Increase time for repolarization (phases 2 & 3) thus prolonging AP duration

Increases time to "reset" excitability (refractoriness)

Increases repolarizing influence (E_K)

Decreases slope of phase 4

Slows HR (ACh/PNS)

Targets nodal cells: decreases slope of phase 4

Decreases excitability of nodal cells

Not as effective in Na-dependent cells

Class 1 Antiarrhymics: Na-channel blockers

- names

Class 1A

- quinidine, procainamide, disopyramide

- moderate Na-channel blockade

- ↑ ERP

Class 2A

- lidocain, mexiletine

- Weak Na-channel blockade

- ↓ ERP

Class 3C

- flecainide, propafenone

- Strong Na-channel blockade

- shifts ERP rightwards (slower depolarization)

Class IA antiarrhythmic

Mechanism:

- Na and K-channel blockade 

Uses:

- treat atrial and ventricular arrhythmias

Side effects/toxicities:

- Cinchonism = tinnitus, blurred vision, HA

- Ventricular arrhythmias/Torsades de pointes (prolonged AP depolarization)

- GI = N/V

- Anticholinergic/ vagolytic

- Thrombocytopenia

- contaminant of herbal preparations from cinchona bark 

Class 1A

Mechanism:

- Na and K-channel blockade

- metabolite = N-acetylprocainamide (Class 3 action, prolong APD) - 50% of Americans are rapid acetylators thus [NAPA] > procainamide

Uses:

- treat atrial and ventricular arrhythmias

Side effects/Toxicities:

- Lupus-like autoimmune syndrome

- Ventricular arrhythmias and prolonged QT: torsades de pointes

- Bonemarrow aplasia

- GI disturbances

Class 1A - similar to quinidine and procainamide but w/ fewer s/e's

Mechanism:

- Na and K-channel blockade

Uses:

- treat atrial and ventricular arrhythmias

Side effects / Toxicities:

- anticholinergic effects (dry mouth, constipation, urinary retention)

- depress cardiac contractility

- fewer GI disturbances

- Prolonged QT can lead to torsades de pointes

Class 1B - local anesthetic w/ fast binding/dissociation kinetics

Mechanism:

- blockade of open or inactive Na-channels; more effective for tachyarrhythmias or depolarized (e.g. injured) tissues

- little effect on SA or AV node

Uses:

- life-threatening ventricular arrhythmias

- PVC's inhibited due to blocked Na channels

Side effects / Toxicities:

- CNS effects = drowsiness, dizziness, confusion w/ low doses. High doses lead to seizures, convulsions

- orally inactive

Class 1B - analog of lidocaine; fast kinetics

Mechanism:

- similar to lidocaine

Uses:

- life-threatening ventricular arrhythmias

- PVC's inhibited due to blocked Na channels

Side effects/Toxicity:

- CNS effects = tremor, blurred vision

- GI = nausea (less w/ food)

Orally effective

Treat chronic pain i.e. diabetic neuropathy

Class 1C - derivative of procainamide w/ slow kinetics

Mechanism:

- Strong inhibiton of phase 0 and general cardiac excitability

- Weaker ability to block K-channels and can prolong APD slightly

- Slight ability to block Ca-channel

Uses:

- supraventricular and ventricular tachycardia, PVC's

- can slow nodal conduction (useful for A-fib)

Side effects / toxicities:

- Proarrhythmic effect = potentially lethal ventricular tachyarrhythmias when given after MI

- Blurred vision

- depression of LV performance

Class 1C - structurally similar to propranolol

Mechanism:

- strong inhibition of phase 0 and general cardiac excitability

- weak ability to block K-channels and can prolong APD slightly

- slight ability to block Ca-channels

Uses:

- supraventricular and ventricular tachycardia, PVC's

- can slow nodal conduction (use for A-fib)

Side effects/Toxicities:

- weak β-adrenergic blocking action (e.g. bronchospasm)

Non-selective and selective agents

Antagonize sympathetic stimulation of beta-1 adrenoreceptors in heart

- increase HR, contractility, conduction

Side effects are typical for beta blockers

Class 2 - nonselective β-adrenergic antagonist

Mechanism:

- inhibition of sympathetic stimulation of the heart

- may block Na channels at high doses

Uses:

- decreased AV conduction: supraventricular arrhythmias

- slow heart rate

- post-MI therapy: reduces mortality 2-3 years after MI probably by decreasing risk of ventricular arrhythmias

- decrease arrhythmias associated with thyrotoxicosis, digoxin, anesthesia, pheochromocytoma

Side effects/Toxicities:

- beta adrenergic blocking action

Metoprolol

Esmolol

Class 2 - cardioselective beta adrenergic antagonist

Mechanism:

