Pharmacotherapy of arrythmias

Pharmacotherapy of
arrhythmias
9/23/2021 Arrythmia for 4th year regular by Tolcha Regasa 1
PHARMACOTHERAPY OF
CARDIAC ARRHYTHMIA

Normal Cardiac Cycle
Systole Diastole
Electrical Depolarization
“activate”
Repolarization
“recovery”
Mechanical Contract
“empty”
Relax
“fill”
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9/23/2021 Arrythmia for 4th year regular by Tolcha Regasa

Conducting system vs contractile
tissue of the heart
• Normal heart rate
• Action potential
• ECG
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Conducting system vs contractile tissue of the heart
Conducting System of the Heart:
Impulse Propagation:
 SA node  AV-node  Bundle of
His  Purkinje fibers  ventricle.
 SA node is the initial pacemaker.
SA node, AV node, Purkinj fibers Atrial & Ventricular muscles
Contractile tissue of the heart

1. Resting membrane potential (RMP)
• In resting state:
• Myocytes are permeable to K+ only.
• RMP determined by K+ conc. (Ko & Ki).
• Ki is 150 mmol/L and Ko 4 mmol/L.
• Resting membrane potential ranges:
• From – 80 to -90 mv in contractile cells
• From -60 to -70 mv in pacemaker cells (SA node, AV node and His-
Purkinj fibers) .
• Phase 4 of AP represents RMP.

2. Cardiac Action Potential
Na+
Ca++
K+
Na+
K+

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Potential Terms
1. Refractory Period (RP): Phases 1,2 & 3.
• ERP (absolute refractory period):
• Phases 1 & 2 represent ERP (no response to any stimuli).
• RRP (Relative Refractory Period):
• Phase 3 represents RRP (respone only to strong stimuli.
2. Action Potential Duration: Phases 1,2 & 3:
- During APD, the heart in refractory state and no impulse
propagation.

Potential Terms
APD
ERP
RRP Relative
Refractory
Period
Effective Refractory Period
Action Potential Duration

Definitions of Arrhythmias & antiarrhythmics
• Arrhythmias or dysrhythmias:
Disturbances in cardiac rhythm (rate and/or regularity) due
to abnormality in impulse origination (ectopic beats) or
abnormality in conductivity (reentry) or both.
• Antidysrhythmic drugs:
Drugs which suppress abnormalities of automaticity and/or
conductivity by blocking specific ion channels (Na+, Ca++
and K+) or by altering autonomic functions.

Causes of Cardiac Arrhythmias
• Electrolyte disturbances: hypokalemia, hyperkalemia).
• Cardiac ischemia & MI: e.g., hypoxia   O2 supply.
• Structural damage: changing the conduction pathway.
• Drug toxicity:: e.g., digitalis toxicity.
• Autonomic changes:  sympathetic or  vagal tone.

Mechanisms of Arrhythmias Genesis
A. Abnormal automaticity:
Altered normal automaticity.
Ectopic beats
Triggered automaticity.
B. Abnormal conductivity
Re-entry
Heart block

1) Abnormal Automaticity
a) Alteration of Normal Automaticity
• In pacemaker cells (SA, AV & H-P fibers.
• Precipitated by:
• Autonomic disturbance:
•  Sympathetic activity  sinus & nodal tachycardia.
•  vagal tone  sinus bradycardia.
• Hypokalemia  sinus tachycardia.

Impulses originate at SA node but at a slow rate
e.g. of Abnormality of Impulse Generation

b) Abnormal Ectopic Pacemakers
• Non pacemaker cells act as pacemaker due to
formation of ectopic foci . e.g., atrial or ventricular
cells.
• Inward K+ & Ca++ currents may be involved in the
genesis of this type of arrhythmia.
• Atrial or ventricular extr-asystoles are the result.

- Impulses originate at ectopic pacemaker
- QRS is wider than normal and distorted in
Shape. Usually no P wave

- Impulses originate at ectopic pacemaker
- P wave is slighly different from normal sinus beat
- PR interval is often long and QRS is narrow.

It is a secondary depolarization that
occurs before complete repolarization

c) Triggered Arrhythmias
• Triggered Automaticity (after depolarization):
• Triggered arrhythmias = persistent abnormal automaticity.
• Two types:
1. Early after depolarization:
• Secondary depolarization during phase 3 repolarization i.e., secondary
depolarization before complete repolarization.
1. Delayed after-depolarization:.
• Secondary depolarization after complete repolarization but during
phase 4.
• Caused by Ca++ overload caused by:
• Catecholamines
• Digitalis
• Cardiac ischemia..

It is a secondary depolarization that
occurs just after complete repolarization

2. Abnormality in Conductivity in
Purkinj Fibers (Re-entry)

Re-entry & Wolf-Parkinson White Syndrome
• Impulse originates in SA node BUT pass in accessory
pathway anterogradely not in AV node, so pass rapidly.
• The conducted impulses then travel retrogradely
through the AVN, re-exciting the atria causing atrial
arrhythmias.

