Hypertension and Heart Failure

1. Introduction
2. Hypertension
   • Blood Pressure Physiology
   • Definitions and Stages
   • Primary vs Secondary Hypertension
   • Why Treat Hypertension?
3. Antihypertensive Drugs
   • ACE Inhibitors and ARBs
   • Calcium Channel Blockers
   • Thiazide and Thiazide-Like Diuretics
   • Beta-Blockers and Alpha-Blockers
   • Mineralocorticoid Receptor Antagonists
4. The NICE Algorithm for Hypertension
5. Heart Failure
   • Pathophysiology
   • HFrEF and HFpEF
   • Symptoms
6. Drug Treatment of Heart Failure
   • Mortality-Reducing Drugs
   • Symptomatic Drugs
7. Acute Coronary Syndromes (Brief Overview)
8. Summary
9. Drug Summary Table
10. Quiz

• Hypertension is defined by NICE as a clinic blood pressure of 140/90 mmHg or higher confirmed on ambulatory (worn while going about the day) or home blood pressure monitoring. The vast majority is primary (idiopathic), meaning there is no single identifiable cause, rather than secondary.
• The three main drug classes are ACE inhibitors (angiotensin-converting enzyme inhibitors) or ARBs (angiotensin II receptor blockers), Calcium channel blockers, and Diuretics (drugs that make the kidneys pass more urine; thiazide-like drugs include indapamide and chlortalidone). Beta-blockers (drugs that block beta-adrenergic receptors) are not part of the first three steps. The NICE step-up algorithm uses these as A or C → two of A, C and D → A+C+D → A+C+D plus spironolactone, an alpha-blocker or a beta-blocker.
• Heart failure is the failure of the heart to pump blood at a rate that matches the body's metabolic demand. It is split by ejection fraction (the percentage of blood in the left ventricle pumped out with each beat) into HFrEF (reduced ejection fraction), HFmrEF (mildly reduced) and HFpEF (preserved ejection fraction).
• The drug classes proven to reduce mortality in HFrEF are ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs, which block the receptor for the hormone aldosterone) and SGLT2 inhibitors (sodium-glucose cotransporter 2 inhibitors). Sacubitril/valsartan (an ARNI: a combined neprilysin inhibitor and angiotensin receptor blocker) can replace the ACE inhibitor in people who still have symptoms, and is offered instead of it if an ACE inhibitor is not tolerated (other than because of angio-oedema, swelling of the lips, tongue, face and airway). Loop diuretics (strong diuretics such as furosemide) relieve symptoms but do not improve survival.

Introduction

Hypertension and heart failure are two of the most common conditions a UK doctor will ever treat. They are also two of the most pharmacologically rich, with several drug classes and a clear, evidence-based hierarchy of choice. This article covers the drugs used at pre-clinical level and connects them to the cardiovascular physiology covered in Control of Cardiac Output, Hypertension, and Heart Failure.

Hypertension

Blood Pressure Physiology

The pressure difference across the systemic circulation (mean arterial pressure, MAP, the average pressure in the arteries over a heartbeat, minus central venous pressure, CVP) equals cardiac output (CO) multiplied by total peripheral resistance (TPR). CVP is the pressure in the great veins as they enter the right atrium. When CVP is small relative to MAP, it can be ignored and MAP is approximately CO × TPR. The full relationship is:

MAP − CVP  =  CO  ×  TPR

Cardiac output is the product of stroke volume and heart rate, while total peripheral resistance is overwhelmingly determined by the radius of arterioles. The Poiseuille equation says that resistance is proportional to 1/r⁴, where r is the radius of the vessel. A small change in arteriolar radius therefore produces a very large change in resistance. This is why drugs that even modestly dilate arterioles can produce a substantial drop in blood pressure.

Every antihypertensive drug works by acting somewhere in this equation: by reducing cardiac output (heart rate or contractility, how forcefully the heart contracts), by reducing peripheral resistance (vasodilation), or by reducing circulating volume (diuresis, passing more urine).

Diagram: The renin-angiotensin-aldosterone system, with the sites of action of ACE inhibitors, ARBs and mineralocorticoid receptor antagonists.

