CLINICAL PHARMACOLOGY 2003 (PART 25A)

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CLINICAL PHARMACOLOGY 2003 (PART 25A)

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Hypertension and coronary heart disease (CHD) are of great importance. Hypertension affects above 20% of the total population of the USA with its major impact on those over age 50. CHD is the cause of death in 30% of males and 22% of females in England and Wales. Management requires attention to detail, both clinical and pharmacological. The way drugs act in these diseases is outlined and the drugs are described according to class. • Hypertension and angina pectoris: how drugs act • Drugs used in both hypertension and angina Diuretics Vasodilators organic nitrates, calcium channel blockers.ACE inhibitors, angiotensin...

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  1. 23 Arterial hypertension, angina pectoris, myocardial infarction SYNOPSIS Hypertension: how Hypertension and coronary heart disease (CHD) are of great importance. Hypertension drugs act affects above 20% of the total population of the USA with its major impact on those over age Consider the following relationship: 50. CHD is the cause of death in 30% of males Blood pressure = and 22% of females in England and Wales. cardiac output x peripheral resistance Management requires attention to detail, both clinical and pharmacological. Therefore drugs can lower blood pressure by: The way drugs act in these diseases is • Dilatation of arteriolar resistance vessels. outlined and the drugs are described according Dilatation can be achieved through direct to class. relaxation of vascular smooth muscle cells, by • Hypertension and angina pectoris: how stimulation of nitric oxide (NO) production, or drugs act by blocking (suppressing) endogenous • Drugs used in both hypertension and angina vasconstrictors, noradrenaline (norepinephrine) and angiotensin. Diuretics • Dilatation of venous capacitance vessels; reduced Vasodilators venous return to the heart (preload) leads to organic nitrates, calcium channel reduced cardiac output, especially in the upright blockers.ACE inhibitors, angiotensin II- position receptor antagonists • Reduction of cardiac contractility and heart rate. Adrenoceptor blocking drugs, and ( • Depletion of body sodium. This reduces plasma Peripheral sympathetic nerve terminal volume (transiently), and reduces arteriolar Autonomic ganglion-blocking drugs response to noradrenaline (norepinephrine) Central nervous system Treatment of angina pectoris Modern antihypertensive drugs lower blood pressure with minimal interference with homeo- • Acute coronary syndromes and myocardial static control, i.e. change in posture, exercise. infarction • Arterial hypertension • Sexual function and cardiovascular drugs • Phaeochromocytoma 461
  2. 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 vasoconstrictors, principally noradrenaline. While Angina pectoris: how this hyposensitivity may be a consequence of the sodium depletion, thiazides are generally more effec- drugs act tive antihypertensive agents than loop diuretics, despite causing less salt loss, and evidence suggests Angina can be viewed as a problem of supply and an independent action of thiazides on an unidentified demand. Drugs used in angina pectoris are those ion-channel on vascular smooth muscle cell mem- that either increase supply of oxygen and nutrients, branes. Maximum effect on blood pressure is delayed or reduce the demand for these — or both. for several weeks and other drugs are best added Supply can be increased by: cardiac work and after this time. Adverse metabolic effects of thiazides myocardial oxygen need by: on serum potassium, blood lipids, glucose tolerance, • dilating coronary arteries and uric acid metabolism led to suggestions that • slowing the heart (coronary flow, uniquely, they should be replaced by newer agents not having occurs in diastole, which lengthens as heart rate these effects. It is, however, now recognised that falls). unnecessarily high doses of thiazides have been used in the past and that with low doses, e.g. bendro- Demand can be reduced by: fluazide (bendroflumethiazide) 1.25-2.5 mg/d or • reducing afterload, (i.e. peripheral resistance), so less (or hydrochlorothiazide 12.5-25 mg), thiazides reducing the work of the heart in perfusing the are both effective and well-tolerated. Moreover, they tissues are not only by far the cheapest antihypertensive • reducing preload, (i.e. venous filling pressure); agents available worldwide but have proved to be according to Starling's Law of the heart, the most effective in several outcome trials in workload and therefore oxygen demand varies preventing the major complications of hypertension, with stretch of cardiac muscle fibres myocardial infarction and stroke. The characteristic • slowing the heart. reduction in renal calcium excretion induced by thiazides may, in long-term therapy, also reduce the occurrence of hip fractures in older patients and benefit women with postmenopausal osteoporosis. Drugs used in hypertension and angina Vasodilators Two groups of drugs, p-adrenergic blockers and calcium channel blockers, are used in both hyper- tension and angina. Several drugs for hypertension ORGANIC NITRATES are used also in the treatment of heart failure. Organic nitrates (and nitrite) were introduced into medicine in the 19th century.1 Denitration in the smooth muscle cell releases nitric oxide (NO), which is the main physiological vasodilator, normally pro- DiuretiCS (see also Ch. 26) duced by endothelial cells. Nitrodilators (a generic term for drugs that release or mimic the action of NO) Diuretics, particularly the thiazides, are useful anti- activate the soluble guanylate cyclase in vascular hypertensives. They cause an initial loss of sodium smooth muscle cells and cause an increase in intra- with a parallel contraction of the blood and extra- cellular cyclic GMP (guanosine monophosphate) con- cellular fluid volume. The effect may reach 10% of total body sodium but it is not maintained. After 1 Murrell, W 1879 Nitroglycerin as a remedy for angina several months of treatment, the main blood press- pectoris. Lancet 1: 80-81. Nitroglycerin was actually first ure lowering effect appears to reflect a reduced synthesised by Sobrero in 1847 who noted when he applied it responsiveness of resistance vessels to endogenous to his tongue it caused a severe headache. 462
  3. VASO OILATORS 23 centrations. This is the second messenger that alters night; alternatively transdermal patches may be calcium fluxes in the cell, decreases stored calcium, removed for a few hours if tolerance is suspected. and induces relaxation. The result is a generalised dilatation of venules (capacitance vessels) and to a Uses. Nitrates are chiefly used to relieve angina lesser extent of arterioles (resistance vessels), causing pectoris and sometimes left ventricular failure. An a fall of blood pressure that is postural at first; the excessive fall in blood pressure will reduce coronary larger coronary arteries especially dilate. Whereas flow as well as cause fainting due to reduced cerebral some vasodilators can 'steal' blood away from blood flow, and so it is important to avoid accidental atheromatous arteries, with their fixed stenoses, to overdosing. Patients with angina should be instructed other, healthier arteries, nitrates probably have the on the signs of overdose — palpitations, dizziness, reverse effect as a result of their supplementing blurred vision, headache and flushing following by the endogenous NO. Atheroma is associated with pallor — and what to do about it (below). impaired endothelial function, resulting in reduced The discovery that coronary artery occlusion by release of NO and, possibly, its accelerated thrombosis is itself 'stuttering' — developing destruction by the oxidised LDL in atheroma (see gradually over hours — and associated with vaso- Ch. 25). spasm in other parts of the coronary tree has made The venous dilatation causes a reduction in the use of isosorbide dinitrate (Isoket) by continuous venous return, a fall in left ventricular filling pressure i.v. infusion adjusted to the degree of pain, a logical, with reduced stroke volume, but cardiac output and effective, form of analgesia for unstable angina. (per min) is sustained by the reflex tachycardia Transient relief of pain due to spasm of other induced by the fall in blood pressure. smooth muscle (colic), can sometimes be obtained, so that relief of chest pain by nitrates does not prove Pharmacokinetics. The nitrates are generally well the diagnosis of angina pectoris. absorbed across skin, and the mucosal surface of Nitrates are contraindicated in angina due to the mouth or gut wall. Nitrates absorbed from the anaemia. gut, however, are subject to extensive first-pass metabolism in the liver, as is shown by the sub- Adverse effects. Collapse due to fall in blood stantially larger doses required by that route over pressure resulting from overdose is the commonest sublingual application (this also explains why side effect. The patient should remain supine, and swallowing a sublingual tablet of glyceryl trinitrate the legs should be raised above the head to