Anti arrhythmic Drugs Marwa A. Khairy , MD

TOPICS COVERED Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV Guide to treat some types of arrhythmia

Electrophysiology of the heart

This is the normal pathway for electricity to travel through the heart

This is the normal pathway for electricity to travel through the heart

This is the normal pathway for electricity to travel through the heart

This is the normal pathway for electricity to travel through the heart

Cardiac Action Potential Resting membrane potential Retention of many intracellular anions. The resting cell membrane is almost 100 times more permeable to potassium than to sodium, Na+K+ATPase pump. Potential inside the cardiac cell is -90 mV relative to outside. Action potentials depolarize the cell and overshoot to +20 mV Fast response predominant in the atria and ventricle Slow response found in the SA and AV nodes The phases of the action potential are associated with changes in the permeability of the cell membrane to Na, K, and Ca. Permeability is controlled by ion channels. Ionic basis of the resting potential The resting cell membrane is relatively permeable to K via the inwardly rectifying K current. The diffusion gradient of K outward is balanced by impermeable anions that create an electrostatic force. The Nerst equation for K predicts a Ek of -94 which is slightly more negative than the resting potential due to slow Na leak If left, the leak would eventually depolarize the cell so the K/Na/ATPase acts to get rid of Na. The RMP is the electrical potential across the cell membrane during diastole and is about −90 mV, the intracellular membrane surface being negative with respect to the extracellular surface. RMP is maintained by the permeability properties of the cell membrane, which retains negative ions in the cell but allows positive ions to diffuse out. The cell membrane is impermeable to negatively charged ions such as proteins, sulphates and phosphates, which, therefore, remain intracellularly. In contrast, membrane permeability to potassium is higher, allowing it to diffuse out of the cell under its concentration gradient of about 30 : 1. Potassium diffuses out of the cell until an equilibrium is reached at which the electrostatic attraction of the retained anions balances the chemical force moving the potassium down its concentration gradient out of the cell. - 90mV Non-Pacemaker potential

Cardiac Action Potential Phase 0: fast upstroke Due to Na+ influx + 20 mV N.B. The slope of phase 0 = conduction velocity Also the peak of phase 0 = Vmax Na Na Genesis of the upstroke (Phase 0) Anything that raises the resting potential beyond threshold (-65 mV) will cause an action potential. Phase 0 due to Na inward. m gates open in Na channels as Vm becomes less negative. Na flows in due to the electric gradient until Vm = 0 then concentration gradient takes over. h gates close the channel due to the rising Vm h gates remain closed until partially repolarization (effective refractory period). Further, the speed at which one cell is depolarized (represented by the slope of phase 0) determines how quickly the next cell is stimulated to depolarize, and thus determines the speed at which the electrical impulse is propagated. If something causes the slope of phase 0 to change, the conduction velocity also changes; the faster the depolarization of the cardiac cells, the faster an electrical impulse moves across the heart Na - 90 mV Non-Pacemaker potential

Depolarization tissue Resting Ready Open, Active M h M h Open Closed threshold Gate Opens Open Slowly Closed Depolarization tissue Na/K/ATPase pump active 3 Na out/2 K in helps repolarization -50 mv M gate closes -85 mv h gate opens Inactive refractory M h Open Repolarization Closed

Depolarization tissue Class IA Resting Ready Open, Active X X M h M h Class IC Open Closed threshold Gate Opens Open Slowly Closed Na channels Blockers Depolarization tissue Na/K/ATPase pump active 3 Na out/2 K in helps repolarization -50 mv M gate closes -85 mv h gate opens Class IB X Inactive refractory M h Open Repolarization Closed

Cardiac Action Potential + 20 mV Phase 1: partial repolarization Due to rapid efflux of K+ Genesis of early repolarization (Phase 1) Transient outward current of K causes a brief efflux of K because the interior is positive relative to exterior. - 90 mV Non-Pacemaker potential

