CVarrhythmias23-24bb.pptx

CV Pharmacology: Arrhythmias Robert Sims HA209 [email protected]  Lecture Plan Explain the electrophysiology behind the cardiac action potential Explain the mechanisms of how antiarrhythmic drugs can alter the ion flux and electrical properties of heart...

CV Pharmacology: Arrhythmias Robert Sims HA209 [email protected]  Lecture Plan Explain the electrophysiology behind the cardiac action potential Explain the mechanisms of how antiarrhythmic drugs can alter the ion flux and electrical properties of heart cells Describe the therapeutic uses and adverse effects of anti- arrhythmic drugs.  Cardiac Electrical Activity Sino-atrial node Atrio-ventricular node Purkinje fibres  Cardiac myocyte AP +30 0. Rapid depolarisation 1 (VG Na+) Membrane Potential (mV) 0 2 1. Partial repolarisation (VG K+) 0 Effective refractory period (ERP) 3 2. Plateau (L-type VG Ca2+ vs. K+) 4 Vm -90 3. Repolarisation gCa 2+ gK + (VG K+) gNa+ 4. Rest 0 200 400 600 (Leak K+) Time (ms)  Cardiac nodal AP +30 0. Depolarisation (T/L-types VG Ca2+) Membrane Potential (mV) 0 0 3. Repolarisation 3 (VG K+) b1/2 4. Pacemaker depolarisation mAChR Vm (Leak K+ & Leak Na+) 4 -90 gCa2+ gK+ Sympathetic (b1/2) & gNa+ vagal (parasympathetic; mAChR) innervation 0 200 400 600 Time (ms)  Electrocardiogram Ventricular depolarisation QRS Not examinable for this lecture 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 Bradycardia (slow) Heart block Arrest Arrythmias – Pharmacology 1  Old skool cardiac pharmacology Vaughan-Williams classification (1970s; outdated). Define by electrophysiological effects. Class I (a,b,c): VG 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 1 MOAs Block VG Na+ channel – main effect to slow AP conduction in myocytes Class 1a: intermediate dissociation (medium block); also block VG K+ channels & prolong repolarisation. Class 1b: fast dissociation (weak block). Shorten repolarisation Class 1c: slow dissociation (strong block). Strong negative inotropes  Class 1: conduction velocity Myocytes form syncytium – cells directly connected by gap junctions Rapid depolarisation depolarises successive cells Slow down depolarisation, longer to depolarise successive cells = reduced conduction velocity Often useful for re-entry disorders 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 Ia drugs Class 1a Quinidine (classic, but obsolete) – high TdP risk Procainamide (obsolete) Disopyramide Can be used for atrial & ventricular tachycardias Anticholinergic side effects (especially disopyramide) Negative inotropic effect (= reduced contractility) due to ↓ Ca 2+ entry: avoid with hypotension or low ventricular output  Class Ib drugs Class 1b Lidocaine (IV only; also used as local anaesthetic) Mexiletine (orally available, rare in UK) Tocainide (obsolete) Rapid dissociation means little effect except at fast heart rates Used for ventricular tachycardia & fibrillation; low effectiveness for most atrial tachycardias  Class 1c drugs Class 1c Flecainide (can cause sudden death after MI) Propafenone (additional b-blocker effects) Used for atrial fibrillations and some ventricular tachycardias (AV nodal re-entrant tachycardia) Potent negative inotropes – risk of heart failure if weak heart  Class II MOA Adrenergic b receptor antagonism Effect of sympathetic innervation on nodal APs: ↓ cAMP → ↓ PKA → ↓ Ca2+ Normal Prolong refractory period (phase 4); esp. AV node +β agonism Negative inotropic effect (esp. myocytes) +β antagonism  Class II drugs: “beta-blockers” Reduce mortality following MI; reduce arrhythmias due to excessive sympathetic activity Standard β-blocker (…lol) e.g. atenolol, metoprolol, propranolol Sotalol (some class III activity) Side effects: Hypotension (dizziness), fatigue, peripheral vasoconstriction. Asthma contraindication. Sotalol may be more potent where class III effects useful, but should otherwise be avoided (e.g. TdP