ANTIARRHYTHMIC DRUGS

Submitted By Bipul Ray, M.Pharm First Year

Submitted To Dr. S.N. Manjula,HOD, Dept. of Pharmacology

Jss College of PharmacyMysuru

IMPULSE GENERATION & FLOW

Normal Conditions Tachyarrythmia 100Beats/Min•Heart rate 60-100beat/min•Origin should be from SA node•Normal conduction pathway•With normal velocity i.e SA-1mitre/sec,AV-0.05mitre/sec & Parkinje Fibre-4-5mitre /sec 60 Beats/MinBradyarrythmia

Heart Rate During Arrhythmia

TACHYARRYTHMIASimple : 100-150 Beat/minit may be due to the abnormality of SA node then it will be called as Sinus tachyarrhythmiaParoxysmal: 150-250 Beat/minIf nodal rhythm occurs very fast its called nodal paroxysmal tachyarrhythmiaFlutters: 250-350 Beat/minSimilarly it may be atrial or ventricular tachyarrythmiaFibrilation: >350Beat/minSimilarly it may be atrial or ventricular tachyarrythmia

Pathophysiology

Abnormalities of Impulse Generation Abnormalities of impulse Conduction

Abnormal Automaticity Impulse Block Triggerd automaticity Re-Entry

EAD DAD

Abnormalies in cardiac Impulse Generation

AUTOMATICITY•The term automaticity is defined as the capability of cells(cardiac) to undergo depolarization spontaneously.•They are like SA NODE, AV NODE, PURKINJE FIBRE etcWHY SOME CELLS HAVE AUTOMATICITY?•They have leaky Na+ Ca2+ channels, so RMP goes towards TP Ca2+ K+ O -40mV -60mV Na+ Ca2+ K+ (very less)

The Non Automatic Cell !

• Other cells like atrial,ventricular cell they do not have leaky cell so they don’t have slope in phase 4!

Phase 0: fast upstroke

Due to Na+ influx

Phase 1: partial repolarization

Due to rapid efflux of K+ Phase 2: plateu

Due to Ca++ influx

Phase 3: repolarization

Due to K+ efflux

Phase 4: resting membrane potential

Why Only SA Node controls the cardiac rhythm not by AV or Purkinje!

• Though several cells has automaticty why only SA Node takes the lead in impulse generation? Not by AV & Purkinje System

• Normaly SA node has more cationic leaky Channels,so threshold is achieved by SA node faster than other. So before AV and Purkijne could fire their current the Sinus current reaches AV Node & its driven by Sinus current conducted by SA Node.

SA AV Purkinje Fibre TP

RMP

It’s the beauty of nature for the back up system if SA node fails any of these can run the heart.

1.ABNORMAL AUTOMATICITY

Abnormal Automaticity•A).Rate of Impulse Generation•B).Site of Impulse generationA).Rate Of Impulse Generation:1. if SA node is under working on Very strong Vagus stimulation,2. Ach is released which act on at M2 receptor and works by Gi pathway.3. When Ach Binds to the serpentine receptor the α, β and γ units gets activated α inhibits the AC further cAMP & PKA4.So it will not phosphorilate both Na+ Ca2+ channel & blocks the cation influx.

5. The , β and γ unit opens K+ Channel and cell will become more electro negative.Ultimately it will take very long time to reach threshold potential ultimately bradycardiya will be there.In other cases when the sympathetic outflow , 1.Adrenergic β 1 receptor is Stimulated, which works by Gs pathway and ultimatly it will bring more Cations inside. 2.So resting membrane potential will go up and the slope will be achieved very radily. So heart rate goes up. So trachyarrythmiya!

So abnormality leads to the brady or trachy arrythmiya

B).SITE OF ACTIONWhen site of action is disturbed means if in some reason SA node Delayed or Fails to produce impulse. Then it will fail to overdrive the AV node then the impulse will go according to AV nodal rhythm.its called escape rhythmIt may be same if AV node fails it will same be with the purkinje system

TRIGGERED AUTOMATICITY:Healthy atrial and ventricular cell do not have tendency to automaticityMeans they do not has phase 4 slope

AFTER DEPOLARIZATION

EAD If the repolarization is prolonged the Na+ channel might have recovered and it shows secondary upstroke.

