Antiarrhythmic drugs


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pharmacotherapy of arrhythmias

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  • Deviation from the normal pattern of cardiac rhythmMay occur when there is disturbance in initiation or conduction of cardiac impulse Range from asymptomatic to life threatening
  • Non automatic fibres: these are ordinary working myocardial fibres, cannot generate the impulse of their own, during diastole RMP remains stable -90mV inside. When stimulated they depolarize rapidly (Fast phase-0) with considerable overshoot (+30mV), rapid return to near isoelectric level 0mV (Phase-1), maintenance of membrane potential at this level for a considerable period of time (Phase-2) plateau phase during which calcium ions flow in and bring about contraction, then relatively rapid repolarization (Phase-3) mainly by continued extrusion of potassium via potassium channel, phase 4 resting phase, in this phase the final ionic reconstitution of cell is achieved by na-k+ exchange pump which actively pushes Na+ out of cell and K+ into the cell. The resting membrane potential once attained doesnot decay (stable- phase4). Automatic fibres: they are present in SA node, AV node and his-purkinje system. i.e the specialized conducting tissue(in addition patches are present around interatrial septum, A-V ring and around openings of great veins. The most charecteristic feature of these fibres is the phae 4 or slow diastolic depolarization i.e after repolarizing to the maximum value membrane potential decays spontaneously when it reaches a critical threshold value –sudden depolariztion occurs automatically . Thus they are capable of generating their own impulse. The rate of impulse generation by a particular fibre depends upon the value of maximum diastolic potential , slope of phase 4 depolarization and value of threshold potential . Why SA node acts as pacemaker: SA node has steepest phase-4 depolarization undergoes self excitation and propogates the implse to the rest of the heart- acts a pacemaker. Other fibres which also undergo phase 4 depolarization but at a slower rate receive propogatedimpulsebefore reaching threshold valueand remain as latent pacemakers.
  • RMP IS -90 MVCardiac boundedby a lipoprotein membrane which has receptor channels crossing itWHEN AN ATRIAL OR VENTRICULAR CELL RECIEVES An action potential it starts depolarising in response to it..and sodium starts entering itIntracellular negativity starts diminishingWhen such depolarisation reaches a threshold potential, the sodium channels open abruptlyNa enters cell in large quantitiesCELL MEMBRANE ACTION POTENTIAL CHANGES FROM -90 TO ALMOST +30MVPhase 0: rapid depolarisation…fast selective inflow of na ionsDuring latter part, ca ions also enter the cell via na channels Frther in phase 1 and 2 ca ions enter thru slow ca channelsTHE CONFORMATION OF THE SODIUM CHANNELS HENCE CHANGES TO INACTIVE STATEThe ca which enters the cell in dis manner causes release of ca from sarcoplasmicreticulumraising the conc of ca within the cellsThis intracellular free ca interacts with actinmyocin system and causes contraction of heartAfetr this, phase 1: short rapid repolarisation due to beginning of outflow of potassium and entry of cloride ions into the cells, MEMBRANE CHARGE CHANGES FROM +30 TO ALMOST 0 MV IN VERY SHORT TIMEPhase 2 : prolonged plateau phase.. Balance bw ca enterin the cell and k leavin the cell..VOLTAGE SENSITIVE SLOW l type CA CHANNELS OPEN …SLOW INWARD CA CURRENT BALANCED BY SLOW OUTWARD K CURRENT..DEPOLARISATION = REPOLARISATIONPhase 3 : rapid repolarisation.. CA CHANNELS CLOSE…K CHANNELS OPEN..Contimued extrusion of k…RESUMES INITIAL NEGATIVITYFROM PHASE 0 TO 3 THERE HAS BEEN A GAIN OF NA AND A LOSS OF K ..THIS IS NOW REVERTED AND BALANCED BY NA K ATPASEPhase 4: resting phase..ELECTRICALLY STABLE… Ionic reconstitution of cell is reachieved by na k exchange pumpRMP MAINTAINED BY OUTWARD K LEAK CURRENTS AND NA CA