Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 25A) pptx

23 Arterial hypertension, angina pectoris, myocardial infarction SYNOPSIS 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 II- receptor antagonists Adrenoceptor blocking drugs, and ( Peripheral sympathetic nerve terminal Autonomic ganglion-blocking drugs Central nervous system Treatment of angina pectoris • Acute coronary syndromes and myocardial infarction • Arterial hypertension • Sexual function and cardiovascular drugs • Phaeochromocytoma Hypertension: how drugs act Consider the following relationship: Blood pressure = cardiac output x peripheral resistance Therefore drugs can lower blood pressure by: • Dilatation of arteriolar resistance vessels. Dilatation can be achieved through direct relaxation of vascular smooth muscle cells, by stimulation of nitric oxide (NO) production, or by blocking (suppressing) endogenous vasconstrictors, noradrenaline (norepinephrine) and angiotensin. • Dilatation of venous capacitance vessels; reduced venous return to the heart (preload) leads to reduced cardiac output, especially in the upright position • Reduction of cardiac contractility and heart rate. • Depletion of body sodium. This reduces plasma volume (transiently), and reduces arteriolar response to noradrenaline (norepinephrine) Modern antihypertensive drugs lower blood pressure with minimal interference with homeo- static control, i.e. change in posture, exercise. 461 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 Angina pectoris: how drugs act Angina can be viewed as a problem of supply and demand. Drugs used in angina pectoris are those that either increase supply of oxygen and nutrients, or reduce the demand for these — or both. Supply can be increased by: cardiac work and myocardial oxygen need by: • dilating coronary arteries • slowing the heart (coronary flow, uniquely, occurs in diastole, which lengthens as heart rate falls). Demand can be reduced by: • reducing afterload, (i.e. peripheral resistance), so reducing the work of the heart in perfusing the tissues • reducing preload, (i.e. venous filling pressure); according to Starling's Law of the heart, workload and therefore oxygen demand varies with stretch of cardiac muscle fibres • slowing the heart. Drugs used in hypertension and angina Two groups of drugs, p-adrenergic blockers and calcium channel blockers, are used in both hyper- tension and angina. Several drugs for hypertension are used also in the treatment of heart failure. DiuretiCS (see also Ch. 26) Diuretics, particularly the thiazides, are useful anti- hypertensives. They cause an initial loss of sodium with a parallel contraction of the blood and extra- cellular fluid volume. The effect may reach 10% of total body sodium but it is not maintained. After several months of treatment, the main blood press- ure lowering effect appears to reflect a reduced responsiveness of resistance vessels to endogenous vasoconstrictors, principally noradrenaline. While this hyposensitivity may be a consequence of the sodium depletion, thiazides are generally more effec- tive antihypertensive agents than loop diuretics, despite causing less salt loss, and evidence suggests an independent action of thiazides on an unidentified ion-channel on vascular smooth muscle cell mem- branes. Maximum effect on blood pressure is delayed for several weeks and other drugs are best added after this time. Adverse metabolic effects of thiazides on serum potassium, blood lipids, glucose tolerance, and uric acid metabolism led to suggestions that they should be replaced by newer agents not having these effects. It is, however, now recognised that unnecessarily high doses of thiazides have been used in the past and that with low doses, e.g. bendro- fluazide (bendroflumethiazide) 1.25-2.5 mg/d or less (or hydrochlorothiazide 12.5-25 mg), thiazides are both effective and well-tolerated. Moreover, they are not only by far the cheapest antihypertensive agents available worldwide but have proved to be the most effective in several outcome trials in preventing the major complications of hypertension, myocardial infarction and stroke. The characteristic 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. Vasodilators ORGANIC NITRATES 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- duced by endothelial cells. Nitrodilators (a generic term for drugs that release or mimic the action of NO) activate the soluble guanylate cyclase in vascular smooth muscle cells and cause an increase in intra- cellular cyclic GMP (guanosine monophosphate) con- 1 Murrell, W 1879 Nitroglycerin as a remedy for angina pectoris. Lancet 1: 80-81. Nitroglycerin was actually first synthesised by Sobrero in 1847 who noted when he applied it to his tongue it caused a severe headache. 