Competency-based

Medical Bachelor Program

Dr. Asmaa fawzy

Lecturer of Pharmacology

Faculty of Medicine

Contact./ 01069625853

Anti-arrhythmic drugs

Objectives

Upon completion of this lesson, the student will be able to:

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1. Classify the anti-arrhythmic drugs.

2. Recognize the mechanism of action, side effects and uses of each anti-arrhythmic drug.

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Materials & resources

- Kaplan USMLE Step 1- 2016 ( page 101-110).

• Lippincott's Illustrated Reviews 6th edition (page 269- 280).
• PHARMACOLOGY: Basic & Applied Approach. Staff�members, Pharmacology Department, Faculty of�Medicine, Tanta University, 2018. (page 186-197). �

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Remember

SAN

AVN

Automaticity

Impulses originate regularly at a rate of

60-100 beat/min.

Arrhythmia

= Is an abnormal rate or rhythm of the heart beat.

1- Rate:

- If heart beat is too fast is called

Tachy-arrhythmia

- If heart beat is too slow is called Brady-arrhythmia

2- Rhythm:

Irregular heart beat

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Cardiac conduction

Normal heart beat and atrial arrhythmia

Normal rhythm

Atrial arrhythmia

AV septum

1. Disturbance of impulse formation

2. Disturbance of impulse conduction

Causes of arrhythmias

Anti-Arrhythmic Drugs

Goals of treating cardiac arrhythmias

• Reduce Automaticity
• Slow Conduction

m

m

m

h

h

h

Resting (Closed)

Active (Open)

Inactive

Sodium Channels

R

R

A

I

-100

-80

-60

-40

-20

0

20

Phase 0

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Phase 1

Phase 2

Phase 3

​

Phase 4

Na⁺

ca⁺⁺

ATPase

mv

Cardiac Action Potential

Resting membrane Potential

​

Na⁺

m

Na⁺

Na⁺

Na⁺

Na⁺

Na⁺

h

K⁺

ca⁺⁺

​

​

K⁺

K⁺

K⁺

ca⁺⁺

ca⁺⁺

(Plateau Phase)

K⁺

K⁺

K⁺

Na⁺

K⁺

Depolarization

Pacemaker potential

Classification of Anti-Arrhythmic Drugs

• Class I:

Na ⁺ channel blockers

• Class II:

Beta - blockers

• Class III:

K ⁺ channel blockers

• Class IV:

Ca ⁺⁺ channel blockers

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Phase 0

Phase 1

Phase 2

Phase 3

Phase 4

R.M.P

(Plateau Phase)

Class I:

Na⁺ channel blockers

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Class III:

K⁺ channel blockers

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Class IV:

Ca⁺⁺channel blockers

Class II:

Beta blockers

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��Class I Anti-Arrhythmic Drugs��

I-a

I-b

I-c

• Quinidine
• Procainamide
• Disopyramide

• Lidocaine,
• Mexiletine,
• Phenytoin

• Flecainide

��Class I-a��

��1. Procainamide��

��Kinetics��

• Absorption: Oral, IM and IV
• Distribution: all over the body, pass BBB
• Metabolism: Hepatic metabolism by acetylation → N-acetyl procainamide (NAPA) (class III activity).
• Rapid acetylators: increase NAPA→ Torsade de pointes.
• Slow acetylators → SLE like syndrome.
• Excretion: in urine.

• Moderate block of activated Na+ channels → moderate slow phase 0 → moderate ↓ excitability and conductivity.

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• Block inactivated Na+ channels → slow phase 4 → slow automaticity.

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• Block K+ channels→ delay repolarization → long phase 3→ long APD and ERP.

• No atropine action.

Mechanism of action

0

​

1

2

3

​

4

Na⁺

ATPase

R.M.P

Na⁺

m

Na⁺

Na⁺

Na⁺

Na⁺

Na⁺

h

Na⁺

K⁺

�Mechanism of Action�

Moderate block of activated Na⁺ channel

●↓ Excitability

●↓conductivity

Block K ⁺ channel

ca⁺⁺

ca⁺⁺

​

​

ca⁺⁺

ca⁺⁺

Block inactivated Na⁺ channel

● long R.P.

● ↓ Automaticity

K⁺

K⁺

K⁺

●↓ Excitability

●Long Refractory Period.