risk)  Class III: MOA 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 are highly effective… although also have severe side effects  Class III drugs Amiodarone (has some class Ia, class II & class IV activity) Toxicity (lungs, liver), thyroid dysfunction, TdP, skin discolouration & photosensitivity Dronedarone; less effective than amiodarone, but less lipophilic & safer. Sotalol; less effective class III effects Use in atrial & ventricular tachycardias (usually when patients refractory to other drugs); Wolfe-Parkinson-White syndrome  Class IV: MOA 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.  Class IV drugs Used in atrial fibrillations and (rarely these days) paroxysmal superventricular tachycardia. Ca2+ blockers also dilate blood vessels. Verapamil (also a-blocker and Na+ channel blocker) Diltiazem Side effects: Hypotension & dizziness, oedema, constipation May also be used as antihypertensive & antianginal medication Arrythmias – Pharmacology 2  Cardiac glycosides: Digoxin Na+ / K+ pump inhibitor (from foxglove) K+ Na+ Degrades K+ and Na+ concentration gradients 2:3 → depolarises cells. Vagus nerve depolarisation: increased ACh K+ Na+ release → M2 receptors (Gi) ↑ K+ efflux in nodal cells = hyperpolarisation + Digoxin Unsafe: very low TI; dizziness, confusion, fatigue, nausea & vomiting Negative chronotrope at nodes  But… 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  Adenosine Preferred to verapamil for acute paroxysmal superventricular tachycardia; IV, very short-acting. Activates A1 receptors (Gi) in AV node: A1 ↑ K+ permeability, hyperpolarisation + K+ Side effects: chest pain, shortness of breath, dizziness, nausea Adenosine also a potent vasodilator  Drugs for Bradyarrhythmias IV Atropine (non-specific muscarinic antagonist) First line treatment for bradycardia; reduce vagus nerve influence IV adrenaline (non-specific adrenergic agonist – b1 in heart) IV dopamine (b1 agonism) IV dobutamine (b1 > b2 agonism) Clinical Use & Summary  Clinical Use & Summary Bradycardia: Drugs for emergencies & short term If chronic, a pacemaker Most drug treatment is therefore for tachycardias …Particularly superventricular tachycardias  Rate Control & Rhythm Control 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 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  Rate control Target nodal (AV node) cells 1) First line treatment: Class II (β-blockers except sotalol) Class IV (diltiazem / verapamil) 2) Digoxin for patients with sedentary lifestyles 3) Two of digoxin, class II or diltiazem  Rhythm Control Prevent atrial tachycardias occurring 1) First line treatment: Class II (β-blockers except sotalol) 2) Class III (amiodarone / dronedarone / sotalol) or class Ic (flecainide, propafenone) Patients with paroxysmal A-fib (i.e. intermittent, recurring) may be given class 1c to take as required for cardioversion  Summary Anti-arrhythmics work by altering the characteristics of cardiac action potentials: Class 1: lengthens rapid depolarisation (myocytes) Class 2: lengthens slow depolarisation (mostly nodes) Class 3: delays repolarisation Class 4: lengthens nodal AP Digoxin & Adenosine General effects are to: lengthen refractory period decrease likelihood of AP generation  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 Objectives M1.I.CAR.PHM7 Outline the mechanisms of action and therapeutic use of drugs that target the heart and vascular system  Additional info This is not crucial for you to know, but may help you understand the topic.  Some 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)  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 in ventricles Delayed afterdepolarisations Occurs during phase 4, elevated Ca2+  Re-entry NORMAL RE-ENTRY 1 2 3 1 2 3 Refractory Conduction delay in one pathway causes AP to re-enter cycle; causes additional beats 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