Definitions and Stages

NICE defines hypertension by clinic blood pressure measurement, with confirmation by ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM):

• Stage 1. Clinic blood pressure (BP) in the range 140/90 to 159/99 mmHg and subsequent daytime ABPM or HBPM average in the range 135/85 to 149/94 mmHg.
• Stage 2. Clinic systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg and subsequent daytime ABPM or HBPM average ≥ 150/95 mmHg. Stage 2 applies only when the clinic systolic BP is below 180 mmHg and the clinic diastolic BP is below 120 mmHg. At or above either figure it is stage 3.
• Stage 3 (severe). Clinic systolic BP ≥ 180 mmHg or diastolic BP ≥ 120 mmHg.

The reason for confirming with ABPM or HBPM is the white coat effect: clinic blood pressure can be higher than the average daytime ABPM or HBPM measurement. The reverse phenomenon, masked hypertension, also occurs.

Primary vs Secondary Hypertension

Around 90% of hypertension is primary (essential, idiopathic). This means there is no single identifiable cause. It emerges from a combination of genetic susceptibility, salt sensitivity, vascular remodelling (structural change in the walls of blood vessels), sympathetic overactivity and the renin-angiotensin-aldosterone system (RAAS).

The remaining 10% is secondary, with the main causes worth knowing for pre-clinical exams:

• Renal disease: the commonest secondary cause overall.
• Renovascular disease: renal artery stenosis (narrowing of the artery to the kidney), which is atherosclerotic in older patients and due to fibromuscular dysplasia (abnormal growth in the artery wall) in younger patients.
• Endocrine: primary hyperaldosteronism (Conn's syndrome, too much aldosterone), phaeochromocytoma (a tumour that releases adrenaline and noradrenaline), Cushing's syndrome (too much cortisol).
• Coarctation of the aorta (a narrowing of the aorta that is present from birth).
• Drugs: alcohol, the combined oral contraceptive pill, non-steroidal anti-inflammatory drugs (NSAIDs), sympathomimetics (drugs that mimic the sympathetic nervous system), corticosteroids, ciclosporin, recreational stimulants.

The clinical importance of identifying a secondary cause is that treating the cause can cure the hypertension, while in primary hypertension the disease is lifelong.

Why Treat Hypertension?

Hypertension is almost always asymptomatic (without symptoms), yet it is one of the leading global causes of premature death. Hypertension has several complications. Treatment reduces the risk of many of them, but not all (see the kidney point):

• Stroke (about 27% fewer strokes for every 10 mmHg fall in systolic blood pressure, in a large meta-analysis, which is a combined analysis of many trials).
• Ischaemic heart disease (about 17% fewer coronary heart disease events for the same fall).
• Heart failure (about 28% fewer cases for the same fall).
• Chronic kidney disease. Hypertension raises the risk, but the same meta-analysis found no significant reduction in renal failure from lowering blood pressure.
• Vascular dementia.
• Retinopathy (damage to the retina at the back of the eye) and aneurysm formation (bulging of a weakened artery wall).

For adults under 80, the general target is below 140/90 mmHg in clinic, or below 135/85 mmHg on home or ambulatory monitoring. For most adults aged 80 and over, the targets are below 150/90 mmHg in clinic and below 145/85 mmHg on home or ambulatory monitoring. A lower clinic target of below 130/80 mmHg applies to adults with chronic kidney disease (CKD) who have an albumin-to-creatinine ratio (ACR, a measure of protein leaking into the urine) of 70 mg/mmol or more. It also applies to adults under 80 with type 1 diabetes and the same ACR. Having type 2 diabetes does not change the general target.

Antihypertensive Drugs

ACE Inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors (ramipril, lisinopril, perindopril, enalapril) block the conversion of angiotensin I to angiotensin II by ACE. ACE sits on the luminal surface of vascular endothelium (the inner lining of blood vessels), particularly in the lung. The downstream effects are:

• Reduced angiotensin II → vasodilation, particularly of the efferent renal arteriole (the small vessel that carries blood out of the glomerulus, the kidney's filter).
• Reduced aldosterone secretion → reduced sodium and water retention.
• Reduced antidiuretic hormone (ADH/vasopressin) release.
• Reduced sympathetic tone.
• Reduced cardiac and vascular hypertrophy over time.

