Cardiac Physiology and Pharmacology Quiz

Antiarrhythmic Drugs

• Antiarrhythmic drugs are used to treat abnormal heart rhythms
• Different classifications exist based on mechanisms of action
• These mechanisms include Na+ channel blockade, β-adrenergic receptor blockade, prolong repolarization (K+ channel blockade), Ca2+ channel blockade, adenosine, and digitalis glycosides.

Electrical and Chemical Gradients for K+ and Na+ in a Resting Cardiac Cell

• Potassium (K+) concentration inside a cardiac cell is 4mM, outside is 150mM
• Sodium (Na+) concentration inside a cardiac cell is 10mM, outside is 140mM
• Membrane potentials for both ions are 0mV to 90mV.
• Electrical gradients are from outside to inside
• Concentration gradients are from high to low concentration

Timing of Life's Fundamental Events

• Fast events involve electrical signaling
• 1 day - DNA replication and cell division
• 1 hour - Gene transcription; protein synthesis
• 1 minute - Hormone regulation
• 0.1-1 second - Typical enzyme activity
• 1 millisecond - Electrical signaling, vision, hearing, nerve conduction, muscle contraction

Voltage-gated Ion Channel Superfamily

• More than 140 members
• Conductance varies by 100-fold
• Variable gating
• K+, Ca2+, Na+
• Bacterial ancestor likely similar to KcsA channel

Nernst Equation

• Equilibrium potential is the membrane potential that balances diffusion gradients
• Depends on the ratio of ion concentration on both sides of the membrane
• Allows calculation of theoretical potential for a given ion
• Ex = 61/Z log[X+]o/[X+]i, where:
  • Ex = equilibrium potential for ion in millivolts (mV)
  • [X+]o = concentration of ion outside the cell
  • [X+]i = concentration of ion inside the cell
  • Z = valence of ion

Control of Membrane Potential

• If membrane potential equals the Nernst potential for an ion, there is no net flux
• Varying membrane potential affects ion flux
• Hyperkalemia increases intracellular K+ causing influx and depolarization
• When Em is positive to Ek, K+ efflux causes hyperpolarization

Functional Properties of Voltage-Gated Sodium Channels

• Inactivation state makes cardiomyocytes resistant to immediate second action potential firing
• Activation and inactivation processes ensure appropriate temporal and directional spread of electrical activity
• Coordinated contraction is necessary to propel blood throughout the body

Electrical Signal of a Single Sodium Channel

• 15 picoamp (pAmp)
• 10 million Na+ ions per second
• One trillionth of the typical 15 Amp household wall socket

Conformational Cycle of a Voltage-gated Sodium Channel

• Resting, depolarization, activated, inactivated, hyperpolarization, inactivation

Voltage-gated Sodium Channel

• Extracellular and intracellular components are visualized

Structural and Pharmacological Characterization of Voltage-Gated Sodium Channels

• Structural components of the channel are shown
• Drugs and molecules interacting with the channel are visualized

Action Potential Waveforms and Underlying Ionic Currents in Adult Human Cardiac Myocytes

• Action potential phases: rapid depolarization (0), partial repolarization (1), plateau (2), repolarization (3), pacemaker depolarization (4)
• Ionic current changes (Na+, K+, and Ca2+) accompany the action potential phases
• Conduction of the impulse through the heart, with the ECG trace

Pacemaking Mechanisms

• Mechanisms of control for pacemaking are shown
• Ion channels are mentioned

Temporal Relationship Between AP, Cytoplasm Ca2+, and Contraction

• Relationship of action potential, calcium, and contraction are shown

Congenital Long-QT Syndrome: Channelopathies

• Long QT Syndrome, prolongation of QT interval, syncope, and sudden death described
• Genes and proteins associated with the syndrome are listed

hERG Current and LQTS

• hERG current is associated with LQTS
• Action potential waveforms and ionic currents shown

M₂ Muscarinic and A₁ Adenosine Receptors Coupling to and Activating Kir Currents

• Mechanism showing inward rectifier K+ channels

Early and Late Components of Sodium Current (INa)

• Shows early and late sodium current
• Calcium, late sodium, and hERG potassium

Indirect Effects on QT Interval

• QT interval affects are shown

Electrical Remodeling in Heart Failure (HF)

• Electrical remodeling in heart failure is shown with associated genes and proteins

