CLINICAL PHARMACOLOGY 2003 (PART 25B)

ADRENOCEPTOR Overdose Overdose, including self-poisoning, causes bradycardia, heart block, hypotension and low output cardiac failure that can proceed to cardiogenic shock; death is more likely with agents having membrane stabilising action (see Table 23.1) Bronchoconstriction can be severe, even fatal, in patients subject to any bronchospastic disease; loss of consciousness may occur with lipid-soluble agents that penetrate the central nervous system Receptor blockade will outlast the persistence of the drug in the plasma Rational treatment includes: • Atropine (1-2 mg i.v as or bolus doses) to eliminate the unopposed vagal activity that contributes to bradycardia Most patients will also require direct cardiac pacing 20 Practolol was developed to the highest current scientific standards; it was marketed (1970) as the first cardioselective -blocker and only after independent review by the UK drug regulatory body All seemed to go well for about years (though skin rashes were observed) by which time there had accumulated about 200 000 patient years of experience with the drug, and then, wrote the then Research Director of the industrial developer, 'came a bolt from the blue and we learnt that it could produce in a small proportion of patients a most bizarre syndrome, which could embrace the skin, eyes, inner ear, and the peritoneal cavity' and also the lung (oculomucocutaneous syndrome) The cause is likely to be an immunological process to which a small minority of patients are prone, 'with present knowledge we cannot say it will not happen again with another drug' That the drug caused this peculiar syndrome was recognised by an alert opthalmologist who ran a special clinic for external eye diseases In 1974 he suddenly became aware that he was seeing patients complaining of dry eyes but with unusual features Instead of the damage (blood vessel changes with metaplasia and keratinisation of the conjunctive) being on the front of the eye exposed by the open lids, it was initially in the areas behind and protected by the lids He noted that these patients were all taking practolol Quite soon the whole syndrome was defined, as above Some patients became blind and some required surgery for the peritoneal disorder and a few died as a consequence The drug was first restricted to brief use by injection in emergency control of disorders of heart rhythm, but is now obsolete even for that The developers acknowledged moral (though not legal) liability for the harm done and paid compensation to affected patients They were not negligent because current science did not provide a possibility of predicting the effect, i.e 'state of the art defence' applied The law did not provide for strict liability or no-fault compensation (see p 10) BLOCKING DRUGS 11 • Glucagon, which has cardiac inotropic and chronotropic actions independent of the -adrenoceptor (dose 50-150 micrograms/kg in glucose 5% i.v., repeated if necessary) to be used at the outset in severe cases (an unlicenced indication) • If there is no response, i.v injection or infusion of a -adrenoceptor agonist is used, e.g isoprenaline (4 micrograms/min, increasing at 1-3-min intervals until the heart rate is 50-70 beats/min) • In severe poisoning the dose may need to be high and prolonged to surmount the competitive block.21 • Other sympathomimetics may be used as judgement counsels, according to the desired receptor agonist actions ( 1, 2, ) required by the clinical condition, e.g dobutamine, dopamine, dopexamine, noradrenaline, adrenaline • For bronchoconstriction, salbutamol may be used; aminophylline has nonadrenergic cardiac inotropic and bronchodilator actions and should be given i.v very slowly to avoid precipitating hypotension Treatment may be needed for days With prompt treatment death is unusual Interactions Pharmacokinetic Agents metabolised in the liver provide higher plasma concentrations when another drug that inhibits hepatic metabolism, e.g cimetidine, is added Enzyme inducers enhance the metabolism of this class of -blockers p-adrenoceptor blockers themselves reduce hepatic blood flow (fall in cardiac output) and reduce the metabolism of blockers and other drugs whose metabolic elimination is dependent on the rate of delivery to the liver, e.g lignocaine (lidocaine), chlorpromazine Pharmacodynamic The effect on the blood pressure of sympathomimetics having both a- and receptor agonist actions is increased by block of P21 For example, 115 mg of isoprenaline i.v were infused over 65 h to treat one case Lagerfelt J et al 1976 Acta Medica Scandinavica 199: 517 479 23 A R T E R I A L H Y PER T EN SI O N , A N G I N A P E C T O R I S , receptors leaving the -receptor vasoconstriction unopposed (adrenaline added to local anaesthetics may cause hypertension); the pressor effect of abrupt clonidine withdrawal is enhanced, probably by this action Other cardiac antiarrhythmic drugs are potentiated, e.g hypotension, bradycardia, heart block Combination with verapamil (i.v.) is hazardous in the presence of atrioventricular nodal or left ventricular dysfunction because the latter has stronger negative inotropic and chronotropic effects than other calcium channel blockers Most NSAIDs attenuate the antihypertensive effect of -blockers (but not perhaps of atenolol), presumably due to inhibition of formation of renal vasodilator prostaglandins, leading to sodium retention -adrenoceptor blockers potentiate the effect of other antihypertensive particularly