Cardiac Action Potential + 20 mV Phase 2: plateau Due to Ca++ influx Genesis of the plateau (Phase 2) Two types of Ca channels; L and T type. L-type are long lasting and open when Vm -10 mV and enhanced by cAMP T-type are transient and open when Vm -70 mV but inactivate quickly. The positive Vm favours the efflux of K but K current drops which prevents excessive loss of K and loss of the plateau Ca and some Na enters through slower activating and inactivating channels. Ca channels are voltage regulated and activated as Vm becomes less negative. - 90 mV Non-Pacemaker potential

Cardiac Action Potential + 20 mV Phase 3: repolarization Due to K+ efflux Genesis of final repolarization (Phase 3) Repolarization occurs when K efflux exceeds influx of Ca. Three K channels with different physiochemical properties are responsible for repolarization. - 90 mV Non-Pacemaker potential

Phase 4: Resting Membrane Potential Cardiac Action Potential Phase 4: Resting Membrane Potential + 20 mV Restoration of ionic concentrations Ca is pumped out by a Na/Ca exchanger and Na is ejected by the Na/K/ATPase pump. Small component of Ca/ATPase. Fortunately, the essential features of repolarization are relatively simple: (1) repolarization returns the cardiac action potential to the resting transmembrane potential; (2) this process takes time; (3) this time, roughly corresponding to the width of the action potential, is the refractory period of cardiac tissue; (4) depolarization mainly depends on sodium channels, and repolarizationmainly depends on potassium channels - 90 mV Non-Pacemaker potential

Cardiac Action Potential Phase 4: pacemaker potential Na influx and K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously - 40 mV - 60 mV Pacemaker potential

Cardiac Action Potential Phase 0: upstroke: Due to Ca++ influx - 40 mV Depolarization due to calcium NOT sodium! - 60 mV Pacemaker potential

Cardiac Action Potential Phase 3: repolarization Due to K+ efflux - 40 mV - 60 mV Pacemaker potential

And less leaky to potassium Cardiac Action Potential K+ Channels Open more Slow Ca++ Channels Open - 40 mV Na+ Leak And less leaky to potassium - 60 mV Pacemaker potential

Sympathetic and Parasympathetic Sympathetic – speeds heart rate by  Ca++ & I-f channel flow Parasympathetic – slows rate by  K+ efflux &  Ca++ influx

Cardiac Action Potential

Mechanism of Cardiac Contractile Cell Muscle Excitation, Contraction & Relaxation

Cardiac Action Potential It is also called absolute refractory period (ARP) : In this period the cell can’t be excited Takes place between phase 0 and 3 Cardiac action potentials have long refractory periods (RP). No stimulus can produce another action potential during the effective refractory period.

Transmembrane action potential occurring in an automatic cardiac cell and the relationship of this action potential to events depicted on the electrocardiogram (ECG).

Arrhythmia: Definition, Mechanisms, Types

Arrhythemia Arrhythmia /dysrhythmia: abnormality in the site of origin of impulse, rate, or conduction If the arrhythmia arises from atria, SA node, or AV node it is called supraventricular arrhythmia If the arrhythmia arises from the ventricles it is called ventricular arrhythmia

Factors Precipitating Cardiac Arrhythmias 1. Ischemia pH & electrolyte abnormalities 80% – 90% asstd with MI 2. Excessive myocardial fiber stretch/ scarred/ diseased cardiac tissue 3. Excessive discharge or sensitivity to autonomic transmitters 4. Excessive exposure to foreign chemicals & toxic substances 20% - 50% asstd with General Anesthesia 10% - 20% asstd with Digitalis toxicity

Mechanisms of Arrhythmogenesis Abnormal heart pulse formation Sinus pulse Ectopic pulse Triggered activity Abnormal heart pulse conduction Reentry Conduct block Abnormal Automaticity Non-pacemaker cells begin to spontaneously and initiate an impulse. Reduced RMP bringing it closer to the threshold potential. Ischemia and electrolyte imbalances

