KEYNOTE ADDRESS

Drug Therapy of Hypertension: What We Have,

What W-e Need, What We Expect

FRANZ GROSS, MD

Since 1949, decisive progress has been made in the treatments of hypertension. Whereas until the late 1940’s, only sedatives, vasodilators and inefficacious drugs were given to patients suffering from high blood pressure, the situation changed drastically when ganglionic blocking agents became available. Subsec&ently, in 1951, hydralazine and dihydralazine were marketed; in 1953 reserpine; in 195859 the thiazide saluretic drugs; in 1960 guanethidine; in 1962 alpha methyldopa, and in 1966-67 clonidine; since 1970, the beta adrenergic blocking agents have been increasingly used in the treatment of hyperten- sion. The forthcoming development will probably be focused on vasodilators, especially minoxidil, which in various respects supersedes hydralazine, In the United States, neither clonidine nor beta adrenergic blockers nor vasodilators other than hydralazine are accepted as antihypertensive agents. Undoubtedly the progress we experienced from about 1950 to 1965 has now leveled off, and it may take a rather long time until drugs can be expected that have a mode of action different from that of the preparations we have in hand.

What bo Wi Have?

According to their mechanism of action, the avail- able antihypertensive agents may be classified in three categories:

1. Drugs acting on the efferent sympathetic ner- vous system.

2. Drugs acting directly on arteriolar smooth mus- cle.

3. Drugs affecting the salt-water balance and, sec- ondarily, total peripheral resistance.

1. Drugs acting on the efferent sympathetic nervous system: These drugs may be classified as those acting only peripherahy, those acting mainly centrally and those acting both in the periphery and in the central. nervous system. Drugs acting exclu- sively in the periphery are the ganglionic blocking agents guanethidine and bethanidine, which do not pass the blood-brain barrier. Acting mainly centrally are drugs such as alpha methyldopa and clonidine;

the monamine oxidase inhibitor pargyline may also be mentioned, although it plays only a secondary role in the treatment of hypertension today. The drugs that act both in the periphery and in the central ner- vous system are, of course, reserpine and probably the beta adrenergic blocking drugs, although the cen- tral action of the latter has not been definitely estab- lished.

The peripherally acting drugs have a great ten- dency to induce severe orthostatic reactions and, in addition, have several other unpleasant side effects. Canglionic blocking drugs are only rarely used today since, with the appearance of guanethidine, drugs have become available that act exclusively on the pe- ripheral sympathetic nervous system. The drawbacks of guanethidine are that it is poorly and irregularly absorbed and, besides causing severe orthostatic reactions, may induce severe diarrhea and inhibit. ejaculation. Bethanidine is better tolerated and bet- ter absorbed but has not been accepted in the way one would have expected. In addition, it has been in- troduced in only a few countries.

The mechanism of action of the centrally acting drugs, which pass the blood-brain barrier, has been elucidated only recently. It seems that most of them act as sympathomimetic agents on central adrenergic receptors, the stimulation of which induces a reduc- tion in blood pressure. Such an effect can be demon- strated when noradrenaline is infused into the cere- bral ventricles, and the same is the case for alpha methylnoradrenaline, which in the central nervous system is formed from alpha methyldopa by way of alpha methyldopamine.’

The older concept that alpha methylnoradrenaline acts as a false transmitter in the central nervous sys- tem is therefore correct, but in the periphery it seems to be an effective replacement for noradrenaline as an adrenergic transmitter. That alpha methylnora- drenaline stimulates central adrenergic receptors could be demonstrated by administering alpha ad- renergic blocking agents, such as phentolamine or yo- himbine, both of which diminish the reduction in blood pressure induced by cerebral intraventricular

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DRUG THERAPY OF HYPERTENSION-GROSS

administration of either alpha methylnoradrenaline or noradrenaline.

Clonidine is a sympathomimetic agent that was initially studied in man as a nasal vasoconstrictor. It, too, probably acts on central adrenergic receptors, in a manner similar to alpha methylnoradrenaline.3 In addition, it exerts a peripheral sympathomimetic ac- tivity by reducing blood flow in the skin.

Monaminoxidase inhibitors may act centrally by increasing the concentration of noradrenaline, which subsequently affects alpha adrenergic receptors.

