Antiarrhythmic Drugs

Question 1

Normal myocardial electrophysiology?

Answer 1

The pumping function of the heart provides a coordinated contraction of all four parts of the heart,
which depends on the conduction system propagating the electrical impulses from the sinoatrial node (pacemaker) to all other parts of the heart.

The impulses spread from the sinus node, located in the right atrium, to the
atrioventricular node (AV node), located in the lower part of the atrial septum, and
then through His bundle they reach Purkinje fibers of the ventricle.

All these structures are His-Purkinje system.

Like all electrically excitable cells, myocardial cells have a resting potential and an action potential.

The resting potential is the difference in voltage on both sides of the membrane. Normally, it is – 90 mV.

The resting potential depends mainly on the transport of Nations through the membrane.

When heart cells are excited, there is a decrease in the value of this potential due to the influx of Nations into the cells and Ca++.

The changes in membrane potential
due to the movement of ions through the membrane are called the action
potential.

Question 2

Phases of action potential?

Answer 2

●It is divided into 5 phases.

●During phase 0,
the Na+ ions move into the cell.

●During phase 1,
Na+ channels are closed and the K+ ions move outside the cells, thereby initiating returning of the original resting potential (repolarization); inward current of CI also contributes to this process.

●During phase 2,
the outward current of K+ ions is balanced by the simultaneous entering of positively charged Ca++ ions
(plateau phase).
This phase is not present in the cells of the cardiac conduction system
(the sinus node, the atrioventricular node, the His-Purkinje system).

●During phase 3,
the repolarization process ends,
K+ ions go out of the cell.
By the end of phase 3, the sodium channels are not able to conduct Na+ ions.
(refractory period or non-excitability period).

●The resting potential is achieved during phase 4.
The action potential can occur in a heart cell during the transfer of this potential from the other cells, or it emerges spontaneously in the cells of the sinus and atrioventricular node in the His-Purkinje system.

The latter process is called spontaneous diastolic depolarization.
It occurs in the cells of the cardiac conduction system during phase 4
, the inward currents of Na+ and
Ca++ are responsible for this process.

●The cells with the ability to spontaneous diastolic depolarization have the function of automaticity.

Question 3

Properties necessary for normal heart function?

Answer 3

1) the excitability (the ability to respond to an electrical impulse).

2) the automaticity
(spontaneous diastolic depolarization).

3) the conductivity
(impulse propagation on the cardiac conduction system)

4) effective refractory period, the period of cellular non-excitability
(it lasts from the phase 0 to the phase 3, inclusive).

Question 4

What is arrhythmia?

Answer 4

●Arrhythmia is the disturbance of impulse formation or its conduction
in the heart.
●All arrhythmias are divided into two groups:
bradyarrhythmias (“brady” - rare)
and
tachyarrhythmias (“tachy” - often).

●Bradyarrhythmia can be bradycardia or slowing of the impulse conduction from the atria to the ventricles (AV blockade).
Bradyarrhythmias are caused by the organic heart diseases or toxic influence of the drugs
(beta-blockers, clonidine, cardiac glycosides, calcium channel blockers, and others).

●Tachyarrhythmias arise due to the disturbances of automatism, conduction, or a combination of both.

●Tachyarrhythmias are caused by functional and organic heart diseases and intoxications.

●All tachyarrhythmias are divided
into:
a) sinus tachycardia

b) extrasystole (a premature contraction of the heart,
it is independent of the normal heart rhythm and it arises in response to an impulse in some part of the heart, different from the normal impulse
of the SA node)

c) the type of arrhythmia re-entry (excitation re-entry waves in the same place)

d) WPW syndrome
(premature ventricular stimulation).

Re-entry arrhythmias are
atrial flutter or fibrillation,
paroxysmal supra- and ventricular, tachycardia,
ventricular fibrillation.

●Ventricular tachyarrhythmias are the most dangerous as they lead to non-effective heart functioning, insufficient blood supply to the brain and, ultimately, death.

Question 5

Classification of antiarrhythmic drugs?

Answer 5

》》They are divided into two groups according to the rhythm frequency.