Mechanisms of Arrhythmogenesis Triggered activity Early afterdepolarizations associated with QT prolongation (torsades de pointes) Delayed afterdepolarizations associated with Ca2+ overload (e.g. digoxin) Spontaneous depolarizations requiring a preceding impulse (a triggering beat) are called afterdepolarizations (or triggered activity). If afterdepolarizations originate during phase 2 or 3 of the monophasic action potential (MAP) they are classified as early afterdepolarizations (EAD) (Fig 2). Afterdepolarizations originating from phase 4 of the MAP are classified as delayed afterdepolarization (DAD) (Fig 3). An example of early afterdepolarization (EAD) is drug induced torsade de pointe, a polymorphic form of ventricular tachycardia that is a potentially lethal complication of anti arrhythmic and other drugs that prolong the QT-interval. The extrusion of potassium from myocardial cells allows the cell’s membrane potential to go back to its resting potential. This process is called repolarization, and is carried via a potassium channel (IK channel). The process involves bringing the transmembrane potential back to its resting value. The less negative the trans membrane potential, the less sodium channels are available to depolarize the cell making it refractory to any received impulse (unexcitable). The extrusion of potassium determines the duration of the action potential, the cell’s refractory period and the length of the QT interval (the electrocardiographic equivalent of repolarization). Drugs that block this channel such as quinidine, procainamide, sotalol and dofetilide can result in torsade de pointe. Ventricular arrhythmias secondary to digoxin toxicity is an example of delayed afterdepolarization. Digoxin mediated increased intracellular Ca++ is believed to be the mechanism of this type of arrhythmia.

The “Re-Entry” Mechanism of Ectopic Beats & Rhythms Most common mechanism Requires two separate paths of conduction Requires an area of slow conduction Requires unidirectional block

Re-entry Circuits as Ectopic Foci and Arrhythmia Generators Atrio-Ventricular Nodal Re-entry supraventricular tachycardia Ventricular Re-entry ventricular tachycardia Atrial Re-entry atrial tachycardia atrial fibrillation atrial flutter Atrio-Ventricular Re-entry Wolf Parkinson White supraventricular tachycardia

Antiarrhythmic drugs

Pharmacologic Rationale & Goals The ultimate goal of antiarrhythmic drug therapy: Restore normal sinus rhythm and conduction Prevent more serious and possibly lethal arrhythmias from occurring. Antiarrhythmic drugs are used to: Suppressing automaticity in pacemaker Prolonging the effective refractory period Facilitating impulse conduction along normal conduction pathways Suppressing automaticity in pacemaker cells by decreasing the slope of phase 4 depolarization, Prolonging the effective refractory period to eliminate reentry circuits Facilitating impulse conduction along normal conduction pathways to prevent conduction over a reentrant pathway.

Classification of Antiarrhythmic Drugs Class I: Sodium channel blockers (membrane-stabilizing agents) 1 a: Block Na+ channel and prolong action potential 1 b: Block Na+ channel and shorten action potential 1 c: Block Na + channel with no effect on action potential Class II: β- blockers Class III: Potassium channel blockers (main effect is to prolong the action potential) Class IV: Slow (L-type) calcium channel blockers Class I -membrane- stabilising agents (sodium channel blockers) ( a ) Block Na + channel and prolong action potential Quinidine , disopyramide , procainamide ( b ) Block Na + channel and shorten action potential Lidocaine , mexiletine ( c ) Block Na + channel with no effect on action potential Flecanide , propafenone Class II - β- adrenoceptor antagonists ( β- blockers) Atenolol , bisoprolol , metoprolol , I- sotalol Class III -drugs whose main effect is to prolong the action potential Amiodarone , d- sotalol Class IV -slow calcium channel blockers Verapamil , diltiazem

duration, amplitude of AP, CLASS IA Procainamide, Quinidine, Disopyramide Block Na channels Intermediate (< 5 s) binding Kinetics prolong AP duration, amplitude of AP, As you can see here, it blunts the upstroke and prolongs phase 2 Slowing of the rate of rise in phase 0  ↓conduction velocity ↓of Vmax of the cardiac action potential They prolong muscle action potential & ventricular (ERP) They ↓ the slope of Phase 4 spontaneous depolarization (SA node)  decrease enhanced normal automaticity Vmax They make the slope more horizontal

