Ch. 21 Antiarrhythmic Drugs & Lecture.pdf

Ch. 21: Antiarrhythmic Drugs Perioperative Cardiac Arrhythmias • The majority of perioperative cardiac arrhythmias do not require therapy, unless hemodynamic compromise is noted. • Benign (causes below) o Transient changes in physiology ▪ hypovolemic (NPO) o Surgical stimuli ▪ placing central lines...

Ch. 21: Antiarrhythmic Drugs Perioperative Cardiac Arrhythmias • The majority of perioperative cardiac arrhythmias do not require therapy, unless hemodynamic compromise is noted. • Benign (causes below) o Transient changes in physiology ▪ hypovolemic (NPO) o Surgical stimuli ▪ placing central lines (going past SVC/RA → ectopy) ▪ retractors affect heart ▪ pneumoperitoneum—reduces CO Ch. 21: Antiarrhythmic Drugs ▪ baroreceptor fx in carotid endarterectomy Effect of anesthetic agent ▪ inhalation gases Requiring Treatment o Hemodynamic compromise ▪ low O2 delivery state Chronic Arrhythmias (Preoperative Assessment) o Pacemakers (Identify underlying rhythm and pacemaker settings) ▪ magnet over pacer to turn it to asynchronous mode ▪ have transcutaneous pacer ready o Ablations ▪ may still have arrhythmias after ablation Chronic pharmacological treatment o need to make sure drug is working well for pt AICD with pharmacological treatment Look for: o new onset? o controlled? if not new o hemodynamic compromise? ▪ blood pressure ▪ level of consciousness o • • • • • Intraoperative Arrhythmias: Prevention and Treatment • correction of identifiable precipitators o electrolytes → check labs before surgery o want to optimize pt‼ o want to prevent these factors to prevent enhanced automaticity o Reentry and Enhanced Automaticity o Hypoxemia ▪ ensure adequate O2 delivery ▪ monitor oxygenation o Electrolyte and Acid-base Disturbances ▪ Acidosis and *alkalosis ▪ K, Mg (assess with patients taking diuretics) o Myocardial Ischemia ▪ watch EKG for changes o Altered SNS activity o Bradycardia o Administration of certain drugs o Increased SNS activity with beta blockade and vagal stimulation o Enlargement of a failing Left Ventricle o **know what acidosis and alkalosis looks like • pharm tx Relative A&P: ECG and Cardiac Cells • Basics of the ECG o Conduction System ▪ SA ▪ AV ▪ Bundle of HIS ▪ Bundle Branches ▪ Purkinje Fibers • Cardiac Cell Types o Pacemaker Cells (Nodal Cells) ▪ also called atrial cells ▪ SA, AV nodes; Bundle of His and Purkinje Ch. 21: Antiarrhythmic Drugs o Contractile Cells (Muscle Cells) ▪ also called ventricular cells Cardiac Cells – Pacemaker Cells ▪ automaticity ▪ SA node—primary pacemaker, reaches threshold the fastest o SA node: beta-1 receptors, muscarinic receptors o primary pacemaker ▪ AV node, bundle of His, Purkinje fibers—latent pacemakers o secondary pacemakers ▪ pacer cells are independent and can generate action potential Action Potentials ▪ cardiac cells are surrounded by extracellular fluid ▪ primary ions causing cardiac cell activity are: sodium, potassium, calcium ▪ action potentials occur in both pacemaker and muscle cells ▪ **know what happens in each phase of the ventricular action potential Action Potential of Pacemaker Cell ▪ phases 4, 0, 3 ▪ ion activity: potassium, sodium, calcium ▪ mV potentials: -60, -40, +10 Action Potential of Cardiac Muscle Cell ▪ phases 4, 0, 1, 2, 3 ▪ ion activity: potassium, sodium, calcium ▪ mV potentials: -90, +40 Arrhythmias ▪ normally, action potentials are generated at the SA node. o normal conduction pathway o normal velocity o rate: 60-100 bpm ▪ bradyarrhythmias: less than 60 bpm ▪ tachyarrhythmias: greater than 100 bpm Bradycardia ▪ symptomatic bradycardia is treated with a pacemaker Ch. 21: Antiarrhythmic Drugs ▪ pharm treatment with appropriate sympathomimetic o isoproterenol o atropine o glycopyrrolate o atropine works faster than glycopyrrolate‼ ▪ consider transcutaneous pacing Mechanisms of Tachyarrhythmias ▪ abnormal automaticity o cell membrane becomes more permeable to sodium during phase 4 o increase in slope of phase 4 depolarization o increases conduction rate ▪ triggered activity o abnormal leakage of positive ions into cardiac cell ▪ any positive entry will increase cellular activity (beating) ▪ could lead to tachyarrhythmia o bump in depolarization in phases 2, 3, or 4 o can trigger premature action potentials ▪ triggers a beat before its time ▪ reentry activity o alternative (accessory) conduction pathway exists between the upper and lower chambers o WPW syndrome—12 lead o AVNrT (fast and slow pathways) Antiarrhythmic Drugs • arrhythmias common in perioperative period • most are benign; d/t transient changes in physiology, surgical stimulation, or anesthetic effects • arrythmias that require tx → usually supraventricular o a-fib common after cardiac sx • re-entry and enhanced automaticity → 2 most common major physiologic mechanisms that cause ectopic arrhythmias • factors in periop that facilitate arrhythmias: o hypoxemia o electrolyte and acid-base abnormalities o myocardial ischemia o altered SNS activity o bradycardia o certain drugs • hypokalemia and hypomagnesemia → predispose to ventricular arrhythmias o suspect low K+ and Mg2+ in pts on diuretics • increased SNS activity during DL or surgical stimulation lowers the threshold for v-fib o v-fib incidence is usually weakened by beta blockers and vagal stimulation • bradycardia can lead to ventricular arrhythmias by causing temporal dispersion of refractory periods among Purkinje fibers → creates electrical gradient btwn adjacent cells • enlargement of failing LV → stretches myocardial cells o induces arrhythmias o this is controlled by dec LV volume with digitalis, diuretics, or vasodilators • drugs administered for chronic suppression of arrhythmias pose little threat to anesthesia → continue until time of surgery • arrhythmias require tx when hemodynamics are compromised OR the disturbance predisposes to more serious arrythmias Mechanism of Action • antiarrhythmics block passage of Na+, K+, Ca2+ across ion channels in the heart • the cardiac action potential results from multiple inward and outward currents via specific ion channels responsible for each phase • ion channels—large membrane-bound glycoproteins that provide pathways across cell membranes to allow ions to pass o exist in different states—open, inactivated, closed o inactivated state: ion channel not responsive to a new or continued stimulus ▪ occurs during plateau phase of repolarization o resting state: more prevalent in diastole o active state: occurs during upstroke of action potential Ch. 21: Antiarrhythmic Drugs • • • drugs that block inward Na+ flow → slow down conduction; suppress the max upstroke velocity of the cardiac action potential drugs that block K+ → prolong repolarization by increasing the duration of cardiac action potential and the effective refractory period. This results in prolonged QTc on ECG. calcium channels are located in myocardial cells. o the alpha subunit of L and T type calcium channels is the site of action of some antiarrhythmics. Classification • Vaughn-Williams classification (table 21.1) Antiarrhythmic Agent Classification: • Vaughn-Williams Classification → know • based on dominant mechanism of action • looking at ion influx/efflux • 4 Classes • Class I, II, III, IV • Class I (MEMBRANE STABILIZERS) • Block fast Na channels in the open or inactivated state • Decreases rise in Phase 0 depolarization • 3 subclasses according to effect on cardiac action potential • Class IA, IB, and IC → affect cardiac action potentials • Used to treat: • Acute and chronic SVT • Slow atrial rate in Afib • Suppress tachyarrhythmias in WPW • slow everything down Ch. 21: Antiarrhythmic Drugs Ch. 21: Antiarrhythmic Drugs Class I Drugs • inhibit fast Na+ channels during depolarization (phase 0) • this decreases depolarization rate and conduction velocity Class 1A • quinidine, procainamide, disopyramide, moricizine • make action potential and effective refractory period longer o due to inhibition of Na+ channels and prolonged repolarization d/t K+ channel blockade • proarrhythmic and negative inotropic effects • MOA: o Moderately depress Phase 0 depolarization o Blocks fast Na channels o Prolong repolarization by blocking some K channels o Result: Prolonged AP and Prolonged Refractory Period • Agents: o Procainamide o Quinidine o Disopyramide o Moricizine Ch. 21: Antiarrhythmic Drugs • • Class 1B • • • • • • • • Class 1C • • • • • • • • • Clinical Uses: Wide variety; VT and Afib Side Effects: Blurred vision, HA, tinnitus, anticholinergic effects, Potential to cause arrythmias lidocaine, mexiletine, tocainide, phenytoin less powerful Na+ channel blockers shorten duration of action potential and refractory period lidocaine blocks ATP-dependent channels, which prevents ischemia-mediated shortening of ventricular depolarization MOA o Weak effect on Phase 0 depolarization; minimal blockade on fast Na channels o Shorten repolarization by blocking Na channels in late phase 2 of AP o Shortened duration action potential and refractory period Agents o Lidocaine—local anesthetics block sodium channels, so it will also block sodium channels in the heart. o Mexiletine o Tocainide o Phenytoin Uses: Ventricular arrhythmias Side Effects: o Lidocaine-CNS toxicity o Mexiletine-N&V o Both- Potential to cause arrythmias flecainide, propafenone potent Na+ channel blockers decrease the rate of phase 0 depolarization and speed of conduction little effect on duration of action potential and refractory period in ventricular cells o shorten action potential in Purkinje fibers may have proarrhythmic effects MOA o Potent; Fast Na channel blockers o Depress Phase 0 depolarization markedly o Inhibit His-Purkinje conduction system o Limited action on repolarization and refractory period Uses: Refractory Ventricular Arrhythmias; not first line tx Agents: o Flecainide o Propafenone Side Effects: Dizziness, Blurred Vision, Nausea, Potential to cause arrhythmias Class II Drugs • beta blockers • beta blockers decrease the rate of spontaneous phase 4 depolarization → results in dec SNS