CLINICAL PHARMACOLOGY 2003 (PART 25B)

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CLINICAL PHARMACOLOGY 2003 (PART 25B)

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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 1 or 2 bolus doses) to eliminate the unopposed vagal activity that contributes to bradycardia. Most patients will also...

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ADRENOCEPTOR BLOCKING DRUGS 11 Overdose • Glucagon, which has cardiac inotropic and chronotropic actions independent of the Overdose, including self-poisoning, causes brady- -adrenoceptor (dose 50-150 micrograms/kg in cardia, heart block, hypotension and low output glucose 5% i.v., repeated if necessary) to be used cardiac failure that can proceed to cardiogenic shock; at the outset in severe cases (an unlicenced death is more likely with agents having membrane indication). stabilising action (see Table 23.1). Bronchoconstriction • If there is no response, i.v. injection or infusion of can be severe, even fatal, in patients subject to any a -adrenoceptor agonist is used, e.g. bronchospastic disease; loss of consciousness may isoprenaline (4 micrograms/min, increasing at occur with lipid-soluble agents that penetrate the 1-3-min intervals until the heart rate is central nervous system. Receptor blockade will 50-70 beats/min). outlast the persistence of the drug in the plasma. • In severe poisoning the dose may need to be Rational treatment includes: high and prolonged to surmount the competitive • Atropine (1-2 mg i.v. as 1 or 2 bolus doses) to block.21 eliminate the unopposed vagal activity that • Other sympathomimetics may be used as contributes to bradycardia. Most patients will judgement counsels, according to the desired also require direct cardiac pacing. receptor agonist actions ( 1, 2, ) required by the clinical condition, e.g. dobutamine, dopamine, dopexamine, noradrenaline, 20 Practolol was developed to the highest current scientific adrenaline. standards; it was marketed (1970) as the first cardioselective • For bronchoconstriction, salbutamol may be -blocker and only after independent review by the UK drug regulatory body. All seemed to go well for about 4 years used; aminophylline has nonadrenergic cardiac (though skin rashes were observed) by which time there had inotropic and bronchodilator actions and should accumulated about 200 000 patient years of experience with be given i.v. very slowly to avoid precipitating the drug, and then, wrote the then Research Director of the hypotension. industrial developer, 'came a bolt from the blue and we Treatment may be needed for days. With prompt learnt that it could produce in a small proportion of patients a most bizarre syndrome, which could embrace the skin, treatment death is unusual. 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 Interactions are prone, 'with present knowledge we cannot say it will not happen again with another drug'. That the drug caused this Pharmacokinetic. Agents metabolised in the liver peculiar syndrome was recognised by an alert provide higher plasma concentrations when another opthalmologist who ran a special clinic for external eye drug that inhibits hepatic metabolism, e.g. cimetidine, diseases. In 1974 he suddenly became aware that he was seeing patients complaining of dry eyes but with unusual is added. Enzyme inducers enhance the metabolism features. Instead of the damage (blood vessel changes with of this class of -blockers. p-adrenoceptor blockers metaplasia and keratinisation of the conjunctive) being on themselves reduce hepatic blood flow (fall in the front of the eye exposed by the open lids, it was initially cardiac output) and reduce the metabolism of - in the areas behind and protected by the lids. He noted that blockers and other drugs whose metabolic elimi- these patients were all taking practolol. Quite soon the whole syndrome was defined, as above. Some patients became nation is dependent on the rate of delivery to the blind and some required surgery for the peritoneal disorder liver, e.g. lignocaine (lidocaine), chlorpromazine. and a few died as a consequence. The drug was first restricted to brief use by injection in Pharmacodynamic. The effect on the blood press- emergency control of disorders of heart rhythm, but is now ure of sympathomimetics having both a- and - obsolete even for that. The developers acknowledged moral (though not legal) receptor agonist actions is increased by block of P- liability for the harm done and paid compensation to affected patients. They were not negligent because current 21 science did not provide a possibility of predicting the effect, For example, 115 mg of isoprenaline i.v. were infused over i.e. 'state of the art defence' applied. The law did not provide 65 h to treat one case. Lagerfelt J et al 1976 Acta Medica for strict liability or no-fault compensation (see p. 10). 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 , Ml receptors leaving the -receptor vasoconstriction not to need dose-ranging, unlike propranolol, but unopposed (adrenaline added to local anaesthetics this was in part because the initial dose was already may cause hypertension); the pressor effect of at the top of the dose-response curve. Some 90% of abrupt clonidine withdrawal is enhanced, probably absorbed drug is excreted by the kidney and the by this action. Other cardiac antiarrhythmic drugs dose should be reduced when renal function is are potentiated, e.g. hypotension, bradycardia, heart impaired, e.g. to 50 mg/day when the glomerular block. Combination with verapamil (i.v.) is hazardous filtration rate is 15-35 ml/min. The il/2 is 7 h. in the presence of atrioventricular nodal or left ventricular dysfunction because the latter has stronger Bisoprolol is more selective than atenolol (ratio negative inotropic and chronotropic effects than do 1:50). Although a relatively lipid-soluble agent, its other calcium channel blockers. tl/2 is one of the longest (11 h), and there is not the Most NSAIDs attenuate the antihypertensive wide range of dose-requirement seen with pro- effect of -blockers (but not perhaps of atenolol), pranolol. As with atenolol, it is worth starting at a presumably due to inhibition of formation of renal low dose (5 mg), to avoid causing unnecessary vasodilator prostaglandins, leading to sodium tiredness, and especially when trying to obtain the retention. maximum benefit of its selectivity. There is no need -adrenoceptor blockers potentiate the effect of to alter doses when renal or hepatic function is other antihypertensive particularly when an increase reduced. in heart rate is part of the homeostatic response (Ca- channel blockers and -adrenoceptor blockers). Nebivolol resembles bisoprolol in terms of lipo- Non-selective -receptor blockers potentiate hypo- philicity and t1/2 (10 h) but is more 1-selective (ratio glycaemia of insulin and sulphonylureas. 1:300). Its unique feature is a direct vasodilator action (due to the d-isomer of the racemate, the 1- isomer being the 1-antagonist). The mechanism Pregnancy appears to be through direct activation of nitric (3-adrenoceptor blocking agents are used in hyper- oxide production by vascular endothelium. tension of pregnancy, including pre-eclampsia. Both lipid- and water-soluble members enter the Combined ,- and -adrenoceptor fetus and may cause neonatal bradycardia and hypo- blocking drug glycaemia. They are not teratogenic in pregnancy. Labetalol is a racemic mixture, one isomer is a - Notes on some individual -adrenoceptor adrenoceptor blocker (nonselective), another blocks blockers -adrenoceptors; its dual effect on blood vessels minimises the vasoconstriction characteristic of (For general pharmacokinetics, see p. 476) nonselective -blockade so that for practical pur- poses the outcome is similar to using a 1-selective Propranolol is available in standard (b.d. or t.i.d.) p-blocker (see Table 23.1). It is less effective than and sustained-release (once daily) formulations. drugs like atenolol or bisoprolol for the routine When given i.v. (1 mg/min over 1 min, repeated treatment of hypertension, but is useful for some every 2 min up to 10 mg) for cardiac arrhythmia or specific indications. thyrotoxicosis it should be preceded by atropine The P-blockade is 4-10 times greater than the - (1-2 mg i.v.) to prevent excessive bradycardia; blockade, varying with dose and route of adminis- hypotension may occur. tration. Labetalol is useful as a parenterally admin- istered drug in the emergency reduction of blood Atenolol has a 1:2 selectivity of 1:15. It is widely pressure. Ordinary -blockers may lower blood used for angina pectoris and hypertension, in a pressure too slowly, in part because reflex stimu- dose of 25-100 mg orally once a day. The tendency lation of unblocked -receptors opposes the fall in in the past has been to use higher than necessary blood pressure. In most patients, even those with doses. When introduced, atenolol was considered severe hypertension, a gradual reduction in blood 480
