Antihypertensive therapy: New pharmacological approaches

Appraisal and reappraisal of cardiac therapy Edited by Arthur C. DeGraff and Julian Frieden

Antihypertensive therapy: New

pharmacological approaches

Gordon S. Stokes, M.D., F.R.A.C.P. Helen F. Oates, B.Sc. (Hon. I), Ph.D. E. Paul MacCarthy, M.B., B.Ch., M.R.C.P.I. Sydney, Australia

Over the last 30 years an increasing proportion of hypertensive subjects have come to be treated with antihypertensive drugs. The first drugs used, though life-saving in their day, were too toxic .and were replaced by others which produced fewer side effects. Knowledge of the sites and mechanisms of action of antihypertensive agents has greatly increased. Newer agents have been developed for greater selectivity. However, there has not been a corresponding growth in the understanding of the patbogenesis of hypertension, nor is it yet feasible in the clinic to analyze the mechanisms giving rise to hypertension in individual patients. Indeed, it has been claimed that the concept of prospectively individualizing antihypertensive therapy remains largely hypothetical.’ These considerations may help to explain why, despite a steady flow of interesting new antihypertensive substances from the pharmaceutical industry, clinical trials have often failed to con- firm that greater specificity in drug action achieves a better therapeutic result. We appear to have reached a plateau in therapeutic efficacy.* It may then be asked, does a precise knowledge of the specific sites and mechanisms of drug action really help in choosing treatment for the individual patient with high blood pressure? Further, what justification exists for prescribing the more selective drugs?

We propose that understanding the action of an antihypertensive agent helps to predict and

From the Cardio-Renal Unit, Medical Research Department, Kane- matsu Memorial Institute, Sydney Hospital, Sydney, Australia.

Received for publication Oct. 15, 1979.

Reprint requests: Dr. Gordon S. Stokes, Cardio-Renal Unit, Medical Research Dept., Kanematsu Memorial Institute, Sydney Hospital, Sydney, Australia 2000.

0002-8703/80/110741+ 12$01.20/O 0 1980 The C. V. Mosby Co.

recognize its side effects, to avoid adverse interactions with other drugs, and to obtain additive hypotensive effects by combining it with drugs acting elsewhere. Such information is integral to the design of systems of stepped-care therapy, through which individualization of treatment, though empirical, can proceed along rational lines. In this review, we will outline what is known about the modes of action, the side effects, and the applications of currently available antihypertensive drugs, and will analyze their contri- butions to a system of stepped-care therapy.

I. Mechanisms of action and interaction of

antihypertensive drugs

Antihypertensive drugs fall into four main groups: diuretics, angiotensin inhibitors, vascular smooth muscle relaxants, and sympatholytic drugs. The clinical relevance of the angiotensin inhibitors is yet to be clearly defined, and they are restricted to investigational use at present.

1. Diuretics. These act principally by causing renal loss of sodium and water, with reduction in intravascular volume and cardiac output. In the early stage of diuretic therapy, the hypotensive effect reflects mainly a fall in cardiac output.3 In the later stage, secondary adjustments restore cardiac output, but blood pressure control is maintained through peripheral vasodilatation.4 Discussion of the differences between the diuretics in their renal tubular actions is beyond the scope of this paper, but may be found in the review by Seely and Dirks.”

2. Angiotensin inhibitors act by preventing the effects of the renin-angiotensin system upon vascular smooth muscle, and, possibly, upon the adrenal cortex, kidney, and brainstem. Angioten-

American Heart Journal 741

Stokes, O&es, and MacCarthy

Tabie I. Main classes and generic names of antihypertensive drugs in general use

A. Diuretics (a) Thiazide and

related diuretics Chlorothiazide Cyclopenthiazide Bendrot-luazide Methyclothiazide Metolazone

(b) Loop diuretics

Furosemide Ethacrynic acid Bumetanide

(c) Uricosuric

Ticrynafen

(d) K’ conserving

Spironolactone Triamterene Amiioride

B. Angiotensin inhibitors (a) Angiotensin antagonists (5) Converting-enzyme inhibitors

C. Vascular smooth muscle relaxants Hydralazine Diazoxide Nifedipine Minoxidil Verapamil Sodium nitroprusside

D. Sympatholytic drugs (a) Centrally-acting (b) Peripherally-acting” (c) P-adrenergic blockers

(site of action unclear) Reserpine Guanethidine Propranolol Methyidopa Oxprenolol Clonidine Alprenolol Guanabenz Phentolamine Prindolol Tiamenidine Phenoxybenzamine Sotalol Guanfacine Tim0101