activity • slow HR down and dec myocardial O2 demand → good for CAD • slow down conduction through atrial tissue → prolongs the PR interval • do not change the duration of the action potential through the ventricular myocardium. • Beta Blockers (B1) o primarily active on b1 (but also act on b2) o Decrease rate of depolarization o Decrease HR, conduction, contractility • Agents o Esmolol (IV fast onset, short half-life, titrate rapidly) o Propranolol o Acebutolol Ch. 21: Antiarrhythmic Drugs Class III Drugs • amiodarone, dronedarone, sotalol • block K+ channels → prolongs depolarization, action potential, and refractory period • decrease the proportion of the cardiac cycle where myocardial cells are excitable and susceptible to trigger o decrease the time spent in excitation mode • amiodarone exhibits: o sodium channel blockade—class I o beta blockade—class II o calcium channel blockade—class IV • sotalol: long-acting noncardioselective beta blocker o has 2 isomers that exhibit similar class III effects o one isomer has beta blocking properties • MOA: Blocks K channels in Phase 3 of depolarization • Result: Increase in duration of action potential and refractory period • Agents: o *Amiodarone, o Sotalol/BetaPace o Ibutilide o Dofetilide o Bretylium (old ACLS drug) • Uses: SVT, Ventricular tachyarrhythmias, Afib, Aflutter • Amiodarone- Blocks Na, K, Ca Channels, Beta, and Alpha receptors o Acute treatment for refractory ventricular arrhythmias, SVT, Vent arrhythmias in OR. o Side effects: Pulmonary fibrosis, neuropathy, hepatic toxicity, etc. o Long half-life (months after therapy) Class IV Drugs • calcium channel blockers • verapamil, diltiazem (nondihydropyridines) • inhibit slow calcium ion currents that may contribute to the development of tachycardias • good for SVTs and idiopathic VT • the dihydropyridines (nifedipine, nicardipine, nimodipine) → NO antiarrhythmic effect • MOA o SA and AV node action potential o Block Ca channels o Slower conduction in SA and AV node o Reduced contractility in heart • Agents: (Calcium Channel Blockers) o Verapamil o Diltiazem o Nondihydropyridines are selective for cardiac calcium channels • Uses: SVT and Afib o originating above ventricles • Contraindicated in WPW Ch. 21: Antiarrhythmic Drugs Class 0 Drugs • ivabradine—selectively inhibits the current through the SA node • slows down HR and depolarization → “funny current” • ivabradine slows HR—more effective in high HRs • no hemodynamic effects Proarrhythmic Effects (new arrythmias as a result of antiarrhythmic agents) Torsades de Pointes ▪ class I and class III o class 1A—quinidine, disopyramide o class III—amiodarone ▪ marked QT prolongation by blocking potassium channels ▪ hypokalemia and hypomagnesemia potentiate torsades in this setting ▪ treatment: o magnesium sulfate, even if serum magnesium levels are normal o isoproterenol/Isuprel—chemical pacemaker drug; beta agonist o cardiac pacing o raise serum potassium to 4.5-5.0 Incessant Ventricular Tachycardia ▪ class 1A and 1C ▪ these drugs slow conduction enough to create a continuous ventricular tachycardia circuit ▪ more likely to occur with high doses of class IC Wide Complex Ventricular Rhythm ▪ class 1C ▪ calcium channel blockers—diltiazem and verapamil Efficacy and Results of Treatment with Cardiac Antiarrhythmic Drugs Prophylactic Antiarrhythmic Drug Therapy Decision to Treat Cardiac Arrhythmias Antiarrhythmic Drug Pharmacology Quinidine • class 1A • effective for tx of acute and chronic supraventricular arrhythmias • rarely used—not good side effect profile, low therapeutic index • actions of quinidine: o prevents recurrence of supraventricular tachyarrhythmias o suppresses PVCs o slows ventricular rate in a-fib o effective in supraventricular tachyarrhythmias in WPW • usual dosing—oral; 200-400 mg 4x/day • peak: 60-90 min • T ½: 5-12 hrs • IV quinidine rarely used; vasodilates and depresses myocardial fx Mechanism of Action • antimalarial & antipyretic effects • dec slope of phase 4 depolarization • increases fibrillation threshold in the atria and ventricles • abolishes re-entrant arrhythmias by prolonging conduction of cardiac impulses • alpha blocking effects Metabolism and Excretion • metabolism: liver • excretion: renal • enzyme induction shortens the duration of action of quinidine Ch. 21: Antiarrhythmic Drugs • concurrent admin of phenytoin, phenobarbital, rifampin → lowers blood levels of quinidine by enhancing liver clearance • 80-90% protein bound (albumin) Side Effects • low therapeutic index • adverse effects: o heart block o hypotension o proarrhythmic • when plasma concentration > 2 mcg/mL → PR interval, QRS, QTc are prolonged • allergic rxns—rash, fever, leukocytosis, thrombocytopenia, N/V/D • cinchonism—tinnitus, hearing decreased, blurred vision, GI upset • alpha blocking effects → has an additive effect with other drugs that cause vasodilation • interferes with normal neuromuscular transmission → enhances effects of NMBD o recurrence of paralysis is associated w/ quinidine Procainamide • tx of ventricular tachyarrhythmias, PVCs, paroxysmal VT • IV admin may cause hypotension • IV dosing: o no more than 100 mg every 5 min until rhythm controlled ▪ do not exceed 15 mg/kg o when rhythm controlled, can do continuous infusion → 2-6 mg/min • therapeutic blood level: 4-8 mcg/mL Mechanism of Action • procaine analogue (local anesthetic) • has EP action similar to quinidine, but has less QTc prolongation o paradoxical VT → rare • no vagolytic effect • can be used in pts with a-fib to suppress ventricular irritability w/o increasing ventricular rate • may prolong QRS and cause ST-T changes Metabolism and Excretion • metabolism: liver • excretion: renal o decrease dose in renal impairment • in the liver, procainamide that has NOT been excreted unchanged by kidneys is acetylated into NAPA o NAPA is cardio-active → contributes to antiarrhythmic effects of procainamide o renal failure → NAPA accumulates to toxic levels • 15% protein bound Side Effects • decreased use d/t side effects • hypotension—d/t direct myocardial depression • asystole or v-fib when given in heart block or dig toxicity • chronic admin produces a syndrome that mimics SLE o serositis, arthritis, pleurisy, pericarditis o often develop antinuclear antibodies o leukopenia, thrombocytopenia o symptoms disappear when procainamide discontinued Disopyramide • comparable to quinidine • suppresses atrial and ventricular tachyarrhythmias • T ½: 8-12 hours • oral admin only Side Effects • dry mouth • urinary hesitancy Ch. 21: Antiarrhythmic Drugs • the drug has anticholinergic activity, leading to dry mouth and urinary hesitancy. • blurred vision • nausea Moricizine • phenothiazine derivative • treats sustained ventricular arrhythmias • pro-arrhythmic effects, so it is reserved only for life-threatening ventricular arrhythmias when amiodarone isn’t available or is contraindicated (ex.: allergic to amiodarone) • NOT effective for atrial arrhythmias; ventricular only • decreases fast inward sodium ion current • decreases automaticity Side Effects • proarrhythmic effects Lidocaine • used primarily for suppression of ventricular arrhythmias • minimal to no effect on supraventricular tachyarrhythmias • effective in suppressing re-entry arrhythmias → PVCs, VT • dosing: o 2 mg/kg IV initial bolus o continuous infusion: 1-4 mg/min o therapeutic plasma concentration: 1-5 mcg/mL • during anesthesia (or any other time) when there is decreased CO or hepatic blood flow, decrease initial dose and maintenance rate by 50% • concurrent use of propranolol and cimetidine → decreases hepatic clearance of lidocaine • more rapid onset, greater therapeutic index, better side effect profile than procainamide and quinidine • effects terminate quickly after discontinuation • IV lidocaine → no preservative (LA lidocaine has preservative) • IM lidocaine has nearly complete absorption. o 4-5 mg/kg IM → therapeutic plasma conc. in 15 min ▪ maintained for 90 min Mechanism of Action • delays rate of spontaneous phase 4 depolarization by preventing/diminishing the gradual decrease in K+ permeability • not effective in supraventricular tachyarrhythmias → can’t alter the rate of spontaneous phase 4 depolarization in the atria • normal doses—no effect on QRS, QTc, or AV conduction • high doses—can decreases conduction in the AV node and His-Purkinje system Metabolism and Excretion • oral admin: well absorbed; extensive first-pass hepatic uptake o only 1/3 of oral lidocaine reaches circulation • metabolism: liver Side Effects • plasma conc. < 5 mcg/mL → no EKG effects • does not alter QRS or SNS activity • depresses cardiac contractility less than other drugs used to suppress ventricular arrhythmias • toxic plasma conc. → >5-10 mcg/mL o peripheral vasodilation, direct myocardial depression → hypotension o slowed conduction may manifest as bradycardia, prolonged PR interval, widened QRS o dose-depending CNS stimulation ▪ seizures o > 10 mcg/mL: ▪ CNS depression ▪ apnea ▪ cardiac arrest o convulsive threshold of lidocaine is decreased during hypoxemia, hyperkalemia, acidosis Mexiletine • oral amine analogue of lidocaine Ch. 21: Antiarrhythmic Drugs • used for chronic suppression of ventricular tachydysrhythmias Side Effects • epigastric burning • take with food Tocainide • oral amine analogue of lidocaine • no longer used Phenytoin • good for suppressing ventricular arrhythmias associated with digoxin toxicity • less effective than quinidine, procainamide, and lidocaine • IV dose: 100 mg (1.5 mg/kg) every 5 min until arrhythmia controlled OR 10-15 mg/kg (max 1,000 mg) has been given o give slowly Mechanism of Action • shortens QTc interval • no effect on ST-T waves or QRS complex • improves AV node conduction • may depress SA node Metabolism and Excretion • hydroxylated and conjugated with glucuronic acid • excreted in urine • T ½: 24 hours Side Effects • phenytoin toxicity manifests as: o CNS and cerebellar disturbances ▪ ataxia ▪ nystagmus ▪ vertigo ▪ slurred speech ▪ sedation ▪ mental confusion • inhibits insulin