antiarrhythmic drugs - drdhriti
DESCRIPTION
A PowerPoint Presentation on Basics of Arrhythmic Disorders and their Drug therapy suitable for study by Undergraduate Students of PharmacologyTRANSCRIPT
Antiarrhythmic DrugsAntiarrhythmic Drugs
Department of PharmacologyDepartment of Pharmacology
NEIGRIHMS, ShillongNEIGRIHMS, Shillong
ContentContent
Physiology of normal cardiac rhythmPhysiology of normal cardiac rhythm Definition and mechanisms of arrhythmiasDefinition and mechanisms of arrhythmias Classification of drugs to treat arrhythmiasClassification of drugs to treat arrhythmias Important anti-arrhythmic drugs Important anti-arrhythmic drugs
(mechanism and pharmacological (mechanism and pharmacological characteristics)characteristics)
Arrhythmias in clinical practiceArrhythmias in clinical practice
Cardiac PhysiologyCardiac Physiology
Recall: to function efficiently, heart needs Recall: to function efficiently, heart needs to contract sequentially (atria, then to contract sequentially (atria, then ventricles) and in synchronicityventricles) and in synchronicity
Relaxation must occur between Relaxation must occur between contractions (not true for other types of contractions (not true for other types of muscle [exhibit tetany muscle [exhibit tetany contract and hold contract and hold contraction for certain length of time]contraction for certain length of time]
Coordination of heartbeat is a result of a Coordination of heartbeat is a result of a complex, coordinated sequence of changes complex, coordinated sequence of changes in membrane potentials and electrical in membrane potentials and electrical discharges in various heart tissuesdischarges in various heart tissues
Cardiac Physiology – Cardiac Physiology – Myocardial CellsMyocardial Cells
2 types2 types – Pacemaker and non – Pacemaker and non pacemakerpacemaker
Pacemaker and conducting Pacemaker and conducting cellscells – SAN, AVN, Bundle of – SAN, AVN, Bundle of His and Purkinje`s fibresHis and Purkinje`s fibres
Non pacemakerNon pacemaker – Working – Working Myocardial Cell (WMC) or CMCMyocardial Cell (WMC) or CMC
Sinus rhythm means rhythm Sinus rhythm means rhythm originates in SANoriginates in SAN
Sinus tachycardia means Sinus tachycardia means tachycardia but rhythm tachycardia but rhythm originates in SAN – fever, originates in SAN – fever, exercise etc.exercise etc.
Tachycardia = heart rate Tachycardia = heart rate > > 100 per minute100 per minute
Bradycardia = heart rate < 60 Bradycardia = heart rate < 60 per min.per min.
Cardiac Electrophysiology Cardiac Electrophysiology
A transmembrane electrical gradient (potential) is A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative maintained, with the interior of the cell negative with respect to outside the cellwith respect to outside the cell
Caused by unequal distribution of ions inside vs. Caused by unequal distribution of ions inside vs. outside celloutside cell Na+ higher outside than inside cellNa+ higher outside than inside cell Ca+ much higher “ “ “ “ Ca+ much higher “ “ “ “ K+ higher inside cell than outsideK+ higher inside cell than outside
Maintenance by ion selective channels, active Maintenance by ion selective channels, active pumps and exchangerspumps and exchangers
Cardiac Action Potential - Cardiac Action Potential - WMCsWMCs
Cardiac Action Potential Cardiac Action Potential
Divided into five phases (0,1,2,3,4)Divided into five phases (0,1,2,3,4) Phase 4Phase 4 - resting phase (resting membrane potential) - resting phase (resting membrane potential)
Phase cardiac cells remain in until stimulatedPhase cardiac cells remain in until stimulated Associated with diastole portion of heart cycle Associated with diastole portion of heart cycle
Addition of current into cardiac muscle (stimulation) causes Addition of current into cardiac muscle (stimulation) causes Phase 0Phase 0 – opening of fast Na channels and rapid – opening of fast Na channels and rapid
depolarization depolarization Drives NaDrives Na++ into cell (inward current), changing membrane into cell (inward current), changing membrane
potentialpotential Transient outward current due to movement of ClTransient outward current due to movement of Cl-- and K and K++
Phase 1Phase 1 – initial rapid repolarization – initial rapid repolarization Closure of the fast NaClosure of the fast Na++ channels channels Phase 0 and 1 together correspond to the R and S waves Phase 0 and 1 together correspond to the R and S waves
of the ECGof the ECG
Cardiac Na+ channelsCardiac Na+ channels
Cardiac Action Potential – Cardiac Action Potential – contd.contd. Phase 2 - plateau phasePhase 2 - plateau phase
sustained by the balance between the inward movement of Ca+ sustained by the balance between the inward movement of Ca+ and outward movement of K+ and outward movement of K+
Has a long duration compared to other nerve and muscle tissueHas a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals (other muscle Normally blocks any premature stimulator signals (other muscle
tissue can accept additional stimulation and increase tissue can accept additional stimulation and increase contractility in a summation effect)contractility in a summation effect)
Corresponds to ST segment of the ECG.Corresponds to ST segment of the ECG.
