MOA: Inhibition of sarcolemmal Na⁺/K⁺ ATPase; binds to K⁺ binding site of α subunit

• Induces depolarization by preventing potassium influx
• Increases force and velocity of myocardial systolic contraction
• Reduces sympathetic activity (increase baroreflex, therefore decrease RAA system) and increases parasympathetic activity (reduce AV conductio velocity and heart rate)

Kinetics:

Absorption: Oral

Distribution: Binding to skeletal muscle; affected by chronic renal failure or hypokalemia

Drug INX:

Must increase digoxin dose:

Vasodilators- increase digoxin clearance

Must reduce digoxin dose:

Spironolactone, amiodarone, and quinidine- reduces digoxin clearance

Verapamil- synergy of slowing impulse conduction, leading to bradycardia and AV block

Loop diuretics- increase K⁺ excretion

Side effects (digoxin toxicity):

Psychiatric

Delirium, fatigue, confusion, dizziness, abnormal dreams

Visual

Blurred, yellow vision; halos; photophobia; scotoma (black dots in vision)

GI (common)

Anorexia, n/v, abdominal pain

Respiratory

Increased breathing response to hypoxia (increased baroreceptor and chemoreceptor sensitivity)

Cardiac

All kinds of arrhythmia

Clinical uses: Slow ventricular rate in rapid persistent A-fib; tx CHF after failed attempts on diuretics and ACE-Is (Digoxin is NOT first line)

**Note** Milrinone is 10x more potent than inamrinone and preferred over inamrinone

MOA: Phosphodiesterase inhibitor

Increased cAMP means more protein kinase A activity and more phosphorylation of target proteins (L-type Ca²⁺ channel, Ryanodine Receptor, contractile protein, phospholamban)

Positive inotropic effect

Dilation of peripheral vessels --> reduced BP, heart size, and filling pressure

Kinetics: Give IV loading dose followed by continuous infusion

Side effects:

Arrhythmia or hypotension (1-10%)

Inamrinone only: high n/v, thrombocytopenia, liver toxicity

Clinical uses:

Last resort, short term therapy for acute heart failure or exacerbation of CHF

MOA: β receptor stimulator

Stimulates adenylyl cyclase, resulting in increased cAMP

This causes an increase in intracellular Ca²⁺ --> positive inotropic effect

Side effects:

Similar to NE

Angina and arrhythmia (due to coronary artery constriction)

Tachyphylaxis

Clinical uses:

Low dose: vasodilation and diuresis

High dose: vasoconstriction and positive inotropic effect

MOA: β receptor stimulator

Increase contractility and dilation

Stimulates AC, leading to increased cAMP

This causes increased Ca²⁺ --> positive inotropic effect

Kinetics:

Only give IV (first pass metabolism by COMT)

Side effects:

Angina and arrhythmia

Tachyphylaxis

Clinical uses:

Limited to critical episodes

Positive inotropic effect

Little effect on vasculature (+ and - enantiomers have opposite effects)

MOA: Blocks Na⁺ channel and K⁺ channel; α-adrenergic block and vagal inhibition

Prolongs action potential

Prolongs refractoriness in most tissues

Decreases ectopic pacemaking

Depresses conduction/excitability (increases threshold)

Kinetics:

Absorption: Oral

Distribution: Bound to plasma proteins

Metabolism: Hepatic oxidative metabolism

Excretion: Renal; 20% unchanged

Drug INX:

CYP2D6 inhibitor (INX with codeine and propafenone)

Inhibits digoxin excretion

Metabolism induced by CYP inducers (phenobarbital, phenytoin)

Side effects:

Cardiac

QT prolongation, torsades de pointes, ventricular tachycardia, CHF exacerbation

GI

N/v (30-50%), diarrhea

Immune

Thrombocytopenia, hepatitis, bone marrow depression, Lupus syndrome (arthritis, unexplained fever/fatigue, malar rash)

Cinchonism (headache, dizziness, tinnitus, deafness, anaphylaxis)

Quinidine syncope

Clinical uses:

Maintain sinus rhythm (tx atrial or ventricular fib and tachycardia); prevent recurrence of ventricular fib/tachycardia

MOA: Blocks open Na⁺ channels and blocks K⁺ channels

Na⁺ block --> slower AP upstroke and conduction; prolonged QRS

K⁺ block --> prolonged APD

Decreased automaticity

Increased refractory period

Kinetics:

Hepatic metabolism to active metabolite, N-acetyl procainamide

Does not block Na⁺ channel, but still prolongs AP, increases refractoriness, and prolongs QT interval

Metabolite concentration exceeds parent drug

Renal elimination for both

Side effects:

Cardiac

Hypotension (but less pronounced than quinidine)

New arrhythmias (Torsades de pointes): from EAD and QT prolongation

Lupus syndrome

From both procainamide and metabolite

Usually comes from long term tx

Antinuclear antibodies, rash, and small-joint arthralgia

N/v

Rash, fever, hepatitis

Clinical uses:

Well tolerated IV (less vagal and α adrenergic block compared to quinidine)

Not well tolerated orally

Loading and maintence IV infusion for acute therapy of supraventricular and ventricular arrhythmia

MOA: Blocks Na⁺ channel

Decrease ectopic pacemaking

Depress conduction/excitability (esp. in depolarized tissue)

Kinetics:

Good oral absorption

Conc.-dependent protein binding

Hepatic and renal elimination

Side effects:

Heart failure (Contra: CHF)

Atropine-like action (antimuscarinic)

