Drugs Used in Cardiac Arrhythmias - DSA

Question 1

Class 1 Sodium Channel-Blocking drugs

Answer 1

1A drugs:
Quinidine
Procainamide
Disopyramide

1B drugs:
Lidocaine
Mexiletine

1C drugs:
Flecainide
Propafenone

Question 2

Class 2 Beta Blockers

Answer 2

Esmolol

Propranolol

Question 3

Class 3 Potassium channel-blocking drugs

Answer 3

Amiodarone
Dronedarone
Sotalol
Dofetilide
Ibutilide

Question 4

Class 4 Cardioactive Calcium channel blockers

Answer 4

Verapamil

Diltiazem

Question 5

Misc. agents

Answer 5

adenosine

Question 6

Class 1 A drugs

Answer 6

– Block sodium channels, slow impulse conduction, reduce automatism of latent (ectopic) pacemakers

– Use-dependent block – preferentially bind to open (activated) sodium channels
• Ectopic pacemaker cells with faster rhythms will be preferentially targeted

– Dissociate from channel with intermediate kinetics

– Block potassium channels

– Prolong action potential duration

– Prolong QRS and QT intervals of the ECG

Question 7

Procainamide

Answer 7

– Used to treat sustained ventricular tachycardias, may be used in
arrhythmias associated with myocardial infarction
– Directly depresses the activities of SA and AV nodes
– Possesses antimuscarinic activity

– Has ganglion-blocking properties, reduces peripheral vascular resistance – may cause hypotension

Question 8

Procainamide pharmacokinetics

Answer 8

Active metabolite N-acetylprocainamide has Class 3 activity, has longer half-life, accumulates in renal dysfunction – measurements of both parent drug and metabolite are necessary in pharmacokinetic studies

Question 9

Procainamide adverse effects

Answer 9

Cardiac:
• QT interval prolongation
• Induction of torsade de pointes arrhythmias and syncope
• Excessive inhibition of conduction

Extra cardiac:
• Lupus erythematosus syndrome with arthritis, pleuritis,
pulmonary disease, hepatitis and fever
• Nausea, diarrhea
• Agranulocytosis

Question 10

Quinidine

Answer 10

Natural alkaloid from Cinchona bark

– Used occasionally for restoring rhythm in atrial flutter/fibrillation patients with normal (but arrhythmic) hearts
– Sustained ventricular arrhythmia
– In clinical trials patients on quinidine twice as likely have normal sinus
rhythm, but the risk of death is increased two to three-fold
– Affords antimuscarinic effect on the heart – may enhance AV conductance
– May cause hypotension  tachycardia

Question 11

Quinidine adverse effects

Answer 11

Cardiac:
• QT interval prolongation
• Induction of torsade de pointes arrhythmia and syncope
• Excessive slowing of conduction throughout the heart

Extra cardiac:
• GI side effects (diarrhea, nausea, vomiting)
• Headache, dizziness, tinnitus (cinchonism)
• Thrombocytopenia, Hepatitis, Fever

Question 12

Disopyramide

Answer 12

– Used for the treatment of
• Recurrent ventricular arrhythmias
– Affords potent antimuscarinic effect on the heart

Question 13

Disopyramide adverse effects

Answer 13

Cardiac: QT interval prolongation, induction of torsade de pointes arrhythmia and syncope, negative inotropic effect – may precipitate heart failure, excessive depression of cardiac conduction

Extracardaic: atropine-like symptoms – urinary retention, dry mouth, blurred vision, constipation, exacerbation of glaucoma

Question 14

Class 1B drugs

Answer 14

– Block sodium channels

– Use-dependent block – bind to inactivated sodium channels
• Preferentially bind to depolarized cells

– Dissociate from channel with fast kinetics – no effect on conduction in
normal tissue

– May shorten action potential

– More specific action on sodium channels – do not block potassium
channels, do not prolong action potential or QT duration on ECG

Question 15

Lidocaine

Answer 15

– Blocks inactivated sodium channels (use-dependence) – selectively
blocks conduction in depolarized tissue, making damaged tissue
completely “electrically silent”
– Rapid kinetics results in recovery from block between AP, with no effect
on cardiac conductivity in normal tissue
– Used in mono- and polymorphic ventricular tachycardias
• Very efficient in arrhythmias associated with acute myocardial infarction

Question 16

Lidocaine pharmacokinetics

Answer 16

extensive first-pass metabolism – used only by the intravenous route

Question 17

Lidocaine adverse effects

Answer 17

• The least toxic of all Class 1 drugs
• Cardiovascular: may cause hypotension in patients with heart
failure by inhibiting cardiac contractility, proarrhythmic effects are
uncommon
• Neurological effects: paresthesias, tremor, slurred speech,
convulsions

Question 18

Mexiletine

Answer 18

– Orally active drug

– Electrophysiological and antiarrhythmic effects are similar to lidocaine

– Clinical use
• Ventricular arrhythmias
• To relieve chronic pain, especially the pain due to diabetic
neuropathy and nerve injury