462 VASO OILATO RS 23 centrations. This is the second messenger that alters calcium fluxes in the cell, decreases stored calcium, and induces relaxation. The result is a generalised dilatation of venules (capacitance vessels) and to a lesser extent of arterioles (resistance vessels), causing a fall of blood pressure that is postural at first; the larger coronary arteries especially dilate. Whereas some vasodilators can 'steal' blood away from atheromatous arteries, with their fixed stenoses, to other, healthier arteries, nitrates probably have the reverse effect as a result of their supplementing the endogenous NO. Atheroma is associated with impaired endothelial function, resulting in reduced release of NO and, possibly, its accelerated destruction by the oxidised LDL in atheroma (see Ch. 25). The venous dilatation causes a reduction in venous return, a fall in left ventricular filling pressure with reduced stroke volume, but cardiac output (per min) is sustained by the reflex tachycardia induced by the fall in blood pressure. Pharmacokinetics. The nitrates are generally well absorbed across skin, and the mucosal surface of the mouth or gut wall. Nitrates absorbed from the gut, however, are subject to extensive first-pass metabolism in the liver, as is shown by the sub- stantially larger doses required by that route over sublingual application (this also explains why swallowing a sublingual tablet of glyceryl trinitrate terminates its effect). They are first denitrated and then conjugated with glucuronic acid. The t1/2 periods vary (see below) but for glyceryl trinitrate (GTN) it is 1-4: minutes. Tolerance to the characteristic vasodilator headache comes and goes quickly (hours). 2 Ensuring that a continuous steady-state plasma concentration is avoided prevents tolerance. This is easy with occasional use of glyceryl trinitrate, but with nitrates having longer t 1 /2 (see below) and sustained release formulations it is necessary to plan the dosing to allow low plasma concentration for 4-8 h, e.g. over- 2 Explosives factory workers exposed to a nitrate- contaminated environment lost it over a weekend and some chose to maintain their intake by using nitrate impregnated headbands (transdermal absorption) rather than have to accept the headaches and reacquire tolerance so frequently. night; alternatively transdermal patches may be removed for a few hours if tolerance is suspected. Uses. Nitrates are chiefly used to relieve angina pectoris and sometimes left ventricular failure. An excessive fall in blood pressure will reduce coronary flow as well as cause fainting due to reduced cerebral blood flow, and so it is important to avoid accidental overdosing. Patients with angina should be instructed on the signs of overdose — palpitations, dizziness, blurred vision, headache and flushing following by pallor — and what to do about it (below). The discovery that coronary artery occlusion by thrombosis is itself 'stuttering' — developing gradually over hours — and associated with vaso- spasm in other parts of the coronary tree has made the use of isosorbide dinitrate (Isoket) by continuous i.v. infusion adjusted to the degree of pain, a logical, and effective, form of analgesia for unstable angina. Transient relief of pain due to spasm of other smooth muscle (colic), can sometimes be obtained, so that relief of chest pain by nitrates does not prove the diagnosis of angina pectoris. Nitrates are contraindicated in angina due to anaemia. Adverse effects. Collapse due to fall in blood pressure resulting from overdose is the commonest side effect. The patient should remain supine, and the legs should be raised above the head to restore venous return to the heart. Nitrate headache, which may be severe, is prob- ably due to the stretching of pain-sensitive tissues around the meningeal arteries resulting from the increased pulsation that accompanies the local vasodilatation. If headache is severe the dose should be halved. Methaemoglobinaemia occurs with heavy dosage. Interactions. An important footnote to the use of nitrates (and NO-dilators generally) has been the marked potentiation of their vasodilator effects observed in patients taking the phosphodiesterase (PDE) inhibitor sildenafil (Viagra). This agent targets an isoform of PDE (PDE-5) expressed in the blood vessel wall. Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors of PDE-5, even at the doses effective in asthma. A 463 23 ARTERIAL H Y P E R T E N S I O N , A N G I N A PECTORIS, Ml number of pericoital deaths reported in patients taking sildenafil have been attributed to the substantial fall in blood pressure that occurs when used with a nitrate. This is an ironic twist for an agent in first-line use in erectile dysfunction that was originally developed as a drug to treat angina. 