The Rise and Fall of Modern Medicine (20 page)

T
here is no more certain way of increasing the chances of living to a ripe old age (besides, of course, not smoking) than dropping in periodically to see the family doctor to have one's blood pressure checked and – if it is found to be elevated – taking regular medication to lower it. For, as everyone now knows, if raised blood pressure is left untreated it can burst a blood vessel in the brain to cause a stroke which, if not lethal, can have catastrophic complications including paralysis, loss of the power of speech or many other highly undesirable variations of functional impairment.

The prevention of strokes merits inclusion in the pantheon of the major events of post-war medicine for two reasons. First, strokes are the third most common cause of death, and thus the ability to prevent them is of enormous significance. The second reason is subtler. The need to identify and then treat those with raised blood pressure – or hypertension – expands the scope and influence of medicine enormously. In the past people visited their doctors because they were ill or had some distressing symptoms about which they were concerned. Hypertension changed all this because it usually does not cause any symptoms, so there
is no way to know if the blood pressure is elevated other than by visiting the doctor's surgery. Thus the contentment that comes from feeling healthy can be illusory, concealing the damage being wrought by raised blood pressure. We now need doctors not only when we are ill, but also when we feel well.

Hypertension is very common (though how common is a contentious matter) and nowadays much the most frequent reason for people to consult their doctor and take medication is for a condition that previously they would never have known they had. Nor does it stop there. For once it is accepted that identifying and treating hypertension is a good thing then the same principle can be applied to any number of other ‘silent killer' conditions that cause no symptoms – such as raised cholesterol levels, or detecting hidden cancers of the breast or cancer of the cervix by screening. The evolution of this type of ‘preventive screening' in which doctors screen the healthy looking for disease has led inevitably to the ‘mass medicalisation' of society. Now everyone, not just the sick, is a potential patient. And it all started with the successful treatment of hypertension.

The word ‘stroke', which for the young carries the gentle resonance of affection and physical comfort, acquires by middle age the much gloomier connotation of its other meaning – a devastating blow. A stroke is a catastrophe. The damage to the brain cannot be repaired so the only rational approach is prevention. Most strokes are caused by raised blood pressure, which either accelerates narrowing of the arteries to the brain or may cause a blood vessel to burst, resulting in a haemorrhage. Logically, then, drugs that lower the blood pressure should reduce the risk of strokes. They do, and dramatically so, as first demonstrated in 1967 in a famous study of 140 US veterans, seventy of whom received treatment, the other seventy acting as ‘controls'. Just two of the actively treated went on to have a
stroke, compared to twenty-seven of those taking a placebo. It is hard to conceive of a more powerful verdict on the imperative of treating hypertension.
¹

These findings have a special historical significance as, prior to the 1960s, the absence of effective treatment for hypertension had a profound effect not just on individuals but on the fate of whole nations. Both the President of the United States, Franklin D. Roosevelt, and the Russian leader, Josef Stalin, had raised blood pressure, with devastating consequences for world politics in the post-war era. On 12 April 1945 Franklin Roosevelt died of a cerebral haemorrhage which his physician, Admiral Ross McIntire, said had ‘come out of the clear sky', as only a few days earlier the President had apparently been ‘given a thorough examination by eight physicians including some of the most eminent in the country and pronounced physically sound in every way'.
²
The admiral was lying; Roosevelt had been diagnosed as having hypertension almost ten years earlier, which by the time of the Yalta conference with Churchill and Stalin in February 1945 (just eight weeks before his death) had caused so much damage to his heart and kidneys that he was ‘a dying man'. At this crucial moment in world politics, Roosevelt's ailing health so impaired his political judgement as to produce ‘a deadly hiatus' in the leadership of the United States that would lead to ‘the betrayal of the Poles, the imposition of communist governments in Eastern Europe, the Czechoslovakian coup and – on the other side of the world – the loss of China and the invasion of South Korea'.
³

Eight years later, in 1953, Josef Stalin also fell victim to a stroke, at the age of seventy-three. Again, the history of the post-war world would have been very different if his hypertension had been treatable with appropriate medication. He could well have lived on for another decade, up to and including the
Cuban missile crisis, which might then have had a very different outcome, culminating in the Soviet Union, under his demented leadership, launching a full-scale nuclear war against the United States. One way or another, hypertension has had a crucial impact on the fate of nations and the survival of the human race. So how did hypertension become treatable?

The blood pressure is the pressure generated by the contraction of the heart muscle to pump blood into the arteries and around the circulation. It is determined by two factors. The first is the volume of blood in the arteries (the higher the volume, the greater the pressure needed to pump it round the circulation), and the second is the diameter of the vessels through which the blood travels (the narrower the arteries, the greater the pumping pressure that is required). Hence, prior to the discovery of effective drugs, the two ways of lowering the blood pressure were either to reduce the volume of fluid in the circulatory system or to dilate the blood vessels.

