CV Pharmacology: Arrhythmias PDF

CV Pharmacology: Arrhythmias Robert Sims HA209 [email protected] Lecture objectives The electrophysiology behind the cardiac action potential Mechanisms of how antiarrhythmic drugs can alter the ion flux and electrical properties of heart cells Sodium channel blo...

CV Pharmacology: Arrhythmias Robert Sims HA209 [email protected] Lecture objectives The electrophysiology behind the cardiac action potential Mechanisms of how antiarrhythmic drugs can alter the ion flux and electrical properties of heart cells Sodium channel blockers Beta-blockers Potassium channel blockers Calcium channel blockers Others Describe the therapeutic uses and adverse effects of anti-arrhythmic drugs  Cardiac Electrical Activity Sino-atrial node Atrio-ventricular node Purkinje fibres Cardiac syncytium Syncytium – network of cells connected by gap junctions Electrical signals (action potentials) pass directly through gap junctions from one myocyte to another – organised, synchronised contraction Histological picture of cardiac myocytes Schematic of cardiac myocytes  Cardiac myocyte AP +30 1 0. Rapid depolarisation (VG Na+) Membrane Potential (mV) 0 2 1. Partial repolarisation (VG K+) 0 Effective refractory period (ERP) 2. Plateau 3 (L-type VG Ca2+ vs. K+) Vm 3. Repolarisation 4 (VG K+) -90 gCa2+ gK+ 4. Rest gNa+ (Leak K+) 0 200 400 600 Time (ms)  Cardiac nodal AP +30 0. Depolarisation (T/L-types VG Ca2+) Membrane Potential (mV) 0 3. Repolarisation 0 (VG K+) 3 4. Pacemaker depolarisation β1/2 (Leak K+ & Leak Na+) mAChR Vm 4 Sympathetic (β1/2) & vagal -90 gCa2+ (parasympathetic; mAChR) gK+ innervation gNa+ 0 200 400 600 Time (ms)  Electrocardiogram Ventricular depolarisation QRS Ventricular P T repolarisation Atrial depolarisation Sino-atrial node Atrial cell Atrio-ventricular node Purkinje fibre Ventricular cell 0 200 400 600 800 Time (ms) Dysrhythmia classifications Location Superventricular Atrial Junctional (AV node) Ventricular Rate Tachycardia (fast) Fibrillation: irregular tachycardia Flutter (atria): regular tachycardia Bradycardia (slow) Heart block Arrest Note: all antiarrhythmics can be pro-arrhythmic as an adverse effect Terminology Chronotropic: altering the rate of the heart Inotropic: altering the strength of heart contraction Automaticity: property of heart cells to generate spontaneous action potentials Ectopic beats: where action potentials are generated in the wrong place (e.g. in myocytes, out of phase with the nodes) Common causes of tachycardias After-polarisation: Abnormally high [Ca2+]i triggering trains of APs. Often causes ectopic beats. Re-entry: Impulse re-exictes previously active tissue; AP circulation. Often associated with damaged heart tissue Ectopic pacemaker activity: Excessive automaticity; overactivity of nodes or ectopic activity outside nodes Triggered activity Normal Early afterdepolarisations Occurs during phase 2/3, elevated Ca2+ e.g. Torsade de pointes (TdP) in ventricles Delayed afterdepolarisations Occurs during phase 4, elevated Ca2+ Re-entry NORMAL RE-ENTRY 1 2 3 1 2 3 Refractory AP passes through myocardium AP blocked in part of myocardium from node (cells in refractory period) Myocardial cells depolarise Refractory cells activated by synchronously backpropagation, depolarise out of phase and may trigger additional contractions Example: Wolfe-Parkinson-White syndrome Re-entry: accessory electrical pathway bypassing AV node Atrial tachycardias transmitted to ventricles May cause retrograde re-entry tachycardia (ventricular → atrial) Long-term treatment with surgical ablation Abnormal automaticity Normal Pacemaker cells normal Pacemaker cells Tachycardia excessively active Common in nodes Usually caused by: Increased phase 4 depolarisation Decrease in AP threshold Vaughan-Willians classification Vaughan-Williams classification (1970s). Defined by electrophysiological effects. Although clinically outdated, useful to base learning