Phase 3 – repolarization Phase 3 – repolarization K+ channels remain open, K+ channels remain open, Allows K+ to build up outside the cell, causing the cell to Allows K+ to build up outside the cell, causing the cell to
repolarizerepolarize K + channels finally close when membrane potential reaches K + channels finally close when membrane potential reaches
certain levelcertain level Corresponds to T wave on the ECGCorresponds to T wave on the ECG
Cardiac Action Potential – Cardiac Action Potential – Pacemaker CellsPacemaker Cells
• PCs - Slow, continuous depolarization during restSlow depolarization during 0 phase• Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)•Funny current (If)
Cardiac Electrophysiology – Cardiac Electrophysiology – contd.contd.
ECG (EKG) showing wave segments
Contraction of atria
Contraction of ventricles
Repolarization of ventricles
The Normal EKGThe Normal EKG
P
Q
R
S
T
Right Arm
Left Leg
QTPR
0.12-0.2 s approx. 0.44 s
Atrial muscledepolarization
Ventricular muscledepolarization
Ventricular musclerepolarization
Cardiac arrhythmiasCardiac arrhythmias
Cardiac ArrhythmiasCardiac Arrhythmias
Cardiac dysrhythmia (arrhythmia)Cardiac dysrhythmia (arrhythmia) Large and heterogeneous group of conditions in which Large and heterogeneous group of conditions in which
there is abnormal electrical activity in the heartthere is abnormal electrical activity in the heart The hearts too fast or too slow, and may be regular or The hearts too fast or too slow, and may be regular or
irregularirregular Results in rate and/or timing of contraction of heart muscle Results in rate and/or timing of contraction of heart muscle
that is insufficient to maintain normal cardiac output (CO)that is insufficient to maintain normal cardiac output (CO) Result from disorders of impulse formation, Result from disorders of impulse formation,
conduction, or both conduction, or both Causes of arrhythmiasCauses of arrhythmias
Cardiac ischemiaCardiac ischemia Excessive discharge or sensitivity to autonomic transmittersExcessive discharge or sensitivity to autonomic transmitters Exposure to toxic substancesExposure to toxic substances Unknown etiologyUnknown etiology
Cardiac Arrhythmias – Clinical Cardiac Arrhythmias – Clinical ClassificationClassification
Heart rate (increased / decreased)Heart rate (increased / decreased) TachycardiaTachycardia – heart rate fast (>100 beats/min) – heart rate fast (>100 beats/min) BradycardiaBradycardia – heart rate slow (<60 beats/min) – heart rate slow (<60 beats/min)
Heart rhythm (regular/irregular)Heart rhythm (regular/irregular) Site of origin (supraventricular / ventricular)Site of origin (supraventricular / ventricular) Complexes on ECG (narrow/broad)Complexes on ECG (narrow/broad)
PR interval, QRS complex, ST segment or QT PR interval, QRS complex, ST segment or QT complex etc complex etc
Normal Vs Atrial ArrhythmiaNormal Vs Atrial Arrhythmia
Normal RhythmNormal Rhythm Atrial RhythmAtrial Rhythm
Ventricular ArrhythmiaVentricular Arrhythmia
Ventricular arrhythmias are Ventricular arrhythmias are common in most people and common in most people and are usually not a problem are usually not a problem but…but…
VA’s are most common cause VA’s are most common cause of sudden deathof sudden death
Majority of sudden death Majority of sudden death occurs in people with neither occurs in people with neither a previously known heart a previously known heart disease nor history of VA’sdisease nor history of VA’s
Medications which decrease Medications which decrease incidence of VA’s do not incidence of VA’s do not decrease (and may increase) decrease (and may increase) the risk of sudden deaththe risk of sudden death treatment may be worse then treatment may be worse then the disease!the disease!
