Pharmacology 4 Dr. Khalil Makki. Antiarrhythmic Drugs.
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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.
Transcript of Pharmacology 4 Dr. Khalil Makki. Antiarrhythmic Drugs.
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)
0
+ 30
- 30
- 60
- 90
Depolarization
Repolarization
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Fast Sodium Channels
Time (ms)
Phase 0
Na+
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Potassium Channels
Time (ms)
Na+
Phase 1
K+
Partial Repolarization
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Voltage-gated Calcium Channels
Time (ms)
Na+
Phase 2
K+
Plateau
Ca2+
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Potassium Channels
Time (ms)
Na+
Phase 3
K+
Repolarization
Ca2+
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Na+ - K+ ATPase
Time (ms)
Phase 4
“ Resting “ Membrane Potential
Na+
K+
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
Membrane Potential (mV)
0
+ 30
- 30
- 60
- 90
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
Na+
K+
Ca2+
[ Vaughan Williams Classification ]
1970
Na+
K+
Ca2+
Class I Class IV
Class III
Class II
Class V
β-blockers
?Miscellaneous
Class I Na+
0
+ 30
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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
Na+
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
β1
inotropydromotropychronotropy
NEGATIVE
Class II β-blockers
[ Heart RATE-controlling antiarrhythmics ]
Tachyarrhythmias
Post MI prophylaxis
Class III K+
0
+ 30
- 30
- 60
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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+
0
+ 30
- 30
- 60
- 90
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
?
Class V Miscellaneous
Digoxin• Vagal stimulation.
• Sympathetic downregulation.
• Atrial fibrillation in heart failure patients.
Class V Miscellaneous
Adenosine• Transient block in AV nodal conduction.
• Significant systemic vasodilation.
Class V Miscellaneous
Adenosine• Very short half life
15 seconds
• IV injection.Saline Flush
• Acute supraventricular tachycardia.
Class V Miscellaneous
Adenosine
• Flushing.
• Hypotension.
• Angina-like chest pain.
S/E
[ Paroxysmal Atrial Fibrillation ]
Amiodaroneor
Metoprolol
+
Warfarin