on. Class I (a,b,c): Voltage gated Na+ channel blockers Class II: Anti-sympathetics (beta blockers) Class III: Voltage-gated K+ channel blockers Class IV: Voltage-gated Ca2+ channel blockers Others: Anything else (e.g. digoxin, adenosine) Class I: sodium channel blockers Na+ channel blockers also used as local anaesthetics and Control Membrane potential (mV) anticonvulsants Slows down generation of APs Adverse effects – oedema (feet / AP threshold ankles), dizziness This slows down conduction Time through conductive tissue Effect of sodium channel blockers with moderate (red) and high (orange) concentration on neuronal APs Na+ channel blocker use dependency Closed Open Inactivated The faster the cell fires APs, the more drug binds and slows AP generation Therefore minimal effect at low heart rate Class 1a drugs Class 1a Quinidine (classic, but obsolete) – high TdP risk Procainamide (obsolete) Disopyramide Intermediate dissociation: can be used for atrial & ventricular tachycardias. Also K+ channel blockers – lengthen AP. Anticholinergic side effects (especially disopyramide) Negative inotropic effect (= reduced contractility) due to ↓ Ca2+ entry: avoid with hypotension or low ventricular output Class Ib drugs Class 1b Lidocaine (usually IV; emergency medication for ventricular tachycardias, but others now often preferred) Mexiletine (orally available) Tocainide (obsolete) Rapid dissociation means little effect except at fast heart rates Used for ventricular tachycardia & fibrillation; low effectiveness for most atrial tachycardias Class Ic drugs Class 1c Flecainide (can cause sudden death after MI) Propafenone (additional β-blocker effects) Slow dissociation: used for atrial fibrillations and some ventricular tachycardias Can be used for chemical cardioversion Potent negative inotropes – risk of heart failure if weak heart Class II mechanism Sympathetic innervation and nodal APs: Adrenergic β receptor antagonism Normal β1 > β2 receptors in number and function in heart tissues +β agonism β receptor agonism in heart: +β antagonism ↑ cAMP → ↑ PKA → ↑ Ca2+ entry β-blockers Ca2+ Delay AP generation in nodes β1/2 But negative inotropic effect in Gs myocytes (↓ Ca2+ entry) + Beta-blockers (class II) Good general use for atrial tachycardias. Also reduce mortality following MI; reduce arrhythmias due to excessive sympathetic activity β1-selective preferred e.g. atenolol, bisoprolol, metoprolol Alternatively non-selective e.g. propranolol Sotalol (some class III activity) Side effects: Hypotension (+ dizziness), fatigue, peripheral vasoconstriction. Contraindicated with asthma Sotalol may be more potent where additional class III effects useful, but should otherwise be avoided (e.g. TdP risk) Class III mechanism Block K+ channels. Reverse use dependency – potentially pro-arrhythmic in bradycardia. Effect on myocyte & nodal APs: Extend ERP: delays repolarisation (phase 3) Negative chronotropic, positive inotropic + class III Class III drugs highly effective… although also have severe adverse effects Potassium channel blockers (class III) Pharmacokinetic issues: highly lipophilic, accumulation in fatty tissue very long half life Amiodarone (has some class 1a, class 2 & class 3 activity) Highly effective antiarrhythmic, chronic & acute use Toxicity (lungs, liver), thyroid dysfunction, TdP, skin discolouration & photosensitivity Other options: Dronedarone – less effective than amiodarone, but safer Sotalol – less effective class III effects, also class II Class IV mechanism Use dependent block of voltage-gated Ca2+ channels (L-type). Therapeutic effect on nodal AP: Decreases amplitude of AP Increases length of nodal AP (ERP) Effects on other myocytes: + class IV Negative inotrope (myocytes) Decreases length of myocyte AP – risk with ventricular tachycardias. Calcium channel blockers (class IV) Used in atrial fibrillations and (rarely these days) paroxysmal superventricular tachycardia. Ca2+ blockers