when an increase in heart rate is part of the homeostatic response (Cachannel blockers and -adrenoceptor blockers) Non-selective -receptor blockers potentiate hypoglycaemia of insulin and sulphonylureas Pregnancy (3-adrenoceptor blocking agents are used in hypertension of pregnancy, including pre-eclampsia Both lipid- and water-soluble members enter the fetus and may cause neonatal bradycardia and hypoglycaemia They are not teratogenic in pregnancy Notes on some individual blockers -adrenoceptor (For general pharmacokinetics, see p 476) Propranolol is available in standard (b.d or t.i.d.) and sustained-release (once daily) formulations When given i.v (1 mg/min over min, repeated every up to 10 mg) for cardiac arrhythmia or thyrotoxicosis it should be preceded by atropine (1-2 mg i.v.) to prevent excessive bradycardia; hypotension may occur Atenolol has a 1:2 selectivity of 1:15 It is widely used for angina pectoris and hypertension, in a dose of 25-100 mg orally once a day The tendency in the past has been to use higher than necessary doses When introduced, atenolol was considered 480 Ml not to need dose-ranging, unlike propranolol, but this was in part because the initial dose was already at the top of the dose-response curve Some 90% of absorbed drug is excreted by the kidney and the dose should be reduced when renal function is impaired, e.g to 50 mg/day when the glomerular filtration rate is 15-35 ml/min The il/2 is h Bisoprolol is more selective than atenolol (ratio 1:50) Although a relatively lipid-soluble agent, its tl/2 is one of the longest (11 h), and there is not the wide range of dose-requirement seen with propranolol As with atenolol, it is worth starting at a low dose (5 mg), to avoid causing unnecessary tiredness, and especially when trying to obtain the maximum benefit of its selectivity There is no need to alter doses when renal or hepatic function is reduced Nebivolol resembles bisoprolol in terms of lipophilicity and t1/2 (10 h) but is more 1-selective (ratio 1:300) Its unique feature is a direct vasodilator action (due to the d-isomer of the racemate, the 1isomer being the 1-antagonist) The mechanism appears to be through direct activation of nitric oxide production by vascular endothelium Combined ,- and blocking drug -adrenoceptor Labetalol is a racemic mixture, one isomer is a adrenoceptor blocker (nonselective), another blocks -adrenoceptors; its dual effect on blood vessels minimises the vasoconstriction characteristic of nonselective -blockade so that for practical purposes the outcome is similar to using a 1-selective p-blocker (see Table 23.1) It is less effective than drugs like atenolol or bisoprolol for the routine treatment of hypertension, but is useful for some specific indications The P-blockade is 4-10 times greater than the blockade, varying with dose and route of administration Labetalol is useful as a parenterally administered drug in the emergency reduction of blood pressure Ordinary -blockers may lower blood pressure too slowly, in part because reflex stimulation of unblocked -receptors opposes the fall in blood pressure In most patients, even those with severe hypertension, a gradual reduction in blood PERIPHERAL SYMPATHETIC pressure is desirable to avoid the risk of cerebral or renal hypoperfusion, but in the presence of a great vessel dissection or of fits a more rapid effect is required (below) Postural hypotension (characteristic of oc-receptor blockade) is liable to occur at the outset of therapy and if the dose is increased too rapidly But with chronic therapy when the -receptor component is largely responsible for the antihypertensive effect, it is not a problem Labetalol reduces the hypertensive response to orgasm in women The tl/2 is h; it is extensively metabolised in the hepatic first-pass The drug needs to be taken thrice daily in a dose of100-400mg t.d.s For emergency control of severe hypertension the most convenient regime is to initiate infusion at mg/min, and titrate upwards at half-hourly intervals as required The infusion is stopped as blood pressure control is achieved, and re-initiated as frequently as required until regular oral therapy has been successfully introduced Serotonin (5-HT) receptor + otadrenoceptor blocking drugs Ketanserin appears to act principally to block serotonin vasoconstrictor (subtype 5-HT2) receptors but also has significant -adrenoceptor blocking activity (its affinity ratio for the two receptors is 1:5) The latter explains its hypotensive action and use in Raynaud's disease It is not available in many countries and offers no advantages over pure -blockers such as doxazosin Serotonin (5-hydroxytryptamine, 5-HT) is synthesised in enterochromaffin cells, largely in the gut, and also extensively taken up into blood platelets from which it is released to have vascular effects It has complex effects on the cardiovascular system, varying with the vascular bed and its physiological state; it generally constricts arterioles and veins and induces blood platelet aggregation; it stimulates intestinal and bronchial smooth muscle Carcinoid tumours secrete serotonin and symptoms may be benefited by serotonin antagonists, e.g cyproheptadine, methysergide and sometimes by octreotide (see Index) It is a neurotransmitter in the brain N E RV E T E R M I N A L 23 Peripheral sympathetic nerve terminal ADRENERGIC NEURON BLOCKING DRUGS Adrenergic neuron blocking drugs are selectively taken up into adrenergic nerve endings by the active, energy-requiring, saturable