secretion, so may lead to hyperglycemia • suppress the bone marrow—so, may see leukopenia, granulocytopenia, thrombocytopenia Flecainide • fluorinated local anesthetic analogue of procainamide • more effective in suppressing ventricular premature beats and VT than quinidine and disopyramide • effective in tx of atrial tachyarrhythmias • delays conduction in bypass tracts, so it is effective in re-entrant tachycardias such as WPW • not recommended for ventricular arrythmia tx after MI → sudden death Metabolism and Excretion • good oral absorption • no IV admin • decreased elimination in CHF and renal failure • may increase plasma conc. of digoxin and propranolol • coadministration with amiodarone will double plasma flecainide concentrations. • phenytoin (& other drugs that stimulate CYP450) will speed up elimination of flecainide. • therapeutic plasma conc.: 0.2 – 1.0 mcg/mL • moderately negative inotropic & proarrhythmic o esp. in pre-existing LV dysfunction Side Effects • vertigo, difficulty in visual accommodation • prolongs QRS; prolongs PR to a lesser extent o suggests AV or infranodal conduction block • may depress SA node fx (just like beta blockers & CCBs) o so, DO NOT administer in 2nd or 3rd degree AV heart block Ch. 21: Antiarrhythmic Drugs • increases the capture threshold of pacemakers Propafenone • oral admin • suppresses ventricular and atrial tachyarrhythmias • weak beta blocking and calcium blocking effects • may be proarrhythmic → more common if poor LV fx and sustained VT • good oral absorption • peak: 3 hours • metabolism: liver Side Effects • proarrhythmic effects if pre-existing ventricular arrhythmias • depresses myocardium → may cause conduction abnormalities such as SA node slowing, AV block, BBB • small doses of quinidine inhibit metabolism of propafenone • propafenone interferes w/ metabolism of propranolol and metoprolol → results in increased plasma conc. of these drugs • increases plasma conc. of warfarin → prolongs prothrombin time • common side effects: vertigo, taste disturbances, blurred vision, N/V, cholestatic hepatitis (rare) o may worsen asthma (rare) Beta Blockers • effective tx for arrhythmias r/t enhanced activity of the SNS (periop stress, thyrotoxicosis, pheo) • propranolol & esmolol → control rate of ventricular response in a-fib and a-flutter • mutifocal atrial tachycardia → may respond to esmolol or metoprolol; best tx with amiodarone • acebutolol → tx of frequent PVCs • propranolol → really good for torsades in pts w/ prolonged QTc • acebutolol, propranolol, & metoprolol → prevention of sudden death after MI Mechanism of Action • antiarrhythmic effects of BBs reflects blocking of beta receptors in the heart to SNS stimulation & the effects of circulating catecholamines o result: decreased rate of spontaneous phase 4 depolarization and SA node firing • slows down conduction → reflected by prolonged PR interval • little effects on ST-T wave • may shorten QTc • depress myocardium by blocking beta receptors and depressing the muscle itself • in addition to blocking beta receptors, beta blockers change the electrical activity in myocardial cells • propranolol: chronic suppression of ventricular arrhythmias o usual daily dose: 10-80 mg q 6-8 hrs o total daily dose determined by physiologic effects on HR and BP o effective beta blockade achieved when resting HR is 55-60 bpm o emergent suppression of dysrhythmias → IV propranolol 1 mg/min (3-6 mg) ▪ onset: 2-5 min ▪ peak: 10-15 min ▪ duration: 3-5 hrs ▪ admin at 1 min intervals to minimize likelihood of excessive pharmacologic effects on conduction ▪ if BP marginal or existing LV dysfunction → max dose should be 3 mg or less and increase the time btwn doses Metabolism and Excretion • oral propranolol → metabolized by liver o hepatic first-pass effect is responsible for variable plasma conc. o therapeutic plasma conc.: 10-30 ng/mL • readily crosses blood-brain barrier • metabolite: 4-hydroxypropranolol o weak beta blocking activity • t ½: 2-4 hrs (antiarrhythmic effects last up to 8 hrs) Side Effects • because beta blockers suppress SNS activity, common side effects include: o bradycardia Ch. 21: Antiarrhythmic Drugs o hypotension o myocardial depression o bronchospasm • pts w/t CHF depend on increased SNS activity, so weakening their SNS activity will exacerbate CHF. o propranolol is directly suppressive on the myocardial contractility → may worsen CHF • do not give propranolol if pre-existing AV block • may cause drug fever, rash or nausea • may increase esophageal reflux • cold extremities, worsened Raynaud dz • interferes w/ glucose metabolism → hypoglycemia in those being treated for DM • most common CNS effects: depression and fatigue • reversible alopecia may occur • chronic admin of beta blockers leads to upregulation of beta receptors in the heart. o abrupt discontinuation of BBs can lead to SVT → bad for CAD o slowly taper beta blockers to prevent withdrawal responses Amiodarone • potent antiarrhythmic • protects against refractory supraventricular and