2024 Action Potential and Antiarrhythmics FCC PDF

Purity Ng’etich ACTION POTENTIAL AND ANTIARRHYTHMICS Objectives Understand the cardiac cell action potential; Discuss the role of Ca, Na and K; Relate the AP to the mechanical response of the myocardium; Discuss some of the frequently used antiarrhythmic medications. University of...

Purity Ng’etich ACTION POTENTIAL AND ANTIARRHYTHMICS Objectives Understand the cardiac cell action potential; Discuss the role of Ca, Na and K; Relate the AP to the mechanical response of the myocardium; Discuss some of the frequently used antiarrhythmic medications. University of Adelaide 2  Review of A&P cardiac muscle cell University of Adelaide 3 University of Adelaide 4 University of Adelaide 5 University of Adelaide 6 University of Adelaide 7 University of Adelaide 8 Electrical-Mechanical Coupling As part of the action potential mechanism calcium comes into the cell and triggers the release of more Calcium from the sarcoplasmic reticulum; The Calcium binds to Troponin C which induces a change in the shape of tropomyosin that exposes the active site between actin and myosin causing CONTRACTION! University of Adelaide 9  The basis of myocardial excitation Before the heart can contract it must be stimulated – Electrical activity precedes mechanical activity Unlike other muscle types the heart does not require neural innervation for excitation Pacemaker cells of the heart have the property of automaticity The basis of electric current An electrical impulse results from the flow of charged ions across the cardiac cell membrane – Sodium (Na+) – Potassium (K+) – Calcium (Ca++) What is another electrolyte essential to the efficient functioning of ion channels? Movement of ions Ions move through specific channels in the cell membrane These channels are voltage gated which means that they open and close when the membrane potential reaches a certain value Two major forces drive ion transport: – A concentration gradient across cell membrane – An electrical gradient across cell membrane  Concentration of Ions Intracellular Extracellular Na 15 mmol ↓ Na 145 mmol ↑ (9.6x more) K 150 mmol ↑ K 5 mmol ↓ (30x less) Cl 5 mmol ↓ Cl 120 mmol ↑ (24x more) Ca 10−7 mmol ↓ Ca 2 mmol ↑ (20 mi x more) University of Adelaide 13 The three phases of excitation Resting state – No electrical activity takes place Depolarisation – The cell is stimulated & Na+ ions move into the cell causing depolarisation & propagation of an impulse Repolarisation – The cell attempts to return to its resting state – Involves a complex exchange of Na+, K+ & Ca++ ions Action Potential of pacemaker cells Have no resting phase during phase 4 Once the cell repolarises to its resting potential it begins to slowly spontaneously depolarise during phase 4 – Na+ ions slowly move into the cell Once the threshold potential is reached → cell depolarises AP of pacemaker cells They start already at -70mV  Action Potential – White Board University of Adelaide 17 Refractory period Normal property of cardiac tissue Cardiac cell cannot depolarise again until it has repolarised The refractory period is divided into 2 periods: – Absolute refractory period (ARP) – Relative refractory period (RRP) Absolute refractory period No stimulus can evoke a response Cardiac cells have depolarised After depolarisation cardiac cells cannot be re-exited until the cell has repolarised to its threshold potential Phases 0,1,2 and early phase 3 Refractory period ARP RRP Relative refractory period (RRP) Cardiac cells have repolarised to their threshold potential – Not the resting potential A stronger than normal stimulus can cause a response Late phase 3 & early phase 4 Also called the vulnerable period of repolarisation Corresponds to the downslope of the T wave Refractory periods QT interval Classes of Antiarrhythmic Drugs (Vaughan Williams) Class I – Blocks fast sodium channels Class II – Blocks -adrenergic receptors Class III – Blocks potassium channels – Mainly blocks repolarisation – Significantly prolongs the action potential duration (APD) Class IV – Blocks slow calcium channels Class I Agents Inhibit fast Na+ channels – Slows depolarisation during phase O Slows impulse conduction – Reduces automaticity of Purkinje fibres – Prolongs QT 1a: Procainamide – Mod block – VT and recurrent AF 1b: Lignocaine – Weak block - VT 1c: Flecainide – Strong block – VT, VF  Class II Agents -blockers – Competitively inhibit catecholamines receptors – Block -receptors - inhibiting SNS activity 1-blockade – Affects the heart – Accounts for most of the therapeutic effect 2-blockade – Affects bronchial & vascular smooth muscle – Accounts for most of the side effects Antiarrhythmic Effects -blockers inhibit sympathetic tone Reduce automaticity of pacemaker cells – Depress slow sodium & calcium channels – Reduces automaticity of SA node & Purkinje fibres Increase the refractory period of the AV node – Interrupts reentry arrhythmias that pass through it Anti-ischaemic effects also important – Reduce myocardial oxygen demand – Improve flow toward ischemic regions – Have mild antiplatelet and antiarrhythmic effects  Beta Blockers ß1 Blockers (selective): Negative inotrope Negative chronotrope No effect on lungs (bronchospasm – B2) Atenolol, metoprolol, bisoprolol Non selective B Blockers are not used anymore unless they are special… Non selective (third generation): Sotalol: B1, B2, and Class 3 Antiarrhythmic (K blocker, increases the Refractory Period) Carvedilol: B1, B2 and A1 Labetalol: B1, B2 and A1 AND can be given IV (dissections) University of Adelaide 29 Class II Effects Class II Effects  -blockers are close to the ideal antiarrhythmics agent: – They have a broad spectrum of activity – They have a proven safety record – Can be used in combination with other antiarrhythmics – Are the only class to have demonstrated a convincing reduction of SCD post MI University of Adelaide 32 Class III Agents Block potassium channels – Blocks the outward K+ current during repolarisation – Notably prolongs the APD & hence refractoriness Lengthening the APD → prolongs the QT-interval – May precipitate torsades de pointes – Low K+, low Mg2+ & bradycardia add to the risk – QT prolongation is more common in sotalol which simultaneously slow the HR & prolongs the APD Sotalol is mixed, not a pure class III agent Amiodarone is the main one Indications: SVT, VT, VF, A Fib and Flutter Sotalol Non-selective -blocker (class II effect) – Competitively blocks -receptors Heart, peripheral vasculature, bronchi, kidney – Depress SA function & AV conduction Prolongs APD & QT (class III effect) Amiodarone Prolongs APD & therefore refractoriness of all myocardial tissue (class III effect) – SA & AV node – Atrial, ventricular, accessory pathways Blocks fast Na+ channels (class I effect) Blocks -adrenergic receptors (class II effect) Blocks Ca++ channels (class IV effect) Highly lipid soluble - accumulates in liver, lungs, skin. Half-life > 50 days Liver excretion Contains iodine in the chemical structure – amiodarone (increased risk on thyroid abnormalities)  Unlike other antiarrhythmics amiodarone appears relatively safe with little or no increase in mortality There is a low risk of arrhythmia In ‘out of hospital arrest’ amiodarone has been shown to increase survival to hospital admission Not recommended for prophylaxis - no evidence Class IV Agents Calcium channel blockers – SVT and AF – Non-dihydropyridine calcium channel blockers Nifedipine, amlodipine, felodipine, nicardipine Mostly act as a vasodilators – Verapamil Phenylalkylamine calcium channel blocker Mostly acts on SA & AV node →  HR – Diltiazem Benzothiazepine calcium channel blocker  Class IV Agents Drug Systemic & Negative Effects on SA coronary inotropic & AV nodes vasodilatation effect Amolodipine +++ 0 0 Diltiazem + + ++ Verapamil ++ +++ +++  Others (that don’t fit anywhere else) Adenosine Digoxin Acts in the atrium, on the SA and AV nodes; Inhibits the Na/K ATPase pump and the Ca exchanger ↑ Refractory Period; after phase 3; ↓ Automaticity; ↓ Conduction Velocity; ↑ Inotropy (by increasing intracellular Ca); Indications: SVT, diagnostic aid. ↑ Refractory Period Stimulates parasympathetic Magnesium activity to ↓ HR; Participates in the trans Indications: HFrEF, AF, AV membrane transport of Na/Ca/K; nodal re-entry, Junctional Mechanism is unknown! Oh no! Arrhythmia Indications: Eclampsia… and Torsade de Pointe 40 Adenosine Summary Learned about mechanical-electrical coupling; Reviewed action potentials for both nodal and myocardial cells; Discussed antiarrhythmic therapies and specific mechanisms of action. University of Adelaide 42 Questions? University of Adelaide 43