Fast onset/offset binding CLASS IB Lidocaine Mexiletine Phenytoin Tocainide Block Na channels Fast onset/offset binding kinetics (< 500 ms) shortened AP duration, The IB drugs blunt the upstroke slightly because it is a weak sodium channel blocker, but it also has action at potassium channels which Is why it shortens the action potential durationThey shorten Phase 3 repolarization ↓ the duration of the cardiac action potential They suppress arrhythmias caused by abnormal automaticity They show rapid association & dissociation (weak effect) with Na+ channels with appreciable degree of use-dependence No effect on conduction velocity no change Vmax

but minimal prolongation CLASS IC Flecainide, Propafenone, Moricizine Block Na channels Slow binding kinetics (10–20 s) slow conduction but minimal prolongation of refractoriness. They markedly slow Phase 0 fast depolarization They markedly slow conduction in the myocardial tissue They possess slow rate of association and dissociation (strong effect) with sodium channels They only have minor effects on the duration of action potential and refractoriness They reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization. Vmax

Blockade of β-adrenoceptor CLASS II Propranolol Atenolol Metoprolol Timolol, Esmolol Blockade of β-adrenoceptor

CLASS III Block K channels Amiodarone Sotalol, Bretylium Dofetilide Ibutilide Includes sotalol and amioderone Block K channels

CLASS IV Verapamil Diltiazem Block slow Ca2+ channel

modification of the Sicilian Gambit drug classification system This is a modification of the Sicilian Gambit drug classification system and includes designation by the Vaughan Williams system. The sodium channel blockers are subdivided into the A, B, and C subgroups based on their relative potency. The targets of antiarrhythmic drugs are listed across the top in columns. These targets are the ion channels—sodium, calcium, and potassium—and the receptors—α-adrenergic, β-adrenergic, cholinergic (ACh), and adenosinergic (Ado). The next columns show a comparison of the clinical actions of the drugs, including proarrhythmic potential (Proarrhy), effect on left ventricular function (LV FX), effects on heart rate (Heart Rate), and potential for extra cardiac side effects (Extra Cardiac). The electrocardiographic tracings indicate the changes (in color) that are caused by usual dosages of the drug: PR interval (blue), QRS interval (red), and QT interval (green). The drugs are listed in rows with their brand names shown in parentheses. The symbols in the table indicate the relative potency of the drugs as agonists or antagonists. The solid triangle indicates the biphasic effects of bretylium to initially release norepinephrine and act as an agonist and subsequently to block further release and to act as an antagonist of adrenergic tone. The number of arrows and their directions indicate the magnitude and direction, respectively, of the effect of the drugs on heart rate and left ventricular function (i.e., inotropy).

Proarrhythmia effect of antiarrhythmia agents Ia, Ic class: Prolong QT interval, will cause VT or VF in coronary artery disease and heart failure patients III class: Like Ia, Ic class agents II, IV class: Bradycardia

Class I

duration, amplitude of AP, Procainamide Mechanism of Action INa (primary) and IKr (secondary)blockade. Slowed conduction velocity and pacemaker activity. Prolonged action potential duration and refractory period. Vmax prolong AP duration, amplitude of AP,

Procainamide Clinical Applications Most atrial and ventricular arrhythmias Drug of second choice for most sustained ventricular arrhythmias associated with acute myocardial infarction

Procainamide Pharmacokinetics Oral and parenteral; oral slow-release forms available Duration: 2–3 h eliminated by hepatic metabolism to (NAPA) and renal elimination NAPA implicated in torsades de pointes in patients with renal failure

Procainamide Toxicities, Interactions Increased arrhythmias, hypotension, lupus-like syndrome Dose For stable wide-QRS tachycardia IV dose: 20-50 mg/min slowly until Arrhythmia suppressed, hypotension ensues, QRS duration increases 50%, or maximum dose 17 mg/kg given Maintenance infusion: 1-4 mg/min Avoid if prolonged QT or CHF For stable wide-QRS tachycardia IV dose: 20-50 mg/min slowly until Arrhythmia suppressed, hypotension ensues, QRS duration increases 50%, or maximum dose 17 mg/kg given Maintenance infusion: 1-4 mg/min Avoid if prolonged QT or CHF

