Anti-arrhythmic drugs

Course Name: Advanced Pharmacology-II

Course Code: PHR5011

Dr. Ferdous Khan (FrK)

Associate Professor, Department of Pharmaceutical Sciences
North South University

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Electrical conduction system of the heart
 The electrical conduction system of the heart transmits signals generated principally by the sinoatrial
(SA) node to cause contraction of the heart muscle.
 This signal triggers the contraction of the right and left atrium, and then the right and left ventricles.
 Dysfunction of the conduction system can cause irregular, fast, or slow heart rhythms.
 This electrical conduction system has 5 components:
 Sinoatrial (SA) node
 Atrioventricular (AV) node
 Bundle of His
 Right and left branches of bundle of His
 Purkinje fiber

 Heart muscle has 3 layers: Epicardium, myocardium, and endocardium.

 The myocardium is the thickest layer and made up of cardiomyocytes (myocardiocytes, cardiac muscle fiber).
 Only one percent of the cardiomyocytes are modified to from electrical conduction system of the
heart.
Pace maker Type BPM
SA node The natural (primary) pacemaker 60-100 bpm
AV node The secondary pacemaker 60-40 bpm
Bundle of His No such designation 20-40 bpm
Purkinje fiber 20-40 bpm

Cardiac pacemaker
 The specialized cardiomyocytes that create the rhythmic electrical impulses, setting the pace for
blood pumping, are called pacemaker cells.
 The contraction of cardiac muscle in all animals is initiated by rhythmic electrical impulses known as
action potentials.
 The rate at which these impulses fire, controls the rate of cardiac contraction, that is, the heart rate.
 In most humans, the concentration of pacemaker cells is highest in the sinoatrial (SA) node, hence
SA node is considered as the natural pacemaker.

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  The SA node is a group of cells positioned on the wall of the right atrium, near the entrance of the
superior vena cava.
Sinoatrial (SA) node
 Cells in the SA node spontaneously depolarizes and repolarize which ultimately results in
contraction.
 This contraction occurs approximately 100 times in each minute.
 This native rate is constantly modified by the activity of sympathetic and parasympathetic nervous
system.
 Hence the resultant resting cardiac rate in adult humans is about 70 beats per minute.
 As the SA node is responsible for the heart's electrical activity, it is sometimes called the primary
pacemaker.
Atrioventricular node
 The atrioventricular node (AV node) is a part of the electrical conduction system of the heart that
coordinates the top of the heart.
 It electrically connects the atria and ventricles.
 The AV node collects, holds and conducts the normal electrical impulse from the atria to the
ventricles.
 It holds the electrical impulse coming from the SA node for approximately 100 milliseconds.
 This holding is necessary for the complete contraction and emptying of the atria.
 Without this holding effect all four chambers of heart would contract simultaneously.
Bundle of His and its branches
 Bundle of His is a collection of heart muscle cells specialized for electrical conduction.
 As part of the electrical conduction system of the heart, it transmits the electrical impulses from the
atrioventricular node to the apex via the left and right bundle branches.
 The fascicular branches then lead to the Purkinje fibers, which provide electrical conduction to the
ventricles, causing the cardiac muscle of the ventricles to contract at a paced interval.
 Fascicle: a bundle of structures, such as nerve or muscle fibers or conducting vessels in plants.
The Purkinje fibers
 The Purkinje fibers are located in the inner ventricular walls of the heart, just beneath the
endocardium in a space called the subendocardium.
 The Purkinje fibers are specialized conducting fibers composed of electrically excitable cells.
 These cells are larger than cardiomyocytes with fewer myofibrils and many mitochondria.
 They conduct cardiac action potentials more quickly and efficiently than any other cells in the heart.
 Purkinje fibers allow the heart's conduction system to create synchronized contractions of its
ventricles, and are essential for maintaining a consistent heart rhythm.
Arrhythmia
 Arrhythmia, also known as cardiac arrhythmia, is a pathological condition in which the heartbeat is
irregular, too fast, or too slow.
 A heartbeat that is too fast is called tachycardia.
 In adults, resting heart rate faster than 100 beats per minute is labeled as tachycardia.
 A heartbeat that is too slow (less than 60 beats/min) is called bradycardia.
 Irregular heartbeat is termed as fibrillation.

