Class I: Na⁺ Channel Blockers

Class II: Beta-adrenoceptor blockers

Class III: K⁺ Channel Blockers

Class IV: Ca²⁺ Channel Blockers

1. Frequency, use or state dependent:

- depresses tissue that is frequently depolarized (tachycardia)

- depresses tissue that is relatively depolarized during rest (hypoxia)

2. Voltage dependent

3. Delayed recovery from inactivation: prolonged effective refractory period

Pacemaker:

1. Reduce the Vmax in pacemaker

2. Decrease slope

Purkinje:

2. Increase phase 0 = slows conduction

3. Prolonged AP duration and ERP (inhibits K⁺ channels)

Drug Examples:

1. Procainamide

2. Quinidine

3. Amiodarone (often classified here)

Target:

Atrial & ventricular arrhythmias

*Block I_Na, thus they reduce conduction velocity in atria, purkinje fibers and ventricles.

ECG:

Increase QRS duration ↔ reduction in ventricular conduction

Increase QT interval duration ↔ increase in AP duration (due to increase in refractory period by K⁺ block)

Pacemaker:

1. Less effect on Vmax

Purkinje:

1. (phase 0) at therapeutic levels

2. Rapid rate of binding/unbinding

3. Shortened AP duration

4. ERP is not changed or lengthened according to book

Drug Examples:

1. Lidocaine

2. Mexilitine

3. Phenytoin (anticonvulsant)

Target:

1. Selectively affects ischemic or depolarized purkinje & ventricular tissue; little effect on atria

ECG:

Lacks significant effects on normal ECG (have little effect on normal cells)

Pacemaker:

1. More strongly reduced Vmax

2. Slow rate of binding/unbinding

Purkinje:

3. Little effect on AP duration and ERP

Drug examples:

Flecainide

Target:

Both atrial and ventricular arrhythmias

ECG:

1. No effect on AP duration or QT interval

2. Prolong the QRS segment ↔ block I_Na, thus depress conduction veolicty through ventricles and atria

Classification:

Class Ia

Pharmacologic effects:

1. Reduced Vmax

2. Increased threshold

3. Increased ERP

4. Slowed conduction velocity and pacemaker activity

Clinical uses:

Atrial & ventricular arrhythmias

Toxicity:

1. Arrhythmias

2. Hypotension

3. Lupus-like syndrome

Classification:

Class Ia

Pharmacologic effects:

1. Reduced Vmax

2. Increased threshold

3. Increased ERP

4. Antimuscarinic activity (class)

Clinical uses:

1. Suprventricular arrhythmia

2. Ventricular arrhythmia

Toxicity:

1. Arrhythmias

2. Cinchonism (tinnitus, headache, GI disturbances)

Classification:

Class Ib

Pharmacologic effects:

1. Small effect on Vmax

2. Shortens action potential duration and ERP in His-purkinje fibers and venticles

3. Reduces automaticity in His-purkinje fibers

Clinical uses:

1. NOT for endogenous supraventicular arrhythmias

2. Ventricular arrhythmias in surgery/ICU

3. IV with short half life

4. Digoxin-induced arrhythmias in all regions

Toxicity:

High TI

1. CNS effects (drowsiness, irritability, convulsions)

Classification:

Class Ib (stable lidocaine derivative)

Pharmacologic effects:

1. Small effect on Vmax

2. Shortens action potential duration and ERP in His-purkinje fibers and venticles

3. Reduces automaticity in His-purkinje fibers

Clinical uses:

1. NOT for endogenous supraventicular arrhythmias

2. Ventricular arrhythmias in surgery/ICU

3. Oral administraction 10-15 hr half life.

4. Digoxin-induced arrhythmias in all regions

Toxicity:

High TI

1. CNS effects (drowsiness, irritability, convulsions)

Classification:

Class Ic

Pharmacologic effects:

1. Greatest reduction in Vmax

2. Less effect on action potential duration and ERP (book says no effect)

Clinical uses:

1. All supraventicular tachyarrhythmias

Toxicity:

1. Increased risk of ventricular fibrillation

2. Restricted to atrial arrhythmias in patients without MI

1. K⁺ channel blockade and other effects

2. Delayed repolarization

3. Prolonged AP duration and ERP

Clincial use:

1. Atrial flutter or fibrillation

2. Amiodarone/dronedarone = all types of arrhythmias

ECG:

Increase in QT interval ↔ prongation of AP

Classification:

Class III

Pharmacologic effects:

1. High affinity block of K⁺ channels

2. Class Ia block of Na⁺ channels

3. Lower affinity block of Ca⁺ channels and β-receptors

Clinical uses:

1. Recurrent ventricular tachycardia or fibrillation (high dose)

2. Atrial tachycardia in patients resistant to other drugs (low dose)

*considered most efficacious of all antiarrhythmic drugs

Toxicity:

1. Hypotension due to vasodilation and depressed myocardium

2. Iodine moities in drug structure:

- pulmonary fibrosis (rare in low dose atrial therapy)

- corneal and tissue microdeposits --> photosensitivity

- Thyroid and liver dysfunction

- Headache, tremor and parethesisas

3. Frequent drug interactions (especially lipophilic drugs)

Classification:

Class III

Pharmacologic effects:

1. Higher affinity block of K⁺ channels (3x)

2. Class Ia block of Na⁺ channels (10x)

3. Lower affinity block of Ca⁺ channels and β-receptors

Clinical uses:

1. Atrial fibrillation or flutter

Toxicity:

1. Chemical derivitce of amiodarone without iodine moieties.

*Much lower frequency of unwanted side effects than amiodarone

Classification:

Class III

Pharmacologic effects:

1. Specific block of K⁺ channels = prolongation of AP duration

2. Increased effective refractory period (ERP) = reduces ability of heart to respond to rapid tachycardias

3. Increase in QT interval on ECG

Clinical uses:

1. Treatment and prophylaxis in patients atrial fibrillation (maintains sinus rhythm)

Toxicity:

1. Prolonged QT

2. Ventricular arrhythmia (1% to 3%)

Classification:

Class III

Pharmacologic effects:

1. Specific block of K⁺ channels = prolongation of AP duration

2. Increased effective refractory period (ERP) = reduces ability of heart to respond to rapid tachycardias

3. Increase in QT interval on ECG

Clinical uses:

1. Immediate conversion of atrial flutter or fibrillation to sinus rhythm

Toxicity:

1. Prolonged QT

2. Ventricular arrhythmia (6%)

Classification:

Class II & III hybrid (racemic mixture)

Pharmacologic effects:

1. β-adrenergic blocker (L-sotalol >> D-sotalol)

2. Specific block of K⁺ channels (L-sotalol = D-sotalol)

- prolongation of AP duration

- increased effective refractory period (ERP)

- Decreases SA nodal automaticity

- Slows AV nodal conduction

- Prolongs AV nodal ERP

Clinical uses:

1. Racemic mixture is used:

- Low dose = β-blockade

- High dose = β-blockdae + K⁺ channel block

2. Ventricular tachyarrythmias

3 Supraventricular tachyarrhythmias including atrial fibrillation

Toxicity:

1. Prolonged QT (ventricular AP)

2. Ventricular tachycardia (15% in high doses)

3. After depolarizations

*Arrhythmogenic!

1. β-adrenergic blocking durgs

2. Decrease sympathetic tone

3. Na⁺ blockade in case of propanolol

Classification:

Class II

Pharmocologic effects:

1. Decrease sympathetic tone (low doses):

- Reduced automacity in SA node and purkinje fibers

- Slowed conduction and increased ERP in AV node

- Increased APD and ERP in atria and ventricles

2. Sodium channel blockade (high doses):

- Reduced Vmax

- Reduced APD and ERP

Clinical use:

1. Supraventricular tachycardia -->

- slow AV nodal conduction slows ventricular rate and reduces reentrant excitation of atria

2. Ventricular tachycardia

Toxicity:

1. Bronchospasm

2. Cardiac depression

3. AV block

4. Hypotension

Other:

Metoprolol and Esmolol =

- no effect on Na channels

- β₁ selective

Classification:

Miscellaneous

Pharmacologic Effect:

1. Activates K_ir channel in atria --> hyperpolarization by increase efflux of baseline K⁺

- Reduced automaticity

2. Antagonizes sympathetic activation of Ca²⁺ channels

- Reduces cAMP

- Slows AV nodal conduction

- Increases AV nodal ERP

- Inhibits Ca²⁺-dependent afterdepolarizations

Clinical Use:

1. Acute conversion of re-entrant supraventricular tachycardias

2. Ventricular tachycardia from afterdepolarizations

3. Best in acute AV nodal arrhythmias!!!

Pharmacokinetics:

1. Rapid onset (10-15s duration)

2. Rapid reversal by active uptake into cells (seconds)

3. Effective dose requires rapidly administered bolus

Toxicity:

1. Flushing

2. Bronchospasm

3. Chest pain

4. Headache

1. Three structural classes:

- Dihydropyradines: nifedipine & others

- Phenylalkylamines: verampamil

- Benzothiazepines: ditiazem

*Bind to distinct receptor sites on Ca²⁺ channel

2. Block phase 2 Ca²⁺ current (increase ARP) and Ca²⁺ channels in Ca²⁺-dependent tissue (AV node slowed conduction)

3. Frequency dependent

- verapamil > diltiazem >> nifedipine

4. Voltage dependent

- nifedipine < diltiazem = verapamil

5. Effects:

- AV conduction veolcity decreased

- ERP increased

- PR interval increased

*Dihydropyradines are not useful in treating arrhythmias (probably due to little prequency dependence)

ECG:

increase in PR interval ↔ conduction of AV node is slowed

Classification:

Class IV (Ca²⁺ channel blocker)

Pharmacologic effects:

1. Reduced SA nodal automacity

2. *Slowed AV nodal conduction*

3. Increased ERP in AV node

4. Little effect on Vmax

5. Shortened phase 2 plateau and APD in atria

6. Frequency dependent block

Clinical uses:

1. Supraventricular arrhythmias ONLY

- Atrial flutter and fibrillation

- Paroxysmal supraventricular tachycardia

Toxicity:

1. Can cause hypotenstion when given with vasodilators or β-blockers

2. Contraindicated for patients with slowed AV nodal conduction

3. Caution in CHF due to depresses ventricular performance

1. Phase 0:

Sodium Channels (I_Na):

- In most parts of heart, the I_Na dominates phase 0 and is most important determinant of conduction velocity.

- After brief period of activation, I_Na enters a longer period of inactivation.

AV Node (Ca²⁺-dependent):

- Ca²⁺ current (I_Ca) dominates the phase 0 and AP conduction velocity

2. Phase 2:

- Dominated by K⁺ efflux and Ca²⁺ influx.

3. Phase 3:

At end of AP, rapid repolarization is due to I_K.

Refractory Period:

- RF of most Na-dependent cardiac cells is a function of how quickly I_Na recover from inactivation, which depends on:

 1) mem. potential (varies with repolarization time)

 2) Extracellular K⁺ concentration

- In AV node, rate of recovery is dependent on recovery of I_Ca from inactivation

1. Beta blocker action:

- reduced cAMP →

- reduction of Na⁺ and Ca²⁺ currents

2. Suppression of abnormal pacemakers

ECG:

PR interval prolongation

*Sotolol and amiodarone have properties too.