Antiarrythmic drugs-DR.BRAN

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Electro physiology and pharmacology of antiarrythmic drugs

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Antiarrhythmic Drugs :

Antiarrhythmic Drugs DR.B.R.ASOKAN.MD.,DMCH.,MBA.,PGDHM., ASST.PROFESSOR., DEPT OF PHARMACOLOGY., AVMC&H.

content:

content Physiology of normal cardiac rhythm Classification of drugs to treat arrhythmias Important anti-arrhythmic drugs (mechanism and pharmacological characteristics) Arrhythmias in clinical practice Definition and mechanisms of arrhythmias

Arrhythmia:

Arrhythmia Arrhythmia occurs due to abnormal impulse generation or impaired impulse conduction or both To understand how antiarrhythmic drugs work, need to understand electrophysiology of normal contraction of heart

Sinus rhythm:

Sinus rhythm Sinoatrial node is cardiac pacemaker Normal sinus rhythm 60-100 beats/min Depolarisation triggers depolarisation of atrial myocardium (‘forest fire’) Conducts more slowly through AV node Conducts rapidly through His bundles and Purkinje fibres

Sinus rhythm:

Sinus rhythm Sinoatrial rate controlled by autonomic nervous system Parasympathetic system predominates (M2 muscarinic receptors) Sympathetic system (ß1 receptors) Increased heart rate (positive chronotropic effect) Increased automaticity Facilitation of conduction of AV node

:

1. Impulse generation: O ccurs in automatic fibres . Sinoatrial , atrioventricular nodes, His- purkinje system, interatrial septum, A-V ring and around openings of great veins). - Myocardial fibres cannot generate impulse of their own

(Contd…):

(Contd…) 2. Conduction: is a function of membrane responsiveness which is defined by the rate of rise of action potential A more completely polarized membrane depolarizes faster 3. Excitability: is defined by the strength of stimulus required to elicit a response

(Contd…):

(Contd…) 4. Refractory period: which is the minimum interval between two propagating Aps or a short period after a muscle cell fires during which the cell cannot respond to additional stimulation. . It is closely related to AP duration (APD). An AP can be evoked in fast channel fibres even before complete repolarization . ERP/APD ratio is >1 in slow channel. -Most antiarrhythmic drugs increase ERP/APD ratio

IMPULSE:

IMPULSE SA NODE

Electrophysiology - resting potential:

Electrophysiology - resting potential A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell Caused by unequal distribution of ions inside vs. outside cell Na + higher outside than inside cell Ca + much higher “ “ “ “ K + higher inside cell than outside Maintenance by ion selective channels, active pumps and exchangers

CARDIAC CELL:

CARDIAC CELL

Physiology of cardiac rate and rhythm:

Physiology of cardiac rate and rhythm Cardiac myocytes are electrically excitable Resting intracellular voltage of myocardial cells is negative -90mV (SA node is -40mV) Resting state - K + inside and Na + outside cell (Na + /K + pump) Action potential occurs when Na + enters the cell and sets up a depolarising current Stimulation of a single muscle fibre causes electrical activity to spread across the myocardium

Cardiac Action Potential:

Cardiac Action Potential Divided into five phases (0,1,2,3,4) Phase 4 - resting phase (resting membrane potential) Phase cardiac cells remain in until stimulated Associated with diastole portion of heart cycle Addition of current into cardiac muscle (stimulation) causes Phase 0 – opening of fast Na channels and rapid depolarization Drives Na + into cell (inward current), changing membrane potential Transient outward current due to movement of Cl - and K + Phase 1 – initial rapid repolarization Closure of the fast Na + channels Phase 0 and 1 together correspond to the R and S waves of the ECG

Cardiac Action Potential (con’t):

Cardiac Action Potential (con’t) Phase 2 - plateau phase sustained by the balance between the inward movement of Ca + and outward movement of K + Has a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals Corresponds to ST segment of the ECG. Phase 3 – repolarization K + channels remain open, Allows K + to build up outside the cell, causing the cell to repolarize K + channels finally close when membrane potential reaches certain level Corresponds to T wave on the ECG

Phases of action potential of cardiac cells:

Phases of action potential of cardiac cells Phase 0 rapid depolarisation (inflow of Na +) Phase 1 partial repolarisation (inward Na + current deactivated, outflow of K + ) Phase 2 plateau (slow inward calcium current) Phase 3 repolarisation (calcium current inactivates, K + outflow) Phase 4 pacemaker potential (Slow Na + inflow, slowing of K + outflow) ‘ autorhythmicity ’ Refractory period (phases 1-3) Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV -80mV II I III IV

Disorder of impulse generation:

Disorder of impulse generation Enhanced automaticity Sinus tachycardia The number of impulses arising from the SA node increases Emotional excitement, fever, thyrotoxicosis Beta stimulation, hypokalemia & mechanical stretch of the myocardium

Failure of impulse generation:

Failure of impulse generation Decreased automaticity Sinus bradycardia Old age, athletes, hypothyroidism The number of impulses arising from SA node is decreased

Disorders of impulse formation:

Disorders of impulse formation No signal from the pacemaker site Development of an ectopic pacemaker May arise from conduction cells (most are capable of spontaneous activity) Usually under control of SA node  if it slows down too much conduction cells could become dominant Often a result of other injury (ischemia, hypoxia) Development of oscillatory afterdepolarizations Can initiate spontaneous activity in nonpacemaker tissue May be result of drugs (digitalis, norepinephrine ) used to treat other cardiopathologies

Abnormal automaticity:

Abnormal automaticity Impulses arise from sites that normally lack pacemaker activity Eg . from ventricular cells- as in Ischemia

Disorder of impulse conduction:

Disorder of impulse conduction Triggered rhythms After depolarizations Early After Depolarization (EAD) Delayed after Depolarization (DAD) Re entrant arrhythmias

EAD :

EAD Occurs when the Cardiac AP is markedly prolonged Can be caused by drugs that prolong phase 3 Torse de pointes is a form of EAD

DAD :

DAD A normal AP is followed by DAD Myocardial ischemia, adrenergic stress, digitalis toxicity or heart failure

Re entrant arrhythmia:

Re entrant arrhythmia Occurs when impulses propagate through more than one pathway- accessory pathway Two types Anatomical re entry & functional re entry

PowerPoint Presentation:

Anatomical re entry Impulses from SA node traverses through normal as well as accessory pathway Two types – AV re entry & AV nodal re entry

PowerPoint Presentation:

Functional re entry Due to infarction scarring Can occur in the atria or ventricle AF & VF

Disorders of impulse conduction:

Disorders of impulse conduction May result in Bradycardia (if have AV block) Tachycardia (if reentrant circuit occurs) Reentrant circuit

Re Entry:

Re Entry

Drug induced :

Drug induced Sinus bradycardia Digoxin AV block Verapamil Diltiazem, B blockers Sinus tachycardia Adrenergics Beta blocker withdrawal All anti arrhythmics

Normal heartbeat and atrial arrhythmia:

Normal heartbeat and atrial arrhythmia Normal rhythm Atrial arrhythmia AV septum

Ventricular Arrhythmia:

Ventricular Arrhythmia Ventricular arrhythmias are common in most people and are usually not a problem but… VA’s are most common cause of sudden death Majority of sudden death occurs in people with neither a previously known heart disease nor history of VA’s Medications which decrease incidence of VA’s do not decrease (and may increase) the risk of sudden death  treatment may be worsen the disease!

Bundle Branch Blocks:

Bundle Branch Blocks Normal BBB WPW

Antiarrhythmic drugs:

Antiarrhythmic drugs Biggest problem – antiarrhythmics can cause arrhythmia! Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmia Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing antiarrhythmics

DRUGS THAT PROLONG Q-T INTERVAL:

DRUGS THAT PROLONG Q-T INTERVAL 1.Antiarrhythmics: quinidine,procainamide , disopyramide,propafenone,amiodarone . 2.Antimicrobials: sparfloxacin,gatifloxacin 3.Antimalarials: Quinine,mefloquine,artemisinin halofantrine 4.Antihistaminics: terfenadine,astemizole,ebastine 5.Antidepressants :Amitryptyline & other TCAs 6.Antipsychotics: Thioridazine,risperidone 7.Prokinetics: Cisapride

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TORSADES DE POINTS (Twisting of points) Rapid asynchronus complexes with an undulating baseline

CLASSIFICATION Vaughan Williams’system:

CLASSIFICATION Vaughan Williams’system

V. OTHERS(not in VW class.):

V. OTHERS(not in VW class.) Atropine: Sinus bradycardia Digoxin: AF,AFl,PSVT Adenosine: PSVT Orciprenaline: A-V block Isoprenaline: A-V block Magnisium sulfate: VF,Digoxin toxicity Adrenaline: Cardiac arrest Calcium chloride: VT due to hyperkalaemia

Classification of antiarrhythmics (based on mechanisms of action):

Classification of antiarrhythmics (based on mechanisms of action) Class I – blocker’s of fast Na + channels Subclass IA Cause moderate Phase 0 depression Prolong repolarization Increased duration of action potential Includes Quinidine – 1 st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period Procainamide - increases refractory period but side effects Disopyramide – extended duration of action, used only for treating ventricular arrthymias

