Anti-Arrhythmics-2Dr Nauman

Learning ObjectivesClassify Anti-Arrhythmic DrugsDescribe mechanism of action, uses and adverse effects of Quinidine, Procainamide, Lignocaine Amiodarone and AdenosineDescribe role of Beta Blockers and Calcium Channel Blockers in treatment of arrhythmias

Basic Mechanisms of Anti-Arrhythmic Drugs1. Decreasing Automaticitya) Decreasing Slope of Phase 4 of AP (Gradual Depolarization)

All Anti-arrhythmic Decrease Enhanced AutomaticityBy blocking Na, or Ca Channels

b) Shifting Threshold Potential Towards Zero (Making Threshold Potential Less Negative)Decreases Automaticity and ConductionClass 1A, Class II, Class IV

c) Shifting Resting Potential away from Zero (Making it more negative)Slows the rate of Diastolic Depolarization

2. Decreasing Re-entry

a) Increase Refractory PeriodBy increasing action potential durationIncrease in RP in tissues near the block, the greater the chance the tissue will still be refractory when reentry is attempted

Class IA, Class III

Re-entryPurkinje fibreVentricular muscleDamage e.g. thrombotic clot, causes muscle to become ischaemic

b) Decrease Refractory PeriodBy decreasing the action potential The shorter the RP in depressed region, the less likely it is that unidirectional block will occurClass IB Drugs

c) Slow Conduction(By decreasing Na or Ca Current)Conduction fails due to weak impulse or impulse arrives so late that it collides with the next regular impulse

d) Increase ConductionImpulse will travel around the obstacle too rapidly and hence reach tissue that is still refractory

State Dependent BlockMost Anti-arrhythmic agents block myocardial Na, Ca or K Channels in a state dependent mannerThat means they bind with a higher affinity to activated or inactivated channels than to resting channels

The central concept is of use-dependent block. This feature enables Drugs to block the high frequency excitation of the myocardium that occurs in tachycardias, without preventing the heart from beating at normal frequencies

Thus with each action potential, drugs bind to Na channels and block them and with each diastolic interval drugs dissociate and unblockWhen Heart rate increases, time available for unblocking decreases, and steady state Na Channel Block increases

The rate of recovery from block also slows as cells are depolarized, as in ischemia (Hence more block in ischemic tissues)Increase in action potential duration causes increase time spent in inactivated state

Class 1 Drugs-The Na Channel Blockers

Effects of Blockage of Na Channels1. Slowing of the Rate and amplitude of Phase 0 Depolarization2. Reduces cell excitability3. Reduces conduction velocity4. They decrease the slope of Phase 4 depolarization in cells with abnormal automaticity

5. The RMP becomes more negative which decreases automaticity and excitability6. Some may also increase threshold potential

Class I drugs are subdivided into 3 groups according to their rate of dissociation from the channels and according to the AP and RP duration

Class IAThese drugs bind more to open channels than inactivated channels and they dissociate slowly from the channelsThese drugs block Na as well as K+ channels and thus prolong action potential duration and refractory period

In therapeutic concentrations, they 1. Raise threshold for excitation (lengthen AP duration)2. Cause minor slowing of Intracardiac conduction3. Widen QRS Complex4. Prolong RP in atria and ventricles

QuinidineThis is the Prototype 1A DrugDextro-isomer of QuinineMechanism of Actiona) Blocks Na Channels in open state and thus reduces automaticity and maximal rate of Phase 0 Depolarization

b) Prolongation of AP duration is due to K Channel Block and the increase in RP due to its moderate effect on recovery of Na Channels

c) Mild alpha and Vagolytic Actions

Mode of Action in Arrythmias1. Decrease Automaticity bya) Decreasing slope of Phase 4 Depolarizationb) Shifting threshold potential towards zero and thus decrease excitabilityc) Shifting resting potential away from zero (making it more negative)

2. Decrease Re-entry by:a) Increasing Refractory PeriodBy Potassium Channel Blockage and by slow recovery of Na channels b) Slowing conduction

Effects on ECGProlonged PR IntervalWidening of QRS ComplexBlood PressureDecrease in Blood Pressure due to alpha blockage and direct relaxant effect on blood vessels

Therapeutic Uses1. Atrial Fibrillation and Atrial Flutter given after digitalization2. Paroxysmal Atrial and Nodal Tachycardia and Ventricular Tachycardia3. Atrial, nodal and Ventricular Premature Beats4. Prevention of Ventricular Fibrillation and Ventricular Flutter

Adverse Effects1. Myocardial Depression2. AV Block3. Higher Doses: Ventricular Arrythmias prolonged QRS Complex and QT interval precipitating Heart failure4. Decreased BP and syncope5. Paradoxical Tachycardia (Vagolytic effect)

4. Torsades de pointes (Twisting of Points), Serious multiform ventricular tachycardia with rapid asynchronous complexes associated with prolonged QT IntervalCan progress to ventricular fibrillation or reverse spontaneously Precipitated by Class 1A, 1C and some Class III drugs

Extra-Cardiac Adverse Effects1. GIT Intolerance: Nausea, Vomiting and Diarrhea2. Cinchonism: Higher doses: Ringing in ears, deafness, vertigo, headache, visual disturbances, mental changes, delirium3. Hypersensitivity ReactionsFever, Thrombocytopenia, hepatitis, bone marrow depression