All of these compounds have similar side effects; they diminish mental alertness, induce drowsiness and a decrease in physical capacity, and reduce libido in man. In addition, tolerance to alpha methyldopa may develop, and the doses may have to be increased during the first weeks of treatment. All compounds that interfere with the efferent sympathetic nervous system prevent reflex tachycardia subsequent to the reduction in blood pressure, but bradycardia is espe- cially pronounced with clonidine, a fact previously known from the administration of sympathetic amines used as nasal vasoconstrictors, such as napha- zoline (Privinem) or xylometazoline (Otrivin@).

Reserpine acts peripherally and centrally; it de- pletes central and peripheral stores of noradrenaline and serotonin, especially by inhibiting the reuptake mechanism of noradrenaline into the adrenergic nerve terminals. It has a mild antihypertensive effect and reduces sympathetic tone in general, but it is not a strong sympathetic inhibitor, such as guanethidine or bethanidine. Its side effects are well known: stuffy nose, fatigue, drowsiness, tendency to develop de- pressive reactions, diminished activity and decrease in libido.

The most important recent advance in the treat- ment of hypertension is the use of beta adrenergic blocking agents. Outside the United States, about 12 of these agents are available today, of which the best studied compound is propranolol. Beta adrenergic blocking drugs act as antihypertensive agents by their direct effect on high blood pressure and by their prevention of tachycardia induced by vasodilators.

As competitive antagonists to adrenaline, the main endogenous beta stimulator, the beta adrenergic blocking drugs have a peripheral mechanism of ac- tion. In addition, they reduce the release of renin from the kidney and, in this way, diminish the forma- tion of angiotensin. Recently, their antihypertensive effect has been ascribed to their inhibition of renin release, and it has been claimed that they would be active only in cases of hypertension with elevated or normal plasma renin activity, but not in patients with low plasma renin concentration.4 This hypothe- sis has not been confirmed by other investigators5 who observed that the drugs also reduce blood pres- sure when plasma renin activity is low. However, it may be that the doses of propranolol that decrease blood pressure in, patients with low plasma renin lev- els are larger than in patients with high plasma renin activity.6*7 The data available do not justify limiting

the use of beta adrenergic blocking drugs in the treat- ment of hypertension to patients with high or normal plasma renin activity. In addition to having a periph- eral mechanism of action, these drugs may also act centrally, and it was recently demonstrated that in- traventricular (cerebral) administration of propran- 0101 induced an initial increase in blood pressure, which was followed by a prolonged decrease.s

Beta adrenergic blocking agents are useful not only in treating malignant hypertension, in which the renin-angiotensin system is markedly activated, but also in treating hyperkinetic hypertension, in which they may be given together with alpha adrenergic blockers, such as phentolamine. Propranolol may not be the most suitable beta blocking agent for the treatment of hypertension, since it has a wide dosage range, and doses of 320 up to 1,000 mg daily have to be given in various patients. Pindolol or timolol may be more suitable, since their dosage range seems to be narrower, and an average dose of 30 mg may be ade- quate. In general, the beta blocking agents are well tolerated, except by asthmatic patients and patients with impending heart failure. Side effects may be cardiodepression, especially with propranolol, dreams and nightmares with pindolol; suppressive moods (but less marked than with reserpine) and cold hands and feet, a sensation probably caused by the reduced muscle blood flow that occurs after inhi- bition of beta adrenergic receptors in the muscle vas- cular bed.

2. Drugs acting directly on the arteriolar smooth muscle: Of this group of drugs, hydralazine and dihydralazine have been used for nearly 25 years, and it is surprising that efforts to replace them have been made only recently. They have the disadvantage of producing reflex tachycardia and also have a direct stimulatory effect on the heart. Acute side reactions are headache, nausea, vomiting, tachycardia and an- gina, and-after prolonged treatment-rheumatoid arthritis and a syndrome similar to lupus erythema- tosus. During the past 15 years, hydralazine has been especially used in combination with reserpine or salu- retie agents, or both. Other vasodilators are diazox- ide, which has been accepted for short-term treat- ment of hypertensive crises, since its diabetogenic ef- fect prevents prolonged use. The most active vasodi- lator for the treatment of hypertensive crises is sodi- um nitroprusside, which has to be given by continu- ous infusion and is not yet available commercially. Despite its marked hypotensive effect it causes less tachycardia than other vasodilators. Guancydine, an- other drug that acts directly on smooth vascular mus- cle and has been widely studied by clinical investiga- tors, induces psychic disturbances. The position of prazosine, another similarly acting drug, has not yet been established.g

