CLINICAL PHARMACOLOGY 2003 (PART 24)

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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 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...

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22 Adrenergic mechanisms and drugs SYNOPSIS Adrenaline, noradrenaline and dopamine are formed in the body and are used in therapeutics. Anyone who administers drugs acting on The natural synthetic path is: cardiovascular adrenergic mechanisms requires tyrosine —> dopa —> dopamine —> noradrenaline —> an understanding of how they act in order to adrenaline. use them to the best advantage and with safety. Adrenergic mechanisms Classification of sympathomimetics: by mode of action and selectivity for adrenoceptors Classification of Individual sympathomimetics sympathomimetics Mucosal decongestants Shock Chronic orthostatic hypotension 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 Adrenergic mechanisms replenished by i.v. infusion of noradrenaline, and abolished by reserpine or by cutting the sympathetic The discovery in 1895 of the hypertensive effect of neuron. Sympathomimetics may be classified as those adrenaline (epinephrine) was initiated by Dr Oliver, a physician in practice, who conducted a series of that act: experiments on his young son into whom he injected 1. directly: adrenoceptor agonists, e.g. adrenaline, an extract of bovine suprarenal. The effect was confirmed in animals and led eventually to the iso- 1 'Compounds which ... simulate the effects of sympathetic lation and synthesis of adrenaline in the early 1900s. nerves not only with varying intensity but with varying Many related compounds were examined and, in precision ... a term ... seems needed to indicate the types of 1910, Barger and Dale invented the word sympatho- action common to these bases. We propose to call it mimetic1 and also pointed out that noradrenaline "sympathomimetic". A term which indicates the relation of the action to innervation by the sympathetic system, without (norepinephrine) mimicked the action of the involving any theoretical preconception as to the meaning of sympathetic nervous system more closely than did that relation or the precise mechanism of the action/ Barger adrenaline. G, Dale H H 1910 Journal of Physiology XLI: 19-50. 447
22 ADRENERGIC MECHANISMSAND DRUGS noradrenaline, isoprenaline (isoproterenol), same year, Ahlquist hypothesised that this was due methoxamine, xylometazoline, oxymetazoline, to two different sorts of adrenoceptors (a and (3). metaraminol (entirely); and dopamine and For a further 10 years, only antagonists of a-receptor phenylephrine (mainly) effects (a-adrenoceptor block) were known, but in 2. indirectly: by causing a release of noradrenaline 1958 the first substance selectively and competitively from stores at nerve endings, e.g. to prevent p-receptor effects ((3-adrenoceptor block), amphetamines, tyramine; and ephedrine dichloroisoprenaline, was synthesised. It was, how- (largely) ever, unsuitable for clinical use because it behaved 3. by both mechanisms (1 and 2, though often as a partial agonist, and it was not until 1962 that with a preponderance of one or other): other pronethalol (an isoprenaline analogue) became the synthetic agents. first (3-adrenoceptor blocker to be used clinically. Unfortunately it had a low therapeutic index and Tachyphylaxis (rapidly diminishing response to was carcinogenic in mice, and was soon replaced by repeated administration) is a particular feature of propranolol (Inderal). group 2 drugs. It reflects depletion of the 'releasable' It is evident that the site of action has an important pool of noradrenaline from adrenergic nerve ter- role in selectivity, e.g. drugs that act on end-organ minals that makes these agents less suitable as, for receptors directly and stereospecifically may be example, pressor agents than drugs of group 1. highly selective, whereas drugs that act indirectly by Longer-term tolerance (see p. 95) to the effects direct discharging noradrenaline indiscriminately from sympathomimetics is much less of a clinical nerve endings, e.g. amfetamine, will have a wider problem and reflects an alteration in adrenergic range of effects. receptor density or coupling to second messenger Subclassification of adrenoceptors is shown in systems. Table 22.1. Interactions of sympathomimetics with other vasoactive drugs are complex. Some drugs block Consequences of adrenoceptor the reuptake mechanism for noradrenaline in adre- activation nergic nerve terminals and potentiate the pressor All adrenoceptors are members of the G-coupled effects of noradrenaline e.g. cocaine, tricyclic anti- family of receptor proteins i.e. the receptor is coupled depressants or highly noradrenaline-selective re- to its effector protein through special transduction uptake inhibitors such as roboxetine. Others de- proteins called G-proteins (themselves a large protein plete or destroy the intracellular stores within family). The effector protein differs amongst adreno- adrenergic nerve terminals (e.g. reserpine and ceptor subtypes. In the case of [3-adrenoceptors, the guanethidine) and thus block the action of indirect effector is adenylyl cyclase and