choice of antihypertensive drug therapy

11
THE PRESENT-ANTIHYPERTENSIVE DRUGS IN PRACTICE Choice of antihypertensive drug therapy B. N. C. Prichard and B. Tomlinson. London, England The drugs that are available for treating hyperten- sion can be divided into three groups: diuretics, sympathetic inhibitory drugs, and vasodilators, that is, drugs that reduce peripheral resistance other than by alpha-receptor inhibition. This vasodilator group includes calcium antagonists and converting enzyme inhibitors. Diuretics might also be included in this group as part of their action is vasodilator. The sympathetic inhibitory drugs fall into two major groups: (1) those which inhibit innervation of the alpha receptor, either centrally (e.g., methyldo- pa), at the adrenergic nerve ending (e.g., guanethi- dine), or at the peripheral alpha-l receptor (e.g., prazosin); and (2) those which inhibit the beta- adrenergic receptor. The question of which should be the drug of first choice is of prime importance in the treatment of hypertension. Diuretics, although still widely used, are becoming less popular, whereas beta-adrenocep- tor-blocking drugs have been used with increasing frequency. There has been increasing interest in beta-adrenoceptor-blocking drugs with multiple actions, that is, those with an additional vasodilator or alpha-blocking effect. More recently, calcium antagonists, converting enzyme inhibitors, and selective alpha-l-receptor-blocking drugs are begin- ning to be regarded as first-choice agents by some physicians. It is becoming more usual to try one of these options first and then, if that fails because of either inadequate blood pressure control or side effects, to change therapy completely to an alterna- tive drug. The stepped-care approach, at least in the first instance, is less often the routine it was until recently. The drug of first choice may often be determined by other factors, such as angina, heart failure, or diabetes. SYMPATHETIC INHIBITORY DRUGS Drugs lnhlbltlng the innervation of the alpha recep tom. Alpha-receptor innervation may be affected at From the Department of Clinical Pharmacology, University College Lon- don, The Rayne Institute. Reprint requests: B. N. C. Prichard, Department of Clinical Pharmacology, University College London, The Rayne Institute, 5 University St., London WCIE 6JJ, England. 1030 various sites: centrally (e.g., methyldopa and clonid- ine), at sympathetic ganglia (e.g., ganglion-blocking drugs), at adrenergic nerve endings (e.g., guanethi- dine, bethanidine, and reserpine), and at the post- synaptic alpha-l receptor (e.g., prazosin).’ With the exception of the alpha-l-receptor inhibitory drugs, such as prazosin, use of these drugs has declined in recent years, and they are usually held in reserve. At all sites of action, an agent that inhibits the innervation of alpha receptors is likely to produce a greater effect under physiological conditions which require increased alpha-mediated sympathetic activity to maintain blood pressure. There may, therefore, be a greater decrease in blood pressure on standing, after exercise, in a hot environment, after eating, or from reduced blood volume. Not all drugs inhibiting the innervation of alpha receptors do so to the same degree; for instance, methyldopa has less postural effect than guanethidine, which in turn has slightly less effect than bethanidine.2 Alpha-receptor inhibition. The alpha-receptor inhibitory drugs can be divided into noncompetitive (e.g., phenoxybenzamine) and competitive agents, and further into nonselective and alpha-l selective agents. The use of noncompetitive alpha-receptor- blocking drugs, alone or in combination, is particu- larly associated with a decrease in blood pressure on standing and other physiological conditions requir- ing increased alpha-mediated vasoconstriction to maintain blood pressure. This is the result of the irreversible, noncompetitive nature of the blockade, which prevents any compensatory vasoconstrictor response to, for example, erect posture.3 If inhibition of the alpha receptor is competitive, increased sym- pathetic outflow may result in sufficient reversal of the alpha-receptor inhibition so that a postural decrease of blood pressure does not occur. IIowever, at a high drug dosage even the competitive block may be great enough to prevent sufficient compen- satory vasoconstriction and, therefore, a decrease in blood pressure on standing may occur.4 Alpha-l blockade in hypertension. The useful antihypertensive alpha-receptor inhibitory drugs are selective for the alpha-l receptor.6 These agents do not block the alpha-2 receptor. This means that

