The executive’s medical check-up
• review mechanisms which control blood pressure (BP) and the ideal range for adult BP;
• explain the mechanism of action of agents currently available to treat hypertension;
• explain how antihypertensive agents may cause postural hypotension;
• outline lifestyle factors which affect blood pressure.
Part 1
The chief executive of a European company, Sam Smart, is now 60 years old and has a high-profile, stressful job with frequent travel and business entertaining. He enjoys the good life and his weight has increased significantly over the years. Sam’s wife tries to help him lose weight by preparing sensible meals, but he eats out so often that her efforts are without effect. However, Sam feels pretty fit on the whole, except for occasional mild asthma attacks, usually following a chest infection. This is well controlled with an inhaled beta-2-agonist (β2 agonist).
Sam missed his check-up with the company doctor last year because of a delayed return from a business trip. At his most recent medical, two years ago, Sam’s BP was a little higher than expected, 145/93 mmHg. At the time the doctor advised Sam to modify his lifestyle to help lower his BP. However, Sam’s self-control was never very good and, although he tried to eat and drink sensibly for a while, he soon went back to his old ways.
What is the normal BP range for Sam’s age group and what mechanisms maintain the BP in this range?
The normal range of blood pressure for adults over the age of 18 years is 120-140 mmHg systolic and 75-80 mmHg diastolic. However, blood pressure increases with age and body weight, varies between individuals and in a single individual blood pressure naturally varies during a 24-hour period. In new guidelines for management of high blood pressure (hypertension), the target pressure to be achieved in treating hypertensive patients has been revised downwards because there is clear evidence that high blood pressure is associated with increased risk of heart failure, vascular and kidney disease and stroke.
Sam’s blood pressure two years ago was higher than normal, but could have been lowered by lifestyle changes such as weigh reduction, increased exercise and salt restriction. Now he has gained more weight and his blood pressure is likely to be higher than before.
The short-term mechanism controlling blood pressure from minute to minute involves arterial baroreceptors. When changing body position, baroreceptors detect changes in blood pressure and elicit reflex responses via the cardiovascular centre in the medulla, which reverse the change and return blood pressure to the original level. Baroreceptors operate these reflexes in hypertension, but adapt to the increased pressure so that they operate around a higher set point. The long-term control of blood pressure over weeks or months involves the renin-angio-tensin system and the kidney, which regulate the salt and water content of the body. Blood volume is a major determinant of blood pressure, and if blood volume increases because of salt and water retention blood pressure also increases. Similarly, salt and water depletion or blood loss causes decrease in both blood volume and pressure.
Does stress affect blood pressure? How might Sam decrease his stress level?
The heart and blood vessels are innervated by sympathetic nerves. The ‘fight or flight’ response of the sympathetic system is activated in stress, and epinephrine (adrenaline) is released into the blood. These responses increase the rate and force of the heart and constrict many blood vessels, both of which raise blood pressure. In addition, continued sympathetic stimulation eventually causes structural changes in blood vessels, activation of the renin-angiotensin system and procoagulant effects. If stress is prolonged, these responses contribute to a sustained increase in blood pressure.
Sam could decrease the stress in his job by reducing the number of overseas trips he makes and working shorter hours He could stop rushing, slow down a little and take things more calmly.
If BP continues to rise and is not treated, what adverse effects (including tissue damage) may occur?
Sustained hypertension damages the walls of blood vessels, leading to dysfunction in the tissues perfused. The heart is often affected: ventricular hypertrophy, coronary disease, angina, congestive or sudden heart failure may occur. The brain and eyes can be damaged as exudates and haemorrhages occur in the retina and there may be kidney damage, leading to renal failure.
It is usual to start treating hypertension with either a beta-blocker (β-blocker) or a thiazide diuretic. What is the mechanism of action of the beta-adrenoceptor (β-adrenoceptor) antagonists (β-blockers)?
Beta-adrenoceptor (£-adrenoreceptors) antagonists were originally introduced as anti-anginal agents. It was then noted that patients’ blood pressure decreased over a period of weeks: these agents have now been used to treat hypertension for many years. The beta-blockers (β-blockers) are the agents of choice for young hypertensive patients. Their mechanism of action is unclear, but there are several components:
(1) Reduction in sympathetic stimulation of the heart via antagonism at β1-adrenoceptors in cardiac muscle.
(2) Antagonism of β1-receptors on the juxtaglomerular cells of the kidney that reduce the release of renin.