EXCHANGERSThe cycle is then repeatedInactivation gates of sodium channels in resting membranes close over the potential range of -75 to -55mvCardiac sodium channel protein shows 3 different conformationsDepolarisation to threshold voltage results in opening of the activation gates of sodium channel thus causing markerdly increased sodium permeabilityBrief intense sodium current , conductance of fast sodium channel suddenly increases in response to depolarisingstimulUsVery large influx of na accounts for phase 0 depolarisationClusure of inactivation gates resultRemain inactivated till mid phase 3 to permit a new propagated response to external stimulus…refractory period..Cardiac calcium channels are L typePhase 1 and 2 : turning off nodium current, waxing and waning of calcium curent, slow development of repolarising potassium current, calcium enters ..potassium leaves..Phase 3: complete inactivation of sodium and calcium currents and full opening of potassium 2 types of main potassium currents involved in phase 3 : ikr and iksCertain potassium channels are open at rest also…”inward rectifier” channelsIn addition there are 2 energy requiring exchange pumps in cardiac myocyte cell membrane…na k exchange pump…and andna-ca exchange pumpNormally na ions concentrated extracellularly and vice versa for k cionsThus have a tendency odf diffusion along concentration gradientThis diffusion is opposed by na k pumpThis pump operates contimuously and does not switch on and off during action potential of cardiac cells
  • Action potential in automatic tissuesless negative resting membrane potential ,Maximum diastolic potential lies near -60 mvslow diastolic depolarization (phase 4), which generates an action potential as the membrane voltage reaches thresholdaction potential upstrokes (phase 0) are slow(mediated by calcium rather than sodium current)Action potential is longerConduction velocity is slow, Refractory period longerLess overshoot low amplitude RMP not stable and full repolarisation at -60mVPhase 1 2 3 indistinguishable Spontaneous Depolarisation occurs due to: Slow, inward Ca2+ currents Slow, inward Na+ currents called “Funny Currents”Ca influx and not of na dominates the depolarisation and is largely responsible for initiation and propagation of apThus cardiac automaticity is decreased by calcium channel blockers in case of slow channel AP Steeper the diastolic depolarisation, higher is the pacemaker rateSA node has the steepest phase 4 depolarisationOther nodal cells can become pacemakers when their own intrinsic rate of depolarisation is greater than SA node(latent pacemakers)In all pacemaker cells, the outward potassium current during phase 4 is smaller, which keeps the cell with automaticity in a less negative potential (near depolarisation state -60mv).The depolarising inward calcium currents are large enough to gradually depolarise the cell during diastoleVagal discharge and beta blockers slow the phase 4 slopeTachycardia is caused by increased paceamkers discharge ..due to increased phase 4 slope..reasons may be: hypokalemia, beta stimulation, positive chronotropic drugs, fibrestrech, acidosis, partial depolarisation by currents of injury
  • Coronary sinus opening also ERP< APD in fast channel, ERP> APD in slow channel , slow channel AP can occur in purkinjefibres also, but it has much longer duration with prominent plateu phase.
  • In normal heart automaticity is maximum in SA node (Pacemaker). In diseased heart, other areas of myocardium may may develop automaticity and become focus of ectopic impulse generation and arrhythmias. Excitability: can be conceived in terms of minimum intensity of stimulus required to depolarize the cell membrane. It depends upon the level of resting(diastolic) intracellular negativity, if negeativity decreases eg from -90mV TO -70mV excitability of cell increases. Threshold potential: if threshold potential is raised changed from -70 to -60 mV Automaticity of tissue is supressed.