Cardiac Na+ channels:

Cardiac Na+ channels

Classification of antiarrhythmics (based on mechanisms of action):

Classification of antiarrhythmics (based on mechanisms of action) Subclass IB Weak Phase 0 depression Shortened depolarization Decreased action potential duration Includes Mexiletine - oral lidocaine derivative , similar activity Phenytoin – anticonvulsant that also works as antiarrhythmic similar to lidocane

Lignocaine Class Ib (blocks Na+ channels, reduces AP duration) :

Lignocaine Class Ib (blocks Na + channels, reduces AP duration) Lidocaine (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmias Ventricular arrhythmias (acute Rx) IV infusion only (2 hour half life, high first pass metabolism) Hepatic metabolism (inhibited by cimetidine , propranolol ) SE mainly CNS - drowsiness, disorientation, convulsions, hypotension

Classification of antiarrhythmics (based on mechanisms of action):

Classification of antiarrhythmics (based on mechanisms of action) Subclass IC Strong Phase 0 depression No effect of depolarization No effect on action potential duration Includes Propafenone slows conduction Weak β – blocker Also some Ca 2+ channel blockade

Flecainide class Ic (block Na+ channels, no change to AP) :

Flecainide class Ic (block Na + channels, no change to AP) Flecainide (initially developed as a local anesthetic) Also inhibits abnormal automaticity Slows conduction in all cardiac cells Acute Rx /prophylaxis Supraventricular tachycardias Paroxysmal atrial fibrillation Ventricular tachycardias Oral/IV Long acting (T1/2 14 hours) Hepatic metabolism, urinary elimination

Flecainide:

Flecainide CAST (Cardiac Arrhythmia Suppression Trial) 1989 – increased mortality post MI (VF arrest) SE- cardiac failure, ventricular arrhythmias, blurred vision, abdominal discomfort, nausea, paraesthesia, dizziness, tremor, metallic taste

Classification of antiarrhythmics (based on mechanisms of action):

Classification of antiarrhythmics (based on mechanisms of action) Class II – β –adrenergic blockers Based on two major actions 1) blockade of myocardial β –adrenergic receptors 2) Direct membrane-stabilizing effects related to Na + channel blockade Includes Propranolol causes both myocardial β –adrenergic blockade and membrane-stabilizing effects Slows SA node and ectopic pacemaking Can block arrhythmias induced by exercise or apprehension Other β –adrenergic blockers have similar therapeutic effect Metoprolol Nadolol Atenolol Acebutolol Pindolol Sotalol Timolol Esmolol

Classification of antiarrhythmics (based on mechanisms of action):

Classification of antiarrhythmics (based on mechanisms of action) Class III – K + channel blockers Developed because some patients negatively sensitive to Na channel blockers . Cause delay in repolarization and prolonged refractory period Includes Ibutilide – slows inward movement of Na + in addition to delaying K + influx. Bretylium – first developed to treat hypertension but found to also suppress ventricular fibrillation associated with myocardial infarction Dofetilide - prolongs action potential by delaying K + efflux with no other effects

Amiodarone :

Amiodarone Class III - increases refractory period and AP – prolongs action potential by delaying K + efflux but many other effects characteristic of other classes Major effect acutely is depression of AV node Acute Rx/prophylaxis Atrial and ventricular arrhythmias Oral or IV (central line) Loading and maintenance doses T1/2 54 days Large volume of distribution Accumulates Hepatic metabolism- biliary and intestinal excretion

Amiodarone – adverse effects:

Amiodarone – adverse effects Photosensitive rashes Grey/blue discolouration of skin Thyroid abnormalities 2% Pulmonary fibrosis Corneal deposits CNS/GI disturbance Pro-arrhythmic effects (torsades de pointes) Heart block Nightmares 25% Abnormal LFT 20% Interacts with digoxin, warfarin (reduces clearance)

Classification of antiarrhythmics (based on mechanisms of action):

Classification of antiarrhythmics (based on mechanisms of action) Class IV – Ca 2+ channel blockers slow rate of AV-conduction in patients with atrial fibrillation Includes Diltiazem verapamil

Verapamil:

Verapamil Class IV (calcium channel blocker) Prolongs conduction and refractoriness in AV node, slows rate of conduction of SA node Acute Rx /prophylaxis Used IV/oral SUPRAVENTRICULAR NOT VENTRICULAR ARRHYTHMIAS (cardiovascular collapse) Do not use IV verapamil with ß- blocker (heart block) T1/2 6-8 hours

Verapamil- adverse effects:

Verapamil- adverse effects Heart failure Constipation Bradycardia Nausea

OTHER ANTIARRHYTHMIC DRUGS :