PERIPHERAL SYMPATHETIC N E RV E T E R M I N A L 23 pressure is desirable to avoid the risk of cerebral or renal hypoperfusion, but in the presence of a great Peripheral sympathetic vessel dissection or of fits a more rapid effect is required (below). nerve terminal Postural hypotension (characteristic of oc-receptor blockade) is liable to occur at the outset of therapy ADRENERGIC NEURON BLOCKING and if the dose is increased too rapidly. But with DRUGS chronic therapy when the -receptor component is Adrenergic neuron blocking drugs are selectively largely responsible for the antihypertensive effect, it taken up into adrenergic nerve endings by the active, is not a problem. energy-requiring, saturable amine (noradrenaline) Labetalol reduces the hypertensive response to pump mechanism (uptake-1). They accumulate in orgasm in women. the noradrenaline storage vesicles from which they The tl/2 is 4 h; it is extensively metabolised in the are released in response to nerve impulses, diminish- hepatic first-pass. The drug needs to be taken thrice ing the release of noradrenaline and so all sym- daily in a dose of100-400mg t.d.s. pathetic function. They do not adequately control For emergency control of severe hypertension the supine blood pressure and are prone to interactions most convenient regime is to initiate infusion at with other drugs affecting adrenergic function, 1 mg/min, and titrate upwards at half-hourly inter- e.g. tricyclic antidepressants and topical nasal vals as required. The infusion is stopped as blood decongestants. They are virtually obsolete in pressure control is achieved, and re-initiated as hypertension. frequently as required until regular oral therapy has been successfully introduced. Guanethidine has been used to reduce intraocular pressure in open angle glaucoma and to reduce Serotonin (5-HT) receptor + ot- thyrotoxic eyelid retraction for cosmetic effect. adrenoceptor blocking drugs Other members of the group are debrisoquine and bethanidine. Metaiodobenzylguanidine (MIBG) is Ketanserin appears to act principally to block used diagnostically as a radioiodinated tracer, to serotonin vasoconstrictor (subtype 5-HT2) receptors locate chromaffin tumours (mainly phaeochromo- but also has significant -adrenoceptor blocking cytoma) which accumulate drugs in this class (p. 495). 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 DEPLETION OF STORED countries and offers no advantages over pure TRANSMITTER (NORADRENALINE) -blockers such as doxazosin. Reserpine is an alkaloid from plants of the genus Serotonin (5-hydroxytryptamine, 5-HT) is syn- Rauwolfia, used in medicine since ancient times in thesised in enterochromaffin cells, largely in the southern Asia, particularly for insanity; more recently, gut, and also extensively taken up into blood reserpine was extensively used in psychiatry but is platelets from which it is released to have vascular now obsolete. Reserpine depletes adrenergic nerves effects. It has complex effects on the cardiovascular of noradrenaline primarily by blocking amine storage system, varying with the vascular bed and its phy- within vesicles present in the nerve ending, so siological state; it generally constricts arterioles and reducing stores of releasable transmitter. Its anti- veins and induces blood platelet aggregation; it hypertensive action is due chiefly to peripheral stimulates intestinal and bronchial smooth muscle. action, but it enters the CNS and depletes cate- Carcinoid tumours secrete serotonin and symptoms cholamine stores there too; this explains the sedation, may be benefited by serotonin antagonists, e.g. depression and parkinsonian (extrapyramidal) side cyproheptadine, methysergide and sometimes by effects that can accompany its use. The effects on octreotide (see Index). It is a neurotransmitter in the catecholamine storage persist for days to weeks brain. 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 , Ml It has also had an important veterinary use in Trimetaphan, a short-acting agent (given by i.v. preventing the death of domestic male turkeys, infusion, initially at 3-4mg/min), also has direct which are liable to fatal hypertensive dissecting vasodilator effect; it is used for producing hypo- aortic aneurysms. This can cause serious economic tension to provide a blood-free field during surgery, loss. The addition of reserpine to their drinking and can be used for emergency control of hyper- water reduces their blood pressure and preserves tension; pressure may be adjusted by tilting the their lives without noticeably moderating their body; it provides 'minute-to-minute' control, when natural rage as may -adrenoceptor blockers.22 the lack of selectivity is important. Histamine release during infusion is occasion- ally a problem. INHIBITION OF SYNTHESIS OF TRANSMITTER Metirosine ( -methyl-p-tyrosine) is a competitive inhibitor of the enzyme tyrosine hydroxylase, which Central nervous system converts tyrosine to dopa; as dopa is further con- verted to noradrenaline and adrenaline they are 2-ADRENOCEPTOR AGONISTS similarly depleted by metirosine. It is used as an adjuvant (with phenoxybenzamine) to treat phaeo- Clonidine (Catapres) is an imidazoline which is an chromocytomas that cannot be removed surgically. agonist to 2-adrenoceptors (postsynaptic) in the Catecholamine synthesis is reduced by up to 80% brain, stimulation of which suppresses sympathetic over 3 days. It also readily penetrates the CNS and outflow and reduces blood pressure. At high doses depletes brain noradrenaline and dopamine causing it also activates peripheral 2-adrenoceptors (pre- reserpine-like side effects (see above). Hence, in synaptic autoreceptors) on the adrenergic nerve patients whose life expectancy is threatened more ending; these mediate negative feedback suppression by tumour invasion than by mild or moderate of noradrenaline release. In overdose clonidine can hypertension, the need for the drug should be stimulate peripheral 1-adrenoceptors (postsynaptic) weighed carefully. 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 Autonomic ganglion- drops for a common cold.24 The t1/2 is 6 h. blocking drugs Clonidine reduces blood pressure with little pos- tural or exercise related drop. Its most serious handicap is that abrupt or even gradual withdrawal Hexamethonium was the first orally active drug to causes rebound hypertension. This is characterised treat hypertension. Like all agents in this group it by plasma catecholamine concentrations as high as blocks sympathetic and parasympathetic systems those seen in hypertensive attacks of phaeochro- alike. Severe side effects have rendered them of mocytoma. The onset may be rapid (a few hours) or historical interest only in hypertension therapy.23 delayed for as long as 2 days; it subsides over 2-3 days. The treatment is either to reinstitute clonidine, i.m. if necessary, or to treat as for a phaeochro- 22 Conference on use of tranquillising agent Serpasil in mocytoma. Clonidine should never be used with a animal and poultry production 1959 College of Agriculture, 3-adrenoceptor blocker which exacerbates withdrawal Rutgers State University, USA. Wild turkeys have a blood pressure of 120/60 mmHg, but domestic turkeys are hypertension (see phaeochromocytoma). Common hypertensive (204/144 mmHg). Digoxin increases the 23 incidence of aneurysm. It seems that it is the rate of rise of Page L H 1981 New England Journal of Medicine 304:1371. pressure in the aorta that is important in this disease The eminent pharmacologist, Sir John Gaddum, also dubbed (probably in man also) and that reserpine and (3- the characteristic appearance as 'hexamethonium man'. 24 adrenoceptor blockers benefit by attenuating this. Page L H 1981 New England Journal of Medicine 304:1371. 482
