Cardiology: Anatomy Physiology and Pharmacology

• Anatomy: Chambers and Valves | Coronary Arteries | The Conduction System | Pericardium, Great Vessels and Surface Anatomy | Embryology and Fetal Circulation
• Physiology: The Cardiac Cycle | Cardiac Output and Starling's Law | Control of Blood Pressure | Cardiac Action Potentials | Excitation–Contraction Coupling | Autonomic Control of the Heart | Coronary Blood Flow | Normal Values
• Disease mechanisms: Atherosclerosis | Thrombosis and Clotting | How Heart Failure Develops | How Arrhythmias Arise | Lipids and Lipoproteins
• Pharmacology: Antiplatelet Drugs | Anticoagulants | Heparins | Thrombolytics | Lipid-lowering Drugs | Nitrates and Other Antianginals | Beta-blockers | Calcium Channel Blockers | ACE Inhibitors, ARBs and ARNI | Diuretics and MRAs | SGLT2 Inhibitors | Antiarrhythmic Drugs | Amiodarone | Digoxin | Adenosine | Inotropes and Vasopressors
• Revision: Drug Reference Table | Spot the Answer | Exam-style Scenarios | Key Points | Guidelines and Further Reading

❤️ Cardiac anatomy, physiology, science and pharmacology — understanding how the heart is built, how it pumps, how it is controlled electrically, and how drugs act on it makes the rest of cardiology much easier. Almost every cardiac drug works by changing heart rate, contractility, preload, afterload, electrical conduction or clotting.
Your four questions for every drug: How does it work (mechanism)? What is it used for? What are the important side effects and contraindications? What does it interact with, and what needs monitoring?

Chambers and Valves

• Right side (low pressure — lungs):
  • Right atrium — receives blood from the superior and inferior vena cava and the coronary sinus; contains the SA node and AV node.
  • Tricuspid valve — three leaflets, between the right atrium and right ventricle.
  • Right ventricle — thin-walled, crescent-shaped; most anterior chamber (lies behind the sternum).
  • Pulmonary valve — three cusps; into the pulmonary artery.
• Left side (high pressure — body):
  • Left atrium — receives oxygenated blood from four pulmonary veins; the most posterior chamber (lies just in front of the oesophagus — hence transoesophageal echo); contains the left atrial appendage (where clots form in AF).
  • Mitral valve — two leaflets (anterior and posterior), held by chordae tendineae and papillary muscles (papillary muscle rupture after MI causes acute mitral regurgitation).
  • Left ventricle — thick-walled (about 1 cm), forms the apex.
  • Aortic valve — three cusps (bicuspid in about 1–2% of people — early aortic stenosis); the coronary arteries arise from the sinuses just above it.
• Heart borders on chest X-ray — right border: right atrium; left border: left ventricle (and left atrial appendage, pulmonary artery, aortic knuckle); inferior border: mainly right ventricle.
• Wall layers — endocardium (inner), myocardium (muscle), epicardium (visceral pericardium).

Coronary Arteries

• Left main stem — from the left coronary sinus; divides into:
  • Left anterior descending (LAD) — runs down the front of the heart: anterior LV wall, anterior two-thirds of the septum, apex. Branches — diagonals and septal perforators. ECG — V1–V4.
  • Circumflex — runs in the groove between left atrium and ventricle: lateral and posterior LV walls. Branches — obtuse marginals. ECG — I, aVL, V5–V6.
• Right coronary artery (RCA) — from the right coronary sinus: right atrium, right ventricle, inferior LV wall, posterior third of the septum. ECG — II, III, aVF.
  • Supplies the SA node in about 60% of people and the AV node in about 90% — so inferior MI often causes bradycardia and heart block.
• Dominance — the artery that gives the posterior descending artery is "dominant": right dominant in about 80%, left (circumflex) in about 10%, co-dominant in the rest.
• Venous drainage — mainly via the coronary sinus into the right atrium.
• Left main or proximal LAD disease — a large area of muscle at risk; prognostically important.