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Page 1: Choice of antihypertensive drug therapy

THE PRESENT-ANTIHYPERTENSIVE DRUGS IN PRACTICE

Choice of antihypertensive drug therapy

B. N. C. Prichard and B. Tomlinson. London, England

The drugs that are available for treating hyperten- sion can be divided into three groups: diuretics, sympathetic inhibitory drugs, and vasodilators, that is, drugs that reduce peripheral resistance other than by alpha-receptor inhibition. This vasodilator group includes calcium antagonists and converting enzyme inhibitors. Diuretics might also be included in this group as part of their action is vasodilator. The sympathetic inhibitory drugs fall into two major groups: (1) those which inhibit innervation of the alpha receptor, either centrally (e.g., methyldo- pa), at the adrenergic nerve ending (e.g., guanethi- dine), or at the peripheral alpha-l receptor (e.g., prazosin); and (2) those which inhibit the beta- adrenergic receptor.

The question of which should be the drug of first choice is of prime importance in the treatment of hypertension. Diuretics, although still widely used, are becoming less popular, whereas beta-adrenocep- tor-blocking drugs have been used with increasing frequency. There has been increasing interest in beta-adrenoceptor-blocking drugs with multiple actions, that is, those with an additional vasodilator or alpha-blocking effect. More recently, calcium antagonists, converting enzyme inhibitors, and selective alpha-l-receptor-blocking drugs are begin- ning to be regarded as first-choice agents by some physicians. It is becoming more usual to try one of these options first and then, if that fails because of either inadequate blood pressure control or side effects, to change therapy completely to an alterna- tive drug. The stepped-care approach, at least in the first instance, is less often the routine it was until recently. The drug of first choice may often be determined by other factors, such as angina, heart failure, or diabetes.

SYMPATHETIC INHIBITORY DRUGS

Drugs lnhlbltlng the innervation of the alpha recep tom. Alpha-receptor innervation may be affected at

From the Department of Clinical Pharmacology, University College Lon- don, The Rayne Institute.

Reprint requests: B. N. C. Prichard, Department of Clinical Pharmacology, University College London, The Rayne Institute, 5 University St., London WCIE 6JJ, England.

1030

various sites: centrally (e.g., methyldopa and clonid- ine), at sympathetic ganglia (e.g., ganglion-blocking drugs), at adrenergic nerve endings (e.g., guanethi- dine, bethanidine, and reserpine), and at the post- synaptic alpha-l receptor (e.g., prazosin).’ With the exception of the alpha-l-receptor inhibitory drugs, such as prazosin, use of these drugs has declined in recent years, and they are usually held in reserve.

At all sites of action, an agent that inhibits the innervation of alpha receptors is likely to produce a greater effect under physiological conditions which require increased alpha-mediated sympathetic activity to maintain blood pressure. There may, therefore, be a greater decrease in blood pressure on standing, after exercise, in a hot environment, after eating, or from reduced blood volume. Not all drugs inhibiting the innervation of alpha receptors do so to the same degree; for instance, methyldopa has less postural effect than guanethidine, which in turn has slightly less effect than bethanidine.2

Alpha-receptor inhibition. The alpha-receptor inhibitory drugs can be divided into noncompetitive (e.g., phenoxybenzamine) and competitive agents, and further into nonselective and alpha-l selective agents. The use of noncompetitive alpha-receptor- blocking drugs, alone or in combination, is particu- larly associated with a decrease in blood pressure on standing and other physiological conditions requir- ing increased alpha-mediated vasoconstriction to maintain blood pressure. This is the result of the irreversible, noncompetitive nature of the blockade, which prevents any compensatory vasoconstrictor response to, for example, erect posture.3 If inhibition of the alpha receptor is competitive, increased sym- pathetic outflow may result in sufficient reversal of the alpha-receptor inhibition so that a postural decrease of blood pressure does not occur. IIowever, at a high drug dosage even the competitive block may be great enough to prevent sufficient compen- satory vasoconstriction and, therefore, a decrease in blood pressure on standing may occur.4

