Advanced Principles & Practice of Anesthesia Week 2 Antiarrhythmic Pharm PDF

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University of Louisville

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cardiology arrhythmia electrophysiology heart anatomy

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This document covers advanced principles and practice of anesthesia, focusing on week 2's topics regarding antiarrhythmic drug pharmacology. It details the properties, types, and functions of myocardial cells and the cardiac conduction system, along with neural modulation of contractility and cardiac transplantation. The document includes various diagrams and illustrations to aid understanding.

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**ADVANCED PRINCIPLES & PRACTICE OF ANESTHESIA II** **WEEK 2: Antiarrhythmic Drug Pharmacology** ![](media/image2.jpg)**MYOCARDIAL CELLS-ELECTRICITY** - Properties - Automaticity - Conductivity - Rhythmicity - Excitability - Types - Pacemaker cells-generate...

**ADVANCED PRINCIPLES & PRACTICE OF ANESTHESIA II** **WEEK 2: Antiarrhythmic Drug Pharmacology** ![](media/image2.jpg)**MYOCARDIAL CELLS-ELECTRICITY** - Properties - Automaticity - Conductivity - Rhythmicity - Excitability - Types - Pacemaker cells-generate and conduct electrical impulses - Transitional cells-slow impulse conduction - Purkinje cells-facilitate rapid impulse conduction ![](media/image4.jpeg)**CARDIAC CONDUCTION SYSTEM** - Sino-atrial node - Internodal & Interatrial pathways - Atrioventricular (AV) node - Junction - Bundle of His - Right bundle branch - Left Bundle branch - Purkinje system ![](media/image6.jpeg) **NEURAL MODULATION OF CONTRACTILITY** Chronotropic: rate/speed Dromotropic: conduction through AV node Inotropic: contractility Lusitropic: relaxation after contraction **CARDIAC TRANSPLANTATION-TYPICAL INCISIONAL APPROACHES** ![](media/image8.jpg) **FLUID & ELECTROLYTE BALANCE** [Nernst Equation]-electrical potential for ions [Goldman Hodgkin-Katz Equation]-allows calculation when membrane is permeable to different ions ![](media/image10.jpg) **SA NODE PACEMAKER CELLS** **AUTONOMIC NERVOUS SYSTEM & PACEMAKER CELLS** ![](media/image12.png) **ELECTROPHYSIOLOGY** - Resting membrane potential - Threshold potential - Phase 0 (depolarization) - Phase 1-4 (repolarization **ELECTROPHYSIOLOGY- PHASE REPOLARIZATION** - Phase 0-depolarization - Phase 1- early or initial repolarization - Phase 2- the plateau phase - Phase 3- rapid repolarization - ![](media/image14.jpg)Phase 4- polarized state is resumed **REFRACTORY PERIODS IN REPOLARIZATION** - ![](media/image17.jpg)Time periods for repolarization - An absolute or effective refractory period-cell cannot be depolarized ***no matter how strong the stimulus*** - A relative refractory period-cell can be depolarized if the stimulus is ***strong enough*** - Supernormal or vulnerable period-*any stimulus can initiate depolarization* **ACTION POTENTIALS** **CARDIAC CHANNELOPATHIES** ![](media/image19.jpg) **CALCIUM-INDUCED CALCIUM RELEASE** ![](media/image21.jpeg) ![](media/image23.jpg) **CARDIAC SARCOMERE** ![](media/image25.jpg) **MYOCYTE RELAXATION** - Repolarization occurs; calcium detaches from troponin and some leaves the cell (most returns to the sarcoplasmic reticulum). - T-T complex reattaches to binding sites on actin - ![](media/image27.jpeg)Muscle relaxation occurs **WHY ARRYTHMIAS?