PRIMARY OR ESSENTIAL HYPERTENSION

In the management of any patient with a significant hypertension, irre¬spective of whether or not a decision is reached to treat him with drugs, certain general principles apply. These include advice regarding the general regulation of his life in respect of work, physical activity and rest ; the reduction of obesity when such is present; the restriction of salt in the diet; and not least "In importance the securing of the patient's co-operation and the allaying of the natural apprehension of a sensitive individual regarding his disorder and its possible consequences.

GENERAL MANAGEMENT

It is probable that the pace of modern life and the stress and strain to which an is subjected are in large measure responsible for his liability to hypertension and to the acceleration of its progress. It is reasonable, therefore, to counsel the victim of hypertension to moderate his activities reasonably both as regards recreation and work. While the doctor can do much to guide a patient in this respect, there is a danger that well-meaning but ill-advised interference in a • man's affairs may lead to great hardship. If a man's livelihood and the welfare of his family depend on his earning capacity it is probably more harmful to insist on his giving up his work than to allow him to carry on with some sensible restrictions. The personal qualities of the doctor, his wisdom and judgment are of the greatest importance in the management of hypertension. From the nature of things business and financial worries are inseparable from our lives, and it is impossible for a man to continue in an active earning capacity and to avoid such traumata. Modification of activities rather than drastic alteration is generally the best counsel. Even the most drastic curtailment of activity in a severe hyper¬tensive is no guarantee that life will be prolonged, and even if it were, " length of days can be purchased at too great a price ". It is wiser to allow the patient to continue with some of his work, restricted possibly in scope, than to compel premature retirement with its legacy of frustration, financial worry and boredom.
Weight Reduction.—As in valvular disease and coronary artery disease, obesity in the hypertensive imposes an added and avoidable cardiac burden. Many hypertensive patients are obese and should be encouraged to reduce their weight, aiming at a figure rather under the ideal weight for age, sex and height as given in conventional tables. In those who already have cardiac symptoms, loss of weight may be accompanied by a remarkable increase in exercise tolerance.
Salt Restriction.—There is good evidence that retention of sodium plays a part in the genesis and maintenance of a raised blood pressure. For this reason it is logical to advise some restriction in consumption of salt. It should not be added to food at table, and salty foods should be avoided. There is no need for drastic restriction, however, and the very strict salt-poor diets contain¬ing say 0-2 g. of sodium per day, e.g. the Kempner rice diet, have onlv a limited place in therapy and none in prophylaxis. On such drastic regimens the blood pressure certainly falls steeply after a few days, but most patients find such meals intolerable for protracted use, and there is evidence that with continued use of the rice diet there is a risk of striking deterioration in renal function.

DRUG TREATMENT OF HYPERTENSION

Preliminary Assessment of Case.—When a patient is diagnosed as having high blood pressure, a decision must be made regarding the necessity for and feasibility of drug treatment. To this end various simple investigations should be carried out. In the first place an estimate should be made of the patient's basal pressure, taken as already described. He can then be classified as a mild, moderate, severe, or gross hypertensive on this basis. Attempts to assess the true basal pressure with the patient heavily sedated with a barbiturate (say amylobarbitone 0-2 g. three times at hourly intervals) have fallen into disuse, since the lability of the pressure under these circumstances bears little relation to the effects of treatment.
The next point is to determine what effects, if any,»have been produced by the hypertension on the so-called target organs—brain, retinse, heart and kidney. Evidence of affection of these organs can be taken as an indication for vigorous treatment, irrespective of the actual height of the blood pressure. For example, the patient who has marked cerebral symptoms, whether they be transient paresis of angiospastic type, hypertensive encephalopathy or a frank cerebrovascular accident, is in urgent need of treatment. The size of the heart determined clinically and by radiological examination, and the extent of the hypertrophy and degree of muscle damage as shown electrocardiographically are indices for therapy. The examination of the retina; is a valuable procedure, particularly useful in the detection of the so-called malignant hypertension, in which papilloedema is present in addition to alterations in calibre of vessels, hasmorrhages, and exudates. An estimation of kidney function should be made, since early renal involvement is an indication for vigorous treatment and severe renal damage may preclude the use of hypotensive drugs. Finally, before treatment of hypertension is initiated, it is essential to establish that the case is indeed one of primary or essential hypertension and not secondary hypertension due to a remediable cause.