Acebutolol I Labetolol Metoprolol

Atenolol

*Ganglion blocking drugs excluded. ~Neurori blocking drugs. $Alpha-adrenergic receptor blocking drugs. SCombined alpha- and beta-adrenergic receptor blocking drug.

sin antagonists competitively block the action of angiotensin II on its receptors, whereas converting enzyme inhibitors interfere with the conver- sion of angiotensin I to angiotensin II. Unfortu- nately, controversy surrounds the mode of action of the potentially most useful member of this group, the converting enzyme inhibitor, captopril. This drug, the only angiotensin inhibitor yet developed which is effective by the oral route, also potentiates the kinin system, and possibly produces its hypotensive action in part through this or other, still undefined, pharmacologic mechanisms.6 Nevertheless, a recent review of 19 hypertensive patients treated for periods of up to 6 months has shown that the blood pressure reduction produced by captopril was correlated both with the pretreatment plasma renin activity and with the suppression of urinary aldosterone excretion.’

3. Vascular smooth muscle relaxant drugs alter cellular calcium flux and cause direct vasodilatation.8 Their actions are independent of alpha- and beta-adrenoreceptors.

. Sympatholytic drugs interfere with neuro-

humoral transmission at various points in the sympathetic nervous system. This, the largest group, can be divided on a pharmacological basis into many classes. However, from a therapeutic viewpoint, the simple classification &own in Table I will suffice.

The ways in which the centrally-acting class lower blood pressure are still unclear, but they have in common the ability to reduce central sympathetic outflow. This may be demonstrated most graphically by showing the decreased rate of spontaneous firing of pre-ganglionic sympathetic neurons after administration of the drug into t cerebral ventricular system.9 In the case of methyldopa, clonidine, and clonidine-like drugs (guanabenz, tiamenidine, and guanfacine) the reduction of sympathetic traffic appears to result from an alpha-adrenergic agonist effect operating on the central inhibitory pathways leading to the vasomotor center, although other central mechanisms of action have been proposed for clonidine.‘” Reserpine causes depletion of catecholamines from both central and sympathetic neurons.“’ The action of methyldopa is thought to

November, 1980, Vol. 100, No. 5

Antihypertensive therapy

SYNAPTIC CLEFT PRE-JUNCTIONAL

NERVE CLONIDINE GUANFACINE TIAMENIDINE /

PliENOXYi3ENZAMlNE PHENTOLAMINE

POST-JUNCTIONAL

CELL

Fig. 1. Actions of some antihypertensive agents on the alpha-adrenergic receptors of the peripheral neuro-effector junction. + = agonist effect; --I receptor blockade

depend on its active metabolites, including alpha-methylnorepinephrine, which has a potent alpha-agonist effect centrally, but little peripheral effect.12 Clonidine and its congeners have been shown to exert a potent agonist effect at the pre-synaptic alpha-receptors of the sympathetic neuroeffector junction (see Fig. 1). This property, which causes a diminished release of neurotransmitter, may contribute to the decrease in circulating catecholamines observed in patients treated with clonidine’” or guanfacine.14 These agents also have a relatively weak peripheral post-junctional alpha-agonist effect, which may result in an initial pressor response following their intravenous administration.15

Those antihypertensive drugs which are known to have a predominantly peripheral site of action include the adrenergic neuron blocking agents and the alpha-adrenergic receptor blockers (Ta- ble I). The ganglion blockers, which interfere with parasympathetic as well as sympathetic pathways, are now of histaorical interest only and have no part in the present-day treatment of hypertensive cardiovascular disease (although they still have a limited role in blood pressure control during anesthesia anld in the treatment of aortic dissection, e.g., trimethaphan). The adrenergic neuron blockers are taken up into the nerve ending by “uptake,,” the mechanism responsible

American Heart Journal

for re-uptake of neurotransmitter norepinephrine. They displace the neurotransmitter in stor- age granules and also interfere directly with the coupling of nerve impulses to exocytotic release. Alpha-adrenergic receptor blockers lower blood pressure by preventing the agonist effect of neurotransmitter upon the post-junctional alpha- receptors at the sympathetic myoneural junc- tions of vascular smooth muscle (Fig. 1). They may be classed as relatively selective (e.g., prazosin) or non-selective (e.g., phenoxybenzamine), depending upon the degree to which the pre- junctional alpha-receptors are also blocked. It has been suggested that pre-junctional alpha- adrenergic blockade, which interferes with the negative feedback control of neurotransmitter release, is disadvantageous”j and may account for the greater problems encountered with phenoxybenzamine in clinical practice than with prazosin.16 Labetalol, a new antihypertensive agent with both alpha- and beta-adrenergic receptor blocking actions, is more potent at beta-receptors than at alpha-receptors in man, but it is not known which of these effects is of the greater importance in reducing blood pressure during chronic oral administration.17