  • A drug which reduces phase zero slope(at any given RMP) will shift membrane responsiveness curve to right and impede the conduction. Reverse occurs if a drug shifts curve to left. Normally purkinjefibres have highest conduction velocity 4000 mm/sec
  • Protective mechanism and keeps the heart rate in check, prevents arrhythmias and coordinates muscle contractionIt extends from phase 0 uptill sufficient recovery of Na channels. Divided into:
  • Ectopic pacemaker activity is encouraged by Faster phase 4 depolarization due to ishemiaLess negative resting membrane potential More negative threshold potential due to ishemia
  • After depolarizations are secondary depolarizations accompanying normal or premature action potentials. Early AfterdepolarizationPhase 3 of repolarization interruptedResult from inhibition of Delayed Rectifier K+ CurrentMarked prolongation of Action PotentialSlow heart rate, ↓ Extracellular K+, Drugs prolonging APDDEPRESSION OF DELAYED RECTIFIER POTASSIUM CURRENTREPOLARISATION DURING PHASE 3 IS INTERRUPTEDMEMBRANE POTENTIAL OSSILATESMarkedly prolongs cardiac repolarisation…development of polymorphic ventricular tachycardia…with long qt interval…known as torsades de pointes syndrome..Some drugs may give rise to ead..and thus torsades..If amplitude of these ossilations is sufficiently large..neighbouring tissue is activated..series of impulses are propagatedThus slow repolarisationLong APAssociated with long QT intervalProminent among the factors that modulate phase 4 is autonomic nervous system tone. The negative chronotropic effect of activation of the parasympathetic nervous system is the result of release of acetylcholine that binds to muscarinic receptors, releasing G protein subunits that activate a potassium current (IKACh) in nodal and atrial cells. The resulting increase in K+ conductance opposes membrane depolarization, slowing the rate of rise of phase 4 of the action potential. Conversely, augmentation of sympathetic nervous system tone increases myocardial catecholamine concentrations, which activate both and receptors. The effect of 1-adrenergic stimulation predominates in pacemaking cells, augmenting both L-type Ca current (ICa-L) and If, thus increasing the slope of phase 4. Enhanced sympathetic nervous system activity can dramatically increase the rate of firing of SA nodal cells, producing sinus tachycardia with rates >200 beats/min. By contrast, the increased rate of firing of Purkinje cells is more limited, rarely producing ventricular tachyarrhythmias >120 beats/min.abnormal impulse formation is due to the development of triggered activity. Triggered activity is related to cellular afterdepolarizations that occur at the end of the action potential, during phase 3, and are referred to as early afterdepolarizations, or they occur after the action potential, during phase 4, and are referred to as late afterdepolarizations. Afterdepolarizations are attributable to an increase in intracellular calcium accumulation. If sufficient afterdepolarization amplitude is achieved, repeated myocardial depolarization and a tachycardic response can occur. Early afterdepolarizations may be responsible for the VPCs that trigger the polymorphic ventricular arrhythmia known as torsades des pointes (TDP). Late afterdepolarizations are thought to be responsible for atrial, junctional, and fascicular tachyarrhythmias caused by digoxin toxicity and also appear to be the basis for catecholamine-sensitive VT originating in the outflow tract. In contrast to automatic tachycardias, tachycardias due to triggered activity (Fig. 226-2B ) can frequently be provoked with pacing maneuvers.
  • Late AfterdepolarizationsSecondary deflection after attaining RMPIncreased intracellular Ca2+ overloadAdrenergic stress, digitalis intoxication, ischemia-reperfusionAFTRE attaining Resting membrane potential, a secondary deflection occurs..If this reaches threshold initiates a single premature APGENERALLY OCCURS FROM CALCIUM OVERLOAD..digitalis toxicity..ischaemia reperfusion
  • Requirements for a reentry circuitPresence of an anatomically defined circuitHeterogeneity in refractoriness among regions in the circuitSlow conduction In one part of circuitReentry is underlying mechanism for premature beats, paroxysmal supraventricular tachycardia, atrial flutter, ventricular fibrillation
  • Anatomically defined re-entrnt pathway , patients have accesory pathway known as bundle of kent
  • Surprisingly few mechanisms of antiarythmic actionIn general these drugs have these action..they act by altering..Rate of phase 0 depolarisationSlope of phase 0 depolarisation..blocks reentrant impulses…quinidine, procainamide, disopyramide, lignocaine and verapamilposess this actionIncreasing the effective refractory period..thus duration of action potential..and blocking reentrant impulses…quinidine, procainamide, propanolol and potassium posess this actionMaking the resting membrane potential even more negative and decreasing the slope of phase 4..thus supressing automaticity…this action is shown by all antiarrythmic drugs….it supresses the enhanced automaticity of ectopic foci ..examples are lignocaine and phenytoinMaking the threshold potential less negative i.e. shifting it towards 0…again supresses enhanced automaticity of ectopic focii..quinidine..procainamide, propanolol and potassium posess this actionIn general, altering the na and ca channels, alter the threshold potential and altering the potassium channels will alter the length of refractory period and thus duration of action potential
