All

arrhythmias result from! disturbances in impulse formation or disturbances in impulse conduction and can
be supraventricular (at or above the AV node) or ventricular

Effects:
• Bradycardia
• Tachycardia
• Sinus tachycardia/bradycardia (originates from the SA node)
• Atrial fibrillation (most common cause)

Factors that precipitate arrhythmias: Ischemia, Hypoxia, Acidosis/alkalosis, Electrolyte abnormalities, Excessive
catecholamine exposure, Autonomic influences, Drug toxicity (Especially antiarrhythmics)

Phase 0: Fast Upstroke Use/Sate dependence: drugs bind more rapidly to open or inactivated Na+ channels, not channels that are at rest;
Na+ channels openàfast inward current cells discharging at abnormally high frequency are preferentially blocked
Upstroke ends as Na+ channels are inactivated


Phase 1: Partial Repolarization Non-drug therapies:
Na+ channels inactivate → Electrical Cardioversion: admin short acting anesthesiaàelectric shock to synchronize heart

K+ channels rapidly open & closeàtransient outward current → Pacemaker: sends small electrical impulses to heart to maintain HRàprevents bradycardia

→ Implantable cardioverter-defibrillator (ICD): TXTs V-tach & V-fib; monitors rhythm constantly & will
Phase 2: Plateau deliver energy to make heart rhythm normal when needed

L-type Ca2+ channels openàslow inward → Catheter Ablation: high-frequency electrical energy delivered via catheter to the tissue that’s causing

(depolarizing) currentàbalances slow outward the abnormal rhythm. TXTs PSVTs, atrial flutter, atrial-fib & some atrial/ventricular tachycardia

(polarizing) movement of K+
Drugs:
Phase 3: Repolarization •
•
Class
Class
I: Na channel blockers (no effect on SAN/AVN)
II: ß-blockers
L-type Ca2+ channels close • Class III: K channel blockers
K+ channels openàoutward(polarizing) current • Class IV: Ca channel blockers
• Misc
Net result: gain of Na+ and loss of K+ (imbalance is
corrected by Na+/K+ ATPase

Phase 4: Forward current
Increasing depolarization d/t gradual increase in Na+
permeabilityàcell is brought to threshold of next action potential
Abnormal Automaticity Re-entrant circuits Afterdepolarization Accessory Tract Pathways
Areas other than the SA node generate Most common cause; unidirectional block Normal AP triggers extra depolarizations Arise in the bypass tract and
competing stimuli → abnormal conduction pathway Early → when they occur during phase 2 or 3 and re triggered by are faster than SA and AV
(Disturbance in impulse formation) (Disturbance in impulse conduction) drugs prolonging the AP [i.e. QT prolongation] node AP’s
Late → after complete repolarization during phase 4 i.e. Bundle of Kent

Goal of most antiarrhythmics is to block Na+ Prevention of re-entry by slowing conduction Prevented by slowing conduction and/or increasing the refractory
or Ca2+ channels → ↓ slope of phase 4 and/or and/or increasing the refractory period period (Disturbance in impulse
increase the threshold → ↓ frequency of The unidirectional block is converted into a formation)
discharge bidirectional block (Disturbance in impulse formation)



Antiarrhythmic Drugs
Types of Arrhythmias:
→ Premature Atrial Contractions: extra early beats that originate in the atria!harmless and do not require treatment
→ Premature Ventricular Contractions (PVCs): common; occur in pts with or w/o heart disease; skipped beats caused by stress, nicotine, exercise etc. !usually harmless and do not require treatment
→ Atrial Fibrilation: very common irregular heat rhythm!results in the atria contracting abnormally
→ Atrial Flutter: caused by one or more rapid circuits in the atrium; ocurrs in pts with heart disease and in the 1st week following heart surgery; converts to atrial fibrillation
→ Paroxysmal Supraventricular Tachycardia (PSVT): rapid HR w/ regular rhythm; begins and ends suddenly; two types!accessory path tachycardias or AV nodal reentrant tachycardias
→ Ventricular Tachycardia (V-Tach): rapid heart rhythym orginiating from the ventricles; requires immediate treatment
→ Ventricular fibrillation: erratic, disorganized firing of impulses from the ventricles; ventricles are unable to contract/pump bloof; medical emergency
→ Sinus Node Dysfunction: slow HR d/t abnormal SA node; requires txt with a pacemaker
Classification Mechanism Effect
Inhibit phase 0 depolarizationby blocking Na+ channels!
↓excitability and conduction velocity

Na+ Channel Blocker Block K+ channels!↑refractory period in atria & ventricles
(phase 3)!QT interval prolongation
(Fast channel blockers)
Class IA ↑threshold for excitation & inhibition of ectopic pacemaker
Suppress Ventricular and activity! ↓myocardial excitability
Supraventricular arrhythmias
slows down heart. Intermediate speed of binding & dissociation
do not give when bradycardia