1) drugs for the treatment of bradyarrhythmias.

2) drugs for the treatment of tachyarrhythmias or, in fact, true antiarrhythmic drugs.

In pharmacological manuals, the antiarrhythmics include the drugs for tachyarrhythmias treatment only.

Question 6

Drugs for the treatment of bradyarrhythmias?

Answer 6

●They affect the autonomic innervations of the heart,

a) drugs that decrease the influence of the parasympathetic nerve system on the heart,
》》M-cholinoblockers - atropine

b) drugs that increase the influence of the sympathetic nerve system on the
heart
(through stimulation of beta-1 adrenergic receptors),

》》beta adrenergic agonists with beta-1 adrenergic activity -
isoprenaline (isoproterenol).

Question 7

Drugs for the treatment of tachyarrhythmias.

Answer 7

●They are a very large group of substances.
》They differ in their effect on the ionic channels Na+, K+, Ca++, passing across the membrane of the heart cells.

》This drugs are divided into 4 classes (classification of Vaughan-Williams).

Question 8

Class I?

Answer 8

●Blockers of sodium channels have a difference in effect on,
a) duration of the refractory period (subclass IA slows down,
IB shortens,
IC does not significantly change).

b) intracardiac conduction
(subclass IA decreases,
IB has no effect,
IC strongly reduces).
Subclass IA has a direct inhibitory and an indirect (atropine-like) effect on AV conduction that promotes the passage of atrial tachyarrhythmias to ventricles.

Question 9

Class IA (Examples)?

Answer 9

》Quinidine (+|+++)
》Procainamide (+|+++)
》Disopyramide (+|+++)

Question 10

Quinidine (IA) Facts?

Answer 10

●Quinidine is a toxic drug.
It causes hypotensive effect
(due to alpha-adrenoceptor
blocking action and inhibition of myocardial contractility),

●”cinchonism”
(ringing in the ears,
headache,
confusion,
etc.)

rarely -
idiosyncrasy and autoimmune reactions
(thrombocytopenia,
hepatitis,
angioedema,
fever)

Question 11

Procainamide (IA) Facts?

Answer 11

●It causes hypotension
(due to the ganglionic-blocking action and
decrease of myocardial contractility)

●lupus syndrome
(arthritis,
skin rash,
etc.)

Question 12

Disopyramide (IA) Facts?

Answer 12

● It inhibits myocardial contractility (dangerous in the presence of heart failure).

●It has the most prominent atropine-like effect among IA drugs.

Therefore it is not used for atrial arrhythmias.

Question 13

Class IB (Examples)?

Answer 13

●Lidocaine (0|+++)
●Mexiletine(0|+++)

Question 14

Lidocaine (IB) Facts?

Answer 14

●Lidocaine decreases the duration of the action potential in normal myocardiocytes and prolongs it in the pathological cells.

●Lidocaine is the least toxic representative of class I.

●Adverse effects are
rare and mild.

●There are neurological disorders typical of systemic effects of local anesthetics,
》paresthesia,
》tremors,
》hearing loss,
》and others

Question 15

Mexiletine (IB) Facts?

Answer 15

●Lidocaine-like drug for oral administration.
》It is more toxic and less effective than
lidocaine.

Question 16

Class IC (Examples)?

Answer 16

●Flecainide (+|++++)
●Propafenone (+|+++)
●Moracizine (0|+++)
●Aethacizinum (++|+++)

Question 17

Flecainide (IC) Facts?

Answer 17

●Particularly effective in the WPW syndrome.

》antiarrhythmics,
Like the other class IC of it has strong proarrhythmogenic action in patients with organic heart disease
(an acute phase of myocardial
infarction, etc.)

Question 18

Propafenone (IC) Facts?

Answer 18

●It has proarrhythmogenic action
(see flecainide above).

》It has low toxicity
(metallic taste in the mouth
&
constipation)

Question 19

Moracizine (IC) Facts?

Answer 19

●It has proarrhythmogenic action
(see flecainide above).

》It has low toxicity
(rarely cause nausea)

Question 20

Aethacizinum (IC) Facts?