  • ↓ Automaticity ↓ Excitability↓ Conduction velocity Refractory period Direct action : prolonged in all cardiac tissues Vagolytic action : Atria: ↑AV node : ↓Ventricles : unaltered Over all : ↑ atrial , ↑ ventricular, ↓ AV node Contractility BPECG ExtracardiacDepresses skeletal muscle Quinine like antimalarial , antipyretic and oxytocic action
  • Prominent cardiac depressant and antivagal action Use: second line drug for preventing recurrences of ventricular arrhythmia No affect on sinus rate due to opposing actions Can also cause mental depression, erectile dysfunction, and hypotension
  • 50 % EXCRETED UNCHANGED IN URINEAlso discuss about procaine
  • Class Ib drug blocks sodium channels more in inactivated state than open state but do not delay the channel recovery they do not deprss AV condcution or prolong APD Even shorten Than with long APD ( Na + channels remain inactivated for long period of time Normal ventricular fibres are minmally affected , depolarized damaged fibres are significantly depressed Brevity of AP and lack of lidocaine effect on channel recovery may explain its inefficacy in atrial arrhythmias No significant hemodynamic effectNo significant autonomic actions
  • IV preparation must not contain preservative , symapthomimetic or vasoconstrictor1-3 mg/min infusion Clinical Pharmacokinetics High first pass metabolism half-life 1–2 hoursa loading dose of 150–200 mg administered over about 15 minutes should be followed by a maintenance infusion of 2–4 mg/min
  • 400 mg loading dose then 200 mg 8hrlyContraindicated in patients with AV block as it may accelerate AV block 450- 750 mg of mexiletine orally per day provides significant relief in diabetic neuropathy
  • Although uses are similar to lidocaine3:1000Can also cause nausea, dizziness, paraesthesia, numbness
  • Can precipitate CHF by depressing AV CONDUCTION and ALSO CAN CAUSE bronchospasm. Dose = 200 mg tdsMorcizine has properties of all 3 classes but as it prolongs qrs it has been placed along with class Ic drugs
  • Usual dose = 100- 200 mg bd orally how ever these drugs are proarrhythmic even when normal doses are administered to patients with sick sinus syndrome pre exixting ventricular tachyarrhythmia, ventricular ectopy or previous MI Currently reserved for life threatening refractory ventricular arrhythmias who do not have CORONARY ATRETY DISEASE. LIKELY HOOD OF DEVELOPING TORSADES DE POINTES IIS SERIOUS DRAWBACK OF THESE DRUGS, OTHER ADVERSE EFFECTS INCLUDE VISUAL DISTURBANCES , DIZZINESS, NAUSEA AND HEADACHE.
  • Beta receptor stimulation causes increased automaticity, steeper phase 4, Increased AV conduction velocity and decreased refractory period Beta adrenergic blockers competitively block catecholamine induced stimulation of cariac beta receptors, slow
  • Slow sinus as well as av nodal conduction which results in decrease in HR and increase PR atrial depolarization, QT and QRS are not significantly altered.
  • Propranolol, acebutololesmolol have been aprroved for antiarrhythmic use
  • Class III drugs block outward K+ channels during phase III of action potential These drugs prolong the duration of action potential without without affecting phase 0 of action potential or resting membrane potential they instead prolong ERP
  • HENCE IT DECREASES HEART RATE AS WELL AS av conduction, better efficacy with lower risk of development of Torsades de pointes
  • Many drug interactions
  • Bretylium became obsolete because of poor bioavailability and development of tolerance, reintroduced as antiarrhythmic for parenteral use. Main adverse effect is postural hypotension , nausea, vomiting . Long term use may result in swelling of parotid gland particularly at meal time. It is contraindicated in digitalis induced arrhythmias and cardiogenic shock.
  • Dronaderone: amiodarone like drug without iodine atoms so no pulmonary or thyroid toxicity. Has shorter half life 1-2 days compared to months Vernakalant mixed sodium and potassium channel blocker Azimilide: blocks rapid and slow components of potassium channels low incidence of torsades de pointes Tedisamil:
  • Antiarrhythmic drugs

    1. 1. Antiarrhythmic drugs
    2. 2. Antiarrhythmics ???? – In a textbook  Interesting but sedative. • Try it if you have insomnia –In the lecture  Confusion ?????????? • As always –In the exam hall  Panic! • Don’t worry rarely asked
    3. 3. • A-RHYTHM –IA • Defn- Arrhythmia is deviation of heart from normal RHYTHM. • RHYTHM 1) HR- 60-100 2) Should origin from SAN 3) Cardiac impulse should propagate through normal conduction pathway with normal velocity.