Hypotensive Drugs and their Use.—A wide variety of drugs is available today. In addition to their approved or official names, each is marketed by drug firms under their own trade names and this causes confusion. New preparations which are widely advertised appear with embarrassing frequency, each claimed to have advantages over their predecessors, so that the bewildered doctor is tempted to switch from one to another and fails to acquire true familiarity with any one of them. It is most desirable that the practitioner should make himself thoroughly acquainted with the action of one or two drugs of each of the groups to be described, and that he should confine his prescribing to those drugs with which he is familiar. It should be emphasized that the evaluation of the action of a new drug should be carried out in properly controlled large-scale therapeutic trials, and that the piecemeal trying out of drugs by individual doctors in practice or in hospital has little to commend it, and may in fact lead to quite erroneous conclusions.
The drugs available may be grouped as follows :
(1) Centrally acting (depressant) drugs of the Rauwolfia group.
(2) Ganglion-blocking agents, which block the transmission of impulses at both sympathetic and parasympathetic ganglia.
(3) Adrenolytic agents, acting solely on the sympathetic effector mechanism.
(4) A mixed group comprising hydrallazine, veratrum, and dehydrogenated ergot alkaloids.
(5) Dopa decarboxylase inhibitors.
Rauwolfia Compounds.—These drugs are derived from the dried roots^ of the Indian shrub Rauwolfia serpentina. They have a moderate hypotensive action which is centrally mediated. They are active given by mouth and their action develops gradually. The full effect may not be manifest for several weeks with standard doses, but once a maximum effect has been attained it is often possible to maintain this indefinitely with considerably reduced doses. While of value in cases of moderate hypertension, particularly in those patients in whom anxiety is prominent, they have side-effects which are a considerable dis¬advantage. Their usual tranquillizing effect is salutary, but they may on occasion produce considerable and sometimes suicidal depression. Less serious and less persistent undesirable effects are their tendency to cause nasal congestion and diarrhoea. The drug may be administered as the pure alkaloid, reserpine, in a dose of 0-25 mg. three times daily, or as one of the preparations of which a considerable number are on the. market (reserpine, rauwolfia); it is claimed that a derivative, methoserpidine, preserves the hypotensive action of the parent drug but is less prone to produce depression. As with many of the hypotensive agents described below the effect of reserpine may be enhanced by the simul¬taneous administration of a thiazide drug (chlorothiazide, hydroflumethiazide).
The main value of the Rauwolfia compounds lies in the treatment of tense, anxious patients with moderate hypertension. They are also of value as adjuvants to the more powerful agents to be described below. In any individual case the assessment of the success of the Rauwolfia treatment can be reached only after a trial of six to eight weeks. By this time it should be clear whether the drug is producing a satisfactory response without untoward side-effects. Should a satisfactory response be achieved it is usually possible to reduce the dose considerably, perhaps to a single 0-25 mg. tablet daily, for long-term treatment. It should be kept in mind that the depressant action of Rauwolfia may result in a gradual deterioration in higher cerebral functions, loss of drive and initiative and loss of qualities necessary for the successful prosecution of business life, which can be very serious for the patient. Such deterioration may be so gradual as to escape notice or may be attributed to the progress of the hypertension. It is more frequently detected by the patient's family or employer than by either the doctor or patient himself.
Ganglion-blocking Agents.—While the principle governing the use of. ganglion-blocking agents would appear to be sound and to promise good results in treatment, the number of members of this group which have been successively introduced (hexamethonium ; pentolinium ; mecamylamine ; pempidine) is sufficient evidence that none has proved satisfactory. Some are absorbed so erratically from the gastrointestinal tract that accurate oral dosage is impossible;
others are drugs to which tolerance is readily acquired so that increasing doses are necessary to control the pressure; all have side-effects of greater or less intensity which are in part at least due to the essential action of the drugs.
These drugs block not only sympathetic but also parasympathetic ganglia, so that side-effects on the parasympathetic nervous system are prominent. These include dryness of the mouth, dilatation of the pupil, difficulty in accommodation, and constipation progressing in extreme cases to intestinal ileus. In addition their effect on the blood pressure varies considerably with posture, being minimal when the patient is recumbent and maximal when erect. This has a two-fold disadvantage in that the profound hypotension in the erect posture may of itself produce alarming or inconvenient symptoms, while lack of pressure reduction when recumbent implies uncontrolled hypertension during the hours of sleep. Other factors militating against their successful use are erratic absorption and the development of tolerance, and these have proved serious drawbacks. The erratic absorption of the original hexamethonium compounds, for example, led to serious difficulties, not the least of which was an increased risk of obstinate constipation or actual paralytic ileus since there is a tendency for the unabsorbed drug to accumulate in the gut and then to be absorbed in excessive amounts. With some compounds tolerance is rapidly acquired and continual increases in dose may prove necessary. These- undesirable qualities are most prominent with the quaternary ammonium compounds of which hexamethonium is an example, and less marked with the secondary amines.