ANGINA PECTORIS 23 adverse effects include sedation and dry mouth. tongue, positive Coombs test with occasionally Tricyclic antidepressants antagonise the anti- haemolytic anaemia, leucopenia, thrombocytopenia, hypertensive action and increase the rebound hepatitis. hypertension of abrupt withdrawal. Low dose Gynaecomastia and lactation occur due to inter- clonidine (Dixarit, 50-100 microgram/d) also has a ference with dopaminergic suppression of prolactin minor role in migraine prophylaxis, menopausal secretion. Any failure of male sexual function is flushing and choreas. probably secondary to sedation. Because of its Rebound hypertension is a less important problem adverse effects methyldopa is no longer a drug of with longer-acting imidazolines, since omission of a first choice in routine long-term management of single dose will not trigger the rebound. Such drugs hypertension, but remains popular with obstertricians include moxonidine and rilmenidine. These drugs are for the hypertension of pregnancy. 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 knock- out experiments have shown that it is the 2-receptor Drug treatment of angina, which is required for the blood pressure lowering action of imidazoline drugs. It is unsurprising myocardial infarction and therefore that no drug has truly succeeded in hypertension separating the sedative and hypotensive effects of this class. FALSE TRANSMITTER Angina pectoris25 Chemotransmitters and receptors in the CNS are An attack of angina pectoris26 occurs when myo- similar to those in the periphery, and the drug in cardial demand for oxygen exceeds supply from the this section also has peripheral actions, as is to be coronary circulation. expected. The principal forms relevant to choice of drug therapy are angina of exercise (commonest) and its Methyldopa (Aldomet) probably acts primarily in worsening form, unstable (preinfarction or crescendo) the brain stem vasomotor centres. It is a substrate angina (see below), which occurs at rest. Variant (in the same manner as L-DOPA) for the enzymes (Prinzmetal) angina (very uncommon) results from that synthesise noradrenaline. The synthesis of - spasm of a large coronary artery. methylnoradrenaline results in tonic stimulation of CNS 2-receptors since a-methylnoradrenaline Antiangina drugs act as follows: cannot be metabolised by monoamine oxidase, and selectively stimulates the 2-adrenoceptor. Stimu- • Organic nitrates reduce preload and afterload and lation of this receptor in the hindbrain nuclei dilate the main coronary arteries (rather than the concerned with blood pressure control results in a arterioles). fall in blood pressure, i.e. methyldopa acts in the • -adrenoceptor blocking drugs reduce myocardial same way as clonidine. -Methylnoradrenaline is contractility and slow the heart rate. They may also produced at peripheral adrenergic endings, but increase coronary artery spasm in variant to a lesser extent and peripheral action is clinically angina insignificant. • Calcium-channel blocking drugs reduce cardiac Methyldopa is reliably absorbed from the contractility, dilate the coronary arteries (where gastrointestinal tract and readily enters the CNS. 25 The t1/2 is 1.5 h. Adverse effects, largely expected Angina pectoris: angina, a strangling; pectoris, of the chest. 26 For a personal account by a physician of his experiences of from its mode of action, include: sedation (frequent), angina pectoris, coronary bypass surgery, ventricular nightmares, depression, involuntary movements, fibrillation and recovery, see Swyer G I M 1986 British nausea, flatulence, constipation, score or black Medical Journal 292: 337. Compelling and essential reading. 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 , Ml there is evidence of spasm) and reduce afterload • Drug therapy may be adapted to the time of (dilate peripheral arterioles). attacks, e.g. nocturnal (transdermal glyceryl trinitrate, or isosorbide mononitrate orally at These classes of drug complement each other night). and can be used together. The combined nitrate • Antiplatelet therapy (aspirin or clopidogrel) and potassium-channel activator, nicorandil, is an reduces the incidence of fatal and of nonfatal alternative when any of the other drugs is myocardial infarction in patients with unstable contraindicated. angina, used alone or with low-dose heparin. • Surgical revascularisation in selected cases. SUMMARY OFTREATMENT In treating angina, it is important to remember • Any contributory cause is treated when possible, not only the objective of reducing symptoms but e.g. anaemia, arrhythmia. also that of preventing complications, particularly • Life style is changed so as to reduce the number myocardial infarction and sudden death. This of attacks. Weight reduction can be very helpful; requires vigorous treatment of all risk factors stop smoking. (hypertension, hyperlipidaemia, diabetes mellitus) • For immediate pre-exertional prophylaxis: and, of course, cessation of smoking. There is little glyceryl trinitrate sublingually or nifedipine (bite evidence that the symptomatic treatments, medical the capsule and hold the liquid in the mouth or or surgical, themselves affect outcome except in swallow it). patients with stenosis of the main stem of the left • For an acute attack: glyceryl trinitrate (sublingual) coronary artery, who require surgical inter- or nifedipine (bite capsule, as above). vention. Although aspirin has not specifically been studied in patients with stable angina, it is now reasonable to extrapolate from the studies of For long-term prophylaxis: aspirin in other patient groups. • 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 Myocardial infarction (Ml) others recommend that if complete relief is not obtained the dose should be raised to the (See also Ch. 28) maximum tolerated, provided the resting heart rate is not reduced below 55/min; or raise the AN OVERVIEW dose to a level at which an increase causes no further inhibition of exercise tachycardia. In The acute coronary syndromes (ACS) are now classified severe angina a pure antagonist, i.e. an agent on the basis of the ECG and plasma troponin lacking partial agonist activity, is preferred, since measurements into (1) patients with ST elevation the latter may not slow the heart sufficiently. myocardial infarction (STEMI), (2) non-ST elevation Warn the patient of the risk of abrupt withdrawal. myocardial infarction (non-STEMI, by ECG and a • A calcium-channel blocking drug, e.g. nifedipine or positive troponin test) and (3) unstable angina (by diltiazem, is an alternative to a -adrenoceptor ECG and negative troponin test). The present blocker: use especially if coronary spasm is account recognises that this is a rapidly evolving suspected or if the patient has myocardial field, but therapeutic strategies are likely to evolve insufficiency or any bronchospastic disease. It according to these forms of ACS. can also be used with a -blocker, or A general practitioner or paramedic can appro- • A long-acting nitrate, isosorbide dinitrate or priately administer the initial treatment before a mononitrate: use so as to avoid tolerance (p. 463). definite diagnosis is established or the patient reaches • Nicorandil, a long-acting potassium-channel hospital, namely: activator: this does not cause tolerance like the • morphine or diamorphine (2.5 or 5 mg nitrates. intravenously, because of the certainty of 484