Posess Use/state dependance
Drug Description Uses PK Adverse Effects
+ tachycardia: state dependence Torsades de pointes
Concomitant class III activity (block K channels) - binds frequently active channels
Rapid oral absorption SA & AV block/asystole :K inhibition affects SAN/AVN also
Pro-arrhythmic!↑QT interval
Nausea, vomiting, diarrhea
Replaced by Ca2+ antagonists’ d/t toxicity A-fib
Forms active metabolites via Thrombocytopenic purpura

Quinidine CYP3A4 Hemolytic anemia hyperkalemia increases + charge of cells: easily excitable
Contraindicated in pts w/ complete heart block; Suppress ventricular and
Toxic dose!V-tach (worsened by hyperkalemia)
caution in pts w/ ↑QT interval, Torsades de pointes, supraventricular arrhythmias
Inhibits CYP2D6, CYP3A4, and Chinchonism!blurry vision, tinnitus, HA, psychosis
incomplete heart block, uncompensated HF,
P-glycoprotein Mixed α-block and antimuscarinic properties
myocarditis, and myocardial damage
↑digoxin by ↓renal clearance
Derivative of local anesthetic procaine DOC for mgmt. of stable pre-
Pro-arrhythmic!↑QT interval excited A-fib IV
Block Na+ channels in activated state Metabolized by cyp2D6 Reversible lupus like syndrome
Block K+channels Suppress ventricular and Toxic dose!asystole, v-tach
Procainamide Antimuscarinic properties :vasodilation supraventricular arrhythmias Partly acetylated to N- CNS!depression, hallucination, psychosis
acetylprocainamide (NAPA) Weak anticholinergic effect
Contraindicated in HSN, complete heart block, 2nd Reserved for life-threatening !prolong duration of AP Hypotension
degree AV block, SLE, torsades de pointes, QT arrhythmias d/t pro arrhythmic (class III) GIT intolerance
Hypersensitivity: anaphylaxis (aggravates hypotensive crisis)
prolongation, CHF; caution in pts w/ HF and HTN effect
Strong (-) ve inotropic effect (strongest)
Strong antimuscarinic properties Pronounce (-)ve inotropic effect
Suppress ventricular and
Causes peripheral vasoconstriction (↑resistance) Severe antimuscarinic effects (dry mouth, urinary retention,
supraventricular arrhythmias
Disopyramide Blocks K+channels blurry vision, constipation etc.)

Pro-arrhythmic!↑QT interval Can induce hypotension and cardiac failure w/o pre-existing
A-fib
myocardial dysfunction (due to strong Na inhibition)
Contraindicated in pts with uncompensated HF
intermediate speed of binding & receptor dissociation
• Class IA:
most rapid speed of binding & receptor dissociation
• Class IB:
• Class IC: slowest speed of binding & receptor dissociation


 Antiarrhythmic Drugs Continued
Classification Mechanism Effect

Slow Phase 0 & decrease slope of phase 4

rapid
+ dissociation
Na Channel Blocker Shorten phase 3 repolarization! Decrease duration of AP rapid
(Fast channel blockers) association

Class IB Little effect on depolarization phase of AP in normal cells

Suppress Ventricular arrhythmias
Rapidly associated and dissociate with Na+ channels
only

• effect on arrhythmic tissue
• (minor) effect on healthy tissue Posess Use/state dependance

Drug Description Uses PK Adverse Effects
Wide toxic therapeutic ratio
Local anesthetic
DOC for termination of V-tach and prevention of V- IV only CNS!drowsiness, slurred speech, agitation etc.
More effect on ischemic/diseased tissue
fib after cardioversion (acute) (extensive Little effect on LV fxn
Lidocaine
first pass NO (-) ve inotropic effect
LITTLE EFFECT on K+channels, atrial arrhytmias or
Txt of digitalis-induced arrhythmia metabolism) Cardiac arrhythmias
AV junction arrhythmias
Toxic dose!convulsions, coma
Mexiletine Orally active derivative of Lidocaine Mgmt. of severe ventricular arrhythmias Oral and IV Mainly CNS and GI ≈ slightly higher effect on healthy tissue

Classification Mechanism Effect

no effect on
Markedly depress Phase 0 of AP!marked slowing of conduction K channels
(no class 3)

Na+ Channel Blocker of AP, but little effect on duration or ventricular effective
refractory period
(Fast channel blockers)
Class IC Associate and re-associate slowly with Na+ channels
Suppress Ventricular and
Supraventricular arrhythmias Show prominent effects even at normal HR
• effect on healthy tissue (most potent of all Class I)
• effect on arrhythmic tissue
greatest effect is on bundle of his & purkinje fibers