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  When an entire chamber of the heart is involved in multiple micro-reentry circuits and is, therefore,
quivering with chaotic electrical impulses, it is said to be in fibrillation.

Major types of arrhythmias

Fibrillation
 Fibrillation can affect the atrium (atrial fibrillation, A-Fib) or the ventricle (VF or V-Fib).
 A-Fib is not typically a medical emergency.
 But if left untreated, V-fib can lead to death within minutes.
 V-fib is considered as a form of cardiac arrest.
 An individual suffering from it will not survive unless cardiopulmonary resuscitation (CPR) and
defibrillation are provided immediately.
 CPR can prolong the survival of the brain in the lack of a normal pulse, but defibrillation is the only
intervention that can restore a healthy heart rhythm.
Fibrillation

Electrophysiological manifestation of A-Fib

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 Atrial Flutter Atrial Fibrillation
Atrial Rate 250 to 400bpm 400bpm
Ventricular Rate/Rhythm Usually, regular Varies with conduction
Grossly irregular
Pattern Saw tooth baseline Irregular or almost flat baseline
“Irregularly irregular”

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Symptoms of arrhythmia
 The term cardiac arrhythmia covers a very large number of very different conditions.
 The most common symptom of arrhythmia is an awareness of an abnormal heartbeat, called
palpitations.
 Some have minor effects on heart, some have fatal.
 These may be infrequent, frequent, or continuous.
 If an arrhythmia results in a heartbeat that is too fast, too slow, or too weak to supply the body's
needs, this manifests as lower BP, weakness, shortness of breath, palpitations, dizziness, decreased
exercise tolerance, fainting or syncope.
 Risk factors: Being male, age, inherited gene defects, obesity, medications, and hypertension.

Causes of arrhythmias
Abnormal automaticity:
 Abnormal automaticity refers to the ability of certain cardiac cells to generate electrical impulses
spontaneously, outside of the normal pacing mechanisms controlled by the sinoatrial (SA) node.
 This phenomenon can lead to cardiac arrhythmias, which are abnormal rhythms of the heart.
 SA node has a faster rate of discharge than other pacemaker cells and thus, it normally sets the pace
of contraction for myocardium.
 If cardiac sites other than the SA node show enhanced automaticity, they may generate competing
stimuli, and arrhythmias may arise.
 This may occur due to increased sympathetic nervous system activity, electrolyte imbalances,
changes in ion channel function, or tissue damage.
Abnormalities in impulse conduction:
 Impulses from higher pacemaker centers are normally conducted downwards and bifurcate to
activate the entire ventricular surface.
 A phenomenon called reentry can occur if a unidirectional block caused by myocardial injury or a
prolonged refractory period results in an abnormal conduction pathway.
 Reentry is the most common cause of arrhythmias, and it can occur at any level of the cardiac
conduction system.
 This short-circuit pathway results in re-excitation of cardiac muscle, causing premature contraction
or a sustained arrhythmia.
 Antiarrhythmic agents prevent reentry by slowing conduction and/or by increasing the refractory
period.

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Pacemaker current or funny current
 The pacemaker current (funny current) is an electric current in the heart that flows through the
hyperpolarization-activated cyclic nucleotide–gated (HCN) channel or pacemaker channel.
 Such channels are important parts of the electrical conduction system of heart and form a component
of the natural pacemaker.
 The funny current is generated in the spontaneously active cardiac regions, such as the SA node, AV
node, and the Purkinje fibers.
 The funny current is a mixed sodium–potassium current that activates when the voltage is less than -
40 mV.
 Among the unusual features which justified the name "funny" are mixed Na + and K+ permeability,
activation on hyperpolarization, and very slow kinetics.