MYOCARDIAL INFARCTION (Ml) 23 haematoma formation when intramuscular circulating fibrinogen as well as fibrin by streptokinase injections are followed by thrombolytic gives this drug some anticoagulant activity, which therapy) is lacking from alteplase, so that administration of • aspirin 150-300 mg orally alteplase needs to be accompanied and followed by • 60% oxygen. administration of heparin (see p. 579 for further The immediate objectives are relief of pain and details of thrombolytics). initiation of treatment demonstrated to reduce mor- tality. Subsequent management of proven myocardial infarction is concerned with treatment of com- Haemorrhagic diathesis Pregnancy plications, arrhythmias, heart failure and thromboemboli, Recent symptoms of peptic ulcer, or Gl bleeding and then secondary prevention of further myo- Recent stroke (previous 3 months) cardial infarctions. Recent surgery (previous 10-14 days), especially When STEMI is diagnosed, instituting myocardial neurosurgery reperfusion as early as possible provides the greatest Prolonged cardiopulmonary resuscitation (during benefit. Most commonly, the basis of this is thrombo- current presentation) lysis (although its benefit will be increasingly Proliferative diabetic retinopathy Severe, uncontrolled hypertension (DBP > 120) compared with angioplasty, with or without stenting). This is initiated following arrival at hospital, In addition to thrombolysis and aspirin, a third preferably directly to the coronary care unit to avoid treatment has been shown to reduce mortality in further delays, and provided there are no contra- MI, namely -blockade. In the ISIS-1 study,27 atenolol indications to thrombolysis (see below). Patients 50 mg was given i.v. followed by the same dose with non-STEMI may still benefit, especially those orally. The reduction in mortality is due mainly to with left bundle branch block. Several trials have prevention of cardiac rupture, which appears shown that patients without ECG changes (or with interestingly to remain the only complication of MI ST depression), and patients with unstable angina, benefit only slightly if at all from thrombolytic that is not reduced by thrombolysis. The usual therapy. contraindications to (3-blockade apply, but most The choice of thrombolytic is in most places patients with a first MI should be able to receive this treatment. 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 Other antiplatelet agents. The final common path- way to platelet aggregation and thrombus 1 500 000 units infused over 1 h, unless they are in cardiogenic shock. For subsequent infarcts, the formation involves the expression of the glyco- protein Ilb/IIIa receptor at the cell surface. This presence of antistreptokinase antibodies dictates receptor binds fibrinogen with high affinity and can the use of the recombinant tissue plasminogen activator (rt-PA) alteplase (or reteplase). Human rt- be blocked using either a specific monoclonal TPA was one of the first naturally-occurring human antibody (abciximab) or one of a rapidly expanding proteins to be manufactured in bulk by recombi- class of specific antagonists, e.g. eptifibatide and tirofiban. Another agent, dopidogrel, acts by inhibiting nant DNA technology. Both alteplase and strepto- kinase bind plasminogen and convert it to plasmin, ADP-dependent platelet aggregation. It is more effective than aspirin for the prevention of ischaemic which lyses fibrin. Alteplase has a much higher stroke or cardiovascular death in patients at high affinity for plasminogen bound to fibrin than in the circulation. This selectivity does not, however, risk (see p. 582). confer any therapeutic advantage as originally anticipated, since severe haemorrhage following 27 Randomised trial of intravenous atenolol among 16 027 thrombolysis is almost always due to lysis of an cases of suspected acute myocardial infarction: ISIS-1. First appropriate clot at previous sites of bleeding or International Study of Infarct Survival Collaborative Group. trauma. Indeed, the tendency for some lysis of 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 , Ml These drugs appear to be very useful adjuncts incidence of reinfarction by 20-25%, although their for the treatment of unstable angina, and in the benefit has not been shown to be additive. In the prevention of thrombosis following percutaneous 'SAVE' study,28 captopril 50 mg x 3/d or placebo revascularisation procedures such as angioplasty was started 3-16 days after a myocardial infarction and coronary artery stenting. Their role in prevent- in 2231 patients without overt cardiac failure but ing infarction in patients with acutely compromised with a left ventricular ejection fraction of < 40%. myocardium is likely to expand rapidly. The captopril group had a lower incidence of recurrent myocardial infarction (133) and deaths Unstable angina requires admission to hospital, (228) than the placebo group (170 and 275). Similar the objectives of therapy being to relieve pain, and results have been achieved in several other trials of avert progression to myocardial infarction and ACE inhibitors. An exception was the CONSENSUS- sudden death. Initial management is with aspirin II study, which found no benefit from enalapril. (In 150-300 mg chewed or dispersed in water followed this study, large and rapid falls in BP caused by i.v. by heparin, or one of the low molecular weight prep- enalaprilat probably precipitated cardiovascular arations, e.g. dalteparin or enoxaparin. Nitrate is events in some patients.) Whereas most studies given preferably as isosorbide dinitrate by i.v. have used echo or isotope scanning to assess infusion until the patient has been pain-free for 24 h. cardiac function, the AIRE study showed a A -adrenoceptor blocker, e.g. metoprolol, should reduction in deaths (170 vs 222) in the active group, added orally or i.v. unless it is contraindicated, when receiving ramipril 5 mg x 2/d, started 3-10 days a calcium channel blocker is substituted, e.g. after a myocardial infarction in 2006 patients with diltiazem or verapamil. Patients perceived to be at only clinical signs of heart failure.28 Indeed, in high risk may also receive a glycoprotein II b/III a addition to these drugs, most patients should inhibitor, e.g. eptifibatide or tirofiban. receive a statin, regardless of their plasma cholesterol level. Long-term benefit from LDL reduction after MI has been shown for high-dose SECONDARY PREVENTION simvastatin (20-10 mg/d) and pravastatin (40 (See also Ch. 28) mg/d). Patients with previous MI constituted one- The best predictor of risk of a myocardial infarction third of the Heart Protection Study of 20536 high- is to have had previous a myocardial infarction. risk patients. Those randomly assigned to After the measures instituted in the first few hours, simvastatin 40 mg daily or placebo had a 12% the principal objective of treatment therefore becomes reduction in all cause mortality, and 24% reduction in prevention of future infarcts. Patients should receive strokes and coronary heart disease.29 advice about exercise and diet before discharge, There is no place for routine antiarrhythmic and most enter a formal rehabilitation programme prophylaxis, and long-term anticoagulation is after leaving hospital. In particular, patients need to similarly out of place, except when indicated by reduce saturated fat intake, and there is increasing arrhythmias or poor left ventricular function. evidence of the benefit of increased intake of fish and olive oil. 28 SAVE = Survival and Ventricular Enlargement Trial; AIRE = Acute Infarction Ramipril Efficacy study; CONSENSUS = DRUGS FOR SECONDARY Cooperative New Scandinavian Enalapril Survival Study. PREVENTION References: Rutherford J D et al 1994 Effects of captopril on ischemic events after myocardial infarction. Results of the All patients should receive aspirin and a -blocker Survival and Ventricular Enlargement trial. SAVE for at least two years, unless contraindicated. The Investigators. Circulation 90:1731-1738. AIRE Study commonest contraindication to -blockade after MI Investigators 1993 Effect of ramipril on mortality and is heart failure, although this should now be morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 342: 821-828. uncommon after a first MI. In such patients, an ACE Swedberg K P et al 1992 Effects of the early administration of inhibitor should replace -blockade. All three of enalapril on mortality in patients with acute myocardial these drug groups have been shown to reduce the infarction. New England Journal of Medicine 327: 678-684. 486