(3) Reduction of sympathetic activity via a central effect in the brain.
Part 2
Sam is available for his medical this year, but arrives late and in a rush. He has enjoyed a big lunch – steak and chips with deep-fried onion rings, followed by jam sponge pudding and custard. He has drunk most of a bottle of wine plus a brandy, and so is easily able to produce a urine sample. The company doctor checks Sam’s weight and BP and sends blood and urine samples for analysis. Sam now weighs 99 kg (220 lb), his urine appears normal but his plasma cholesterol is rather high at 6.5 mmoll-1 (ideal value <5.2 mmoll-1). The first measurement of Sam’s BP is 168/115 mmHg. After Sam sits quietly for 15 minutes, his blood pressure decreases to 150/108 mmHg, a significant increase compared to the previous medical.
The doctor decides to prescribe Sam an angiotensin-converting enzyme (ACE) inhibitor, captopril. However, a few weeks later Sam is back, complaining about his throat and a dry, hacking cough, which disrupts his business discussions and, worse, annoys his wife!
The doctor is sympathetic: cough is sometimes a problem for patients taking captopril; she prescribes an alpha-adrenoceptor (α-adrenoceptor) antagonist, prazosin, instead. Sam has problems initially with orthostatic hypotension; however, after dosage reduction, prazosin is well tolerated and Sam’s BP settles at 143/87 mmHg.
Explain why more than one measurement of a patient’s BP is necessary, and outline factors which might have contributed to the difference observed between Sam’s two blood pressure readings.
blood pressure varies considerably according to the activities and anxieties of the patient and time of day. If a patient rushes in late to a medical appointment and is very anxious or worried, their blood pressure is likely to be much higher than usual. Waiting a few minutes to allow time for the patient to calm down facilitates a more accurate measurement to be made. It is usual to measure blood pressure on more than one visit, to ensure that it is consistently raised, before starting antihypertensive therapy. In Sam’s case he was late and rushed to his appointment, which would increase the activity of his sympathetic nervous system and temporarily raise his cardiac output and blood pressure.
Outline the major features of the renin-angiotensin system and its relationship to BP control.
The renin-angiotensin system is involved in long-term regulation of body fluid volume and blood pressure. When the β1-receptor on juxtaglomerular cells is stimulated by reduced blood pressure or sodium depletion, the proteolytic enzyme renin is released. Renin converts angiotensinogen into angiotensin I, which is then converted to angiotensin II, a potent vasoconstrictor peptide, by angiotensin converting enzyme (ACE). Angiotensin causes release of the salt-retaining steroid aldosterone from the adrenal cortex. Sodium and water are retained by the kidney to increase blood volume and blood pressure.
Explain why Sam should be prescribed an antihypertensive agent; indicate factors (such as mechanism of action and Sam’s history) which would be considered when choosing to prescribe an ACE inhibitor in preference to another type of antihypertensive agent.
Sam’s blood pressure has now increased significantly. British Hypertension Society guidelines recommend that patients with systolic pressure >160mmHg or diastolic pressure >100mmHg should be treated; so an appropriate antihypertensive agent is now required. Although young patients are treated initially with a β-adrenoceptor antagonist, older patients like Sam are normally started on a thiazide diuretic, unless there is a particular reason or concomitant condition which contraindicates these agents. In Sam’s case there is evidence of an increased plasma cholesterol concentration. Thiazide diuretics are safe and effective antihypertensive agents, but tend to raise blood lipid levels. So, for Sam, an agent which reduces the activity of the renin-angiotensin system by inhibiting the production of angiotensin II from angiotensin I, with no adverse effect on blood lipids, appears to be a reasonable alternative. Note: even if Sam had been a much younger person, a β-blocker would not have been suitable for him since he has occasional asthma. Beta-blockers can cause bronchoconstriction and so are contraindicated in asthmatic patients. Sam did not do well on captopril as he developed an irritating, dry cough. ACE inhibitors not only inhibit conversion of angiotensin I to angiotensin II but also inactivate the degradation of vasodilator bradykinin and other peptides, which may contribute to their effectiveness in lowering blood pressure. Kinin accumulation around the larynx may cause the dry cough that is a common side effect of some ACE inhibitors. These agents also sometimes cause taste disturbances. A more suitable alternative, an alpha-adrenoceptor (α-adrenoceptor) antagonist, which improves the patient’s lipid profile by decreasing the low-density lipoproteins and increasing the high-density lipoproteins, was then selected for Sam.