restore terminates its effect). They are first denitrated and venous return to the heart. then conjugated with glucuronic acid. The t1/2 Nitrate headache, which may be severe, is prob- periods vary (see below) but for glyceryl trinitrate ably due to the stretching of pain-sensitive tissues (GTN) it is 1-4: minutes. around the meningeal arteries resulting from the increased pulsation that accompanies the local Tolerance to the characteristic vasodilator headache vasodilatation. If headache is severe the dose should comes and goes quickly (hours).2 Ensuring that a be halved. Methaemoglobinaemia occurs with heavy continuous steady-state plasma concentration is dosage. avoided prevents tolerance. This is easy with occasional use of glyceryl trinitrate, but with nitrates Interactions. An important footnote to the use of having longer t1/2 (see below) and sustained release nitrates (and NO-dilators generally) has been the formulations it is necessary to plan the dosing to marked potentiation of their vasodilator effects allow low plasma concentration for 4-8 h, e.g. over- observed in patients taking the phosphodiesterase (PDE) inhibitor sildenafil (Viagra). This agent targets 2 an isoform of PDE (PDE-5) expressed in the blood Explosives factory workers exposed to a nitrate- vessel wall. Other methylaxanthine PDE inhibitors, contaminated environment lost it over a weekend and some chose to maintain their intake by using nitrate impregnated such as theophylline, do not cause a similar headbands (transdermal absorption) rather than have to interaction because they are rather weak inhibitors accept the headaches and reacquire tolerance so frequently. of PDE-5, even at the doses effective in asthma. A 463
  4. 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 number of pericoital deaths reported in patients the sublingual or buccal route is preferred; an oral taking sildenafil have been attributed to the metered aerosol that is sprayed under the tongue substantial fall in blood pressure that occurs when (nitrolingual spray) is an alternative. used with a nitrate. This is an ironic twist for an agent in first-line use in erectile dysfunction that For prophylaxis, GTN can be given as an oral was originally developed as a drug to treat angina.3 (buccal, or to swallow, Sustac) sustained-release formulation or via the skin as a patch (or ointment); these formulations can be useful for victims of GLYCERYLTRINITRATE (see also above) nocturnal angina.4 Glyceryl trinitrate (1879) (trinitrin, nitroglycerin, GTN) (t1/2 3 min) is an oily, nonflammable liquid Venepuncture: the ointment can assist difficult that explodes on concussion with a force greater venepuncture and a transdermal patch adjacent to than that of gunpowder. Physicians meet it mixed an i.v. infusion site can prevent extravasation and with inert substances and made into a tablet, in phlebitis and prolong infusion survival. which form it is both innocuous and fairly stable. But tablets more than 8 weeks old or exposed to Isosorbide dinitrate (Cedocard)(t1/220 min) is used heat or air will have lost potency by evaporation for prophylaxis of angina pectoris and for and should be discarded. Patients should also be congestive heart failure (tabs sublingual, and to warned to expect the tablet to cause a burning swallow). An i.v. formulation 500 micrograms/ml sensation under the tongue if it is still contains (Isoket) is available for use in left ventricular failure active GTN. An alternative is to use a nitroglycerin and unstable angina. spray (see below); formulated as a pressurised liquid GTN has a shelf life of at least 3 years. Isosorbide mononitrate (Elantan) (t1/2 4 h) is used GTN is the drug of choice in the treatment of an for prophylaxis of angina (tabs to swallow). Hepatic attack of angina pectoris. The tablets should be first-pass metabolism is much less than for the chewed and dissolved under the tongue, or placed dinitrate so that systemic bioavailability is more in the buccal sulcus, where absorption is rapid and reliable. reliable. Time spent ensuring that patients under- stand the way to take the tablets and that the feeling Pentaerythritol tetranitrate (Peritrate) (t1/2 8h) is of fullness in the head is harmless, is time well less efficacious than its metabolite pentaerythritol spent. The action begins in 2 min and lasts up to 30 trinitrate (t1/211 h). min. The dose in the standard tablet is 300 micro- grams, and 500 or 600 microgram strengths are also CALCIUM CHANNEL BLOCKERS available; patients may use up to 6 mg daily in total but those who require more than 2-3 tablets per Calcium is involved in the initiation of smooth week should take a long-acting nitrate preparation. muscle and cardiac cell contraction and in the pro- GTN is taken at the onset of pain and as a pro- pagation of the cardiac impulse. Actions on cardiac phylactic immediately before any exertion likely pacemaker cells and conducting tissue are described to precipitate the pain. Sustained-release buccal in Chapter 24. tablets are available (Suscard), 1-5 mg. Absorption from the gastrointestinal tract is good, but there is Vascular smooth muscle cells. Contraction of such extensive hepatic first-pass metabolism that these cells requires an influx of calcium across the cell membrane. This occurs through ion channels 3 It has been argued that deaths on sildenafil largely reflect 4 the fact that it is used by patients at high cardiovascular risk. Useful, but not always safe. Defibrillator paddles and But recent postmarketing data shows that death is 50 times nitrate patches make an explosive combination, and it is not more likely after sildenafil taken for erectile failure than always in the patient's interest to have the patch as alprostadil, the previous first-line agent. Mitka M 2000 unobtrusive as possible (Canadian Medical Association Journal of the American Medical Association 283: 590. Journal 1993 148: 790). 464
  5. VASODILATORS 23 that are largely specific for calcium and are called undergo metabolism to less active products, pre- 'slow calcium channels' to distinguish them from dominantly by cytochrome P-450 CYP3A, which is 'fast' channels that allow the rapid influx and efflux the source of interactions with other drugs by enzyme of sodium. induction and inhibition. As their action is ter- Activation of calcium channels by an action po- minated by metabolism, dose adjustments for patients tential allows calcium to enter the cells. There follows with impaired renal function are therefore either a sequence of events which results in activation of minor or unnecessary. the contractile proteins, myosin and actin, with shortening of the myofibril and contraction of Indications for use smooth muscle. During relaxation calcium is released from the myofibril and, as it cannot be stored in the • Hypertension: amlodipine, isradipine, cell, it passes out again through the channel. Calcium nicardipine, nifedipine, verapamil channel (also called calcium entry) blockers inhibit • Angina: amlodipine, diltiazem, nicardipine, the passage of calcium through the voltage- nifedipine, verapamil dependent L- (for 'long-opening') class membrane • Cardiac arrhythmia: verapamil channels in cardiac muscle and conducting tissue, • Raynaud's disease: nifedipine and vascular smooth muscle, reduce available intra- • Prevention of ischaemic neurological damage cellular calcium and cause the muscle to relax.5 following subarachnoid haemorrhage: There are three structurally distinct classes of nimodipine. calcium channel blocker: Adverse effects. Headache, flushing, dizziness, • Dihydropyridines (the most numerous) palpitations and hypotension may occur during the • Phenylalkylamines (principally verapamil) first few hours after dosing, as the plasma concen- • Benzothiazepine (diltiazem). tration is increasing, particularly if the initial dose is The differences between their clinical effects can too high or increased too rapidly. Ankle oedema be explained in part by their binding to different may also develop. This is probably due to a rise in parts of the L-type calcium channel. All members of intracapillary pressure as a result of the selective the group are vasodilators, and some have negative dilatation by calcium blockers of the precapillary cardiac inotropic action and negative chronotropic arterioles. Thus the oedema is not a sign of sodium effect via pacemaker cells and depress conducting retention. It is not relieved by a diuretic but dis- tissue. The attributes of individual drugs are de- appears after lying flat, e.g. overnight. In theory the scribed below. oedema should also be attenuated by combining The therapeutic benefit of the calcium blockers the calcium blocker with another vasodilator which in hypertension and angina is due mainly to their is more effective (than calcium blockers) at relaxing action as vasodilators. Their action on the heart the postcapillary venules, e.g. a nitrate or an gives non-dihydropyridines an additional role as ACE inhibitor. Bradycardia and arrhythmia may Class 4 antiarrhythmics. occur. Gastrointestinal effects include constipation, nausea and vomiting; palpitation and lethargy may Pharmacokinetics. Calcium channel blockers in be felt. general are well absorbed from the gastrointestinal There has been some concern that the shorter- tract and their systemic bioavailability depends on acting calcium channel blockers may adversely the extent of first-pass metabolism in the gut wall affect the risk of myocardial infarction and cardiac and liver, which varies between the drugs. All death. The evidence is based on case-control studies which cannot escape the possibility that sicker 5 patients, i.e. with worse hypertension or angina, Several calcium-selective channels have been described in received calcium channel blockade. The safety and different tisues, e.g. the N (present in neuronal tissue) and T (transient, found in brain, neuronal and cardiovascular efficacy of the class has been strengthened by the tissue); the drugs discussed here selectively target the L recent findings of two prospective comparisons channel for its cardiovascular importance. with other antihypertensives.6 465