Drug Description Uses PK Adverse Effects
(-)ve inotropic effects!worsens CHF
Decreases slope of phase 0 w/o affecting the Symptomatic ventricular arrhythmias, PVC, or V-tach
CNS: dizziness, blurry vision, HA
duration of the AP that are resistant to other therapy

Gi: nausea, vomiting, diarrhea

Life threatening ventricular arrhythmia & prevent

Flecainide Slight prolongation of refractory period paroxysmal A-fib Oral
Associated with potential for fatal ventricular arrhythmias&

"rhythm control drugs"

V-tach in persons with structural heart disease

Automaticity is reduced by increase in threshold Suppression of atrial arrhythmias in a structurally

potential (slope of phase 4 not affected) normal heart
Contraindicated in pts w/ post-MI PVC
β-blocking activity
(-)ve inotropic effects!worsens CHF
Decreases slope of phase 0 w/o affecting the Life threatening ventricular arrhythmia & maintain CNS: dizziness, blurry vision, HA
duration of the AP sinus rhythm in pts w/ symptomatic A-fib Gi: nausea, vomiting, diarrhea
Propafenone β-blocker activity!bronchospasm!worsens CHF etc.
(class I & II) Prolongs conduction and refractoriness in all areas Suppression of atrial arrhythmias in a structurally
of the myocardium normal heart Associated with potential for fatal ventricular arrhythmias&
V-tach in persons with structural heart disease
Reduces spontaneous automaticity



Antiarrhythmic Drugs Continued
Classification Mechanism Effect
predominantly effects AVN (via SNS)

Reduce HR and contractility (β1)

β-Blockers
Slow conduction of impulses (phase 0)

Class II Suppress Ventricular and Reduce rate of spontaneous depolarization in cells with
Supraventricular arrhythmias pacemaker activity (block adrenergic release) :reduce
automacity

Little effect on AP
• negative inotropy
• negative chronotropy

• negative desmotropy (increase PR interval)

Drug Description Uses PK Adverse Effects

Reduce incidence of sudden arrhythmic death after MI Bradycardia
Propranolol
propanolol Control supraventricular tachycardia (a-fib, a-flutter, AV nodal re-entrant tachycardia) Hypotension
ß nonspecific Metoprolol
V-tach (Catecholamine induced arrhythmias, digoxin toxicity) CNS effects
metoprolol
esmolol
ß1 specific Acute arrhythmias occurring during surgery or IV
Esmolol Short acting β1 Selective antagonist Contraindicated in acute CHF, severe bradycardia or heart block
emergencies t½= 9min
and severe hyperactive airway disease (asthma)
Classification Mechanism Effect

Block repolarizing K+ channels

K+ Channel Blocker Prolong AP (QT interval) w/o altering Phase 0 or resting
Class III membrane potential
Suppress Ventricular and
Prolong effective refractory period
Supraventricular arrhythmias

All have potential to induce arrhythmias :increased risk of • prolong AP
afterdepolarizations
• increase ERP in all tissues

• QT interval increase

Drug Description Uses PK Adverse Effects

Oral and IV (well >50% show AE w/ long term use!dose related and reversible on
-
Structurally related to thyroxine (contains IIodine)
) Most common antiarrhythmic absorbed) decreasing dose:
Shows Class I, II, and III (some IV) effects interstitial pulmonary fibrosis, GI intolerance, tremor, ataxia,
Dominant effect= K+ channel blockers Mgmt. of ventricular & supraventricular arrhythmias t½=several weeks dizzy, hyper/hypothyroidism, liver toxicity, photosensitivity,
↓AV conduction & sinus node fxn (high Vd in neuropathy, mm. weakness
Amiodarone
• class I
Blocks mostly inactivated Na+ channels DOC for acute VT refractory to cardioversion shock adipose)!need Blue skin discoloration d/t iodine
• class II Weak Ca2+channel blocker loading dose
• class III
• (some) class 4 Inhibits adrenergic stimulation (α & β blocker) Low dose!maintain normal sinus rhythm in pts w/ Contraindicated in pts taking Digoxin, Theophylline, Warfarin
• α & β blocker Antianginal and antiarrhythmic activity A-fib may to up to 6 wks to and Quinidine and in pts w/ bradycardia, SA/AV block, severe
see full clinical effects hypotension, respiratory failure
Potent non-selective β blocker Life threatening ventricular arrhythmias
Lowest rate of acute/long term AE
Inhibits outward K+ current Maintain sinus rhythm in pts w. A-fib, A-flutter
Sotalol Torsades de pointe (prolonged QT interval)
Prolongs repolarization and duration of AP DO NOT use for asymptomatic arrhythmias d/t pro-
• class II
Cation in pts. with renal impairment
• class III Lengthens refractory period arrhythmic effects
Conversion of a-fib/a-flutter to normal sinus rhythm
Excreted in urine 80% HA, chest pain, dizziness, V-tach
Dofetilide Potent and pure K+ channel blocker Maintain sinus rhythm in pts w. chronic A-fib, A-
unchanged Torsades de pointes (prolongs QT interval)
flutter of longer than 1 week must have been stabilized