CONDITIONS•Due to the abnormality of K channel ,when the action potential is repolarizing due to the prolongation of this part some of the Na channel might have recovered and it causes secondary upstroke!•Prolongation of QT Interval( In ECG) disorder!

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

• Hypokalemia may lead to the arrhythmia (e.g. Furosemide diuretics) So slower with the phase 3 so early after depolarization occur and lead to ventricular tachyarrhythmia.

• Even defective Na Channel( activated too Early) may lead to arrhythmia.

• Low heart rate produces EAD. Due to prolongation of repolarization.

DAD• Secondary upstroke occurs once the normal action

potential completed.CONDITIONS• Adrenergic stress. (stimulation Of β1 receptor) which

increase the influx of cation. So it causes DAD.

DIGITALIS INTOXICATION •During the normal phenomenon of action potential Cation comes in and depolarization occurs and during repolarization Na+ K+ ATPase exchanges the Na+ out and K+ in.•Digitalis binds with the Na+ K+ ATPase and blocks then the Na+ finds an another way to go out i.e. Na+ Ca2+ exchanger. Where Ca2+ comes in and leads to the DAD. Though its helps in the mechanical activity it disturbs the electrical activity in the heart!ISCHAEMIA•If some myocardial cells are ischaemic (means Lake of Oxygen) they cant make enough ATP so Na+ K+ ATPase will work less. So they will trigger the . Na+ Ca2+ exchanger. Where Ca2+ comes in and leads to the DAD

2.ABNORMALITIES OF IMPULSE CONDUCTION

Two Reasons are found they are,•IMPULSE BLOCK•RE-ENTRYIMPULSE BLOCK•When AV nodes Fails due to ischaemic or suppressed by Drug like β blocker Calcium Channel Blocker etc.•Then ventricle will work under purkinje fibre. And lead to arrhythmia.RE-ENTRY•A)Anatomicaly Defined•B)Functionally DefinedA)Anatomicaly Defined•Wolff–Parkinson–White syndrome (WPW)•In healthy person impulses are travelled through SA-AV-Purkinje Fibre. In WPW there is also an abnormal pathway Exists.

Here is an accessory

pathway in the heart called

Bundle of Kent

• As per conduction Concern there are two types of cells are there one is fast response and slow response cell

• SA node and AV node dependent on Calcium & Atria and Ventricle Dependent on Sodium influx for depolarization.

• Calcium dependent tissues are slow responsive and Vice Versa.• The bundle of Kent consist of sodium dependent (fast response

cell).• In normaly it does causes arrythmiya as through the both pathway

impulses goes and wherever they meets its die out. Because whenever current passes it goes forward by inactivating the Na channel so the opposite pathway finds it as in inactivated state.

• So in normal condition RE-ENTRY Does not Occur.

• Condition• When piece of Myocardiam Damaged and produces Ectopic beat

Ectopic Beat

Pathway 1

Pathway 2

•When an abnormal myocardium cells produces or fires Ectopic beat.•May be first impulse would have passed in a normal pattern and depolarized and deactivated the bundle of kent.•In second time it activates abnormal cell which has two pathway. But just now through Bundle of Kent ( pathway 2) passed normal impulses and Na channels have been deactivated.•So it will go through pathway 1 and by the time it reaches Bundle of kent it will recover and it will RE-ENTER through AV node.•As SA node beats Every 0.8Sec and in Pathway 2 beats at 0.3 sec so abnormal current leads to trachy arrhythmiya.

FUNCTIONALLY DEFINED RE-ENTRY•Is seen in ischaemic patient , here overloaded with Calcium.

Ca2+(produces DAD)

Inactivated

DRUGS• It has the capability to alter the electro- physiological property of myocardial cell.CLASSIFICATION :-CLASS I MEMBRANE STABLIZING AGENT(Na+ CHANNEL BLOCKER)• IA Moderately decrease dv/dt of 0 phase – Quinidine , Procainamide ,

Disopyramide , Moricizine• IB little decrease dv/dt of 0 phase – Lidocaine , Maxiletine• IC Marked decrease dv/dt of 0 phase -- Flecainide , PropafenoneCLASS II ANTI ADRENERGIC AGENTS ( B- BLOCKER)• a) NON–SELECTIVE :- PROPRANALOL• b) SELECTIVE:- atenolol , metanalol , sotalolCLASS III AGENT WIDENING AP/ K+ CHANNEL BLOCKER-- Amiodarone ,

brytilium , ibutilide , dofetilideCLASS IV Ca++ CHANNEL BLOCKER – Verapamil , diltiazem , nifedipine ,

felodipine.