Quinidine Similar to procainamide but more toxic (cinchonism, torsades); rarely used in arrhythmias The effective dosage of quinidine varies among individuals because of several factors. Although quinidine sulfate is usually administered every 6 hours, there are wide interindividual differences in its elimination half-life, which ranges from 3 to 19 hours.11 Plasma protein binding also varies widely, ranging from 50% to 95%.11 Oral bioavailability is approxi- Quinidine metabolism is inhibited by cimetidine35 and induced by phenytoin, phenobarbital,36 and rifampicin,24 with the latter agents leading to reduced, often subtherapeutic, quinidine concentrations. Clinical digoxin toxicity has been described in 20% to 40% of patients receiving quinidine and digoxin concurrently.35 The magnitude of this interaction is dependent on quinidine dosage, and in some patients it may not appear until the dosage is increased to higher levels.37,38 The rise in digoxin levels appears with the first dose of quinidine; therefore, it is suggested that digoxin dosage be halved when quinidine therapy is initiated. A similar interaction has been reported for quinidine and digitoxin. Quinidine is a potent inhibitor of the hepatic cytochrome P450 (CYP) specific for debrisoquine metabolism (CYP2D6),39,40 although it is not metabolized by this specific CYP isozyme.41,42 Thus, it may interfere with the biotransformation and actions of pharmacologic agents that are dependent on this cytochrome for their metabolism, which include propafenone, mexiletine, flecainide, metoprolol, timolol, sparteine, and bufuralol.43 Quinidine worsens neuromuscular blockade in patients with myasthenia gravis44 and may prolong the effects of succinylcholine

Disopyramide Similar to procainamide but significant antimuscarinic effects; may precipitate heart failure; not commonly used

Lidocaine Mechanism of Action Sodium channel (INa) blockade Blocks activated and inactivated channels with fast kinetics Does not prolong and may shorten action potential

Lidocaine Clinical Applications Terminate ventricular tachycardias and prevent ventricular fibrillation after cardioversion Dosage: 1.5 mg/kg IV, then 1– 4 mg/min; repeat 1/2 initial dose after 10 min

Lidocaine Pharmacokinetics IV first-pass hepatic metabolism Reduce dose in patients with heart failure or liver disease Toxicities Neurologic symptoms

Mexiletine Orally active congener of lidocaine; used in ventricular arrhythmias, chronic pain syndromes

Flecainide Mechanism of Action: Sodium channel (INa) blockade Dissociates from channel with slow kinetics no change in action potential duration

Flecainide Clinical Applications: Supraventricular arrhythmias in patients with normal heart do not use in ischemic conditions (post-myocardial infarction)

Flecainide Pharmacokinetics: Oral hepatic and kidney metabolism half life ∼ 20 h Toxicities: Proarrhythmic Notice: Class 1C drugs are particularly of low safety and have shown even increase mortality when used chronically after MI

Propafenone Orally active, weak b-blocking activity; supraventricular arrhythmias; hepatic metabolism.

Moricizine Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic. Withdrawn in USA.

Class II

Propranolol Mechanism of Action: Direct membrane effects (sodium channel block) and prolongation of action potential duration slows SA node automaticity and AV nodal conduction velocity

Propranolol Clinical Applications: Atrial arrhythmias and prevention of recurrent infarction and sudden death Pharmacokinetics: Oral, parenteral duration 4–6 h

Propranolol Dose: 1 mg over 1 min (total 10-12 mg; 0.15 mg/kg). onset:5 min Toxicities: Asthma, AV blockade, acute heart failure Interactions: With other cardiac depressants and hypotensive drugs

Esmolol Short-acting, IV only; used for intraoperative and other acute arrhythmias Loading dose of 200-500 mcg/kg IV over 1 min, then 50-100 mcg/kg/min; titrate by 50 mcg/kg/min q 15-20 min. up to 200 mcg/kg/min Onset: 2-3 min. 0.5 mg/kg over 1 min, followed by 0.05-0.2 mg/kg/min for 4 min; if no response after 5 min, 0.5 mg/kg for 1 min, followed by 0.1 mg/kg for 4 min; infusion 0.05-0.2 mg/kg/min for rate control.

