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 or home measurement. The vast majority is primary (idiopathic) rather than secondary.
• The four mainstay drug classes are ACE inhibitors / ARBs, Calcium channel blockers, Diuretics (thiazide-like) and beta-blockers. The NICE step-up algorithm uses these as A → A+C → A+C+D → A+C+D+spiro/β-blocker/α-blocker.
• Heart failure is the failure of the heart to pump blood at a rate commensurate with metabolic demand. It is split into HFrEF (reduced ejection fraction) and HFpEF (preserved ejection fraction).
• The drug classes proven to reduce mortality in HFrEF are ACE inhibitors / ARBs, beta-blockers, mineralocorticoid receptor antagonists, sacubitril/valsartan, and SGLT2 inhibitors. Loop diuretics 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 equals cardiac output multiplied by total peripheral resistance. When central venous pressure (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, so a small change in arteriolar radius produces a very large change in resistance, which 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 (rate or contractility), by reducing peripheral resistance (vasodilation), or by reducing circulating volume (diuresis).

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 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. Both clinic components must remain below the severe thresholds of 180 mmHg systolic and 120 mmHg diastolic.
• 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), without a single identifiable cause but emerging from a combination of genetic susceptibility, salt sensitivity, vascular remodelling, 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 (atherosclerotic in older patients, fibromuscular dysplasia in younger).
• Endocrine: primary hyperaldosteronism (Conn's), phaeochromocytoma, Cushing's syndrome.
• Coarctation of the aorta.
• Drugs: alcohol, the combined oral contraceptive pill, NSAIDs, sympathomimetics, 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, yet it is one of the leading global causes of premature death. Treatment reduces the risk of:

• Stroke (the strongest single benefit).
• Ischaemic heart disease.
• Heart failure.
• Chronic kidney disease.
• Vascular dementia.
• Retinopathy and aneurysm formation.

The general target is below 140/90 mmHg (clinic) or 135/85 mmHg (home/ABPM). A tighter target of below 130/80 mmHg is recommended for patients with type 1 diabetes and for type 2 diabetics with albuminuria or significant CKD.

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 on the luminal surface of vascular endothelium, particularly in the lung. The downstream effects are:

• Reduced angiotensin II → vasodilation, particularly of the efferent renal arteriole.
• 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, so ACE inhibitors increase circulating bradykinin: the cause of the most distinctive ACE inhibitor side effect, the dry cough (around 10% of patients, more common in women).

Angiotensin II receptor blockers (ARBs): losartan, candesartan, valsartan, irbesartan: block angiotensin II at the AT₁ receptor. They produce essentially the same haemodynamic effects as ACE inhibitors, but they do not inhibit ACE-mediated bradykinin breakdown. Cough can still occur, as listed in the losartan SmPC. ARBs are therefore the standard alternative when an ACE inhibitor is not tolerated.

Side effects of ACE inhibitors and ARBs:

• Dry cough (ACE inhibitors only).
• First-dose hypotension, particularly in volume-depleted patients.
• Hyperkalaemia (reduced aldosterone).
• Renal impairment, especially in bilateral renal artery stenosis where the kidneys depend on angiotensin II to maintain GFR.
• Angio-oedema: rare but potentially life-threatening, more common in patients of African descent.
• Pregnancy and breastfeeding: avoid ACE inhibitors and ARBs during pregnancy. Breastfeeding is not an absolute contraindication to all medicines in these classes: NICE NG133 recommends enalapril for postnatal hypertension, with monitoring of maternal renal function and potassium. Where possible, avoid ARBs in women who are breastfeeding or expressing milk; assess treatment and infant monitoring individually.

Calcium Channel Blockers

Calcium channel blockers (CCBs) block voltage-gated L-type calcium channels, reducing calcium entry into vascular smooth muscle and cardiac myocytes. 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, prolong AV node refractory period. Used for arrhythmias and as anti-anginal therapy.
• Benzothiazepines (diltiazem): intermediate between the two. Some vasodilation, some cardiac slowing.

Side effects of dihydropyridine CCBs:

• Ankle oedema: common, due to arteriolar dilation outpacing venular dilation.
• Flushing and headache.
• Reflex tachycardia and palpitations.

Side effects of verapamil and diltiazem:

• Constipation (verapamil: classic in exam questions).
• Bradycardia and heart block.
• Negative inotropy: can worsen heart failure. Verapamil and diltiazem must not be combined with beta-blockers because of additive bradycardia and risk of complete heart block.

Thiazide and Thiazide-Like Diuretics

Thiazide and thiazide-like diuretics block the Na⁺/Cl⁻ cotransporter in the distal convoluted 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 and hyponatraemia.
• Hypercalcaemia (calcium-retaining).
• Hyperuricaemia: can precipitate gout.
• Impaired glucose tolerance: relative caution in diabetes.
• Hyperlipidaemia.
• 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 (a relative contraindication in asthma and an absolute one in severe asthma; selective β₁-blockers are safer but not entirely safe), bradycardia, fatigue, cold peripheries (Raynaud's), masking of hypoglycaemia in diabetics, and erectile dysfunction.

Alpha-blockers (doxazosin) block α₁-adrenergic receptors on vascular smooth muscle, causing vasodilation. They are now mainly used as fourth-line antihypertensives or for symptomatic benign prostatic hyperplasia. The major side effect is postural hypotension, 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, they are used as fourth-line agents in resistant disease, particularly when serum potassium is below 4.5 mmol/L.

The principal side effect of spironolactone is gynaecomastia (because it also blocks androgen receptors). Eplerenone is more selective and avoids this. 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: start with C. (Patients of African or Caribbean descent tend to have a low-renin form of hypertension, so ACE inhibitors are less effective. They also have a higher risk of angio-oedema with ACE inhibitors.)
• Diabetes of any age: start with A, regardless of ethnicity, because of the renal protective effect.

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

1. A or C alone (depending on starting choice).
2. A + C.
3. A + C + D.
4. Add a fourth agent depending on serum potassium: spironolactone if K⁺ < 4.5, an alpha-blocker or beta-blocker if K⁺ ≥ 4.5.

In pregnancy, NICE NG133 recommends labetalol first-line, with nifedipine and methyldopa as alternatives. ACE inhibitors and ARBs are absolutely contraindicated, as are most other antihypertensives.

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; from ischaemia, valve disease, hypertension, cardiomyopathy or arrhythmia; 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, retaining salt and water (worsening congestion), 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:

• HFrEF (heart failure with reduced ejection fraction): ejection fraction below 40%. 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 limited; SGLT2 inhibitors are the only drug class with strong evidence.
• HFmrEF (mildly reduced): 40-49%, treated similarly to HFrEF.

Symptoms

The cardinal symptoms of heart failure are breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, fatigue, and peripheral oedema. The classic syndrome is described in Heart Failure.

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