Minoxidil is the most promising new vasodilator. It is active in smaller doses then hydralazine, has a prolonged duration of action and is definitely more potent and better tolerated than hydralazine.‘O-l2 However, because of the tachycardia it induces, it has

472 October 1, 1974 The American Journal of CARDIOLOGY Volume 34

to be given together with a beta adrenergic blocking agent and, since sodium and water retention may occur, it also has to be combined with a diuretic agent. In addition to fluid retention and tachycardia, other side effects are nausea and hypertrichosis, which also develops after administration of other va- sodilators. It may be expected that vasodilators will soon find wider application in the treatment of hy- pertension, since their tachycardic effect may be pre- vented by beta adrenergic blocking agents, and a syn- ergistic effect of diuretic drugs is also demonstrable.

3. Drugs affecting salt-water balance and pe- ripheral resistance: Saluretic agents not only act on sodium and water balance, but also reduce total pe- ripheral resistance. l3 In addition, they may have a di- rect action on the arteriolar smooth muscle. An im- portant step forward is the development of potas- sium-sparing diuretic drugs, which, together with saluretic drugs, may be active in the elimination of salt but prevent the simultaneous loss of potassium. The combinations of hydrochlorothiazide and triam- terene or, recently, of hydrochlorothiazide and amilo- ride, are promising and are to be preferred to supple- ments of potassium chloride which, if given together with diuretic agents, may be rapidly eliminated. Spi- ronolactone in combination with saluretic drugs belongs to the same category, but has the disadvan- tage of producing gynecomastia. The most suitable saluretic agent for treatment of hypertension is the long-acting drug chlorthalidone; furosemide, al- though it is an excellent diuretic agent, is not suitable as an antihypertensive drug because of the rapid onset and short duration of its action.

What Do We Need?

The ideal antihypertensive drug should do the fol- lowing:

1. Induce a decrease in blood pressure that is of slow onset, not too pronounced, and similar in supine and standing positions.

2. Have a duration of action of 12 to 24 hours. 3. Be active when taken by mouth. 4. Produce no negative inotropic effect on the

heart, no tachycardia. 5. Cause no tolerance. 6. Cause no or only mild adverse reactions or side

effects, no reduction of physical capacity or mental alertness.

7. Be suitable for long-term treatment. The main goal for future antihypertensive therapy

should be to have more specifically acting and better tolerated drugs that also have a long duration of ac- tion.

Most of the requirements for antihypertensive agents are met by the drugs available today or by combinations of them. However, we are far from hav- ing an ideal drug since all those at hand have major disadvantages with respect to the side effects or ad- verse reactions they produce. In addition, with a few exceptions, such as hypertension caused by pheo- chromocytoma or primary aldosteronism, only symp-

DRUG THERAPY OF HYPERTENSION--GROSS

tomatic treatment is possible so far. Only recently, discriminating treatment according to pathogenesis has been started; for example, patients with sup- pressed renin response were found to benefit most from the administration of diuretic agents, not neces- sarily aldosterone antagonists, such as spironolac- tone, but also other saluretic drugs or combinations, such as triamterene or amiloride plus hydrochlo- rothiazide.

We need, above all, long-acting beta adrenergic blocking agents that can be given only once daily, have no cardiodepressive effect and do not induce bronchoconstriction; furthermore, centrally acting drugs that do not induce drowsiness and fatigue, and do not affect alertness or sexual performance in man, are required. Vasodilator drugs that do not induce tachycardia, or at least produce less tachycardia than hydralazine or minoxidil, do not elicit headache or edema formation, and have a long duration of action have a place in antihypertensive therapy as well.

There is much talk about the possible use of pros- taglandins in the treatment of hypertension. Some of these agents may be of interest as vasodilators, but it is very doubtful that they will find a place as antihy- pertensive drugs.

It will be necessary to elaborate simple dosage schedules, especially when various drugs must be given together, and their actions are synergistic or additive. The schedule for the antihypertensive treatment must be simple enough to guarantee good compliance of the patient and should have no nega- tive effect on the patient’s professional or private life. It has recently been suggested that something com- parable to vitamin Bis therapy, which has to be given only once a month or at even longer intervals, might also be suitable for the treatment of hypertension, but we are far away from such a goal.