Alpha-l blockade in hypertension. The useful antihypertensive alpha-receptor inhibitory drugs are selective for the alpha-l receptor.6 These agents do not block the alpha-2 receptor. This means that

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Volume 114 Number 4, Part 2 Choice of antihypertensive regimen 1031

there is no prejunctional alpha-2 receptor block which would cut off the negative feedback mecha- nism and result in an increased noradrenaline out- put. This would antagonize the postjunctional alpha-l blockade, in part, and also, by presynaptic alpha-2 inhibition at the innervation of cardiac beta receptors, would result in a tachycardia from increased beta-receptor stimulation; likewise, there is increased renin release when a nonselective alpha antagonist is used.

There are many open studies which have evalu- ated the effects of prazosin in hypertension.6 Trima- zosin,7T* diazosin,g and terazosirQ”~ l1 and other relat- ed quinazoline alpha-blocking drugs have also been found to be effective antihypertensive agents.

A further alpha-l-receptor-blocking drug, indo- ramin, has an additional antihistamine effect, which may be responsible for the not uncommon incidence of sedation. It is likewise an effective antihypertensive agent.13-17

Role of alpha blockade in hypertension. The alpha-blocking drugs can be considered to have certain advantages in hypertension: first their hemo- dynamic profile which, like that of other drugs that are peripheral vasodilators, appears to reverse the changes of hypertensiorP; second, the relative ease of patient selection; and third, an apparent absence of long-term adverse metabolic side effects. In fact, a favorable effect on lipid profiles has been re- ported.lg

Clearly, it is necessary that care be taken to minimize or avoid an overt first-dose phenomenon in susceptible patients, such as the elderly popula- tion, but generally problems in patient selection seen with other antihypertensive agents are absent. In contrast to the beta-adrenoceptor-blocking drugs, the alpha-blocking drugs do not cause heart failure in susceptible patients; on the contrary, they are useful in its treatment.” Similarly, they do not worsen asthma; on the contrary, prazosin20 and indoramin21s22 have been found to possess some antiasthmatic effects, and some investigatorP have found indoramin to be without effects. Alpha-block- ing drugs increase peripheral blood flow% and have been used in the treatment of Raynaud’s phenome- non,25 and may therefore be considered particularly indicated if this coexists with hypertension.

The first-dose phenomenon, which results from too rapid a commencement of alpha-receptor inhibi- tion, was a considerable problem in the early stages of the use of prazosin. Symptoms of severe postural hypotension26-28 and loss of consciousness developed in several instances, suggesting a specific effect on cerebral blood flow. However, prazosin does not appear to alter cerebral blood flow directly.2g There

is some dose dependence2’s 28 and use of a low initial dose of 0.5 mg, particularly if given just before bed, is likely to result in only minimal dizziness or none. The long-term administration of prazosin probably leads to an increase in systemic blood volume30 and therefore the excessive sensitivity to the alpha blockade declines. There are other factors besides a low initial dose which influence the first-dose phe- nomenon. A high-sodium diet has been found to abolish it, whereas a low-sodium diet enhances it.= If the patient is already receiving a beta-adrenocep- tor-blocking drug, this may also increase the drop in blood pressure associated with the first dose of prazosin.31

Beta-adrenoceptor-blocking drugs. Beta-adreno- ceptor-blocking drugs are often used as first-choice agents in the treatment of hypertension32; neverthe- less, their antihypertensive mode of action remains debatable, although they have been in use for over 20 years. Blood pressure decreases regardless of the presence or absence of the associated properties, beta-l selectivity, intrinsic sympathomimetic activi- ty (ISA), and membrane activity, except perhaps a high level of pure beta-l stimulation. The mem- brane-active, nonbeta-blocking isomers are without antihypertensive effect.33T34 Beta-adrenoceptor- blocking drugs, therefore, do lower blood pressure as a result of their beta-receptor-blocking action. A number of suggestions have been made to explain the hypotensive action. These include a direct action on the central nervous system, adrenergic neurone blocking perhaps via presynaptic beta-2 receptors, antirenin activity, an increase of vasodilator prosta- glandins, effects secondary to reduced cardiac out- put, and resetting of baroreceptors secondary to reduced pressor peaks to various pressor stimuli from the reduction in cardiac activity consequent to beta blockade.32 The exact mode of action remains unclear, and it may be that in different patients different mechanisms may be operative.