** - Enhanced automaticity - Triggered automaticity - [Reentr]ant (circus movement) ![](media/image29.jpeg) **H's & T's [NOT] Just PEA** ![](media/image31.png) **ARRHYTHMIAS & VOLATILE ANESTHETICS** - Volatile anesthetics interact with the main repolarizing cardiac potassium channels (hERG), as well as with calcium and sodium channels at slightly higher concentrations. - Inhibition of these ion channels alters both action potential shape (triangulation) and electrical impulse conduction, which facilitate arrhythmogenesis & is potentiated by catecholamines. - Action potential triangulation by regionally heterogeneous inhibition of calcium (Ca^++^) and potassium (K^+^) channels will facilitate catecholamine-induced afterdepolarizations, triggered activity, and enhanced automaticity. - Inhibition of cardiac sodium channels reduces conduction velocity & alters the refractory period & is potentiated by catecholamines, and promotes reentry arrhythmias. **ON TO THE DRUGS!!** **ANTIARRHYTHMIC/ARRHYTHMIC CLASSES** - MECHANISM OF ACTION (MOA)-BLOCK PASSAGE OF IONS ACROSS SODIUM, POTASSIUM, & CALCIUM ION CHANNELS OF THE HEART +-----------------+-----------------+-----------------+-----------------+ | **Class I** | **Class II** | **Class III** | **Class IV** | | | | | | | - Inhibit | - Decreases | - Inhibit | - Inhibit | | fast sodium | rate of | potassium | slow | | channels | depolarizat | ion | calcium | | | ion | channels | channels | | - Depression | (beta) | | | | of phase 0 | | - Prolongs | - Calcium | | depolarizat | - B-adrenergi | repolarizat | channel-blo | | ion | c | ion | cking | | (block | blocking | (blocks | effects | | sodium | effects | potassium | | | channels) | | channels) | | +=================+=================+=================+=================+ | **Class IA** | **esmolol** | **amiodarone** | **verapamil** | | | | | | | - Moderate | | | | | depression | | | | | and | | | | | prolonged | | | | | repolarizat | | | | | ion | | | | +-----------------+-----------------+-----------------+-----------------+ | **~~quinidine~~ | **propranolol** | **dronedarone** | **diltiazem** | | ** | | | | +-----------------+-----------------+-----------------+-----------------+ | **procainamide* | **acebutolol** | **sotalol** | | | * | | | | +-----------------+-----------------+-----------------+-----------------+ | **disopyramide* | **metoprolol** | **ibutilide** | | | * | | | | +-----------------+-----------------+-----------------+-----------------+ | **Class IB** | **timolol** | **dofetilide** | | | | | | | | - Weak | | | | | depression | | | | | and | | | | | shortened | | | | | repolarizat | | | | | ion | | | | +-----------------+-----------------+-----------------+-----------------+ | **lidocaine** | **pindolol** | **bretylium** | | +-----------------+-----------------+-----------------+-----------------+ | **~~tocainide~~ | **atenolol** | | | | ** | | | | +-----------------+-----------------+-----------------+-----------------+ | **mexiletine** | **nadolol** | | | +-----------------+-----------------+-----------------+-----------------+ | **phenytoin** | **carvedilol** | | | +-----------------+-----------------+-----------------+-----------------+ | **Class IC** | **labetalol** | | | | | | | | | - Strong | | | | | depression | | | | | with little | | | | | effect on | | | | | repolarizat | | | | | ion | | | | +-----------------+-----------------+-----------------+-----------------+ | **flecainide** | | | | +-----------------+-----------------+-----------------+-----------------+ | **propafenone** | | | | +-----------------+-----------------+-----------------+-----------------+ | **~~moricizine~ | | | | | ~** | | | | | (listed in | | | | | Stoelting as | | | | | 1A) | | | | +-----------------+-----------------+-----------------+-----------------+ ![](media/image33.jpg) **[Class I]** INHIBIT fast SODIUM channels Depression of phase 0 depolarization (block sodium channels) - **Class 1A -- MODERATE depression and PROLONGED repolarization** - **quinidine\* (CARDIOQUIN)** - Reintroduced to US market