ARTERIAL HYPERTENSION 23 been done by the high blood pressure before treat- Arterial hypertension ment is started; then renal failure may progress despite treatment, left ventricular hypertrophy may Clinical evaluation of antihypertensive drugs seeks not fully reverse and arterial damage leads to to answer two types of question: ischaemic events (stroke and MI). It is obviously desirable to start treatment before 1. Whether long-term reduction of blood pressure irreversible changes occur and in mild and moderately benefits the patient by preventing complications severe cases this usually means advising treatment and prolonging life; these studies take years, for symptom-free people whose hypertension was require enormous numbers of patients and are revealed by screening. extremely costly. 2. Whether a drug is capable of effective, safe and comfortable control of blood pressure for about THRESHOLD ANDTARGETS FOR one year. There is now sufficient evidence of the TREATMENT benefit of reducing elevated blood pressure that The British Hypertension Society guidelines30 require regulatory authorities do not demand trials of that antihypertensive drug therapy be initiated: the first kind for all new drugs. Shorter studies are therefore deemed sufficient to allow the • when sustained BP exceeds 160/100 mmHg or introduction of a new drug. However, such trials • when BP is in the range 140-159/90-99 mmHg may not reveal the long-term consequences of and there is evidence of target organ damage, some metabolic effects, e.g. on blood glucose, cardiovascular disease or a 10-year CHD risk which may adversely affect the risk of coronary over 15% or heart disease. Placebo effects are prominent in • for diabetics when BP exceeds 140/90 mmHg. these shorter trials and must be carefully The optimal target is to lower BP to or below controlled in trial design. 140/85 mmHg in nondiabetics and 140/80 mmHg in diabetics. The World Health Organization/ International Society for Hypertension sets a more AIM OF TREATMENT rigorous target of 130/85 mmHg. The principal long-term aim in most patients is the Effective treatment reduces the risk of all com- prevention of stroke and myocardial infarction; plications: strokes and myocardial infarction, but reduction in the latter also requires attention to also heart failure, renal failure, and possibly dementia. other risk factors such as smoking and plasma It is easier in individual trials to demonstrate the cholesterol. The more immediate aim of treatment benefits of treatment in preventing stroke, because is to reduce the blood pressure as near to normal as the curve relating risk of stroke to blood pressure is possible without causing symptomatic hypotension almost twice as steep as that for myocardial infarc- or otherwise impairing wellbeing (quality of life). tion. What this tells us is not that the relative risk of When this aim is achieved in severe cases there is myocardial infarction due to hypertension is irre- great symptomatic improvement: retinopathy clears versible but that substantial reduction in the absolute and vision improves; headaches are abolished. A risk of myocardial infarction needs attention to variable amount of irreversible damage has often hypercholesterolaemia as well as hypertension.31 29 30 The authors estimated that 5 years of statin treatment will The British Hypertension Society Guidelines are available prevent 100 major vascular events in every 1000 patients with in summary form in the BMJ 1999 319: 630-635 or online at previous myocardial infarction, or 70-80 events in patients http://www.bhsoc.org 31 with other forms of coronary heart disease or diabetes. There Relative risk refers to the increased likelihood of a patient was no upper age limit to this benefit, and no lower limit to having a complication compared to a normotensive patient the level of LDL at which benefit was seen. Heart Protection of the same age and gender. Absolute risk refers to the Study Collaborative Group 2002 MRC/BHF Heart Protection number of patients out of 100, with the same age, gender and Study of cholesterol lowering with simvastatin in 20 536 blood pressure, predicted to have a complication of the next high-risk individuals. Lancet 360: 7-22. 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 , Ml Treatment will almost always be lifelong for essential of the actions listed at the beginning of this chapter hypertension, since discontinuation of therapy leads (p. 46). The large number of different drug classes to prompt restoration of pretreatment blood for hypertension reduces, paradoxically, the likeli- pressures. If it does not, one should suspect the hood of a randomly selected drug being the best for original diagnosis of hypertension, which should not an individual patient. Patients and drugs can broadly be made unless blood pressure is elevated on at least be divided into two groups depending on their three occasions over 3 months. renin status and drug effect on this (Fig. 23.1). Type The relative risks of hypertension and the benefits 1, or high-renin patients, are the younger Caucasians of treating the condition in the elderly are less than (aged < 55), and they respond better to a -blocker in those under 65s, but the absolute risks and benefits or ACE inhibitor. Other patients are type 2, or low- are greater. Given the large choice of treatments renin, in whom diuretics or calcium blockers are available, doctors cannot cite improved quality of more likely to be effective as single agents. life as an excuse for not treating hypertension in the Since each drug acts on only one or two of the elderly. Starting doses, however, should often be blood pressure control mechanisms, the factors that halved and, pending further evidence, less chal- are uninfluenced by monotherapy are liable to lenging targets for blood pressure reduction may be adapt (homeostatic mechanism), to oppose the use- acceptable. ful effect and to restore the previous state. There are It is obvious that adverse effects of therapy are two principal mechanisms of such adaptation or important in that very large numbers of patients tolerance: must be treated so that a few may gain; this is a 1. Increase in blood volume: this occurs with any salient feature of the use of drugs to prevent disease. drug that reduces peripheral resistance (increases intravascular volume) or cardiac PRINCIPLES OF ANTIHYPERTENSIVE output (reduces glomerular flow) due to THERAPY activation of the renin-angiotensin system. The result is that cardiac output and blood pressure General measures may be sufficient to control mild rise. Adding a diuretic in combination with the cases as follows: 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 Fig. 23.1 Effects of drugs on the renin-angiotensin system (AURA: Engl J Med 344: 3-10. angiotensin II receptor antagonists) 488
ARTERIAL HYPERTENSION 23 2. Baroreceptor reflexes: a fall in blood pressure drug from the other pair, e.g. a thiazide evokes reflex activity of the sympathetic system, Diuretic should be replaced by a fi-Blocker, causing increased peripheral resistance and and vice versa. cardiac activity (rate and contractility). 3. If the blood pressure is still not controlled, a Therefore, whenever high blood pressure is second agent should be added, using the proving difficult to control and whenever a opposite pair to the first drug e.g. if the patient number of antihypertensives are used in is on an ACE inhibitor add a Calcium channel combination, the drugs chosen should between blocker or thiazide Diuretic (A+C or A+D), them act on all three main determinants of blood since both vasodilatation or diuresis will pressure, namely: stimulate the renin-angiotensin system and turns nonrenin-dependent hypertension into • blood volume renin-dependent hypertension). The • peripheral resistance combination B+D is associated with increased • the heart. risk of diabetes and should be avoided in at- Such combinations will: risk patients (obesity, family history). The combinations A+B or C+D usually produce a • maximise antihypertensive efficacy by exerting less than additive effect on blood pressure, but actions at three different points in the should be tried in patients still uncontrolled on cardiovascular system; more standard combinations. • minimise the opposing homeostatic effects by 4. If blood pressure control is still inadequate on blocking the compensatory changes in blood dual therapy A+C+D is the ideal triple volume, vascular tone and cardiac function; regimen. • minimise adverse effects by permitting smaller 4a. If additional therapy is required, a-blockade is doses of each drug each acting at a different site effective at this stage by blocking the and having different unwanted effects. vasoconstrictor component of the baroreflex First-dose hypotension is now uncommon and response to some of the other drugs. A very occurs mainly with drugs having an action on veins (a-adrenoceptor blockers, ACE inhibitors) when AB/CD Rule for optimisation of baroreflex activation is impaired, e.g. old age or with antihypertensive treatment contracted intravascular volume following diuretics. 