- inhibition of sympathetic stimulation of heart

- preference for beta-1 adrenoceptor

Uses:

- similar to propranolol

- Esmolol is very rapidly metabolized I.V. so is used for acute management of ventricular rate in atrial flutter/fibrillation

Side effects/Toxicities:

- fewer side effects compared to propranolol

- peripheral beta-2 receptors left intact

AP duration and ERP are prolonged

Most Class 3 drugs are K-channel blockers

Phase 0 not affected

Prolongation of AP can increase risk of Torsades de pointes

Class 3 - iodinated thyroxine derivative exhibiting Class 1-4 action; most prescribed anti-arrhythmic

Mechanism:

- K-channel block to increase repolarization time (increased ERP)

- weak alpha and beta adrenergic receptor blocking effect and Ca-channel antagonism reduces automaticity (decreases phase 4 slope in pacemaker cells), decreases AV node conduction

Uses:

- recurrent V-tach or V-fib resistant to other drugs

- first-line therapy for acute V-tach/fib

Side effects/toxicities:

- Thyroid = hyper- or hypothyroidism

- Blue skin discoloration (iodine)

- Pulmonary toxicity / fibrosis

- Corneal microdeposits

- Peripheral neuropathy

- Hepatic dysfunction

- Hypotension, esp w/ IV admin

- QT prolongation has lower risk of Torsades de pointes compared to other Class 3 drugs

- Very lipophilic so it requires a high loading dose

Class 3 - nonselective beta blocker that also blocks K-channels

Mechanism:

- blocks K channels to increase APD and ERP

- Automaticity can also be decreased due to beta blockade

- slows SA and AV node conduction

Uses:

- Supraventricular and ventricular tachyarrhythmias

- Approved for pediatric populations

Side effects/Toxicities:

- risk for Torsades de Pointes (3-5%) necessitates inpatient monitoring

- can magnify SA node dysfunction

- effects typically associate with beta adrenergic blockers

Class 3 - pure K-channel blocker (at clinical doses)

Mechanism:

- blocks K-channels to increase APD and ERP

Uses:

- Anti-fibrillatory effect in atria

- Maintain NSR in atrial flutter / fibrillation

Side effects / Toxicities:

- Life-threatening ventricular arrhythmias can occur

- use restricted to physicians who have undergone manufacturer's training on how to administer dofetilide

Block "slow" inward calcium current

Non-dihydropyridine agents

- dihydropyridines have greater affinity for vascular calcium channels

Target calcium dependent cells: SA/AV nodes

Decrease slow of phase 4 depolarization

Class 4 - blocks voltage-sensitive Ca-channels

Mechanism:

- decreases automaticity (depresses phase 4 slope) and afterdepolarization formation

- slows conduction in SA and AV nodes

- ventricular contractility can be decreased (phase 2)

Uses:

- primarily atrial tachyarrhythmias

Side effects/toxicities:

- negative inotropic effect- limited use in patients w/ LV dysfunction

- Hypotension due to vasodilatory effect (reflex tachycardia?)

- bradycardia and AV block

- constipation

Class 4 - blocks voltage sensitive Ca-channels

Mechanism:

- decreases automaticity (depresses phase 4 slope) and afterdepolarization formation

- slows conduction in SA and AV nodes

- Ventricular contractility can be decreased (phase 2)

Uses:

- primarily atrial tachyarrhythmias

Side effects/Toxicities:

- negative inotropic effect limits use in patients with LV dysfunction

- Hypotension due to vasodilatory effect

- Bradycardia and AV block

Non-classified; causes a rapid, transient depression (i.e. asystole = flatline); resets heart

Mechanism:

- Stimulates the ACh-sensitive K current to decrease phase 4 slope

- Antagonizes the effects of cAMP to reduce calcium currents (increase nodal refractoriness and inhibit DADs)

- rapid uptake and metabolism (deamination)

Uses:

- primarily for acute treatment of supraventricular tachycardia

-produces transient asystole (~ 5 sec)

Side effects/Toxicities:

- limited because of very short duration of action

- vasodilation: flushing, headache

- bronchoconstriction (i.e. CI for asthmatics)

Non-classified; cardiac glycoside; primary use = positive inotropic effect

Mechanism:

- inhibit Na/K ATPase activity

- Vagotonic action = inhibit Ca current, increase ACh-stimulated K-current

- increased AV node refractoriness / lower conductance

- increased Ca = higher tendency for DADs

Uses:

- control ventricular rate in atrial flutter/fibrillation

Side effects/Toxicities:

- low therapeutic index

- ventricular arrhythmias (e.g. VT, PVC's)

- Hypokalemia increases risk of arrhythmias