L53: Antiarrhythmic Drugs Flashcards
Regulation of pacemaker activity
- Change in pacemaker potential slope
- Sympathetic activation (steeper slope)
- Parasympathetic activation (shallower slope) - Change K permeability during repolarisation
- Parasympathetic activation —> lower resting potential - Change in threshold
Regulation of impulse propagation
- Gap junctions geometry
- gap junction at ends > sides —> along cells faster than across cells - Magnitude of depolarising current
- Na current
- Ca current in AV node
Mechanism of arrhythmia
- Abnormalities in Generation (abnormal automaticity: origin/rate/regularity)
- Tachycardia
- Bradycardia
- Fibrillation - Abnormalities in Conduction (A, V, AV junction)
- Blockade of impulse conduction e.g. AV node
- ↓ rate
- Re-entry circuit due to unidirectional block
Effect of hypokalaemia
- promote funny Na channel opening —> faster depolarisation —> ↑ HR
- Inhibit K channel closing —> ↑ action potential duration —> ↑ repolarisation —> ↑ ERP (risk of TDP)
Abnormalities in Generation (abnormal automaticity: origin/rate/regularity)
Reduced resting membrane potential (↓ K conductance), enhanced by:
—> sympathetic activity
—> hypokalaemia —> hyper excitability (due to earlier opening of funny current channels + inhibition of K channel during repolarisation —> prolonged repolarisation)
Afterdepolaisation (triggered beat):
- Early afterdepolarisation (EAD)
- ∵ prolongation of repolarisation phase (phase 2,3)
- e.g. ↓ K repolarisation current (outward), ↑ Ca, ↑ Na, ↑ Na-Ca exchange current - Delayed afterdepolarisation (DAD)
- phase 4
- ∵ ↑ intracellular Ca
Torsades de Pointes
Polymorphic Ventricular Tachycardia
- multiple QRS complex
- caused by Early afterdepolarisation (EAD)
- functional re-entry (X anatomical)
Classification of cardiac arrhythmia
- Supraventricular
- Atrial
- Nodal - Ventricular
Causes of cardiac arrhythmia
- Myocardial infarction
- Ischaemia
- Hypoxia - Electrolyte abnormalities
- Autonomic influence
- Drug toxicity
Classification of Anti-arrhythmic drugs
Vaughan-Williams classification
- Class I - Na blocker
- Class II - β blocker
- Class III - K blocker
- Class IV - Ca blocker
Class I: Na channel blocker
- Use-dependence ( bind preferentially to inactivated + open Na channel —> more frequently channels activated —> greater degree of block) (想用就制止不准用)
Mechanism:
- ↓ Na influx —> ↓ conduction speed / propagation of nerve impulse —> block tachycardia
Class Ia (intermediate kinetics, oldest): Procainamide
- Intermediate dissociation from Na channel
—> inhibit automaticity
—> ↓ conduction
- blockage of ***K channel
—> ↓ rate of repolarisation
—> ↑ duration of action potential
—> ↑ ERP —> inhibit automaticity + disable re-entry —> block premature beats
- SE: pro-arrrhythmia (due to K blockage —> EAD, TDP), Anticholinergic effect (Tachycardia), GI disturbance, lupus-related symptoms, ↓ force of heart
Class Ib (rapid kinetics, block premature beats): Lidocaine
- inhibit automaticity
- Rapid dissociation within normal heart beat
—> allow generation of next heart beat (NOT affect HR, may shorten ERP)
—> block premature beat
- Selective for refractory channels
—> suppress depolarised cell
—> prevent Na influx during repolarisation
—> not allow EAD/DAD —> inhibit automaticity
- SE: CNS disturbance (due to inhibition of propagation of impulse)
Class Ic (slow kinetics, ↓ conduction speed): Flecainide
- Slow dissociation
—> ↓ conduction markedly
- NO effect on ERP
- SE: pro-arrhythmia, cardiac death in presence of heart failure
—> Propafenone (weak β blocker): worsen heart failure
Class II: β blocker
Mechanisms:
- ↓ HR
- ↓ AV conduction
- ↓ intracellular Ca overload (prevent DAD)
Selective β1 blocker (metoprolol, esmolol)
- esmolol: short half life —> IV injection during surgery for acute arrhythmia
Non-selective β blocker (propanolol)
- Arrhythmia caused by adrenaline-induced hypokalaemia during MI
SE:
- ↓ force and HR —> heart failure
- bronchospasm —> obstructive airway disease
- hypoglycaemia —> diabetes
Class III: K channel blocker
Mechanism: - ↓ rate of repolarisation —> ↑ action potential duration —> ↑ ERP —> ↓ automaticity + disable re-entry
Dofetilide:
- pure blocker for rapidly activating delayed-rectifier K channel
- risk of TDP
- caution with hypokalaemia (↓ K channel activity —> blockade by Dofetilide —> too much prolongation of action potential —> TDP)
- avoid in kidney failure / renal cation transport inhibitor
Amiodarone
- Highly effective
- block K, block inactivated Na channels, weak β blocking, weak Ca blocking
- low risk of TDP
- SE: pulmonary fibrosis, photosensitivity (grey blue skin discolouration), corneal deposits, hepatitis, pro-arrhythmia
- Precaution: CYP3A4 metabolism, ↑ pacing and defibrillation threshold —> retesting of cardioverter-defibrillator
Dronedarone - same as amiodarone, lower incidence of SE, ↑ absorption with food (take with empty stomach)
Sotalol
- Class III drug with class II activity (l-isomer with β blocking effect)
- SE: pro-arrhythmia (TDP risk), heart failure
- for use in pediatric group
Class IV: Ca channel blocker
Cardiac-selective only (Verapamil, Diltiazem)
Mechanisms:
- ↓ HR
- ↓ AV conduction
- ↓ intracellular Ca overload (prevent DAD)
SE: - Heart failure —> ↓ force of heart —> ↓ AV block —> Hypotension - peripheral oedema
Precaution: hepatic dysfunction, avoid in ventricular tachycardia (hypotension)
Adenosine
Mechanism:
1. Activate presynaptic purinergic receptor on sympathetic nerve
—> ↓ NE release —> ↓ automaticity
- Activate A1 receptors in SA + AV nodes
—> inhibit adenylyl cyclase —> ↓ cAMP —> ↓ Ca overload - Activate K channel in SA + AV nodes
—> ↑ maximal diastolic potential —> ↓ conduction velocity
SE: flushing, hypotension, chest pain, SOB (rapid uptake —> short half life, adverse effects rapily resolved)
Magnesium
Affect ion channel activity