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 1. Depending on the patient's age (see above) use either a (3 Blocker or thiazide Diuretic as first- line 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. 2. If the blood pressure is not controlled in 4 weeks by the first-line drug then switch to a 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 33 Dickerson J E C et al 1999 Lancet 353: 2008-2013. 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 supplements are not required routinely, but hypo- to an older class of drug such as minoxidil kalaemia will occasionally occur (and should raise (provided that a loop diuretic and (3-blocker suspicion of Conn's syndrome). Uncomplicated can also be given to block the severe fluid patients may not need monitoring if the lowest retention and tachycardia) or methyldopa. possible doses are used, e.g. no more than bendro- 5. Patients whose blood pressure remains fluazide (bendroflumethazide) 2.5 mg. Vulnerable substantially above target on triple therapy are patients, e.g. the elderly, should be monitored for likely to have aldosterone-sensitive potassium loss at 3 months and thereafter every hypertension that responds well to 6-12 months. In general a potassium-retaining spironolactone. A particularly effective diuretic (amiloride) in a fixed-dose combination combination is spironolactone with a second with a thiazide (co-amilozide) is preferred over the generation AURA (e.g. irbesartan or use of fixed-dose diuretic/KC1 formulations (most candesartan). supplements, typically 8 mmol of KC1, are in any case inadequate). Control of potassium balance is particularly Treatment and severity important if the patient is also taking digoxin A single drug may adequately treat mild hyper- (hypokalemia potentiates the action of digoxin). tension. The treatment target blood pressures of Because of the risk of hyperkalaemia, amiloride
ARTERIAL HYPERTENSION 23 • Severe hypertension is not on its own an indication these organs. It is therefore vital not to reduce for urgent (or large) reductions in blood pressure. diastolic BP by more than 20 mmHg on the first day • Blood pressure (BP) can occasionally require of treatment. To ignore this is to risk cerebral urgent (emergency) reduction even when the infarction. hypertension is not severe, especially where the BP has risen rapidly. Treatment. Unless contraindicated, the best treat- • Accelerated phase (malignant) hypertension rarely ment for all circles in the Venn diagram is (3- requires urgent reduction, and should instead be Uockade, e.g. atenolol 25 or 50 mg orally. In regarded as an indication for slow reduction in emergencies, a vasodilator should be given blood pressure during the first few days. intravenously, in addition. A theoretically preferable, but often impractical The indications for emergency reduction of blood alternative is i.v. infusion of the vasodilator, nitro- pressure are rare. They are: prusside (see p. 470). In dissecting aneurysm, vaso- • Hypertensive encephalopathy (including dilators should not be used unless patients are first eclampsia) (3-blocked since any increase in the rate of rise of the • Acute left ventricular failure (due to pulse stroke is undesirable. Labetalol provides a hypertension) convenient method of treating all patients within • Dissecting aneurysm. the three circles (except asthmatics), using either oral or parenteral therapy as appropriate. It is not In these conditions, blood pressure should be the most effective, however, and should be combined reduced over the course of an hour. In patients with with a long-acting formulation of nifedipine, orally, a dissecting aneurysm, where the BP may have been where further blood pressure reduction is required. completely normal prior to dissection, the target is a Low doses of all drugs should be used if anti- BP of 110/70 mmHg. Otherwise even small reduc- hypertensive drugs have recently been taken or if tions will usually remove the emergency. renal function is impaired. Oral maintenance treatment for severe hyper- Accelerated phase hypertension was previously tension should be started at once if possible; called 'malignant' hypertension because the lack of parenteral therapy is seldom necessary for more treatment heralded death within a year of diag- than 48 h. nosis. It is characterised pathologically by fibrinoid necrosis of the small arteries. An important con- sequence is the loss of autoregulation of the cerebral PREGNANCY HYPERTENSION and renal circulation, so that any reduction in blood Effective treatment of pregnancy-induced hyper- pressure causes a proportional fall in perfusion of tension improves fetal and perinatal survival. There is a lack of good clinical trial evidence on which to base recommendations of one agent over another. Instead, drug usage reflects longevity of use with- out obvious harm to the fetus. Hence methyldopa is still the drug of choice for many obstetricians.35 Calcium-channel blockers (especially nifedipine) are common second-line drugs; parenteral hydra- lazine is reserved for emergency reduction of blood pressure in late pregnancy, preferably in combi- nation with a (3-blocker to avoid unpleasant tachy- cardia. B-blockers (labetalol and atenolol) are often 35 Methyldopa: follow-up studies show no intellectual Fig. 23.3 Venn diagram illustrating intersections of three impairment in children up to age 7.5 years (for atenolol, see: overlapping clinical states defined in the text Butters L 1990 British Medical Journal 301: 587). 491
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 , Ml effective and are probably the drugs of choice in the responses to treatment (measurement of the y- third trimester; there is anecdotal evidence to glutamyl transpeptidase and red cell mean cor- suggest growth retardation with (3-blockade used in puscular volume may be useful). first and second trimester. Diuretics reduce the Prostaglandin synthesis. Nonsteroidal anti-inflam- chance of developing pre-eclampsia, but are avoided matory drugs (NSAIDs), e.g. indomethacin, attenuate in pre-eclampsia itself because these patients already the antihypertensive effect ofB-adrenoceptorblockers have a contracted circulatory volume. ACE-inhibitors and of diuretics, perhaps by inhibiting the synthesis (and by implication angiotensin ATa receptor of vasodilator renal prostaglandins. This effect can antagonists) are absolutely contraindicated during also be important when a diuretic is used for severe pregnancy, where they cause fetal death, typically left ventricular failure. mid-trimester. There is no definite evidence that Enzyme inhibition. Ciprofloxacin and cimetidine ACE inhibitors — or any of the commonly used inhibit hepatic metabolism of lipid-soluble B- antihypertensive drugs — are teratogenic, and adrenoceptor blockers, e.g. metoprolol, labetalol, women who become pregnant while receiving propranolol, increasing their effect. Methyldopa these should be reassured but should, of course, plus an MAO inhibitor may cause excitement and then discontinue the ACE inhibitor or ATj receptor hallucinations. antagonist. Pharmacological antagonism. Sympathomimetics, Raised blood pressure and proteinuria (pre- e.g. amphetamine, phentolamine (present in eclampsia) complicates 2-8% of