  6. 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, M Interactions are quite numerous. The drugs in this manoeuvre; it should not be used in a hypertensive group in general are extensively metabolised, and emergency because the blood pressure reduction is there is risk of decreased effect with enzyme inducers, unpredictable and sometimes large enough to cause e.g. rifampicin, and increased effect with enzyme cerebral ischaemia (see p. 492). inhibitors, e.g. cimetidine. Conversely, calcium channel blockers decrease the plasma clearance of Amlodipine has a t1/2 (40 h) sufficient to permit the several other drugs by mechanisms that include same benefits as the longest-acting formulations of delaying their metabolic breakdown. The conse- nifedipine without requiring a special formulation. quence, for example, is that diltiazem and verapamil Its slow association with L-channels and long cause increased exposure to carbamazepine, quinidine, duration of action render it unsuitable for emergency statins, ciclosporin, metoprolol, theophylline and reduction of blood pressure where frequent dose (HIV) protease inhibitors. Verapamil increases adjustment is needed. On the other hand an plasma concentration of digoxin, possibly by occasional missed dose is of little consequence. interfering with its biliary excretion. Beta-adreno- Amlodipine differs from all other dihydropyridines ceptor blockers may exacerbate atrioventricular listed in this chapter in being safe to use in patients block and cardiac failure. Grapefruit juice raises the with cardiac failure (the PRAISE7 Study). plasma concentration of dihydropyridines (except amlodipine) and verapamil. Verapamil (t l / 2 4 h) is an arterial vasodilator with some venodilator effect; it also has marked negative myocardial inotropic and chronotropic actions. It is Individual calcium blockers given thrice daily as a conventional tablet or daily as a sustained-release formulation. Because of its Nifedipine (tl/2 2h) is the prototype dihydro- negative effects on myocardial conducting and pyridine. It selectively dilates arteries with little contracting cells it should not be given to patients effect on veins; its negative myocardial inotropic with bradycardia, second or third degree heart and chronotropic effects are much less than those of block, or patients with Wolff-Parkinson-White verapamil. There are sustained-release formulations syndrome to relieve atrial flutter or fibrillation. of nifedipine that permit once daily dosing with Amiodarone and digoxin increase the AV block. minimal peaks and troughs in plasma concentration Verapamil increases plasma quinidine concen- so that adverse effects due to rapid fluctuation of tration and this interaction may cause dangerous concentrations are also lessened. Various methods hypotension. have been used to prolong, and smooth, drug delivery, and bioequivalence between these formu- Diltiazem (tl/2 5 h) is given thrice daily, or once or lations cannot be assumed; prescribers should twice daily if a slow-release formulation is pre- specify the brand to be dispensed. The adverse scribed. It causes less myocardial depression and effects of calcium blockers with a short duration of prolongation of AV conduction than does verapamil action may include the hazards of activating the but should not be used where there is bradycardia, sympathetic system each time a dose is taken. The second or third degree heart block or sick sinus dose range for nifedipine is 30-90 mg daily. In syndrome. addition to the adverse effects listed above, gum hypertrophy may occur. Nifedipine can be taken Isradipine (t1/2 8 h) is given once or twice daily (it is 'sublingually', by biting a capsule and squeezing similar to nifedipine). the contents under the tongue. In point of fact, absorption is still largely from the stomach after this Nicardipine (t1/2 4 h) is given x 3/d. 6 Both the NORDIL and INSIGHT trials (Lancet 2000 356: 7 359-365, 366-372) confirmed that a calcium channel blocker PRAISE = Prospective Randomised Amlodipine Survival (diltiazem and nifedipine respectively) had the same efficacy Evaluation (see Packer M et al 1996 The effect of amlodipine as older therapies (diuretics and/or -blockers) in on morbidity and mortality in severe chronic heart failure. hypertension with no evidence of increased sudden death. New England Journal of Medicine 335: 1107-1114). 466
  7. VASODILATORS 23 Nimodipine has a moderate cerebral vasodilating recognition that the AT1-receptor subtype is the action. Cerebral ischaemia after subarachnoid important target for drugs antagonising angiotensin haemorrhage may be partly due to vasospasm; II has led, a little confusingly, to two alternative clinical trial evidence indicates that nimodipine nomenclatures for these drugs: either AT1-receptor given after subarachnoid haemorrhage reduces blockers, or angiotensin II receptor antagonists cerebral infarction (incidence and extent).8 Although (AURA). the benefit is small, the absence of any more effec- Bradykinin (an endogenous vasodilator occurring tive alternatives has led to the routine administration in blood vessel walls) is also a substrate for ACE. of nimodipine (60 mg every 4 hours) to all patients Potentiation of bradykinin contributes to the blood for the first few days following subarachnoid pressure lowering action of ACE inhibitors in haemorrhage. No benefit has been found in similar patients with low-renin causes of hypertension. trials following other forms of stroke. Either bradykinin or one of the neurokinin substrates of ACE (such as substance P) may stimulate cough Other members include felodipine, isradipine, laci- (below). The AT1 blockers differ from the ACE dipine, lercanidipine, nisoldipine. inhibitors in having no effect on bradykinin and do not cause cough. Those that achieve complete blockade of the receptor are slightly more effective ANGIOTENSIN CONVERTING than ACE inhibitors at preventing angiotensin II ENZYME (ACE) INHIBITORS AND vasoconstriction. ACE inhibitors are more effective ANGIOTENSIN (AT) II RECEPTOR at suppressing aldosterone production in patients ANTAGONISTS with normal or low plasma renin. Renin is an enzyme produced by the kidney in response to a number of factors including adrenergic Uses activity ( 1-receptor) and sodium depletion. Renin converts a circulating glycoprotein (angiotensinogen) Hypertension. The antihypertensive effect of ACE into the biologically inert angiotensin I, which is inhibitors and AT1 receptor blockers results primarily then changed by angiotensin converting enzyme from vasodilatation (reduction of peripheral resist- (ACE or kininase II) into the highly potent vaso- ance) with little change in cardiac output or rate; constrictor angiotensin II. ACE is located on the renal blood flow may increase (desirable). A fall in luminal surface of capillary endothelial cells, parti- aldosterone production may also contribute to the cularly in the lungs; and there are also renin- blood pressure lowering action of ACE inhibitors. angiotensin systems in many organs, e.g. brain, Both classes slow progression of glomerulopathy. heart, the relevance of which is uncertain. Whether the long-term benefit of these drugs in Angiotensin II acts on two G-protein coupled hypertension exceeds that to be expected from receptors, of which the angiotensin 'AT1 subtype blood pressure reduction alone remains controversial. accounts for all the classic actions of angiotensin. As ACE inhibitors and AT1-receptor blockers are well as vasoconstriction these include stimulation most useful in hypertension when the raised blood of aldosterone (the sodium-retaining hormone) pressure results from excess renin production (e.g. production by the adrenal cortex. It is evident that renovascular hypertension), or where concurrent angiotensin II can have an important effect on use of another drug (diuretic or calcium blocker) blood pressure. In addition, it stimulates cardiac renders the blood pressure renin-dependent. The and vascular smooth muscle cell growth, contributing fall in blood pressure can be rapid, especially with probably to the progressive amplification in hyper- short-acting ACE inhibitors, and low initial doses of tension once the process is initiated. The AT2 these should be used in patients at risk: those with receptor subtype is coupled to inhibition of muscle impaired renal function, or suspected cerebrovascular growth or proliferation, but appears of minor disease. These patients may be advised to omit any importance in the adult cardiovascular system. The concurrent diuretic treatment for a few days before the first dose. The antihypertensive effect increases 8 Packard J D et al 1989 British Medical Journal 289: 636. progressively over weeks with continued adminis- 467