ventricular tachyarrhythmias • if VT or v-fib resistant to electrical defibrillation → give 300 mg amiodarone IV • preop oral amiodarone decreases the incidence of a-fib after cardiac surgery • suppresses tachyarrhythmias associated with WPW o depresses AV node conduction and the accessory bypass tracts • after oral tx initiation, decreases in ventricular tachyarrhythmias occurs within 72 hours. • maintenance dose: 400 mg for ventricular tachyarrhythmias; 200 mg for supraventricular arrhythmias • IV admin: 5 mg/kg over 2-5 min o prompt antiarrhythmic effect o lasts up to 4 hrs • therapeutic blood conc.: 1-3.5 mcg/mL • after d/c’ing chronic oral therapy, the pharmacologic effects of amiodarone last for up to 60 days. o prolonged t ½ Mechanism of Action • prolongs refractory period in all cardiac tissues—SA node, atrium, AV node, His-Purkinje system, ventricle, accessory bypass tracts (WPW) • anti-adrenergic effects → noncompetitive blocking of alpha and beta receptors • minor negative inotropic effects →may be offset by its vasodilating effects • antianginal properties → dilates coronaries and increases coronary blood flow Metabolism and Excretion • prolonged T ½ (29 days) • large Vd • minimally dependent on renal excretion • principal metabolite: desethylamiodarone → pharmacologically active o longer T ½ than amiodarone o will accumulate with chronic amio therapy • extensive protein binding • not easily removed with dialysis • concentration in the myocardium is 10-50x that in the plasma Side Effects • common, esp. when dose > 400 mg/day • recommended to regularly screen with CXR, PFTs, TSH, LFTs o except for PFTs, other screening tests should be repeated every 3, 6, 12 mo and annually thereafter Pulmonary Toxicity • most serious effect of amiodarone: alveolitis (pneumonitis) • incidence 5-15% • amiodarone enhances the production of oxygen free radicals in the lungs that oxidize cellular proteins, membrane lipids, and nucleic acids Ch. 21: Antiarrhythmic Drugs o • • • high FiO2 may accelerate these rxns ▪ beneficial to reduce FiO2 in pts under GA on amio to the lowest acceptable level chronic amiodarone has been associated with post-op pulmonary edema pts with pre-existing amiodarone-induced pulmonary toxicity are at risk for ARDS after surgery that requires CPB 2 types of presentations of amiodarone-induced pulmonary toxicity: o slow insidious onset → most common ▪ progressive dyspnea, cough, weight loss, pulmonary infiltrates o 2nd form—more acute onset ▪ dyspnea, cough, hypoxemia, fever (may mimic infectious pneumonia) ▪ post-op pulmonary edema is of this second, more acute form. CV • • • prolongs QTc → leads to increased incidence of ventricular tachyarrhythmias (incl. torsades) HR slows → resistant to atropine inhibits alpha and beta receptors. o decreased responsiveness to catecholamines and SNS stimulation • IV amiodarone → hypotension (d/t peripheral vasodilation) o AV block common • negative inotropic effects are seen with concurrent use of BBs, GA, and CCBs • drugs that inhibit SA node automaticity (lidocaine) → enhance effects of amiodarone and increase likelihood of sinus arrest • potential need for temporary pacing or admin of isoproterenol if undergoing surgery and being tx with amiodarone Ocular, Dermatologic, Neurologic, Hepatic • corneal microdeposits • optic neuropathy o insidious onset o milder degree of vision loss o longer duration of disc edema o bilateral o discontinuation of amiodarone leads to slow improvement in visual acuity. • may have photosensitivity and rash. • may have cyanotic/slate-gray facial color (will persist even after drug stopped) • neuro toxicity: o peripheral neuropathy, tremors, sleep disturbance, HA, proximal skeletal muscle weakness • hepatic: o transient, mild increases in plasma transaminases o fatty liver infiltration Pharmacokinetics • INHIBITS CYP450 o results in increased plasma conc. of digoxin, procainamide, quinidine, warfarin, cyclosporine • amiodarone displaces digoxin from protein-binding sites • amio potentiates the effects of warfarin because it directly depresses the vit-K dependent clotting factors. Endocrine • amiodarone contains iodine → effects thyroid metabolism causing either hyper- or hypothyroidism in 2-4% of pts • thyroid dysfunction develops insidiously • hyperthyroidism—occurs up to 5 months after stopping amiodarone • pts w/ pre-existing thyroid dysfunction are more likely to develop amiodarone-related alterations in thyroid fx • hyperthyroidism → detected via increased plasma conc. of T3 • hypothyroidism → detected via increased plasma conc. of TSH • amiodarone-induced hyperthyroidism reflects the release of iodine from the parent drug → resistant to tradition therapy o pts may be intolerant of BBs d/t underlying cardiomyopathies o may require thyroidectomy to regulate/control metabolism Dronedarone Mechanism of Action Metabolism and Excretion Side Effects Ch. 21: Antiarrhythmic Drugs Sotalol/BetaPace • nonselective beta blocker that prolongs cardiac action potential in the