Types of Cardiac Arrhythmias
A) Supraventricular arrhythmias:
• Sinus tachycardia  90 beats min.
• Sinus bradycardia  60 beats  min.
• Premature atrial contractions (PACs)
• Atrial tachycardia (regular pulse; up to 200 beats  min).
• Atrial flutter (regular pulse; 200-300 beats  min).
• Atrial fibrillation (irregular pulse;  300 beats  min).
• Nodal tachycardia (AV nodal reentry; a common type of [SVT]).
B) Ventricular Arrhythmias:
• Premature ventricular contractions (PVCs),
• Ventricular tachycardia (VT),
• Ventricular fibrillation (VF),
• Bundle branch block,
• Torsade de pointes.
N.B. Ventricular arrhythmias are life-threatening arrhythmias.

Classes Examples
Class I: Na –channel blockers
I A Quinidine, Procainamide (IV), Disopyramide
I B Lidocaine, phenytoin, Mexiletine
IC Flecainide, Propafenone
Class II: -blockers Propranolol, sotalol, esmolol
Class III: K+-channel blockers Amiodarone, Dofetilide, Sotalol, Ibutilide
Class IV: Ca2+-channel blockers Verapamil, diltiazem
Class V: Miscellaneous Adenosin, digoxin & Magnesium
Vaughan-Williams Classification
Arbitrary classification (not absolute):
e.g., quinidine has class I and class III effects
e.g., Sotalol has class II and class III effects.

Mechanism of action of class I

SUPRAVENTRICULAR ARRHYTHMIAS: Sinus Bradycardia
• Sinus bradycardia, originating in the SA node, is defined by a sinus rate less than 60 beats/min
• Can occur in those involved in vigorous activity: eg. Athletes
• Idiopathic ( sick sinus syndrome) in advanced age
- The prevalence of sick sinus syndrome is approximately 1 in 600 individuals older than 65 years
- Can occur as tachy-brady syndrome/brady-tachy syndrom
• Sick sinus syndrome leading to sinus bradycardia may be caused by degenerative changes in the
sinus node that occur with advancing age

Treatment
• Treatment of sinus bradycardia is only necessary in patients who
become symptomatic
• The patient is taking any medication(s) that may cause symptomatic
sinus bradycardia, they should be discontinued whenever possible
• Acute hemodynamically unstable patient: atropine
• Hemodynamically unstable with severe symptoms unresponsive to
atropine: adrenaline and/or dopamine
• Long-term management of patients with sick sinus syndrome requires
implantation of a permanent pacemaker

AV Nodal Block
• AV nodal block occurs when conduction of electrical impulses through
the AV node is impaired to varying degrees
• Classified as
1. First degree
2. Second degree (Mobitz type I (also known as Wenckebach) and
Mobitz type II)
3. Third degree heart block ( complete heart block)

Treatment
• Similar to treatment of symptomatic sick sinus syndrome

Atrial Fibrillation
• Arrythmias that need clinician attention. Why?
- AF is the most common arrhythmia encountered in clinical practice
- It is important for clinicians to understand AF because it is associated
with substantial morbidity and mortality
- Some drugs used to treat AF have a narrow therapeutic index and a
broad adverse effect profile

AF: epidemiology and Etiology
• The prevalence of AF increases with advancing age; roughly 8% of patients
between the ages of 80 and 89 years have AF
• Common in men than women
• Hypertension, CAD, HF is increasingly recognized as a cause of AF
- HF is increasingly recognized as a cause of AF; approximately 25% to 30% of
patients with New York Heart Association (NYHA) class III HF have AF and
the arrhythmia is present in as many as 50% of patients with NYHA class IV
HF
• Drug-induced AF is relatively uncommon

Pathophysiology
• AF may be caused by both abnormal impulse formation and abnormal impulse
conduction
• AF is triggered by electrical impulses generated within the pulmonary veins
• A substantial amount of the atrial electrical activity occurring during AF is
conducted through the AV node into the ventricles, resulting in ventricular rates
ranging from 100 to 200 beats/min
• Classified in to paroxysmal, persistent an permanent

Complications of AF
• AF is associated with substantial morbidity and mortality
- The risk of stroke is increased two to sevenfold in patients with AF compared to
patients without this arrhythmia
- Patients with AF are also at increased risk for systemic thromboembolism
- AF is associated with a threefold increase in the risk of HF as a result of
tachycardia-induced cardiomyopathy
- AF increases the risk of dementia and mortality approximately twofold
compared to patients without AF

Treatment
• The goals of individualized therapy for AF are:
(a) ventricular rate control
(b) termination of AF and restoration of sinus rhythm (commonly referred to
as “cardioversion” or “conversion to sinus rhythm”)
(c) maintenance of sinus rhythm, or reduction in the frequency of episodes
of paroxysmal AF and/or
(d) prevention of stroke and systemic thromboembolism