●↓Conductivity

●↓ Automaticity

Pharmacological effects:

- Cardiac:

1. Anti-Arrhythmic

Depress SAN

-ve inotropic effect.

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​

Bradycardia: direct ↓ S.A.N.

2. Contractility

3. Heart rate:

- Prolong PR, QT intervals. - Broaden QRS

4. ECG:

• No atropine like action

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• No α blocking action

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• Local anaesthetic action: block of Na⁺ channels

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• CNS excitation.

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- Extra-cardiac:

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Side effects

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• Heart: Bradycardia, heart block.
• Bl. Pr.: Hypotension
• C.N.S.: Psychosis, hallucinations
• Systemic lupus erythematosis like syndrome with slow acetylators.
• Torsade de pointes (prolonged QT interval), with rapid acetylators.

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N.B. Torsade de pointes

Torsades de pointes (TdP) is a form of ventricular tachycardia , it has a characteristic morphology in which the QRS complexes “twist” around the isoelectric line.

Tdp is associated with a condition whereby prolonged QT intervals are visible on the ECG.

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QT prolongation leading to Tdp

QT interval prolongation

Uses:

Ventricular and supraventricular arrhythmia:

For short term course. ????

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Kinetics

• Absorption: Oral
• Distribution: Binds to plasma proteins.
• Metabolism Metabolized in liver by dealkylation.
• Excretion: excreted in urine.

Class I-a

��2. Disopyramide��

Heart:

• More potent than procainamide.
• Strong atropine like action.

SAN

AVN

M₂

Direct myocardial depressant

Atropine like action.

• Paradoxical tachycardia

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• Increase ventricular rate

A.V conduction

This can be prevented by ????????

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Previous digitalization

Uses

1. Ventricular arrhythmia.
2. Maintenance (after cardioversion) of atrial flutter or fibrillation (long term therapy).

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Side effects

1. Atropine like: Constipation, dry mouth, urine retention, blurred vision and precipitate glaucoma.
2. Depression of cardiac contractility, ↓ COP and heart failure.
3. Direct VC → Hypertension.

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• Heart failure
• Heart block

• Glaucoma

• Enlarged prostate

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Contraindications:

Class IB

• Lidocaine,
• Mexiletine,
• Phenytoin

Portal v.

HME

Well absorbed orally

But

has extensive hepatic metabolism

Given IV

↓↓ the dose in liver disease

Lidocaine

Mechanism of action:

• Minimal block of activated Na+ channels→ minimal effect on excitability and conductivity.

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• Block mainly inactivated Na+ channels → slow phase 4 → slow automaticity.

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• Activate K+ channels → rapid repolarization → short phase 3 → Short APD & ERP.

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0

​

1

2

3

​

4

Na⁺

ATPase

R.M.P

Na⁺

m

Na⁺

Na⁺

Na⁺

Na⁺

Na⁺

h

Na⁺

K⁺

R.M.P

Minimal block of activated Na + channel

​

●↓ Excitability

●↓conductivity

activate K + channel

ca⁺⁺

ca⁺⁺

​

​

ca⁺⁺

ca⁺⁺

Block mainly inactivated Na+ channel

● Short R.P.

●↓ Automaticity

K⁺

K⁺

K⁺

K⁺

● ↓ Excitability

● Short refractory Period.

● ↓ Conductivity

● ↓ Automaticity

- Heart:

1. Anti-Arrhythmic

- Extra-cardiac:

• Local anaesthesia. -No atropine like action.

Uses:

Emergency ventricular arrhythmia as in:

• Myocardial infarction
• Digitalis toxicity

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Side effects:

• Least cardio-toxic, but excessive doses → cardiac depression and hypotension.
• Neural: Tremors, nausea of central origin and convulsions.
• Nystagmus is early sign of toxicity.

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Mexiletine

Similar to lidocaine but effective orally.

Class Ic

• Flecainide
• Propafenone

0

​

1

2

3

​

4

Na⁺

R.M.P

Na⁺

m

Na⁺

Na⁺

Na⁺

Na⁺

Na⁺

h

R.M.P

Marked block of activated Na ⁺ channel

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Marked ↓

● Excitability

● Conductivity

Class Ic Anti-Arrhythmic Drugs� Flecainide

Flecainide

Uses:

- life-threatening ventricular arrhythmia

Side effects:

Cardiac arrest & Sudden death

Similar to flecainide but has β-blocking activity

Propafenone

Class II

Beta - blockers

Propranolol

1. ↓ conductivity of AVN→ protect ventricles from fatal high atrial rate.
2. Na⁺ channel block …..> Membrane stabilization.