Drug Interactions1. Displaces digoxin from tissue binding sites and decreases its renal and biliary clearance ---Increased digoxin levels

Procainamide & DisopyramideProcainamide:SLE like syndrome

DisopyramideMost Anti-muscarinic effects

Class IB DrugsThese drugs rapidly associate and dissociate from sodium channelsThey block inactivated channels moreActions are thus manifested when the cardiac cell is depolarized or firing rapidlyThus Particularly useful in treating ventricular arrhythmias

LIGNOCAINEPrototype 1B Drug Local anesthetic (amide); extensive first pass; given IM/IVDoes not effect electrophysiological function of atria, SA node and AV NodesThus NOT Effective in Supraventricular arrhythmias

Produces minimum change in ECG

Toxicity minimal and of short durationLittle depression of cardiac contractility or arterial BPNo autonomic actions

Anti-arrythmic Actions of Class IB1. Decreased AutomaticityDecreases slope of Phase 4 Depolarization in Purkinje fibers2. Decreased Re-entryDecreases refractory period of Purkinje fibers and ventricles ---abolishes one way block

Indications1. Used to control ventricular arrythmias especially in emergency e.g. after MI2. Suitable for treatment of digitalis induced ventricular arrythmias because it lacks action on atrioventricular nodal conduction3. Prophylactically used to prevent ventricular arrythmias during electroversion

4. Used as a local anaesthetic alone or with adrenalineAdverse EffectsCardiacSafest Anti-arrythmicOnly excessive doses cause cardiac depression and hypotension

ExtracardiacNeurological-like all other local anaesthetics-parasthesias, tremor, lightheadedness, hearing disturbances, slurred speech and convulsionsDrowsiness, disorientation, muscle twitchings

Class IC DrugsThese drugs markedly slow Phase 0depolarizationThey have a very slow rate of association and dissociation with sodium ChannelsUsed for refractory ventricular arrhythmiasMinor effect on AP and RP durationsVery arrhythmogenic-rarely used

Class III DrugsThese agents block Potassium Channels Thus they diminish outward potassium current during repolarizationThey prolong the duration of AP without altering phase 0 DepolarizationProlong Effective Refractory Period

AmiodaroneBroad Spectrum Anti-arrythmic DrugContains Iodine: Structure similar to ThyroxineBlocking ActionsPotassium Channel BlockerSodium Channel BlockerWeak Ca Channel BlockerWeak Beta Blocker

Anti-arrythmic Effects1. Decreased AutomaticityPreferentially block inactivated Na Channels with rapid rate of Channel Recovery2. Decreased Reentrya) Increase Refractory PeriodProlonged AP duration and ERP due to K Channel Block

b) Slowed ConductionCalcium channel blockage and Beta Blockade cause slowed conduction and prevents reentryTherapeutic Usesa) Chronic Ventricular Arrhythmiasb) Atrial Fibrillation and atrial flutter

Adverse Effects of AmiodaroneCardiacHeart Block, bradycardia, and induction of ventricular arrythmias, Torsades de points-Prolonged QT intervalExtracardiac1. Pulmonary Toxicity-Pulmonary Fibrosis

2. Hepatitis-abnormal LFTs3. Hypothyroidism-Contains Iodine-May cause Hypo or Hyperthyroidism4. Skin Deposits-Photodermatitis, Grey-blue Skin Discoloration5. Corneal MicrodepositsVisual Disturbances and Photophobia, optic neuritis and blindness

Role of Beta Blockers in Treatment of Arrythmias1. Beta Blockers block beta 1 receptors of the heartDecrease levels of cAMPdecrease Calcium and Sodium influx2. Sympathetic stimulation increases the activity of the SA NodeActivity of many excitable foci is due to presence of catecholaminesBeta blockers are very effective in treating these arrhythmias

3. Beta Blockers prolong the refractory period of AV Node (Slow down AV conduction) -Negative Dromotropic effect)-Decrease number of impulses passing on to ventricles-Decrease re-entry

4. They depress Phase 4 Depolarization leading to decreased automaticity5. HR and contractility are decreased leading to decreased EADs and DADs6. Some Beta Blockers have MSA Activity

7. Sotalol is also a K channel blocker and thus also classified under Class III drugIt is useful in supraventricular arrythmias but causes Ventricular Tachycardias and Torsades de pointes

Calcium Channel BlockersMechanism:They block L-Type Calcium channels and thus decrease calcium currentMainly Verapamil and Diltiazem are used because they have more effects on heartVerapamil

Mode of Action:a) Slow AV Conduction and thus decrease transmission of the number of impulses passing onto ventricles, thus useful in supraventricular arrythmias b) Prevent Reentry again by slowing AV Conduction

Miscellaneous Group of DrugsAdenosineMechanism of ActionBinds to G-Protein linked adenosine receptorsa) Activates K Inward current in the atria, SA and AV Nodes---Shortening of AP Duration, hyperpolarization and slowing of normal automaticity

b) Inhibits the effects of Increased cAMP that occur with sympathetic stimulationthus it reduces calcium currents and increases AV Nodal RefractorinessUseDrug of Choice for PSVT

Adverse Effects of AdenosineChest fullness and dyspnea, flushing and hypotension, AV Block, atrial fibrillationDrug InteractionsMethylxanthines: e.g. Caffeine blocks adenosine receptors ---more dose of adenosine requiredDipyridamole: Potentiates action of adenosine