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Ashley EA, Niebauer J. Cardiology Explained. London: Remedica; 2004.

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Cardiology Explained.

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Chapter 6Hypertension

Background

Approximately one in four adults in the western world suffers from hypertension. Of these, 32% are not aware that they have it, 15% are not on any therapy, and 26% are on inadequate therapy. Only 27% are receiving adequate therapy.

Hypertension is a difficult condition to manage because patients are generally asymptomatic and treatment is preventative rather than palliative. Convincing patients of the need for poorly tolerated medication in the face of well-being is one of the challenges confronting clinicians involved in improving the cardiovascular morbidity and mortality caused by high blood pressure (BP). If untreated, hypertension has serious consequences, including renal disease, myocardial infarction (MI), and cerebrovascular accident. However, many patients do not receive sufficiently aggressive management.

Definition

There is no natural cut-off between normal and high BP. As a result, many threshold values for treatment have been proposed. Table 1 provides a synthesis of guidelines from the major bodies. Accurate BP measurements are complicated by several factors. For example, there is an approximately 12/7 mm Hg difference between BP measurements taken in the clinic and those taken at home – and in many patients it can be significantly more. Similarly, measurements in the clinic cannot control for a large element of random biological variation, diurnal variation, and variation due to chance stress (eg, stress due to being in a traffic jam on the way to the clinic). Consequently, it is recommended that at least three readings are taken.

Table 1. Guidelines for threshold values between normal and high blood pressure.

Table 1

Guidelines for threshold values between normal and high blood pressure.

The annual risk of death from cardiovascular disease (including stroke) or coronary artery disease can be calculated from the European Society of Cardiology tables or Framingham risk tables. Some bodies recommend that mild hypertensives should only be treated if their cardiovascular risk exceeds 2% per year. This consideration of individual risk is welcome, since until recently most clinical trials have involved head-to-head comparisons of monotherapy, whereas in practice most patients require combination therapy.

Causes

No cause is identified in 95% of hypertension patients. However, awareness of treatable causes is important, especially in younger patients in whom there is a higher probability of the hypertension being secondary to some other cause. Causes of secondary hypertension are outlined in Table 2.

Table 2. Causes of secondary hypertension.

Table 2

Causes of secondary hypertension.

Assessment

History

History-taking is straightforward since, in most cases, hypertension is asymptomatic. However, symptoms can include headaches, transient ischemic attacks, mild visual disturbances, epistaxes, exertional dyspnea (if heart failure has developed), angina, claudication, weight gain (in Cushing's syndrome), nocturia, and hematuria (with renal disease).

A full drug history is important and must include pharmacologically active preparations such as the combined contraceptive pill and herbal remedies, which are often not regarded by patients as drugs. Other important medications are steroids, sympathomimetics (eg, in cold cures), and nonsteroidal anti-inflammatory drugs, which can reduce the antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEIs) and β-blockers.

As with any cardiovascular disease, risk factors should be especially well documented. As full a family tree as possible should be drawn to document hypertension, diabetes, or early cardiac death. A history of smoking and physical activity should also be taken. More specific to hypertension, caffeine and alcohol intake should be recorded and some insight into diet and lifestyle stress should be acquired.

Examination

The physical examination has three specific objectives:

  • documenting an accurate BP
  • excluding possible secondary causes
  • quantifying end-organ damage

The BP should be measured in both arms, with the arm and manometer at the patient's heart level. Readings should be taken manually in a standardized way (most clinical trials use Korotkoff I and V – from the first sound heard to the complete disappearance of sounds). The use of a large-diameter cuff is essential in those with large arms.

The general appearance of the patient may suggest Cushing's syndrome, a thyroid disorder, polycystic ovarian disease, sleep apnea, or acromegaly. All peripheral pulses should be taken to screen for vascular disease, but special attention should be paid, especially in young people, to radiofemoral delay (diminished and late pulses in the femoral arteries), which suggests aortic coarctation. If positive, the BP should be measured in all four limbs. Auscultation should also be carried out over the aorta and renal arteries for bruits suggestive of stenosis. Abdominal examination may reveal palpable kidneys in polycystic disease or a pheochromocytoma.