pregnancies and anorectics and cold and cough remedies) may lead may proceed to fitting (eclampsia), a major cause of to loss of antihypertensive effect, and indeed to a mortality in mother and child. Magnesium sulphate hypertensive reaction when taken by a patient already halves the risk of progress to eclampsia (typically 4 on a B-adrenoceptor blocker, due to unopposed g i.v. over 5-10 min followed by 1 g/hour by i.v. a-adrenergic stimulation. infusion for 24 hours after the last seizure).36 Surgical anaesthesia may lead to a brisk fall in Additionally, if a woman has one fit (treat with blood pressure in patients taking antihypertensives. diazepam), then the magnesium regimen is Antihypertensive therapy should not be routinely superior to diazepam or phenytoin in preventing altered before surgery, although it obviously can further fits.37 complicate care both during and after the operation. Aspirin, in low dose, was reported in early Anaesthetists must be informed. studies to reduce the incidence of pre-eclampsia in at-risk patients, but a more recent meta-analysis has not supported this. Consequently, it is not routinely recommended. Sexual function and UNWANTED INTERACTIONS WITH cardiovascular drugs ANTIHYPERTENSIVE DRUGS All drugs that interfere with sympathetic autonomic Specific interactions are described in the accounts of activity, including diuretics, can potentially interfere individual drugs. The following are general examples with male sexual function, expressed as a failure of for this diverse group of drugs. ejaculation or difficulty in sustaining an erection. Alcohol intake is the commonest contributing Nevertheless, placebo-controlled trials have em- factor, or even cause of hypertension, and should phasised how common a symptom this is in the always be considered as a cause of erratic or failed untreated male population (approaching sometimes 20-30%). It is also likely that hypertension itself is 36 associated with an increased risk of sexual dys- The Magpie Trial Collaborative Group 2002 Lancet 359: function since loss of NO production by the 1877-1890. 37 The Eclampsia Trial Collaborative Group 1995 Which vascular endothelium is an early feature of the anticonvulsant for women with eclampsia? Evidence from pathophysiology of this disease. Laying the blame the Collaborative Eclampsia Trial. Lancet 345:1455-1463. on antihypertensive medication is probably 492
SEXUAL FUNCTION AND CARDIOVASCULAR DRUGS 23 incorrect in most instances, especially with drugs There are few if any records of sudden from newer drug categories. Calcium channel cardiovascular death amongst women under these blockers, ACE inhibitors and angiotensin II (AT1) circumstances. receptor antagonists all have reported rates of If there is substantial concern about cardio- sexual dysfunction that did not differ from vascular stress (hypertension or arrhythmia) during placebos. If symptoms persist with these drugs sexual intercourse in either sex, a dose of labetalol other causes should be sought. It is important to about 2 hours before the event may well be justified listen to the patient but also reassure them that the (taking account of other therapy already in use). drug is not necessarily to blame; sexual dysfunction But patients taking a B-blocker long term for angina as a perceived adverse drug effect is a potent cause prophylaxis have shown reductions in peak heart of compliance failure. Sildenafil (Viagra) can be rate during coitus from 122 to 82 beats/min. safely used in patients receiving any of the Patients suffering from angina pectoris should commonly used antihypertensive drugs. also use glyceryl trinitrate or isosorbide dinitrate as As well as the concerns about sexual perform- usual for pre-exertional prophylaxis 10 min before ance in treated hypertensives there may be concerns intercourse. They should be aware of the potentially about fitness per se to attempt intercourse. The real fatal interaction of sildenafil (Viagra) with nitrates possibility that it is hazardous is compounded often (see above, p. 545). by their age and concurrent coronary artery disease. • The treatment of both hypertension and angina SEXUAL INTERCOURSE AND THE requires drugs that reduce the work of the heart CARDIOVASCULAR SYSTEM either directly or by lowering peripheral vascular Normal sexual intercourse with orgasm is ac- resistance. • B-blockade, which acts mainly through reduced companied by transient but brisk physiological cardiac output, and calcium channel blockade, acting changes, e.g. tachycardia of up to 180 beats/min, by selective arterial dilatation, may be used in either with increases of 100 beats/min over less than one condition. min, can occur. Systolic blood pressure may rise by • Other vasodilators are suited preferentially to 120 mmHg and diastolic by 50 mmHg. Orgasm may hypertension (ACE inhibitors, angiotensin AT, be accompanied by transient pressure of 230/130 receptor antagonists and cc-adrenoceptor blockers) or mmHg even in normotensive individuals. Electro- to angina (nitrates). • The treatment of myocardial infarction requires cardiographic abnormalities may occur in healthy thrombolysis, aspirin and B-adrenoceptor blockade men and women. Respiratory rate may rise to acutely, with the latter two continued for at least two 60/min. years as secondary prevention of a further myocardial Such changes in the healthy may reasonably be infarction. thought to bode ill for the unhealthy (with hyper- • Other important steps in secondary prevention tension, angina pectoris, post myocardial infarction). include ACE inhibitors and statins in selected patients Sudden deaths do occur during or shortly after with cardiac failure and hypercholesterolaemia, respectively. sexual intercourse (ventricular fibrillation or sub- arachnoid haemorrhage), usually in clandestine circumstances such as the bordello or the mistress's boudoir, or when the relationship is between an older man and a younger woman — although this Pulmonary hypertension may just reflect reporting bias in the press. In one series, 0.6% of all sudden deaths were (reportedly) Therapy is determined by the underlying cause. attributable to sexual intercourse and in about half When the condition is secondary to hypoxia of these cardiac disease was present. Clearly it is accompanying chronic obstructive pulmonary undesirable that the older patient with coronary disease, long-term oxygen therapy improves symp- heart disease should aspire to the haemodynamic toms and prognosis; anticoagulation is essential heights attainable in youth. when the cause is multiple pulmonary emboli. 493
23 A R T E R I A L H Y P E R T E N S I O N , A N G I N A P E C T O R I S, Ml Primary pulmonary hypertension: verapamil may A variety of pharmacological tests is now give symptomatic benefit, also continuous intra- available, and these are best performed in specialist venous infusion of prostaglandin. Evidence sug- units to avoid erroneous results, e.g. clonidine gests that endothelin, a powerful endogenous suppression test. Provocation tests are dangerous. vasoconstrictor, may play a pathogenic role, and A phaeochromocytoma may also be stimulated to bosentan, an endothelin-receptor antagonist may secrete and cause a hypertensive attack by meto- improve exercise tolerance. Heart and lung trans- clopramide and by any drug that releases histamine plantation is recommended for younger patients. (opioids, curare, trimetaphan). The search for biochemical evidence for a phaeochromocytoma should always precede the radiological hunt for a tumour. The accurate measurement of adrenaline in Phaeochromocytoma plasma is itself invaluable in determining whether the tumour is likely to be adrenal or extra-adrenal This tumour of chromaffin tissue, usually arising in for only adrenal tumours can synthesise adrenaline. the adrenal medulla, secretes principally nor adrenaline, This is because the enzyme which methylates but also variable amounts of adrenaline. Symptoms noradrenaline to adrenaline needs to be induced by are related to this. Hypertension may be sustained a concentration of cortisol higher than that which or intermittent. If the tumour secretes only nor- normally circulates. Such a