At this point, I should like to digress and discuss the problem of which kinds of hypertension should be treated. What is the limit of blood pressure eleva- tion, and is it systolic or diastolic pressure that needs to be lowered? What is the desired pressure level (1) ideally, and (2) realistically? Systolic pressure may be a stronger determinant for risk of coronary heart disease than mean pressure or diastolic pressure, which is today considered the critical factor with re- gard to starting systematic drug treatment.14 The de- velopment of new drugs depends to a major degree upon medical progress and better insight into the consequences that satisfactory antihypertensive drug treatment will have for the prognosis of the disease. One can state that industry will respond to the re- quirements of the medical profession, and t.he more that is known about the pathogenesis of hypertension and the better the medical profession familiarizes it- self with the treatment of hypertension, the more likely it is that better drugs will be developed.

What May We Expect?

We may undoubtedly expect more beta adrenergic blocking drugs and also more vasodilators. It is to be

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DRUG THERAPY OF HYPERTENSION-GROSS

@ 8-adrenergic -----4( *------_ @Specific antibodies blockers

I ,[Angiotensin]Y

@Specific antibodies

A @ Synthetic analogues

@Enzyme inhibitors

I

(SO 20881 and other peptides)

I (iJ Competitive substrates

I @ Enzyme

(polypeptides) inhibitor (pepstatine)

1 Converting enzyme 1

@ Specific antibodies

@Synthetic analogues

@ Non-specific antagonists

Angiotensinases

I ,

IInactive fragments) 0 Enzyme inhibitors

Figure 1. Various possibilities of interference with the reninagiotensin system.

TABLE I

Products Prescribed (%) in General Practice for the Treatment of Hypertension

United Kingdom Belgium Germany Italy Spain Japan Canada Argentina

Rauwolfia products Rauwolfia combinations Other antihypertensive agents

(guanethidine, methyldopa)

Plain diuretic drugs Cardiac glycosides

6 13 3 5 8 32 5 16 6 30 79 56 77 27 20 46

50 39 6 17 5 13 22 25

29 31 2 11 5 27 41 23 3 1 17 10 2 1 1

TABLE II

Prescription of Antihypertensive Agents in General Practice

u. s.

1971 1973

International

1971 1973

Prescriptions (millions) 54.0 63.4 146.9 173.4 Diuretics 35% 39% 20% 20% Rauwolfia plain 13% 9% 17% 18% Rauwolfia combinations 33% 28% 35% 32% Special antihypertensive agents 19% 24% 16% 18% Beta adrenergic blocking agents . . . . . . -cl% Cl% Vasodilators . . . . . . 12% 12%

hoped that these future drugs will have at least some advantages over those that are already in hand. Anti- hypertensive therapy will be orientated more strong- ly toward combinations -of beta adrenergic blocking drugs and vasodilators with diuretic agents. Synergis- tic effects of these combinations have already been established. In addition, beta adrenergic blocking agents and diuretic drugs that do not induce potassi-

474 October 1,1974 The Amerfcan Journal of CARMOLOGY Volume 34

urn loss, such as moduretic, may be more widely used in the future, and the combined use of various drugs that differ in their mechanism of action will domi- nate the treatment of hypertension in forthcoming years.

Much attention is paid today to substances that in- terfere with the renin-angiotensin system (Fig. 1). We have angiotensin II antagonists, converting en- zyme inhibitors, and may expect perhaps also inhibi- tors of the reaction of renin with its substrate. How- ever, all of these compounds, although they act in pa- tients with an increased activity of the renin-angio- tensin system or high levels of plasma angiotensin II, will remain limited to diagnosis and perhaps emer- gency therapeutics. It is hardly to be expected that these polypeptides will form a major part of ant&y- pertensive therapy in the future.

Prostaglandins may be claimed to be useful as an- tihypertensive agents, but they may be inferior to other vasodilators. Against the role of prostaglandins in the regulation of blood pressure stands the obser- vation that inhibitors of their synthesis, such as aspi-

DRUG THERAPY OF HYPERTENSION-GROSS

rin or indomethacin, do not induce variations in blood pressure.