Urinary retention, dry mouth, blurred vision, constipation, worsening of glaucoma

Therefore, not first line treatment

Clinical uses:

Maintain sinus rhythm (atrial flutter/fib)

Prevent ventricular tachycardia/fib

MOA: Blocks Na⁺ channel in inactive state, blocks K⁺ channel, weak blocker of Ca²⁺ channel and adrenergic receptors

Marked prolongation of QT interval and QRS duration

Increased refractoriness of atria, AV node, and ventricles

Delayed repolarization

Inhibit cell-cell coupling

Broad spectrum of action

Decreased risk of Torsades de pointes despite QT prolongation

Kinetics:

Variable oral absorption; rapid with IV loading dose

Highly lipophilic (distributes to liver, adipose, and heart tissue)

Metabolized by CYP3A4

Slow elimination

Drug INX:

Increased action d/t CYP3A4 inhibitors (cimetidine)

Decreased action d/t CYP3A4 inducers (rifampin)

Inhibits liver enzymes (increase digoxin and warfarin)

Inhibits P-glycoprotein (must decrease flecainide, procainamide, and quinidine doses because renal elim. is inhibited)

Side effects:

Caridac

Bradycardia/heart block in pts. with sinus or AV node disease

Precipiate CHF

Hypotension (d/t vasodilation)

Fatal pulmonary fibrosis

Yellow/brown corneal deposits

Skin deposits --> photodermatitis (25%)

Thyroid dysfunction

Liver damage

Clinical uses:

Oral: recurrent ventricular tachycardia/fib for resistant cases

IV: acute ventricular tachycardia/fib

Also atrial fib in open heart surgery patients (give for 2 days as prophylaxis)

MOA: Exclusively blocks Na⁺ channels (both activated and inactivated)

Suppresses activity of depolarized tissue with minimal effect on normal tissue

Kinetics: Extensive first-pass metabolism (no oral admin)

Side Effects: 

Cardiac- one of the least cardiotoxic

Careful with MI patients (1% precipitate SA block or worsen conduction)

Careful in CHF patients (can decrease contractility, leading to hypotension)

Exacerbates ventricular arrhythmia <10%

Neurologic

Nystagmus (early sign)

Paresthesias

Tremor

Nausea (Central origin)

Lightheadedness

Hearing disturbance

Dysarthria (slurred speech)

Convulsions (treat with diazepam)

Clinical uses: Acute IV therapy for ventricular arrhythmias

Tocainide (Not in US) and Mexiletine are oral versions of lidocaine

SE: tremor, blurred vision, lethargy; Tocainide- fatal bone marrow aplasia, pulmonary fibrosis

MOA: Blocks Na+ and K+ channels; no effect on APD

Kinetics: Hepatic metabolism and renal excretion

Side Effects:

Severe exacerbation of arrhythmia

Blurred vision

Exacerbates CHF

Heart block if conduction system disease

Clinical uses: Supraventricular arrhythmia in otherwise normal patient

MOA: Decrease pacemaker current (HR) by reducing Ca2+ channel current

Increases threshold

Slows down phase 4 depolarization

Slows AV node conduction and prolongs AV node refractoriness

Side Effects:

Fatigue, bronchospasm, hypotension, impotence, depression, aggravation of heart failure

Clinical uses:

Treating Na+ channel blocker induced arrhythmia

Inhibit DAD-mediated arrhythmia (inhibit Ca2+ overload)

Relieve hypokalemia from Epi use

Terminate re-entrant arrhythmias involving AV node

MOA: Nonselective β blocker and K+ channel blocker (prolongs AP)

Decreases automaticity

Slows AV conduction and increases AV refractoriness (d/t Ca2+ channel inhibition)

Kinetics: Renal excretion of unchanged drug

Side Effects:

Torsades de Pointes when plasma concentration is high (get EAD-induced QT interval prolongation)

Clinical uses: Patients with both ventrical tachycardia and atrial fibrillation/flutter

MOA: Potent K+ channel blocker

Kinetics: Renal excretion of unchanged drug

Side Effects:

High likelihood of torsades de pointes!!!

K+ channel inhibition increases APD, leading to EAD-induced QT prolongation

Only available by restricted distribution system

Clinical uses: Maintain sinus rhythm in atrial fib

MOA: K+ channel blocker

Kinetics: Hepatic metabolism and extensive first pass (not given orally)

Side Effects: Torsades de pointes (6%)

Clinical uses: Conversion of atrial fib/flutter to sinus rhythm (IV infusion)

MOA: Reduce inward Ca2+ during AP and phase 4

Decrease conduction and increase refractoriness of AV node

Kinetics: Extensive first pass, but still can give orally because metabolites still block Ca2+ channels

Side Effects:

Hypotension = major SE

Synergy with β blockers: can get severe sinus bradycardia or AV block during IV injection

Constipation from oral admin (verapamil)

Drug INX: Beta blockers, see above

Clinical uses:

AV re-entrant tachycardia (Wolff-Parkinson-White Syndrome)

Reduce ventricular rate during atrial flutter/fib

IV verapamil: convert paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm

MOA: Mediated by adenosine receptors

Stimulates K+ current in atrium, SA node, and AV node --> shorten APD, hyperpolarization, slow automaticity

Inhibit Ca2+ current --> Increased AV refractoriness, inhibit DADs

Side Effects:

Short effect- therefore short SE

Transient asystole (heart stops)

Sense of chest fullness

Rare: bronchospasm, atrial fib

Clinical uses: Slow down sinus rate and AV rate; diagnose CAD