hence cyclic AMP is sympathomimetics. the second messenger molecule. For oc-adrenoceptors, Sympathomimetics are also generally optically phospholipase C is the commonest effector protein active drugs, with only one stereoisomer conferring and the second messenger here is IP3. It is the cascade most of the clinical efficacy of the racemate: for of events initiated by the second messenger mole- instance laevo-noradrenaline is at least 50 times as cules that produces the variety of tissue effects as active as the dextro- form. Noradrenaline, adrenaline shown in Table 22.1 It should be clear that specifi- and phenylephrine are all used clinically as their city is provided by the receptor subtype, not the laevo-isomers. messengers. History. Up to 1948 it was known that the peripheral motor (vasoconstriction) effects of adrenaline were Complexity of adrenergic mechanisms preventable and that the peripheral inhibitory Drugs may mimic or impair adrenergic mechanisms: (vasodilatation) and the cardiac stimulant actions were not preventable by the then available antag- • directly, by binding on adrenoceptors: as agonists onists (ergot alkaloids, phenoxybenzamine). That (adrenaline) or antagonists (propranolol) 448
C L A S S I F I C A T I O N OF S Y M PAT H O M I M E T I C S 22 TABLE 22. 1 Clinically relevant aspects of adrenoceptor functions and actions of agonists ctj-adrenoceptor effects' ( -adrenoceptor effects 2 Eye: mydriasis Heart (( , 2)3 increased rate (SA node) increased automaticity (AV node and muscle) increased velocity in conducting tissue increased contractility of myocardium increased O2 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. 1 2-adrenoceptor effects: 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 endings2 (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 449
22 ADRENERGIC MECHANISMS AND DRUGS noradrenaline ( 2~autoreceptors) zoline), metaraminol, phenylephrine, phen- (clonidine) ylpropanolamine, ephedrine, pseudoephedrine: some • by blocking sympathetic autonomic ganglia are used solely for topical vasoconstriction (nasal (trimetaphan). decongestants). All the above mechanisms operate in both the 2 effects in the central nervous system: clonidine. central and peripheral nervous systems. This dis- cussion is chiefly concerned with agents that effects, nonselective (i.e. 1 + 1): isoprenaline influence peripheral adrenergic mechanisms. (isoproterenol). Its uses as bronchodilator ( 2), for positive cardiac inotropic effect and to enhance SELECTIVITY FOR ADRENOCEPTORS conduction in heart block ( 1, 2) have been largely superseded by agents with a more appropriately The following classification of sympathomimetics selective profile of effects. Other agents with non- and antagonists is based on selectivity for receptors selective effects, ephedrine, orciprenaline, are also and on use. But selectivity is relative, not absolute; obsolete for asthma. some agonists act on both a- and -receptors, some are partial agonists and, if enough is administered, 1 effects, with some a effects: dopamine, used in many will extend their range. The same applies to cardiogenic shock. selective antagonists (receptor blockers), e.g. a 1- selective adrenoceptor blocker can cause severe 1 effects: dobutamine, used for cardiac inotropic exacerbation of asthma (a 2 effect) even at low effect. dose. It is important to remember this because patients have died in the hands of doctors who 2 effects, used in asthma, or to relax the uterus, have forgotten or been ignorant of it.3 include: salbutamol, terbutaline, fenoterol, pirbuterol, reproterol, rimiterol, isoxsuprine, orciprenaline, rit- Adrenoceptor agonists (Table 22.1) odrine. + effects, nonselective: adrenaline is used as a Adrenoceptor antagonists (blockers) vasoconstrictor (a) with local anaesthetics, as a mydriatic and in the emergency treatment of See page 474. anaphylactic shock, for which condition it has the right mix of effects (bronchodilator, positive cardiac Effects of a sympathomimetic inotropic, vasoconstriction at high dose). The overall effect of a sympathomimetic depends on otj effects: noradrenaline (with slight effect on heart) the site of action (receptor agonist or indirect action), is selectively released physiologically where it is on receptor specificity and on dose; for instance adre- wanted; as therapeutic agents for hypotensive naline ordinarily dilates muscle blood vessels ( 2; states (excepting septic shock) dopamine and mainly arterioles, but veins also) but in very large dobutamine are preferred (for their cardiac doses constricts them (a). The end results are often inotropic effect). Also having predominantly 1 complex and unpredictable, partly because of the effects are imidazolines (xylometazoline, oxymeta- variability of homeostatic reflex responses and partly because what is observed, e.g. a change in 3 While it is simplest to regard the selectivity of a drug as blood pressure, is the result of many factors, e.g. relative, being lost at higher doses, strictly speaking it is the vasodilatation ( ) in some areas, vasoconstriction benefits of the receptor selectivity of an agonist or antagonist, (a) in others, and cardiac stimulation ( ). which are dose-dependent. A 10-fold selectivity of an agonist To block all the effects of adrenaline and nor- at the 1-receptor, for instance, is a property of the agonist that is independent of dose, and means simply that 10 times adrenaline, antagonists for both a- and -receptors less of the agonist is required to activate this receptor must be used. This can be a matter of practical compared to the 2-subtype. importance, e.g. in phaeochromocytoma (see p. 495). 450