The Conduction System

• Sinoatrial (SA) node — the natural pacemaker (60–100 beats a minute); in the right atrium near the SVC.
• The impulse spreads through the atria (P wave) to the atrioventricular (AV) node — which delays it (PR interval), letting the ventricles fill and protecting them from fast atrial rhythms.
• Bundle of His → right and left bundle branches (left splits into anterior and posterior fascicles) → Purkinje fibres — rapid spread through the ventricles (QRS).
• Escape rhythms if higher pacemakers fail — junctional (40–60 a minute, narrow QRS), ventricular (20–40, broad QRS).
• Accessory pathways (e.g. bundle of Kent in WPW) bypass the AV node's delay — short PR and delta wave.
• ECG timing — P wave = atrial depolarisation; PR = atria plus AV node delay; QRS = ventricular depolarisation; T wave = ventricular repolarisation; QT = total ventricular electrical activity.

Pericardium, Great Vessels and Surface Anatomy

• Pericardium — a tough outer fibrous layer and an inner serous layer (parietal and visceral) with about 15–50 mL of fluid between. Fluid that collects quickly (even 100–200 mL) can cause tamponade; slowly, much more is tolerated. The phrenic nerves run over it (pericardial pain refers to the shoulder tip).
• Great vessels — ascending aorta → arch (brachiocephalic, left common carotid, left subclavian arteries) → descending aorta; pulmonary trunk divides under the arch; the ligamentum arteriosum (remnant of the ductus) connects the pulmonary artery to the aortic arch, with the left recurrent laryngeal nerve hooking under it.
• Surface anatomy:
  • Apex beat — 5th intercostal space, mid-clavicular line.
  • Sternal angle (angle of Louis) — level of the 2nd rib, the aortic arch and the tracheal bifurcation (T4/T5); reference point for the JVP.
  • Pericardiocentesis — subxiphoid approach, needle aimed towards the left shoulder (ideally under echo guidance).

Embryology and Fetal Circulation

• Development — the heart forms from a single tube that starts beating at about day 22, loops to the right, and divides into four chambers by about week 8. Errors in septation or looping cause congenital heart disease (about 8 per 1,000 births).
• Fetal circulation — the lungs aren't used, so three shunts divert blood:
  • Ductus venosus — oxygenated blood from the umbilical vein bypasses the liver to the IVC.
  • Foramen ovale — blood flows from the right atrium to the left atrium.
  • Ductus arteriosus — blood flows from the pulmonary artery to the aorta.
• At birth — breathing lowers lung resistance and raises left atrial pressure, so the foramen ovale closes (remains probe-patent — PFO — in about 25% of adults); higher oxygen and falling prostaglandins close the ductus arteriosus within days.
• Drugs and the duct — prostaglandin E1 (alprostadil) keeps the duct open in duct-dependent heart lesions; NSAIDs (ibuprofen, indomethacin) or paracetamol close a PDA in preterm babies; NSAIDs late in pregnancy can close the fetal duct early.

The Cardiac Cycle

• Systole (ventricular contraction):
  • Isovolumetric contraction — ventricles start to contract; the mitral and tricuspid valves close (S1); pressure rises with all valves shut.
  • Ejection — ventricular pressure exceeds aortic and pulmonary pressure, so the aortic and pulmonary valves open and blood is ejected.
• Diastole (relaxation):
  • Isovolumetric relaxation — the aortic and pulmonary valves close (S2); pressure falls with all valves shut.
  • Rapid filling — the mitral and tricuspid valves open; blood rushes in (an S3 can occur here).
  • Atrial contraction ("atrial kick") — tops up filling by about 20–30% (an S4 occurs here with a stiff ventricle); lost in AF.
• Diastole shortens more than systole as heart rate rises — so fast rates reduce filling time and coronary blood flow (important in mitral stenosis, aortic stenosis and ischaemia).
• JVP waveform — a wave (atrial contraction), c wave (tricuspid bulging), x descent (atrial relaxation), v wave (atrial filling against a closed tricuspid valve), y descent (tricuspid opening).
• Pressure–volume loop — plots LV pressure against volume through one beat; its width is the stroke volume and its area is stroke work. It shifts right in volume overload, upwards in pressure overload.