It has not been established how beta-adrenoceptor blocking drugs lower blood pressure. Vari- ous central and peripheral sites of action have

743

Stokes, O&es, and MacCarthy

le il. Homeostatic reflexes opposing bloo pressure control

1. Baroreceptor reflexes (a) Alpha-adrenoceptor mediated vasoconstriction jb) Beta-adrenoceptor mediated cardiac stimulation

2. Renal retention of salt and water 3. Renin-angiotensin system

been proposed.18 However, agents recently developed for beta-l receptor blocking selectivity (metoprolol, atenolol) have proved to be at least as effective in reducing blood pressure as the non- selective beta-l and beta-2 receptor antagonists. Thus it has been possible to decrease some of the undesired effects of beta-2 receptor blockade without loss of antihypertensive efficacy.

Proper application of drugs of the sympatholytic group may be of critical importance in the treatment of severe hypertension, because they counteract the baroreceptor-mediated homeostatic reflexes which combat the antihypertensive effect of the other groups of drugs (see Table 11). Wbile there are several types of drugs, acting at different sites, which can interrupt sympathetic neural traffic to the vascular al~ba-adre~orece~- tom, the only antihypertensive agents which block the cardiac limb of the baroreceptor re are the beta-adrenergic blockers. It should noted that they serve this important function in addition to exerting a hypotensive effect of their own. Agents which diminish reflex cardioacceler- ation in less specific ways include clonidine (by central vagotonic and peripheral pre-synaptic alpha-receptor agonist interactions) and indoramin (by direct negative chronotropic effect).

A second homeostatic function that may interfere with blood pressure control is the renal retention of salt and water which occurs whenev-

ney perfusion pressure drops. This mecba- nism operates, tending to restore the blood pressure to a high level, when potent smooth muscle relaxant or sympatholytic drugs are used without adequate diuretic therapy.‘g The term “‘false tolerance” has been coined to emphasize the subtle nature of this problem, which can exist in the absence of demonstrable edema.20 To overcome such tolerance it may be necessary to use large doses of loop diuretics, especially in patients with renal impairment.

Another renal mechanism which can override the effects of antihypertensive agents is activa-

tion of the renin-angistensin system. Increased circulating levels of renin and angiotensin, together with an increased hypotensive response to angiotensin ~nb~~itors, are found during treatment with diuretics or smooth muscle relaxant

rugs. Conversely, maintenance therapy with beta blockers reduces plasma renin activity to an extent determined mainly by the intrinsic sympa- thomimetic activity of the particular beta-bloek- er used,” and the influence of concomitant therapy.‘” In general, the centrally-acting sympatholytic drugs also decrease renin release, whereas the peripherally-acting class have a variable effect.

To summarize, the primary action of hypotensive drugs can be opposed by homeostatic reflexes listed in Table 11, Failure to respond to therapy may reflect the influence of one or more of these. It is often possible to recognize the particular mechanism operative in an individual patient. For example, during treatment with a potent vasodilator agent, the occurrence of e weight gain, or an increase in measured volume would point to the need for additional diuretic therapy, whereas the pr cardia and a high cardiac output for the addition of a beta-blocker peutic regimen.

A tborough knowledge of the side effects encountered with various antihypertensive drugs is essential for choosing the most suitable agent for each individual patient. Side effects which can be anticipated and which may inAuence such a C are discussed below.

ovolemia. A fall in blood volume may occur immediately after the introduction of diuretic therapy, or with the intermittent use of a diuretic. Because of the associated hazards of hypotension and blood hyperviscosity, a risk of precipitating cerebral ischemia exists in patients with eerebrovascular disease. Thus, the potent diuretics such as furosemide should rarely be used in elderly subjects, and diuretic therapy should be avoided altogether in patients with transient ischemic attacks.