 Antiarrhythmic Drugs Continued
Classification Mechanism Effect
Block L-type Ca2+ channels

↓inward Ca2+ current! ↓rate of phase 0 depolarization
Ca2+ Channel Blockers
Slows conduction in tissues dependent on Ca2+ current (AV node
and SA node)
Class Iv Suppress Supraventricular
arrhythmias Major effects on both bascular and cardiac smooth muscle

↓contractility (-ve inotropy)
↓HR (-ve chronotropy)

↓conduction velocity (-ve Dromotropy)
Drug Description Uses PK Adverse Effects
Verapamil!Selective for myocardium and is less
(-) ve inotropes
effective as a systemic vasodilator drug
Transient ↓BP
Diltiazem!Intermediate selectivity for More effective against atrial than VT arrhythmias Oral
CNS effects!HA, fatigue, dizziness
Verapamil myocardium SV-tach
GI!constipation, nausea
Diltiazem Use/state dependent! bind only to open, ↓ventricular rate in A-fib and A-flutter Verapamil!extensively

depolarized channels preventing repolarization! HTN & angina metabolized by liver
Verapamil!↑concentration of digoxin, Dofetilide, simvastatin
slow conduction and ↑effective refractory second line to adenosine for converting
& lovastatin
period PSVT --> normal sinus rythmn

Miscellaneous Antiarrhythmics
Drug Description MOA Uses Adverse Effects
HF: +ve inotrope!↑Intracellular Ca2+

AFib + systolic heart failure

↓refractory period in atrial & Arrhythmias:

ventricular myocardial cells Direct AV blocking effects (inhibits Ca2+ currents) &
Control of ventricular response rate in A- Toxic dose!ectopic ventricular beats!V-tach
Digoxin vagomimetic effects (activate ACh-mediated K+ current)
fib and A-flutter w/ impaired LV fxn or HF and V-fib
↑effective refractory period &
↓conduction velocity in AV node Indirect actions:
Hyperpolarization, ↓atrial AP, ↑AV refractoriness(↓ fraction
of impulses conducted through the AV node & ↑PR interval)
P1 receptor agonist Short t½= 15s ; given IV
Low toxicity!flushing, burning, chest pain,
Adenosine High dose!↓conduction velocity, ↑K+ conductance + ↓cAMP-mediated Ca2+ influx! DOC for abolishing acute SV-tach hypotension, bronchoconstriction in
↑refractory period, ↓automaticity in hyperpolarization esp. in AV node (SVT) asthmatics
AV node
Torsades de Pointes (prolonged QT)
Magnesium Functional Ca2+ agonist Digitalis-induced arrhythmias
Prophylaxis of arrhythmia in acute MI
Atropine Will decrease vagal tone!↑HR Bradyarrhythmias

Atrial Fibrillation:
→ Most common arrhythmias
→ Can be paroxysmal (intermittent) or persistent (Chronic) but not life-threatening
→ Mgmt. focused on symptom control and prevention of long-term mortality/morbidity
→ Two TXT approachesàbased on pt. characteristics and preference
o Rhythm control: induction/maintenance of sinus rhythmàClass IC and Class III
o Rate control: -ve dromotropic agentsàCa2+ blockers, β-blockers, Digoxin (1st line txt in
pts. with ↓EF or CHF) or Amiodarone (when other agents can’t be used)
→ Prevent Thromboembolism:
o Heparin (IV) used in unstable pts. who need immediate cardioversion
o Warfarin (oral) used in stable pts where cardioversion should be delayed 3-4 wks until
pt. develops adequate anticoagulation and continued for 4wks after cardioversion
o
Cardiac Tissue Antiarrhythmic
SA Node -blockers (II), calcium-channel blockers (IV)
& digoxin
AV Node Calcium channel blockers (IV)
Calcium-channel (IV), -blockers
blockers (II)
& digoxin
Atrial myocytes Class’s IA & IC & K+ channels blockers (III)
Ventricular Na+ channel blockers (I) & K+ channel
myocytes blockers (III)
Accessory
A Cl
Class IA & K+ channel
h l bl
blockers
k (III)
Pathways

99
 A h th i
Arrhythmia A ti h th i
Antiarrhythmic
Ventricular & Class’s IA & IC & K+ channels blockers (III)
supraventricular
Mainly Ventricular Lidocaine (IB) & mexiletine (IB)
y
Mainly Calcium-channel blockers ((IV)) & -blockers
Supraventricular (II)

100