Cardiac Output and Starling's Law

• Cardiac output (CO) = heart rate (HR) × stroke volume (SV) — about 5 L/min at rest (70 × 70 mL); can rise 4–6 times in exercise.
• Stroke volume depends on three things:
  • Preload — how much the ventricle is stretched before it contracts (end-diastolic volume); increased by fluids, reduced by diuretics, nitrates and venodilators.
  • Afterload — the resistance the ventricle pumps against (aortic pressure, systemic vascular resistance, aortic stenosis); reduced by vasodilators (ACE inhibitors, hydralazine, dihydropyridines).
  • Contractility (inotropy) — the strength of contraction at a given preload; increased by sympathetic stimulation and inotropes (dobutamine, adrenaline, milrinone, digoxin); reduced by beta-blockers, rate-limiting calcium channel blockers, ischaemia, acidosis and hypoxia.
• Frank–Starling law — the more the heart muscle is stretched in diastole, the more forcefully it contracts (up to a point). In heart failure the curve is flatter: extra filling raises pressure (congestion) more than output.
• Ejection fraction (EF) = stroke volume ÷ end-diastolic volume — normal about 55–70%.
• Mean arterial pressure (MAP) = cardiac output × systemic vascular resistance; roughly diastolic + one-third of the pulse pressure (normal 70–100 mmHg; aim over 65 mmHg in shock).
• Laplace's law — wall stress = (pressure × radius) ÷ (2 × wall thickness): a dilated ventricle has higher wall stress (more oxygen demand); hypertrophy reduces stress but makes the wall stiff.
• Oxygen delivery = cardiac output × arterial oxygen content (mainly haemoglobin × saturation) — why anaemia and hypoxia worsen ischaemia.

💡 Clinical Pearl: Classify a heart drug by what it does to the four determinants: heart rate, preload, afterload and contractility. Nitrates cut preload, ACE inhibitors cut afterload, beta-blockers cut rate and contractility, and diuretics cut preload.

Control of Blood Pressure

• Short-term — baroreceptor reflex (seconds):
  • Stretch receptors in the carotid sinus (glossopharyngeal nerve) and aortic arch (vagus nerve) sense BP.
  • BP falls → less firing → more sympathetic output (faster heart, stronger contraction, vasoconstriction) and less vagal tone.
  • BP rises → the opposite (carotid sinus massage slows the heart).
  • Blunted in older people, diabetes and autonomic failure — causes orthostatic hypotension.
• Medium and long-term — renin–angiotensin–aldosterone system (RAAS) (hours to days):
  • Low kidney perfusion, low sodium at the macula densa, or sympathetic stimulation → renin released from the juxtaglomerular cells.
  • Renin converts angiotensinogen (from the liver) to angiotensin I.
  • ACE (mainly in the lungs) converts angiotensin I to angiotensin II (and breaks down bradykinin — hence ACE inhibitor cough and angioedema).
  • Angiotensin II — vasoconstriction, aldosterone release (sodium and water retention, potassium loss), ADH release and thirst, efferent arteriole constriction in the kidney (maintains GFR), cardiac and vascular remodelling.
• ADH (vasopressin) — from the posterior pituitary; water retention and vasoconstriction.
• Natriuretic peptides (ANP, BNP) — released by stretched atria and ventricles; promote sodium and water loss and vasodilatation; broken down by neprilysin (blocked by sacubitril).
• Local control — nitric oxide (vasodilator from the endothelium), endothelin (vasoconstrictor), prostacyclin.

Cardiac Action Potentials

• Ventricular muscle action potential (resting potential about −90 mV, maintained by the Na+/K+ ATPase):
  • Phase 0 — rapid depolarisation: fast sodium channels open (blocked by class I antiarrhythmics — flecainide, lidocaine).
  • Phase 1 — brief early repolarisation (potassium out).
  • Phase 2 — plateau: calcium enters through L-type channels, balanced by potassium leaving — triggers contraction; long plateau prevents tetany (long refractory period).
  • Phase 3 — repolarisation: potassium channels (e.g. hERG) let potassium out — blocked by class III drugs (amiodarone, sotalol) and many QT-prolonging drugs.
  • Phase 4 — resting.
• Pacemaker cell action potential (SA and AV nodes):
  • No stable resting potential — phase 4 slowly depolarises through the "funny" (If) sodium current (blocked by ivabradine) and T-type calcium channels.
  • Phase 0 — slower upstroke via L-type calcium channels (blocked by verapamil and diltiazem — slowing AV conduction).
  • Sympathetic stimulation steepens phase 4 (faster rate); vagal stimulation (acetylcholine) and adenosine flatten it and slow AV conduction.
• Electrolytes — hyperkalaemia reduces the resting potential (peaked T waves, then broad QRS, then arrest); hypokalaemia and hypomagnesaemia prolong repolarisation (U waves, long QT, torsades); calcium affects phase 2 (low calcium — long QT).