  8. 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 tration (as with other antihypertensives) and the Myocardial infarction (MI). Following a myocardial dose may be increased at intervals of 2 weeks. infarction, the left ventricle may fail acutely from the loss of functional tissue or in the long-term from Cardiac failure (see p. 517). ACE inhibitors have a a process of 'remodelling' due to thinning and useful vasodilator and diuretic-sparing (but not enlargement of the scarred ventricular wall. Angio- diuretic-substitute) action in all grades of heart tensin II plays a key role in both of these processes failure. Their reduction of mortality in this condition, and an ACE inhibitor given after an MI markedly due possibly to their being the only vasodilator reduces the incidence of heart failure. The effect is which does not reflexly activate the sympathetic seen even in patients without overt signs of failure, system, has made the ACE inhibitors more critical but who have low left ventricular ejection fractions to the treatment of heart failure than of hyper- during the convalescent phase (3-10 days) follow- tension, where they are not usually an essential part ing their MI. Patients such as this receiving of management. The AT1 blockers have not yet been captopril in the SAVE trial,11 had a 37% reduction in introduced for the treatment of cardiac failure. This progressive heart failure over the 60-month follow- may only be a matter of time, but the establishment up period compared to placebo. The benefits of of new drugs for cardiac failure encounters the ACE inhibition after MI are additional to those problem of demonstrating efficacy against a back- conferred by thrombolysis, aspirin and -blockers. ground of existing ACE inhibitor therapy, where a placebo control is no longer ethically acceptable. Cautions. Certain constraints apply to the use of ACE. Diabetic nephropathy. In patients with type I • Heart failure: severe hypotension may result in (insulin dependent) diabetes, hypertension often patients taking diuretics, or who are accompanies the diagnosis of frank nephropathy hypovolaemic, hyponatraemic, elderly, have and aggressive blood pressure control is essential to renal impairment or with systolic blood slow the otherwise inexorable decline in renal func- pressure < 100 mmHg. A test dose of captopril tion that follows. ACE inhibitors appear to have a 6.25 mg by mouth may be given because its specific renoprotective effect, possibly because of effect lasts only 4-6 h. If tolerated, the preferred the role of angiotensin II in driving the underlying long-acting ACE inhibitor may then be initiated glomerular hyperfiltration in these patients.9 These in low dose. drugs are now considered first-line treatment for • Renal artery stenosis (whether unilateral, bilateral hypertensive type I diabetics, although most patients renal or suspected from the presence of will need a second or third agent to reach the new generalised atherosclerosis): an ACE inhibitor BP targets for these patients (see below). There is may cause renal failure and is contraindicated. also evidence that ACE inhibitors have a proteinuria- • Aortic stenosis/left ventricular outflow tract sparing effect in type I diabetics with 'normal' BP, obstruction: an ACE inhibitor may cause severe, but here it is less clear whether this effect extends sudden hypotension and, depending on severity, beyond just a BP-lowering effect.10 For hypertensive is relatively or absolutely contraindicated. type 2 diabetics with nephropathy, there are better • Pregnancy represents a contraindication (see data to support use of AT1-receptor blockers than below). ACE inhibitors for a renoprotective effect indepen- • Angioedema may result (see below). dent of the blood pressure lowering effect. 9 For a review, see: Cooper M E 1998 Pathogenesis, Adverse effects prevention and treatment of diabetic nephropathy. Lancet 352:213-219. ACE inhibitors cause persistent dry cough in 10 The EUCLID study group 1997 The EUCLID study. 10-15% of patients. Urticaria and angioedema (< 1 Randomised, placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and 11 normoalbuminuria or microalbiminuria. Lancet 349: Swedberg K P et al 1992 New England Journal of Medicine 1787-1792. 327: 669-677. 468
  9. VASODILATORS 23 in 100 patients) are much rarer, occurring usually in Other members include cilazapril, fosinopril, imidapril, the first weeks of treatment. The angioedema varies lisinopril, moexipril, perindopril, quinapril, mmipril, from mild swelling of the tongue to life-threatening and trandolapril. Of these, lisinopril has a marginally tracheal obstruction, when s.c. adrenaline (epine- longer t1/2 than enalapril, probably justifying its phrine) should be given. The basis of the reaction is popularity as a once-daily ACE inhibitor. Some of probably pharmacological rather than allergic, due the others are longer-acting, with quinapril and to reduced breakdown of bradykinin. ramipril having also a higher degree of binding to Impaired renal function may result from reduced ACE in vascular tissue. The clinical significance of glomerular filling pressure, systemic hypotension these differences is disputed. In the Heart Out- or glomerulonephritis, and plasma crearinine should comes Prevention Evaluation (HOPE) Study of 9297 be checked before and during treatment. Hypo- patients, ramipril reduced, by 20-30%, the rates of natraemia may develop, especially where a diuretic death, myocardial infarction, and stroke in a broad is also given; clinically significant hyperkalaemia range of high-risk patients who were not known to (see effect on aldosterone above) is confined to have a low ejection fraction or heart failure.12 The patients with impaired renal function. ACE inhi- authors considered that the results could not be bitors are fetotoxic in the second trimester, causing explained entirely by blood pressure reduction. reduced renal perfusion, hypotension, oligohy- dramnios and fetal death. Neutropenia and other Losartan was the first AT1 receptor antagonist blood dyscrasias occur. Other reported reactions licensed in the UK. It is a competitive blocker with a include rashes, taste disturbance (dysguesia), noncompetitive active metabolite. The drug has a musculoskeletal pain, proteinuria, liver injury and short t// (2 h) but the metabolite is much longer pancreatitis. lived (t1/2 10 h) permitting once daily dosing. Other AT1 receptor blockers are contraindicated in AT1 receptor antagonists in clinical use include pregnancy, but avoid most other complications — candesartan, eprosartan, irbesartan, telmisartan and particularly the cough and angioedema. They are valsartan. Some of these appear more effective than the only antihypertensive drugs for which there is losartan, which is generally used in combination no 'typical' side effect. with hydrochlorothiazide. In a landmark study this combination was 25% more effective than atenolol Interactions. Hyperkalaemia can result from use plus hydrochlorothiazide in preventing stroke.13 with potassium-sparing diuretics. Renal clearance This class of drug is very well tolerated; in clinical of lithium is reduced and toxic concentrations of trials their side effect profiles are indistinguishable or plasma lithium may follow. Severe hypotension can even better than placebo. Unlike the ACE inhibitors occur with diuretics (above), and with chlorpro- they do not produce cough, and are a valuable mazine, and possibly other phenothiazines. alternative for the 10-15% of patients who dis- continue their ACE inhibitor for this reason. AT1 Individual drugs receptor antagonists are used to treat hypertension but any role in cardiac failure or after myocardial Captopril (Capoten) has a tl/2 of 2 h and is partly infarction (as have ACE inhibitors) remains to be metabolised and partly excreted unchanged; adverse established. effects are more common if renal function is The cautions listed for the use of ACE inhibitors impaired; it is given twice or thrice daily. Captopril (above) apply also to AT1 receptor blockers. is the shortest-acting of the ACE inhibitors, one of 12 Yusuf S, Sleight P, Pogue J et al 2000 Effects of an the few where the oral drug is itself active, not angiotensin-converting-enzyme inhibitor, ramipril, on requiring de-esterification after absorption. cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New Enalapril (Innovace) is a prodrug (tl/2 35 h) that is England Journal of Medicine 342:145-53. 13 Dahlof B et al 2002 Cardiovascular morbidity and converted to the active enalaprilat (tl/2 10 h). Effec- mortality in the Losartan Intervention for Endpoint tive 24-h control of blood pressure may require reduction in hypertension study (LIFE): a randomised trial twice daily administration. against atenolol. Lancet 359: 995-1010. 469