Uses: (mainly atrial & supraventricular)

1. Sinus tachycardia.
2. Sympathetic induced tachycardia (exercise and emotions).
3. Control ventricular rate in atrial fibrillation.

Esmolol:

Short acting used for intra-operative and acute arrhythmia.

Class III

Amiodarone

Pharmacokinetics:

• Well absorbed orally.
• Extensively bound to plasma proteins & tissues (large Vd).
• Slowly metabolized to active metabolite → long t _½

_{(80 days).}

Amiodarone

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Mechanism of action:

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Class III:

K ⁺ channel blocker.

Class I:

Weak Na ⁺ channel blocker.

Class II:

Weak Beta - blocker.

Class IV:

Weak Ca ⁺⁺ channel blocker

Pharmacological effects:

Cardiac:

• Conduction is slowed and automaticity decreased.
• Myocardial depression and hypotension with IV route.

Extra-Cardiac:

• Change thyroid function.

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Uses:

1. Ventricular and supraventricular arrhythmia.

2. Resistant ventricular tachycardia and Recurrent ventricular fibrillation (most important).

3. Maintain sinus rhythm after failure of other drugs.

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Side effects

• Corneal deposits (opacities).
• Photosensitivity ….. gray blue skin discoloration.
• Thyroid dysfunction.
• Pulmonary fibrosis…. most serious !!!!!
• Hepatotoxicity.
• Oral (GIT upset): Constipation

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Class IV

Verapamil

Verapamil

Dynamics:

• Block L-type Ca⁺⁺ channels so ↓ Ca⁺⁺ dependent depolarization.
• Suppress SA, AV nodal conduction.

Uses:

1. Paroxysmal Supraventricular tachycardia, if no heart failure or hypotension.

Contraindications:

Heart block, heart failure, hypotension.

Kinetics

- Absorption: taken by rapid IV bolus as slow administration eliminate it before reaching the heart.

- Metabolism: Deamination by adenosine deaminase. t½ 10 seconds.

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Mechanism:

• Activate K+ channel in atrium, SA, AV node ( hyperpolarization).
• Bind to adenosine receptors → decrease cAMP.
• When given IV bolus → ↓ A-V conduction.

• Uses:

by rapid IV bolus

(drug of choice in supraventricular arrhythmia)

• Controlled hypotension during some surgery.

• Side effects:
• Bronchospasm
• Heart block
• Hypotension, flushing, headache.

1. Which one of the following is wrongly matched combination of anti-arrhythmic drugs and their class:

1. Mexiletine -IB
2. Verapamil -IV
3. Amiodarone -III
4. Lidocaine -IA

MCQ

1. Which one of the following is wrongly matched combination of anti-arrhythmic drugs and their class:

1. Mexiletine -IB
2. Verapamil -IV
3. Amiodarone -III
4. Lidocaine -IA

2. Lidocaine is useful for the treatment of which of the following disorsers?

A. Atrial fibrillation

B. Paroxysmal supraventricular tachycardia

C. Atrial flutter

D. Digitalis induced ventricular arrhythmia

2. Lidocaine is useful for the treatment of which of the following disorsers?

A. Atrial fibrillation

B. Paroxysmal supraventricular tachycardia

C. Atrial flutter

D. Digitalis induced ventricular arrhythmia

3. A 65-year-old woman admitted to the emergency department with a myocardial infarction developed sustained ventricular tachycardia. Neither amiodarone nor lidocaine was effective, and the cardiologist decided to try another drug that acts mainly by blocking activated Na+ channels and K+ channels. Which of the following drugs was most likely administered?

A. Adenosine

B. Sotalol

C. Verapamil

D. Procainamide

3. A 65-year-old woman admitted to the emergency department with a myocardial infarction developed sustained ventricular tachycardia. Neither amiodarone nor lidocaine was effective, and the cardiologist decided to try another drug that acts mainly by blocking activated Na+ channels and K+ channels. Which of the following drugs was most likely administered?

A. Adenosine

B. Sotalol

C. Verapamil

D. Procainamide

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Thank

you

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