Mecamylamine is a member of the latter group and is one of the most dependable of the ganglion-blocking agents. It is completely absorbed and the response to a given dose is relatively constant from day to day. The hypotensive action comes on gradually from one to two hours after ingestion and persists for some six to twelve hours. It is supplied in tablets of 2-5 mg. and 10 mg. for oral administration ; a recommended initial dose is 2-5 mg. twice a day, which may be increased by a daily increment of 2-5 mg. every two or three days until the desired effect on the blood pressure is obtained. As with all members of the group the action is enhanced by the simultaneous adminis¬tration of a thiazide drug, for example 0-5 g. of chlorothiazide or 50 mg. of hydrochlorothiazide twice daily. With such adjuvant therapy the dose of mecamylamine can be considerably reduced, and care must in fact be exercised that over-dosage does not occur. Thiazide drugs also promote potassium loss and it is desirable to give a potassium supplement, say i to 2 g. of potassium chloride daily, as a precaution.
There are many other drugs of this class. The original, hexamethonium tartrate, is absorbed so erratically that its use has been largely abandoned. A later representative, pentolinium tartrate tends to induce tolerance when given orallv, and if injected necessitates repeated doses each day. The drug has largely been superseded by mecamylamine or pempidine which, given orally, are more effective.
Pempidine is claimed to be less toxic and less variable in effect than its precursors. Orally, the initial dose is 2-5 mg. four times per day, increasing by 2-5 mg. each day until a satisfactory reduction in pressure is achieved. Since it is rapidly excreted the therapeutic dosage may be reached with safety in a few days.
Side-effects.—When ganglion-blocking agents are given, the parasympathetic effects may be sufficiently marked to demand symptomatic relief. Constipation is commonlv troublesome and may require the regular administration of aperients. Drvness of the mouth is a nuisance and may to some extent be relieved by mouth washes. If these fail, tablets containing 5 mg. of pilocarpine nitrate may be tried. Paralysis of accommodation can be a considerable handicap, but can be counteracted by the local instillation of eye drops of 0-5 or i per cent. eserine solution or by the wearing of glasses sufficiently strong to compensate for the accommodation defect. Difficulty in micturition, impotence and an undue sensitivity to insulin are other not uncommon side-effects.
Drugs Causing Adrenergic Neurone Paralysis.—The inconvenient and occasionally dangerous side-effects of the ganglion-blocking drugs led to a search for substances which lowered the blood pressure without such disadvantages. From this search there have emerged drugs which act by paralysing the adrenergic neurones without effect on the parsympathetic nervous system. Bretylium tosylate, the first of these drugs was for a time very popular; but while effective in mild cases, it failed to control many severe hypertensions; its absorption and action were erratic; tolerance was rapidly acquired; and side-effects remained troublesome.
Guanethidine has a similar action to bretylium, but differs in its dependable absorption and regular action, while tolerance is seldom acquired. It is slowly excreted and its action is prolonged, lasting at least three days, so that a single daily dose suffices to keep the pressure controlled. It also produces side-effects which on occasion can be troublesome. Prominent among these are diarrhcea, bradycardia, weakness and lassitude with, on occasion, fluid retention to the point of precipitating early cardiac failure. Failure of ejaculation is common. Many patients taking guanethidine develop marked hypotension following muscular exercise, particularly early in the day, and this can lead to syncope. Matutinal weakness may occasionally be so marked that a man cannot shave. through sheer asthenia. The fall in blood pressure with exercise may be remarkable : for example a fall from 220/130 to 90/40 has been recorded. Gross hypotension leading to syncope may also be induced by the vasodilatation produced by a hot bath. Patients should be warned of these hazards and considerable care must be exercised in the use of all such drugs.
A safe initial dose is 10 mg. given in the morning and increments of 10 nag. per day may be made at intervals. The aim is to reduce the standing blood pressure to 160/100 or thereby. The long term maintenance dose to achieve this object varies from 10 to 300 mg. per day, but usually lies in the narrower range of 30 to 120 mg. The smooth stable action and lack of acquired tolerance render it preferable to the older drugs.
Bethanid.ine, chemically akin to bretyllium tosylate and to guanethidine, is a newer drug. Its main advantage over guanethidine is its shorter action, permit¬ting earlier adjustment of dosage. Diarrhoea is a less troublesome side-effect. The initial doseis5mg. orally twice daily, increased at short intervals as necessary up to as much as 50 mg. twice daily.