C L A S S I F I C A T I O N OF S Y M P AT H O M I M E T I C S 22 Physiological note. The termination of action of a result of leakage from i.v. infusions. The effects on noradrenaline released at nerve endings is by: the heart ( 1) include tachycardia, palpitations, cardiac arrhythmias including ventricular tachy- • reuptake into nerve endings where it is stored cardia and fibrillation, and muscle tremor (( 2). Sym- and also subject to MAO degradation pathomimetic drugs should be used with great • diffusion away from the area of the nerve ending caution in patients with heart disease. and the receptor (junctional cleft) The effect of the sympathomimetic drugs on the • metabolism (by extraneuronal MAO and pregnant uterus is variable and difficult to predict, COMT). but serious fetal distress can occur, due to reduced These processes are slower than the very swift placental blood flow as a result both of contraction destruction of acetylcholine at the neuromuscular of the uterine muscle (a) and arterial constriction junction by extracellular acetylcholinesterase seated (a). 2-agonists are used to relax the uterus in pre- alongside the receptors. This difference reflects the mature labour, but unwanted cardiovascular actions differing signalling requirements: almost instan- can be troublesome. Sympathomimetics were parti- taneous (millisecond) responses for voluntary muscle cularly likely to cause cardiac arrhythmias ( 1 effect) movement versus the much more leisurely con- in patients who received halothane anaesthesia traction of arteriolar muscle to control vascular (now much less used). resistance. Sympathomimetics and plasma potassium. Adrenergic mechanisms have a role in the physio- Synthetic noncatecholamines in clinical use have logical control of plasma potassium concentration. t// of hours, e.g. salbutamol 4h, because they are The biochemical pump that shifts potassium into more resistant to enzymatic degradation and cells is activated by the ( 2-adrenoceptor agonists conjugation. They may be given orally although (adrenaline, salbutamol, isoprenaline) and can cause much higher doses are required. They penetrate the hypokalaemia. 2-adrenoceptor antagonists block central nervous system and may have prominent the effect. effects, e.g. amphetamine. Substantial amounts The hypokalaemia effects of administered ( 2) appear in the urine. Sympathomimetics may be clinically important, particularly in patients having pre-existing hypo- Pharmacokinetics kalaemia, e.g. due to intense adrenergic activity such as occurs in myocardial infarction,4 in fright Catecholamines (adrenaline, noradrenaline, dopa- (admission to hospital is accompanied by transient mine, dobutamine, isoprenaline) (plasma t1/2 approx. hypokalaemia), or with previous diuretic therapy, 2 min) are metabolised by two enzymes, monoamine and taking digoxin. In such subjects the use of a oxidase (MAO) and catechol-O-methyltransferase sympathomimetic infusion or of an adrenaline- (COMT). These enzymes are present in large amounts containing local anaesthetic may precipitate a in the liver and kidney and account for most of the cardiac arrhythmia. Hypokalaemia may occur metabolism of injected catecholamines. MAO is during treatment of severe asthma, particularly also present in the intestinal mucosa (and in nerve where the 2-receptor agonist is combined with endings, peripheral and central). Because of these theophylline. enzymes catecholamines are ineffective when -adrenoceptor blockers, as expected, enhance swallowed, but noncatecholamines, e.g. salbutamol, the hyperkalaemia of muscular exercise; and one of amphetamine, are effective orally. their benefits in preventing cardiac arrhythmias Adverse effects 4 Normal subjects, infused i.v. with adrenaline in amounts that approximate to those found in the plasma after severe These may be deduced from their actions (Table myocardial infarction, show a fall in plasma K of about 0.8 22.1, Fig. 22.1). Tissue necrosis due to intense mmol/1 (Brown M J 1983 New England Journal of Medicine vasoconstriction (a) around injection sites occurs as 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 Adrenaline (epinephrine) 2-receptor-inducedhypokalaemia. Adrenaline ( - and -adrenoceptor effects) is used: Overdose of sympathomimetics is treated according • as a vasoconstrictor with local anaesthetics to rational consideration of mode and site of action (1:80 000 or weaker) to prolong their effects (see Adrenaline, below). (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 Individual route must be chosen with care. For adults, sympathomimetics adrenaline 500 micrograms (i.e. 0.5 ml of the 1 in 1000 solution) may be given i.m. and repeated The actions are summarised in Table 22.1. The classic, mainly endogenous substances will be described first 5 Traditionally catecholamines have had a dual nomenclature despite their limited role in therapeutics, and then (as a consequence of a company patenting the name the more selective analogues that have largely Adrenalin), broadly European and N. American. The latter replaced them. 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. CATECHOLAMINES5 Because uniformity has not yet been achieved and because of the scientific literature, we use both. For pharmacokinetics, see above. For pharmacokinetics, see above. 452