Excitation–Contraction Coupling

• The action potential spreads into the muscle cell through T-tubules → L-type calcium channels let a little calcium in.
• This triggers much larger calcium release from the sarcoplasmic reticulum through ryanodine receptors ("calcium-induced calcium release").
• Calcium binds troponin C → tropomyosin moves → actin and myosin cross-bridges form → contraction (uses ATP).
• Relaxation — calcium is pumped back into the sarcoplasmic reticulum by SERCA (regulated by phospholamban) and removed from the cell by the sodium–calcium exchanger. Relaxation is active and uses energy — so ischaemia causes diastolic dysfunction early.
• Drug links:
  • Digoxin inhibits the Na+/K+ ATPase → more sodium inside → less calcium removed by the exchanger → more calcium → stronger contraction.
  • Beta-agonists (dobutamine) → cAMP → more calcium entry and faster uptake (stronger contraction and faster relaxation).
  • PDE3 inhibitors (milrinone) → less cAMP breakdown → same effect plus vasodilatation.
  • Levosimendan sensitises troponin C to calcium.
• Troponin I and T are released into the blood when muscle cells are damaged — the basis of the troponin test.

Autonomic Control of the Heart

• At rest, vagal tone dominates — the intrinsic SA node rate is about 100; resting rate is lower because of vagal braking (transplanted hearts have no autonomic supply and run at about 100).
• Vagal manoeuvres (Valsalva, carotid sinus massage) increase vagal tone and can stop SVT.

Coronary Blood Flow

• The heart extracts about 70–80% of the oxygen from coronary blood even at rest — so it can only meet extra demand by increasing flow.
• LV coronary flow happens mainly in diastole (the contracting muscle squeezes the vessels shut in systole) — tachycardia shortens diastole and reduces flow.
• Coronary perfusion pressure ≈ aortic diastolic pressure − LV end-diastolic pressure — so low diastolic BP (aortic regurgitation, shock) and high LV filling pressure (heart failure) reduce perfusion; the subendocardium is most vulnerable.
• Autoregulation — adenosine, nitric oxide and low oxygen dilate the coronary arterioles when demand rises.
• Myocardial oxygen demand is set by heart rate, contractility and wall stress (preload and afterload) — antianginal drugs work by lowering these (beta-blockers, nitrates, calcium channel blockers, ivabradine) or improving flow.
• Coronary flow reserve — the ability to increase flow on demand; reduced by stenoses and microvascular disease (the basis of stress testing and FFR).

Normal Values

Atherosclerosis

• What it is: A chronic inflammatory disease of the artery wall — the cause of most coronary disease, strokes and peripheral arterial disease.
• How it develops:
  • Endothelial damage — from smoking, hypertension, diabetes, high LDL, turbulent flow (branch points).
  • LDL cholesterol enters the wall and is oxidised.
  • Monocytes enter, become macrophages, take up oxidised LDL and become foam cells — the "fatty streak" (seen even in teenagers).
  • Smooth muscle cells migrate and make collagen — a fibrous cap over a lipid-rich necrotic core (the mature plaque).
  • Calcification develops (seen on calcium scoring).
• Stable plaque — thick cap, gradually narrows the lumen — causes stable angina (symptoms usually from about 70% narrowing).
• Vulnerable plaque — thin cap, large lipid core, inflammation — plaque rupture (or erosion) exposes the core → platelet activation and thrombosis → acute coronary syndrome. Many ACS events arise from plaques that weren't severely narrowed.
• Risk factors — non-modifiable (age, male sex, family history, ethnicity — South Asian), modifiable (smoking, hypertension, LDL and non-HDL cholesterol, diabetes, obesity, inactivity, CKD, inflammatory diseases, lipoprotein(a)).
• Treatment logic — lower LDL (statins stabilise plaques), control BP and glucose, stop smoking, antiplatelets to prevent thrombosis.