Another recently introduced drug, methyldopa has proved effective. It inhibits the decarboxylation step in the biosynthesis of nor-adrenaline, and was introduced on this basis to lower arteriolar tonus, but its undoubted hypotensive action is not yet fully explained. It is given orally (0-25 g. tablets) four times daily, the number of tablets being regulated by the response. The daily requirement varies widely up to-two grammes or even more. Side-effects, particularly depression and disturbances of sleep rhythm, are infrequent. The effects on the pressure are comparable to those of guanethidine.
In summary, it may be said that a patient already stabilized on a ganglion-blocking drug with a satisfactory pressure reduction and. without undue parasympathetic side-effects, should be kept on the regimen which has been found to suit him. New patients, however, should probably be tried first on guanethidine, bethanidine or methyldopa which may afford adequate control with minimal side-effects. Nevertheless, if hypotension after exercise or other symptom proves a bar to continued treatment with these, recourse should be had to one of the ganglion-blocking drugs. Among these, mecamylamine and pempidine are the drugs of choice; their action should be enhanced by the simultaneous administration of a thiazide drug. The reserpine group are best reserved for mild cases of hypertension associated with worry or tension, and they may be used as adjuvants to other hypotensive drugs.
Other Hypotensive Drugs.—Chlorothiazide and other thiazides have an effect on hypertension in about one-third of patients, particularly those with milder forms of the disorder. Given as the sole remedy, such drugs are useful in the management of the milder cases, but their main use is as adjuvants to the ganglion-blocking agents, the dosage of which can usually be reduced to one-half if a thiazide is administered simultaneously. Potassium supplements should be given.
Hydrallazine, a potent hypotensive agent, probably acts directly on the peripheral vessels and also increases cardiac output. It has been claimed that renal blood flow is increased, but there is no evidence that glomerular filtration rate is increased or that azotasmia is improved. Because of its renal action its use has been advocated in patients with severe impairment of renal function, but it is relatively little used in this country. Its great disadvantage is that as a long-term side-effect the patient may develop either rheumatic symptoms or a condition closely resembling disseminated lupus erythematosus.
Veratrum alkaloids have the great disadvantage that the therapeutic level is very close to the toxic one, and nausea and vomiting are readily produced by doses little above those required to produce a significant fall in pressure. The dehydrogenated ergot alkaloids (0-5 mg. tablets) have a mild hypotensive action and achieve some reduction in pressure in long-term use.
Combined Treatment.—The simultaneous administration of a thiazide drug with a ganglion-blocking or sympathetic adrenolytic agent strikingly potentiates the activity of the hypotensive drug. Similarly, reserpine may be used as adjuvant therapy and may allow reduction in the daily requirement of the ganglion-blocking or adrenolytic agents. While there is every reason for combining these drugs in an endeavour to find the optimum for the particular patient under treatment, there is some danger in the use of the proprietary mixtures of drugs now on the market. It is highly desirable that the physician should administer each drug in the dosage he finds appropriate to his particular patient, rather than to give them in a set prescription of unvarying proportions at the whim of the manufacturer. Such preparations make elasticity in treatment difficult.
General Considerations in the use of Hypotensive Agents.—Pharma¬cological research has placed in the hands of the doctor potent remedies for the management of hypertension. To realize their full potentialities, however, close attention to the detail of administration is necessary and there is no doubt that today the widespread use of active drugs without adequate supervision is responsible for much inefficient therapy or iatrogenic illness. It is not good therapy, having discovered that a patient has high blood pressure and having decided that he requires treatment, to prescribe a potent hypotensive drug and dismiss him without supervision for several weeks. The institution of treatment with these drugs demands close medical supervision, since patients vary widely in their response to a given dose and a catastrophic fall in pressure may be induced. In sensitive subjects, such untoward complications as myocardial infarction, cerebral thrombosis or renal failure may be precipitated. Again, when a patient has been stabilized on a dose sufficient to control his hypertension, he must be seen at frequent intervals, his pressure checked when recumbent, standing, after exercise, and a watch maintained for undesirable side-effects. Such close supervision is essential because variation of response to hypotensive drugs is so great that no hard and fast schedule of dosage is possible. The initial treatment should be undertaken in hospital, preferably at an out-patient clinic organized for this purpose under the charge of a doctor who is interested in the problems of hypertension and prepared to give time and trouble to the close supervision of individual patients. Treatment of hypertension with these modern drugs can be highly rewarding, but the rewards are bought at the price of hard work and close attention to detail.