3 GLYCERYLTRINITRATE (see also above) Glyceryl trinitrate (1879) (trinitrin, nitroglycerin, GTN) (t 1 /2 3 min) is an oily, nonflammable liquid that explodes on concussion with a force greater than that of gunpowder. Physicians meet it mixed with inert substances and made into a tablet, in which form it is both innocuous and fairly stable. But tablets more than 8 weeks old or exposed to heat or air will have lost potency by evaporation and should be discarded. Patients should also be warned to expect the tablet to cause a burning sensation under the tongue if it is still contains active GTN. An alternative is to use a nitroglycerin spray (see below); formulated as a pressurised liquid GTN has a shelf life of at least 3 years. GTN is the drug of choice in the treatment of an attack of angina pectoris. The tablets should be chewed and dissolved under the tongue, or placed in the buccal sulcus, where absorption is rapid and reliable. Time spent ensuring that patients under- stand the way to take the tablets and that the feeling of fullness in the head is harmless, is time well spent. The action begins in 2 min and lasts up to 30 min. The dose in the standard tablet is 300 micro- grams, and 500 or 600 microgram strengths are also available; patients may use up to 6 mg daily in total but those who require more than 2-3 tablets per week should take a long-acting nitrate preparation. GTN is taken at the onset of pain and as a pro- phylactic immediately before any exertion likely to precipitate the pain. Sustained-release buccal tablets are available (Suscard), 1-5 mg. Absorption from the gastrointestinal tract is good, but there is such extensive hepatic first-pass metabolism that 3 It has been argued that deaths on sildenafil largely reflect the fact that it is used by patients at high cardiovascular risk. But recent postmarketing data shows that death is 50 times more likely after sildenafil taken for erectile failure than alprostadil, the previous first-line agent. Mitka M 2000 Journal of the American Medical Association 283: 590. the sublingual or buccal route is preferred; an oral metered aerosol that is sprayed under the tongue (nitrolingual spray) is an alternative. For prophylaxis, GTN can be given as an oral (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 nocturnal angina. 4 Venepuncture: the ointment can assist difficult venepuncture and a transdermal patch adjacent to an i.v. infusion site can prevent extravasation and phlebitis and prolong infusion survival. Isosorbide dinitrate (Cedocard) (t 1 /2 20 min) is used for prophylaxis of angina pectoris and for congestive heart failure (tabs sublingual, and to swallow). An i.v. formulation 500 micrograms/ml (Isoket) is available for use in left ventricular failure and unstable angina. Isosorbide mononitrate (Elantan) (t 1 /2 4 h) is used for prophylaxis of angina (tabs to swallow). Hepatic first-pass metabolism is much less than for the dinitrate so that systemic bioavailability is more reliable. Pentaerythritol tetranitrate (Peritrate) (t1/ 2 8h) is less efficacious than its metabolite pentaerythritol trinitrate (t1/211 h). CALCIUM CHANNEL BLOCKERS Calcium is involved in the initiation of smooth muscle and cardiac cell contraction and in the pro- pagation of the cardiac impulse. Actions on cardiac pacemaker cells and conducting tissue are described in Chapter 24. Vascular smooth muscle cells. Contraction of these cells requires an influx of calcium across the cell membrane. This occurs through ion channels 4 Useful, but not always safe. Defibrillator paddles and nitrate patches make an explosive combination, and it is not always in the patient's interest to have the patch as unobtrusive as possible (Canadian Medical Association Journal 1993 148: 790). 464 VASODILATORS 23 that are largely specific for calcium and are called 'slow calcium channels' to distinguish them from 'fast' channels that allow the rapid influx and efflux of sodium. Activation of calcium channels by an action po- tential allows calcium to enter the cells. There follows a sequence of events which results in activation of the contractile proteins, myosin and actin, with shortening of the myofibril and contraction of smooth muscle. During relaxation calcium is released from the myofibril and, as it cannot be stored in the cell, it passes out again through the channel. Calcium channel (also called calcium entry) blockers inhibit the passage of calcium through the voltage- dependent L- (for 'long-opening') class membrane channels in cardiac muscle and conducting tissue, and vascular smooth muscle, reduce available intra- cellular calcium and cause the muscle to relax. 5 There are three structurally distinct classes of calcium channel blocker: • Dihydropyridines (the most numerous) • Phenylalkylamines (principally verapamil) • Benzothiazepine (diltiazem). The differences between their clinical effects can be explained in part by their binding to different parts of the L-type calcium channel. All members of the group are vasodilators, and some have negative cardiac inotropic action and negative chronotropic effect via pacemaker cells and depress conducting tissue. The attributes of individual drugs are de- scribed below. The therapeutic benefit of the calcium blockers in hypertension and angina is due mainly to their action as vasodilators. Their action on the heart gives non-dihydropyridines an additional role as Class 4 antiarrhythmics. Pharmacokinetics. Calcium channel blockers in general are well absorbed from the gastrointestinal tract and their systemic bioavailability depends on the extent of first-pass metabolism in the gut wall and liver, which varies between the drugs. All 5 Several calcium-selective channels have been described in different tisues, e.g. the N (present in neuronal tissue) and T (transient, found in brain, neuronal and cardiovascular tissue); the drugs