Cardiac action potential

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Phase 0: Depolarization: Sodium rapidly and calcium slowly enter into the cell
Phase 1: Brief repolarization: Sodium channels close
Potassium channels (called Ito1) open and close rapidly
Phase 2: Plateau phase: Potassium rapidly goes out of the cell
Calcium slowly enters into the cell
Phase 3: Rapid repolarization: Calcium channels close
Potassium rapidly goes out of cell
Phase 4: Resting potential: Leak potassium channels
Sarcolemma impermeable to sodium
Ion channels of cardiac action potential
CHANNEL CHARACTERISTICS
Sodium Channels
+ Phase 0 depolarization of non-pacemaker cardiac action potentials
Fast Na
+ "Funny" pacemaker current (If) in cardiac nodal tissue
Slow Na
Potassium Channels
Contributes to late phase 3 repolarization; maintains phase 4
Inward rectifier (Iir or IK1)
negative potential
Transient outward (Ito) Contributes to phase 1 of cardiac action potentials
Delayed rectifiers (Ikr, IKs) Phase 3 repolarization of cardiac action potentials
Acetylcholine-activated (IK, ACh) Activated by acetylcholine; Gi-protein coupled
Calcium-activated (IK, Ca, BKCa) Open in response to Ca++ influx in vascular smooth muscle
Calcium Channels
L-type (ICa-L) Slow inward, long-lasting current; phase 2 non-pacemaker cardiac
action potentials and late phase 4 and phase 0 of SA and AV nodal

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 cells; important in vascular smooth muscle contraction
Transient current that contributes to early phase 4 pacemaker
T-type (ICa-T)
currents in SA and AV nodal cells

Intra- and extracellular ion concentrations (mmol/L)

Element Ion Extracellular (mM/L) Intracellular (mM/L) Ratio
Sodium + 140 10 14:1
Na
Potassium + 4.5 155 1:30
K
Chloride − 100 20 5:1
Cl
Calcium 2+ 2 −4 20000:1
Ca 10

 Although intracellular Ca2+ content is about 2 mM, most of this is bound or sequestered in
intracellular organelles (mitochondria and sarcoplasmic reticulum).

Cell type Rest. mem. pot Threshold Overshoot

Cardiomyocytes -90 mV -70 mV +20 to +30 mV
Pacemaker cells -60 mV -40 mV +10 to +20 mV
Neuron -70 mV -55 mV +30 to +40 mV

Pacemaker and cardiac action potential

Drugs used to treat arrhythmias

 Anti-arrhythmic agents are drugs used to suppress abnormal rhythms of the heart. They act to:

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  Either interfere with the dynamics of cardiac action potentials by blocking a certain ion
channel.
 Or block the sympathetic effects of the autonomic nervous system on the heart, to slow down
heart rate.
There are 5 classes of antiarrhythmic drugs:
 Class I: Sodium-channel blockers
 Class II: Beta blockers
 Class III: Potassium channel blockers
 Class IV: Calcium channel blockers
 Class V: Miscellaneous
Four classes of antiarrhythmic drugs

Class I: Sodium-channel blockers

 These drugs block the fast Na+ channel that are responsible for the depolarizing phase in contractile
myocytes.
 This results in a slower depolarization with a smaller amplitude.
 While subclass IC has no effect on refractory period, IA prolongs and IB shortens refractory period,
respectively.
 Changes in refractory period may have different outcomes for different types of arrhythmias.
 A longer refractory period generally reduces cardiac excitability.
 But prolonged repolarizations may increase the risk of some type of
tachycardia caused by afterdepolarizations.
 The slope of phase 0 depends on the activation of “fast sodium-channels” and
the rapid entry of sodium ions into the cell.
 Blockade of fast sodium channels decreases the slope of phase 0, which leads
to a decrease in the amplitude of action potential.
 Class I agents are divided further into subclass IA, IB and IC.
 These subclasses differ in the:

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  strength of sodium channel blockage
 duration of action potentials
 refractory period
Parameter Class IA Class IB Class IC
Na+ blockade Moderate Weak, rapid Strong, slow
Phase 0 Depolarization Moderately slows Phase Weakly slows Phase 0 Strongly slows Phase 0
0 depolarization depolarization depolarization
Refractory period Increase Decrease Unchanged
Effect on P-3 Prolongs P-3 Shorten P-3 No effect on P-3
Repolarization Repolarization Repolarization Repolarization
Example Quinidine Lidocaine Flecainide
Procainamide Mexiletine Moricizine
Disopyramide Tocainide Propafenone
Class II: β-adrenergic antagonists
 These drugs bind to beta1-adrenergic receptors and block the sympathetic influences that act through
these receptors.
 Sympathetic nerves release catecholamines (epinephrine and norepinephrine) which act to increase
SA node firing rate and cardiac conductibility.
 These drugs diminish Phase 4 thus depress automaticity, prolongs AV conduction, and decrease HR
and contractility.
 Class II agents are useful in treating tachyarrhythmias caused by increased sympathetic activity.
 They are also used for atrial flutter and fibrillation.
 Common adverse effects with β-blockers include bradycardia, hypotension, and fatigue.
 Sympatholytic activity with decreased heart rate and conduction velocity, inhibit SA node pacemaker
activity, increase the duration of myocyte action potential and increasing refractory period.
 The electrophysiologic effects of beta blockers are manifested solely by their blunting of the actions
of catecholamines.
 In areas where there is rich adrenergic innervation, beta blockers can have a pronounced effect.
 Since the sympathetic innervation of the heart is greatest in the sinoatrial (SA) and atrioventricular
(AV) nodes, these structures are highly affected by the beta blockers.
 Compared with other antiarrhythmic drugs, these agents are only mediocre at suppressing overt
cardiac arrhythmias.
 In both the SA and AV nodes, phase 4 depolarization is blunted by beta-blocking agents, leading to a
decrease in automaticity, and hence to a slowing in the heart rate.
 In the AV node, beta blockers cause a marked slowing in conduction and a prolongation in refractory
periods.
 Beta blockers have very little effect on conduction velocity or refractoriness in normal atrial or
ventricular myocardium.

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  Metoprolol
 Metoprolol is the β-adrenergic antagonist most widely used in the treatment of cardiac
arrhythmias.
 Compared to propranolol, it reduces the risk of bronchospasm.
 Esmolol
 Esmolol is a very short and fast-acting β-blocker used for intravenous administration in acute
arrhythmias that occur during surgery or emergency situations.
 Propranolol (Less commonly used)
 Propranolol reduces the incidence of arrhythmic death after MI, the most common cause of
death in this group.
 The mortality rate in the first year after a heart attack is significantly reduced by propranolol.
Class III: K+ channel blockers
 These drugs block potassium channels and, thus, diminish the outward potassium current during
repolarization of cardiac cells.
 Since these agents do not affect the sodium channel, conduction velocity is not decreased.
 These agents prolong the duration of action potential without altering phase 0 of depolarization or
resting membrane potential.
 These agents prolong the refractory period.
 This reduces the heart’s excitability and suppresses tachycardias.
 Amiodarone has been a mainstay of therapy for the rhythm management of atrial fibrillation or
flutter.
 Other agents are sotalol, dofetilide, dronedarone, ibutilide etc.

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Mechanism of action of amiodarone
Amiodarone is a blocker of voltage gated potassium (KCNH2) channel which mediates the repolarizing (I kr)
current in the cardiac action potential.

 Amiodarone slows conduction rate and prolongs the refractory period of the SA and AV nodes.
 It also prolongs the refractory periods of the ventricles, bundles of His, and the Purkinje fibres
without exhibiting any effects on the conduction rate.
 Amiodarone has been shown to prolong the myocardial cell action potential duration and refractory
period.
Class IV: Calcium channel blockers
 Calcium channel blocking agents inhibit the slow calcium (L-type) channel that is responsible for the
depolarization of the sinoatrial (SA) and atrioventricular (AV) nodes.
 The major electrophysiologic effects of CCBs are limited to these two structures.
 Blocking these channels results in a lower sinus rate and slower conduction through the AV node.
 As a general rule, calcium blockers have minimal or no electrophysiologic effect on the atrial or
ventricular myocardium.