Thrombosis and Clotting

• Virchow's triad — stasis of blood, vessel wall injury, and hypercoagulability.
• Arterial thrombosis (MI, stroke from atheroma) — platelet-rich "white" clot on a ruptured plaque — prevented mainly by antiplatelets.
• Venous and low-flow thrombosis (DVT, PE, left atrial appendage clot in AF, LV thrombus, mechanical valves) — fibrin-rich "red" clot — prevented mainly by anticoagulants.
• Platelet activation — platelets stick to exposed collagen (via von Willebrand factor and GPIb), become activated (ADP via P2Y12 receptors, thromboxane A2 made by COX-1, thrombin), and clump together through GPIIb/IIIa receptors binding fibrinogen.
• Coagulation cascade (simplified):
  • Tissue factor activates factor VII → activates factors IX and X.
  • Factor Xa (with Va) converts prothrombin (II) to thrombin (IIa).
  • Thrombin converts fibrinogen to fibrin (and activates platelets and factors V, VIII, XIII).
  • Natural anticoagulants — antithrombin (enhanced by heparin), proteins C and S.
• Fibrinolysis — tissue plasminogen activator (tPA) converts plasminogen to plasmin, which breaks down fibrin (producing D-dimer); thrombolytics are tPA drugs.
• Where drugs act — aspirin (COX-1), clopidogrel/prasugrel/ticagrelor (P2Y12), warfarin (vitamin K-dependent factors II, VII, IX, X), heparins (antithrombin), apixaban/rivaroxaban/edoxaban (Xa), dabigatran (thrombin), alteplase/tenecteplase (plasminogen).

How Heart Failure Develops

• Initial injury — MI, hypertension, valve disease, cardiomyopathy, toxins (alcohol, chemotherapy), arrhythmia.
• The body's response (helpful short term, harmful long term):
  • Sympathetic activation — faster rate and vasoconstriction; long term it is toxic to muscle and causes arrhythmias → beta-blockers.
  • RAAS activation — salt and water retention, vasoconstriction, fibrosis → ACE inhibitors, ARBs, ARNI, MRAs.
  • Natriuretic peptides rise (counter-regulatory; measured as BNP and NT-proBNP) → sacubitril boosts them.
  • Remodelling — the ventricle dilates and becomes spherical (HFrEF), or thick and stiff (HFpEF); fibrosis.
• Results — congestion (raised filling pressures → pulmonary and peripheral oedema — treated with diuretics) and low output (fatigue, kidney impairment).
• Types — reduced EF (40% or less), mildly reduced (41–49%), preserved (50% or more).
• The "four pillars" of HFrEF treatment each block a harmful pathway: ARNI (or ACE inhibitor/ARB), beta-blocker, MRA, SGLT2 inhibitor.

How Arrhythmias Arise

• Abnormal automaticity — cells fire spontaneously faster than the SA node (ectopic atrial tachycardia, accelerated idioventricular rhythm after reperfusion); worse with ischaemia, catecholamines and electrolyte disturbance.
• Triggered activity — extra depolarisations after an action potential:
  • Early afterdepolarisations — during repolarisation when it is prolonged (long QT) → torsades de pointes; treated with magnesium and by speeding up the heart.
  • Delayed afterdepolarisations — from calcium overload (digoxin toxicity, catecholamines, CPVT).
• Re-entry — the commonest mechanism: an impulse travels around a circuit with two pathways of different conduction speed and recovery time, repeatedly re-exciting tissue:
  • AVNRT (circuit within the AV node), AVRT (accessory pathway — WPW), atrial flutter (circuit around the tricuspid valve), scar-related VT (after MI).
  • Cured by ablating part of the circuit; terminated by blocking the circuit (adenosine at the AV node; DC shock).
• AF — triggers from the pulmonary veins plus an atrial substrate (stretch, fibrosis) that sustains many chaotic wavelets — hence pulmonary vein isolation ablation.
• Conduction block — fibrosis or ischaemia of the conduction system (heart block), drugs (beta-blockers, calcium channel blockers, digoxin, amiodarone), hyperkalaemia.