2. Hyperuricemia. Most diuretics tend to raise serum uric acid concentration, probably because of an increased passive reabsorption of urate in

November, 1980, Vol. 100, I’fo~ 5


the kidney accompanying compensatory shifts of proximal tubular fluid. In the case of ticrynafen, this tendency is countered by specific inhibition of the re-absorption of both filtered and secreted urate.23-25 Clinical gout is precipitated in only a small proportion of patients who develop hyperuricemia as a result of treatment with a diuretic. In such individuals, or in those who present with a history of gout of hyperuricemia, a number of therapeutic strategies are available. a. Avoid the use of diuretics completely. b. Use ticrynafen. c. Use a diuretic plus probenecid (which inhibits renal tubular reabsorption of urate). d. Use a diuretic plus allopurinol, which inhibits the pro- duction of uric acid. If there is evidence of increased uric acid turnover, options (a) and (d) are preferable to (b) and (c), both of which promote uricosuria and can cause crystallu- ka 26. 37

3. Changes in serum potassium levels, All diuretics except those of the potassium-conserving class (Table I) increase distal tubular potassium secretion and can lead to an appreciable fall in serum potassium concentration. This may have serious consequences in patients receiving digital- is, or in those with primary aldosteronism, liver disease, or pre-existing potassium depletion. How- ever, diuretic-induced hypokalemia rarely produces problems in patients with uncomplicated hypertension. Potassium-conserving diuretics tend to produce hyperkalemia when given to patients with diabetes mellitusZ8 or impaired renal function. Means of potassium supplementation, and their relative e;@cacy and safety, have been reviewed recently.‘9

4. Carbohydrate intolerance. Thiazide diuretics may cause a rise in blood sugar in diabetic patient@’ and may occasionally induce hypergly- cemia and glycosuria in previously normal peo- ple.“’ Carbohydrate intolerance has also been reported with the use of loop diuretics.32 The mechanism is not wholly understood,33 but there is evidence for both impaired pancreatic insulin release and defective glucose utilization by peripheral tissues. Thus, a relative contraindica- tion to diuretic therapy exists in patients with diabetes mellitus or known carbohydrate intolerance. This, however, should not countermand the use of diuretics in such subjects when their hypertension is resistant to other therapy or is complicated by fluid retention.

5. Hypercalcemia. Chronic administration of

thiazide and related diuretics reduces calcium excretion by a mechanism analogous to that which pertains to urate. 34 A rise in serum calcium may result. This is usually minor, but could be deleterious in patients with pre-existing hypercalcemia due to metabolic disorders, such as hyper- parathyroidism.

B. Angiotensin inhibitors. Administration of the oral converting enzyme inhibitor, captopril, has induced febrile reactionq7 rashes,? loss of taste sensation3j and reversible renal failure.36 Intravenous administration of the angiotensin analog, saralasin acetate, has been associated with pheochromocytoma crisis, occurring during the infusion,37 and rebound hypertension with encephalopathy occurring one to three hours after stopping the infusion.38 In general, angiotensin inhibitors may produce severe depressor responses in conditions of strong angiotensin II dependency, such as extreme sodium depletion, renovascular hypertension, and intercurrent therapy with diuretic or vasodilator drugs.39

C. Vascular smooth muscle relaxants. 1. Side effects common to all smooth muscle

relaxant drugs. The symptoms of a hyperkinetic circulatory state (flushing, headache, and pound- ing in the ears or chest) may be observed with any drug which produces vasodilatation by a direct action on arteriolar smooth muscle. Tachycardia and fluid retention, resulting from unopposed homeostatic adjustments (already outlined), are also common to all drugs pf this group. All these symptoms may be countered by the adjunctive use of sympatholytic or diuretic agents, this being essential with the more potent drugs of the group, such as minoxidil.

2. Side effects peculiar to particular smooth muscle relaxant drugs.

HYDRALAZINE. The most important side effect of hydralazine is the development of a syndrome resembling systemic lupus erythematosus. The drug is best avoided in patients with a family history of lupus, and dosage should be restricted to a ceiling of 200 mg. per day in known slow acetylators or in subjects with renal impairment. Other side effects specific to hydralazine have been reviewed by Alarcon-Segovia and asso- ciates.“O

MPNOXIDIL. This drug, the most potent of the orally active peripheral vasodilators, is potentially life-saving for refractory hypertension coupled with progressive renal impairment, but may cause


Stokes, Bates, and MacCarthy

severe fluid retention.41-43 Pericardial effusion may Occur without generalized edema.44 Hyper- trichosis occurs in both sexes, and the growth of facial hair commonly causes distress in women However, calcium thioglycolate depilatory cream is effective in removing unwanted facial hair, and causes little or no skin irritation, thus allowing continuation of minoxidil therapy in women with hypertension resistant to other agents.45