I N D I V I D U A L SYM P A T H O M I METI CS 22 at 5-min intervals according to the response and so raising the total peripheral resistance, with (see Ch. 8, p. 143). If the circulation is reduced blood flow (except in coronary arteries compromised to a degree that is immediately which have few 1-receptors). Though it does have life-threatening, adrenaline 500 micrograms some cardiac stimulant ( a) effect, the tachycardia may be given by slow i.v. injection at a rate of of this is masked by the profound reflex bradycardia 100 micrograms/min (i.e. 1 ml/min of the caused by the hypertension. Noradrenaline is given dilute 1 in 10 000 solution) with continuous by i.v. infusion to obtain a gradual sustained response; monitoring of the ECG. This course requires the effect of a single i.v. injection would last only a extreme caution and use of a further x 10 minute or so. It is used where peripheral vaso- dilution (i.e. a 1 in 100 000 solution) may be constriction is specifically desired, e.g. vasodilation preferred as providing finer control and greater of septic shock. Adverse effects include peripheral safety. The s.c. route is generally not gangrene and local necrosis; tachyphylaxis occurs recommended as there is intense and withdrawal must be gradual. vasoconstriction, which slows absorption. Isoprenaline (isoproterenol) Adrenaline is used in anaphylactic shock because Isoprenaline (isopropylnoradrenaline) is a non- its mix of actions, cardiovascular and bronchial, selective (3-receptor agonist, i.e. it activates both Pj- provide the best compromise for speed and sim- and P2-receptors. It relaxes smooth muscle, including plicity of use in an emergency; it may also stabilise that of the blood vessels, has negligible metabolic or mast cell membranes and reduce release of vaso- vasoconstrictor effects, but a vigorous stimulant active autacoids (see p. 280). Patients who are effect on the heart. This latter is its main dis- taking nonselective -blockers may not respond to advantage in the treatment of bronchial asthma. Its adrenaline (use salbutamol i.v.) and indeed may principal uses are in complete heart block and develop severe hypertension (see below). occasionally in cardiogenic shock (hypotension). Adrenaline (topical) decreases intraocular pressure in chronic open-angle glaucoma, as does dipivefrine, Dopamine an adrenaline ester prodrug. They are contra- indicated in closed-angle glaucoma because they Dopamine activates different receptors depending are mydriatics. Hyperthyroid patients are intolerant on the dose used. At the lowest effective dose it of adrenaline. stimulates specific dopamine (Da) receptors in the CNS and the renal and other vascular beds (dilator); Accidental overdose with adrenaline occurs it also activates presynaptic autoreceptors (D2) which occasionally. It is rationally treated by propranolol suppress release of noradrenaline. As dose is raised, to block the cardiac effects (cardiac arrhythmia) dopamine acts as an agonist on P^adrenoceptors in and phentolamine or chlorpromazine to control the the heart (increasing contractility and rate); at high a effects on the peripheral circulation that will be doses it activates a-adrenoceptors (vasoconstrictor). It prominent when the (3 effects are abolished. Labetalol is given by continuous i.v. infusion because, like all ( + block) would be an alternative. p-adrenoceptor catecholamines, its il/2 is short (2 min). An i.v. in- block alone is hazardous as the then unopposed ot- fusion (2-5 micrograms/kg/min) increases renal receptor vasoconstriction causes (severe) hyper- blood flow (partly through an effect on cardiac out- tension (see Phaeochromocytoma, p. 494). Use of put). As the dose rises the heart is stimulated, antihypertensives of most other kinds is irrational resulting in tachycardia and increased cardiac out- and some may also potentiate the adrenaline. put. At these higher doses, dopamine is referred to as an 'inoconstrictor'. Dopamine is stable for about 24 h in sodium Noradrenaline (norepinephrine) (chiefly OL chloride or dextrose. Subcutaneous leakage causes and , effects) vasoconstriction and necrosis and should be treated The main effect of administered noradrenaline is to by local injection of an a-adrenoceptor blocking raise the blood pressure by constricting the arterioles agent (phentolamine 5 mg, diluted). 453