    5. 5. 100 60 Normal range 150 Simple tachyarrythmia 200 Paroxysmal TA 350 Atrial flutter . 500 Atrial fibrillation 40 Mild bradyarrhythmias 20 moderate BA Severe BA
    6. 6. ARRHYTHMIAS Sinus arrythmia Atrial arrhythmia Nodal arrhythmia (junctional) Ventricular arrhytmia SVT
    7. 7. Electrophysiology of cardiac tissue • Impulse generation and transmission • Myocardial action potential • Depolarization and repolarization waves as seen in ECG
    8. 8. Types of cardiac tissue (on the basis of impulse generation) • AUTOMATIC/ PACEMAKER/ CONDUCTING FIBRES (Ca++ driven tissues) Includes SA node, AV node, bundle of His, Purkinje fibres Capable of generating their own impulse Normally SA node acts as Pacemaker of heart • NON-AUTOMATIC MYOCARDIAL CONTRACTILE FIBRES (Na+ driven tissues) Cannot generate own impulse Includes atria and ventricles
    9. 9. Impulse generation and transmission
    10. 10. Myocardial action potential In automatic tissues In non-automatic tissues
    11. 11. Action potential in Non automatic myocardial contractile tissue
    12. 12. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ K+ Na+ Phase zero depolarization Early repolarization Plateau phase Rapid Repolarization phase Phase 4 depolarization
    13. 13. Action potential in nodal tissues
    14. 14. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ K+
    15. 15. Fast channel Vs slow channel AP Fast channel AP • Occurs in atria, ventricles, PF • Predominant ion in phase-0 is Na+ • Conduction velocity more • Selective channel blocker is tetradotoxin , LA Slow channel AP • Occurs in SA node, A-V node • Predominant ion in phase-0 is Ca2+ • Less • Selective channel blockers are calcium channel blockers
    16. 16. Common terms • Automaticity – Capacity of a cell to undergo spontaneous diastolic depolarization • Excitability – Ability of a cell to respond to external stimulus by depolariztion • Threshold potential – Level of intracellular negativity at which abrupt and complete depolarization occurs
    17. 17. Common terms • Conduction velocity of impulse – Determined primarily by slope of action potential and amplitude of phase-0, any reduction in slope leads to depression of conduction • Propagation of impulse – Depends on ERP & Conduction velocity
    18. 18. Refractory period
    19. 19. Depolarization & Repolarization waves seen in ECG
    20. 20. ECG is used as a rough guide to some cellular properties of cardiac tissue • P wave: atrial depolarization • PR-Interval reflects AV nodal conduction time • QRS DURATION reflects conduction time in ventricles • T-wave: ventricular repolarization • QT interval is a measure of ventricular APD
    21. 21. Mechanisms of cardiac arrythmia • Abnormal impulse generation: • Depressed automaticity • Enhanced automaticity • Triggered activity (after depolarization): • Delayed after depolarization • Early after depolarization • Abnormal impulse conduction: • Conduction block • Re-entry phenomenon • Accessory tract pathways
    22. 22. a) Enhanced automaticity Automatic behavior in sites ordinarily lacking pacemaker activity CAUSES: Ischaemia/digitalis/catecholamines/acidosis/ hypokalemia/stretching of cardiac cells Nonpacemaker nodal tissues: membrane potential comes to -60mv Increased slope of phase 4 depolarisation Become ECTOPIC PACEMAKERS.(AV nodal rhythm, idioventricular rhythm, ectopic beats)
    23. 23. Less negative RMP More negative TP Ectopic pacemaker activity encouraged by
    24. 24. b) Trigerred automaticity +30 mV 0 mV -80 mV -90 mV