amine (noradrenaline) pump mechanism (uptake-1) They accumulate in the noradrenaline storage vesicles from which they are released in response to nerve impulses, diminishing the release of noradrenaline and so all sympathetic function They not adequately control supine blood pressure and are prone to interactions with other drugs affecting adrenergic function, e.g tricyclic antidepressants and topical nasal decongestants They are virtually obsolete in hypertension Guanethidine has been used to reduce intraocular pressure in open angle glaucoma and to reduce thyrotoxic eyelid retraction for cosmetic effect Other members of the group are debrisoquine and bethanidine Metaiodobenzylguanidine (MIBG) is used diagnostically as a radioiodinated tracer, to locate chromaffin tumours (mainly phaeochromocytoma) which accumulate drugs in this class (p 495) DEPLETION OF STORED TRANSMITTER (NORADRENALINE) Reserpine is an alkaloid from plants of the genus Rauwolfia, used in medicine since ancient times in southern Asia, particularly for insanity; more recently, reserpine was extensively used in psychiatry but is now obsolete Reserpine depletes adrenergic nerves of noradrenaline primarily by blocking amine storage within vesicles present in the nerve ending, so reducing stores of releasable transmitter Its antihypertensive action is due chiefly to peripheral action, but it enters the CNS and depletes catecholamine stores there too; this explains the sedation, depression and parkinsonian (extrapyramidal) side effects that can accompany its use The effects on catecholamine storage persist for days to weeks after it is withdrawn 481 23 A R T E R I A L H Y PER T EN SI O N , A N G I N A P E C T O R I S , It has also had an important veterinary use in preventing the death of domestic male turkeys, which are liable to fatal hypertensive dissecting aortic aneurysms This can cause serious economic loss The addition of reserpine to their drinking water reduces their blood pressure and preserves their lives without noticeably moderating their natural rage as may -adrenoceptor blockers.22 INHIBITION OF SYNTHESIS OF TRANSMITTER Metirosine ( -methyl-p-tyrosine) is a competitive inhibitor of the enzyme tyrosine hydroxylase, which converts tyrosine to dopa; as dopa is further converted to noradrenaline and adrenaline they are similarly depleted by metirosine It is used as an adjuvant (with phenoxybenzamine) to treat phaeochromocytomas that cannot be removed surgically Catecholamine synthesis is reduced by up to 80% over days It also readily penetrates the CNS and depletes brain noradrenaline and dopamine causing reserpine-like side effects (see above) Hence, in patients whose life expectancy is threatened more by tumour invasion than by mild or moderate hypertension, the need for the drug should be weighed carefully Autonomic ganglionblocking drugs Hexamethonium was the first orally active drug to treat hypertension Like all agents in this group it blocks sympathetic and parasympathetic systems alike Severe side effects have rendered them of historical interest only in hypertension therapy.23 22 Conference on use of tranquillising agent Serpasil in animal and poultry production 1959 College of Agriculture, Rutgers State University, USA Wild turkeys have a blood pressure of 120/60 mmHg, but domestic turkeys are hypertensive (204/144 mmHg) Digoxin increases the incidence of aneurysm It seems that it is the rate of rise of pressure in the aorta that is important in this disease (probably in man also) and that reserpine and (3adrenoceptor blockers benefit by attenuating this 482 Ml Trimetaphan, a short-acting agent (given by i.v infusion, initially at 3-4mg/min), also has direct vasodilator effect; it is used for producing hypotension to provide a blood-free field during surgery, and can be used for emergency control of hypertension; pressure may be adjusted by tilting the body; it provides 'minute-to-minute' control, when the lack of selectivity is important Histamine release during infusion is occasionally a problem Central nervous system 2-ADRENOCEPTOR AGONISTS Clonidine (Catapres) is an imidazoline which is an agonist to 2-adrenoceptors (postsynaptic) in the brain, stimulation of which suppresses sympathetic outflow and reduces blood pressure At high doses it also activates peripheral 2-adrenoceptors (presynaptic autoreceptors) on the adrenergic nerve ending; these mediate negative feedback suppression of noradrenaline release In overdose clonidine can stimulate peripheral 1-adrenoceptors (postsynaptic) and thus cause hypertension by vasoconstriction Clonidine was discovered to be hypotensive, not by the pharmacologists who tested it in the laboratory but by a physician who used it on himself as nose drops for a common cold.24 The t1/2 is h Clonidine reduces blood pressure with little postural or exercise related drop Its most serious handicap is that abrupt or even gradual withdrawal causes rebound hypertension This is characterised by plasma catecholamine concentrations as high as those seen in hypertensive attacks of phaeochromocytoma The onset may be rapid (a few hours) or delayed for as long as days; it subsides over 2-3 days The treatment is either to reinstitute clonidine, i.m if necessary, or to treat as for a phaeochromocytoma Clonidine should never be used with a 3-adrenoceptor blocker which exacerbates withdrawal hypertension (see phaeochromocytoma) Common 23 Page L H 1981 New England Journal of Medicine 304:1371 The eminent pharmacologist, Sir John