End-organ damage can be detected by palpation of the apex beat, detection of bibasal crackles, and examination of the fundi. Diagnosis of hypertensive retinopathy is based on a four-stage grading system, as outlined in Table 3.

Table 3. Stages of hypertensive retinopathy (Keith–Wagener classification).

Table 3

Stages of hypertensive retinopathy (Keith–Wagener classification).

Investigations

Investigations are aimed at diagnosing rare secondary causes and quantifying end-organ damage.

Only electrolytes, creatinine, fasting glucose, and lipids should be requested in every patient. A low potassium and raised sodium level suggests hyperaldosteronism – either primary (Conn's syndrome) or secondary to renal artery stenosis. This should prompt measurement of renin and aldosterone levels. It should be noted that the potassium level is normal in 50% of cases of primary hyperaldosteronism.

Raised calcium levels suggest possible hyperparathyroidism. If the symptoms suggest a thyroid problem, thyroid function should be tested. A low threshold should be adopted for the following:

  • renal ultrasound
  • urine microscopy (for casts and cells – glomerulonephritis)
  • urine samples for testing:
    • catecholamine metabolites (three samples, one every 24 hours, required in acid bottles)
    • urinary free cortisol (one sample in a plain bottle – this can also be used for glomerular filtration rate and 24-hour protein tests)

Once hypertension has caused end-organ damage, the risks associated with any given level of BP are higher. Evidence of end-organ damage should therefore be sought in all patients. Dip-stick urinalysis, tests for urea and electrolytes, and a renal ultrasound can reveal renal insufficiency. Left ventricular hypertrophy (LVH) can be readily detected by electrocardiography or echocardiography (a chest x-ray is rarely necessary). Hypertension with LVH carries a particularly poor prognosis (the 5-year mortality is around 30%–40%) and is a powerful predictor of cardiovascular and all-cause mortality.

A useful tool, both for generalists and specialists, is the 24-hour ambulatory BP recording. It is particularly useful when clinic measurements show variability, with resistant hypertension, or most commonly to diagnose "white coat" hypertension. An ambulatory BP measurement (ABPM) is not required for those who are at high risk already, either because of target organ damage or cardiovascular complications. Such patients can be treated on the basis of clinic measurements. Equally, an evidence-based approach suggests that those with mild hypertension, no target organ damage, and low estimated risk may be left untreated (but followed) without ABPM.

Management

Many randomized controlled trials have shown that BP reduction prevents the complications of hypertension. Early trials showed a significant improvement in the risk of stroke, but little or no reduction in coronary heart disease (CHD) events. Later trials, particularly those in the elderly, have also shown a reduction in CHD events, although the benefit is not as great as observational studies predicted. A summary of hypertensive treatments is shown in Table 4.

Table 4. Summary of hypertensive treatment.

Table 4

Summary of hypertensive treatment.

Lifestyle change

Lifestyle changes are important in the management of patients with hypertension and can be used alone during an initial period for those with mild hypertension and low risk.

Increasing fruit and vegetable intake can improve BP via an effect on potassium; in combination with a low-fat diet, this can reduce BP by up to 11/6 mm Hg. In addition, weight loss is associated with an approximately 2.5/1.5 mm Hg drop for each kilogram lost. Specific advice on abstaining from adding salt to food – during cooking and at the table – should be given to reduce salt intake to 1 teaspoon per day. Foods such as bread, stock cubes, and breakfast cereals are often surprisingly high in salt. Reducing salt intake can cut BP by approximately 5/3 mm Hg. Alcohol, particularly when taken in a binge pattern, is associated with increased risk. The current American Heart Association guidelines state: "If an individual chooses to consume alcohol, the limit should be one drink [ie, half a pint of beer, one glass of wine, or one short drink] a day for women and two drinks a day for men. People who do not normally drink alcohol should not begin drinking." Regular exercise (walking rather than weight training), stopping smoking, and limiting caffeine intake can all assist in lowering BP and may independently reduce cardiac risk.