Cardiac Arrhythmias - MechanismCardiac Arrhythmias - Mechanism
1.1. Enhanced or ectopic pacemaker activityEnhanced or ectopic pacemaker activity Catecholamine over activityCatecholamine over activity Injury current in damaged myocardial cells, Injury current in damaged myocardial cells,
e.g. Myocardial ischemiae.g. Myocardial ischemia2.2. Oscillatory After-depolarizationOscillatory After-depolarization
EAD: depolarization at phase 3 interrupted EAD: depolarization at phase 3 interrupted and MP oscillatesand MP oscillates
DAD: Related to Ca++ current. After DAD: Related to Ca++ current. After attaining RMP premature action potential attaining RMP premature action potential develops, e.g. digitalis toxicitydevelops, e.g. digitalis toxicity
3.3. Reentry PhenomenonReentry Phenomenon
After depolarization – EAD and After depolarization – EAD and DADDAD
Cardiac Arrhythmias - Reentry Cardiac Arrhythmias - Reentry PhenomenonPhenomenon
Probably the cause of most arrhythmiasProbably the cause of most arrhythmias Common abnormality of conduction also called Common abnormality of conduction also called
“circus movement”“circus movement” One impulse reenters and excites areas of heart One impulse reenters and excites areas of heart
more than oncemore than once Path of re-entering impulses may be Path of re-entering impulses may be
small areas of heart (near AV node) small areas of heart (near AV node) Large (atrial or ventricular wall) – atrial and ventricular Large (atrial or ventricular wall) – atrial and ventricular
fibrillationfibrillation Anatomically determined (WPW syndrome) – reentry Anatomically determined (WPW syndrome) – reentry
circuit consists of atrial tissue, AV node, ventricular wall circuit consists of atrial tissue, AV node, ventricular wall and accessory ventricular connection (a bypass tract)and accessory ventricular connection (a bypass tract)
Reentry Phenomenon – Reentry Phenomenon – Functional reentryFunctional reentry
Reentry Phenomenon – Reentry Phenomenon – Accessory pathway (WPW Accessory pathway (WPW
syndrome)syndrome)
Arrhythmia ConditionsArrhythmia Conditions
Extrasystole:Extrasystole: abnormal automaticity/after depolarization abnormal automaticity/after depolarization Paroxysmal Supraventricular Tachycardia:Paroxysmal Supraventricular Tachycardia: 150-200/minute 150-200/minute
(1:1), reentry phenomenon (AV node) (1:1), reentry phenomenon (AV node) Atrial Flutter:Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right 200-350/minute (2:1), reentrant circuit in right
atriumatrium Atrial Fibrillation:Atrial Fibrillation: 350-550/min, electrophysiological 350-550/min, electrophysiological
inhomogenicity of atrial muscles (bag of worms)inhomogenicity of atrial muscles (bag of worms) Ventricular tachycardia:Ventricular tachycardia: 4 or more consecutive extrasystole of 4 or more consecutive extrasystole of
ventriclesventricles Ventricular Fibrillation:Ventricular Fibrillation: rapid irregular contractions – fatal (MI, rapid irregular contractions – fatal (MI,
electrocution)electrocution) Torsades de pointes:Torsades de pointes: polymorphic ventricular tachycardia, polymorphic ventricular tachycardia,
rapid asynchronous complexes, rise and fall in baseline of rapid asynchronous complexes, rise and fall in baseline of ECG ECG
Atrio-ventricular Block (A-V Block):Atrio-ventricular Block (A-V Block): vagal influence or vagal influence or ischaemia - 1st, 2ischaemia - 1st, 2ndnd and 3 and 3rdrd degree degree
Antiarrhythmic DrugsAntiarrhythmic Drugs
Biggest problemBiggest problem – antiarrhythmics can cause – antiarrhythmics can cause arrhythmia!arrhythmia! Example: Treatment of a non-life threatening Example: Treatment of a non-life threatening