Gaddum, also dubbed the characteristic appearance as 'hexamethonium man' 24 Page L H 1981 New England Journal of Medicine 304:1371 ANGINA PECTORIS adverse effects include sedation and dry mouth Tricyclic antidepressants antagonise the antihypertensive action and increase the rebound hypertension of abrupt withdrawal Low dose clonidine (Dixarit, 50-100 microgram/d) also has a minor role in migraine prophylaxis, menopausal flushing and choreas Rebound hypertension is a less important problem with longer-acting imidazolines, since omission of a single dose will not trigger the rebound Such drugs include moxonidine and rilmenidine These drugs are said to be selective for an imidazoline receptor, rather than 2-receptor However, no such receptor has been identified at the molecular level, and genetic knockout experiments have shown that it is the 2-receptor which is required for the blood pressure lowering action of imidazoline drugs It is unsurprising therefore that no drug has truly succeeded in separating the sedative and hypotensive effects of this class FALSE TRANSMITTER Chemotransmitters and receptors in the CNS are similar to those in the periphery, and the drug in this section also has peripheral actions, as is to be expected Methyldopa (Aldomet) probably acts primarily in the brain stem vasomotor centres It is a substrate (in the same manner as L-DOPA) for the enzymes that synthesise noradrenaline The synthesis of methylnoradrenaline results in tonic stimulation of CNS 2-receptors since a-methylnoradrenaline cannot be metabolised by monoamine oxidase, and selectively stimulates the 2-adrenoceptor Stimulation of this receptor in the hindbrain nuclei concerned with blood pressure control results in a fall in blood pressure, i.e methyldopa acts in the same way as clonidine -Methylnoradrenaline is also produced at peripheral adrenergic endings, but to a lesser extent and peripheral action is clinically insignificant Methyldopa is reliably absorbed from the gastrointestinal tract and readily enters the CNS The t1/2 is 1.5 h Adverse effects, largely expected from its mode of action, include: sedation (frequent), nightmares, depression, involuntary movements, nausea, flatulence, constipation, score or black 23 tongue, positive Coombs test with occasionally haemolytic anaemia, leucopenia, thrombocytopenia, hepatitis Gynaecomastia and lactation occur due to interference with dopaminergic suppression of prolactin secretion Any failure of male sexual function is probably secondary to sedation Because of its adverse effects methyldopa is no longer a drug of first choice in routine long-term management of hypertension, but remains popular with obstertricians for the hypertension of pregnancy Drug treatment of angina, myocardial infarction and hypertension Angina pectoris25 An attack of angina pectoris26 occurs when myocardial demand for oxygen exceeds supply from the coronary circulation The principal forms relevant to choice of drug therapy are angina of exercise (commonest) and its worsening form, unstable (preinfarction or crescendo) angina (see below), which occurs at rest Variant (Prinzmetal) angina (very uncommon) results from spasm of a large coronary artery Antiangina drugs act as follows: • Organic nitrates reduce preload and afterload and dilate the main coronary arteries (rather than the arterioles) • -adrenoceptor blocking drugs reduce myocardial contractility and slow the heart rate They may increase coronary artery spasm in variant angina • Calcium-channel blocking drugs reduce cardiac contractility, dilate the coronary arteries (where 25 Angina pectoris: angina, a strangling; pectoris, of the chest For a personal account by a physician of his experiences of angina pectoris, coronary bypass surgery, ventricular fibrillation and recovery, see Swyer G I M 1986 British Medical Journal 292: 337 Compelling and essential reading 26 483 23 A R T E R I A L H Y P E RT E N S I O N , A N G I N A P E C T O R I S , there is evidence of spasm) and reduce afterload (dilate peripheral arterioles) These classes of drug complement each other and can be used together The combined nitrate and potassium-channel activator, nicorandil, is an alternative when any of the other drugs is contraindicated SUMMARY OFTREATMENT • Any contributory cause is treated when possible, e.g anaemia, arrhythmia • Life style is changed so as to reduce the number of attacks Weight reduction can be very helpful; stop smoking • For immediate pre-exertional prophylaxis: glyceryl trinitrate sublingually or nifedipine (bite the capsule and hold the liquid in the mouth or swallow it) • For an acute attack: glyceryl trinitrate (sublingual) or nifedipine (bite capsule, as above) For long-term prophylaxis: • A 1-adrenoceptor blocking drug, e.g bisoprolol, given continuously (not merely when an attack is expected) Dosage is adjusted by response Some put an arbitrary upper limit to dose, but others recommend that if complete relief is not obtained the dose should be raised to the maximum tolerated, provided the resting heart rate is not reduced below 55/min; or raise the dose to a level at which an increase causes no further inhibition of exercise tachycardia In severe angina a pure antagonist, i.e an agent lacking partial agonist activity, is preferred, since the latter may not slow the heart sufficiently Warn the patient of the risk of abrupt withdrawal • A calcium-channel blocking drug, e.g nifedipine or diltiazem, is an alternative to a -adrenoceptor blocker: use especially if