Question 19

Mexiletine adverse effects

Answer 19

• Tremor
• Blurred vision • Nausea
• Lethargy

Question 20

Class 1C drugs

Answer 20

– Block sodium channels, slow impulse conduction
– Preferentially bind to open (activated) sodium channels
– Dissociate from channel with slow kinetics
– Block certain potassium channels
– Do not prolong action potential duration and QT interval duration of the ECG
– Prolong QRS interval duration

Question 21

Flecainide

Answer 21

– Blocks sodium and potassium channels

– Has no antimuscarinic effects

– Clinical use
• In patients with normal hearts
• Treatment of supraventricular arrhythmias including AF,
paroxysmal SVT (AVNRT, AVRT)
• Life-threatening ventricular arrhythmias, such as sustained
ventricular tachycardia

Question 22

Flecainide adverse effects

Answer 22

May be very effective in suppressing premature ventricular contractions, but may cause severe exacerbation of ventricular arrhythmias when administered to
• Patients with preexisting ventricular tachyarrhythmias
• Patients with a previous myocardial infarction
• Patients with ventricular ectopic rhythms

Question 23

Propafenone

Answer 23

– Possesses weak -blocking activity

– Used
• To prevent paroxysmal AF and SVT in patients without structural
disease
• In sustained ventricular arrhythmias

Question 24

Propafenone adverse effects

Answer 24

• Exacerbation of ventricular arrhythmias
• A metallic taste
• Constipation
• Do not combine with the CYP2D6 and CYP3A4 inhibitors as the
risk of proarrhythmia may be increased

Question 25

Class 2 drugs

Answer 25

• Pacemaker action potential – Sinoatrial node – decrease HR (increase RR interval) – AV node – decrease AV conductance (Increase PR interval • Ventricular myocardium – Decrease Ca2+ overload, prevent delayed after depolarizations

Question 26

Propranolol

Answer 26

Clinical indications for use in cardiac arrhythmias • Arrhythmias associated with stress • Re-entrant arrhythmias that involve AV node – AV nodal reentrant tachycardia (AVNRT) – AV reentrant tachycardia (AVRT) • Atrial fibrillation and flutter • Arrhythmias associated with MI – Decrease mortality in patients with acute MI

Question 27

Esmolol

Answer 27

* Short-acting selective beta-1 blocker * Half-life is 10 min because of hydrolysis by blood esterases * Used as a continuous i.v. infusion, with rapid onset and termination of its action • Clinical use – Supraventricular arrhythmias – Arrhythmias associated with thyrotoxicosis – Myocardial ischemia or acute myocardial infarction with arrhythmias – As an adjunct drug in general anesthesia to control arrhythmias in perioperative period

Question 28

Class 3 drugs

Answer 28

– Block potassium channels – Prolong action potential duration and QT interval on ECG – APD prolongation is rate-dependent, with the most marked effect at slow heart rates – Prolong refractory period

Question 29

Amiodarone

Answer 29

– Blocks potassium channels – Prolongs QT interval and APD uniformly over a wide range of heart rates – Blocks inactivated sodium channels – Possesses adrenolytic activity – Has calcium channel blocking activities – Causes bradycardia and slows AV conduction – Causes peripheral vasodilation (effect may be related to the action of the vehicle) – Clinical use • Treatment of ventricular arrhythmias • Atrial fibrillation (not an FDA approved indication)

Question 30

Amiodarone pharmacokinetics

Answer 30

* Metabolized by CYP3A4 – its half-life is affected by drugs that inhibit CYP3A4 (cimetidine), or induce it (rifampin) * Major metabolite is active, with very long elimination half-life (weeks-months) * Effects are maintained 1 to 3 months after discontinuation, and metabolites are found in the tissues 1 year after discontinuation * Inhibits many CYP enzymes – may affect the metabolism of many other drugs * All medications should be carefully reviewed in patients on amiodarone – dose adjustments may be necessary

Question 31

Amiodarone adverse effects

Answer 31

* Cardiac * AV block and bradycardia * Incidence of torsade de pointes is low as compared to other Class 3 drugs • Extracardiac • Fatal pulmonary fibrosis • Hepatitis • Photodermatitis, deposits in the skin, gives blue-grey skin discoloration in sun-exposed areas • Deposits of drug in cornea and other eye tissues, optical neuritis • Blocks the peripheral conversion of thyroxine to triiodothyronine, also a source of inorganic iodine in the body – may cause hypo- or hyperthyroidism

Question 32

Dronedarone

Answer 32

• Amiodarone derivative (but without the iodine moiety) • Blocks multiple K+ channels – Prolongation of repolarization, action potential duration, and refractory period • Blocks Na+ current • Blocks L-type Ca2+ current – Decreased nodal conduction – Causes bradycardia – Prolongs AV refractory period and P-R interval • Has stronger antiadrenergic effects than Amiodarone