The importance of renin levels has received much attention. Buhler et al.% found that patients with high renin levels responded best to propranolol, patients with normal renin levels less well, and patients with low renin levels had a poor response. This has been suggested by several investigators who found a good correlation between renin levels and response of blood pressure with a variety of beta-adrenoceptor-blocking drugs.35,36 However, while Hollifield et a13’ found that propranolol, at a relatively low dose of 160 mglday, readily lowered blood pressure in high-renin patients, with higher doses of propranolol, 320 to 960 mg/day, blood pressure was lowered in low-renin patients indepen- dent of the effects on renin levels. There is conflict-

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1032 Prichard and Tomlinson October 1987

American Heart Journal

ing evidence as other investigators have not found a correlation between renin levels and response to beta-adrenoceptor-blocking drugs, with proprano- 101,~~~~ alprenolol,4 oxprenolol,45 pindolol,41,46 sota- 101:~ timolol,48 or metoprolol.4g~50 In a general assess- ment of various beta-adrenoceptor-blocking drugs, it was observed by Man In’t Veld and Schalekampsl that although beta-adrenoceptor-blocking drugs with no ISA lowered blood pressure and renin levels, those drugs with ISA, such as, pindolol, also lowered blood pressure but had little effect on renin activity. Finally, it has been found in patients not fully responding to the converting enzyme inhibitor, cap- topril, that suppressing the renin system with the addition of propranolol causes an additional decrease in blood pressure.52

Role in hypertension. Care is required in patient selection, because these drugs should be avoided in patients with heart failure as such patients are critically dependent on sympathetic drive.32 Similar- ly, patients with asthma are sensitive to inhibition of adrenergic drive to bronchial smooth muscle, and even cardioselective drugs are liable to cause signif- icant increase in airway obstruction.53 Beta-blocking drugs are also likely to increase heart block and worsen Raynaud’s phenomenon.54s55

Although there is some evidence to the contrary, it does not seem to be possible to reliably predict which patients will respond successfully to beta- adrenergic-blocking drugs. Buhler et al.35*56 suggest- ed that renin levels are important and perhaps the basis for the suggestion that older patients are less responsive is that renin concentrations decrease with age.35F37 However, others have not found a clear relationship with renin levels (see above). Some reports have indicated that beta-blocking drugs are effective in elderly patients58s5g and some consider them specifically indicated.60 There is no clear corre- lation between initial cardiac output and response to beta-blocking drugs61-63 or blood volume.61*63 Mea- surements of peripheral resistance, urinary adrena- line and noradrenalin,63s64 aldosterone,‘j3 and heart rate response to isoprenaline4ss63 do not appear to be of value in predicting which patients respond well to beta-blocking drugs.

Although there is variation between the beta- adrenergic-blocking drugs, and not all studies show the trend,32p65 many of them lower high-density lipoproteins and increase total triglyceride levels. Cardioselective agents probably have less effect in this regard and drugs with partial agonist effect possibly have virtually no effect.1gs32*66 However, there are several mechanisms by which this may occur.‘j7 There are many reports that indicate beta-

blocking drugs are effective in reducing the recur- rence rate of myocardial infarction.68-‘5 Some time ago it was suggested that propranolol-treated patients with hypertension may have a lower inci- dence of myocardial infarction than those not given beta-blocking drugs. 76 In another larger but uncon- trolled study, Beevers et al.77 found fewer incidences of heart attack and stroke in hypertensive patients treated with beta-adrenergic-blocking drugs com- pared to those in whom similar blood pressure control was achieved with other antihypertensive drugs. However, large-scale primary prevention tri- als have not shown a clear cardioprotective effect from beta blockade in mild hypertension except in the subset, nonsmoking men.78.7g