    25. 25. b) Trigerred automaticity +30 mV 0 mV -80 mV -90 mV Intracellular cal. Overload (Ischemia reperfusion, adr.stress, digitalis intoxication or heart failure)
    26. 26. c. Abnormal impulse conduction • Conduction block – First degree block – Second degree block – Third degree block • Re-entry phenomenon • Accessory tract pathways
    27. 27. INEXCITABLE TISSUE Re-entry 1 2
    28. 28. Re-entry
    29. 29. Counterclockwise right atrial reentry LA is passively activated
    30. 30. Requirements for re-entry circuit • Presence of anatomically defined circuit • Region of unidirectional block • Re-entry impulse with slow conduction
    31. 31. Anatomical: Wolff- Parkinson-White syndrome Functional: Fibrillation Accessory tract pathways
    32. 32. WPW: Initiation of SVT Supraventricular tachycardia • initiated by a closely coupled premature atrial complex (PAC) • blocks in the accessory pathway • but conducts through the AV node • retrograde conduction via accessory pathway • inverted P wave produced by retrograde conduction visible in the inferior ECG leads
    33. 33. Regulation by autonomic tone Parasympathetic/Vagus Nerve stimulation: • Ach binds to M2 receptors • Activate Ach dependent outward K+ conductance (thus hyperpolarisation) • ↓ phase 4 AP Sympathetic stimulation: • Activation of β1 receptors • Augmentation of L-type Ca2+ current • Phase 4 AP more steeper
    34. 34. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ Na+ Ca++ K+ RATE SLOPE Effective Refractory Period RMP THRESHOLD POTENTIAL Possible MOA of antiarrythmic agents
    35. 35. Classification of Anti-Arrhythmic Drugs (Vaughan-Williams-Singh..1969) Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV - 80m V II I III IV Class I: block Na+ channels Ia (quinidine, procainamide, disopyramide) (1-10s) Ib (lignocaine) (<1s) Ic (flecainide) (>10s) Class II: ß-adrenoceptor antagonists (atenolol, sotalol) Class III: prolong action potential and prolong refractory period (amiodarone, dofetilide, sotalol) Class IV: Ca2+ channel antagonists (verapamil, diltiazem)
    36. 36. Classification based on clinical use • Drugs used for supraventricular arrhythmia`s – Adenosine, verapamil, diltiazem • Drugs used for ventricular arrhythmias – Lignocaine, mexelitine, bretylium • Drugs used for supraventricular as well as ventricular arrhythmias – Amiodarone, - blockers, disopyramide, procainamide
    37. 37. Na+ channel blocker • Bind to and block Na+ channels (and K+ also) • Act on initial rapid depolarisation (slowing effect) • Local Anaesthetic (higher concentration): block nerve conduction • Do not alter resting membrane potential (Membrane Stabilisers) • At times, post repolarization refractoriness. • Bind preferentially to the open channel state • USE DEPENDENCE : The more the channel is in use, the more drug is bound
    38. 38. Ia Ib Ic Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS
    39. 39. Class I: Na+ Channel Blockers • IA: Ʈrecovery moderate (1-10sec) Prolong APD • IB: Ʈrecovery fast (<1sec) Shorten APD in some heart tissues • IC: Ʈrecovery slow(>10sec) Minimal effect on APD
    40. 40. Class IA
    41. 41. Quinidine • Historically first antiarrhythmic drug used. • In 18th century, the bark of the cinchona plant was used to treat "rebellious palpitations“ pharmacological effects threshold for excitability automaticity prolongs AP
    42. 42. Quinidine • Clinical Pharmacokinetics • well absorbed • 80% bound to plasma proteins (albumin) • extensive hepatic oxidative metabolism • 3-hydroxyquinidine, • is nearly as potent as quinidine in blocking cardiac Na+ channels and prolonging cardiac action potentials.