concentration is achieved adrenaline, which stimulates a and B1 adrenoceptors, within the normal adrenal gland by the porto- rises in blood pressure are accompanied by reflex capillary circulation from cortex to medulla. The bradycardia due to vagal activation; this is suffi- circulation is progressively disrupted as the rumour cient to overcome the chronotropic effect of B1 grows, so that very large adrenal tumours may receptor stimulation. The recognition of bradycardia cease to secrete adrenaline. at the time of catecholamine-induced symptoms (e.g. anxiety, termor or sweating) is useful in alert- Control of blood pressure preoperatively or when ing the physician to the possibility of this rare the tumour cannot be removed is achieved by oc- syndrome, since physiological sympathetic nervous adrenoceptor blockade which reverses peripheral activation causes is coupled to vagal withdrawal, vasoconstriction. B-blockade may also be required and causes tachycardia. If the tumour also secretes to control tachycardia in patients with adrenaline- adrenaline, which stimulates a, B1 and B2 adreno- secreting tumours. Since adrenaline secretion, as ceptors, blood pressure and heart rate change in explained above, tends to fall as tumours enlarge, parallel. This is because stimulation of the vasodilator tachycardia is not usually a major problem. Initiation B2receptor in resistance arteries attenuates the rise in of a-blocker treatment can unmask tachycardia, diastolic pressure, and vagal activation is insufficient since there is no longer baroreceptor induced vagal then to oppose the chronotropic effect of combined B1 and B2 receptor stimulation in the heart. 38 On the other hand, a positive test must not be ignored. In 1954, a hospital clinical chemistry laboratory was asked to set Diagnostic tests include measurement of cate- up a biological assay for catecholamines in the urine. The cholamine metabolites in urine followed by cate- head of the laboratory tested urine from the lab staff to cholamine concentrations in blood when the urine obtain a reference range for the assay. All were negative except his own which was strongly positive. He felt well and results are equivocal or high. With modern analytical regarded the result as showing insufficient specificity of the techniques interference by drugs and diet is less test. Two years later a fluorometric assay became available. troublesome than formerly. The urines of the lab staff were tested again with the same Antihypertensive drugs may alter catecholamine result. The head of the laboratory still felt well, but this time concentrations (particularly those that induce a he decided to consult a physician colleague. A few days later, before the consultation, he was quietly reading a newspaper reflex increase in sympathetic activity, e.g. vaso- at home in the evening when he had a fatal cerebral dilators). False-positive results in tests can then infarction. Autopsy revealed a phaeochromocytoma. occur and in the past patients have undergone (Robinson R 1980 Tumours that-secrete catecholamines. unnecessary operations.38 Wiley, Chichester.) 494
PHAEOCHROMOCYTOMA 23 activation to oppose B-receptor stimulation of the Braunstein J B et al 2000 Unstable angina pectoris. heart. A B-receptor blocker should never be given New England Journal of Medicine 342:101-114 alone, since abolition of the peripheral vasodilator British Cardiac Society (and other Societies) 2000 Joint effects of adrenaline leaves the powerful a effects British recommendations on prevention of unopposed. The injunction not to use a B-blocker in coronary heart disease in clinical practice: any patient with a suspected phaeochromocytoma summary. British Medical Journal 320: 705-710 can be circumvented by judicious use of low dose B1 Brown M J 1995 Phaeochromocytoma. In: Weatherall selective blockade (e.g. bisoprolol 5 mg), which will D, Ledingham J, Warrell D (eds) Oxford textbook not prevent adrenaline induced vasodilatation. of medicine. Oxford University Press, Oxford, For phaeochromocytoma the preferred a blocker pp.2553-2557 is not one of the selective a1 blockers, as in essential Burnier M, Brunner H R 2000 Angiotensin 11 receptor hypertension, but the irreversible oc-blocker, phen- antagonists. Lancet 355: 637-645 oxybenzamine, whose blockade cannot be overcome Dickerson J E C, Brown M J 1995 Influence of age on by a catecholamine surge. Treatment should be for general practitioners' definition and treatment of several weeks, if possible, prior to surgery, to allow hypertension. British Medical Journal 310: 574 the intravascular volume depletion, which is always Freemantle N et al 1999 B-blockade after myocardial present in phaeochromocytoma patients, to be infarction: systematic review and meta regression reversed. analysis. British Medical Journal 318:1730-1737 Guidelines Subcommittee. 1999 World Health During surgical removal, phentolamine (or sodium Organization-International Society of nitroprusside) should be at hand to control rises in Hypertension Guidelines for the Management of blood pressure when the tumour is handled. When Hypertension. Journal of Hypertension 17:151-183 the adrenal veins have been clamped, volume expan- Maxwell S 1999 Emergency management of acute sion is often required to maintain blood pressure myocardial infarction. British Journal of Clinical even after adequate preoperative a-blockade. If a Pharmacology 48: 284-298 pressor infusion is still needed, isoprenaline is more Manhapra A, Borzak S 2000 Treatment possibilities for use than the usual oc-agonists, to which the patient unstable angina. British Medical Journal 321: will be insensitive due to existing a-receptor blockade. 1269-1275 Metirosine (a-methyltyrosine) has been used with Maynard S J et al 2000 Management of acute coronary some success to block catecholamine synthesis in syndromes. British Medical Journal 321: 220-223 malignant phaeochromocytomas. Messerli F H 1995 This day 50 years ago. New Metaiodobenzylguanidine (MIBG, an analogue of England Journal of Medicine 332:1038-1039 (An guanethidine) is actively taken up by adrenergic account of the hypertension and stroke suffered by tissue and is concentrated in phaeochromocytomas. US President F D Roosevelt.) Radioiodinated MIBG (123I-MIBG) allows local- Norwegian Multicentre Study Group 1981 Timolol- isation of tumours and detection of metastases; also induced reduction in mortliaty and reinfarction in selective therapeutic irradiation of functioning patients surviving acute myocardial infarction. New metastases or other tumours of chromaffin tissue, England Journal of Medicine 304: 803 — a classic e.g. carcinoid. O'Brien E et al 2000 Use and interpretation of ambulatory blood pressure monitoring: recommendations of the British Hypertension Society. British Medical Journal 320:1128-1134 GUIDE TO FURTHER READING Pahor M et al 2000 Health outcomes associated with Blood Pressure Lowering Treatment Trialists calcium antagonists compared with other first-line Collaboration 2000. Effects of ACE inhibitors, antihypertensive therapies: meta-analysis of calcium antagonists, and other blood-pressure- randomised controlled trials. Lancet 356:1949-1954 lowering drugs: results of prospectively designed Parker J D, Parker J O 1998 Nitrate therapy for stable overviews of randomised trials. Lancet 355: angina pectoris. New England Journal of Medicine 1955-1964 338:520-531 495
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 , Ml Redman C W G, Roberts J M 1995 Management of pre- protection and blood pressure reduction: a meta- eclampsia. Lancet 341:1451-1454 analysis. Lancet 358:1305 Robson J et al 2000 Estimating cardiovascular risk for Stewart P M 1999 Mineralocorticoid hypertension. primary prevention: outstanding questions for Lancet 353:1341-1347 primary care. British Medical Journal 320: 702-704 Vaughan O J, Delanty N 2000 Hypertensive Safian R D, Textor S C 2001 Renal-artery stenosis. New emergencies. Lancet 356:411-117 England Journal of Medicine 334: 431-142 Yla-Herttuala S, Martin J F 2000 Cardiovascular gene Staessen J A, Wang J-G, Thijs L 2001 Cardiovascular therapy. Lancet 355: 213-222 496

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