Question 33

Dronedarone clinical indication

Answer 33

– Approved for the treatment of atrial fibrillation/flutter – Not as effective as Amiodarone in maintaining sinus rhythm in these patients

Question 34

Dronedarone adverse effects

Answer 34

– Worsening HF – GI manifestations abdominal pain, nausea, vomiting, diarrhea – Less side effects as compared with Amiodarone (no iodine moiety, shorter half-life, less drug interactions)

Question 35

Dronedarone contraindication

Answer 35

– Black Box FDA warning: Increases risk of mortality in patients with decompensated HF (Class IV) and in patients with a recent decompensation of heart failure requiring hospitalization

Question 36

Sotalol

Answer 36

– Class 2 (non-selective beta-blocker) and class 3 agent (prolongs APD) – Clinical use • Treatment of life-threatening ventricular arrhythmias • Maintenance of sinus rhythm in patients with atrial fibrillation – Adverse effects * Depression of cardiac function * Provokes torsade de pointes

Question 37

Dofetilide

Answer 37

– Specifically blocks rapid component of the delayed rectifier potassium current – effect is more pronounced at lower heart rates – Eliminated by kidneys, has very narrow therapeutic window – dose has to be adjusted based on creatinine clearance – Used to convert AF to the sinus rhythm and maintain the sinus rhythm after cardioversion – Adverse effects • QT interval prolongation and increased risk of ventricular arrhythmias

Question 38

Class 4 drugs

Answer 38

• Block both activated and inactivated L-type calcium channels • Active in slow response cells – decrease the slope of phase 0 depolarization • Slow sinoatrial node depolarization, cause bradycardia • Prolong action potential duration and refractory period in AV node • Prolong AV node conduction time • May suppress delayed afterdepolarizations – may be effective in DAD-induced ventricular arrhythmias

Question 39

Clinical use of verapamil and diltiazem

Answer 39

– Prevention of paroxysmal SVT | – Rate control in AF and atrial flutter

Question 40

Adverse effects of verapamil and diltiazem

Answer 40

``` – Cardiac • Negative inotropy • AV block • Sinoatrial node arrest • Bradyarrhythmias • Hypotension – Extracardiac • Constipation (Verapamil) ```

Question 41

Adenosine

Answer 41

– Activates potassium current and inhibits Ca2+ and Funny currents, causing marked hyperpolarization and suppression of action potentials in pacemaker cells – Inhibits AV conduction and increases nodal refractory period – Clinical use • Conversion to sinus rhythm in paroxysmal SVT

Question 42

Adenosine adverse effects

Answer 42

* Shortness of breath * Bronchoconstriction (both A1 and A2B adenosine receptors cause bronchoconstriction) * Chest burning * AV block * Hypotension

Question 43

Proarrhythmia

Answer 43

drug-induced significant new arrhythmia or worsening of an existing arrhythmia.

Question 44

Drugs causing long QT syndrome and torsade de pointes arrhythmias

Answer 44

* Antiarrhythmic drugs – classes 1A and 3 (amiodarone very rarely induces TdPs) * Antipsychotics * Antihistamines * Antibiotics * Antidepressants

Question 45

Drug-induced torsade de pointes

Answer 45

``` A rapid form of polymorphic VT associated with the evidence of prolonged ventricular repolarization (long QT syndrome). ```

Question 46

Mechanism of TdPs arrhythmias

Answer 46

A type of a triggered activity resulting from early afterdepolarizations – Triggered activity are depolarizing oscillations in the membrane potential induced by the preceding action potentials – Early afterdepolarizations • Often associated with the impaired function of potassium channels leading to a prolonged period of repolarization • Abnormal depolarizations that occur during phase 2 or phase 3 of AP are due to the opening of Ca2+ or Na+ channels, respectively

Question 47

Prevention of drug-induced torsade de pointes

Answer 47

– Monitoring of QTc is necessary | – Do not give TdP-inducing drugs if QTc is >450 ms

Question 48

Digoxin-induced tachyarrythmias and ectopic rhythms

Answer 48

• Mechanism: A type of a triggered activity resulting from delayed afterdepolarization • Occur during phase 4 as a result of increased cytosolic Ca2+ due to Ca2+ overload • Spontaneous Ca release from SR activates 3Na+/Ca2+ exchange leading to a net depolarizing current

Question 49

Digoxin-induced bradyarrhythmias and AV blocks

Answer 49

Mechanism: central parasympathomimetic activity and accentuation of vagal effects on the heart

Question 50

Tx of digoxin-induced arrhythmias

Answer 50

* Cancel digoxin * Anti-digoxin antibodies (Digibind, Digifab) * Potassium supplementation to upper normal levels

Question 51

Class 1C drugs

Answer 51

• Cause ventricular arrhythmias, such as PVCs, sustained VT, and VF • Cardiac Arrhythmia Suppression Trial (CAST) was terminated prematurely because Flecainide and other class 1C drugs increased the mortality by 2.5-fold