    43. 43. Quinidine • Uses • to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation • to prevent recurrence of ventricular tachycardia or VF
    44. 44. Quinidine Adverse Effects- Non cardiac • Diarrhea, thrombocytopenia, • cinchonism & skin rashes. cardiac marked QT-interval prolongation &torsades de pointes (2-8% ) hypotension tachycardia
    45. 45. Drug interactions • Metabolized by CYP450 • Increases digoxin levels • Cardiac depression with beta blockers • Inhibits CYP2D6
    46. 46. Disopyramide • Exerts electrophysiologic effects very similar to those of quinidine. • Better tolerated than quinidine • exert prominent anticholinergic actions • Negative ionotropic action. • A/E- • precipitation of glaucoma, • constipation, dry mouth, • urinary retention
    47. 47. Procainamide • Lesser vagolytic action , depression of contractility & fall in BP • Metabolized by acetylation to N-acetyl procainamide which can block K+ channels • Doesn’t alter plasma digoxin levels • Cardiac adverse effects like quinidine • Can cause SLE not recommended > 6 months • Use: Monomorphic VT, WPW Syndrome
    48. 48. Ia Ib Ic Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS
    49. 49. Class IB drugs Lignocaine, phenytoin, mexiletine Block sodium channels also shorten repolarization
    50. 50. Class Ib
    51. 51. Lignocaine • Blocks inactivated sodium channels more than open state • Relatively selective for partially depolarized cells • Selectively acts on diseased myocardium • Rapid onset & shorter duration of action • Useful only in ventricular arrhythmias , Digitalis induced ventricular arrnhythmias
    52. 52. • Lidocaine is not useful in atrial arrhythmias??? • atrial action potentials are so short that the Na+ channel is in the inactivated state only briefly compared with diastolic (recovery) times, which are relatively long
    53. 53. Pharmacokinetics • High first pass metabolism • Metabolism dependent on hepatic blood flow • T ½ = 8 min – distributive, 2 hrs – elimination • Propranolol decreases half life of lignocaine • Dose= 50-100 mg bolus followed by 20-40 mg every 10-20 min i.v
    54. 54. Adverse effects • Relatively safe in recommended doses • Drowsiness, disorientation, muscle twitchings • Rarely convulsions, blurred vision, nystagmus • Least cardiotoxic antiarrhythmic
    55. 55. • Local anaesthetic • Inactive orally • Given IV for antiarrhythmic action • Na+ channel blockade which occurs • Only in inactive state of Na+ channels • CNS side effects in high doses • Action lasts only for 15 min • Inhibits purkinje fibres and ventricles but • No action on AVN and SAN so • Effective in Ventricular arrhythmias only
    56. 56. Mexiletine • Oral analogue of lignocaine • No first pass metabolism in liver • Use: – chronic treatment of ventricular arrhythmias associated with previous MI – Unlabelled use in diabetic neuropathy • Tremor is early sign of mexiletine toxicity • Hypotension, bradycardia, widened QRS , dizziness, nystagmus may occur
    57. 57. Tocainide • Structurally similar to lignocaine but can be administered orally • Serious non cardiac side effects like pulmonary fibrosis, agranulocytosis, thrombocytopenia limit its use
    58. 58. Class I C drugs Encainide, Flecainide, Propafenone Have minimal effect on repolarization Are most potent sodium channel blockers • Risk of cardiac arrest , sudden death so not used commonly • May be used in severe ventricular arrhythmias
    59. 59. Class Ic
    60. 60. Propafenone class 1c • Structural similarity with propranolol & has - blocking action • Undergoes variable first pass metabolism • Reserve drug for ventricular arrhythmias, re- entrant tachycardia involving accesory pathway • Adverse effects: metallic taste, constipation and is proarrhythmic
    61. 61. Flecainde (Class Ic) • Potent blocker of Na & K channels with slow unblocking kinetics • Blocks K channels but does not prolong APD & QT interval • Maintain sinus rhythm in supraventricular arrhythmias • Cardiac Arrhythmia Suppression Test (CAST Trial): When Flecainide & other Class Ic given prophylactically to patients convalescing from Myocardial Infarction it increased mortality by 2½ fold. Therefore the trial had to be prematurely terminated
    62. 62. Class II: Beta blockers • -receptor stimulation: • ↑ automaticity, • ↑ AV conduction velocity, • ↓ refractory period • -adrenergic blockers competitively block catecholamine induced stimulation of cardiac - receptors