ACE also degrades bradykinin (a peptide that widens blood vessels), so ACE inhibitors increase circulating bradykinin. This is thought to contribute to the most distinctive ACE inhibitor side effect, the dry cough. Reported rates range from about 5% to 35% of patients depending on the study, and cough is more common in women.

Angiotensin II receptor blockers (ARBs) (losartan, candesartan, valsartan, irbesartan) block angiotensin II at the AT₁ receptor (the angiotensin II type 1 receptor). They have essentially the same effects on blood pressure and blood flow (haemodynamic effects) as ACE inhibitors, but they do not inhibit ACE-mediated bradykinin breakdown. Cough is less frequent with ARBs than with ACE inhibitors, but it can still occur. The BNF (British National Formulary, the UK drug reference) lists it as a side effect of ARBs. ARBs are therefore the standard alternative when an ACE inhibitor is not tolerated, for example because of cough.

Side effects of ACE inhibitors and ARBs:

• Dry cough (mainly ACE inhibitors; less frequent with ARBs).
• First-dose hypotension, particularly in volume-depleted patients.
• Hyperkalaemia (high blood potassium, caused by reduced aldosterone).
• Renal impairment, especially in bilateral renal artery stenosis, where the kidneys depend on angiotensin II to maintain the glomerular filtration rate (GFR, how fast the kidneys filter blood).
• Angio-oedema (swelling of the lips, tongue, face and airway): rare but potentially life-threatening, and more common in patients of Black African or African-Caribbean origin.
• Pregnancy and breastfeeding: ACE inhibitors and ARBs carry an increased risk of congenital abnormalities (birth defects) if taken in pregnancy. NICE guideline NG133 (hypertension in pregnancy) advises stopping them if a woman becomes pregnant, preferably within 2 working days of notification, and offering alternatives. After birth, NICE NG133 advises offering enalapril (an ACE inhibitor) for hypertension, with monitoring of maternal renal function and potassium. For women of Black African or Caribbean family origin, it advises considering nifedipine instead, or amlodipine if the woman has used it before to control her blood pressure successfully. Where possible, avoid ARBs and diuretics in women who are breastfeeding or expressing milk. The MHRA (the UK medicines regulator) advises that ACE inhibitors and ARBs are generally not recommended during breastfeeding but are not absolutely contraindicated: for mothers breastfeeding older infants, enalapril, captopril or quinapril may be considered if an ACE inhibitor is necessary. Women taking any antihypertensive while breastfeeding should be advised to watch their baby for drowsiness, lethargy (unusual tiredness), pallor (pale skin), cold peripheries (cold hands and feet) or poor feeding.

Calcium Channel Blockers

Calcium channel blockers (CCBs) block voltage-gated L-type calcium channels (calcium channels that open when the cell membrane depolarises), reducing calcium entry into vascular smooth muscle and cardiac myocytes (heart muscle cells). Three subclasses exist, each with a different tissue selectivity:

• Dihydropyridines (amlodipine, felodipine, nifedipine): selective for vascular smooth muscle. Cause vasodilation with little direct effect on the heart. Amlodipine is the standard first-line CCB for hypertension.
• Phenylalkylamines (verapamil): selective for cardiac tissue. Reduce heart rate and contractility, and prolong the refractory period (the short recovery time after each impulse, when the node cannot fire again) of the atrioventricular (AV) node (the electrical link between the atria and ventricles), which slows conduction. Used for abnormal heart rhythms (arrhythmias) and to prevent angina (chest pain caused by reduced blood flow to the heart muscle).
• Benzothiazepines (diltiazem): intermediate between the two. Some vasodilation, some cardiac slowing.

Side effects of dihydropyridine CCBs:

• Ankle oedema: common, because the arterioles (small arteries) widen more than the venules (small veins).
• Flushing and headache.
• Reflex tachycardia (a fast heart rate, as a reflex response to the fall in blood pressure) and palpitations (awareness of the heartbeat).