Class III

Amiodarone Mechanism of Action: Blocks IKr, INa, ICa-L channels,β adrenoceptors Prolongs action potential duration and QT interval slows heart rate and AV node conduction Low incidence of torsades de pointes Amiodarone is a drug of multiple actions and is still not well understood It is extensively taken up by tissues, especially fatty tissues (extensive distribution) t1/2 = 60 days Potent P450 inhibitor Amiodarone antiarrhythmic effect is complex comprising class I, II, III, and IV actions Dominant effect: Prolongation of action potential duration and refractoriness It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak β-adrenergic blocker Toxicity Most common include GI intolerance, tremors, ataxia, dizziness, and hyper-or hypothyrodism Corneal microdeposits may be accompanied with disturbed night vision Others: liver toxicity, photosensitivity, gray facial discoloration, neuropathy, muscle weakness, and weight loss The most dangerous side effect is pulmonary fibrosis which occurs in 2-5% of the patients

Amiodarone Clinical Applications: Serious ventricular arrhythmias and supraventricular arrhythmias

Amiodarone Pharmacokinetics: Oral, IV variable absorption and tissue accumulation hepatic metabolism, elimination complex and slow Dose • First dose: IV 300 mg over 10 minutes • Repeat as needed if VT recurs • Follow by maintenance infusion of 900 mg over 24 hrs When amiodarone is loaded intravenously, 1 g is delivered during the first 24 hours as follows: 150 mg is infused during the first 10 minutes (15 mg/min), followed by 360 mg during the next 6 hours (1 mg/min), and then followed by 540 mg during the next 18 hours (0.5 mg/min). If intravenous therapy is still desired after the first 24 hours, the infusion can continue at 0.5 mg/min (720 mg/24 h).

Amiodarone Toxicities: Bradycardia and heart block in diseased heart, peripheral vasodilation, pulmonary and hepatic toxicity hyper- or hypothyroidism. Interactions: Many, based on CYP metabolism

Sotalol Sotalol IV dose: B-Adrenergic and IKr blocker, direct action potential prolongation properties, use for ventricular arrhythmias, atrial fibrillation Dose: Sotalol IV dose: 100 mg (1.5 mg/kg) over 5 minutes Avoid if prolonged QT

Dofetilide Mechanism of Action: IKr block Prolongs action potential, effective refractory period

Dofetilide Clinical Applications: Maintenance or restoration of sinus rhythm in atrial fibrillation

Dofetilide Pharmacokinetics: Oral renal excretion Toxicities: Torsades de pointes (initiate in hospital) Interactions: Additive with other QT-prolonging drugs

Ibutilide Potassium channel blocker, may activate inward current; IV use for conversion in atrial flutter and fibrillation

Dronedarone Amiodarone derivative; multichannel actions, reduces mortality in patients with atrial fibrillation