Pharmacotherapy

In most patients, altering lifestyle factors is not enough. For these people, there is the difficult balance of pharmacotherapy. Fewer than half of all hypertensive patients can be controlled on monotherapy, whilst one third require three or more drugs. Knowledge of the mechanisms of action of antihypertensives is important as it allows rational combinations to be chosen based on complementary mechanisms of action.

There are four major groups of drug treatments for hypertension and several less frequently used classes. The sites of action of these antihypertensive agents are shown in Figure 1.

Figure 1. Major physiological mechanisms of antihypertensives.

Figure 1

Major physiological mechanisms of antihypertensives. See Figure 2 for details of centrally acting hypertensives. ACE: angiotensin-converting enzyme; AT: angiotensin.

Beta-blockers

Beta-adrenoreceptor blockers have been used for many decades in the treatment of hypertension and are one of the few classes of agents that have been proven to reduce mortality. They work by reducing cardiac output via negative inotropic and chronotropic actions. In addition, they block sympathetic nervous system stimulation of renin release by juxtaglomerular cells. As with all medications, their use is limited primarily by adverse effects. Asthma is generally considered to be an absolute contraindication, even with agents selective for the cardiovascular system (β1-receptors). Peripheral vascular disease and bradycardia are relative contraindications. In susceptible patients, heart block and heart failure may be initiated.

The most commonly reported adverse effect is lethargy, and nightmares can occur with lipid-soluble β-blockers. As with all antihypertensives, erectile dysfunction (ED) is a problem. The best guide as to whether ED is iatrogenic is to determine whether the symptoms appeared suddenly. Nevertheless, β-blockers have significant advantages in patients with coexistent angina and anxiety, and also after MI.

Diuretics

Thiazide diuretics, such as bendrofluazide, are another class of agent for which randomized controlled trial evidence indicates an improvement in survival, and should be the first-line drug in the elderly and in those with systolic hypertension. They work by inhibiting NaCl reabsorption in the distal tubule. This initially leads to an increase in Na+ loss and a reduction in plasma volume. However, the plasma volume soon recovers, leaving a reduced total peripheral resistance, for which the mechanism is unknown. Thiazide diuretics are widely used and very cheap, with a moderate side-effect profile (most commonly hypokalemia, dyslipidemia, and gout). Potassium levels should be checked regularly.

Loop diuretics have a role to play in the place of thiazides when renal function is compromised (creatinine >180 μmol/L or 2 mg/dL) and on a short-term basis, in addition to thiazides, in resistant hypertension, where a significant proportion of patients suffer plasma volume overload.

Calcium-channel blockers

A large number of calcium-channel blockers have been developed and there is good evidence of their ability to reduce BP. There are three subclasses: the dihydropyridines (nifedipine-like), the phenylalkylamine derivatives (verapamil), and the benzothiazepines (diltiazem). All work by blocking the entry of calcium into the smooth muscle cells of resistance vessels, thereby causing vasodilatation. Dihydropyridines cause vasodilatation without the bradycardic and negatively inotropic effects of diltiazem and verapamil (which limits the use of the latter agents to patients with normal left ventricular function) – so a simpler classification is "rate-limiting" and "non-rate-limiting". Short-acting dihydropyridines have become unpopular following reports of increased risk of MI at high doses. Longer-acting calcium-channel blockers are useful antihypertensives, especially as they are lipid-neutral. Side effects include ankle edema, headache, and flushing.

Renin/angiotensin system antagonists

Angiotensin is a potent vasoconstrictor, but also increases activity of the sympathetic nervous system by both central and peripheral mechanisms. Fortunately, the renin–angiotensin system provides a series of targets for pharmacological attack by ACEIs, angiotensin type 1 receptor blockers (ARBs), and aldosterone antagonists (spironolactone). ACEIs and ARBs tend to be well tolerated and have few contraindications, the most important of which is renal artery stenosis. It is important to monitor renal function and potassium levels during initiation and maintenance of these agents. ACEIs are contraindicated in women of child-bearing potential and may cause a troublesome cough through their inhibition of the enzyme responsible for bradykinin degradation. First-dose hypotension can be a problem in elderly patients on diuretics, although newer, longer-acting formulations have reduced this concern. ACEIs are lipid-neutral, improve insulin resistance, and may be able to induce regression of LVH.