in 2019 - Antimalarial (d-isomer of quinine) schizonticide & an antiarrhythmic agent - MOA: Sodium channel blocker/𝛼 blockade & potassium channel blockade - Prolongs the refractory period in atrial, ventricular, and Purkinje cells (Phase 4 & 0) - ![](media/image35.jpeg)Effective in SVT^++^ (including Wolff-Parkinson-White), PVC^++^ & atrial fibrillation (slows ventricular response in 25% of patients - 80-90% protein bound - Metabolized via hydroxylation in the liver to an inactive metabolite with renal excretion (20% excreted unchanged) - Narrow therapeutic index (*due to inducing*\...heart block, hypotension, \>2 mcg/ml results in prolonged PRi, QRS & QTc - Increased morbidity and mortality in heart failure led to decreased use. - Prolonged QTc-predisposes patients for Torsades de Points) - High doses also result in cinchonism (aspirin like toxicity) - Potentiates NMDBs - **procainamide (PRONESTYL)** - Analogue of the local anesthetic procaine - MOA: modifies the sodium channel and inhibiting the outward potassium current resulting in QT prolongation - Increases the duration of the action potential, increases threshold potential toward zero, and decreases the slope of phase 4 of the action potential - Suppresses ventricular tachyarrhythmias & to a lesser extent atrial arrhythmias (atrial fibrillation) - 15% protein bound; hepatic metabolism (acetylation) with active metabolite (*N*-acetyl procainamide or *NAPA*) & renal excretion (40- 60% excreted unchanged) - IV dose 100 mg q minutes (up to 15 mg/kg) or until arrhythmias are controlled, then infusion of 2-6 mg/min - Direct myocardial depression results in hypotension (especially with rapid IV bolus)-worsened in hyperkalemia - Contraindicated in heart block-results in asystole - Chronic administration is associated with lupus like syndrome (serositis, arthritis, pleurisy & pericarditis) - Positive antinuclear antibody test - **disopyramide (NORPACE)** - Suppresses atrial (atrial fibrillation)^+^ & sustained ventricular tachycardia^++^, ventricular pre-excitation^++^ & cardiac dysrhythmia - Potent treatment for hypertrophic cardiomyopathy (most frequent of cardiomyopathies 1:5000) - MOA: blocks fast sodium channel conductance during Phase 0, decreasing inward sodium current/also blocks potassium channels (increases refractory period) - Dosing: IV: Initially, 1.5 mg/kg over \> 5 minutes followed by an infusion of 0.4 mg/kg/hour - Metabolized via acetylation in liver to an active metabolite (*N*-acetyl procainamide or *NAPA*) with renal excretion (40-60% excreted unchanged) - 60% protein binding; hepatic metabolism & renal excretion (50% unchanged) - Anticholinergic like side effects are common (dry mouth, urinary retention, blurred vision, and nausea) - Pyridostigmine used to mitigate anticholinergic adverse effects - Potent myocardial depressant, will result in hypotension-contraindicated in heart failure-*significant negative inotrope* - *Drug should be used cautiously in patients with impaired LV function.* - **Class IB -- WEAK depression and SHORTENED repolarization** - **lidocaine (XYLOCAINE)** - ![](media/image37.jpeg)Amide local anesthetic routes IV, IM, topical, & neuroaxial - MOA: blocks internal sodium channels, delays the rate of phase 4 depolarization- decreases potassium ion permeability - Effective in suppressing ventricular arrhythmias (PVCs^++^, Pulseless VT\*^++^ (pVT) & reentry arrhythmias) - *\*NOT* effective in VT resulting from acute myocardial infarction - 55% protein bound; hepatic metabolism (95%) with active metabolites (monoethylglycinexylidide (MEGX-85%) with renal excretion-Elimination Half-time 1.4-8h - Dose for suppressing ventricular arrhythmia (VT, symptomatic PVC) - IV dose 2 mg/kg loading dose