There are other reasons why a beta-blocking drug might be chosen to treat hypertension. The beta- blocking drugs are widely used in therapeutics, and there are a number of conditions responsive to beta-blocking drugs that not infrequently coexist with hypertension, such as angina pectoris, migraine, or anxiety with somatic features.’ Also, the beta-adrenergic-blocking drugs, in contrast to other potent drugs available at the time of their introduc- tion, the adrenergic neurone blocking drugs, or methyldopa, do not produce postural or excessive hypotension.32

Combination of beta and alpha blockade or vasodila- tor activity. Labetalol is the only drug with beta- and alpha-receptor-blocking properties generally avail- able at present. 8o It has been extensively evaluated in hypertension.81s82 Its use is not associated with postural hypotension at usual dosages, but in those few patients requiring a high dose, over approxi- mately 2 gm a day, some postural effects may be seen.82 Another drug that possesses both beta- and alpha-blocking properties is medroxalol, but this probably has an additional vasodilator effect medi- ated by beta-2-adrenergic stimulation.s3~84 Its beta- and alpha-blocking properties have been confirmed in humans,s5 and it is an effective drug in the treatment of hypertension.% Celiprolol has beta- l-blocking properties and also a vasodilator action which seems to be a combination of some beta-2 stimulatory action besides a direct vasodilator action.87 Celiprolol is also effective in hyperten- sion.88r8g

More recently, several drugs have been described that possess both beta-blocking plus vasodilator properties. Prizidolol~ has been extensively evalu- ated, but it has been withdrawn because of toxicity in animals. Bucindololg1~g2 and carvedilolg3-g6 and other similar drugs are, at present, in an early stage of evaluation.

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Volume 114 Number 4, Part 2 Choice of antihypertensive regimen 1033

CALCIUM CHANNEL BLOCKING DRUGS

While the calcium antagonists vary in their tissue selectivity, they share the common property of slowing calcium entry through voltage-activated, ion-selective channels, and thus they produce a vasodilatation.s7 It has recently been suggestedgE that the previous classification of Fleckensteingg should be superseded to now include four groups. The type I agents, the phenylalkylamine derivatives such as verapamil, gallopamil, and the benzothiaze- pine derivatives (diltiazem), besides dilating blood vessels, have important action on cardiac conduc- tion tissue, prolonging atrioventricular conduction and refractoriness but with little effect on the atria1 or ventricular refractory period. Although the type II drugs, the dihydropyridines (e.g., nifedipine, nitrendepine, felodipine, etc.), have no electrophysi- ological effects in vivo on conducting tissue, they are potent peripheral vasodilators. The piperazines, type III, cinnarizine, and flunarizine are highly selective in vitro as well as in vivo for vascular smooth muscle relative to cardiac muscle.‘O” The type IV group is more complex; this group includes perhexiline, bepridil, and lidofluazine which, in addition to their inhibitory action on calcium chan- nels, block the fast sodium channels to a variable degree.

Many investigators have demonstrated that acute administration of nifedipine leads to a rapid decrease in blood pressure.lol-lll The chronic oral administration of nifedipine is effective in the con- trol of hypertension,102~0’4~ 112-114 and studies using continuous intraarterial recording of blood pressure confirm these findings.“5*‘*6 Hornung et a1.115 studied delayed-release nifedipine tablets (up to 60 mg twice a day), which give lower peak levels but more prolonged plasma levels than the standard capsules and are now generally preferred in the treatment of hypertension.

Verapamil has been shown to lower blood pres- sure when given intravenously.117*11s It was only recently that its value in chronic oral treatment was demonstrated11s-123 and confirmed with intraarterial studies.124 A slow-release formulation has been described which controls blood pressure125 and can be given once daily. 126 Other calcium antagonists have also been effective in the control of blood pressure in hypertensive patients.127-12g As might be expected from the reflex sympathetic activity to the heart, the combination of nifedipine with beta- adrenoceptor blockade, of propranolol,‘03* 130 or ate- n0101,131~ 132 or several different drugs133 results in an additional decrease in blood pressure. Nifedipine has also been assessed in combination with methyl-

dopa and found to be additive.134 Furthermore, the combination of a diuretic plus a beta-blocking drug with nifedipine is useful in more resistant patients.‘35-137 There is some concern over the combi- nation of verapamil and beta-blocking drugs, because of similar effects on conduction tissue and negative inotropic effects, but given orally in hyper- tensive patients the prolonged PR interval is proba- bly not important138~ 13g in the absence of preexisting conduction disturbances or cardiac failure.