Alpha-adrenoceptor antagonists

Alpha1-antagonists (such as doxazosin and prazosin) are becoming more widely used in the treatment of hypertension. They have a good side-effect profile (palpitations and occasional postural hypotension). In addition, they are reported to have beneficial effects on lipid profile and insulin resistance, and lack the negative effects on sexual potency of other antihypertensives, which is a particular advantage for diabetics. They work to reduce total peripheral resistance by blocking the sympathetic activation of α1-receptors on resistance vessels.

Centrally acting sympathomimetics

Clonidine and α-methyldopa, centrally acting α2-adrenoceptor agonists, were once popular choices, but are now less widely initiated outside specialist scenarios such as pre-eclampsia. They carry a risk of rebound hypertension on withdrawal.

Other vasodilators

Other vasodilators, such as hydralazine and the very potent minoxidil, are mostly used in resistant hypertension when standard agents fail. Use of the latter is generally restricted by unpleasant side effects such as hypertrichosis.

Imidazoline type 1 receptor agonists

The identification of imidazoline receptors has revealed that the effects of older agents on the central nervous system reflect a relatively nonspecific central site of action mediated primarily through α2-adrenoceptor agonism (see Figure 2). It seems that some of the adverse effects of these agents, which are also mediated through this pathway, can be avoided by the use of selective imidazoline type 1 receptor agents. Early results suggest these agents are well tolerated, with a dry mouth being the only frequently reported unwanted effect (13% at 3 weeks, 2% at 12 months).

Figure 2. Centrally acting antihypertensives.

Figure 2

Centrally acting antihypertensives.

Pharmacotherapy selection

In the absence of compelling reasons to choose other medications, the first-line choice should remain a β-blocker or thiazide diuretic. These are the drugs for which clear evidence of mortality reduction exists. In addition, they are generally well tolerated. There are good reasons to consider β-blockers first in younger people and thiazides first in older people. However, the majority of patients will require more than one drug, and the choice should be rational. Here, synergistic action is important (see Figure 2). Good combinations are:

  • thiazides (which cause secondary hyperreninemia) and ACEIs or ARBs (which block it)
  • β-blockers (which act to reduce renin release and cardiac output) and calcium-channel blockers (which cause vasodilatation – do not combine β-blockers with verapamil or diltiazem)

Following this, it is generally worth trying one of the other classes mentioned above. Treatment will be highly individualized depending on patient tolerance and efficacy, but some guidelines are outlined in Table 5. It is worth taking readings after each change of drug so that agents with no effect can be stopped.

Table 5. Guidelines for hypertension pharmacotherapy.

Table 5

Guidelines for hypertension pharmacotherapy.

Systolic versus diastolic hypertension

The question as to the relative importance of systolic and diastolic BP is common in the management of hypertension. For many years it was felt that as systolic hypertension was more common in the elderly it was an inevitable part of aging and arteriolar stiffening. As a result, the focus was primarily on diastolic BP. In fact, both systolic and diastolic BP predict mortality equally well. However, in the elderly population with predominantly systolic BP, recent evidence suggests it is not the absolute values of systolic or diastolic hypertension, but the difference between the two that predicts mortality best, ie, the pulse pressure. This means that a patient with a BP of 160/80 mm Hg may be at higher risk than a patient with a BP of 160/90 mm Hg. This finding, which actually fits well with current thinking on reflected pressure waves in the stiffer arteries of older people, has little therapeutic relevance as yet because we do not have agents that preferentially improve pulse pressure. Thiazides and calcium-channel blockers reduce systolic hypertension more than diastolic, so these are the rational choices. However, the key for the future may be drugs that can restore vascular elasticity, and in this respect nitrates – which donate nitric oxide – are the most promising.

