Drugs Used in Cardiac Arrhythmias - DSA Flashcards
Class 1 Sodium Channel-Blocking drugs
1A drugs:
Quinidine
Procainamide
Disopyramide
1B drugs:
Lidocaine
Mexiletine
1C drugs:
Flecainide
Propafenone
Class 2 Beta Blockers
Esmolol
Propranolol
Class 3 Potassium channel-blocking drugs
Amiodarone Dronedarone Sotalol Dofetilide Ibutilide
Class 4 Cardioactive Calcium channel blockers
Verapamil
Diltiazem
Misc. agents
adenosine
Class 1 A drugs
– 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
Procainamide
– 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
Procainamide pharmacokinetics
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
Procainamide adverse effects
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
Quinidine
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
Quinidine adverse effects
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
Disopyramide
– Used for the treatment of
• Recurrent ventricular arrhythmias
– Affords potent antimuscarinic effect on the heart
Disopyramide adverse effects
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
Class 1B drugs
– 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
Lidocaine
– 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
Lidocaine pharmacokinetics
extensive first-pass metabolism – used only by the intravenous route
Lidocaine adverse effects
• 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
Mexiletine
– 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
Mexiletine adverse effects
- Tremor
- Blurred vision • Nausea
- Lethargy
Class 1C drugs
– 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
Flecainide
– 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
Flecainide adverse effects
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
Propafenone
– Possesses weak -blocking activity
– Used
• To prevent paroxysmal AF and SVT in patients without structural
disease
• In sustained ventricular arrhythmias
Propafenone adverse effects
• 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
Class 2 drugs
• 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
Propranolol
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
Esmolol
- 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
Class 3 drugs
– 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
Amiodarone
– 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)
Amiodarone pharmacokinetics
- 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
Amiodarone adverse effects
- 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
Dronedarone
• 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
Dronedarone clinical indication
– Approved for the treatment of atrial fibrillation/flutter
– Not as effective as Amiodarone in maintaining sinus rhythm in these
patients
Dronedarone adverse effects
– 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)
Dronedarone contraindication
– 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
Sotalol
– 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
Dofetilide
– 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
Class 4 drugs
• 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
Clinical use of verapamil and diltiazem
– Prevention of paroxysmal SVT
– Rate control in AF and atrial flutter
Adverse effects of verapamil and diltiazem
– Cardiac • Negative inotropy • AV block • Sinoatrial node arrest • Bradyarrhythmias • Hypotension – Extracardiac • Constipation (Verapamil)
Adenosine
– 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
Adenosine adverse effects
- Shortness of breath
- Bronchoconstriction (both A1 and A2B adenosine receptors cause bronchoconstriction)
- Chest burning
- AV block
- Hypotension
Proarrhythmia
drug-induced significant new arrhythmia or worsening of an existing
arrhythmia.
Drugs causing long QT syndrome and torsade de pointes arrhythmias
- Antiarrhythmic drugs – classes 1A and 3 (amiodarone very rarely induces TdPs)
- Antipsychotics
- Antihistamines
- Antibiotics
- Antidepressants
Drug-induced torsade de pointes
A rapid form of polymorphic VT associated with the evidence of prolonged ventricular repolarization (long QT syndrome).
Mechanism of TdPs arrhythmias
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
Prevention of drug-induced torsade de pointes
– Monitoring of QTc is necessary
– Do not give TdP-inducing drugs if QTc is >450 ms
Digoxin-induced tachyarrythmias and ectopic rhythms
• 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
Digoxin-induced bradyarrhythmias and AV blocks
Mechanism: central parasympathomimetic activity and accentuation of vagal
effects on the heart
Tx of digoxin-induced arrhythmias
- Cancel digoxin
- Anti-digoxin antibodies (Digibind, Digifab)
- Potassium supplementation to upper normal levels
Class 1C drugs
• 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