discussed here selectively target the L channel for its cardiovascular importance. undergo metabolism to less active products, pre- dominantly by cytochrome P-450 CYP3A, which is the source of interactions with other drugs by enzyme induction and inhibition. As their action is ter- minated by metabolism, dose adjustments for patients with impaired renal function are therefore either minor or unnecessary. Indications for use • Hypertension: amlodipine, isradipine, nicardipine, nifedipine, verapamil • Angina: amlodipine, diltiazem, nicardipine, nifedipine, verapamil • Cardiac arrhythmia: verapamil • Raynaud's disease: nifedipine • Prevention of ischaemic neurological damage following subarachnoid haemorrhage: nimodipine. Adverse effects. Headache, flushing, dizziness, palpitations and hypotension may occur during the first few hours after dosing, as the plasma concen- tration is increasing, particularly if the initial dose is too high or increased too rapidly. Ankle oedema may also develop. This is probably due to a rise in intracapillary pressure as a result of the selective dilatation by calcium blockers of the precapillary arterioles. Thus the oedema is not a sign of sodium retention. It is not relieved by a diuretic but dis- appears after lying flat, e.g. overnight. In theory the oedema should also be attenuated by combining the calcium blocker with another vasodilator which is more effective (than calcium blockers) at relaxing the postcapillary venules, e.g. a nitrate or an ACE inhibitor. Bradycardia and arrhythmia may occur. Gastrointestinal effects include constipation, nausea and vomiting; palpitation and lethargy may be felt. There has been some concern that the shorter- acting calcium channel blockers may adversely affect the risk of myocardial infarction and cardiac death. The evidence is based on case-control studies which cannot escape the possibility that sicker patients, i.e. with worse hypertension or angina, received calcium channel blockade. The safety and efficacy of the class has been strengthened by the recent findings of two prospective comparisons with other antihypertensives. 6 465 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, M Interactions are quite numerous. The drugs in this group in general are extensively metabolised, and there is risk of decreased effect with enzyme inducers, e.g. rifampicin, and increased effect with enzyme inhibitors, e.g. cimetidine. Conversely, calcium channel blockers decrease the plasma clearance of several other drugs by mechanisms that include delaying their metabolic breakdown. The conse- quence, for example, is that diltiazem and verapamil cause increased exposure to carbamazepine, quinidine, statins, ciclosporin, metoprolol, theophylline and (HIV) protease inhibitors. Verapamil increases plasma concentration of digoxin, possibly by interfering with its biliary excretion. Beta-adreno- ceptor blockers may exacerbate atrioventricular block and cardiac failure. Grapefruit juice raises the plasma concentration of dihydropyridines (except amlodipine) and verapamil. Individual calcium blockers Nifedipine (t l / 2 2h) is the prototype dihydro- pyridine. It selectively dilates arteries with little effect on veins; its negative myocardial inotropic and chronotropic effects are much less than those of verapamil. There are sustained-release formulations of nifedipine that permit once daily dosing with minimal peaks and troughs in plasma concentration so that adverse effects due to rapid fluctuation of concentrations are also lessened. Various methods have been used to prolong, and smooth, drug delivery, and bioequivalence between these formu- lations cannot be assumed; prescribers should specify the brand to be dispensed. The adverse effects of calcium blockers with a short duration of action may include the hazards of activating the sympathetic system each time a dose is taken. The dose range for nifedipine is 30-90 mg daily. In addition to the adverse effects listed above, gum hypertrophy may occur. Nifedipine can be taken 'sublingually', by biting a capsule and squeezing the contents under the tongue. In point of fact, absorption is still largely from the stomach after this 6 Both the NORDIL and INSIGHT trials (Lancet 2000 356: 359-365, 366-372) confirmed that a calcium channel blocker (diltiazem and nifedipine respectively) had the same efficacy as older therapies (diuretics and/or -blockers) in hypertension with no evidence of increased sudden death. manoeuvre; it should not be used in a hypertensive emergency because the blood pressure reduction is unpredictable and sometimes large enough to cause cerebral ischaemia (see p. 492). Amlodipine has a t 1 /2 (40 h) sufficient to permit the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation. Its slow association with L-channels and long duration of action render it unsuitable for emergency reduction of blood pressure where frequent dose adjustment is needed. On the other hand an occasional missed dose is of little consequence. Amlodipine differs from all other dihydropyridines listed in this chapter in being safe to use in patients with cardiac failure (the PRAISE 7 Study). 