Cardiac Arrhythmias and Pacemaker Potential

Cardiac Arrhythmias

• Cardiac arrhythmias are irregular heartbeats

Sinoatrial Node Pacemaker Potential

• Pacemaker cells contain HCN-gated channels
• Hyperpolarization activates the channels
• This causes slow depolarization toward the AP threshold
• Phase 4: Prepotential enables automaticity
• HCN channels trigger a "funny current"
• Simultaneously, potassium efflux and sodium influx occur
• Reaches the threshold, upstroke, then inactivates HCN channels
• Phase 0: Upstroke of slow pacemaker action potential initiated at the threshold potential (-55 mV)
• Ca2+ movement increases into the cell
• Phase 3: Ca2+ channels inactivate, delayed K+ efflux leads to membrane hyperpolarization
• Phase 4: Pacemaker Na+ influx (If), Ca2+ channels recover, ion gradients restored
• The SA node firing rate establishes the heart rate, initiating the cardiac cycle

Sympathetic Nerves and Heart Rate

• Activation releases norepinephrine (NE) onto B1 adrenoreceptors on cardiac cells
• Opening of HCN channels increases
• Increased Na+ influx
• Opens Ca2+ channels; increased Ca2+ influx
• Increases slope of prepotential (phase 4)
• Heart rate increases

Parasympathetic Nerves and Heart Rate

• Activation releases acetylcholine (ACh) onto muscarinic receptors
• Decreases opening of HCN channels; decreased Na+ influx
• Slows opening of Ca2+ channels, decreased Ca2+ influx
• Opens additional K+ channels; increased K+ efflux
• Hyperpolarization reduces prepotential slope and heart rate

Ventricular Myocyte Action Potentials

• Phase 0: Rapid depolarization, membrane potential reaches the critical firing threshold (-60 mV) due to inward Na+ current
• Phase 1: Partial repolarization (Na+ channels inactivate; fast K+ channels open)
• Phase 2: Calcium channels open; fast K+ channels close
• Phase 3: Ca2+ channels inactivate; slow K+ channels activated
• Phase 4: Resting potential

Vagal Tone

• Intrinsic rate of firing of SAN cells is ~100–110 APs per minute
• Constant tonic activation of some parasympathetic nerves on the SA node

Early After Depolarizations (EADs)

• Occurs when heart rate is low, suppressed by high HR
• AP is prolonged; some Ca channels inactivated during an earlier part of the AP
• Reactivate to give EAD
• Ca L channels – end phase 2
• Ca T channels – mid phase 3
• Need different drugs to treat

Delayed After Depolarizations (DADs)

• Seen at increased HRs
• Associated with elevated Ca2+
• Ca2+ activation of Na/K channels (depolarizing)
• Na/Ca exchange 3:1 = electrogenic
• Toxic doses of cardiac glycosides

Drugs to Treat Bradycardias

• Atropine: Switches to vagus nerve
• Isoproterenol (Isoprenaline): Activates beta receptors
• Pacing

Atropine

• Naturally occurring antimuscarinic alkaloid (from deadly nightshade)
• Blocks vagal inhibition of sinus and AV nodes
• Given intravenously (IV)
• Predominantly metabolized by the liver
• Short half-life (~3 hours)
• Anticholinergic effects (e.g., dry mouth, mydriasis, postural hypotension)

Adenosine

• Used to treat, primarily re-entry supraventricular tachycardia
• Action on AV node, slows rate of pacemaker potential rise
• Usually administered intravenously (IV) to terminate paroxysmal SVTs
• Action lasts 20-30 seconds; patient returns to sinus rhythm
• Side effects: chest pain, shortness of breath, dizziness, nausea

Drug Treatment for Cardiac Arrest

• Asystole: No cardiac stimulation; give adrenaline
• Ventricular fibrillation: Electric activity, but ventricles don't contract together; give amiodarone and lignocaine

Drugs to Treat Tachycardia

• Class 1 Na channel blockers (blocks phase 0)
• Class 2 Beta blockers (affecting SA node)
• Class 3 K channel blockers (block phase 3)
• Class 4 Ca channel blockers (block phase 2)

Class 1 Antiarrhythmic Drugs

• Divided into 3 groups based on action potential duration effects
• Class 1a: Lengthen action potential duration and refractory period (e.g., Quinidine, Procainamide, Disopyramide.)
• Class 1b: Shortens action potential duration and refractory period (e.g., Lignocaine/Lidocaine)
• Class 1c: No effect on action potential duration and refractory period; delays conduction velocity in Purkinje fibers (e.g., Flecainide)

Lidocaine

• Blocks fast sodium channels, slows phase 0 depolarization, shortens action potential duration
• Used for ventricular arrhythmias
• Indications: Treating specific diseases or conditions
• Short half-life; given intravenously (IV)
• Adverse effects: Hypotension, heart block, neurotoxicity, seizures

Class 2 Drugs (Beta Blockers)

• Beta blockers, either non-selective (affects both B1 and B2) or cardio selective (affects only B1)
• Reduces intrinsic rate of sinus and AV nodes; reduces HR and BP, cardiac work, renin secretion
• Examples: Propranolol. Atenolol, Metoprolol
• Useful in treating supraventricular and atrial fibrillation

Adverse Effects of Class 2 Drugs

• B1 effects: Bradycardia and heart failure
• B2 effects: Exacerbation of asthma, peripheral cooling, muscle aches, intermittent claudication
• Other severe effects: Fatigue, nightmares, sleep disturbances, angina, MI, unawareness of hypoglycemia
• Beta blockers can cross the blood-brain barrier

Class 3 Drugs

• Amiodarone prolongs AP duration & refractory period, lengthening QT interval
• Indicated for ventricular and supraventricular tachycardia, first-line therapy for ventricular fibrillation
• Long half-life; hepatic metabolism
• Adverse effects: Thyroid disturbances, pulmonary fibrosis , pro-arrhythmia, torsades de pointes

Class 4 Drugs

• Dihydropyridines (e.g., Nifedipine, Amlodipine): Primarily arterial vasodilation
• Benzothiazepines (e.g., Diltiazem): Mixed vascular and cardiac effects
• Phenylalkylamines (e.g., Verapamil): Primarily cardiac effects (negative inotrope and chronotrope, antiarrhythmic)

Verapamil

• A Ca2+ channel blocker that slows phase 4 Ca2+ entry
• Reduces rate and contraction velocity in sinus and AV node
• Indications: Supraventricular arrhythmias
• Pharmacology: Acts on the heart, oral and IV use; first pass hepatic metabolism
• Adverse effects: Heart failure, hypotension, constipation, vasodilation, edema, flushing