Special populations

Elderly patients

It is a myth that hypertension is "normal" in the elderly and they have less to lose because of a shorter life expectancy. In fact, the absolute benefit from treatment of the elderly is much greater than that for younger hypertensives because of their larger absolute risk. However, it is true that the prevalence of hypertension is higher amongst the elderly. Optimum BP levels are the same for older people as they are for younger people, and evidence for treatment benefit extends until at least 80 years. Taking pulse pressure into account (see "Systolic versus diastolic hypertension", above), the best agents are thiazide diuretics and long-acting dihydropyridine calcium-channel blockers.

Ethnic groups

Afro-Caribbean blacks have a particularly high prevalence of hypertension and severe complications. Their presentation is unusual in that the renin–angiotensin system is often suppressed. As a result, β-blockers and ACEIs are unlikely to be successful as monotherapy in these patients. Diuretics, calcium-channel blockers, and salt restriction are all effective.

Diabetics

Hypertension is common in diabetics and plays a major role in the vascular complications of the disease. Recent studies have suggested there is more to gain from controlling hypertension in diabetics than there is in achieving normoglycemia. For this reason, particularly aggressive BP-lowering treatment is warranted in these patients. ACEIs, preferably combined with a thiazide diuretic, are the treatment of choice. Previous avoidance of β-blockers or thiazide diuretics because of possible worsening of glycemic control needs to be reassessed in light of this information. Most recent studies show that both groups of drugs can be safely administered in diabetics.

Pregnancy

Hypertension occurs in up to 10% of pregnancies. The key distinction is between chronic hypertension in a pregnant woman and pregnancy-induced hypertension (pre-eclampsia) – defined as a rise in BP of >30/15 mm Hg from early pregnancy. Little is known about which agents are truly safe in pregnancy, but methyldopa is generally considered first line, with calcium antagonists or hydralazine regarded secondarily. Labetalol is sometimes used in the third trimester. In addition, trials in pregnant women with pre-eclampsia have suggested that magnesium sulfate injections may reduce the risk of eclampsia developing by as much as half. ACEIs should be avoided.

Erectile dysfunction

ED is a common problem in hypertensives. It is common because it can be caused by both hypertension (via vascular disease) and its treatment. Differentiating the two from psychogenic causes is a challenge. However, it is made easier by taking a full history: ask about desire, morning erections, erections during masturbation, the exact timing of onset, life stress, sexual history, alcohol, and nonprescription medication. Palpation of the penis for Peyronie's disease and the testes for atrophy should be added to the routine examination. If ED clearly relates to one particular medication, it is worth trying alternatives. If ED remains resistant, then possible treatments are vacuum devices, intraurethral alprostadil, and sildenafil. Patients with more than three risk factors for coronary disease should have an exercise test before starting sildenafil.

Generalist management

Hypertension is one of the few cardiovascular conditions where, in theory, the generalist can manage the whole process. Because of the overwhelming likelihood that any given hypertensive patient will have "essential" hypertension, only a small number of routine investigations are warranted. These are:

  • urine dipstick
  • blood glucose, electrolyte, and creatinine levels
  • total cholesterol to high-density lipoprotein ratio
  • electrocardiography

However, in a young patient, a patient with severe hypertension without a family history, or with signs or symptoms suggesting a secondary cause, the full investigative program detailed above (see "Investigations") should be instituted. This is normally done predominantly within a specialist center.

Refer with confidence

In practice, hypertension specialists tend to see patients from one of the following four categories:

  • patients with resistant hypertension
  • patients from special groups with hypertension, eg, pregnant women or young people
  • patients with known secondary hypertension
  • patients with possible accelerated hypertension (see below)

Most generalists would expect to try at least three agents and carry out basic investigations before referring the patient to a specialist for the management of resistant hypertension. Certainly, it would be unusual to make use of vasodilators in the community. However, in the special groups mentioned above, it would not be uncommon for the full work-up to be done from the beginning in a special center. Clearly, any suspicion of accelerated hypertension should result in immediate referral.