CLASS I – Na+ CHANNEL BLOCKER :- These drugs limits the conductance of Na+ (K+) across cell membrane , thus acts as local anaesthetics.CLASS IA- These are open state Na+ channel blocker which also delays channel recovery , suppress AV conduction and prolong refractoriness. •Eg:- QUINIDINE- it blocks myocardial Na+ channel thus reduces automaticity and prolongs its recovery . it also prolongs APD (action potential duration) due to K+ channel blockade. At high dose it also blocks L-type Ca++ channel.CLASS IB- They block Na+ channel in inactivated state but doesn’t delays in its recovery. •Eg:- Lidocaine CLASS IC- They are most potent Na+ channel blocker in open state and has longest recovery period. •Eg:- flecainide , propafenone

CLASS IQUINIDINE: it blocks the sodium channel in Open state so it inhibits the action potential.•Pharmacokinetics•Given orally, 90% bound to plasma protein, metabolized in LIVER and excreted in Urine.•Dose:- 100-200mg TDS•ADR: Hypotension, Prolongation of QT interval !, Diarrhoea, Nausea.•Drug Interaction: reduces the clearance of digitoxin and cause digitoxin toxicity•Synergistic cardiac depression with Beta Blocker

• Procainamide & Disopyramide is better tolerated than quinine.• But procanamide has less t half and Disopyramide has

anticollinergic property so patient may feel dry mouth,blurred vision and constipation etc

• USES• In this category almost all drugs are used in all type of arrythmiyas.• Used in atrial fibrilation & flutter.CLASS IB• Lidocaine: it blocks the sodium channel in open and inactivated

state.• Its most popular arrhythmatic drug in intensive care.• It supresses the automaticty and ectopic foci.

Pharmacokinetics•It undergoes first pass metabolism if given orally. And has low t half so used parentrally.DOSE •50-100Mg every 10mins.ADR•Causes drowsiness, hypotension, blurred vision,

CLASS II β BLOCKER :- •Class II agents are conventional β blocker.They act by selectively blocking the effects of at the β1 receptor, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of tachycardiyas. They decrease conduction through the AV NODEEg:- propranolol , atenolol , metanalol

BLOCK

PROPRANOLOL•It’s a beta blocker, its used to suppress sinus tachycardia, and digitalis induced arrhythmias.DOSE•Oral dose is useful 40-50mg BDS•Even SOTALOL which is non selective beta blocker are also used.its contraindicated with patient with long QT intervals.•And ESMOLOL is short acting Beta 1 blocker used I this category

CLASS IIIK+ CHANNEL BLOCKER:- •Class III agents predominantly block the potassium channels, thereby prolonging repolarization. •Since these agents do not affect the sodium channel, conduction velocity is not decreased. •The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias Eg:- Amiodarone , brytilium , ibutilide , dofetilide

AMIODARONE•It blocks the potassium channels and prolongs the action potential duration.ts an iodine containing compound.•Its and powerful antiarrhythmic drug. It depresses the SA nodal activityPharmacokinetics•Its incomplete and slowly absorbed in GIT,Onset action is slow.•t half is 3-8 weeks!DOSE:•400-600mg/day orallyUSE•Wide range of ventricular arrhythmias•Even WPW tachyarrhythmia

CLASS IVCa++ CHANNEL BLOCKER:- •Class IV agents are slow calcium channel blocker.• They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential.•They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility Eg:- verapamil , diltiazem , nifedipine

VERAPAMIL•Calcium channel blocker, it suppresses the automaticity and Re-entry.•Phase 4 SA node depolarization is reducedPharmacokinetics•Given IV in a dose of 5mgContraindication•Its contraindicated in partial heart block•Also not recommended in digitalis toxicity

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