Treatment Goals According to AF Classification
Ventricular Rate Control Ventricular rate control can be achieved by inhibiting
the proportion of electrical impulses conducted from the atria to the ventricles
through the AV node

Conversion to Sinus Rhythm
• Termination of AF in hemodynamically stable patients may be
performed using antiarrhythmic drug therapy or elective DCC
• DCC is generally more effective than drug therapy for conversion of
AF to sinus rhythm

Maintenance of Sinus Rhythm/Reduction in the Frequency of Episodes of
Paroxysmal AF
• amore realistic goal for many patients is not permanent maintenance of sinus rhythm, but
rather reduction in the frequency of episodes of paroxysmal AF
• Maintenance of sinus rhythm is more likely to be successful in patients with AF duration of
less than 6 months
• Studies are available to compare maintenance of sinus rhythms versus rate control
- No significant difference in terms of mortality
- Increased hospitalization and adverse drug effects
• Therefore, drug therapy for the purpose of maintaining sinus rhythm or reducing the
frequency of episodes of AF should be initiated only in those patients with episodes of
paroxysmal AF who continue to experience symptoms despite maximum tolerated doses of
drugs for ventricular rate control

Prevention of Stroke and Systemic
Thromboembolism
• Most patients with paroxysmal, persistent, or permanent AF should
receive therapy for prevention of thromboembolism unless compelling
contraindications exist
• In general, most patients require oral anticoagulation; however, in
patients with nonvalvular AF and a CHA2DS2-VASc score of 0,
anticoagulation is not recommended

Ventricular tachy arrythymia
life-threatening ventricular tachyarrhythmias (Sustained ventricular
tachycardia and ventricular fibrillation)
torsades de pointes
normal heart ventricular tachycardia
non-sustained ventricular tachycardia
ventricular premature beats

Ventricular Arrhythmias
Ventricular tachycardia (VT)
A condition in which an electrical signal is sent from the ventricles at a very fast but often
regular rate.
 The ECG shows a rapid ventricular rhythm with broad (often 0.14 s or more), abnormal
QRS complexes. AV dissociation may result in visible P waves
Treatment: in haemodynamically compromised patients, emergency DC cardioversion may
be required. If the blood pressure and cardiac output are well maintained, intravenous
therapy with class I drugs or amiodarone is usually used. First-line drug treatment consists of
lidocaine (50-100 mg i.v. over 5 minutes) followed by a lidocaine infusion (2-4 mg i.v. per
minute). DC cardioversion is necessary if medical therapy is unsuccessful.
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Ventricular Tachycardia
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Ventricular Arrhythmias
Ventricular fibrillation (VF)
A condition in which many electrical signals are sent from the ventricles at a very fast and
erratic rate. As a result, the ventricles are unable to fill with blood and pump.
This rhythm is life-threatening because there is no pulse and complete loss of
consciousness.
The ECG shows shapeless, rapid oscillations and there is no hint of organized complexes
A person in VF requires prompt defibrillation to restore the normal rhythm and function of
the heart. It may cause sudden cardiac death. Basic and advanced cardiac life support is
needed
Survivors of these ventricular tachyarrhythmias are, in the absence of an identifiable
reversible cause (e.g. acute myocardial infarction, severe metabolic disturbance), at high
risk of sudden death. Implantable cardioverter-defibrillators (ICDs) are first-line therapy in
the management of these patients
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Ventricular Fibrillation
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Torsades de Pointes
• Torsades de Pointes (TdP) is a specific polymorphic VT associated with
prolongation of the QT interval in the sinus beats that precede the
arrhythmia

Etiology and pathophysiology
• Inherited or acquired
• TdP is caused by circumstances, often drugs, that lead to prolongation in the
repolarization phase of the ventricular action potential
• Prolongation of ventricular repolarization promotes the development of early ventricular
afterdepolarizations during the relative refractory period, which may provoke reentry
leading to TdP
• Drug-induced TdP rarely occurs in patients without specific risk factors for the
arrhythmia

Treatment
• Desired outcomes include
(a) prevention of TdP,
(b) termination of TdP,
(c) prevention of recurrence, and
(d) prevention of sudden cardiac death

Treatment
• Hemodynamically stable TdP is often treated with IV magnesium sulfate, irrespective
of whether the patient is hypomagnesemic; magnesium has been shown to terminate
TdP in normomagnesemic patients
• Magnesium sulfate should be administered IV in doses of 1 to 2 g, diluted in 50 to 100
mL 5% dextrose in water (D5W), administered over 5 to 10 minutes; doses may be
repeated to a total of 12 g
• Alternatively, a continuous magnesium infusion (0.5 to 1 g/hour) may be initiated after
the first bolus

Pharmacotherapy of arrythmias

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