Side effects of verapamil and diltiazem:

• Constipation (verapamil: classic in exam questions).
• Bradycardia (slow heart rate) and heart block (impaired passage of electrical signals from the atria to the ventricles).
• Negative inotropy (weaker heart contraction): can worsen heart failure. Verapamil and diltiazem should be avoided with beta-blockers, or used only with great caution and monitoring, because of additive bradycardia and cardiodepression (reduced heart rate and contractility).

Thiazide and Thiazide-Like Diuretics

Thiazide and thiazide-like diuretics block the Na⁺/Cl⁻ cotransporter (a protein that carries sodium and chloride together into the cell) in the distal convoluted tubule (the part of the nephron after the loop of Henle, the U-shaped section of the tubule), producing modest diuresis and arteriolar vasodilation. The classical thiazide is bendroflumethiazide; the thiazide-like drugs (with similar mechanism but different chemistry) are indapamide and chlortalidone. NICE specifically prefers the thiazide-like drugs over bendroflumethiazide in hypertension because of stronger outcome data. The full mechanism is described in Diuretics and Renal Pharmacology.

Side effects:

• Hypokalaemia (low blood potassium) and hyponatraemia (low blood sodium).
• Hypercalcaemia (high blood calcium, because thiazides make the kidneys retain calcium).
• Hyperuricaemia (high blood uric acid): can precipitate gout (painful joint inflammation).
• Impaired glucose tolerance: these drugs can raise blood glucose, so use them with care in diabetes.
• Hyperlipidaemia (high blood lipids, or fats).
• Erectile dysfunction.

Beta-Blockers and Alpha-Blockers

Beta-blockers (atenolol, bisoprolol, metoprolol, propranolol, carvedilol) reduce sympathetic drive to the heart, lowering heart rate and contractility, which reduces cardiac output and renin secretion. They are no longer first-line for uncomplicated hypertension in NICE guidance, but remain important when there are coexisting indications: ischaemic heart disease, heart failure, arrhythmias, or in pregnancy (labetalol).

Side effects include bronchospasm (airway narrowing that causes wheeze). Beta-blockers are a relative contraindication in asthma and an absolute one in severe asthma. Selective β₁-blockers are safer but not entirely safe. Other side effects are bradycardia, fatigue, cold peripheries (including Raynaud's, where the fingers turn white or blue in the cold), masking of hypoglycaemia (low blood glucose) in diabetics, and erectile dysfunction.

Alpha-blockers (doxazosin) block α₁-adrenergic receptors (receptors that respond to noradrenaline) on vascular smooth muscle, causing vasodilation. In hypertension, NICE suggests considering an alpha-blocker (or a beta-blocker) only as a step 4 option (see the NICE algorithm below) in resistant hypertension (blood pressure still uncontrolled on three drugs) when blood potassium is above 4.5 mmol/L. They are also used for symptomatic benign prostatic hyperplasia (BPH, an enlarged prostate gland). The major side effect is postural hypotension (a fall in blood pressure on standing up), particularly with the first dose.

Mineralocorticoid Receptor Antagonists

Spironolactone and eplerenone are aldosterone receptor antagonists. They cause potassium-sparing diuresis and have proven mortality benefit in heart failure. In hypertension, NICE advises considering low-dose spironolactone as a step 4 agent. This is for resistant hypertension, when blood pressure is still uncontrolled on the best tolerated doses of an ACE inhibitor or ARB, a calcium channel blocker and a thiazide-like diuretic, and the blood potassium is 4.5 mmol/L or less. Use particular caution if the estimated glomerular filtration rate (eGFR, a measure of how well the kidneys filter blood) is reduced, because the risk of hyperkalaemia is higher. Sodium, potassium and kidney function should be checked within 1 month of starting, and repeated as needed after that.

A classic side effect of spironolactone is gynaecomastia (breast enlargement in men), because it also blocks androgen receptors (the receptors for male sex hormones such as testosterone). Eplerenone is more selective, and gynaecomastia is uncommon with it. Both can cause hyperkalaemia.