Mechanisms of Cardiac Arrhythmias

• Ectopic automaticity
• Afterdepolarizations and triggered activity
• Reentry

Mechanisms of Ectopic Firing

• Enhanced automaticity
• Early afterdepolarizations (EADs)
• Delayed afterdepolarizations (DADs)

Afterdepolarizations and Triggered Activity

• Hypokalemia, congenital long QT syndrome, loss of repolarization reserve, drug-induced action potential duration

Reentry Circuit in Small Branches of Purkinje System

• Circus movement (reentry excitation) in heart muscle
• Shortened refractory period and reduced conduction velocity promote reentry

AF Mechanisms

• Ectopic focus, single-circuit reentry, multiple-circuit reentry mechanisms for AF

Abnormal Impulse Formation or Propagation Underlying Atrial Fibrillation

• Abnormal impulse propagation (vulnerable substrate) and abnormal impulse formation (ectopic activity) are underlying atrial fibrillation

Vaughn-Williams Classification

• Based on cellular properties of normal His-Purkinje cells
• Classification based on drugs’ ability to block specific ionic currents and adrenergic receptors

Antiarrhythmic Agents

• Vaughan-Williams Classification scheme:
  • Class I - Na+ channel blockers
  • Class II - Sympatholytic agents
  • Class III - Prolong repolarization
  • Class IV - Ca2+ channel blockers
  • Purinergic agonists
  • Digitalis glycosides

Antiarrhythmic Drug Mechanisms

• Na+ channel blockade
• β-adrenergic receptor blockade
• Prolong repolarization (K+ channel blockade)
• Ca2+ channel blockade
• Adenosine
• Digitalis glycosides.

Classification of Antiarrhythmics: Subclass IA

• Cause moderate reduction in Phase 0 slope
• Increase effective refractory period (ERP)
• Increased action potential duration (APD)
• Includes quinidine, procainamide, disopyramide

Classification of Antiarrhythmics: Subclass IB

• Small decrease in Phase 0 slope
• May decrease ERP
• May decrease APD
• Brief duration of blockade
• Negligible interaction with voltage-gated K+ channels.
• Preferentially interacts with inactivated sodium channels
• Includes lidocaine and mexiletine

Classification of Antiarrhythmics: Subclass IC

• Pronounced decrease in Phase 0 slope
• Markedly slow conduction
• Little effect on APD and ERP
• Long duration of blockade
• Includes flecainide and propafenone

Class I Antiarrhythmic Drugs

Class II Antiarrhythmics

• Based on two major actions (ß-adrenergic blockade and Na+ channel blockade)
• Includes propranolol, metoprolol, atenolol, sotalol, and esmolol

Class III Antiarrhythmics

• Cause delay in repolarization and prolonged refractory period
• Includes amiodarone, ibutilide, bretylium, dofetilide

Class IV Antiarrhythmics

• Slow rate of AV-conduction
• Includes verapamil and diltiazem

Antiarrhythmic Drugs List

• Quinidine
• Procainamide
• Disopyramide
• Lidocaine
• Mexiletine
• Flecainide
• Propafenone
• Propranolol
• Metoprolol
• Atenolol
• Sotalol
• Esmolol
• Amiodarone
• Ibutilide
• Bretylium
• Dofetilide
• Verapamil
• Diltiazem
• Adenosine
• Digoxin
• Atropine

Lidocaine

• Blocks both open and inactivated cardiac Na+ channels
• Decreases automaticity, especially in ectopic pacemakers
• Not useful for atrial arrhythmias

Adverse Reactions for Lidocaine

• Large intravenous doses may produce seizures.
• Tremor, dysarthria, and altered levels of consciousness more common

Mexiletine

• Congener of lidocaine
• Orally effective
• Used in the treatment of ventricular arrhythmias

Flecainide

• Potent inhibitor of cardiac sodium channels (Nav1.5)
• Very long recovery from Na+ channel block
• Blocks ryanodine receptor calcium release channels
• Cornerstone rhythm control strategy for AF without structural heart disease, but with adverse effects.