atria, ventricles, and accessory bypass tracts • given to treat sustained VT or v-fib • also approved for tx of atrial tachyarrhythmias → a-fib • NOT recommended in asthma, LV dysfunction, conduction abnormalities (prolonged QTc) • proarrhythmic effects → usually restricted for use in pts with life-threatening ventricular arrhythmias • daily oral dose: 240-320 mg 2x/day • renal excretion; increase dosing interval if renal impairment • NOT plasma protein bound • NOT metabolized • does NOT cross BBB Side Effects • most dangerous side effect: torsades (d/t QTc prolongation) • torsades is dose-related • beta blocking effects of sotalol result in decreased myocardial contractility, bradycardia, and delayed conduction through the AV node • other side effects: o fatigue o dyspnea o vertigo o nausea Ibutilide • effective for converting recent onset a-fib or a-flutter to normal sinus rhythm • metabolism: hepatic • may lead to polymorphic ventricular tachycardia with or without QTc prolongation o this is especially likely if impaired LV function, pre-existing prolonged QTc intervals, hypokalemia, or hypomagnesemia Dofetilide Verapamil and Diltiazem • greatest efficacy among the CCBs for tx of cardiac arrhythmias • verapamil is very effective in terminating paroxysmal SVT (a re-entrant tachycardia whose pathway includes the AV node) o effectively controls ventricular rate in pts with a-fib or a-flutter o does not depress accessory bypass tracts, so it won’t slow the ventricular response rate in WPW o may cause reflex SNS activity that enhances conduction over accessory tracts, which increases the ventricular response similar to digitalis o not effective for ventricular ectopic beats • verapamil dosing: for suppressing SVT o 5-10 mg (75-150 mcg/kg) IV over 1-3 min followed by continuous infusion (5 mcg/kg/min) ▪ 1 g calcium gluconate 5 min before verapamil admin will decrease verapamil-induced hypotension o oral: 80-120 mg q 6-8 hrs is useful for preventing paroxysmal SVT and for controlling ventricular response in a-fib or a-flutter • diltiazem 20 mg IV produces antiarrhythmic effects similar to diazepam Mechanism of Action • inhibit flux of Ca2+ ions across the slow channels of vascular smooth muscle and cardiac cells • effect on calcium ion flux manifests as decreased rate of spontaneous phase 4 depolarization • verapamil—substantial depressing effect on AV node; negative inotropic effect on SA node o moderate vasodilation of the coronaries and systemic arteries Metabolism and Excretion • verapamil: 70% excreted by kidneys; 15% present in bile o metabolite: norverapamil may contribute to the parent drug’s antiarrhythmic effects o extensive first-pass hepatic effect → why it requires a big oral dose Side Effects • AV block is more likely in pts with pre-existing defects in conduction • direct myocardial depression and decreased CO are exaggerated in pts with poor LV fx • peripheral vasodilation → hypotension Ch. 21: Antiarrhythmic Drugs • • • • exaggerated effects of NMBD cimetidine decreases hepatic blood flow, so there will be increased plasma conc. of verapamil. verapamil increases plasma conc. of digoxin by 50-75%. concurrent verapamil and propranolol use leads to excessive bradycardia. Other Cardiac Antiarrhythmic Drugs Digitalis • digoxin • stabilize atrial electrical activity • treat and prevent atrial tachyarrhythmias • vagolytic effects → slow conduction of cardiac impulses through the AV node o slows down ventricular response in A-fib • can enhance conduction of impulses through accessory bypass tracts o dangerously increases ventricular response in WPW • oral dose: 0.5-1 mg in divided doses over 12-24 hours • dig toxicity may manifest as any dysrhythmia, but most commonly as atrial tachycardia with block • digoxin as an antiarrhythmic: o normal physiology: ▪ sodium slowly leaks in and potassium leaks out of the cell ▪ action potential: pumps are needed to restore ion balance ▪ sodium-potassium pump—sodium goes out, potassium comes in ▪ sodium-calcium exchanger—calcium out and sodium in, or vice versa o mechanism of action: ▪ inhibits sodium-potassium pump by binding to potassium → increases intracellular sodium → sodiumcalcium exchanger pumps sodium out and calcium in → increased intracellular calcium leads to increased myocardial contractility ▪ acts on parasympathetic NS to stimulate vagus nerve → slows SA node rate & decreases conduction through AV node o uses: atrial fibrillation (a-fib) and heart failure • how do you treat digoxin toxicity dysrhythmias? o usually, it’s PVCs o treat when patient is hemodynamically compromised. o lidocaine—1st line treatment; fastest o procainamide o phenytoin o propranolol o cardioversion • what 4 drugs should be avoided in patients taking digoxin? o quinidine—increases plasma concentration of cardiac glycosides (digoxin) o succinylcholine—increases PNS activity at the heart, additive effect with cardiac glycosides o beta agonists—increases likelihood of dysrhythmias o IV calcium—may precipitate cardiac dysrhythmias