also dilate blood vessels. Verapamil (cardioselective, also α-blocker and Na+ channel blocker) Diltiazem (non-cardioselective – more effect on blood pressure) Side effects: Hypotension & dizziness, oedema, constipation May also be used as antihypertensive & antianginal medications Digoxin Na+ / K+ pump inhibitor (from foxglove) K+ Na+ Degrades K+ and Na+ concentration 2:3 gradients → depolarises cells. Vagus nerve depolarisation: increased K+ Na+ ACh release → M2 receptors (Gi) M2 receptors = ↑K+ efflux in nodal cells = hyperpolarisation + Digoxin Unsafe: very low TI; dizziness, confusion, fatigue, nausea & vomiting Negative chronotrope at nodes  Digoxin – myocytes Also inhibits Na+ / K+ pump in myocytes K+ Na+ Ca2+ Myocytes depolarised 2:3 3:1 Increased intracellular [Ca2+]: Positive inotrope K+ Na+ Ca2+ Reduced Ca2+ entry (shorter AP) + Digoxin SR Increased [Na+]i decreases efficacy of Na+ / Ca2+ pump = ↑ [Ca2+]i Adenosine Emergency medication for superventricular tachycardias; IV administration, very short-acting (8-10s). Activates A1 receptors (Gi) in AV node: ↑ K+ permeability → hyperpolarisation A1 Gi K+ + Side effects: chest pain, shortness of breath, dizziness, nausea Adenosine also a potent vasodilator, bronchoconstrictor Drugs for bradyarrhythmias Drugs for acute use (e.g. intraoperative) and emergencies IV Atropine (non-specific muscarinic antagonist) First line treatment for bradycardia; M2 Gi reduce vagus nerve influence on M2 receptors K+ + Drugs to increase beta-adrenoceptor activity IV adrenaline (non-specific adrenergic agonist) IV dopamine (β1 agonism) IV dobutamine (β1 > β2 agonism) Chronic bradycardia = pacemaker Atrial tachycardias Key is to ensure an orderly activation of ventricles; prevent atrial tachycardia being passed to ventricles In practice, treatment for A-fib and atrial flutter are very similar but flutter less responsive to pharmacology Rate control: negative chronotropic agents to prevent atrial tachycardia being passed to ventricles Rhythm control: Cardioversion to restore sinus rhythm, drugs to maintain sinus rhythm A-fib: rate and rhythm control Rate control Rhythm control Target AV node to prevent tachycardia Use normally if rate control ineffective: reaching ventricles. Also used for atrial prevent tachycardia in atria flutter. “Pill in the pocket” if paroxysmal More reliable than rhythm control 1. Beta-blocker 1. Beta-blocker or Ca2+ channel 2. K+ channel blocker (inc. sotalol) or blocker Na+ channel blocker (flecainide, 2. Digoxin (sedate lifestyle only) propafenone) 3. Combination of two of β-blocker, diltiazem, digoxin May need cardioversion (electrical, 4. Try rhythm control flecainide, amiodarone) Ventricular tachycardias Slide non-examinable Non-haemodynamically stable ventricular tachycardias are severely life- threatening If haemodynamically stable: Surgery; cardioverter defibrillator fitted and / or amiodarone, sotalol, beta-blockers Pharmacological cardioversion options: Amiodarone preferred Then flecainide / propafenone, lidocaine third line Summary Anti-arrhythmics alter the characteristics of cardiac action potentials General negative chronotropic effects are: ↑ refractory period slow AP generation Class 1: Na+ channel blockers; lengthen rapid depolarisation (myocytes) Class 2: beta-blockers; lengthen slow depolarisation (mostly nodes) Class 3: K+ channel blockers: delay repolarisation (nodes and myocytes) Class 4: Ca2+ channel blockers: lengthen action potential (nodes) Digoxin & adenosine Atropine for bradycardia Rate control and rhythm control strategies  Pictoral summary Extracellular Class 4 Ca2+ - Class 1 Digoxin - Class 3 Adenosine Na+ - + K+ - Class 2 & 4 Ca2+ Intracellular K+ Sicilian gambit 1990s: More complex antiarrhythmic drug classification, including clinical & ECG effects. MBBS learning outcomes M2.I.CAR.PHM7 Outline the mechanisms of action and therapeutic use of drugs that target the heart and vascular system