Pharmacology 4 Dr. Khalil Makki. Antiarrhythmic Drugs.

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البشري الطب لجنة

تميزكم دروب تنير رؤية

Pharmacology 4Dr. Khalil Makki

Antiarrhythmic Drugs

Arrhythmias• Abnormalities in impulse formation and conduction

in the myocardium. They are common: • MI(80%), anesthesia(50%),Digitalis(25%). • should be treated if cause poor circulation or

threatened to do so.• All antiarrhythmic drugs are pro-arrhythmic in some

circumstances.• Electrical tt of arrhythmia is becoming more

commonly used.• AF is the most common type, with high risk of

stroke, AC TT is essential.

Types of Cardiac tissues• i.Ordinary myocardial muscle – contraction and

pumping action.• ii.Specialized conducting tissue – cardiac impulse

initiation and determines the order in which the muscle cells contract.

• Automaticity: the capacity of cells to initiate an impulse without an external stimulus – a feature of certain parts of conducting tissue as SAN, AVN & His – purkinje system.

• These pacemaker cells show slow, spontaneous depolarization during diastole Phase 4, (Ca & Na inflow).

SA node AV node

Setting the Membrane Potential

Membrane Potential (mV)

Time (ms)

Depolarization

Repolarization

Fast Sodium Channels

Time (ms)

Phase 0

Potassium Channels

Time (ms)

Phase 1

Partial Repolarization

Voltage-gated Calcium Channels

Time (ms)

Phase 2

Plateau

Potassium Channels

Time (ms)

Phase 3

Repolarization

Na+ - K+ ATPase

Time (ms)

Phase 4

“ Resting “ Membrane Potential

Atria / Ventricles SA / AV Nodes

Phase 0 Phase 3

Phase 4

NO Fast Sodium Channels

SA node AV node

[ Automaticity ]

[ Delay ]

[ Electrical Conduction ]

Classification of Arrhythmia

• According to: site of origin of abnormality: Atrial, Junctional or Ventricular. Rate: Tachicardia or bradicardia.Their diagnosis depends on surface ECG.

Precipitating Factors• Ischemia, Hypoxia, Acid base and Electrolytes

disturbancies.• Autonomic effects.• Drug toxicities as digitalis and even antiarrhythmic

drugs.• Overstretching of cardiac fibers or presence of

scarred or diseased tissues.• However all arrhythmias result from disturbance in

impulse formation and/or conduction.

Re-entry Phenomenum• Normal conduction: the impulse dies out after

activation of the myocardium(?). It is surrounded by refractory tissues.• Re-entry : the impulse re-excites regions of the myocardium after the refractory period has subsided, causing continuous circulation of APs.• It can result from myocardial damage(IHD) or

congenital anamolies.• It is a common cause of many types of arrhytmias.

Classification of Antiarrhythmic Drugs

Vaughan-Williams Classification(1970)Class Mechanism Example

IaIbIc

Na channel blockersIntermediate dissociationfast dissociationSlow dissociation

DisoperamideLidocaineFlecanide

II Beta Blockers Propranolol

III K channel blockers Amiodarone & Sotalol

IV Ca channel blockers Verapamil

OtherV

Digoxin, Adenosine,CaCl, MgCl,Atropine,Epinephrine

&Isoprenaline

[ Vaughan Williams Classification ]

Class I Class IV

Class III

Class II

Class V

β-blockers

?Miscellaneous

Class I Na+

Phase 0

Class I Drugs,Na-blockers(memb. Stabilizing)

• Slow phase 0 depolarization, prolong AP and slow conduction.

• They produce Use dependent channel block i.e. They bind strongly to the open and refractory channels and less strongly to the resting channels. This means, the more frequently the channels are activated, the greater the degree of block produced.

• They block the high frequency excitation of the myocardium with out preventing the heart from beating at normal frequency.

Clinical Uses and ADRs

• Ia, Disopyramide (oral): VA, prevention of recurrent paroxysmal AF.

Has atropine like effects.• Ib, Lidocaine (IV): tt and prevention of VT &VF

during or after MI. CNS ADRs and convulsion.• Ic, Flecainide (oral):prevention of paroxysmal AF

and recurrent tachyarrhythmia. can produce life threatening resistant VT.

Class I Na+

• Slowing of depolarization and conduction.

• Decreased slope of phase 0.

• Widening of the QRS complex.

• Membrane-stabilizing agents.

Class I

1B 1A 1C

Degree of Blockade

Class II drugs

• β- Blockers: Propranolol, Timolol, Atenolol• Inhibit phase 4 depolarization i.e. the pace maker

potential Inhibiting automaticty and prolonging AV conduction & decreasing the HR and contractility.