Adverse Effects of Flecainide

• Dose-related blurred vision is a common non-cardiac adverse effect
• Has negative inotropic effects
• Does not cause EADs or torsades de pointes
• Maintenance of sinus rhythm in patients with supraventricular arrhythmias
• Increased mortality (2.5-fold) in patients convalescing from myocardial infarction

-adrenergic Receptor Blockers: Propranolol

• β-blockade
• Quinidine-like effect
• Reduces automaticity of SA node
• Reduces automaticity and conduction velocity in AV node, His Purkinje and ventricles
• May reverse effects of epinephrine on mean arterial pressure

Effects of Vasoconstrictor on Local Anesthetic Action

• Duration of anesthesia

Cardiovascular Effects of Epinephrine

• Patients medicated with nonselective beta-blockers

Administration of Epinephrine

• Administration of epinephrine after propranolol

Adverse Effects of Propranolol

• Reduced myocardial contractility, bradycardia, angina upon sudden withdrawal, bronchospasm
• Used for supraventricular tachycardia

Amiodarone HCl – Pharmacologic Effects

• Widely-used antiarrhythmic
• Indications: unstable VT, VF, SVT, and AF
• Class III effects: duration of action potential and effective refractory period
• Systemic toxicity: pulmonary toxicity and bradyarrhythmias with loading dose

Amiodarone Actions

• Blocks Na+, Ca2+, and β-adrenoceptors
• Delays repolarization and increases refractory period via K+ channel blockade
• Decreases automaticity
• Slows conduction
• A vasodilator

Dofetilide

• A "pure" class III antiarrhythmic
• Potent and selective Ikr blocker
• Can prolong the QT interval (1-3% incidence of torsades)
• Therapy must be initiated in a hospital
• Maintenance of sinus rhythm in patients with atrial fibrillation

Proarrhythmia: Torsades de Pointes

• Class IA (quinidine, procainamide, disopyramide): 2-9%, 2-3%, 2-3%
• Class III (d,l-sotalol, ibutilide, dofetilide, amiodarone): 1-5%, 1-2%, 6%, 1-3%, < 1%

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation (EAST-AFNET 4)

• First primary outcome: events/person-year
• Cardiac outcomes: death from cardiovascular causes, stroke, hospitalization with worsening of heart failure or acute coronary syndrome, and second primary outcome
• Efficacy of early rhythm control compared to usual care

Guideline recommendations for antiarrhythmic drug use in patients with AF

• No structural heart disease
• Structural heart disease: CAD, HF

Catheter Ablation or Antiarrhythmic Drugs for Ventricular Tachycardia

• Survival free of primary end-point
• Comparison of catheter ablation with drug therapy (sotalol or amiodarone)

Calcium Channel Blockers: Verapamil, Diltiazem

• Block slow inward Ca2+ current
• Reduce automaticity
• Increase refractory period and decrease conduction velocity of AV Node
• Inhibit contractility
• Vasodilation

Calcium Channel Blockers (Adverse Effects)

• Flushing
• Reduced contractility of the heart
• AV node conduction defects
• Constipation
• Used for supraventricular arrhythmias

Self-administered intranasal etripamil for atrioventricular-nodal-dependent SVT

• Cumulative conversion rate (%)
• Symptom-prompted, repeat-dose regimen

Ranolazine

• Initially approved for treatment of chronic angina pectoris
• Beneficial antianginal effects and unique antiarrhythmic efficacy in AF and ventricular tachyarrhythmias
• Works primarily by preferentially blocking Na+ channel late phase of influx
• Less [Na+], allows Na+/Ca2+ exchanger to operate in normal forward mode
• Also blocks Ikr at therapeutic concentrations

Ivabradine

• Approved by FDA for treatment of chronic stable angina
• Reduces heart rate through inhibition of the If current
• Exerts an antianginal effect

Adenosine (Adenocard®)

• Released by most cells
• Normal plasma levels ~300 nM
• Can reach micromolar levels in ischemic tissue

Adenosine Receptors

• Four receptor subtypes (A1, A₂A, A₂B, A₃) classified
• All four are G-protein coupled receptors
• Methylxanthines (caffeine, theophylline) are competitive antagonists

Adenosine (Effects)

• Stimulates adenosine receptors (A1 receptors in the heart)
• Increases K+ conductance
• Inhibits opening of Ca²⁺ channels
• Reduces norepinephrine release
• Reduces automaticity and AV nodal conduction

Adenosine (Adverse Effects)

• Flushing
• Asthma
• Dyspnea
• Chest pain
• SA nodal arrest
• AV nodal block

Test your knowledge on cardiac membrane potentials, the Nernst equation, and the effects of various antiarrhythmic medications. This quiz covers key concepts including ion channel properties and drug interactions in cardiac therapy. Perfect for students studying cardiovascular physiology and pharmacology.