  10. 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 Other vasodilators Sodium nitroprusside is used in hypertensive emergencies, refractory heart failure and for con- Several older drugs are powerfully vasodilating, trolled hypotension in surgery. An infusion14 may but precluded from routine use in hypertension by begin at 0.3-1.0 micrograms/kg/min and control of their adverse effects. Minoxidil and nitroprusside blood pressure is likely to be established at 0.5-6.0 still have special indications. micrograms/kg/min; close monitoring of blood pressure is mandatory usually with direct arterial Minoxidil is a vasodilator selective for arterioles monitoring of blood pressure; rate changes of infu- rather than for veins, similar to diazoxide and sion may be made every 5-10 min. hydralazine. Like the former, it acts through its sulphate metabolite as an ATP-dependent potassium Diazoxide is chemically a thiazide but has no channel opener. It is highly effective in severe appreciable diuretic effect; indeed, like other potent hypertension, but causes increased cardiac output, arterial vasodilators it causes salt and water retention. tachycardia, fluid retention and hypertrichosis. The It reduces peripheral arteriolar resistance through hair growth is generalised and although a cosmetic activation of the ATP-dependent potassium channel problem in women, it has been exploited as a (c.f. nicorandil and minoxidil), with little effect on topical solution for the treatment of baldness in veins. Thet1/2is 36 h. men. The principal use of diazoxide has been in the emergency treatment of severe hypertension. The Sodium nitroprusside is a highly effective anti- maximum effect after an i.v. bolus occurs within hypertensive agent when given i.v. Its effect is 5 min and lasts for at least 4 h. The dangers from almost immediate and lasts for 1-5 min. Therefore it excessive hypotension are now recognised to out- must be given by a precisely controllable infusion. weigh the benefit, and emergency use of diazoxide It dilates both arterioles and veins, which would is almost obsolete. cause collapse if the patient stands up, e.g. for toilet Because it stimulates the same potassium purposes. There is a compensatory sympathetic channel in the pancreatic islet cells as is blocked by discharge with tachycardia and tachyphylaxis to sulphonylureas, diazoxide causes hyperglycaemia. the drug. The action of nitroprusside is terminated This effect renders diazoxide unsuitable for chronic by metabolism within erythrocytes. Specifically, use in hypertension, but a useful drug to treat electron transfer from haemoglobin iron to nitro- insulinoma. Long-term oral administration causes prusside yields methaemoglobin and an unstable the same problem of hair growth seen with nitroprusside radical. This breaks down, liberating minoxidil (see below and 'alopecia'). cyanide radicals capable of inhibiting cytochrome oxidase (and thus cellular respiration). Fortunately Hydralazine now has little use long-term for hyper- most of the cyanide remains bound within erythro- tension, but it may have a role as a vasodilator (plus cytes but a small fraction does diffuse out into the nitrates) in heart failure. It reduces peripheral plasma and is converted to thiocyanate. Hence, resistance by directly relaxing arterioles, with negli- monitoring plasma thiocyanate concentrations during gible effect on veins. In common with all potent prolonged (days) nitroprusside infusion is a useful arterial vasodilators, its hypotensive action is marker of impending systemic cyanide toxicity. accompanied by a compensatory baroreceptor- Poisoning may be obvious as a progressive metabolic mediated sympathetic discharge, causing tachycardia acidosis or manifest as delirium or psychotic symp- and increased cardiac output. There is also renin toms. Toxic subjects are also reputed to emit the release with secondary salt and water retention, characteristic bitter almond smell of hydrogen cyanide. Clearly nitroprusside infusion should not 14 Light causes sodium nitroprusside in solution to be undertaken without meticulous regard for the decompose; hence solutions should be made fresh and manufacturer's recommendations and precautions; immediately protected by an opaque cover, e.g. metal foil. outside specialist units it may be safer overall to The fresh solution has a faint brown colour; if the colour is choose another more familiar drug. strong it should be discarded. 470
  11. VASODILATORS 23 which antagonises the hypotensive effect (so-called especially into and around arteries and veins to 'tolerance' on long-term use). Therefore, hydralazine, relieve spasm during vascular surgery and when when used, is combined with a (3-blocker and setting up i.v. infusions. It is also used to treat male diuretic. Thet1/2is 1 h. erectile dysfunction (see p. 546). In most hypertensive emergencies (except for dissecting aneurysm) hydralazine 5-20 mg i.v. may Alprostadil is a stable form of prostaglandin Er It be given over 20 min, when the maximum effect is effective in psychogenic and neuropathic penile will be seen in 10-80 min; it can be repeated accord- erectile dysfunction by direct intracorporeal injection ing to need and the patient transferred to oral (see p. 545) and is used i.v. to maintain patency of therapy within 1-2 days. the ductus arteriosus in the newborn with congenital Prolonged use of hydralazine at doses above heart disease. 50mg/day may cause a systemic lupus-like syn- drome, more commonly in white than in black Vasodilators in heart failure (see p. 517) races, and in those with the slow acetylator phenotype. Vasodilators in peripheral vascular disease Three other vasodilators find a role outside hypertension. The aim has been to produce peripheral arteriolar vasodilatation without a concurrent significant drop Nicorandil is an effective vasodilator through two in blood pressure, so that an increased blood flow actions. It acts as a nitrate by activating cyclic GMP in the limbs will result. Drugs are naturally more (see above) but also opens the ATP-dependent useful in patients in whom the decreased flow of potassium channel to allow potassium efflux and blood is due to spasm of the vessels (Raynaud's hyperpolarisation of the membrane which reduces phenomenon) than where it is due to organic calcium ion entry and induces muscular relaxation. obstructive changes that may make dilatation in It is indicated for use in angina, where it has similar response to drugs impossible (arteriosclerosis, inter- efficacy to -blockade, nitrates or calcium channel mittent claudication, Buerger's disease). blockade. It is administered orally and is an alter- Vasodilators such as naftidrofun/l (Praxilene) and native to nitrates when tolerance to these is a problem, oxpentifylline (pentoxifylline) (Trental) increase blood or to the other classes when these are contraindicated flow to skin rather than muscle; they have also been by asthma or cardiac failure. Adverse effects to successfully used in the treatment of venous leg ulcers nicorandil are similar to those of nitrates, with (varicose and traumatic). headache reported in 35% of patients. It is the only antianginal drug for which at least one trial has Intermittent claudication. Patients should 'stop demonstrated a beneficial influence upon outcome.15 smoking and keep walking' — i.e. take frequent exercise within their capacity. Other risk factors Papaverine is an alkaloid present in opium, but is should be treated vigorously, especially hyper- structurally unrelated to morphine. It inhibits phos- lipidaemia, and patients should also receive aspirin phodiesterase and its principal action is to relax 75-150 mg daily as an antiplatelet agent. Most smooth muscle throughout the body, especially in patients with intermittent claudication succumb to the vascular system. It is occasionally injected into ischaemic or cerebrovascular disease, and therefore an area where local vasodilatation is desired, a major objective of treatment should be prevention of such outcomes. Naftidrofuryl or oxpentifylline 15 The Impact Of Nicorandil in Angina (IONA) study was a (pentoxifylline) may be tried but should be with- double-blind, randomized, placebo-controlled trial drawn if there is no benefit in a few weeks. conducted in the United Kingdom in which high-risk Naftidrofuryl has several actions. It is classed as a patients with stable angina were assigned placebo or metabolic enhancer since it activates the enzyme nicorandil 10-20 mg. Over a mean follow-up of 1.6 years, significantly more placebo-treated patients suffered an acute succinate dehydrogenase, increasing the supply of coronary syndrome or coronary death (15.5% vs 13.1%, ATP and reducing lactate levels in muscle. It also P = 0.01). blocks 5HT2-receptors and inhibits serotonin- 471