tachycardia may cause fatal ventricular arrhythmiatachycardia may cause fatal ventricular arrhythmia Must be vigilant in determining dosing, blood levels, and Must be vigilant in determining dosing, blood levels, and
in follow-up when prescribing antiarrhythmicsin follow-up when prescribing antiarrhythmics Mechanism of action:Mechanism of action:
Sodium channel blockadeSodium channel blockade Blockade of sympathetic autonomic effectsBlockade of sympathetic autonomic effects Blockade of Effective Refractory Period (ERP) – increase Blockade of Effective Refractory Period (ERP) – increase
ERP/APD ratioERP/APD ratio Calcium Channel BlockadeCalcium Channel Blockade
Antiarrhythmic DrugsAntiarrhythmic Drugs
Vaugham-Williams classification:
• Class I – Na+ Channel Blockers• Class II - Beta-adrenergic Blockers• Class III – Prolong Repolarization• Class IV – Calcium Channel Blocker
Class I - antiarrhythmicsClass I - antiarrhythmics
Class IA Class IB Class IC
Class I antiarrhythmics are further classified to IA, IB and IC
QuinidineProcainamideDisopyramide
LidocainePhenytoin
FlecainidePropafenone
Subclass – I A
Lengthen action potential Slow rate of rise of phase 0 Prolong repolarization Prolong refractoriness by blocking several
types of potassium channel Prolong PR, QRS, QT Moderate-marked sodium channel
blockade in Open state E.g, quinidine, procainamide, disopyramide
Shorten action potential Limited effect on rate of rise of phase 0 Shorten repolarization Shorten QT Raise fibrillation threshold in ventricular
tissues Mild-moderate sodium channel blockade Little effect on refractoriness since there is
essentially no blockade of potassium channels E.g, lignocaine, mexilitine, phenytoin,
propafenone
Subclass - IBSubclass - IB
Subclass – IC
No effect on length of action potential Markedly reduces rate of rise of phase 0 Little effect on repolarization Markedly prolongs PR and QRS Refractory period of AV node is increased Marked Na+ channel blockade Prolong refractoriness by blocking outward-
rectifying potassium channels Used in life threatening ventricular fibrillation
since they have highest affinity to Na+ channels E.g, flecainide
Antiarrhythmic Drugs - Antiarrhythmic Drugs - QuinidineQuinidine Dextroisomer of Quinine: N+ channel blocking and antivagal Dextroisomer of Quinine: N+ channel blocking and antivagal
actionaction Actions: Actions:
Inhibition of Na channel – slanted O phase and Decreases phase 4Inhibition of Na channel – slanted O phase and Decreases phase 4 Net result is delay in conductivity and increase in refractorinessNet result is delay in conductivity and increase in refractoriness Other actions include – alpha blockade, decreased skeletal muscle Other actions include – alpha blockade, decreased skeletal muscle
contractility, vomiting and diarrhoea etc contractility, vomiting and diarrhoea etc Kinetics: well absorbed orally, half life – 10 HrsKinetics: well absorbed orally, half life – 10 Hrs Uses: Uses:
Broad spectrum antiarrhythmic Broad spectrum antiarrhythmic Atrial fibrillation and flutter, AF after direct current cardioversion to Atrial fibrillation and flutter, AF after direct current cardioversion to
maintain sinus rhythm, prevention of PSVT and prevention of maintain sinus rhythm, prevention of PSVT and prevention of ventricular tachycardiaventricular tachycardia
Adverse effects: Not used now for adverse effects like Adverse effects: Not used now for adverse effects like Proarrhythmia (torsades de pointes), sudden cardiac arrest, Proarrhythmia (torsades de pointes), sudden cardiac arrest, cinchonism etc.cinchonism etc.