Adenosine • adenosine is an endogenous nucleoside that slows conduction through the AV node • effective alternative to CCBs for acute tx of paroxysmal SVT, including WPW • not effective for a-fib, a-flutter, or VT • usual dosing: o 6 mg IV o if needed, subsequent dose of 6 – 12 mg IV 3 minutes later o pediatric dosing: 50 mcg/kg IV • adenosine receptors → target for tx of pain o adenosine agonists block acute nociception and reduce hypersensitivity to thermal or mechanical stimuli in the presence of sensitization after peripheral inflammation or nerve injury o reflects actions on extracellular GPCRs present in the periphery and CNS, primarily the spinal cord. • NOT effective down ETT Ch. 21: Antiarrhythmic Drugs Mechanism of Action • cardiac EP effects similar to CCBs (verapamil and diltiazem) • adenosine stimulate cardiac adenosine-1 receptors to increase potassium ion currents, shorten duration of action potential, and hyperpolarize cardiac cell membranes • adenosine decreases cAMP concentrations • cardiac transplantation potentiates the effects of adenosine (denervation hypersensitivity) • stimulates A-1 adenosine receptors on the atrium, SA node, and AV node • decreases automaticity and conduction velocity • prolongs the refractory period o asystole on ECG—transient • short duration of action—rapid clearance by plasma enzymes • must be given IV in big doses (6 mg, 6 mg, 12 mg) so it can make it to the heart before its metabolized by plasma enzymes o central line administration is preferred, because it’s closer to the heart • uses: SVT • side effects: relatively nontoxic; may have chest pain, flushing, hypotension Side Effects • rapid IV admin of adenosine → facial flushing, HA, dyspnea, chest discomfort, nausea • transient AV block • bronchospasm • caution use if actively wheezing • bronchoconstriction mechanisms: o activation of adenosine receptors in bronchial smooth muscle o mast cell degranulation o stimulation of prostaglanding formation • antagonized by theophylline and caffeine • potentiated by dipyridamole Ranolazine Magnesium Sulfate as an Antiarrhythmic ▪ mechanism of action: o unknown o plays a role in transport of sodium, potassium, calcium across the cell membrane ▪ uses: o IV administration o treat torsades de point and digoxin-induced arrhythmias ▪ torsades—magnesium is the primary treatment Pharmacological Treatment of Tachycardia ▪ underlying cause? o surgical stimulation o SNS response to intubation o hypotension compensation ▪ hemodynamic stability? ▪ beta blockers are usually the first-line treatment for tachycardia. o esmolol is a good start o metoprolol—longer acting ▪ regular, narrow-complex tachycardias are usually caused by AV nodal re-entry or AV node accessory pathways. o treat with: ▪ adenosine (if giving adenosine in surgery, notify the surgeon) ▪ verapamil ▪ diltiazem ▪ beta blocker ▪ radio-frequency ablation Pharmacological Management of Atrial Fibrillation • Ventricular rate control, anticoagulation, and drug therapy to maintain SR. Ch. 21: Antiarrhythmic Drugs • • • • • • • • If new onset AF prior to case → cardiac consult required Underlying causes? Hemodynamic stability? o If hemodynamic compromise, acute control agents are highlighted in red, alternatives in yellow. Cardioversion may be a treatment option. Ibutilide increases cardioversion effectiveness. May give preventative preoperative dose of Sotalol, Amiodarone, or beta blocker in cardiac surgery. Highly effective (acute control in highlighted in red, alternatives highlighted in yellow) o Sotalol (Betapace, Sorine, Sotylize) o Digitalis Effective o Verapamil o Diltiazem o Propranolol (or other Beta Blockers) o Amiodarone- may take several hours to control rate. o Procainamide or Ibutilide with cardioversion o Lidocaine o Quinidine o Disopyramide (Norpace) Goal: ventricular rate control Ch. 21: Antiarrhythmic Drugs Pharmacological Treatment of SVT • Hemodynamic Stability? • Underlying Cause? • Acute control agents are highlighted in red, alternatives in yellow. • Highly Effective o Verapamil o Diltiazem o Adenosine o Digitalis o Propranolol (Esmolol or another Beta Blocker) o Quinidine o Procainamide o Disopyramide o Amiodarone • Effective o Flecainide o Propafenone o Sotalol Pharmacological Treatment of PVCs • Hemodynamic Stability? • Underlying Cause? o guidewire • Highly Effective o Lidocaine o Amiodarone o Quinidine o Procainamide o Disopyramide o Tocainide o Mexiletine o Moricizine o Flecainide o Propafenone • Effective o Propranolol o Sotalol Pharmacological Treatment of Ventricular Tachycardia • Drugs vs. Cardioversion (Is patient stable?) • Highly Effective o Amiodarone o Lidocaine o Procainamide o Disopyramide o Tocainide o Mexiletine o Moricizine o Flecainide o Propafenone • Effective o Quinidine o Propranolol o Sotalol Ch. 21: Antiarrhythmic Drugs Postoperative Tachycardia • Causes? o increased SNS activity o treat pain, hypotension, anxiety o decompress a full bladder o MH? Acidosis? Hypoxemic? o consider beta blocker o consider underlying causes