22.7 — Heart and Blood Pressure Drugs

Lowering blood pressure by 10 mmHg reduces the risk of stroke by around 27 percent and of heart failure by around 28 percent.

And you will feel nothing at all.

Which is the central difficulty with this entire category of medicine. These are the drugs people take for decades without noticing any benefit, because the benefit is an event that does not happen — a stroke you never had, a heart attack that never came.

Understanding what each one is actually doing makes that much easier to sustain, which is what this chapter is for.

Blood pressure — what determines it

Two things: how much blood the heart pumps out, and how tightly the arteries are squeezed (Chapter 7.6).

Every blood pressure drug lowers one or the other, and once you know which, the whole category becomes organised rather than a list.

ACE inhibitors and ARBs

Names ending in -pril: ramipril, lisinopril, enalapril, perindopril.Names ending in -sartan: losartan, candesartan, valsartan, irbesartan.

They both block the same system, at different points.

The renin-angiotensin-aldosterone system exists to defend blood pressure when it falls (Chapter 10.3).

The kidney senses low pressure and releases renin. A cascade produces angiotensin II, which is a powerful vessel constrictor. Angiotensin II also triggers aldosterone, which makes the kidney retain salt and water, raising volume.

Squeeze the pipes and add fluid — pressure rises.

ACE inhibitors block the enzyme that produces angiotensin II. ARBs block the receptor it acts on. Either way, the vessels relax and less salt and water is retained.

And they do something beyond lowering pressure, which is why they are chosen so often: they reduce the pressure inside the kidney's filtering units specifically, which protects the kidney in diabetes and in chronic kidney disease (Chapter 21.3), and they reduce the harmful remodelling of heart muscle after a heart attack and in heart failure.

The cough. Around 10 to 20 percent of people on an ACE inhibitor develop a persistent dry tickly cough.

The reason is neat: ACE also breaks down bradykinin, a molecule that irritates the airways. Block ACE and bradykinin accumulates.

ARBs do not affect bradykinin, so they do not cause the cough — which is why "switch to a sartan" is the standard answer.

Other effects: raised potassium, because less aldosterone means less potassium excretion; a rise in creatinine on starting, which is expected and acceptable up to a point; and angioedema — swelling of the lips, tongue or throat — which is rare, potentially life-threatening, can occur after years of uneventful use, and means the drug is stopped permanently.

Never in pregnancy. They cause serious fetal kidney damage (Chapter 4.6), so they are stopped before or immediately on pregnancy.

Calcium channel blockers

Amlodipine, felodipine, nifedipine — the ones ending in -dipine, which act mainly on blood vessels.Verapamil and diltiazem, which act more on the heart itself.

Muscle contraction requires calcium entering the cell (Chapter 6.2). Block the channels and the smooth muscle in artery walls relaxes.

The -dipines cause ankle swelling in a substantial proportion, and the reason is worth knowing: they dilate the small arteries feeding the capillaries more than the veins draining them, so fluid is pushed out into the tissue.

Which means diuretics do not fix it — the problem is not excess fluid, it is where the fluid is being pushed. Reducing the dose or adding an ACE inhibitor or ARB, which dilates the veins too, works better.

Also: flushing, headache and, with verapamil, constipation.

And a safety point: verapamil or diltiazem combined with a beta blocker can slow the heart dangerously, so the combination is used only with care.

Diuretics

Thiazides — indapamide, bendroflumethiazide, hydrochlorothiazide. For blood pressure.

They block sodium reabsorption in the kidney tubule, so more sodium and water leave in the urine (Chapter 10.2).

Watch for: low potassium, low sodium, raised uric acid which can trigger gout, and a small effect on glucose.

Loop diuretics — furosemide, bumetanide. Far more powerful, used for fluid overload in heart failure rather than for blood pressure.

They act on the loop of Henle and can remove large volumes (Chapter 10.2).

Taken in the morning for obvious reasons, and people with heart failure are frequently taught to adjust their own dose based on daily weight, which is one of the most useful pieces of self-management in medicine.

Potassium-sparing — spironolactone, eplerenone, amiloride.

Spironolactone blocks aldosterone. It is particularly effective in resistant hypertension — blood pressure not controlled on three drugs — and it improves survival in heart failure, which is a much bigger claim than blood pressure control.

Raises potassium, which is the main hazard, particularly combined with ACE inhibitors or ARBs. Requires blood monitoring.

And it can cause breast tenderness and enlargement in men, because it also blocks androgen receptors — eplerenone avoids this.

Beta blockers

Bisoprolol, atenolol, propranolol, carvedilol, metoprolol.

They block the receptors adrenaline acts on (Chapter 22.1), so the heart beats more slowly and less forcefully.

Which reduces the heart's oxygen demand — the reason they help angina — and controls rate in atrial fibrillation, and reduces the harmful effects of chronic adrenaline stimulation in heart failure.

They are no longer first-line for uncomplicated high blood pressure, having been overtaken by the classes above. They remain first-line where there is angina, previous heart attack, heart failure, or a rhythm problem.

Side effects: tiredness, cold hands and feet, vivid dreams, reduced exercise tolerance, and erectile dysfunction.

Caution in asthma, because blocking beta-2 receptors constricts airways. Cardioselective agents such as bisoprolol are frequently tolerated, and the selectivity is relative (Chapter 22.1).

Masking hypoglycaemia in diabetes — the tremor and palpitations that warn of low glucose are adrenaline effects, and a beta blocker removes them. Sweating still occurs. Worth knowing for anyone on insulin.

And never stopped abruptly, because of rebound (Chapter 22.1).