• Clinical uses and ADRs: 1. Reduce mortality after MI. 2. Prevent recurrence of tachyarrhythmias as

paroxysmal AF provoked by sympathetic over activity.

β- Blockers ADRs

• Increase bronchospasm – asthma.• - ve inotropic effect.• Bradycardia and fatigue.• Sexual dysfunction.• Cold extrimities.

Class II β-blockers

inotropydromotropychronotropy

NEGATIVE

Class II β-blockers

[ Heart RATE-controlling antiarrhythmics ]

Tachyarrhythmias

Post MI prophylaxis

Class III K+

Phase 3

Class III Drugs

• Block K channels, decreasing K out flow during repolarization (phase 3).

• Prolong the duration of AP and the ERP.• Amiodarone: contains I2 ,has a dominant class III

effect and minor I,II and IV effects• Also has antianginal effect.• Sotalol: Class III effect and non selective β- Blocker.

Clinical Uses and ADRs• Amiodarone : In many SV & V

tachyarrhythmias ,which are severe and refractory.• ADRs: GIT upset , pulmonary fibrosis, tremor,

ataxia, diziness, hypo and hyper thyroidism, photosensitivity , hepatotoxicity and blue skin discoloration.

• Satolol: Paroxysmal SVT & V T and V ectopics.• ADRs: very low ,may prolong QT.

Class III K+

Phase 3

• Slowing of repolarization.

• Prolongation of phases 2 and 3.Increased effective refractory period

• QT interval prolongation.

Class III K+

• Iodine-containing thyroxine analog.

• Class I, II, III, and IV pharmacological actions.

• Anti-anginal and antiarrhythmic effects.

Class III K+

Amiodarone

• Oral or Injectable forms.

• Very long half-life (weeks).

• Full clinical effects need 6 weeks without loading doses.

Never start at home!

Class III K+

Amiodarone

• Hypo/hyperthyroid symptoms.

• Nausea.

• Pulmonary Fibrosis (irreversible).

• Liver toxicity.

• Neuropathy.

Class III K+

AmiodaroneS/E

Get baseline:

• CXR.

• PFT.

• TFT.

• LFT.

Class IV Drugs• Ca channel blockers:• Verapamil and Diltiazem, oral.• Slow phase 2 “plateau” ,slow conduction and

prolonging ERP.• They show use dependent block.• Used to:1. Prevent recurrence of paroxysmal SVT

and 2. Reduce ventricular rate in pts with AF and flutter.

3. Hypertension and angina.

Class IV Ca2+Non-dihydropyridinesVerapamil, Diltiazem

inotropy

dromotropyNEGATIVE

AV Nodal Blockade

Class IV Ca2+Non-dihydropyridinesVerapamil, Diltiazem

• Delayed conduction through the AV node.

• Decreased contractility of the heart.

• Prolongation of the PR interval.

Adenosine• Naturally occurring nucleoside.• At high doses: a. Decreases conduction velocity. b. Prolongs RP. c. Decreases the automaticity in AV node

Adenosine• Very rapid onset of action .• Short half- life (seconds)• Given as a rapid I.V. bolus injection

For the acute termination of re-entrant supraventricular tachycardia ( paroxysmal attack) First choice.

ADRs and #s• Bronchospasm, Chest pain. • Shortness of breath.• Flushing of the face.• A-V block.• Hypotension.• #s :Bronchial asthma and A-V block

Others Mg Cl2: Used in:Digitalis induced arrhythmias and

Sinus tachycardia KCl: Digitalis induced arrhythmias. Ca Cl2 :Ventricular tachycardia due to hyperkalemia. Atropine: Sinus bradycardia. Epinephrine : Cardiac arrest. Isoprenaline: Heart block.

Class V Miscellaneous

AV Nodal Blockade

Digoxin

Adenosine

Digoxin• Vagal stimulation.

• Sympathetic downregulation.

• Atrial fibrillation in heart failure patients.

Adenosine• Transient block in AV nodal conduction.

• Significant systemic vasodilation.

Adenosine• Very short half life

15 seconds

• IV injection.Saline Flush

• Acute supraventricular tachycardia.

Adenosine

• Flushing.

• Hypotension.

• Angina-like chest pain.

[ Paroxysmal Atrial Fibrillation ]

Amiodaroneor

Metoprolol

Warfarin

Pharmacology 4 Dr. Khalil Makki. Antiarrhythmic Drugs.

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