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  Although voltage-sensitive calcium channels occur in many different tissues, the major effect of
CCBs is on vascular smooth muscle and the heart.
 Their binding and blocking of the calcium channels increases at more rapid heart rates.
 Both verapamil and diltiazem depress automaticity, slow conduction, and increase refractoriness in
both SA and AV nodes.
 Verapamil shows greater action on the heart than on vascular smooth muscle, and diltiazem is
intermediate in its actions.
 Common adverse effects include bradycardia, hypotension, and peripheral edema.
 Dihydropyridines, such as (nifedipine, felodipine, amlodipine etc) are not clinically useful as
antiarrhythmics, because of their clinically dominant vasodilator effect.

Other agents
Digoxin:
– Digoxin inhibits the Na+/K+-ATPase pump, ultimately shortening the refractory period in
atrial and ventricular myocardial cells while prolonging the effective refractory period and
diminishing conduction velocity in the AV node.
– Digoxin is used to control ventricular response rate in atrial fibrillation and flutter; however,
sympathetic stimulation easily overcomes the inhibitory effects of digoxin.
– At toxic concentrations, digoxin causes ectopic ventricular beats that may result in VT and
fibrillation.
– Serum trough concentrations of 1.0 to 2.0 ng/mL are desirable for atrial fibrillation or flutter,
whereas lower concentrations of 0.5 to 0.8 ng/mL are targeted for systolic heart failure.

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Adenosine:
 Adenosine is a naturally occurring purine nucleoside that forms from the breakdown of adenosine
triphosphate (ATP).
 In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins.
 Activation of this pathway opens potassium channels, which hyperpolarizes the cell.
 Activation of the Gi-protein also decreases cAMP, which inhibits L-type calcium channels and
therefore calcium entry into the cell.
 In cardiac pacemaker cells, located in the SA node, adenosine inhibits the pacemaker current, which
decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous
firing rate (negative chronotropy).

Magnesium sulphate:
– Magnesium is necessary for the transport of sodium, calcium, and potassium across cell
membranes.
– It slows the rate of SA node impulse formation and prolongs conduction time along the
myocardial tissue.
– Intravenous magnesium sulfate is the salt used to treat arrhythmias, as oral magnesium is not
effective in the setting of arrhythmia.
– Magnesium has relatively mild adverse effects.
– Most notably, magnesium is the drug of choice for treating the potentially fatal arrhythmia
torsades de pointes and digoxin-induced arrhythmias.

Further reading
 https://www.youtube.com/watch?v=FThXJUFWUrw
 https://www.google.com.bd/search?
q=ecg&tbm=isch&ictx=1&tbs=rimg:CXoCovrxl6ooIgh6AqL68ZeqKCoSCXoCovrxl6ooEa98ZVYj
MwSq&hl=en&sa=X&ved=0CAEQiRxqFwoTCMCw8L_v6vMCFQAAAAAdAAAAABAD&biw=
1226&bih=516#imgrc=NfS1JhnGlycPMM
 https://www.ahajournals.org/doi/full/10.1161/CIRCEP.108.789081
 https://app.achievable.me/study/usmle-step-1/learn/pharmacology-important-drugs-of-the-
cardiovascular-system-antiarrhythmics
 https://step2.medbullets.com/cardiovascular/121697/antiarrhythmics
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398315/
 https://www.ahajournals.org/doi/full/10.1161/CIRCEP.108.789081
 https://www.msdmanuals.com/professional/cardiovascular-disorders/arrhythmias-and-conduction-
disorders/overview-of-arrhythmias
 https://step2.medbullets.com/cardiovascular/121697/antiarrhythmics

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