In heart failure they are started at a very low dose and increased slowly, because the initial effect can worsen symptoms before the long-term benefit appears — which is exactly the opposite of the intuition that a weak heart should not be slowed.

Statins and lipid drugs

Atorvastatin, simvastatin, rosuvastatin, pravastatin.

They block HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis in the liver.

And the effect is indirect and clever: with less cholesterol being made, liver cells display more LDL receptors on their surface to pull cholesterol out of the blood. So blood LDL falls because the liver is actively removing it.

They also stabilise atherosclerotic plaques, which may matter as much as the number, since it is plaque rupture rather than plaque size that causes heart attacks (Chapter 18.3).

Benefit: around a 20 to 25 percent reduction in cardiovascular events for each 1 mmol/L reduction in LDL, with benefit continuing to accumulate over years.

Muscle symptoms — reported by many, and blinded trials find similar rates on placebo (Chapter 21.6). The symptoms are genuine; the attribution is frequently wrong. The approach is to stop briefly, re-challenge, or switch, rather than to abandon treatment.

Rhabdomyolysis is the serious version and is rare — severe muscle pain with dark urine, needing immediate attention.

Liver enzymes rise mildly in some people and rarely matter.

A small increase in new diabetes diagnoses, mainly in people already close to the threshold — and the cardiovascular benefit outweighs it substantially.

Grapefruit interacts with simvastatin and atorvastatin, not with pravastatin or rosuvastatin (Chapter 22.2).

Ezetimibe — blocking cholesterol absorption in the gut, added when a statin alone is not enough.

PCSK9 inhibitors — injections that dramatically lower LDL, and they came directly out of studying rare families with unusual cholesterol genetics (Chapter 21.8).

Inclisiran — a twice-yearly injection using RNA interference to reduce PCSK9 production.

Anticoagulants and antiplatelets

And the distinction matters, because they are used for different things.

Antiplatelets stop platelets clumping — for arterial clots, which form in fast-flowing blood where platelets dominate. Heart attacks and most strokes.

Anticoagulants block the clotting cascade — for venous clots and for clots forming in a fibrillating atrium, where slow flow lets fibrin dominate (Chapter 7.1).

Aspirin (Chapter 22.5).

Clopidogrel, ticagrelor, prasugrel — blocking a different platelet activation pathway. Used after stents and in acute coronary syndromes, often with aspirin for a defined period.

Warfarin — blocking vitamin K, which is needed to make several clotting factors.

Requires INR monitoring, has a narrow therapeutic index, and interacts with an enormous number of drugs and with dietary vitamin K.

And the dietary advice is frequently given wrongly: the goal is consistent vitamin K intake, not avoidance of green vegetables. A steady amount is manageable; a fluctuating amount is not.

Still required for mechanical heart valves and severe mitral stenosis, where the newer drugs have not worked.

DOACs — apixaban, rivaroxaban, edoxaban, dabigatran.

Directly blocking a single clotting factor. No routine monitoring, far fewer interactions, and lower rates of bleeding into the brain than warfarin. They have largely replaced it for atrial fibrillation and for venous clots.

Dose depends on kidney function, age and weight, and under-dosing is a common and consequential error.

Reversal agents exist — idarucizumab for dabigatran, andexanet for the factor Xa inhibitors — which removed the main early objection to them.

And the universal caution: any anticoagulant means bleeding risk. Report black stools, blood in urine, unusual bruising, or any significant head injury — and head injury on an anticoagulant is assessed even when the person seems completely well, because a slow bleed inside the skull can take hours to declare itself (Chapter 23.8).

Heart failure drugs

And this deserves a note, because the treatment of heart failure with reduced ejection fraction has changed substantially.

Four drug groups now form the foundation, and each independently improves survival:

ACE inhibitor or ARB, or sacubitril-valsartan, which combines an ARB with a drug that preserves the body's own beneficial natriuretic peptides.

Beta blocker.

Mineralocorticoid receptor antagonist — spironolactone or eplerenone.

SGLT2 inhibitor — originally a diabetes drug, and now standard in heart failure regardless of diabetes (Chapter 21.3).

Together these have improved life expectancy in heart failure substantially, and the current emphasis is on starting all four early at low doses rather than adding them one at a time over months.

Plus diuretics for symptoms, which make people feel better without changing survival — the reverse of the four above, which change survival without necessarily changing how you feel.

Rhythm drugs

Rate control — slowing the ventricles in atrial fibrillation: beta blockers, diltiazem or verapamil, digoxin.

Rhythm control — restoring normal rhythm: flecainide, amiodarone, sotalol, or electrical cardioversion.

Amiodarone is effective and remarkably toxic over time — thyroid, lung, liver, eye and skin — so it requires regular monitoring and is chosen when the alternatives will not do.

Digoxin — narrow therapeutic index, and toxicity presents as nausea, confusion, visual disturbance with yellow-green haloes, and arrhythmias. Levels rise if kidney function falls or potassium drops.

Why to keep taking them

The benefit is invisible by design.

A useful way to think about it: these drugs are not treating today. They are lowering the probability of a specific bad event over the next ten years.

And the numbers are real. Blood pressure control, statins and anticoagulation for atrial fibrillation are three of the best-evidenced interventions in all of medicine.

Stopping because you feel fine is a category error — feeling fine is the product, not evidence that the drug is unnecessary.

If side effects are the problem, say so. There are almost always alternatives within or between classes, and stopping silently is the outcome nobody wants.

What the next page fixes

Chapter 22.8 covers diabetes drugs — a field that changed more in ten years than in the previous fifty, and where several drugs turned out to do far more than lower glucose.