coronary spasm is suspected or if the patient has myocardial insufficiency or any bronchospastic disease It can also be used with a -blocker, or • A long-acting nitrate, isosorbide dinitrate or mononitrate: use so as to avoid tolerance (p 463) • Nicorandil, a long-acting potassium-channel activator: this does not cause tolerance like the nitrates 484 Ml • Drug therapy may be adapted to the time of attacks, e.g nocturnal (transdermal glyceryl trinitrate, or isosorbide mononitrate orally at night) • Antiplatelet therapy (aspirin or clopidogrel) reduces the incidence of fatal and of nonfatal myocardial infarction in patients with unstable angina, used alone or with low-dose heparin • Surgical revascularisation in selected cases In treating angina, it is important to remember not only the objective of reducing symptoms but also that of preventing complications, particularly myocardial infarction and sudden death This requires vigorous treatment of all risk factors (hypertension, hyperlipidaemia, diabetes mellitus) and, of course, cessation of smoking There is little evidence that the symptomatic treatments, medical or surgical, themselves affect outcome except in patients with stenosis of the main stem of the left coronary artery, who require surgical intervention Although aspirin has not specifically been studied in patients with stable angina, it is now reasonable to extrapolate from the studies of aspirin in other patient groups Myocardial infarction (Ml) (See also Ch 28) AN OVERVIEW The acute coronary syndromes (ACS) are now classified on the basis of the ECG and plasma troponin measurements into (1) patients with ST elevation myocardial infarction (STEMI), (2) non-ST elevation myocardial infarction (non-STEMI, by ECG and a positive troponin test) and (3) unstable angina (by ECG and negative troponin test) The present account recognises that this is a rapidly evolving field, but therapeutic strategies are likely to evolve according to these forms of ACS A general practitioner or paramedic can appropriately administer the initial treatment before a definite diagnosis is established or the patient reaches hospital, namely: • morphine or diamorphine (2.5 or mg intravenously, because of the certainty of MYOCARDIAL INFARCTION haematoma formation when intramuscular injections are followed by thrombolytic therapy) • aspirin 150-300 mg orally • 60% oxygen The immediate objectives are relief of pain and initiation of treatment demonstrated to reduce mortality Subsequent management of proven myocardial infarction is concerned with treatment of complications, arrhythmias, heart failure and thromboemboli, and then secondary prevention of further myocardial infarctions When STEMI is diagnosed, instituting myocardial reperfusion as early as possible provides the greatest benefit Most commonly, the basis of this is thrombolysis (although its benefit will be increasingly compared with angioplasty, with or without stenting) This is initiated following arrival at hospital, preferably directly to the coronary care unit to avoid further delays, and provided there are no contraindications to thrombolysis (see below) Patients with non-STEMI may still benefit, especially those with left bundle branch block Several trials have shown that patients without ECG changes (or with ST depression), and patients with unstable angina, benefit only slightly if at all from thrombolytic therapy The choice of thrombolytic is in most places dictated by (1) a wealth of comparative outcome data from well designed trials and (2) relative costs For a first infarct, patients should receive streptokinase 500 000 units infused over h, unless they are in cardiogenic shock For subsequent infarcts, the presence of antistreptokinase antibodies dictates the use of the recombinant tissue plasminogen activator (rt-PA) alteplase (or reteplase) Human rtTPA was one of the first naturally-occurring human proteins to be manufactured in bulk by recombinant DNA technology Both alteplase and streptokinase bind plasminogen and convert it to plasmin, which lyses fibrin Alteplase has a much higher affinity for plasminogen bound to fibrin than in the circulation This selectivity does not, however, confer any therapeutic advantage as originally anticipated, since severe haemorrhage following thrombolysis is almost always due to lysis of an appropriate clot at previous sites of bleeding or trauma Indeed, the tendency for some lysis of (Ml) 23 circulating fibrinogen as well as fibrin by streptokinase gives this drug some anticoagulant activity, which is lacking from alteplase, so that administration of alteplase needs to be accompanied and followed by administration of heparin (see p 579 for further details of thrombolytics) Haemorrhagic diathesis Pregnancy Recent symptoms of peptic ulcer, or Gl bleeding Recent stroke (previous months) Recent surgery (previous 10-14 days), especially neurosurgery Prolonged cardiopulmonary resuscitation (during current presentation) Proliferative diabetic retinopathy Severe, uncontrolled hypertension (DBP > 120) In addition to thrombolysis and aspirin, a third treatment has been shown to reduce mortality in MI, namely -blockade In the ISIS-1 study,27 atenolol 50 mg was given i.v followed by the same dose orally The reduction in mortality is due mainly to prevention of cardiac rupture, which appears interestingly to remain the only complication of MI that is not reduced by thrombolysis The usual contraindications to (3-blockade apply, but most patients with a first