessment of the pathophysiology: • whether cardiac output, and so 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 hypo- tension is low peripheral resistance due to reduced vascular tone. The cardiac output can be restored by simply tilting the patient head-down and by increasing the venous filling pressure by infusing fluid. Vasoactive drugs (noradrenaline, dobutamine) may be beneficial. In central circulatory failure (cardiogenic shock, e.g. after myocardial infarction) the cardiac output and blood pressure are low due to 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 circu- latory failure summarised below. Not surprisingly, the use of drugs in low output failure due to acute myocardial damage is dis- appointing. Vasoconstriction (by an -adreno- ceptor agonist), by increasing peripheral resistance, may raise the blood pressure by increasing afterload, but this additional burden on the damaged heart can further reduce the cardiac out- put. Cardiac stimulation with a 1 -adrenoceptor agonist may fail; it increases myocardial oxygen consumption and may cause an arrhythmia. Dobutamine, dopexamine or dopamine offer a reasonable choice if a drug is judged necessary; dobutamine is preferred as it tends to vasodilate, i.e. it is an 'inodilator'. A selective phosphodiesterase inhibitor such as enoximone may also be effective, unless its use is limited by hypotension. If there is bradycardia (as sometimes complicates myocardial infarction), cardiac output can be increased by vagal block with atropine, which acceler- ates the heart rate. 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 organ- isms; these initiate host inflammatory and pro- coagulant responses through the release of cytokines, e.g. interleukins, and the resulting diffuse endo- thelial damage is responsible for many of the adverse manifestations of shock, including multi- organ failure. First, there is a peripheral vaso- dilatation from activation of nitric oxide by LPS and cytokines, with eventual fall in 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 and effective circulatory volume falls because of this, and of fluid loss 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 the taking of blood cultures (see p. 237). Beyond that, the prime aim of treatment is to restore cardiac output and vital organ perfusion by accelerating 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 is the inotrope of choice for septic shock: its potent -adrenergic effect increases the mean arterial pressure and its modest 1 effect may raise cardiac output, or at least maintain it as the peripheral vascular resistance increases. Dobutamine may be added further to augment cardiac output. 456 [...]... e.g 7 Nolan J 2001 Fluid resuscitation for the trauma patient Resuscitation 48: 57-69 457 22 ADRENERGIC M E C H A N I S M S A N D DRUGS 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 levels of noradrenaline (supine and erect) and renin These are elevated in saline... ABC of intensive care Organ dysfunction British Medical Journal 318: 1606-1609 Ewan P W 1998 Anaphylaxis British Medical Journal 316:1442-1445 Insel P A1996 Adrenergic receptors — evolving concepts and clinical implications New England Journal of Medicine 334: 580-585 Lynn W A1999 Severe sepsis In: Pusey C (ed) Horizons in medicine Royal College of Physicians of London, London, p 55-68 Wheeler A P, Bernard . (see p. 95) to the effects direct sympathomimetics is much less of a clinical problem and reflects an alteration in adrenergic receptor density . optically active drugs, with only one stereoisomer conferring most of the clinical efficacy of the racemate: for instance laevo-noradrenaline is