22 ADRENERGIC M E C H A N I S M S A N D DRUGS It may be mixed with dobutamine. which makes it suitable for both prevention and For CNS aspects of dopamine, agonists and treatment of asthma. Of an inhaled dose < 20% is antagonists: see Neuroleptics, Parkinsonism. absorbed and can cause cardiovascular effects. It can also be given by injection, e.g. in asthma, premature labour 2-receptor) and for cardiac Dobutamine inotropic ( 1) effect in heart failure (where the ( 2 Dobutamine is a racernic mixture of d- and 1- vasodilator action is also useful). Clinically imp- dobutamine. The racemate behaves primarily a 1 ortant hypokalaemia can also occur (the shift of adrenoceptor agonist with greater inotropic than potassium into cells). The other drugs above are chronotropic effects on the heart; it has some - similar. agonist effect, but less than dopamine. It is useful in shock (with dopamine) and in low output heart Salmeterol (Serevent) is a variant of salbutamol failure (in the absence of severe hypertension). 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) Dopexamine (see p. 560). Dopexamine is a synthetic catecholamine whose principal action is as an agonist for the cardiac 2- Ephedrine adrenoceptors (positive inotropic effect). It is also a weak dopamine agonist (thus causing renal Ephedrine (t l / 2 approx. 4 h) is a plant alkaloid with vasodilatation) and inhibitor of noradrenaline indirect sympathomimetic actions that resemble uptake thereby enhancing stimulation of cardiac 1- adrenaline peripherally. Centrally (in adults) it pro- receptors by noradrenaline. It is used occasionally duces increased alertness, anxiety, insomnia, tremor to optimise the cardiac output, particularly and nausea; children may be sleepy when taking it. perioperatively. In practice central effects limit its use as a sym- pathomimetic in asthma. Ephedrine is well absorbed when given orally NONCATECHOLAMINES and, unlike most other sympathomimetics, under- Salbutamol, fenoterol, rimiterol, reproterol, pir- goes relatively little first-pass metabolism in the buterol, salmeterol, ritodrine and terbutaline are fi- liver; it is largely excreted unchanged by the kidney. adrenoceptor agonists that are relatively selective for It is usually given by mouth but can be injected. It 2-receptors, so that cardiac (chiefly 1-receptor) differs from adrenaline principally in that its effects effects are less prominent. Tachycardia still occurs come on more slowly and last longer. Tachyphylaxis because of atrial (sinus node) 2-receptor stimulation; occurs on repeated dosing. Ephedrine can be used the 2-adrenoceptors are less numerous in the as a bronchodilator, in heart block, as a mydriatic ventricle and there is probably less risk of serious and as a mucosal vasoconstrictor, but newer drugs, ventricular arrhythmias than with the use of which are often better for these purposes, are dis- nonselective catecholamines. The synthetic agonists placing it. It is sometimes useful in myasthenia are also longer-acting than isoprenaline because they gravis (adrenergic agents enhance cholinergic neuro- are not substrates for catechol-O-methyltransferase, muscular transmission). Pseudoephedrine is similar. which methylates catecholamines in the liver. They Phenylpropanolamine (norephedrine) is similar are used principally in asthma, and to reduce but with less CNS effect. Prolonged administration uterine contractions in premature labour. of phenylpropanolamine to women as an anorectic has been associated with pulmonary valve abnor- malities and led to its withdrawal in some Salbutamol (see also Asthma) countries. Salbutamol (Ventolin) (t1/2 4h) is taken orally, Amfetamine (Benzedrine) and dexamphetamine 2-4 mg up to 4 times/day; it also acts quickly by (Dexedrine) act indirectly. They are seldom used for inhalation and the effect can last as long as 4h, 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 Shock children). (For a general account of amphetamine, see p. 193) Definition. Shock is a state of inadequate capillary perfusion (oxygen deficiency) of vital tissues to an Phenylephrine has actions qualitatively similar to extent that adversely affects cellular metabolism noradrenaline but a longer duration of action, up to (capillary endothelium and organs) causing mal- an hour or so. It can be used as a nasal decongestant function, including release of enzymes and (0.25-0.5% solution), but sometimes irritates. In the vasoactive substances,6 i.e. it is a low flow or hypo- doses usually given, the central nervous effects are perfusion state. minimal, as are the direct effects on the heart. It is The cardiac output and blood pressure are low in also used as a mydriatic and briefly lowers fully developed cases. But a maldistribution of blood intraocular pressure. (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 Mucosal decongestants shock. The essential element, hypoperfusion of vital Nasal and bronchial decongestants (vasoconstrictors) organs, is present whatever the cause, whether are widely used in allergic rhinitis, colds, coughs pump failure (myocardial infarction), maldistribution and sinusitis, and to prevent otitic barotrauma, as of blood (septic shock) or loss of total intravascular nasal drops or nasal sprays. All the sympathomimetic volume (bleeding or increased permeability of vessels vasoconstrictors, i.e. with a effects, have been used damaged by bacterial cell products, burns or anoxia). for the purpose, with or without an antihistamine Function of vital organs, brain (consciousness, (Hj-receptor), and there is little to choose between respiration) and kidney (urine formation) are clinical them. Ischaemic damage to the mucosa is possible if indicators of adequacy of perfusion of these organs. they are used excessively (more often than 3-hourly) or for prolonged periods (> 3 weeks). The occurrence Treatment may be summarised: of rebound congestion is also liable to lead to over- • Treatment of the cause: bleeding, infection, use. The least objectionable drugs are ephedrine adrenocortical deficiency 0.5% and phenylephrine 0.5%. Xylometazoline 0.1% • Replacement of any fluid lost from the circulation (Otrivine) should be used, if at all, for only a few • Perfusion of vital organs (brain, heart, kidneys) days since longer application reduces the ciliary and maintenance of the mean blood pressure. activity and will lead to rebound congestion. Blood flow (oxygen delivery) rather than blood Naphazoline and adrenaline should not be used, pressure is of the greatest immediate importance and nor should blunderbuss mixtures of vaso- for the function of vital organs. A reasonable blood constrictor antihistamine, adrenal steroid and anti- pressure is needed to ensure organ perfusion but biotics. Oily drops and sprays, used frequently and peripheral vasoconstriction may maintain a normal long-term, may enter the lungs and eventually mean arterial pressure despite a very low cardiac cause lipoid pneumonia. output. Under these circumstances, blood flow to It may sometimes be better to give the drugs vital organs will be inadequate and multiple organ orally rather than up the nose. They interact with antihypertensives and can be a cause of unexplained 6 failure of therapy unless enquiry into patient self- In fact, a medley of substances (autacoids), kinins, prostaglandins, leukotrienes, histamine, endorphins, medication is made. Fatal hypertensive crises have serotonin, vasopressin, has been implicated. In endotoxic occurred when patients treated for depression with shock, the toxin also induces synthesis of nitric oxide, the a monoamine oxidase inhibitor have taken these endogenous vasodilator, in several types of cells other than preparations. the endothelial cells which are normally its main source. 455
22 ADRENERGIC M EC H A N I SM S A N D D R U G S failure will ensue unless the patient is resuscitated inhibitor such as enoximone may also be effective, adequately. unless its use is limited by hypotension. The decision how to treat shock depends on If there is bradycardia (as sometimes complicates assessment of the pathophysiology: myocardial infarction), cardiac output can be increased by vagal block with atropine, which acceler- • whether cardiac output, and so peripheral blood ates the heart rate. flow, is inadequate (low pulse volume, cold- constricted periphery) Septic shock is severe sepsis with hypotension that • whether cardiac output is normal or high and is not corrected by adequate intravascular volume peripheral blood flow is adequate (good pulse replacement. It is caused by lipopolysaccharide volume and warm dilated periphery), but there (LPS) endotoxins from Gram-negative organisms is maldistribution of blood and other cell products from Gram-positive organ- • whether the patient is hypovolaemic or not, or isms; these initiate host inflammatory and pro- needs a cardiac inotropic agent, a vasoconstrictor coagulant responses through the release of cytokines, or a vasodilator. e.g. interleukins, and the resulting diffuse endo- thelial damage is responsible for many of the Types of shock adverse manifestations of shock, including multi- organ failure. First, there is a peripheral vaso- In poisoning by a cerebral depressant or after dilatation from activation of nitric oxide by LPS and spinal cord trauma, the principal cause of hypo- cytokines, with eventual fall in arterial pressure. tension is low peripheral resistance due to reduced This initiates a vigorous sympathetic discharge that vascular tone. The cardiac output can be restored by causes constriction of arterioles and venules; the simply tilting the patient head-down and by cardiac output may be high or low according to the increasing the venous filling pressure by infusing balance of these influences. There is a progressive fluid. Vasoactive drugs (noradrenaline, dobutamine) peripheral anoxia of vital organs and acidosis. The may be beneficial. veins (venules) dilate and venous pooling occurs so that blood is sequestered in the periphery and In central circulatory failure (cardiogenic shock, effective circulatory volume falls because of this, e.g. after myocardial infarction) the cardiac output and of fluid loss into the extravascular space from and blood pressure are low due to pump failure; endothelial damage caused by bacterial products. myocardial perfusion is dependent on aortic pressure. When septic shock is recognised, appropriate Venous return (central venous pressure) is normal antimicrobials should be given in high dose or high. The low blood pressure may trigger the immediately after the taking of blood cultures (see sympathoadrenal mechanisms of peripheral circu- p. 237). Beyond that, the prime aim of treatment is latory failure summarised below. to restore