Class IV

Verapamil Mechanism of Action: blocks both activated and inactivated L-type calcium (SA & AV node) AV nodal conduction time and ERP Extracardiac Effects: Peripheral vasodilation (Less than nifedipine) Cardiac Effects Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the SA and AV nodes. AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic concentrations. Verapamil usually slows the SA node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of SA rate. Verapamil can suppress both early and delayed afterdepolarizations and may antagonize slow responses arising in severely depolarized Tissue Toxicity Verapamil’s cardiotoxic effects are dose-related and usually avoidable. A common error has been to administer intravenous verapamil to a patient with ventricular tachycardia misdiagnosed as supraventricular tachycardia. In this setting, hypotension and ventricular fibrillation can occur. Verapamil’s negative inotropic effects may limit its clinical usefulness in diseased hearts (see Chapter 12 ). Verapamil can induce AV block when used in large doses or in patients with AV nodal disease. This block can be treated with atropine and β-receptor stimulants. Adverse extracardiac effects include constipation, lassitude, nervousness, and peripheral edema. Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily, divided into three or four doses. Therapeutic Use Supraventricular tachycardia is the major arrhythmia indication for verapamil. Adenosine or verapamil are preferred over older treatments (propranolol, digoxin, edrophonium, and vasoconstrictor agents) and cardioversion for termination. Verapamil can also reduce the ventricular rate in atrial fibrillation and flutter. It only rarely converts atrial flutter and fibrillation to sinus rhythm. Verapamil is occasionally useful in ventricular arrhythmias. However, intravenous verapamil in a patient with sustained ventricular tachycardia can cause hemodynamic collapse.

Verapamil Clinical Applications: Supraventricular tachycardia. Atrial fibrillation and flutter . Cardiac Effects Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the SA and AV nodes. AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic concentrations. Verapamil usually slows the SA node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of SA rate. Verapamil can suppress both early and delayed afterdepolarizations and may antagonize slow responses arising in severely depolarized Tissue Toxicity Verapamil’s cardiotoxic effects are dose-related and usually avoidable. A common error has been to administer intravenous verapamil to a patient with ventricular tachycardia misdiagnosed as supraventricular tachycardia. In this setting, hypotension and ventricular fibrillation can occur. Verapamil’s negative inotropic effects may limit its clinical usefulness in diseased hearts (see Chapter 12 ). Verapamil can induce AV block when used in large doses or in patients with AV nodal disease. This block can be treated with atropine and β-receptor stimulants. Adverse extracardiac effects include constipation, lassitude, nervousness, and peripheral edema. Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily, divided into three or four doses. Therapeutic Use Supraventricular tachycardia is the major arrhythmia indication for verapamil. Adenosine or verapamil are preferred over older treatments (propranolol, digoxin, edrophonium, and vasoconstrictor agents) and cardioversion for termination. Verapamil can also reduce the ventricular rate in atrial fibrillation and flutter. It only rarely converts atrial flutter and fibrillation to sinus rhythm. Verapamil is occasionally useful in ventricular arrhythmias. However, intravenous verapamil in a patient with sustained ventricular tachycardia can cause hemodynamic collapse.

Verapamil Toxicities: constipation, sinus arrest, hypotension, headache, nervousness Dose: 5-10 mg (0.075-0.15 mg/kg) over 2 min; if no response, additional 5-10 mg after 15-30 min; 3-10 mg every 4-6 h for rate control. Onset:3-5 min. Cardiac Effects Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the SA and AV nodes. AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic Verapamil and diltiazem bind only to open depolarized voltage-operated Ca2+ channels, and hence preventing re-polarization until the drug dissociates from the channels. Therefore, they are use-dependent blocking rapidly beating heart since in a normally-paced heart, Ca2+ channels have enough time to repolarize and the drug to dissociate from the channel before the next conduction cycle Verapamil and diltiazem slow conduction and prolong effective refractory period in Ca2+ current-dependent tissues like AV node concentrations. Verapamil usually slows the SA node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of SA rate. Verapamil can suppress both early and delayed afterdepolarizations and may antagonize slow responses arising in severely depolarized Tissue Toxicity Verapamil’s cardiotoxic effects are dose-related and usually avoidable. A common error has been to administer intravenous verapamil to a patient with ventricular tachycardia misdiagnosed as supraventricular tachycardia. In this setting, hypotension and ventricular fibrillation can occur. Verapamil’s negative inotropic effects may limit its clinical usefulness in diseased hearts (see Chapter 12 ). Verapamil can induce AV block when used in large doses or in patients with AV nodal disease. This block can be treated with atropine and β-receptor stimulants. Adverse extracardiac effects include constipation, lassitude, nervousness, and peripheral edema. Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily, divided into three or four doses. Therapeutic Use Supraventricular tachycardia is the major arrhythmia indication for verapamil. Adenosine or verapamil are preferred over older treatments (propranolol, digoxin, edrophonium, and vasoconstrictor agents) and cardioversion for termination. Verapamil can also reduce the ventricular rate in atrial fibrillation and flutter. It only rarely converts atrial flutter and fibrillation to sinus rhythm. Verapamil is occasionally useful in ventricular arrhythmias. However, intravenous verapamil in a patient with sustained ventricular tachycardia can cause hemodynamic collapse.