Role in hypertension. A fairly high incidence of side effects has been reported140 from calcium antago- nists in some series, with dropout rates of 14% to 22% from nifedipine,106T113*114 and even 31% in one series where nifedipine was used in combination with propranolol. ‘30 On the other hand, some inves- tigators have not found any incidence of dropouts with nifedipine alone. 115 The calcium antagonists may be preferred in patients in whom beta-adreno- ceptor-blocking drugs should be avoided. In patients with poor left ventricular function or bra- dyarrhythmias, nifedipine may be given. Similarly, in asthmatic patients, calcium antagonists do not increase airway obstruction, in contrast to beta- blocking drugs. There has been a report that nifedi- pine reduces exercise-induced asthma.141 Similarly, attacks of Raynaud’s phenomenon are lessened after nifedipine. 142

There is evidence from animal studies that calci- um antagonists have a protective effect in experi- mental ischemia, inhibiting the rise in cytosolic calcium induced by ischemia.‘43 Coronary spasm may be a cause of sudden death and this is inhibited by calcium antagonists;‘“* 145 also, nifedipine inhibits platelet aggregation. 146 Finally, verapamil and simi- lar drugs have a significant antiarrhythmic action;147 however, clinical evidence from postmyocardial infarction trials is not promising thus far.148

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

The first agents which were available to block the renin-angiotensin system were the receptor-blocking drugs such as saralasin. As this drug can only be given parenterally its use is confined to hypertensive crisis, but it can also be used as a diagnostic screening test for renovascular hypertension.‘4s The angiotensin-converting enzyme (ACE) inhibitory drugs are a more recent introduction into therapeu- tics.150-152 While part of their mode of action is the result of inhibition of the production of angiotensin II, and acute antihypertensive effect correlates well with renin levels, these agents are effective in low- renin hypertension, suggesting that other actions may be important in their blood pressure-lowering

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1034 Prichard and Tomlinson October 1887

American Heart Journal

effects.‘6o They have been found also to increase bradykinin levels in blood vessel walls and thus lead to vasodilation from this mechanism. This is the result of inhibition of one of the peptidases respon- sible for its,breakdown, kininase II, which is thought to be the same enzyme as ACE.l@J 153 The decrease in blood pressure is the result of an arteriolar dilata- tion giving a reduction in peripheral resistance.‘”

About 50% of patients may be controlled on captopril alone, and a total of approximately 83% with the addition of a diuretic.155 In earlier studies captopril, the first oral converting enzyme inhibitory drug available, was used in what would now be regarded as large doses (up to 450 mg/day) in the treatment of severe or renovascular hypertension, frequently in combination with a diuretic and in patients with renal impairment.‘56-161 This use of captopril at the higher dosage was associated with a high incidence of side effects. Skin rashes (morbilli- form or maculopapular) occurred in 15% of patients, mostly within a month of the beginning of therapy,162 and more often in patients with renal failure.ls8 There have been more serious side effects reported, proteinuria in up to 5% of patients,163 and leukopenia and agranulocytosis,155 usually within the first 3 months of treatment.‘@ More recently, the use of much lower doses of captopril has been advo- cated, doses which have a lower incidence of minor side effects and do not seem to be associated with the serious renal and hematologic side effects that were the pattern with larger doses.‘65-167

The duration of action of captopril is short, and subsequently enalapril has been introduced, which gives satisfactory enzyme inhibition for 24 hours.188.16Q This has been found to be effective in the treatment of hypertension with a once daily dos- age. 170-172