cardiac output and vital organ perfusion Not surprisingly, the use of drugs in low output by accelerating venous return to the heart and to failure due to acute myocardial damage is dis- reverse the maldistribution of blood. Increasing appointing. Vasoconstriction (by an -adreno- intravascular volume will achieve this, guided by ceptor agonist), by increasing peripheral resistance, the central venous pressure to avoid overloading may raise the blood pressure by increasing the heart. Oxygen is essential as there is often uneven afterload, but this additional burden on the pulmonary perfusion. damaged heart can further reduce the cardiac out- After adequate fluid resuscitation has been put. Cardiac stimulation with a 1-adrenoceptor established, inotropic support is usually required. agonist may fail; it increases myocardial oxygen Noradrenaline is the inotrope of choice for septic consumption and may cause an arrhythmia. shock: its potent -adrenergic effect increases the Dobutamine, dopexamine or dopamine offer a mean arterial pressure and its modest 1 effect may reasonable choice if a drug is judged necessary; raise cardiac output, or at least maintain it as the dobutamine is preferred as it tends to vasodilate, i.e. peripheral vascular resistance increases. Dobutamine it is an 'inodilator'. A selective phosphodiesterase may be added further to augment cardiac output. 456
CHRONIC ORTHOSTATIC HYPOTENSION 22 Some clinicians use adrenaline, in preference to isotonic saline, Hartmann's, Plasma-Lyte, are im- noradrenaline plus dobutamine, on the basis that its mediately effective, but they leave the circulation powerful a and (3 effects are appropriate in the quickly. (Note that dextrose solutions are completely setting of septic shock; it may exacerbate splanchnic ineffective because they distribute across both the ischaemia and lactic acidosis. extracellular and intracellular compartments.) Macro- molecules (colloids) remain in the circulation longer. Hypotension in (atherosclerotic) occlusive vascular The two classes (crystalloids and colloids) may be disease is particularly serious, for these patients used together. are dependent on pressure to provide the necessary The choice of crystalloid or colloid for fluid blood flow in vital organs whose supplying vessels resuscitation remains controversial. There have been are less able to dilate. It is important to maintain an no prospective, randomised trials of sufficient power adequate mean arterial pressure, whichever inotrope in either sepsis or trauma, to detect a significant is selected. difference in mortality. Albumin is relatively expen- sive and offers no advantage over cheaper, synthetic CHOICE OF DRUG IN SHOCK colloids such as etherified starch. Colloidal isotonic solutions of macromolecules On present knowledge the best drug would be one include: dextrans (glucose polymer), gelatin (hydro- that both stimulates the myocardium and selectively lysed collagen) and hydroxyethyl starch. modifies peripheral resistance to increase flow to vital organs. Dextran 70 (mol. wt. 70 000) has a plasma restoring • Dobutamine is used when cardiac inotropic effect effect lasting 5-6 h. Dextran 40 is used to decrease is the primary requirement. blood sludging and so to improve peripheral blood • Adrenaline is used when a more potent inotrope flow. than dobutamine is required, e.g. when the vasodilating action of dobutamine compromises Gelatin products (Haemaccel, Gelofusine) have a mean arterial pressure. plasma restoring effect of 2-3 h (at best). • Noradrenaline is used when vasoconstriction is the first priority, plus some slight cardiac Etherified starch. Several hydroxyethyl starch inotropic effect, e.g. septic shock. solutions are available, with widely differing effects on plasma volume. The high molecular weight (450000) solutions have a volume restoring effect Monitoring drug use for 6-12 h, while that of medium molecular weight Modern monitoring by both invasive and non- (200 000) starches last 4-6 h. invasive techniques is complex and is undertaken in units dedicated to and, equipped for, this activity. Adverse effects include anaphylactoid reactions; The present comment is an overview. Monitoring dextran and hetastarch can impair haemostatic will normally require close attention to heart rate mechanisms. 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 Chronic orthostatic state (especially of peripheral flow) and to other hypotension essential management, treatment of infection and maintenance of intravascular volume. Chronic orthostatic hypotension occurs most com- monly with increasing age, in primary progressive Restoration of intravascular volume7 In an emergency, speed of replacement is more 7 Nolan J 2001 Fluid resuscitation for the trauma patient. important than its nature. Crystalloid solutions, e.g. 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 Some of the variation in reported results of drug and diabetes. The clinical features can be mimicked therapy may be due to differences in adrenergic by saline depletion. The two conditions are clearly function dependent on whether the degeneration is separated by measurement of plasma levels of central, peripheral, preganglionic, postganglionic noradrenaline (supine and erect) and renin. These or due to age-related changes in the adrenoceptors are elevated in saline depletion, but depressed in on end-organs. In central autonomic degeneration, most causes of hypotension due to autonomic failure. 