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 given thrice daily as a conventional tablet or daily as a sustained-release formulation. Because of its negative effects on myocardial conducting and contracting cells it should not be given to patients with bradycardia, second or third degree heart block, or patients with Wolff-Parkinson-White syndrome to relieve atrial flutter or fibrillation. Amiodarone and digoxin increase the AV block. Verapamil increases plasma quinidine concen- tration and this interaction may cause dangerous hypotension. Diltiazem (t l / 2 5 h) is given thrice daily, or once or twice daily if a slow-release formulation is pre- scribed. It causes less myocardial depression and prolongation of AV conduction than does verapamil but should not be used where there is bradycardia, second or third degree heart block or sick sinus syndrome. Isradipine (t 1 /2 8 h) is given once or twice daily (it is similar to nifedipine). Nicardipine (t 1 /2 4 h) is given x 3/d. 7 PRAISE = Prospective Randomised Amlodipine Survival Evaluation (see Packer M et al 1996 The effect of amlodipine on morbidity and mortality in severe chronic heart failure. New England Journal of Medicine 335: 1107-1114). 466 23 Nimodipine has a moderate cerebral vasodilating action. Cerebral ischaemia after subarachnoid haemorrhage may be partly due to vasospasm; clinical trial evidence indicates that nimodipine given after subarachnoid haemorrhage reduces cerebral infarction (incidence and extent). 8 Although the benefit is small, the absence of any more effec- tive alternatives has led to the routine administration of nimodipine (60 mg every 4 hours) to all patients for the first few days following subarachnoid haemorrhage. No benefit has been found in similar trials following other forms of stroke. Other members include felodipine, isradipine, laci- dipine, lercanidipine, nisoldipine. ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND ANGIOTENSIN (AT) II RECEPTOR ANTAGONISTS Renin is an enzyme produced by the kidney in response to a number of factors including adrenergic activity ( 1 -receptor) and sodium depletion. Renin converts a circulating glycoprotein (angiotensinogen) into the biologically inert angiotensin I, which is then changed by angiotensin converting enzyme (ACE or kininase II) into the highly potent vaso- constrictor angiotensin II. ACE is located on the luminal surface of capillary endothelial cells, parti- cularly in the lungs; and there are also renin- angiotensin systems in many organs, e.g. brain, heart, the relevance of which is uncertain. Angiotensin II acts on two G-protein coupled receptors, of which the angiotensin 'AT 1 subtype accounts for all the classic actions of angiotensin. As well as vasoconstriction these include stimulation of aldosterone (the sodium-retaining hormone) production by the adrenal cortex. It is evident that angiotensin II can have an important effect on blood pressure. In addition, it stimulates cardiac and vascular smooth muscle cell growth, contributing probably to the progressive amplification in hyper- tension once the process is initiated. The AT 2 receptor subtype is coupled to inhibition of muscle growth or proliferation, but appears of minor importance in the adult cardiovascular system. The 8 Packard J D et al 1989 British Medical Journal 289: 636. VASODILATORS recognition that the AT 1 -receptor subtype is the important target for drugs antagonising angiotensin II has led, a little confusingly, to two alternative nomenclatures for these drugs: either AT 1 -receptor blockers, or angiotensin II receptor antagonists (AURA). Bradykinin (an endogenous vasodilator occurring in blood vessel walls) is also a substrate for ACE. Potentiation of bradykinin contributes to the blood pressure lowering action of ACE inhibitors in patients with low-renin causes of hypertension. Either bradykinin or one of the neurokinin substrates of ACE (such as substance P) may stimulate cough (below). The AT 1 blockers differ from the ACE inhibitors in having no effect on bradykinin and do not cause cough. Those that achieve complete blockade of the receptor are slightly more effective than ACE inhibitors at preventing angiotensin II vasoconstriction. ACE inhibitors are more effective at suppressing aldosterone production in patients with normal or low plasma renin. Uses Hypertension. The antihypertensive effect of ACE inhibitors and AT 1 receptor blockers results primarily from vasodilatation (reduction of peripheral resist- ance) with little change in cardiac output or rate; renal blood flow may increase (desirable). A fall in aldosterone production may also contribute to the blood pressure lowering action of ACE inhibitors. Both classes slow progression of glomerulopathy. Whether the long-term benefit of these drugs in hypertension exceeds that to be expected from blood pressure reduction alone remains controversial. ACE inhibitors and AT 1 -receptor blockers are most useful in hypertension when the raised blood pressure results from excess renin production (e.g. renovascular hypertension), or where concurrent use of another drug (diuretic or calcium