OTHER ANTIARRHYTHMIC DRUGS Potassium channel openers Adenosine Inhibits SA and AV node Activates potassium current in atria, SA, and AV node Increased potassium conduction inhibits cAMP induced calcium entry Drug of choice for PSVT Extremely short half life – 6 seconds Dose Given IV 6 mg – bolus, another 12 mg 2 minutes later if necessary

Adenosine:

Adenosine Not in Vaughan Williams class Purine nucleotide (activates adenosine receptors) Slows AV nodal conduction Acute Rx Termination of SVT/ diagnosis of VT Given IV only (rapid bolus) T1/2 < 2 seconds

ATP (Adenosine Triphosphate) :

ATP (Adenosine Triphosphate ) Precursor of adenosine Given IV get converted to adenosine Side effects Adenosine is a bronchoconstrictor hence should not be used in bronchial asthma Flushing, dyspnoea, chest pain, transient arrhythmias Contraindicated in heart block Magnesium Magnesium infusion has been found to be effective in Digitalis induced arrhythmias Torsades de pointes

Digoxin:

Digoxin Not in Vaughan Williams class Cardiac glycoside (digitalis, foxglove) Acts on Na/K-ATPase of cell membrane (inhibits Na + /K + pump, increases intracellular Na + and calcium)/ increases vagal activity Increase cardiac contraction and slows AV conduction by increasing AV node refractory period

Digoxin:

Digoxin Atrial fibrillation or flutter (controls ventricular rate) Acute Rx/prophylaxis Oral/IV Loading and maintenance doses T1/2 36 hours Excreted by kidneys Narrow therapeutic index Therapeutic drug monitoring Reduce dose in elderly/renal impairment

Atrial fibrillation:

Atrial fibrillation

Digoxin – adverse effects:

Digoxin – adverse effects Arrhythmias, heart block, anorexia, nausea, diarrhoea, xanthopsia, gynaecomastia, confusion, agitation AE potentiated by hypokalaemia and hypomagnesaemia Overdose –Digibind (digoxin binding antibody fragments), phenytoin for ventricular arrhythmias, pacing, atropine

NON PHARMACOLOGICAL TREATMENT OF ARRHYTHMIAS :

NON PHARMACOLOGICAL TREATMENT OF ARRHYTHMIAS Pacemaker (external as well as internal) Implantable cardiovertor or defibrillator Catheter ablation – deliver radio frequency energy through an appropriately positioned intra cardiac catheter. Open heart surgery – transecting the reentry circuit

CHOICE OF DRUGS:

CHOICE OF DRUGS AES( Atrial extra systole): Disopyramide,Propranolol (chronic and prophylaxis therapy) PSVT: acute therapy-adenosine, chronic therapy- digoxin,verapamil and prophylaxis therapy- Propafenone AFL: Acute- cardioversion , chronic- amiadarone,quinidine,digoxin VES: acute miiocardial infarction- lidocaine chronic ischemia- amiadarone,mexiletine digitalis induced- lidocaine VT- ACUTE - lidocaine , cardioversion chronic- amiadarone,dofelitide Torsades de points- acute- pacing,isoprenaline,magnesium -chronic- propranalol VF -Acute therapy- electri - defibrillation,chronic-amiadarone WPW -acute- cardioversion,chronic - amiodarone,propranolol

Summary:

Summary Anti-arrhythmic drugs are classified by their effect on the cardiac action potential Not all drugs fit this classification In clinical practice treatment of arrhythmias is determined by the type of arrhythmia (SVT, VT) and clinical condition of the patient Anti-arrhythmic drugs are efficacious but may have serious adverse effects Not all arrhythmias are treated with drug therapy alone

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THANK YOU . You have been very kind & patient. !

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Thank you

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Circus re entry

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ECG (EKG) showing wave segments Contraction of atria Contraction of ventricles Repolarization of ventricles

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS:

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS They are classified into major four classes of drugs by Vaughan williams Class 1: Class 1 A Quinidine , Procainamide , Disopyramide Class 1 B Lignocaine,Phenytoin,Mexiletine,Tocainide , Moricizine Class 1 C Flecainide , Encainide , Propafenone , Lorcainide , Indecainide , Recainam All these inhibit the fast sodium channel and decrease phase o depolarization

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS (Contd..):

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS (Contd..) Class II (Beta Blockers) Ptoptsnolol , Esmolol , Acebutalol Class III (Potassium Channel Blockers) Amiodarone , Sotalol , Bretyliu , N-acetyl Procainamide Class IV (Calcium channel Blockers) Verapamil , Diltiazem Others: 1.Digoxin 2.Nicorandil , pinacidil 3.Potassium channel openers- Recainam , Cibenzoline 4.Adenosine

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