  12. 23 ARTERIAL 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 induced vasoconstriction and platelet aggregation. ceptor in competition with adrenaline (epinephrine) Oxpentifylline is thought to improve oxygen supply and noradrenaline (norepinephrine) (and other to ischaemic tissue by improving erythrocyte sympathomimetic amines) whether released in the deformability and reducing blood viscosity, in part body or injected; circulating adrenaline and nor- by reducing plasma fibrinogen. Neither of these adrenaline are antagonised more readily than are drugs is a direct vasodilator, as is the third drug used the effects of adrenergic nerve stimulation. for intermittent claudication, inositol nicotinate. The There are two principal classes of adrenoceptor, evidence in favour of any benefit is stronger for the a and (3: for details of receptor effects see Table 22.1. first two, for which meta-analyses provide some evidence of efficacy (increase in walking distance). a-ADRENOCEPTOR BLOCKING Most vasodilators act selectively on healthy blood DRUGS vessels, causing a 'steal' of blood from athero- matous vessels. There are two main subtypes of -adrenoceptor, Night cramps occur in the disease and quinine has defined by their relative affinity for the drugs which a somewhat controversial reputation in their pre- occupy them: vention. Nevertheless, meta-analysis of six double- • Classic 1-adrenoceptors, on the effector organ blind trials of nocturnal cramps (not necessarily (postsynaptic), mediate vasoconstriction associated with peripheral vascular disease) shows • 2-adrenoceptors are present both on some that the number, but not severity or duration of effector tissues (postsynaptic), and on the nerve episodes, is reduced by a night-time dose.16 The ending (presynaptic). The presynaptic receptors benefit may not be seen for 4 weeks (see ticlopidine). (or autoreceptors) mediate a reduction of release Raynaud's phenomenon may be helped by nife- of chemotransmitter (noradrenaline), i.e. they dipine, reserpine (an a-adrenoceptor blocker, in low provide a negative feedback control of doses) and also by topical glyceryl trinitrate; indeed transmitter release. They are also present in the any vasodilator is worth trying in resistant cases; CNS. enalapril (ACE inhibitor) seems to lack efficacy. In The first generation of a-adrenoceptor blockers severe cases, especially patients with ulceration, were nonselective, blocking both 1- and a2-receptors. intermittent infusions over several hours of the When subjects taking such a drug rise from supine endogenous vasodilator, prostacyclin (epoprostenol), to erect posture or take exercise, the sympathetic achieves long-lasting improvements in symptoms. system is physiologically activated (via baroreceptors). p-adrenoceptor blockers exacerbate peripheral The normal vasoconstrictive (ttj) effect (to maintain vascular disease and Raynaud's phenomenon by blood pressure) is blocked by the drug and the reducing perfusion of a circulation that is already failure of this response causes the sympathetic compromised. Switching to a -selective blocker is system to be further activated and to release more unhelpful, since the adverse effect is due to reduced and more transmitter. This increase in transmitter cardiac output rather than unopposed cc-receptor would normally be reduced by negative feedback induced vasoconstriction. via the 2-autoreceptors; but these are blocked too. The -adrenoceptors however are not blocked Adrenoceptor blocking and the excess transmitter released at adrenergic endings is free to act on them, causing a tachycardia drugs that may be unpleasant. It is for this reason that nonselective -adrenoceptor blockers are not used Adrenoceptor blocking drugs occupy the adreno- alone in hypertension. An a-adrenoceptor blocker that spares the 2- 16 Man-Son-Hing M, Wells G 1995 Meta-analysis of efficacy receptor so that negative feedback inhibition of of quinine for treatment of nocturnal cramps in elderly noradrenaline release is maintained, is more useful people. British Medical Journal 310:13-17. in hypertension (less tachycardia and postural and 472
  13. ADRENOCEPTOR BLOCKING DRUGS 23 exercise hypotension); prazosin is such a drug Indoramin is an older -blocker, which is a less (below). useful antihypertensive, but still used for prostatic For use in prostatic hypertrophy, see page 548. symptoms.17 It is taken twice or thrice daily. Phentolamine is a nonselective a-adrenoceptor blocker. It is given i.v. for brief effect in adrenergic Hypertension hypertensive crises, e.g. phaeochromocytoma or the — essential: doxazosin, labetalol — phaeochromocytoma: phenoxybenzamine; MAOI-sympathomimetic interaction. In addition to phentolamine (for crises) a-receptor block it has direct vasodilator and cardiac Peripheral vascular disease inotropic actions. The dose for hypertensive crisis is Benign prostatic hypertrophy (to relax capsular 2-5 mg i.v. repeated as necessary (in minutes to smooth muscle that may contribute to urinary hours). The use of phentolamine as a diagnostic test obstruction) for phaeochromocytoma is appropriate only when biochemical measurements are impracticable, since it is less reliable. Adverse effects. The converse of the benefit in the treatment of prostatism is the adverse effect of Phenoxybenzamine is an irreversible nonselective micturition incontinence in women. Other adverse a-adrenoceptor blocking drug whose effects may effects of a-adrenoceptor blockade are postural last 2 days or longer. The daily dose must therefore hypotension, nasal stuffiness, red sclerae and, in the be increased slowly. It is impossible to reverse the male, failure of ejaculation. Effects peculiar to each circulatory effects by secreting noradrenaline (nor- drug are mentioned below. epinephrine) or other sympathomimetic drugs because its effects are insurmountable. This makes it the preferred -blocker for treating phaeochro- Notes on individual drugs mocytoma (see p. 495). It is wise to observe the effects of a single test Prazosin blocks postsynaptic -receptors but not dose closely before starting regular administration. presynaptic 2-autoreceptors. It has a curious Indigestion and nausea can occur with oral adverse 'first-dose effect'; within 2h of the first therapy, which is best given with food. (rarely after another) dose there may be a brisk hypotension sufficient to cause loss of conscious- Thymoxamine (moxisylyte) is a nonselective a- ness. Hence the first dose should be small (0.5 mg) blocker for which Raynaud's phenomenon is the and given before going to bed. This side effect only extant indication. together with a rather short duration of action (tl/2 Labetalol has both a- and -receptor blocking 3 h) has meant that newer longer-acting drugs have largely replaced it. actions that are due to different isomers (see under -adrenoceptor block, below). Its parenteral prep- aration is valuable in the treatment of hypertension Doxazosin (t l / 2 8h) was the first a-adrenoceptor emergencies (see p. 491). blocker suitable for once daily prescribing. The first dose effect is also much less marked, although it is Ergot alkaloids. The naturally occurring alkaloids still advisable to start patients at a lower dose than with effective a-adrenoceptor blocking actions are is intended for maintenance. It is convenient, for also powerful -adrenoceptor agonists, i.e. they are instance, to prescribe 1 mg daily, increasing after 1 week to twice this dose without repeating the 17 blood pressure measurement at this stage. A slow- It can be the reflex sympathetic activation, as much as release formulation, Cardura XL, can be started at hypotension itself, which causes problems. Many cardiologists have had their efforts at controlling angina in the maintenance dose of 4 mg daily. elderly patients sabotaged when the patient visits a urologist for his prostatic symptoms, and is treated with one of the Other a blockers are alfuzosin and terazosin. newer, more powerful -blockers. 473
  14. 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 partial agonists; the latter action obscures the constrictor) effects are no longer partially opposed vasodilatation that is characteristic of a-adrenoceptor by 2-adrenoceptor (dilator) effects; peripheral flow is blocking drugs. reduced. With chronic use peripheral resistance returns to about pretreatment levels or a little below, Chlorpromazine has many actions of which a- varying according to presence or absence of ISA. adrenoceptor block is a minor one, but sufficient to But peripheral blood flow remains reduced. The cause hypotension, and to be clinically useful in cold extremities that accompany chronic therapy amphetamine overdose. are probably due chiefly to reduced cardiac output with reduced peripheral blood flow, rather than to the blocking of peripheral ( 2) dilator receptors. P-ADRENOCEPTOR BLOCKING Hepatic blood flow may be reduced by as much as DRUGS 30% which prolongs the t1/2 of the lipid-soluble members whose metabolism is dependent on hepatic Actions flow (i.e. whose first-pass metabolism is extensive These drugs selectively block the -adrenoceptor and actually dependent on the rate of delivery of effects of noradrenaline (norepinephrine) and adre- blood to the liver), including propranolol itself; also naline (epinephrine). They may be pure antagonists lignocaine (lidocaine), which is liable to be used or may have some agonist activity in addition concomitantly for cardiac arrhythmias. (when they are described as partial agonists). Intrinsic heart rate. Sympathetic activity (through Effects