Lipids and Lipoproteins

• Lipoproteins carry fats in the blood:
  • Chylomicrons — dietary triglycerides from the gut.
  • VLDL — triglycerides from the liver → becomes IDL → LDL.
  • LDL ("bad" cholesterol) — carries cholesterol to tissues; cleared by LDL receptors in the liver; the main driver of atherosclerosis.
  • HDL — reverse cholesterol transport back to the liver; higher HDL is associated with lower risk (but drugs that raise HDL haven't reduced events).
  • Lipoprotein(a) — genetically determined LDL-like particle; raises risk; measure once.
• Non-HDL cholesterol (total minus HDL) — includes all atherogenic particles; NICE treatment targets use it (aim for over 40% reduction in primary prevention).
• How LDL is regulated — the liver makes cholesterol via HMG-CoA reductase (blocked by statins); low liver cholesterol increases LDL receptors (more LDL cleared); PCSK9 destroys LDL receptors (PCSK9 inhibitors keep more receptors).
• Familial hypercholesterolaemia — usually LDL receptor mutations (autosomal dominant, about 1 in 250): very high LDL, tendon xanthomas, premature CVD; cascade testing of relatives.
• Very high triglycerides (over 10 mmol/L) — risk of pancreatitis; eruptive xanthomas.

Antiplatelet Drugs

• Aspirin — irreversibly inhibits COX-1 → less thromboxane A2 for the platelet's 7–10 day life.
  • Uses — ACS (300 mg loading, then 75 mg daily), secondary prevention after MI, stroke or PAD; not for primary prevention in most people.
  • Side effects — GI bleeding and ulcers (add a PPI if at risk), aspirin-sensitive asthma, Reye's syndrome in under 16s.
• P2Y12 inhibitors — block ADP-driven platelet activation:
  • Clopidogrel (75 mg) — prodrug activated by CYP2C19 (poor metabolisers respond less; omeprazole may reduce effect — use lansoprazole or pantoprazole); irreversible.
  • Prasugrel (10 mg) — more potent; avoid with previous stroke or TIA, and use with care over 75 or under 60 kg.
  • Ticagrelor (90 mg twice daily) — reversible, more potent; side effects — breathlessness, bradyarrhythmias; interacts with strong CYP3A4 drugs.
• Dual antiplatelet therapy (DAPT) — aspirin plus a P2Y12 inhibitor, usually for 12 months after ACS (shorter if high bleeding risk); after elective stenting often 6 months.
• GPIIb/IIIa inhibitors (tirofiban, eptifibatide) — IV, used in the cath lab for large clot burden.
• Dipyridamole — phosphodiesterase inhibitor; stroke prevention (now less used); potentiates adenosine.
• Before surgery — clopidogrel and ticagrelor usually stopped 5 days, prasugrel 7 days before (balance against stent thrombosis — discuss with cardiology).

Anticoagulants

• Direct oral anticoagulants (DOACs) — first choice for most patients with AF and VTE:
  • Factor Xa inhibitors — apixaban (twice daily), rivaroxaban (once daily with food in AF), edoxaban (once daily).
  • Direct thrombin inhibitor — dabigatran (twice daily; mostly renally excreted; dyspepsia).
  • Doses depend on indication, kidney function (creatinine clearance), age, weight and interacting drugs — check the BNF.
  • Not for mechanical heart valves or moderate–severe mitral stenosis (use warfarin); caution with very low or very high body weight; avoid with antiphospholipid syndrome (triple positive).
  • Reversal — idarucizumab (dabigatran); andexanet alfa or prothrombin complex concentrate (Xa inhibitors) — per local policy.
• Warfarin — vitamin K antagonist: blocks production of factors II, VII, IX and X (and proteins C and S):
  • Takes several days to work fully; early on it can be pro-thrombotic (protein C falls first) — overlap with heparin for VTE.
  • INR monitoring — target usually 2.5 (range 2–3); higher for some mechanical valves.
  • Many interactions — enzyme inhibitors raise INR (amiodarone, clarithromycin, erythromycin, fluconazole, metronidazole, ciprofloxacin, alcohol binges); inducers lower it (rifampicin, carbamazepine, phenytoin, St John's wort); diet (vitamin K-rich foods).
  • Teratogenic (first trimester).
  • Reversal — stop warfarin; vitamin K (IV for major bleeding); prothrombin complex concentrate for life-threatening bleeding.
• Assess bleeding risk (e.g. ORBIT) and correct modifiable factors (BP, alcohol, NSAIDs, anaemia) — but bleeding risk alone rarely justifies withholding anticoagulation in AF.