blocker) renders the blood pressure renin-dependent. The fall in blood pressure can be rapid, especially with short-acting ACE inhibitors, and low initial doses of these should be used in patients at risk: those with impaired renal function, or suspected cerebrovascular disease. These patients may be advised to omit any concurrent diuretic treatment for a few days before the first dose. The antihypertensive effect increases progressively over weeks with continued adminis- 467 23 ARTERIAL H Y P E RT E N S I O N , A N G I N A PECTORIS, Ml tration (as with other antihypertensives) and the dose may be increased at intervals of 2 weeks. Cardiac failure (see p. 517). ACE inhibitors have a useful vasodilator and diuretic-sparing (but not diuretic-substitute) action in all grades of heart failure. Their reduction of mortality in this condition, due possibly to their being the only vasodilator which does not reflexly activate the sympathetic system, has made the ACE inhibitors more critical to the treatment of heart failure than of hyper- tension, where they are not usually an essential part of management. The AT 1 blockers have not yet been introduced for the treatment of cardiac failure. This may only be a matter of time, but the establishment of new drugs for cardiac failure encounters the problem of demonstrating efficacy against a back- ground of existing ACE inhibitor therapy, where a placebo control is no longer ethically acceptable. Diabetic nephropathy. In patients with type I (insulin dependent) diabetes, hypertension often accompanies the diagnosis of frank nephropathy and aggressive blood pressure control is essential to slow the otherwise inexorable decline in renal func- tion that follows. ACE inhibitors appear to have a specific renoprotective effect, possibly because of the role of angiotensin II in driving the underlying glomerular hyperfiltration in these patients. 9 These drugs are now considered first-line treatment for hypertensive type I diabetics, although most patients will need a second or third agent to reach the new BP targets for these patients (see below). There is also evidence that ACE inhibitors have a proteinuria- sparing effect in type I diabetics with 'normal' BP, but here it is less clear whether this effect extends beyond just a BP-lowering effect. 10 For hypertensive type 2 diabetics with nephropathy, there are better data to support use of AT 1 -receptor blockers than ACE inhibitors for a renoprotective effect indepen- dent of the blood pressure lowering effect. 9 For a review, see: Cooper M E 1998 Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 352:213-219. 10 The EUCLID study group 1997 The EUCLID study. Randomised, placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbiminuria. Lancet 349: 1787-1792. Myocardial infarction (MI). Following a myocardial infarction, the left ventricle may fail acutely from the loss of functional tissue or in the long-term from a process of 'remodelling' due to thinning and enlargement of the scarred ventricular wall. Angio- tensin II plays a key role in both of these processes and an ACE inhibitor given after an MI markedly reduces the incidence of heart failure. The effect is seen even in patients without overt signs of failure, but who have low left ventricular ejection fractions during the convalescent phase (3-10 days) follow- ing their MI. Patients such as this receiving captopril in the SAVE trial, 11 had a 37% reduction in progressive heart failure over the 60-month follow- up period compared to placebo. The benefits of ACE inhibition after MI are additional to those conferred by thrombolysis, aspirin and -blockers. Cautions. Certain constraints apply to the use of ACE. • Heart failure: severe hypotension may result in patients taking diuretics, or who are hypovolaemic, hyponatraemic, elderly, have renal impairment or with systolic blood pressure < 100 mmHg. A test dose of captopril 6.25 mg by mouth may be given because its effect lasts only 4-6 h. If tolerated, the preferred long-acting ACE inhibitor may then be initiated in low dose. • Renal artery stenosis (whether unilateral, bilateral renal or suspected from the presence of generalised atherosclerosis): an ACE inhibitor may cause renal failure and is contraindicated. • Aortic stenosis/left ventricular outflow tract obstruction: an ACE inhibitor may cause severe, sudden hypotension and, depending on severity, is relatively or absolutely contraindicated. • Pregnancy represents a contraindication (see below). • Angioedema may result (see below). Adverse effects ACE inhibitors cause persistent dry cough in 10-15% of patients. Urticaria and angioedema (< 1 11 Swedberg K P et al 1992 New England Journal of Medicine 327: 669-677. 