DIAZOXPDE. iazoxide has bad its widest use in hypertension as an injectable solution, given intravenously in a dose of 150 to 300 mg. for the control of hypertensive crises. A rapi fa11 in blood pressure, taehycardia, transient hypergly- cemia, and stimulation of renin release occur after injection. 46 The latter effect has useful in diagnosing renovascular hyperte Because it causes reflex tachycardia and increases cardiac output, diazoxide should not be used to treat the severe hypertension associated with aortic dissection.‘* The chronic administration of diazoxide by mouth, althougb effective in eon- trolling severe hypertension associated with renal failure, is diabetogenic in about two-thirds of subjects,4s and may induce extrapyramidal symp- tQmS.sO

VERAPAMIL. Verapamil as received much more attention as an antianginal and antiarr- hythmic compound than as an antihypertensive agent. However, its potent smooth muscle relaxant effect produces a fall in blood pressurej’ when the drug is administered orally or intravenously. Constipation due to the relaxation of visceral smooth muscle is common5’ Since verapamil impairs atrioventricular conduction an dial contractility, it should not be given to patients with heart block or cardiac failure, nor should it be used in combination with beta- adrenergic blocking drugs.j2

NIFEDIPPNE. This new vasodilator, which was originally proposed for use in coronary vascular disease, has a potent hypotensive action which lasts for 6 to 8 hours after oral or sublingual administration of a 20 mg. dose.j3 Side effects reported with its use include sensations of heat in the face and limbs, and ankle edema. Compared to verapamil, nifedipine has a much less pro- nounced effect on the hearts4 and may be used in combination with a beta-blocking agent.

sonruM rWrRoPRussInE. Infusion of nitroprusside is an alternative to the use of diazoxide infusion in hypertensive crises. Constant monitor- ing of blood pressure and plasma thiocyanate

concentration is required to mamtain blood pressure control and to prevent toxic encephalopathy.“j These objectives can be facilitated use of a microprocessor to control the rate of

. ~yrn~at~o~yt~E drugs. a. ~~~trally-~ct~~~ sy~p~t~~~yt~c agents. 1. SIDE EFFECTS RELATED TO CENTRAL DE-

PRESSANT ACTIVITY AND INTERACTIONS WITH PSY- CHOTROPIC THERAPY. All centrally-acting antiby- pertensive drugs may cause significant daytime sedation, which often improves spontaneously as therapy contineaes. Tbose in widespread clinical use (reserpine, methyldopa, and clonidine) have each been associated with an appreciable inei- dence of severe depression. Tricychc antidepressant drugs may interfere with the antihypertensive actions of clonidinej’. j8 or rnethy~do~a~~~ probably due to interactions at the central alpha-adrenoreceptors in the brainstem. Unfavor- able interactions may also occur between mono- amine oxidase inhibitors and methyldopa. In view of the problems which can arise during the management of depressive patients receiving centrai- ly-acting antihypertensive agents, they shoui not be prescribed for patients with a previous history of endogenous depression, except in the exigency of known resistance to peripheraily- acting antihypertensive agents.

2. WITHDRAWAL REACTIONS. %n patients treated with elonidine for severe hypertension, abrupt withdrawal of this agent can provoke a syndrome characterized by acute by~erte~s~on~ tacbycardia, and other features of sympathetic discharge.59-6Z Similar reactions have been noted after acute withdrawal of methyldopa,53 guanabenz,6” and guanfacine.65 Considerable d ment exists, however, concerning the in magnitude, and chnical importance of tru shoot” hypertension during withdrawal reactions. There have been numerous case reports of severe and occasionally disastrous hypertensive crises after stopping clonidine, and three groups have reported ’ features of sympathetic overactivity with or without overshoot hypertension even after controlled withdrawal of the drug.Go-6’ Con- versely, others have found no evidence of sy thetic overactivity after withdrawal of the drug apart from raised urinary norepinephrine exere- tionG6 All these studies have been criticized on various grounds, including lack of pretreatment blood pressure data and insufficiently close mon- itoring during the withdrawal phase. The obvious


difficulties in carrying out and interpreting appropriate experiments in hypertensive patients has pointed to the need for controlled studies in normotensive subjects and in experimental ani- mals. We have demonstrated significant over- shoots in blood pressure and heart rate 16 to 24 hours after even single doses of clonidine or guanfacine in normotensive rats.67. 68 Another group has confirmed these findings, although they failed to demonstrate overshoot in hypertensive rats.69

It is the authors’ opinion that the hazards of clonidine withdrawal are real enough to warrant avoiding this drug in patients who have a history of poor compliance with drug therapy. If chronic oral medication with clonidine is interrupted by acute gastrointestinal disorders or the need for general anesthesia, therapy may be continued by the intramuscular route.‘O

3. OTHER RELEVANT SIDE EFFECTS OF CEN-

TRALLY-ACTING ANTIHYPERTENSIVE AG.ENTS.