⚠️ Safety Pearl: Never prescribe a DOAC for a patient with a mechanical heart valve — they are less effective and cause more valve thrombosis and strokes. Warfarin is the only oral option.

Heparins

• Mechanism — enhance antithrombin, which inactivates thrombin and factor Xa.
• Low molecular weight heparin (enoxaparin, dalteparin, tinzaparin) — subcutaneous, weight-based dosing; mainly anti-Xa; renally excreted (reduce dose with low creatinine clearance); monitor anti-Xa levels in pregnancy, extremes of weight or CKD; only partly reversed by protamine.
• Unfractionated heparin — IV infusion; short half-life; monitored by APTT (or anti-Xa); fully reversed by protamine; preferred in severe renal impairment, high bleeding risk or when rapid reversal may be needed (before procedures).
• Fondaparinux — synthetic Xa inhibitor (via antithrombin); used in NSTEMI in some protocols.
• Heparin-induced thrombocytopenia (HIT):
  • Immune reaction (antibodies to heparin–platelet factor 4) — usually 5–10 days after starting heparin (sooner if recent exposure).
  • Platelet count falls by over 50%, with paradoxical thrombosis (arterial or venous).
  • Assess with the 4Ts score; test for HIT antibodies; stop all heparin and start a non-heparin anticoagulant (argatroban, danaparoid, fondaparinux); don't give platelets.
• Other side effects — bleeding, hyperkalaemia (aldosterone suppression), osteoporosis with long-term use.

Thrombolytics

• Mechanism — recombinant tissue plasminogen activators (alteplase, tenecteplase) convert plasminogen to plasmin, which dissolves fibrin clot.
• Uses — STEMI when primary PCI can't be done within 120 minutes of when fibrinolysis could be given; massive (high-risk) PE; acute ischaemic stroke within the time window; some blocked catheters.
• Absolute contraindications (examples) — previous haemorrhagic stroke, ischaemic stroke in the past 6 months, CNS tumour or injury, recent major trauma or surgery (past 3 weeks), active bleeding, aortic dissection, known bleeding disorder.
• Relative contraindications — uncontrolled hypertension, pregnancy, anticoagulation, traumatic CPR, recent GI bleeding.
• Side effects — bleeding (intracranial about 1%), allergy, reperfusion arrhythmias, hypotension.
• After thrombolysis for STEMI — transfer to a PCI centre; rescue PCI if ST elevation hasn't fallen by 50% at 60–90 minutes.

Lipid-lowering Drugs

• Statins — inhibit HMG-CoA reductase → less liver cholesterol → more LDL receptors → lower LDL; also stabilise plaques.
  • Primary prevention (QRISK3 10% or more) — atorvastatin 20 mg; secondary prevention — atorvastatin 80 mg (NICE NG238).
  • Side effects — muscle aches (true statin myopathy is uncommon; rarely rhabdomyolysis), raised transaminases, small rise in diabetes risk.
  • Monitoring — lipids and LFTs at baseline, 3 months and 12 months; CK only if muscle symptoms.
  • Interactions — CYP3A4 inhibitors (clarithromycin, erythromycin, itraconazole, grapefruit juice with simvastatin), amiodarone and diltiazem (simvastatin dose limits), fibrates (gemfibrozil — avoid).
  • Contraindicated in pregnancy and breastfeeding.
• Ezetimibe — blocks intestinal cholesterol absorption (NPC1L1); added to statins or used if statins aren't tolerated.
• PCSK9 inhibitors — alirocumab, evolocumab (injections every 2–4 weeks); inclisiran (small interfering RNA, injection every 6 months) — large LDL reductions for high-risk or familial hypercholesterolaemia patients not at target.
• Bempedoic acid — blocks cholesterol synthesis upstream of HMG-CoA reductase (activated in the liver, so fewer muscle effects); can raise urate.
• Icosapent ethyl — purified omega-3 for raised triglycerides in high-risk patients on statins.
• Fibrates (fenofibrate) — mainly lower triglycerides; myopathy risk with statins.