The NICE Algorithm for Hypertension

The current NICE algorithm uses the mnemonic A C D:

A: ACE inhibitor (or ARB if not tolerated)
C: Calcium channel blocker
D: Diuretic (thiazide-like)

The choice of starting drug depends on the patient:

• Under 55 and not Black African or African-Caribbean: start with A.
• 55 or over, or Black African / African-Caribbean of any age, in both cases without type 2 diabetes: start with C. (Patients of Black African or African-Caribbean origin are more likely to have low plasma renin activity. Renin is the kidney enzyme that starts the renin-angiotensin-aldosterone system. ACE inhibitors and ARBs appear to work less well in this group for uncomplicated hypertension. The risk of angio-oedema with ACE inhibitors is also higher.)
• Type 2 diabetes of any age: start with A, regardless of ethnicity, because of the renal protective effect. (For adults of Black African or African-Caribbean family origin, NICE advises considering an ARB in preference to an ACE inhibitor. Blood pressure treatment in type 1 diabetes follows NICE's separate type 1 diabetes guideline.)

If blood pressure is not controlled at one drug, the steps are:

1. A or C alone (depending on starting choice).
2. Two of the three classes: if you started with A, add C or D. If you started with C, add A or D. For adults of Black African or African-Caribbean family origin, NICE advises considering an ARB in preference to an ACE inhibitor.
3. A + C + D.
4. If blood pressure is still uncontrolled on the best tolerated doses of A + C + D, this is resistant hypertension. Consider a fourth agent, or seek specialist advice. The choice depends on the blood potassium (K⁺) level. Consider low-dose spironolactone if K⁺ is 4.5 mmol/L or less. Consider an alpha-blocker or beta-blocker if K⁺ is more than 4.5 mmol/L.

In pregnancy, NICE NG133 advises considering labetalol first. Nifedipine is the alternative if labetalol is not suitable, and methyldopa is used if neither is suitable. ACE inhibitors and ARBs should be stopped if a woman becomes pregnant, because they carry an increased risk of congenital abnormalities. Thiazide and thiazide-like diuretics may also carry an increased risk of congenital abnormalities and problems in the newborn. For most other antihypertensive drugs, the limited evidence available has not shown an increased risk of malformation.

Heart Failure

Pathophysiology

Heart failure (HF) is the inability of the heart to pump blood at a rate that meets the metabolic demands of the body. The fundamental insult is damage to the myocardium (heart muscle) from ischaemia (reduced blood supply), valve disease, hypertension, cardiomyopathy (disease of the heart muscle itself) or arrhythmia (an abnormal heart rhythm). This is followed by a maladaptive neurohormonal response.

The neurohormonal response is the central concept. As cardiac output falls, the sympathetic nervous system is activated, the RAAS is activated, and antidiuretic hormone is released. In the short term, these maintain blood pressure and perfusion. In the long term, they accelerate myocardial damage by increasing afterload (the resistance the ventricle must pump against), retaining salt and water (worsening congestion, meaning fluid backing up in the lungs and body), and promoting fibrosis. Almost every drug that improves survival in heart failure works by interrupting this neurohormonal cascade.

HFrEF and HFpEF

Heart failure is split by ejection fraction (the percentage of blood in the left ventricle pumped out with each beat):

• HFrEF (heart failure with reduced ejection fraction): ejection fraction of 40% or less. The heart's pumping function is impaired. The drugs discussed below all have evidence here.
• HFpEF (heart failure with preserved ejection fraction): ejection fraction 50% or higher with symptoms of heart failure. The heart's filling is impaired. Pharmacological options are more limited than in HFrEF. NICE advises considering an MRA and an SGLT2 inhibitor.
• HFmrEF (mildly reduced): 41 to 49%. NICE advises considering the same four drug classes as in HFrEF: an ACE inhibitor, a beta-blocker, an MRA and an SGLT2 inhibitor.

Symptoms

The cardinal symptoms of heart failure are breathlessness, orthopnoea (breathlessness on lying flat), paroxysmal nocturnal dyspnoea (waking at night gasping for breath), fatigue, and peripheral oedema. The classic syndrome is described in Heart Failure.

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