Antiarrhythmic Drugs - Antiarrhythmic Drugs - ProcainamideProcainamide
Procaine derivative (amide) Identical action with quinidine except:
Minimal antivagal action Lesser suppression of ectopic automaticity Lesser depression of automaticity and AV conduction No alpha blocking action
Kinetics: Absorbed orally and bioavailability is 80% Metabolized in liver to N-acetyl-procainamide (NAPA) – blocks K
channel and prolongs repolarization Dosage – 250 mg tabs and 1gm/ml injections
Antiarrhythmic – 0.5 to 1 gm oral followed by 0.25-0.50 mg every 2 Hrs
Uses: Mainly for monomorphic VTs and to prevent recurrences
Antiarrhythmic Drugs - Antiarrhythmic Drugs - LidocaineLidocaine
Popular antiarrhythmic and also local anaesthetic Actions:
Suppression of automaticity in ectopic foci Slowing of O phase and shortening of phase 3 of CMC and PF No action on SAN and AVN Reduction in APD in ventricular myocardium Suppression of reentry – ventricular
Kinetics: Ineffective orally, given IV lasts for 10-20 minutes. Therefore given as IV bolus 50-100 mg followed by 20-40 mg every 10-20 minutes
Adverse effects: Neurological – drowsiness, paresthesia, blurred vision, nystagmus and fits etc.
Uses: 1st line of drug in Arrhythmia following acute MI and cardiac surgery Prevention of ventricular tachycardia Digitalis toxicity
Class II Antiarrhythmics
They act indirectly on Electrophysiology – by blocking beta-adrenergic receptor, prolong PR interval, but no effects on QRS or QT interval – adrenergically mediated activity
Drugs used are beta-blockers:Propranolol, Sotalol, Esmolol and Acebutlol
Class II – contd.
Block beta-1 receptor in heart and decreases heart rate Adrenline causes ventricular extrasystole and fibrillation by
increasing the slope of phase 4 depolarization Also increases spontaneous firing of SA node
AV conductions also needs sympathetic activity – Beta blockers prevent these activity
Uses: Reduce mortality after MI Arrhythmias associated with increased sympathetic activity –
sinus tachycardia, atrial extrasystoles provoked by emotion and exercise
Less effective in PSVT than adenosine and verapamil Propranolol is used to treat sympathetically mediated
arrhythmias - phaeochromocytoma and halothane anaesthesia
Class III Antiarrhythmics Class III drugs K channel blockers prolong
repolarization (increase refractoriness) by blocking outward potassium conductance Prolongation of Cardiac action potential Also have interaction with the ANS Diverse Pharmacology which is poorly
understood Drugs – Ibutilide, dofetilide, sotalol (II + III
action), amiodarone and bretylium Bretylium is used only in life threatening
arrhythmias
Class III - Amiodarone
MOA: Long acting and highly lipophillic Weak class I, II (beta- blocker) and class IV actions Depresses automaticity of SA and AVN Also non-competitive alpha and beta blocking property Also direct coronray and peripheral vasodiltorKinetics: Incompletely and slowly absorbed – daily oral dose is
give for several days for actions tto develop, t1/2 = 3-8 weeks
Dose: 400-600 mg/day p.o for many days followed by 100-200 mg/day as maintenance (100-300 mg slow IV)
Uses: Most tachyarrhythmic conditions – ventricular and
supraventricular Recurrent VT and VF WPW syndrome
Amiodarone
Adverse effects: Photosensitization Peripheral neuropathy Myocardial depression – bradycardia Pulmonary alveolitis and fibrosis Cornel micro deposits hypothyroidism
Class IV - Antiarrhythmics
Relatively selective AV nodal L-type calcium channel blockers – slow sinus rhythm, prolong PR interval, no effect on QRS complex
(Verapamil, diltiazem and bepridil)
Sinus Bradycardia – SA node and PF AV block – no rentry Negative ionotropic effect – interference with Ca++ mediated
contraction MOA:
Block L-type channels – Phase 4 depolarization of SA and PF reduced
Reduce slow inward current and force of contraction Also slow conduction of AV node due to calcium channel blockade
Class IV – contd.