MI should be able to receive this treatment Other antiplatelet agents The final common pathway to platelet aggregation and thrombus formation involves the expression of the glycoprotein Ilb/IIIa receptor at the cell surface This receptor binds fibrinogen with high affinity and can be blocked using either a specific monoclonal antibody (abciximab) or one of a rapidly expanding class of specific antagonists, e.g eptifibatide and tirofiban Another agent, dopidogrel, acts by inhibiting ADP-dependent platelet aggregation It is more effective than aspirin for the prevention of ischaemic stroke or cardiovascular death in patients at high risk (see p 582) 27 Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1 First International Study of Infarct Survival Collaborative Group Lancet 1986 2: 57-66 485 11 A R T E R I A L H Y P E RT E N S I O N , A N G I N A P E C T O R I S , These drugs appear to be very useful adjuncts for the treatment of unstable angina, and in the prevention of thrombosis following percutaneous revascularisation procedures such as angioplasty and coronary artery stenting Their role in preventing infarction in patients with acutely compromised myocardium is likely to expand rapidly Unstable angina requires admission to hospital, the objectives of therapy being to relieve pain, and avert progression to myocardial infarction and sudden death Initial management is with aspirin 150-300 mg chewed or dispersed in water followed by heparin, or one of the low molecular weight preparations, e.g dalteparin or enoxaparin Nitrate is given preferably as isosorbide dinitrate by i.v infusion until the patient has been pain-free for 24 h A -adrenoceptor blocker, e.g metoprolol, should added orally or i.v unless it is contraindicated, when a calcium channel blocker is substituted, e.g diltiazem or verapamil Patients perceived to be at high risk may also receive a glycoprotein II b/III a inhibitor, e.g eptifibatide or tirofiban SECONDARY PREVENTION (See also Ch 28) The best predictor of risk of a myocardial infarction is to have had previous a myocardial infarction After the measures instituted in the first few hours, the principal objective of treatment therefore becomes prevention of future infarcts Patients should receive advice about exercise and diet before discharge, and most enter a formal rehabilitation programme after leaving hospital In particular, patients need to reduce saturated fat intake, and there is increasing evidence of the benefit of increased intake of fish and olive oil incidence of reinfarction by 20-25%, although their benefit has not been shown to be additive In the 'SAVE' study,28 captopril 50 mg x 3/d or placebo was started 3-16 days after a myocardial infarction in 2231 patients without overt cardiac failure but with a left ventricular ejection fraction of < 40% The captopril group had a lower incidence of recurrent myocardial infarction (133) and deaths (228) than the placebo group (170 and 275) Similar results have been achieved in several other trials of ACE inhibitors An exception was the CONSENSUSII study, which found no benefit from enalapril (In this study, large and rapid falls in BP caused by i.v enalaprilat probably precipitated cardiovascular events in some patients.) Whereas most studies have used echo or isotope scanning to assess cardiac function, the AIRE study showed a reduction in deaths (170 vs 222) in the active group, receiving ramipril mg x 2/d, started 3-10 days after a myocardial infarction in 2006 patients with only clinical signs of heart failure.28 Indeed, in addition to these drugs, most patients should receive a statin, regardless of their plasma cholesterol level Long-term benefit from LDL reduction after MI has been shown for high-dose simvastatin (20-10 mg/d) and pravastatin (40 mg/d) Patients with previous MI constituted onethird of the Heart Protection Study of 20536 highrisk patients Those randomly assigned to simvastatin 40 mg daily or placebo had a 12% reduction in all cause mortality, and 24% reduction in strokes and coronary heart disease.29 There is no place for routine antiarrhythmic prophylaxis, and long-term anticoagulation is similarly out of place, except when indicated by arrhythmias or poor left ventricular function 28 DRUGS FOR SECONDARY PREVENTION All patients should receive aspirin and a -blocker for at least two years, unless contraindicated The commonest contraindication to -blockade after MI is heart failure, although this should now be uncommon after a first MI In such patients, an ACE inhibitor should replace -blockade All three of these drug groups have been shown to reduce the 486 Ml SAVE = Survival and Ventricular Enlargement Trial; AIRE = Acute Infarction Ramipril Efficacy study; CONSENSUS = Cooperative New Scandinavian Enalapril Survival Study References: Rutherford J D et al 1994 Effects of captopril on ischemic events after myocardial infarction Results of the Survival and Ventricular Enlargement trial SAVE Investigators Circulation 90:1731-1738 AIRE Study Investigators 1993 Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure Lancet 342: 821-828 Swedberg K P et al 1992 Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction New England Journal of Medicine 327: 678-684 ARTERIAL HYPERTENSION Arterial hypertension Clinical evaluation of antihypertensive drugs seeks to answer two types of question: Whether long-term reduction of blood pressure benefits the patient by preventing complications and prolonging life; these studies take years, require