Pj-adrenoceptors) accelerates, and parasympathetic activity (through muscarinic M2-receptors) slows Within hours of starting treatment with a -blocker, the heart. If the sympathetic and the parasympathetic blood pressure starts to fall. The mechanism(s) remain drives to the heart are simultaneously and ade- uncertain, and the consistency of antihypertensive quately blocked by a -adrenoceptor blocker plus response in many different types of hypertension atropine, the heart will beat at its 'intrinsic' rate. may reflect a contribution from a variety of mech- The intrinsic rate at rest is usually about 100/min, anisms, -blockers are most effective in patients as opposed to the usual rate of 80/min, i.e. normally who respond also to ACE inhibitors; blockade of there is parasympathetic vagal dominance, which renin secretion is likely therefore to be the main decreases with age. cause of blood pressure reduction. An additional The cardiovascular effects of -adrenoceptor block contributor may be the 2-3-fold increase in natriuretic depend on the amount of sympathetic tone present. peptide secretion caused by -blockade. The chief cardiac effects result from reduction of Most of the blood pressure effect occurs quickly sympathetic drive: (hours, days) but there is often a modest further decrease over several weeks. • Reduced automaticity (heart rate) A substantial advantage of -blockade in • Reduced myocardial contractility (rate of rise of hypertension is that physiological stresses such as pressure in the ventricle) exercise, upright posture and high environmental • Reduced renin secretion from the temperature are not accompanied by hypotension, juxtaglomerular apparatus in the renal cortex. as they are with agents that interfere with a- With reduced rate the cardiac output/min is adrenoceptor-mediated homeostatic mechanisms. reduced and the overall cardiac oxygen consump- With -blockade these necessary adaptive -receptor tion falls. The results are more evident on the constrictor mechanisms remain intact. response to exercise than at rest. With acute admin- At first sight the cardiac effects might seem likely istration of a pure -adrenoceptor blocker (i.e. one to be disadvantageous rather than advantageous, without any instrinsic sympathomimetic activity, and indeed maximum exercise capacity is reduced. ISA), peripheral vascular resistance tends to rise. This But the heart has substantial functional reserves so is probably a reflex response to the reduced cardiac that use may be made of the desired properties in output, but also because the -adrenoceptor (vaso- the diseases listed below, e.g. angina, without 474
  15. ADRENOCEPTOR BLOCKING DRUGS 23 inducing heart failure. Indeed, -blockade is now 1blockers are sufficiently selective to be safely becoming routine practice in patients with established recommended in asthma. Bisoprolol and nebivolol mild-to-moderate heart failure. But heart failure due may be exceptions that can be tried at low doses in to the drug does occur in patients with seriously patients with mild asthma and a strong indication diminished cardiac reserve. for -blockade. There are unlikely ever to be Effect on plasma potassium concentration, see satisfactory safety data to support such use. The page 517. main practical use of 1-selective blockade is in diabetics where 2-receptors mediate both the symptoms of hypoglycaemia and the counter- -Adrenoceptor selectivity regulatory metabolic responses that reverse the Some -adrenoceptor blockers have higher affinity hypoglycaemia. for cardiac 1-receptors than for cardiac and per- Some -blockers (antagonists) also have agonist ipheral 2-receptors (see Table 23.1). The ratio of the action or ISA, i.e. they are partial agonists. These amount of drug required to block the two receptor agents cause less fall in resting heart rate than do subtypes is a measure of the selectivity of the drug. the pure antagonists and as a result may be less (See the note to Table 22.1, p. 449, regarding use of effective in severe angina pectoris in which reduc- the terms 2 selective and cardioselective.) The question tion of heart rate is particularly important. There is is whether the differences between selective and also less fall in cardiac output and possibly fewer nonselective -blockers constitute clinical advan- patients experience unpleasantly cold extremities. tages. In theory 1-blockers are less likely to cause Intermittent claudication, however, may be worsened bronchoconstriction, but in practice few available by -blockade whether or not there is partial agonist TABLE 23. 1 -adrenoceptor blocking drugs: properties at therapeutic doses Drug Partial agonist effect Membrane stabilising effect (intrinsic sympathomimetic effect) (quinidine-like effect) Division 1: nonselective ( 1 + 2) blockade Group 1 oxprenolol + + Group II propranolol - + Group III pindolol + Group IV sotalol timolol - nadolol Division II: ( 1('cardio')' -selective blockade2 Group 1 acebutolol + + Group III esmolol + + Group IV atenolol bisoprolol - metoprolol nebivolol betaxolol celiprolol3 Division III: nonselective -blockade + , -blockade Group II carvedilol - + Group IV labetalol3 1 See Table 22.1, page 449 regarding use of the term cardioselective. Note: hybrid agents having p-receptor block plus vasodilatation unrelated to adrenoceptor have been developed, e.g. nebivolol releases nitric oxide. 2 1selective drugs are considered to be up to 300 times (nebivolol) as effective against 1receptors than 2-receptors.What selectivity really means, however, is that 300 times more of the blocker is required to achieve the same blockade of the 2-receptor as of the 1 receptor. Therefore, as the dose (concentration at receptors) rises the benefit of selectivity is gradually lost. 3 Celiprolol and labetalol both have partial 2-selective agonist activity. 475
  16. 23 ARTERIAL 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 , M effect. Both classes of drug can precipitate heart concentrations of drugs subject to extensive hepatic failure and indeed no important difference is to be first-pass metabolism vary greatly between subjects expected since patients with heart failure already (up to 20-fold) because the process itself is dependent have high sympathetic drive (but note that (3-blockade on two highly variable factors: speed of absorption can be used to treat cardiac failure, p. 477, 517). and hepatic blood flow, with latter being the rate- Abrupt withdrawal may be less likely to lead to a limiting factor. rebound effect if there is some partial agonist action, Lipid-soluble agents readily cross cell mem- since there may be less up-regulation of receptors, branes and so have a high apparent volume of such as occurs with prolonged receptor block. distribution. They also readily enter the central Some -blockers have membrane stabilising nervous system, e.g. propranolol reaches concen- (quinidine-like or local anaesthetic) effect. This pro- trations in the brain 20 times those of the water- perty is clinically insignificant except that agents soluble atenolol. having this effect will anaesthetise the eye (undesir- able) if applied topically for glaucoma (timolol is Water-soluble agents show more predictable plasma used in the eye and does not have this action), and concentrations because they are less subject to liver in overdose. metabolism, being excreted unchanged by the The ankle jerk relaxation time is prolonged by 2- kidney; thus their half-lives are greatly prolonged adrenoceptor block, which may be misleading if the in renal failure, e.g. atenolol tl/2 is increased from reflex is being relied on in diagnosis and manage- 7 to 24 h. Patients with renal disease are best not ment of hypothyroidism. given drugs (of any kind) having a long t1/2 and an action terminated by renal elimination. Water-soluble agents are less widely distributed and may have a Pharmacokinetics lower incidence of effects attributed to penetration The plasma concentration of a -adrenoceptor of the central nervous system, e.g. nightmares. blocker may have a complex relationship with its • The most lipid-soluble agents are propranolol, effect, for several reasons. First-order kinetics usually metoprolol, oxprenolol, labetalol apply to elimination of drug from plasma, but the • The least lipid-soluble (water-soluble) agents are decline in receptor block is zero-order. The practical atenolol, sotalol, nadolol application is important: within 4 h of giving pro- • Others are intermediate. pranolol 20 mg i.v. the plasma concentration falls by 50%, but the receptor block (as measured by exercise- induced tachycardia) falls by only 35%. The relation- Classification of -adrenoceptor blocking ship between the concentration of the parent drug drugs in plasma and its effect is further obscured if pharma- • Pharmacokinetic: lipid-soluble, water-soluble, see cologically active metabolites are also present. above. Additionally, for some of the lipid-soluble -blockers, • Pharmacodynamic (Table 23.1). The associated especially timolol, plasma t1/2 may not reflect the properties (partial agonist action and membrane duration of [3-blockade since the drug remains bound stabilising action) have only minor clinical to the tissues near the receptor when the plasma importance with current drugs at doses concentration is negligible. ordinarily used and may be insignificant in most Most -adrenoceptor blockers can be given orally cases. But it is desirable that they be known, for once daily in either ordinary or sustained-release they can sometimes matter and they may formulations because the t1/2 of pharmacodynamic foreshadow future developments. effect exceeds the elimination t1/2 of the parent sub- stance in the blood. -adrenoceptor blockers18 not listed in Table 23.1 include: Lipid-soluble agents are extensively metabolised (hydroxylated, conjugated) to water-soluble sub- 18 stances that can be eliminated by the kidney. Plasma More than 40 are available worldwide. 476