Outline the locations at which alpha- and beta-receptors are found in the circulation and explain why alpha-blockers cause orthostatic hypotension.
Alpha-adrenocep tors are found on vascular smooth muscle and mediate vasoconstriction. Blood vessels also possess β2-receptors, which mediate vasodilation. Cardiac muscle possesses β1-receptors: stimulation of the latter increases the rate and force of contraction of the heart. Prazosin is an α1-selective adrenoceptor antagonist which causes vasodilation and a fall in blood pressure. Alpha-adrenoceptor antagonists also have a favourable effect on blood lipids and are useful for people with raised cholesterol. However, orthostatic hypotension may occur during treatment because prazosin interferes with the postural reflexes, which are triggered when a patient stands up from a supine or sitting position.
Normally, when a person stands up, gravity shifts blood towards the lower parts of the body. As the baroreceptors pick up this slight drop in blood pressure, they elicit reflex vasoconstriction via a\-receptors in blood vessels and an increase in heat rate via β1 -receptors in the heart. If alpha-adrenoceptors are antagonized, less vasoconstriction occurs and the blood pressure remains low: sometimes this is pronounced and causes the patient to become dizzy or faint on standing.
If Sam had not been able to tolerate prazosin, or if this agent had not produced a satisfactory decrease in his blood pressure, what other classes of antihypertensive agent are suitable for him?
An alternative to the ACE inhibitors is an angiotensin receptor antagonist such as losartan or valsartan. This class of drug also acts on the renin-angiotensin system and appears to offer all the advantages of ACE inhibitors, without causing the dry cough which Sam found unacceptable. Calcium channel blocking agents, such as verapamil and nifedipine are also satisfactory antihypertensive agents. These drugs reduce the influx of calcium ions into vascular muscle cells following excitation and so cause vasodilation. They act mainly on arterial vessels in the circulation.
Sam’s final blood pressure was 143/87 mmHg, is this an appropriate outcome of treatment?
Yes. The target for blood pressure reduction is < 140/<85 mmHg, and the audit standard is currently < 150/< 90 mmHg. So Sam’s blood pressure is within the recommended range and is now satisfactory.
Is Sam’s lunch time diet satisfactory for cardiovascular health? What lifestyle modifications are likely to be useful in lowering Sam’s blood pressure?
If this lunch is typical, Sam’s diet contains a large amount of fat and sugar with little fruit or vegetables. He could cut down on the saturated fat, sugar and salt in his diet and replace the fried foods with grilled meat or fish, fresh fruit and vegetables. Although a small amount of alcohol is thought to reduce the risk of heart disease, drinking a large amount of wine plus brandy is excessive and, for overall health, should be reduced. These dietary changes, plus introducing some exercise into his daily routine, would help Sam to reduce his weight and blood pressure. If he smokes, reducing the number of cigarettes each day or cutting out smoking altogether would also reduce his blood pressure. Each of the lifestyle modifications alone would reduce his blood pressure a little; added together, they would be a very useful adjunct to the antihypertensive therapy he now requires.
Key Points
• The ideal range for adult blood pressure is 120-140 mmHg systolic and 75-80 mmHg diastolic; blood pressure varies over the day and from day to day.
• The short-term mechanism for blood pressure control centres on the baroreceptor reflex. The long-term mechanism involves the renin-angiotensin system and body sodium control via aldosterone.
• Sustained hypertension damages tissues (end organ damage), particularly the heart, brain, eye and kidney tissues.
• Beta-adrenoceptor antagonists are effective antihypertensives and operate partly by blocking β1-receptors on the heart and juxtaglomerular cells of the kidney and partly by central actions which reduce sympathetic activity.
• Thiazide diuretics are effective antihypertensive agents at doses lower than required for diuresis. They decrease body water and sodium and have direct dilator actions on arterial blood vessels
• Alpha-adrenoceptor antagonists are useful antihypertensives; they block the vasoconstrictor effects of α-receptor stimulation. There is sometimes a problem with postural hypotension as reflexes which normally raise blood pressure on standing are interrupted. These agents have a beneficial effect on blood lipids.
• ACE inhibitors are powerful antihypertensives, suitable for patients with an increased renin production. Side effects include cough and taste disturbance; angiotensin receptor antagonists possess the advantages of ACE inhibitors without eliciting cough. Calcium blocking agents are also useful antihypertensive agents.
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