Unclassified

Adenosine Endogenous chemical Mechanism of Action: Increase in potassium efflux decreases calcium influx. This hyperpolarizes cardiac cells Clinical Applications: PSVT Rapid IV injection t 1/2: (2 - 10 sec) S: flushing, chest pain, and dyspnea Caution in patients (AV) block, bronchial asthma Adenosine activates A1-purinergic receptors decreasing the SA nodal firing and automaticity, reducing conduction velocity, prolonging effective refractory period, and depressing AV nodal conductivity It is the drug of choice in the treatment of paroxysmal supra-ventricular tachycardia It is used only by slow intravenous bolus It only has a low-profile toxicity (lead to bronchospasm) being extremly short acting for 15 seconds only Adenosine is formed by serial dephosphorylation of adenosine triphosphate. It is an α-agonist and the drug of choice for pharmacologic termination of hemodynamically stable AVNRT. Sixty percent of patients respond at a dose of 6 mg, and an additional 32% of patients respond at a dose of 12 mg. Its therapeutic effect is short, lasting approximately 10 seconds. This extremely short half-life results from rapid active transport of the drug into red blood cells and endothelial cells, where it is metabolized. To be effective, adenosine should be injected rapidly and flushed quickly through the intravenous tubing with saline. Common side effects of adenosine include facial flushing, dyspnea, and chest pressure. Generally, these effects are transient, lasting less than 60 seconds. Less common side effects include nausea, light-headedness, headache, sweating, palpitations, hypotension, and blurred vision. Several drugs influence the clinical effectiveness of adenosine. Caffeine and theophylline antagonize the actions of

Adenosine Dose: Adenosine IV dose: First dose: 6 mg rapid IV push; follow with NS flush. Second dose: 12 mg if required. Adenosine activates A1-purinergic receptors decreasing the SA nodal firing and automaticity, reducing conduction velocity, prolonging effective refractory period, and depressing AV nodal conductivity It is the drug of choice in the treatment of paroxysmal supra-ventricular tachycardia It is used only by slow intravenous bolus It only has a low-profile toxicity (lead to bronchospasm) being extremly short acting for 15 seconds only Adenosine is formed by serial dephosphorylation of adenosine triphosphate. It is an α-agonist and the drug of choice for pharmacologic termination of hemodynamically stable AVNRT. Sixty percent of patients respond at a dose of 6 mg, and an additional 32% of patients respond at a dose of 12 mg. Its therapeutic effect is short, lasting approximately 10 seconds. This extremely short half-life results from rapid active transport of the drug into red blood cells and endothelial cells, where it is metabolized. To be effective, adenosine should be injected rapidly and flushed quickly through the intravenous tubing with saline. Common side effects of adenosine include facial flushing, dyspnea, and chest pressure. Generally, these effects are transient, lasting less than 60 seconds. Less common side effects include nausea, light-headedness, headache, sweating, palpitations, hypotension, and blurred vision. Several drugs influence the clinical effectiveness of adenosine. Caffeine and theophylline antagonize the actions of

Magnesium Mechanism of Action: unknown Clinical Applications: Used for treatment of torsades de pointes Toxicities: Bradycardia Respiratory paralysis Flushing Headache Given in 2 gm over 10 min

Compare?? class ECG QT Conduction velocity Refractory period IA ++ ↓ ↑ IB no IC + II ↓In SAN and AVN ↑ in SAN and AVN III No IV ↓ in SAN and AVN

Management of some types of arrhythemia

WPW AF

2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care