Role in hypertension. ACE inhibitory drugs in hypertension appear to be well tolerated.173 They do not interfere with the sympathetic reflexes control- ling blood vessels; therefore, there is generally no postural or exercise hypotension and no resultant reflex tachycardia. They are not contraindicated in heart failure; rather, they are used in its treat- ment.‘74 They retain serum potassium, and this may be helpful when they are used in combination with a diuretic but a disadvantage in elderly patients. It should be noted that patients who are on diuretics or who are salt depleted may show a large decrease in blood pressure when ACE inhibitors are first given and therefore special care is needed.175s 176 It is now recognized that the initial doses in renal hyperten- sion should be low (6.25 to 12.5 mg) and captopril should be avoided in bilateral renal artery stenosis

where a precipitous decrease in renal function may occur, possibly a reflection of the importance of angiotensin maintaining glomerular efferent arterio- lar constriction and thus glomerular filtration pres- sure.160 The same applies to unilateral renal artery stenosis when the other kidney is nonfunction- ing.177

DIURETICS

The mode of action of diuretics in lowering blood pressure is, in part, a direct vasodilator action besides producing a small chronic reduction in blood volume. Diuretics have long been regarded as first- choice drugs for the treatment of hypertension. They are often used alone to control blood pressure in milder degrees of hypertension, but they are also very useful in combination.‘, *78 They are the cheap- est antihypertensive agents and can be given once daily,17Q but they are often used in larger than necessary doses. MacGregor et a1.180 found hydro- chlorothiaxide, 12.5 mg/day, to have very similar effects to a 25 mg/day dose in combination with acebutolol.

There are long-term metabolic effects; hypokal- emia, hypomagnesemia, carbohydrate intolerance, uric acid retention, increase in low-density lipopro- tein, and decrease in high-density lipoprotein178* lQ have all been causes or concern and reasons why diuretics are used less often as first-choice agents. Some investigators have suggested that some of the relatively disappointing results in ischemic heart disease in recently reported trials in mild hyperten- sion181-186 may have been the result of these effects, perhaps hypokalemia, in particular, because these studies have tended to use relatively large doses. However, there is one possibly advantageous long- term metabolic effect, a reduction in urinary calci- um loss, so there may be less bone demineralization in patients on long-term thiazides,ls7 which may be of benefit in postmenopausal women.

CONCLUSIONS

There are several possible first-choice agents for treatment of hypertension: beta-adrenoceptor- blocking drugs, a combined alpha/vasodilator beta- adrenoceptor-blocking drug, vasodilators (i.e., drugs acting primarily to reduce peripheral resistance), calcium antagonists, alpha-l-blocking drugs and, more recently, the possibility of ACE inhibitors. Diuretics are also possible first-choice agents, although they are not used quite as frequently as they once were. The selection of a drug may, of course, be influenced by concomitant pathology, with positive indications for a particular drug (e.g.,

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Volume 114 Number 4, Part 2

with coexistent angina, a beta-receptor-blocking drug or calcium antagonist, or with fluid retention, a

diuretic) or contraindications (e.g., in asthma, beta adrenoceptor-blocking drugs). Whether or not a patient’s blood pressure is controlled by one drug, it is likely to react in a similar fashion to other agents belonging to the same class. However, at times a change within a group may be useful as fewer side effects may be seen with an alternative drug. The majority of cases of hypertension can usually be controlled by one drug, even if that drug is not the agent of first choice.

More severe cases may require drugs from two of the three major groups: beta-blocking drugs, vasodi- lators, and diuretics are often required and, finally, in some cases, drugs from each group may be necessary. Drugs like methyldopa, clonidine, and the adrenergic neurone inhibitory drugs are now used more as reserve agents.

