Anti-Arrhythmics 2025 WRF PDF

N306 Pharmacology of anti- arrhythmic drugs Prof Will Ford Email: [email protected] Office: 337  Co-ordinated contraction required for efficient ejection  Atrial contraction squeezes blood into the ventricle  Ventricular contraction squeezes blood past the aortic valve into the...

N306 Pharmacology of anti- arrhythmic drugs Prof Will Ford Email: [email protected] Office: 337  Co-ordinated contraction required for efficient ejection  Atrial contraction squeezes blood into the ventricle  Ventricular contraction squeezes blood past the aortic valve into the circulation  Relaxation allows time for chambers to refill before next contraction  If any part of a chamber contracts out of sequence the efficiency of blood transfer will be reduced Records CHANGES in cardiac membrane current When ‘0’ there is no depolarization or repolarization OR The average of all electrical activity = 0 this = fibrillation] Relationship between cardiac contraction cycle and ECG Quiz: What is happening here? Hint: What element is missing from the ECG?  Cardiomyocyte action potential Ion currents Na+ current - Activated by positive membrane charge - Na enters the cell - makes membrane more positive K+ current - Activated by positive membrane charge - K leaves the cell - makes membrane more negative Ca2+ current If causes membrane - Activated by positive membrane charge charge to drift to - Ca enters the cell more positive - makes membrane more negative voltage If current - Activated by negative membrane charge - Allow cations into the cell - makes membrane more positive The refractory period – the natural protection from arrhythmias = effective refractory period = relative refractory period Voltage-sensitive Na+ channels  Na+ channels move from open to inactivated very quickly (time dependent)  Once inactivated, have to move to closed before can reopen  Move from inactivated to closed needs exposure to –ve voltage  While Na+ channels are inactivated heart is refractory (what proportion determines whether ‘effective’ or ‘relative’). Types of cardiac arrhythmias Classified according to the site of origin of the problem atrial fibrillation, ventricular ectopic beat Supraventricular = above the level of the ventricles Classified according to the direction of any rate change  Tachycardia (heart rate increases)  Bradycardia (heart rate decreases) Lack of discernible rhythm = fibrillation Goodman & Gilman’s The Pharmacological basis of therapeutics p849 Fibrillation Initiation  Conduction through the ventricle is impaired Atrial fibrillation = survivable Fibrillation  ‘Bag of worms’ Ventricular fibrillation = fatal uncoordinated contraction Defibrillator  Anti-arrhythmic drugs Aim: restore normal sinus rhythm 1. Prevent generation of depolarisation outside normal sinus rhyt 2. * * Prevent transmission of non-sinus depolarisations enerally, act to reduce electrical excitability of the hea  No transmission = no dysrhythmia - Dysfunction with no transmission = sinus rhythm - Dysfunction leading to transmission = arrhythmia Normal wave of action potential Normal sinus rhythm Failure of repolarisation failing within refractory period Normal sinus rhythm Failure of repolarisation failing outside refractory period Extra beat  Antidysrhythmic drugs - summary Class Example Mechanism I lidocaine voltage-gated Na+ channel blockers II propranolol β1-adrenoceptor antagonists III amiodorone potassium channel blockers IV verapamil voltage-gated Ca2+ channel blockers Effects on the cardiac action potential  Class 1 – Sodium channel blockers Normal wave of action potential 0 Action potential (AP) in one cell raises the membrane potential of connected cel AP is transmitted if membrane potential is raised above threshold in connected Sodium channel blockers reduce the number of channels able to open Makes it harder to reach threshold Reduces excitability  Class 2 – β1-adrenoceptor antagonists Increase in If current 4 4 Stimulation of β1-adrenoceptors Increase Ca2+ in cardiomyocytes 1. Generally, stimulation of β1-adrenoceptors increases electrically excitability 2. Pharmacological antagonism reduces this excitability  Class 3 – Potassium channel blockers 1. K+ loss from cell drives potential more negative 2. Determines extent of the refractory period 3 3. Reduction in rate K+ loss extends repolarization phase 4. Na+ channels stay inactivated Reduced chance of stimulating another AP Extra beat Normal sinus rhythm  Class 4 – Calcium channel blockers 2. Reducing Ca2+ entry reduces duration of phase 2. Shortens action potential duration - reduces chances of triggering connected cells. Main effects are in: Sinoatrial (SA) node – reduces heart rate Atrioventicular (AV) node – increases AV block. Too much Ca2+ inside cells (calcium overload) can cause arrhythmias  Fibrillation 1. Uncoordinated contraction = 0 ejection 2. Requires electrical cardioversion 3. Apply electrical shock to heart to resynch all cells  Summary  Ventricular fibrillation incompatible with life  Cardiac arrhythmias reduce efficiency and can lead to fibrillatio  Anti-arrhythmic drugs reduce cardiac electrically excitability Class 1 = Sodium channel blockers Class 2 = Beta1-adrenoceptor antagonists Class 3 = Potassium channel blockers Class 4 = Calcium channel blockers