Uses: Verapamil PSVT:
For termination of attack – 5 mg IV over 2-3 minutes (reflex bradycardia)
For prevention of attack 60-120 mg orally tds
Reduce ventricular rate in Atrial fibrillation (AF)
Miscellaneous Agents
Compounds whose actions do not fit the standard four classes – digoxine, adenosine and alinilide (a chloride channel blocker)
Adenosine: Endogenously produced important chemical
mediator used in PSVT MOA:
Activation of Ach sensitive K+ channel - membrane hyper polarization of SA node (G-protein coupled adenosine receptor) – depression of SA node and also slowing of AV conduction and shortening of action potential in atrium
Also indirectly reduces CA++ current in AV node – depression of reentry in PSVT
Adenosine – contd.
Very short half life – 20-30 sec. - Uptake by RBCs and endothelial cells
Administered intravenously 6 mg given as a rapid intravenous bolus
(administered over a 1-2 second period) If the first dose does not result in elimination of
the supraventricular tachycardia within 1-2 minutes - 12 mg should be given as a rapid intravenous bolus
ADR: chest tightness, dyspnoea, fall in BP and flushing etc.
SummarySummary
Anti-arrhythmic drugs are classified by their effect on the Anti-arrhythmic drugs are classified by their effect on the cardiac action potentialcardiac action potential
An ideal antiarrhythmic drug should target ectopic An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissues to a greater pacemakers and rapidly depolarizing tissues to a greater extent than normal tissues of the heartextent than normal tissues of the heart
Many of the Na and Ca channel blockers have this property Many of the Na and Ca channel blockers have this property because they preferentially block sodium and calcium because they preferentially block sodium and calcium channels in the depolarized tissueschannels in the depolarized tissues
Most of the drugs exhibit mixed actionMost of the drugs exhibit mixed action In clinical practice treatment of arrhythmias is determined In clinical practice treatment of arrhythmias is determined
by the type of arrhythmia (SVT, VT) and clinical condition of by the type of arrhythmia (SVT, VT) and clinical condition of the patientthe patient
Anti-arrhythmic drugs are efficacious but may have serious Anti-arrhythmic drugs are efficacious but may have serious adverse effectsadverse effects
Not all arrhythmias are treated with drug therapy aloneNot all arrhythmias are treated with drug therapy alone
Non-pharmacological Non-pharmacological treatmenttreatment
AcuteAcute Vagal manoeuvresVagal manoeuvres DC cardioversionDC cardioversion
ProphylaxisProphylaxis Radiofrequency ablationRadiofrequency ablation Implantable defibrillatorImplantable defibrillator
Pacing (external, temporary, Pacing (external, temporary, permanent)permanent)
PacemakersPacemakers
Surgical implantation of electrical leads attached to a pulse generator
1) Leads are inserted via subclavian vein and advanced to the chambers on the vena cava (right) side of the heart
2) Two leads used, one for right atrium, other for right ventricle3) Pulse generator containing microcircuitry and battery are
attached to leads and placed into a “pocket” under the skin near the clavicle
4) Pulse generator sends signal down leads in programmed sequence to contract atria, then ventricles
Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed.
Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia
The PacemakerThe Pacemaker
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