  17. ADRENOCEPTOR BLOCKING DRUGS 23 • nonselective carteolol, bufuralol hypertrophic subaortic stenosis (angina); some • -receptor selective: betaxolol, esmolol (ultra- cases of mitral valve disease. short acting: minutes) Hepatic portal hypertension and oesophageal var- • - and a-receptor block: bucindolol. iceal bleeding: reduction of portal pressure (see p. 656). Cardiac failure (See also chapter 25). There is now Uses of -adrenoceptor blocking drugs clear evidence from prospective trials that blockade is beneficial in terms of mortality for patients with Cardiovascular uses Angina pectoris ( -blockade all grades of moderate heart failure. Data support reduces cardiac work and oxygen consumption). the use of both nonselective (carvedilol, a-blocker Hypertension -blockade reduces renin secretion as well) and 1-selective (metoprolol and bisoprolol) and cardiac output): there is little interference with agents. The survival benefit exceeds that provided homeostatic reflexes. by ACE inhibitors over placebo. The negative Cardiac tachyarrhythmias: -blockade reduces drive inotropic effects can still be significant, so the to cardiac pacemakers: subsidiary properties (see starting dose is low (e.g. bisoprolol 1.25 mg p.o. or Table 24.1) may also be relevant. carvedilol 3.625 mg b.d.) and may be tolerated only Myocardial infarction and -adrenoceptor blockers. with additional anti-failure therapy e.g. diuretic. There are two modes of use that reduce acute mor- tality and prevent recurrence: the so-called 'cardio- Endocrine uses Hyperthyroidism: -blockade reduces protective' effect. unpleasant symptoms of sympathetic overactivity; there may also be an effect on metabolism of • Early use within 6 hours (or at most 12 h) of thyroxine (peripheral deiodination from T4 to T3. A onset (i.v. for 24 h then oral for 3-4 weeks). nonselective agent (propranolol) is preferred to Benefit has been demonstrated only for counteract both the cardiac ( 1 and 2) effects, and atenolol. Cardiac work is reduced, resulting in tremor ( 2). a reduction in infarct size by up to 25% and Phaeochromocytoma: blockade of -agonist effects protection against cardiac rupture. of circulating catecholamines always in combination Surprisingly, tachyarrhythmias are not less with adequate -adrenoceptor block. Only small frequent — perhaps because the cardiac 2- doses of a -blocker are required. receptor is not blocked by atenolol. Maximum Other uses benefit is in the first 24-36 h but mortality remains lower for up to one year. • Central nervous system Contraindications to early use include Anxiety with somatic symptoms (nonselective bradycardia (< 55/min), hypotension (systolic -blockade may be more effective than < 90 mmHg) and left ventricular failure. A 1-selective). patient already taking a -blocker may be given Migraine prophylaxis. additional doses. Essential tremor, some cases. • Late use for secondary prevention of another Alcohol and opioid acute withdrawal symptoms. myocardial infarction. The drug is started • Eyes between 4 days and 4 weeks after the onset of Glaucoma: (carteolol, betaxolol, levobunolol and the infarct and is continued for at least 2 years. timolol eye drops) act by altering production and • Choice of drug. The agent should be a pure outflow of aqueous humour. antagonist, i.e. without ISA. Aortic dissection and after subarachnoid haemorrhage: Adverse reactions due to -adrenoceptor by reducing force and speed of systolic ejection (contractility) and blood pressure. blockade Obstruction of ventricular outflow where sympathetic Bronchoconstriction ( 2-receptor) occurs as expected, activity occurs in the presence of anatomical abnor- especially in patients with asthma (in whom even malities, e.g. Fallet's tetralogy (cyanotic attacks): eye drops can be fatal).19 In elderly chronic bronchitics 477
  18. 23 ARTERIAL 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 may be gradually increasing broncho- delayed. But since -adrenoceptors are not blocked, constriction over weeks (even with eye drops). Plainly hypertension (which may be severe) can occur as risk is greater with nonselective agents, but 1- the sympathetic system discharges in an 'attempt' receptor selective members are not (1-selective and to reverse the hypoglycaemia. In addition, the may precipitate asthma. symptoms of hypoglycaemia, in so far as they are Cardiac failure may arise if cardiac output is mediated by the sympathetic (anxiety, palpitations), dependent on high sympathetic drive (but -blockade will not occur (though cholinergic sweating will) can be introduced at very low dose to treat cardiac and the patient may miss the warning symptoms of failure (above). The degree of heart block may be hypoglycaemia and slip into coma. 1-selective made dangerously worse. drugs are preferred in diabetes. Incapacity for vigorous exercise due to failure of the Plasma lipoproteins: HDL-cholesterol falls and cardiovascular system to respond to sympathetic triglycerides rise during chronic -blockade with drive. nonselective agents, 1-selective agents have much Hypotension when the drug is given after myo- less impact overall. Patients with hyperlipidaemia cardial infarction. needing a -blocker should generally receive a 1- Hypertension may occur whenever blockade of selective one. -receptors allows pre-existing -effects to be un- Sexual function: interference is unusual and opposed, e.g. phaeochromocytoma. generally not supported in placebo-controlled trials. Reduced peripheral blood flow, especially with non- Abrupt withdrawal of therapy can be dangerous selective members, leading to cold extremities which, in angina pectoris and after myocardial infarction rarely, can be severe enough to cause necrosis; inter- and withdrawal should be gradual, e.g. reduce to a mittent claudication may be worsened. low dose and continue this for a few days. The Reduced blood flow to liver and kidneys, reducing existence and cause of a -blocker withdrawal metabolism and biliary elimination of drugs, is liable phenomenon is debated, but probably occurs due to be important if there is hepatic or renal disease. to up-regulation of 2-receptors. It is particularly Hypoglycaemia, especially with nonselective mem- inadvisable to initiate an -blocker at the same time bers, which block 2-receptors, and especially in as withdrawing a -blocker in patients with diabetes and after substantial exercise, due to impair- ischaemic heart disease, since the -blocker causes ment of the normal sympathetic-mediated homeo- reflex activation of the sympathetic system. The static mechanism for maintaining the blood glucose, -blocker withdrawal phenomenon appears to be i.e. recovery from iatrogenic hypoglycaemia is least common with partial agonists and most com- mon with 1selective antagonists. Rebound hyper- 19 tension is insignificant. A 36-year-old patient with asthma collected from a pharmacy, chlorphenamine for herself and oxprenolol for a friend. She took a tablet of oxprenolol by mistake. Wheezing began in one hour and worsened rapidly; she experienced a Adverse reactions not certainly due to convulsion, respiratory arrest and ventricular fibrillation. (3-adrenoceptor blockade She was treated with positive-pressure ventilation (for 11 h) and i.v. salbutamol, aminophylline and hydrocortisone. She These include loss of general wellbeing, tired legs, survived (Williams I P et al 1980 Thorax 35:160). There is a fatigue, depression, sleep disturbances including logical — or rather pharmacological — link between the use of insomnia, dreaming, feelings of weakness, gut upsets, timolol as eye drops and the risk of asthma. For local administration, a drug needs high potency, meaning that half rashes. the maximal response is achieved with a physically small Oculomucocutaneous syndrome occurred with (and therefore locally administrable) amount of drug. The chronic use of practolol (now obsolete) and even principal determinant of potency of a receptor antagonist is occasionally after cessation of use.20 Other members its affinity for the receptor, which in turn reflects how long either do not cause it, or so rarely do so that they are each molecule remains bound to the receptor — technically, the dissociation rate constant. This is why one drop of under suspicion only and, properly prescribed, the timolol down the lacrimal duct (of the wrong patient) can benefits of their use far outweigh such a very low kill! risk. The mechanism of the syndrome is uncertain. 478
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