Drugs in this class may occasionally cause sexual dysfunction in males and so threaten compliance. Since bowel disturbances may result from treatment with methyld’opa, or clonidine, it is preferable to avoid using these agents in patients with enterocolitis. Reserpine, especially when given in large doses, may aggravate peptic ulcer disease. Postural hypotension occurs infrequently with both methyldopa and clonidine, but is more prominent with guanabenz, which has a subsidia- ry peripheral adrenergic neuron blocking effect.”

b. Peripherally-acting sympatholytic agents. 1. SIDE EFFECTS OF NEURON BLOCKING DRUGS.

The side effects of this class, which is long established in clinical therapy, are well known and will not be detailed here. The most important are postural hypotension, diarrhea, and interrup- tion of the ejaculation reflex. The antihypertensive action of neuron blockers is severely impaired by tricyclic antidepressant therapy,72 probably through competition for the neuronal uptake process.

2. SIDE EFFECTS OF ALPHA-ADRENERGIC RE-

CEPTOR BLOCKING DRUGS. Postural hypotension has been the most frequent and troublesome side effect with alpha-adrenoceptor antagonists. Hence, it is inadvisable to use these drugs in the elderly, or in subjects with known cerebrovascu- lar or coronary insufficiency. Particularly severe reactions have been reported after the initial dose of prazosin or as a response to dosage increments

of this agent.16 This “first-dose phenomenon” is aggravated by prior sodium depletion73 or by the presence of renal failure.‘” It has been attributed to selective blockade of visceral sympathetic activity,75 but usually subsides despite continued therapy. The problem is minimized by starting with a small dose in the evening.lG However, postural hypotension and tachycardia persist during chronic therapy in a small proportion of patients, and may necessitate withdrawal of the drug.16 Postural hypotension necessitated withdrawal of labetalol in three of 16 patients in one series treated with this combined alpha- and beta-receptor blocking drug,76 and has been a prominent side effect in other recent trials with labetalol. Failure of ejaculation occurs occasionally with labetalol, but has not been definitely associated with prazosin or indoramin. The use of indoramin, even in low doses as part of a multiple drug regimen, is limited by its central depressant action.?? The other members of this class of drugs uncommonly cause central side effects, and their acceptance by patients has been generally good, except in the case of phenoxybenzamine.78

3. SIDE EFFECTS OF BETA-ADRENERGIC RECEP-

TOR BLOCKING DRUGS. We will not attempt to give a comprehensive description of the side effects of this class, which have been well reviewed elsewhere.78 However, certain guidelines may be help- ful in selecting therapy.

(i) The side effects of beta-blockers can be readily predicted, for the most part, on the basis of their interference with beta-receptor mediated sympathetic transmission to the heart, bronchi, and peripheral blood vessels. The central nervous and metabolic effects of these drugs are less well understood.

(ii) Since these agents interrupt sympathetic drive to the heart, they should not be used in patients with heart failure, bradyarrhythmias, or atrioventricular conduction block.

(iii) All drugs of this class reduce maximal exercise performance, and tend to induce mild lassitude. These effects are a consequence mainly of cardiac beta-adrenergic blockade, although peripheral vasoconstriction mediated by beta-2 receptor antagonism and central nervous depression may be contributory. Beta-blockers may prove unacceptable to patients who engage in competitive sports.

(iv) Most other side effects including bronchospasm, peripheral vasospasm, and potentiation of hypoglycemia in diabetic subjects appear to be


$ab~e !I 1. Some contraindications to the use of certain drugs in hypertension

G-out Hyperuricemia Hypokalemia

Hypercalcemia

Depression

Poor drug compliance

Transient ischemic attacks

Old age

Treatment with tricyclic substances

Angina pectoris Tachycardia

Cardiac failure Bradyarrhythmia A-V block

Asthma Insomnia

Raynaud’s syndrome Calf Claudication

i Thiazide diuretics Loop diuretics

Tbiazide diuretics

I

Reserpine, metbyldopa Clonidine

Clonidine

Potent diuretics

I

Adrenergic neuron blockers Alpha-zdrenergic blockers

i

Adrenergic neuron blockers Clonidine, methyldopa

Smooth muscle relaxants

! Alpha-adrenergic blockers*

i

Beta-adrenergic biockers Verapamil

Beta-adrenergic blockers

Non-selective beta-blockers

‘Except in the presence of beta-adrenergic blockade.