    63. 63. Beta blockers • Depress phase 4 depolarization of pacemaker cells, • Slow sinus as well as AV nodal conduction : – ↓ HR, ↑ PR • ↑ ERP, prolong AP Duration by ↓ AV conduction • Reduce myocardial oxygen demand • Well tolerated, Safer
    64. 64. β Adrenergic Stimulation β Blockers ↑ magnitude of Ca2+ current & slows its inactivation ↓ Intracellular Ca2+ overload ↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate ↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediated automaticity Epinephrine induces hypokalemia (β2 action) Propranolol blocks this action
    65. 65. Use in arrhythmia • Control supraventricular arrhythmias • Atrial flutter, fibrillation, PSVT • Treat tachyarrhythmias caused by adrenergic • Hyperthyroidism Pheochromocytoma, during anaesthesia with halothane • Digitalis induced tachyarrythmias • Prophylactic in post-MI • Ventricular arrhythmias in prolonged QT syndrome +
    66. 66. Esmolol • β1 selective agent • Very short elimination t1/2 :9 mins • Metabolized by RBC esterases • Rate control of rapidly conducted AF • Use: • Arrythmia associated with anaesthesia • Supraventricular tachycardia
    67. 67. Class III drugs ↑APD & ↑RP by blocking the K+ channels
    68. 68. Vm (mV) -80mV 0mV ↑ APD Block IK
    69. 69. Amiodarone • Iodine containing long acting drug • Mechanism of action: (Multiple actions) –Prolongs APD by blocking K+ channels –blocks inactivated sodium channels –β blocking action , Blocks Ca2+ channels –↓ Conduction, ↓ectopic automaticity
    70. 70. • Pharmacokinetics: –Variable absorption 35-65% –Slow onset 2days to several weeks –Duration of action : weeks to months • Dose –Loading dose: 150 mg over 10min –Then 1 mg/min for 6 hrs –Then maintenance infusion of 0.5 mg/min for 24 hr Amiodarone
    71. 71. Amiodarone • Uses: – Can be used for both supraventricular and ventricular tachycardia • Adverse effects: – Cardiac: heart block , QT prolongation, bradycardia, cardiac failure, hypotension – Pulmonary: pneumonitis leading to pulmonary fibrosis – Bluish discoloration of skin, corneal microdeposits – GIT disturbances, hepatotoxicity – Blocks peripheral conversion of T4to T3 can cause hypothyroidism or hyperthyroidism
    72. 72. • Antiarrhythmic • Multiple actions • Iodine containing • Orally used mainly • Duration of action is very long (t ½ = 3-8 weeks) • APD & ERP increases • Resistant AF, V tach, Recurrent VF are indications • On prolonged use- pulmonary fibrosis • Neuropathy may occur • Eye : corneal microdeposits may occur
    73. 73. • Bretylium: – Adrenergic neuron blocker used in resistant ventricular arrhythmias • Sotalol: – Beta blocker • Dofetilide, Ibutilide : – Selective K+ channel blocker, less adverse events – use in AF to convert or maintain sinus rhythm – May cause QT prolongation
    74. 74. Newer class III drugs • Dronedarone • Vernakalant • Azimilide • Tedisamil
    75. 75. Calcium channel blockers (Class IV) • Inhibit the inward movement of calcium ↓ contractility, automaticity , and AV conduction. • Verapamil & diltiazem
    76. 76. Verapamil • Uses: – Terminate PSVT – control ventricular rate in atrial flutter or fibrillation • Drug interactions: – Displaces digoxin from binding sites – ↓ renal clearance of digoxin
    77. 77. Other antiarrhythmics • Adenosine : – Purine nucleoside having short and rapid action – IV suppresses automaticity, AV conduction and dilates coronaries – Drug of choice for PSVT – Adverse events: • Nausea, dyspnoea, flushing, headache
    78. 78. Vm (mV) -80mV 0mV ↓ APD Hyperpolarization Adenosine
    79. 79. Adenosine • Acts on specific G protein-coupled adenosine receptors • Activates AcH sensitive K+ channels channels in SA node, AV node & Atrium • Shortens APD, hyperpolarization & ↓ automaticity • Inhibits effects of ↑ cAMP with sympathetic stimulation • ↓ Ca currents • ↑AV Nodal refractoriness & inhibit DAD’s
    80. 80. • Atropine: Used in sinus bradycardia • Digitalis: Atrial fibrillation and atrial flutter • Magnesium SO4: digitalis induced arrhythmias Other antiarrhythmics
    81. 81. Magnesium • Its mechanism of action is unknown but may influence Na+/K+ATPase, Na+ channels, certain K+ channels & Ca2+ channels • Use: Digitalis induced arrhythmias if hypomagnesemia present, refractory ventricular tachyarrythmias, Torsade de pointes even if serum Mg2+ is normal • Given 1g over 20mins
    82. 82. Drugs of choices S. No Arrhythmia Drug 1 Sinus tachycardia Propranolol 2 Atrial extrasystole Propranolol, 3 AF/Flutter Esmolol, verapamil ,digoxin 4 PSVT Adenosine ,esmolol 5 Ventricular Tachycardia Lignocaine , procainamide , Amiodarone 6 Ventricular fibrillation Lignocaine, amiodarone 7 A-V block Atropine , isoprenaline