'multisystem atrophy', noradrenaline is still present Since blood pressure can be considered a product in peripheral sympathetic nerve endings. In these of Volume' and 'vasoconstriction', the logical initial patients, an indirect-acting amine may be success- treatment of orthostatic hypotension is to expand ful, and one patient titrated the amount of Bovril (a blood volume using a sodium-retaining adrenocortical tyramine-rich meat extract drink) she required in steroid (fludrocortisone8) or desmopressin (p. 716) order to stand up.9 — plus elastic support stocking to reduce venous Erythropoietin has been used with success (it pooling of blood when erect. increases haematocrit and blood viscosity). It is more difficult to reproduce the actions of the endogenous vasoconstrictors, and especially their selective release on standing, in order to achieve • The adrenergic arm of the autonomic system uses erect normotension without supine hypertension. noradrenaline (norepinephrine) as its Because of the risk of hypertension when the patient neurotransmitter. is supine, only a modest increase in erect blood • Adrenaline (epinephrine), unlike noradrenaline, is a circulating hormone. pressure should be sought; fortunately a systolic • These two catecholamines act on the same blood pressure of 85-90 mmHg is usually adequate adrenoceptors: 1 and 2 which are blocked by to maintain cerebral perfusion in these patients. phenoxybenzamine but not by propranolol, and ( 1 and Few drugs have been formally tested or can be 2 which are blocked by propranolol but not recommended with confidence. Clonidine and phenoxybenzamine. Noradrenaline is a 20-fold weaker pindolol are partial agonists at, respectively, a and agonist at 2-receptors than is adrenaline. receptors, and may therefore be more effective • Distinction between receptor classes is made initially by defining the differing ability of two agonists (or agonists in the absence of the endogenous agonist, antagonists) to mimic (or block) the effects of noradrenaline, than in normal subjects. Midodrine, catecholamines. an a-adrenoceptor agonist, is the only vasoconstrictor • Often these differences correlate with a difference in drug to receive UK regulatory approval for the receptor type on two different tissues: e.g. stimulation treatment of postural hypotension. It should be of cardiac contractility by 1-receptors and given at doses of 5-15 mg t.i.d. bronchodilatation by 2-receptors. Postprandial fall in blood pressure (probably • The distinction between 1- and 2-receptors corresponds to their principal location on blood due to redistribution of blood to the splanchnic vessels (causing vasoconstriction) and neurons. area) is characteristic of this condition; it especially • Catecholamines themselves can be used in therapy occurs after breakfast (blood volume is lower in the when rapid onset and offset are desired. Selective morning). Substantial doses of caffeine (two large mimetics at each of the four main receptor subtypes cups of coffee) can mitigate this, but they need to be are used for individual locations, e.g: 1 for nasal taken before or early in the meal. The action may be decongestion, 2 for systemic hypotension, for due to block of splanchnic vasodilator adenosine heart failure or shock, 2 for bronchoconstriction. • Both a- and -blockade are used in hypertension; receptors. Administration of the somatostatin ana- selective -blockade is used in angina and heart logue, octreotide, prevents postprandial hypotension, failure. but the requirement for twice daily subcutaneous injections makes the drug an unlikely candidate for regular use in this group of patients. 9 Karet F E et al 1994 Bovril and moclobemide: a novel 8 Effective doses may not affect blood volume and may work therapeutic strategy for central autonomic failure. Lancet by sensitising vascular adrenoceptors. 344:1263-1265. 458
CHRONIC ORTHOSTATIC HYPOTENSION 22 GUIDETO FURTHER READING Evans T W, Smithies M 1999 ABC of intensive care. Organ dysfunction. British Medical Journal 318: Ahlquist R P 1948 A study of adrenotropic receptors. 1606-1609 American Journal of Physiology 153: 586-600 Ewan P W 1998 Anaphylaxis. British Medical Journal Astiz M E, Rackow E C 1998 Septic shock. Lancet 351: 316:1442-1445 1501-1505 Insel P A1996 Adrenergic receptors — evolving Bernard G D et al 2001 Efficacy and safety of concepts and clinical implications. New England recombinant human activated protein C for severe Journal of Medicine 334: 580-585. sepsis. New England Journal of Medicine 344: Lynn W A1999 Severe sepsis. In: Pusey C (ed) 699-709 Horizons in medicine. Royal College of Physicians Brown M J 1995 To -block or better block? British of London, London, p 55-68 Medical Journal 311: 701-702 Wheeler A P, Bernard G D 1999 Treating patients with Califf R M, Bengtson J R 1994 Cardiogenic shock. New severe sepsis. New England Journal of Medicine England Journal of Medicine 330:1724-1730 340: 207-214 459