Nitrates and Other Antianginals

• Nitrates (GTN spray or tablets, isosorbide mononitrate) — release nitric oxide → venodilatation (lower preload) and coronary dilatation.
  • Side effects — headache, flushing, dizziness, postural hypotension.
  • Tolerance — needs a nitrate-free period (asymmetric dosing of isosorbide mononitrate, or once-daily modified-release).
  • Contraindicated with PDE5 inhibitors (sildenafil, tadalafil — severe hypotension), severe aortic stenosis, HCM with obstruction, hypotension, RV infarction (preload-dependent).
  • GTN advice — use at the start of pain, repeat after 5 minutes; call 999 if pain persists 5 minutes after the second dose.
• Beta-blockers and calcium channel blockers — first-line regular antianginals (NICE CG126); see below.
• Ivabradine — blocks the If (funny) current in the SA node → slower heart rate without lowering BP; only works in sinus rhythm; side effects — phosphenes (flashing lights), bradycardia; also used in HFrEF (heart rate 75 or more).
• Ranolazine — blocks the late sodium current → reduces calcium overload; QT prolongation; many interactions.
• Nicorandil — potassium channel opener and nitrate effect; side effects — ulceration (mouth, skin, GI, anal), headache.

Beta-blockers

• Mechanism — block beta-adrenergic receptors → slower heart rate, less contractility, slower AV conduction, less renin release, less oxygen demand.
• Types:
  • Cardioselective (beta-1) — bisoprolol, metoprolol, atenolol, nebivolol.
  • Non-selective — propranolol (also used for thyrotoxicosis, migraine, varices, anxiety), sotalol (also class III), carvedilol (also alpha-blocking), labetalol (pregnancy hypertension).
• Uses — angina, after MI, HFrEF (bisoprolol, carvedilol, nebivolol, metoprolol succinate — "start low, go slow"), AF rate control, SVT, hypertension (not first-line alone), thyrotoxicosis.
• Side effects — fatigue, cold peripheries, bradycardia, heart block, sleep disturbance and nightmares (lipid-soluble ones), erectile dysfunction, may mask hypoglycaemia symptoms, bronchospasm.
• Contraindications — asthma (relative for cardioselective ones), second- or third-degree heart block, severe bradycardia, decompensated (acute) heart failure, severe peripheral arterial disease, cocaine-associated chest pain (acute, debated).
• Interactions — never give IV verapamil with a beta-blocker (asystole, severe heart block); caution with diltiazem, digoxin, amiodarone.
• Don't stop suddenly — rebound angina, arrhythmias.
• Overdose — bradycardia and hypotension: atropine, glucagon, high-dose insulin with glucose, pacing (TOXBASE).

Calcium Channel Blockers

• Mechanism — block L-type calcium channels.
• Dihydropyridines (amlodipine, nifedipine, felodipine, lercanidipine) — act mainly on blood vessels → vasodilatation (lower afterload and BP); reflex tachycardia.
  • Uses — hypertension (first-line in people of Black African or African-Caribbean family origin and over 55), angina, Raynaud's.
  • Side effects — ankle oedema (not from fluid overload — diuretics don't help), flushing, headache, gum hyperplasia.
  • Avoid short-acting nifedipine in angina (reflex tachycardia).
• Rate-limiting (verapamil, diltiazem) — act on the heart → slow SA and AV node, reduce contractility.
  • Uses — AF rate control, SVT (verapamil), angina (when beta-blockers aren't suitable).
  • Side effects — constipation (verapamil), bradycardia, heart block.
  • Avoid in HFrEF (negatively inotropic) and with beta-blockers (heart block); avoid verapamil in WPW with AF (and other AV nodal blockers) — can cause VF.
  • Inhibit CYP3A4 — raise levels of simvastatin, ciclosporin and others; raise digoxin levels.