Answer 20

●The least toxic drug from the IC subclass
(rarely cause nausea, dizziness).

》It is popular in ex-USSR countries.

Question 21

Class II?

Answer 21

●Beta-blockers reduce the sympathetic influence on the heart
(for example at hyperthyroidism)
while moderately effective in tachyarrhythmia on the whole.

》Propranolol (+|+)
》Esmolol (+|+)

●Propranolol and esmolol are the most
useful of this class due to the presence
of an injection form
&
rapid onset of action.

●Beta-blockers are contraindicated in
bronchial asthma.
(bronchospasm provocation)

Question 22

Class III? Examples?

Answer 22

●Potassium channel blockers prolong the effective refractory period of heart cells and prolong the action potential.
>Amiodarone (+++|+++)
>Dronedarone (+++|0)
>Sotalol (+++|+++)
>Ibutilide,
Dofetilide (++|0)

Question 23

Amiodarone (III) Facts?

Answer 23

●Amiodarone has properties of all antiarrhythmic classes.

》It is highly effective and safe for a wide various supraventricular and
ventricular tachyarrhythmias,
but
it possesses a variety of extracardiac toxicities,
which sometimes can be life-threatening
(hypothyroidism,
pulmonary fibrosis,
neurological disorders,
and many others)

Question 24

Dronedarone (III) Facts?

Answer 24

●”Amiodarone without iodine” does not
violate the function of the thyroid gland
and
does not cause pulmonary fibrosis,
but it is very hepatotoxic.

Question 25

Sotalol (III) Facts?

Answer 25

●It is a beta-blocker with the properties
of the drug of class III.

》It is the drug of choice for the treatment of arrhythmias in pediatric practice.

Question 26

Ibutilide, dofetilide (III) Facts?

Answer 26

●They are highly effective in atrial fibrillation and flutter.

》Ibutilide is available for intravenous injections,
dofetilide is used orally.

》Both drugs possess strong proarrhythmogenic action

Question 27

Class IV drugs? Facts? Examples?

Answer 27

●Calcium channel blockers block calcium channels
(decrease automaticity
and
conductivity in the sinoatrial (sinus)
and
AV nodes)

●Verapamil (+++|0)
●Diltiazem (+++|0)

●Low toxicity.
●They can cause the decrease of myocardial contractility
and
peripheral vasodilatation
(i.e. hypotensive effect)

Question 28

List out the antiarrhythmics not included in this classification?

Answer 28

》Adenosine
》potassium supplements
》magnesium
》cardiac glycosides

Question 29

Class I of antiarrhythmics? (Explanation)

Answer 29

●Sodium channel blockers
(membrane stabilizing agents).
●This class includes the most popular and effective antiarrhythmic substances that are divided into three subclasses:
●A - quinidine,
procainamide,
disopyramide

●B- lidocaine,
mexiletine

● C- propafenone,
moricizine.

●It slows down the development of an action potential as a result of the Na channels blockade.

The subclasses differ in their effect on
a) the duration of the refractory period (IA prolongs, IB shortens and IC does not
substantially affect, i.e. it slightly prolongs or shortens)
and
b) intracardiac conduction - the greatest impairment
(and most proarrhythmogenic action) is typical for subclass C . For this reason, the subclass C is contraindicated in the patients with recent myocardial infarction and impaired conduction in the heart.

●Class I is effective in both the ventricular and atrial arrhythmias excluding subclass B,
which is applied for the treatment of ventricular tachyarrhythmias only.

Question 30

The influence of antiarrhythmic drugs (AADs) of class I on duration of the action potential (AP)?

Answer 30

●IA - Increase of the duration of AP

●IB - Decrease of the duration

●IC - No effect on the duration

Question 31

Class II antiarrhythmics? (Explanation)

Answer 31

●Class II of antiarrhythmics is beta-blockers
(propranolol,
metoprolol,
esmolol,
etc.).

●Due to the blockade of beta-1 adrenoreceptors of the heart,
they eliminate the stimulating effect of the sympathetic nervous system
on the heart,
reducing the conductivity,
excitability,
contractility
and
cardiac automatism,
and, as a result,
reduce both the heart rate and the blood pressure.