lower in incidence with beta-l selective blockers than with those of indiscriminate beta-l and beta-2 affinity. However, increased selectivity has resulted in limited gains, because receptor selectivity is relative and not absolute, and also because most organs appear to have populations of both beta-l and beta-2 receptors despite a

minance of one type or the other. Presumably, cardioselective drugs should have less tenden-

cy to produce bronchospasm or exacerbate symptoms of peripheral vascular disease. However, severe asthmatic reactions and Raynaud’s phenomenon have been reported with the use of these selective agents. All beta-blockers should be avoided in asthmatic patients or in subjects who give a history of persistent wheeze during respira- tory infections, and similarly in patients with peripheral gangrene or other evidence of severe vasospasm. Beta-blockers are not contraindicated in hypertensive diabetic subjects, except perhaps those whose control is brittle or those prone to frequent hypoglycemic reactions. Beta-l selective blockers are preferable for use in patients.80 The question of whether beta-l selectivity improves diastolic blood pressure control

. Some indications for the use of certam drugs in hypertension

Cardiac failure Diuretics (any) Edema ,l

Hyperuricemia Ticrynafen Hypokalemia K+-conserving diuretics

Migraine 1

Clonidine Beta-adrenergic blockers

Angina Beta-adrenergic blockers Palpitations Verapami! Ectopic beats Arrhythmias (not all)

Recent myocardial Beta-adrenergic blockers infarction

Essential tremor Propranolol

Severe cardiac Prazosin failure Hydralazine

Sodium nitroprusside Nifedipine

during stress is unresolved. Although exogenous epinephrine produces less rise in diastolic pressure during beta-l blockade than during non-selective beta-blockade, this phenomenon does not neces- sarily hold for situations of endogenous catecholamine release from the adrenal medulla or sympathetic nerve terminals.81

III. A system of stepped-care therapy

The questions to be considered in selecting drug treatment for a given patient with hypertension are :

1. What characteristics of the patient consti- tute indications or contraindications for the use of particular drugs?

2. Having decided which drugs suit the patient, what options exist for their use in appropriate combinations if combined therapy proves necessary to control the hypertension?

The first of these decisions involves patient- drug matching, while the second involves the matching of drug to drug in combinations which achieve additive hypotensive effects, but mini- mize side effects. Contraindications to specific drugs and classes of drugs have been discussed, and some of the more important examples are listed in Table III. Certain indications for particular drugs are given in Table IV.

These considerations form a background to


guide the choice of options from the following stepped-care system, which is summarized in Table V.

Steps 1 and 2. A thiazide diuretic remains the best choice for treating most mild cases of hypertension, and as the initial component of stepped- care therapy. More potent diuretics may be required for patients with hypertension and renal impairment or congestive heart failure. Until the role of ticrynafen in treating hyperuricemic hypertensive subjects has been established, it is probably wisest to withhold diuretic treatment in patients with gout or hyperuricemia, and to rely on the use of Step 2 agents.

The reasons for selecting a beta-blocker above the alternatives given in Step 2 are twofold. First, the incorporation of agents at Steps 3 and 4 is facilitated by prior beta-blockade. Second, the symptoms encountered with beta-blocker therapy are usually mild and show little relationship to dose within the conventional therapeutic range (e.g., for propranolol 20 to 480 mg./day).82 Thus, once therapy with a small dose is shown to be well tolerated, dosage may be escalated with little fear of provoking new side effects. In mild to moderate hypertension, adequate blood pressure control may be obtained by giving medication once per day. In severe cases it should be given twice per day, except in the case of atenolol, which has a longer duration of action.s3 Until more toxicolog- ical data have accumulated to show that beta-l blockers are as safe as the established agents of the non-selective type, they should not necessari- ly be regarded as having superseded the latter. However, as already outlined, they are preferred in hypertensive subjects with diabetes or peripheral vasospasm. The conventional dose range for metoprolol is from 50 to 400 mg./day, and for atenolol it is from 50 to 200 mg./day. Since the dose-response curve for atenolol flattens above 200 mg./day, doses higher than this are not recommended.83