For the time being, no breakthrough in the treat- ment of hypertension can be expected, and we shall have to live with the drugs we have in hand or similar compounds that are either chemically or pharmaco- logically related to those already available. For the next 10 years, or even longer, no fundamentally new drug treatment can be anticipated.

Establishing a more uniform method of blood pressure control: Finally, I make a plea for a more efficient and more systematic use of the drugs at our disposal to obtain a satisfactory control of blood pressure. Epidemiologic studies in various countries demonstrate that only between 10 and 15 percent of the patients suffering from hypertension benefit from the available drugs and have their blood pres- sure well controlled. In various countries, antihyper- tensive treatment differs, and for this difference both medical education and the activities of the drug com- panies are responsible. Table I compares the use of antihypertensive drugs in various countries, and

Table II the changes in antihypertensive treatment from 1971 to 1973 in the United States and some in- ternational markets. It would be very useful to study more intensely the reasons for the widely different treatment in various countries and to find out what can be done to establish a more uniform way of con- trolling blood pressure. Furthermore, it is necessary to inform both doctors and the public of the dangers of high blood pressure and the best way to keep blood pressure under control. It should become generally known that high blood pressure is the most common cardiovascular disease and the most common risk factor for stroke, myocardial infarction and renal fail- ure. On the other hand, high blood pressure can be more effectively treated than most chronic diseases. The incidence of cerebrovascular damage can be defi- nitely reduced, whereas the frequency of myocardial infarction seems to be independent of successful con- trol of high blood pressure,ls but further work is nec- essary to find out why different vascular beds re- spond differently to successful blood pressure treat- ment.

References

1. Henning M, van Zwieten PA: Central hypotensive effect of LY- methyidopa. J Pharm Pharmacol20:409-417, 1966

2. Heise A, Kroneberg G: Central nervous a-adrenergic receptors and the mode of action of cu-methyldopa. Naunyn-Schmiede- berg’s Arch Pharmacol 279:285-300, 1973

3. Schmitt H, Schmitt H: Localization of the hypotensive effect of 2-(2-6dichlorophenyiamino)-2-imidazoiine hydrochloride (St 155, Catapresan). Europ J Pharmacoi 66-12. 1969

4. Biihier FR, Laragh JH. Baer L, et al: Propranoioi inhibition of renin secretion. A specific approach to diagnosis and treatment of renindependent hypertensive diseases. N Engl J h&d 287: 1209-1214,1972

5. Stokes GS, Weber MA, Thorneii IR: &Blockers and plasma renin activity in hypertension. Br Med J 1:60-62, 1974

6. Hansson L: Beta-adrenergic blockade in essential hypertension. Acta Med Stand Suppi 550: l-40, 1973

7. Conoiiy ME, Shand GG. Prichard BNC, et al: Betaadrenergic blocking drugs in the treatment of hypertension. in, Handbook of Experimental Pharmacology. New York, Springer Veriag, in press

8. Reid JL, Lewis PJ, Myers MG, et al: Cardiovascular effects of intracerebroventricuiar d-, I- and di-propranoloi in the conscious

rabbit. J Pharrnacoi Exp Titer 186394-399, 1974 9. Kincakf-Smith P, Tang P, Laver MC: A new look at the treat-

ment of severe hypertension. Ciin Sci Moi Med 45:75 S-87 S, 1973

10. Giimore E, Well J, Chidsey C: Treatment of essential hyperten- sion with a new vasodiiator in combination with beta-adrenergic blockade. N Engi J bled 282:521-527, 1970

11. Gottiieb TB, Katz FH, Chidaey CA: Combined therapy with va- sodiiator drugs and beta-adrenergic blockade in hypertension. A comparative study of minoxidii and hydrahzine. Circulation 45: 571-582, 1972

12. Pettinger WA, Mitchell HC: Minoxidii-an alternative to ne- phrectomy for refractory hypertension. N Engi J Med 289:167- 171.1973

13. Viiiareai H, Exaire JE, Revolk A, et al: Effects of chlorothiazide on systemic haemodynamics in essential hypertension. Circula- tion 26:405-408, 1962

14. Koch-Weaer J: The therapeutic challenge of systolic hyperten- sion. N Engi J Med 289:4ai-483, 1973

15. Beevers GG, Fairman MJ. Hamiiton M, et al: Antihypertensive treatment and the course of established cerebral vascular dis- ease. Lancet i:1407-1409, 1973

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