●These drugs are relatively weak, especially for the treatment of
ventricular arrhythmias.

They are the drugs of choice only for the arrhythmias raised on the elevated tone of the SNS (e.g. thyrotoxicosis).

●The main limitation of using the beta-blockers is the threat of bronchospasm in asthmatic patients, so they are contraindicated in bronchial asthma.

Question 32

Class III antiarrhythmics? (Explanation)

Answer 32

●Class III of antiarrhythmics are potassium channel blockers
(drugs are prolonging the refractory period or drugs are lengthening the action potential duration).

●The mechanism of the action is reflected in the group’s name(Fig. 38).

●Amiodarone has high effectiveness in every kind of tachyarrhythmia. ●This is probably due to the fact that amiodarone has the properties of all other antiarrhythmics classes.

●Usually, it is used orally for the prevention and treatment of different chronic tachyarrhythmias.

●The disadvantage of amiodarone is the presence of abundant,
even life-threatening side effects including thyroid dysfunction and pulmonary fibrosis.

●Sotalol is beta-blocker with the properties of class III of antiarrhythmics.

●Sotalol is effective for both atrial and ventricular tachyarrhythmias.
●It can also be used as antiarrhythmic in adolescents.

●Ibutilide and dofetilide are highly
effective in eliminating atrial tachyarrhythmias.

》》Their disadvantage is high toxicity, so they should be used only in a hospital under strict medical
supervision.

Question 33

Class IV of antiarrhythmics? (Explanation)

Answer 33

● (Ca++ antagonists,
calcium channel blockers)
includes verapamil and diltiazem.

Their pharmacological action is due to
the blockade of Ca++ channels.

They reduce the heart rate,
slow down atrioventricular conductivity and
increase a refractory period of the
SA andAV nodes.

●These drugs are used in atrial tachyarrythmias only
(especially nodal).

Question 34

Other antiarrhythmic drugs?

Answer 34

●Adenosine is a nucleotide of the human body.
》it slows down conduction and prolongs the refractory period of AV
node.

●the most effective drug for the treatment of paroxysmal supraventricular tachycardia
(superior to class IV)

2) potassium supplements are used only when tachyarrhythmia occurred on the background of hypokalemia (for example, poisoning with cardiac glycosides) potassium ions restore the resting membrane potential.

3) magnesium supplements are used
for hypomagnesaemia
(poisoning by cardiac glycosides) with ventricular tachycardia or arrhythmia after myocardial infarction

》the mechanism of the action is to restore the normal functioning of the Na+/K+ ATPase,
Na+, K+, Ca++ ion channels)

4) the cardiac glycosides (digoxin)

(see the details in chapter “Drugs used for the treatment of heart failure”).

Question 35

Side effects of antiarrhythmic drugs (AADS)?

Answer 35

●AADs possess an abundance of side effects and the doctor must weigh the advantages and disadvantages.
and decide what is worse,

the arrhythmia without treatment or side effects of AADs.

The most dangerous side effect of AADs is the emergence of new arrhythmias.

Furthermore, AADs have:

1) M-cholinoceptor blocking action (increased heart rate, increased AV conduction, that can lead to the
ventricular fibrillation during the treatment of atrial arrhythmias with drugs of subclass IA especially with disopyramide).

2) alpha-adrenoceptor blocking action (hypotension) of quinidine

3) “quinidine faint” caused by an
attack of ventricular tachycardia.

4) ganglion-blocking action
(hypotension) of procainamide

5) lupus-like syndrome
(after prolonged administration of procainamide).

6) pulmonary fibrosis (amiodarone)

7) deposition in the cornea (amiodarone).

8) neurological disorders such as ataxia,
tremor, paresthesia, headache (amiodarone)

9) dysfunction of thyroid gland (amiodarone).

10) constipation, metallic taste in the mouth
(propafenone).

11) facial redness and bronchospasm (adenosine).

See also side effects of beta-adrenoblockers,

calcium antagonists and cardiac glycosides in other chapters.