468 23 in 100 patients) are much rarer, occurring usually in the first weeks of treatment. The angioedema varies from mild swelling of the tongue to life-threatening tracheal obstruction, when s.c. adrenaline (epine- phrine) should be given. The basis of the reaction is probably pharmacological rather than allergic, due to reduced breakdown of bradykinin. Impaired renal function may result from reduced glomerular filling pressure, systemic hypotension or glomerulonephritis, and plasma crearinine should be checked before and during treatment. Hypo- natraemia may develop, especially where a diuretic is also given; clinically significant hyperkalaemia (see effect on aldosterone above) is confined to patients with impaired renal function. ACE inhi- bitors are fetotoxic in the second trimester, causing reduced renal perfusion, hypotension, oligohy- dramnios and fetal death. Neutropenia and other blood dyscrasias occur. Other reported reactions include rashes, taste disturbance (dysguesia), musculoskeletal pain, proteinuria, liver injury and pancreatitis. AT 1 receptor blockers are contraindicated in pregnancy, but avoid most other complications — particularly the cough and angioedema. They are the only antihypertensive drugs for which there is no 'typical' side effect. Interactions. Hyperkalaemia can result from use with potassium-sparing diuretics. Renal clearance of lithium is reduced and toxic concentrations of plasma lithium may follow. Severe hypotension can occur with diuretics (above), and with chlorpro- mazine, and possibly other phenothiazines. Individual drugs Captopril (Capoten) has a t l / 2 of 2 h and is partly metabolised and partly excreted unchanged; adverse effects are more common if renal function is impaired; it is given twice or thrice daily. Captopril is the shortest-acting of the ACE inhibitors, one of the few where the oral drug is itself active, not requiring de-esterification after absorption. Enalapril (Innovace) is a prodrug (t l / 2 35 h) that is converted to the active enalaprilat (t l / 2 10 h). Effec- tive 24-h control of blood pressure may require twice daily administration. VASODILATORS Other members include cilazapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, mmipril, and trandolapril. Of these, lisinopril has a marginally longer t 1 / 2 than enalapril, probably justifying its popularity as a once-daily ACE inhibitor. Some of the others are longer-acting, with quinapril and ramipril having also a higher degree of binding to ACE in vascular tissue. The clinical significance of these differences is disputed. In the Heart Out- comes Prevention Evaluation (HOPE) Study of 9297 patients, ramipril reduced, by 20-30%, the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who were not known to have a low ejection fraction or heart failure. 12 The authors considered that the results could not be explained entirely by blood pressure reduction. Losartan was the first AT 1 receptor antagonist licensed in the UK. It is a competitive blocker with a noncompetitive active metabolite. The drug has a short t// (2 h) but the metabolite is much longer lived (t 1 /2 10 h) permitting once daily dosing. Other AT 1 receptor antagonists in clinical use include candesartan, eprosartan, irbesartan, telmisartan and valsartan. Some of these appear more effective than losartan, which is generally used in combination with hydrochlorothiazide. In a landmark study this combination was 25% more effective than atenolol plus hydrochlorothiazide in preventing stroke. 13 This class of drug is very well tolerated; in clinical trials their side effect profiles are indistinguishable or even better than placebo. Unlike the ACE inhibitors they do not produce cough, and are a valuable alternative for the 10-15% of patients who dis- continue their ACE inhibitor for this reason. AT 1 receptor antagonists are used to treat hypertension but any role in cardiac failure or after myocardial infarction (as have ACE inhibitors) remains to be established. The cautions listed for the use of ACE inhibitors (above) apply also to AT 1 receptor blockers. 12 Yusuf S, Sleight P, Pogue J et al 2000 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New England Journal of Medicine 342:145-53. 13 Dahlof B et al 2002 Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359: 995-1010. 469 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 Other vasodilators Several older drugs are powerfully vasodilating, but precluded from routine use in hypertension by their adverse effects. Minoxidil and nitroprusside still have special indications. Minoxidil is a vasodilator selective for arterioles rather than for veins, similar to diazoxide and hydralazine. Like the former, it acts through its sulphate metabolite as an ATP-dependent potassium channel opener. It is highly effective in severe hypertension, but causes increased cardiac output, tachycardia, fluid retention and hypertrichosis. The hair growth is generalised and although a cosmetic problem in women, it has been exploited as a topical solution for the treatment of baldness in men. Sodium nitroprusside is a highly effective anti- hypertensive agent when given i.v. Its effect is almost immediate and lasts for 1-5 min. Therefore it must be given by a precisely controllable infusion. It dilates both arterioles and veins, which would cause collapse if the patient stands up, e.g. for toilet purposes. There is a compensatory sympathetic discharge with tachycardia and tachyphylaxis to the drug. The action of nitroprusside is terminated by metabolism within erythrocytes. Specifically, electron