enormous numbers of patients and are extremely costly Whether a drug is capable of effective, safe and comfortable control of blood pressure for about one year There is now sufficient evidence of the benefit of reducing elevated blood pressure that regulatory authorities not demand trials of the first kind for all new drugs Shorter studies are therefore deemed sufficient to allow the introduction of a new drug However, such trials may not reveal the long-term consequences of some metabolic effects, e.g on blood glucose, which may adversely affect the risk of coronary heart disease Placebo effects are prominent in these shorter trials and must be carefully controlled in trial design AIM OF TREATMENT The principal long-term aim in most patients is the prevention of stroke and myocardial infarction; reduction in the latter also requires attention to other risk factors such as smoking and plasma cholesterol The more immediate aim of treatment is to reduce the blood pressure as near to normal as possible without causing symptomatic hypotension or otherwise impairing wellbeing (quality of life) When this aim is achieved in severe cases there is great symptomatic improvement: retinopathy clears and vision improves; headaches are abolished A variable amount of irreversible damage has often 29 The authors estimated that years of statin treatment will prevent 100 major vascular events in every 1000 patients with previous myocardial infarction, or 70-80 events in patients with other forms of coronary heart disease or diabetes There was no upper age limit to this benefit, and no lower limit to the level of LDL at which benefit was seen Heart Protection Study Collaborative Group 2002 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals Lancet 360: 7-22 23 been done by the high blood pressure before treatment is started; then renal failure may progress despite treatment, left ventricular hypertrophy may not fully reverse and arterial damage leads to ischaemic events (stroke and MI) It is obviously desirable to start treatment before irreversible changes occur and in mild and moderately severe cases this usually means advising treatment for symptom-free people whose hypertension was revealed by screening THRESHOLD ANDTARGETS FOR TREATMENT The British Hypertension Society guidelines30 require that antihypertensive drug therapy be initiated: • when sustained BP exceeds 160/100 mmHg or • when BP is in the range 140-159/90-99 mmHg and there is evidence of target organ damage, cardiovascular disease or a 10-year CHD risk over 15% or • for diabetics when BP exceeds 140/90 mmHg The optimal target is to lower BP to or below 140/85 mmHg in nondiabetics and 140/80 mmHg in diabetics The World Health Organization/ International Society for Hypertension sets a more rigorous target of 130/85 mmHg Effective treatment reduces the risk of all complications: strokes and myocardial infarction, but also heart failure, renal failure, and possibly dementia It is easier in individual trials to demonstrate the benefits of treatment in preventing stroke, because the curve relating risk of stroke to blood pressure is almost twice as steep as that for myocardial infarction What this tells us is not that the relative risk of myocardial infarction due to hypertension is irreversible but that substantial reduction in the absolute risk of myocardial infarction needs attention to hypercholesterolaemia as well as hypertension.31 30 The British Hypertension Society Guidelines are available in summary form in the BMJ 1999 319: 630-635 or online at http://www.bhsoc.org 31 Relative risk refers to the increased likelihood of a patient having a complication compared to a normotensive patient of the same age and gender Absolute risk refers to the number of patients out of 100, with the same age, gender and blood pressure, predicted to have a complication of the next 10 years 487 23 A R T E R I A L H Y P E RT E N S I O N , A N G I N A P E C T O R I S , Treatment will almost always be lifelong for essential hypertension, since discontinuation of therapy leads to prompt restoration of pretreatment blood pressures If it does not, one should suspect the original diagnosis of hypertension, which should not be made unless blood pressure is elevated on at least three occasions over months The relative risks of hypertension and the benefits of treating the condition in the elderly are less than in those under 65s, but the absolute risks and benefits are greater Given the large choice of treatments available, doctors cannot cite improved quality of life as an excuse for not treating hypertension in the elderly Starting doses, however, should often be halved and, pending further evidence, less challenging targets for blood pressure reduction may be acceptable It is obvious that adverse effects of therapy are important in that very large numbers of patients must be treated so that a few may gain; this is a salient feature of the use of drugs to prevent disease PRINCIPLES OF ANTIHYPERTENSIVE THERAPY General measures may be sufficient to control mild cases as follows: Ml of the actions listed at the beginning of this chapter (p 46) The large number of different drug classes for hypertension reduces, paradoxically, the likelihood of a randomly selected drug being the best for an individual patient Patients and drugs can broadly be divided into two groups depending on their renin status and drug effect on this (Fig 23.1) Type 1, or high-renin patients, are the younger Caucasians (aged < 55), and