Basic science

BP is a normally distributed, polygenic trait. That is, an individual's BP results from the effects of many genes interacting with each other and the environment. Due in part to this, genetics has so far struggled to explain essential hypertension. However, early studies have suggested that up to 50% of variation within the general population could be explained by genetic factors. The experimental approach has involved studying affected sibling pairs and scanning the whole genome for chromosomal regions with higher levels of genetic marker similarity.

Selectively bred animal models have also been used to study hypertension. Despite much effort, the only mutations that have been convincingly shown to be associated with hypertension are those of the ACE gene, and these gene polymorphisms are more strongly associated with atherosclerotic disease than hypertension.

The role of the sympathetic nervous system in hypertension has been debated over many years. Most agree that, together with inadequate salt excretion, it plays an important initiating role (validating the choice of β-blockers as a first-line agent in young hypertensives). However, there is significant controversy as to its continuing role. The prevalent view is that the sympathetic nervous system plays only a minor part in chronic hypertension, and recent studies showing the benefit of ARBs over β-blockers reinforce this.

Resistant hypertension

Failure to reduce BP to <140/90 mm Hg with three or more drugs qualifies the patient as "resistant". Resistant hypertensives commonly suffer plasma volume expansion, despite the absence of clinical signs. In this situation, a more aggressive diuretic therapy can achieve targets where other combinations have failed to do so. Secondary causes are common in resistant hypertensives – they should be referred to a specialist to ensure a full diagnostic work-up. Apparent therapeutic failure could be due to noncompliance; many patients who have been prescribed several different tablets for an asymptomatic condition respond by not taking all of the tablets as directed. Therefore, before altering the medication, determine whether the patient is actually taking it.

Malignant (or accelerated phase) hypertension

In about 1% of patients with hypertension, the condition follows an accelerated course. BP is markedly raised (diastolic >130 mm Hg) and is associated with grade III–IV retinopathy. There may be encephalopathy (headache, confusion, visual disturbance, seizures, and coma), cardiac failure, and rapidly deteriorating renal function. The vascular lesion associated with malignant hypertension is fibrinoid necrosis of the walls of small arteries and arterioles. The prognosis is very poor: untreated, 90% of patients die within 1 year, and even with treatment the 5-year survival rate is only 60%.

Malignant hypertension is a medical emergency that requires immediate therapy. However, the fall in BP should be controlled and carefully monitored as cerebral and myocardial perfusion can become compromised, which could lead to infarction (an initial target diastolic BP should be around 100–110 mm Hg). The reduction in BP is achieved with parenteral agents, such as nitroprusside or labetalol, ideally with intra-arterial BP monitoring. If a pheochromocytoma is suspected, drugs such as phenoxybenzamine or phentolamine (α-adrenergic blockers) should be used first. Once the acute episode has been successfully treated, the BP can be further titrated down over the following weeks.

Further reading

  1. Graves JW. Management of difficult-to-control hypertension. Mayo Clin Proc. 2000;75:278–84. [PubMed: 10725955]
  2. Hurley ML. New hypertension guidelines. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. RN. 1998;61:25–8. [PubMed: 9544090]
  3. Kjeldsen SE, Erdine S, Farsang C. et al. 1999 WHO/ISH hypertension guidelines – highlights and ESH update. J Hypertens. 2002;20:153–5. [PubMed: 11791039]
  4. O'Brien E, Staessen JA. Critical appraisal of the JNC VI, WHO/ISH and BHS guidelines for essential hypertension. Expert Opin Pharmacother. 2000;1:675–82. [PubMed: 11249509]
  5. Ramsay L, Williams B, Johnston G. et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens. 1999;13:569–92. [PubMed: 10482967]
  6. The American Heart Association guidelines are available at http://www​.americanheart.org.
  7. European guidelines are available at http://www​.escardio.org.
Copyright © 2004, Remedica.
Bookshelf ID: NBK2217

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