In patients with heart failure, asthma, or other contraindications to beta-blockers, there is a wide choice of alternatives, including the three shown in Table V. We do not recommend using any of these agents in maximal dosages, as it is usually better to go to Step 3 instead, adding an additional agent. Thus, the dosage ceiling recommended for methyldopa at Step 2 is about 1 gram/day, for appreciable central depressant symptoms are commonly encountered with higher doses. The

Table V. A stepped-care system of antihypertensive drug treatment

Step 1. Diuretic Step 2. Diuretic + ,&blocker

Or Methyldopa Or Debrisoquine

i Low Dose

Or Clonidine Step 3. Diuretic + P-blocker + prazosin

Or other Or Hydralazine Step 4. Loop

diuretic + P-blocker + minoxidil

ceiling suggested at Step 2 for clonidine is 0.45 mg./day, and for debrisoquine it is 20 mg./day. In mild to moderate hypertension only, prazosin (up to 6 mg./day) or hydralazine (up to 100 mg./day) are also suitable alternatives to beta-blockade.

Step 3. The prior introduction of a diuretic and a beta-blocker allows the commencement of a peripheral vasodilator at Steps 3 and 4 without the development of cardiac stimulation or refrac- toriness due to secondary fluid retention or hyperreninemia. The synergistic actions of propranolol and hydralazine have been well docu- mented.8”. 85 Although the properties of beta- blockers are not as strongly complementary to those of prazosin as they are to those of hydralazine, their hypotensive effects summate with that of prazosin and the following synergistic interactions occur’6: (1) the tendency for prazosin- induced orthostatic tachycardia is countered by the negative chronotropic action of beta-blockers; (2) the blood pressure in the standing position tends to be higher than in the supine position with beta-blockers but lower with prazosin; (3) prazosin will prevent the predominance of unopposed alpha-constrictor vascular tone consequent upon blockade of the beta-2 receptor-mediated vasodilator mechanism; (4) beta-blockers may prevent the provocation of angina pectoris by prazosin.

In the presence of adequate beta-blockade, the dose of prazosin may be increased to 30 mg./day and that of hydralazine to 200 mg./day (or higher in rapid acetylators with normal renal function). However, such doses may not be well tolerated in patients who, because of contraindications to beta blocker therapy, were given one of the other sympatholytic agents at Step 2. Except in regard to the negative chronotropic ,effect of clonidine, additive but not synergistic relationships exist between these agents and prazosin or hydrala-


Stokes, Oates, and MacCatihy

zine. Thus, if the addition of relatively small doses of either prazosin or hydralazine fails to achieve blood pressure control, it may be necessary to increase the dose of methyldopa, debrisoquine, or clonidine above the levels indicated at Step 2.

A further alternative at Step 3 is to substitute labetalol, a combined alpha- and beta-adrenergic blocking drug, for the beta-blocker previously administered.

tep 4. This step should be required only in the most resistant cases of severe, chronic hypertension, associated with evidence of progressive reti- nal, renal, or cardiac damage. TWQ new elements are added: (1) minoxidil, a potent, but potentially toxic, smooth muscle relaxant drug, the use of which is restricted by governmental regulation in most countries (as is that of oral diazoxide, which is more toxic and probably not as frequently effective), (2) a dose-finding escalation of diuretic therapy with furosemide, bumetanide, or ethacrynic acid. The initial dose of minoxidil should be 2.5 mg. twice a day, increasing by increments of 2.5 mg. twice a day to a maximum of 40 mg./day. Beta-blocker therapy is a prerequisite, in order to counteract reflex tachycardia. Doses of loop diuretic well beyond the conventional may be required to overcome the tendency to salt and water retention associated with hypertensive nephrosclerosis and minoxidil therapy; in the case of furosemide, up to 500 mg. twice a day may be required.

snclusions

The deployment of the newer, more selective drugs for the treatment of hypertension can be analyzed from several points of view. Ideally, these drugs should be applied specifically in each case to rect the perturbation inducing hypertension. ecause the pathogenesis of most forms of hypertension is not clearly understood, such a met nistic approach is rarely possible at present. owever, understanding the mode of action and the side effects of an antihypertensive drug does allow, to a limited extent, appropriate matching between drug and patient. Even more importantly, it allows the drug to be fitted into a system of stepped-care therapy, in which antihypertensive agents are combined for synergistic effects. These effects depend upon the correction by one drug of the homeostatic reflexes activated by another, and allow the toxicity produced by single agents in high dosage to be avoided.

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November, 1980, Vol. 100, No. 5

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Antihypertensive therapy: New pharmacological approaches