In 1944 a German-born physician at Duke University, Dr Walter Kempner, reported that the blood pressure returned to ‘normal or almost normal' by reducing the volume of fluid in the circulatory system with a rice/fruit/sugar diet: ‘The rice is boiled or steamed in plain water without salt, milk or fat. All fruit juices and fruit are allowed with the exception of nuts, dates, avocados and any kind of dried or tinned fruit. No water is allowed and the fluid intake is restricted to one litre of fruit juice per day.'
⁴
The problem, as can be imagined, was that the diet itself was so unpalatable that patients could not stick with it. ‘It is insipid, unappetising and monotonous and demands great care in its preparation . . . it is quite impracticable for a member of a large household with minimal domestic help . . . its deadly monotony tends to make it intolerable unless the physician can infuse into the patient some of the asceticism of
the religious zealot.'
⁵
Nor indeed, as it subsequently emerged, was Kempner's diet as effective as he claimed, for when other doctors tried to replicate his results they were less successful. ‘The change of blood pressure does not exceed the random spontaneous variation to be anticipated,' observed Dr Herbert Chasis of University College Hospital in 1950.
⁶

The second approach to treating hypertension – dilating the diameter of the arteries so less pressure is required to push the blood around the body – involved an operation to cut the nerves that control the diameter of the arteries in the legs (a bilateral lumbar sympathectomy). This operation was a major procedure and so was limited to those who were still fairly fit and young.
⁷

The limitations of these treatments are self-evident, so in the post-war years research chemists in the burgeoning pharmaceutical industry started to look for chemical compounds that might work in similar ways. The first, pentaquine – a drug originally used in the treatment of malaria – was introduced in 1947, to be followed by several others – hydrallazine, reserpine, guanethidine and methyldopa. All these drugs were, to a greater or lesser extent, effective, but their widespread use was constrained by their side-effects. Most people with raised blood pressure feel completely well, so the prospect of taking drugs that caused variously a dry mouth, constipation, blurring of vision and impotence was unacceptable, even if they might prevent a potentially catastrophic stroke in the future. Thus for hypertension to become treatable, the drugs would have to interfere so little with people's lives that they would be prepared to take them indefinitely. The two that eventually fulfilled these criteria were the diuretic (or water pill) chlorothiazide, which lowers the blood pressure by reducing the volume of blood in the circulation, and the ‘beta blocker' propranolol, which
theoretically should have raised the blood pressure by narrowing the diameter of the arteries, but turned out to lower it instead.

The story of chlorothiazide's discovery is as follows: soon after the development in the 1930s of the sulphonamides for the treatment of bacterial infection, some patients reported the unusual side-effect of passing large amounts of urine. In 1949, Dr William Schwartz put this side-effect to practical use, giving sulphonamides to three patients with heart failure, in whom the fluid accumulates in the lungs to cause shortness of breath. The daily volume of their urine soared, the fluid in their lungs dispersed and their breathlessness and other symptoms improved. Regrettably, Dr Schwartz observed the drug was ‘too toxic for prolonged or routine use'.
⁸
However, a research chemist, Karl H. Beyer, realised that if he could find a related compound that had the same properties but was non-toxic, it could, by reducing the volume of blood in the circulation, be the long-awaited ‘magic cure' for hypertension. The chemistry involved was sophisticated but essentially routine: take the sulphonamide compound, modify it in some way, give it to dogs and see whether it increases the amount of urine they produce. ‘It seemed only a matter of time and effort until we found what we were looking for,' which they did in the form of chlorothiazide, ‘the best-behaved compound we had ever worked on from the standpoint of safety and efficacy'.
⁹
When given to ten hypertensive patients, their blood pressure fell back to normal levels within a couple of days. ‘Side-effects were mild and infrequent.'
¹⁰

The second drug, propranolol, is almost unique in the annals of drug discovery in being purposefully designed rather than being discovered by accident. Its origin and the name of the group of drugs to which it belongs – the ‘beta blockers' – lay in the phenomenon whereby the hormone adrenaline has different
effects on different tissues. Its action on the beta receptors in the blood vessels causes them to dilate, and on the heart increases the rate and forcefulness of its contractions.
¹¹
In the mid-1950s, the British research chemist (and subsequent Nobel Prize winner) James Black perceived the enormous therapeutic potential of antagonising this effect for those with the heart condition angina, though with the theoretical drawback that this would also cause the arteries to constrict, which, as has been noted, would necessarily raise the blood pressure.
¹²
James Black eventually came up with propranolol which, as he had predicted, markedly reduced the symptoms of angina but which, astonishingly, had the reverse effect on blood pressure to that predicted. Rather than rising, the blood pressure fell.
¹³
It is not clear precisely who saw that this paradoxical – and quite unexpected – effect could be used in the treatment of hypertension, but as it turned out propranolol worked very well.

These two drugs, chlorothiazide and propranolol, transformed the treatment of hypertension. Patients with raised blood pressure no longer had to go on the unpalatable rice and fruit diet, or undergo a bilateral sympathectomy to cut the nerves to their legs, or take drugs with unpleasant side-effects. Instead they needed to take, singly or in combination, one or other of these drugs every day. Subsequently further well-tolerated types of drug became available, but the crucial point was that by the mid-1960s hypertension had become a treatable disease.
¹⁴

The very ease with which hypertension could now be treated posed another problem. Drug treatment markedly reduces the incidence of strokes, but the situation is much less clear-cut in those whose blood pressure is only marginally elevated, so-called ‘mild' hypertension. The question then as to what level of blood pressure merited treatment fuelled a decade-long public and
often acrimonious exchange between two of British medicine's leading figures: Robert (Lord) Platt, Professor of Medicine at Manchester University, and Sir George Pickering, Regius Professor of Medicine at Oxford. In essence, Platt maintained that hypertension was a specific illness caused by one or several genes, and that it was possible and indeed necessary to distinguish between those with a ‘normal' blood pressure and those with an ‘abnormal' one, and only to treat the latter group. Not so, responded Sir George Pickering; hypertension was not an ‘illness' in the commonly accepted sense of the term, but there was a continuous gradient of risk relating blood pressure to the chance of a stroke. Clearly the higher the blood pressure the greater that risk became, but any cut-off point between those who needed treatment and those who did not, between the ‘normal' and the ‘abnormal', was arbitrary. Hypertension was thus not an illness but a matter of opinion.
¹⁵