they respond better to a -blocker or ACE inhibitor Other patients are type 2, or lowrenin, in whom diuretics or calcium blockers are more likely to be effective as single agents Since each drug acts on only one or two of the blood pressure control mechanisms, the factors that are uninfluenced by monotherapy are liable to adapt (homeostatic mechanism), to oppose the useful effect and to restore the previous state There are two principal mechanisms of such adaptation or tolerance: Increase in blood volume: this occurs with any drug that reduces peripheral resistance (increases intravascular volume) or cardiac output (reduces glomerular flow) due to activation of the renin-angiotensin system The result is that cardiac output and blood pressure rise Adding a diuretic in combination with the other drug can prevent this compensatory effect • Obesity: reduce it • Alcohol: stay within recommended limits (e.g 14 units/week for women, 21 units/week for men) • Smoking: stop it • Diet: of proven value for the short-term reduction in blood pressure is reduction in fat content, and increase in fruit, vegetables and fibre.32 There is some additional benefit from reducing intake of salt: avoidance of highly salted foods, and omission of added salt from freshly prepared food • Relaxation therapy: worth considering for highly motivated borderline patients DRUG THERAPY Blood pressure may be reduced by any one or more 32 DASH-Sodium Collaborative Research Group 2001 Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet N Engl J Med 344: 3-10 488 Fig 23.1 Effects of drugs on the renin-angiotensin system (AURA: angiotensin II receptor antagonists) ARTERIAL HYPERTENSION Baroreceptor reflexes: a fall in blood pressure evokes reflex activity of the sympathetic system, causing increased peripheral resistance and cardiac activity (rate and contractility) Therefore, whenever high blood pressure is proving difficult to control and whenever a number of antihypertensives are used in combination, the drugs chosen should between them act on all three main determinants of blood pressure, namely: • blood volume • peripheral resistance • the heart Such combinations will: • maximise antihypertensive efficacy by exerting actions at three different points in the cardiovascular system; • minimise the opposing homeostatic effects by blocking the compensatory changes in blood volume, vascular tone and cardiac function; • minimise adverse effects by permitting smaller doses of each drug each acting at a different site and having different unwanted effects First-dose hypotension is now uncommon and occurs mainly with drugs having an action on veins (a-adrenoceptor blockers, ACE inhibitors) when baroreflex activation is impaired, e.g old age or with contracted intravascular volume following diuretics 23 drug from the other pair, e.g a thiazide Diuretic should be replaced by a fi-Blocker, and vice versa If the blood pressure is still not controlled, a second agent should be added, using the opposite pair to the first drug e.g if the patient is on an ACE inhibitor add a Calcium channel blocker or thiazide Diuretic (A+C or A+D), since both vasodilatation or diuresis will stimulate the renin-angiotensin system and turns nonrenin-dependent hypertension into renin-dependent hypertension) The combination B+D is associated with increased risk of diabetes and should be avoided in atrisk patients (obesity, family history) The combinations A+B or C+D usually produce a less than additive effect on blood pressure, but should be tried in patients still uncontrolled on more standard combinations If blood pressure control is still inadequate on dual therapy A+C+D is the ideal triple regimen 4a If additional therapy is required, a-blockade is effective at this stage by blocking the vasoconstrictor component of the baroreflex response to some of the other drugs A very AB/CD Rule for optimisation of antihypertensive treatment TREATING HYPERTENSION A simple stepped regimen in keeping with the 1999 British Hypertension Society guidelines30 is the AB/CD schema illustrated in Figure 23.2:33 33 Depending on the patient's age (see above) use either a (3 Blocker or thiazide Diuretic as firstline therapy, unless there is a compelling reason to avoid these (e.g asthma and gout, respectively) If the first drug is effective but not tolerated, switch to the other member of the pair: i.e ACE inhibitor (or AURA) instead of (3-blocker, Calcium blocker instead of diuretic If the blood pressure is not controlled in weeks by the first-line drug then switch to a Dickerson J E C et al 1999 Lancet 353: 2008-2013 Fig 23.2 Scheme for escalation of anti-hypertensive therapy A: ACE inhibitor; B: b-adrenoceptor blocker; C: calcium channel blocker; D: diuretic (see text) (From: Dickerson et al 1999 Lancet 353:2008-2011.) 489 23 A R T E R I A L H Y P E R T E N S I O N , ANG I N A P E C T O R I S , Ml small number of patients may need reversion to an older class of drug such as minoxidil (provided that a loop diuretic and (3-blocker can also be given to block the severe fluid retention and tachycardia) or methyldopa Patients whose blood pressure remains substantially above target on triple therapy are likely to have aldosterone-sensitive hypertension that responds well to spironolactone A particularly effective combination is spironolactone with a second generation AURA (e.g irbesartan or candesartan) Treatment and severity A single drug may adequately treat mild hypertension The treatment target blood pressures of