transfer from haemoglobin iron to nitro- prusside yields methaemoglobin and an unstable nitroprusside radical. This breaks down, liberating cyanide radicals capable of inhibiting cytochrome oxidase (and thus cellular respiration). Fortunately most of the cyanide remains bound within erythro- cytes but a small fraction does diffuse out into the plasma and is converted to thiocyanate. Hence, monitoring plasma thiocyanate concentrations during prolonged (days) nitroprusside infusion is a useful marker of impending systemic cyanide toxicity. Poisoning may be obvious as a progressive metabolic acidosis or manifest as delirium or psychotic symp- toms. Toxic subjects are also reputed to emit the characteristic bitter almond smell of hydrogen cyanide. Clearly nitroprusside infusion should not be undertaken without meticulous regard for the manufacturer's recommendations and precautions; outside specialist units it may be safer overall to choose another more familiar drug. Sodium nitroprusside is used in hypertensive emergencies, refractory heart failure and for con- trolled hypotension in surgery. An infusion 14 may begin at 0.3-1.0 micrograms/kg/min and control of blood pressure is likely to be established at 0.5-6.0 micrograms/kg/min; close monitoring of blood pressure is mandatory usually with direct arterial monitoring of blood pressure; rate changes of infu- sion may be made every 5-10 min. Diazoxide is chemically a thiazide but has no appreciable diuretic effect; indeed, like other potent arterial vasodilators it causes salt and water retention. It reduces peripheral arteriolar resistance through activation of the ATP-dependent potassium channel (c.f. nicorandil and minoxidil), with little effect on veins. The t1/2 is 36 h. The principal use of diazoxide has been in the emergency treatment of severe hypertension. The maximum effect after an i.v. bolus occurs within 5 min and lasts for at least 4 h. The dangers from excessive hypotension are now recognised to out- weigh the benefit, and emergency use of diazoxide is almost obsolete. Because it stimulates the same potassium channel in the pancreatic islet cells as is blocked by sulphonylureas, diazoxide causes hyperglycaemia. This effect renders diazoxide unsuitable for chronic use in hypertension, but a useful drug to treat insulinoma. Long-term oral administration causes the same problem of hair growth seen with minoxidil (see below and 'alopecia'). Hydralazine now has little use long-term for hyper- tension, but it may have a role as a vasodilator (plus nitrates) in heart failure. It reduces peripheral resistance by directly relaxing arterioles, with negli- gible effect on veins. In common with all potent arterial vasodilators, its hypotensive action is accompanied by a compensatory baroreceptor- mediated sympathetic discharge, causing tachycardia and increased cardiac output. There is also renin release with secondary salt and water retention, 14 Light causes sodium nitroprusside in solution to decompose; hence solutions should be made fresh and immediately protected by an opaque cover, e.g. metal foil. The fresh solution has a faint brown colour; if the colour is strong it should be discarded. 470 [...]... intermediate Classification of -adrenoceptor blocking drugs • Pharmacokinetic: lipid-soluble, water-soluble, see above • Pharmacodynamic (Table 23.1) The associated properties (partial agonist action and membrane stabilising action) have only minor clinical importance with current drugs at doses ordinarily used and may be insignificant in most cases But it is desirable that they be known, for they can sometimes... the drug (See the note to Table 22.1, p 449, regarding use of the terms 2 selective and cardioselective.) The question is whether the differences between selective and nonselective -blockers constitute clinical advantages In theory 1-blockers are less likely to cause bronchoconstriction, but in practice few available TABLE 23 1 are sufficiently selective to be safely 1blockers recommended in asthma Bisoprolol... since there may be less up-regulation of receptors, such as occurs with prolonged receptor block Some -blockers have membrane stabilising (quinidine-like or local anaesthetic) effect This property is clinically insignificant except that agents having this effect will anaesthetise the eye (undesirable) if applied topically for glaucoma (timolol is used in the eye and does not have this action), and... obscures the vasodilatation that is characteristic of a-adrenoceptor blocking drugs Chlorpromazine has many actions of which aadrenoceptor block is a minor one, but sufficient to cause hypotension, and to be clinically useful in amphetamine overdose P-ADRENOCEPTOR BLOCKING DRUGS Actions These drugs selectively block the -adrenoceptor effects of noradrenaline (norepinephrine) and adrenaline (epinephrine) They . (Table 23.1). The associated properties (partial agonist action and membrane stabilising action) have only minor clinical importance with current drugs . verapamil) • Benzothiazepine (diltiazem). The differences between their clinical effects can be explained in part by their binding to different parts