Three considerations are important in evaluating the response to antihypertensive treatment. An inadequate dose of a drug may be used, which could lead to the false conclusion that the agent is ineffec- tive so that a change is made to another drug. Of course a deliberate choice may be made to limit dosage to an arbitrary level and treatment changed if control is not satisfactory, but it should be under- stood that this may mean a drug is underexploited. On the other hand, in some instances patients may be well controlled by lower dosages than usual, the standard dose merely increasing the likelihood of side effects. Second, too rapid an increase in dosage may result in severe or unnecessary side effects, and this is likely to jeopardize patient confidence and compliance. A dosage achieved by more gradual increments may be better tolerated with fewer or no untoward reactions. Rapid increase in dosage may be indicated in severe hypertension, but unneces- sary haste in less severe instances should be avoided. If one drug is being substituted for another on an outpatient basis, in patients with more severe hyper- tension, it is important to make small increases in doses of the new drug and small decreases in the previous drug in order to avoid excessive decreases in blood pressure or increases which cause blood pressure to rise above safe levels. Clearly, in mild hypertension where treatment is not urgent, an abrupt change in treatment may be made as untreated pressures are not high. Finally, the long- term treatment of hypertension is usually more successful if patients are properly motivated and they understand the long-term preventive objectives of treatment. It is also important to warn patients about side effects in general terms and to tell them

Choice of antihypertensive regimen 1035

that these often subside with time. However, care should be taken not to suggest specific side effects unless particular possible effects of the drug or circumstances dictate an action to the contrary. It is also helpful for patients to understand that if one regime is unsatisfactory for them there are other possibilities.

The choice of antihypertensive drug is based principally on the ability of a given agent to lower blood pressure and reduce complications in relation to the side effects that it produces. The reduction of blood pressure seems to be the principal basis for the therapeutic benefit, although there is the possi- bility of a cardioprotective effect of beta-adrenore- ceptor-blocking drugs. At present, there is no ideal drug.

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Antihypertensive co tam&s as rkythmic agm~ts: Focus on beta4Hockimg clc in veMricu&w arrhythmias

Bramah N. Singh, M.D., D.Phil.(Oxon.), F.R.C.P.(Lond.), F.R.A.C.P., and Koonlawee Nademanee, M.D. Los Angeles, Calif.

Numerous general classes of antihypertensive agents are now available-diuretics, angiotensin- converting enzyme inhibitors, beta-blocking agents, and calcium entry blockers. The cardiovascular properties of these agents differ, often markedly. Some of them exert significant antiarrhythmic actions. This is particularly true of beta blockers and calcium channel blockers. These two classes of agents exert somewhat similar electrophysiologic actions on the sinus node, atria, atrioventricular (AV) node, ventricular myocardium, the His-Pur- kinje system, and on the accessory tracts.

As one might expect, the two classes of drugs exert a qualitatively similar spectrum of activity with respect to supraventricular tachyarrhythmias. For example, beta blockers and calcium entry blockers,

From the Department of Cardiology, Cardiovascular Research Laboratory, and UCLA-Wadsworth Arrhythmia Unit, Wadsworth Veterans Adminis- tration Hospital and the Department of Medicine, UCLA School of Medicine. Supported by grants from the Medical Research Service of the Veterans Administration and the American Heart Association, the Greater Los Angeles Afilliate, Los Angeles, Calif. Reprint requests: Brsmsh N. Singh, M.D., Department of Cardiology 691/111E, Wadsworth VA Hospital, Wilshire and Sawtelle Blvd., Los Angeles, CA 90073.

such as verapamil and its congeners and diltiazem, slow the ventricular response in atrial flutter and fibrillation and occasionally convert them to sinus rhythm, especially those of recent origin.’ When given intravenously they produce a relatively high rate of conversion of reentrant paroxysmal supra- ventricular tachycardia to sinus rhythm. These effects of beta blockers and of verapamil and similar drugs are undoubtedly the result of the actions of these compounds on the AV node. On the other hand, the effects of beta blockers and calcium channel blockers differ markedly in the case of ventricular arrhythmias. Unlike beta antagonists, calcium channel blockers are weak suppressants of premature ventricular contractions; they have not been shown to decrease the incidence of sudden death in survivors of acute myocardial infarction. However, they are effective in preventing ventricu- lar arrhythmias complicating coronary artery spasm and ventricular tachycardia induced by exercise.le3 They are also effective in certain forms of ventricu- lar tachycardia occurring in the context of the normal heart, for example, ventricular tachycardia with the QRS morphology of right bundle branch block and left-axis deviation.2

In this article, the role of calcium channel blockers

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