followed by\... - Infusion of 1-4 mg/min (*Dose may be reduced if used with volatile agents*) (IM injection of 4-5 mg/kg is also appropriate) - Treatment of shock-refractory VF/pulseless VT (pVT) - (ACLS): 1.0 to 1.5 mg/kg IV/IO for the first dose - 0.5 to 0.75 mg/kg IV/IO for a second dose - **tocainide (TONOCARD) \*no longer available\*** - Amine analog of lidocaine administered orally-similar electrophysiologic function - Utilized for suppression of chronic VT - 10-30% protein bound; Elimination half-time 12-15h - Hepatic metabolism with renal excretion 13.5h - \*Associated with bone marrow depression (leukopenia, anemia, thrombocytopenia) & pulmonary fibrosis - **mexiletine (MEXITIL)** - Amine analogue of lidocaine administered orally-similar electrophysiologic function - Utilized for suppression of chronic VT - *Oral slow-release and IV forms are not available in US.* - Synergistic with 𝛽-blocker or antiarrhythmic (quinidine or procainamide)-allows for decreased dosages of components - Post-marketing data indicated abnormal liver function during initiation of therapy (although concomitant with CHF and ischemia) - Also used in ALS & Myotonic dystrophy (reduced muscle spasm) - 60-75% protein bound; Elimination half-time 6-12h - Hepatic metabolism - **phenytoin (DILANTIN)** - Effective in suppression of ventricular arrhythmias associated with digitalis toxicity-less effective in VT from other causes - IV dose is 100 mg (1.5 mg/kg) every 5 minutes until arrhythmia is controlled to maximum of 10-15 mg/kg (or 1000 mg) - Therapeutic blood level is 10-18 mcg/ml - May be effective in prolonged QTc interval induced torsades de pointes*-Shortens QTc interval more than any other antiarrhythmic drug* - MOA: Delays the rate of phase 4 depolarization-decreases potassium ion permeability-Shortens the QTc interval - 90% protein bound; Elimination half-time 24h - Hepatic metabolism (90%) to inactive compound, urinary excretion - **Class IC -- STRONG depression with LITTLE EFFECT on repolarization** - **flecainide (TAMBOCOR)** - Fluorinated local anesthetic analog of procainamide - Possess local anesthetic & negative ionotropic activity\* - Utilized in suppressing VT\*^++^ & PVCs^++^, also atrial tachyarrhythmias due to Wolff-Parkinson-White syndrome *& atrial fibrillation^+^* - \*Not for use in prevention of ventricular arrhythmias *after* Myocardial Infarction - Dosing: IV: 1--2 mg/kg over 10 minutes - MOA: inhibits the action of sodium and potassium ion channels in the heart, raising the threshold for depolarization - 30-45% protein binding, Elimination half-time 6-12h - "extensive" hepatic metabolism, inactive drug excreted - **propafenone (RYTHMOL SR)** - Effective in paroxysmal ventricular^+^, PVC^++^, & atrial tachyarrhythmias prevention - Has 𝛽-blocker effects (including bradycardia & bronchospasm) - May result in widening of QRS complex, second-degree or third- degree AV Blocks (proarrhythmic-requires dose reduction) - Dosing: IV: 2-mg/kg bolus, followed by 2 mg/minute infusion - MOA: weak 𝛽-adrenergic (calcium blocking agent at high doses, but not thought to have an antiarrhythmic effect) - Low rate of serum aminotransferase elevations & rarely can cause a self-limited, acute cholestatic liver injury with long-term use - 97% protein bound - Metabolized incompletely in liver (CYP2D6) to inactive metabolite with renal excretion (50% excreted unchanged) - **moricizine\* (ETHMOZINE) *\*NO LONGER AVAILABLE*** - Phenothiazine derivative, potent local anesthetic - MOA: blocks fast sodium channel conductance during Phase 0, decreasing inward sodium current/also has properties of Class IB & IC - 95% protein bound; Elimination half-time 3h - \*No longer in use due to increased risk of death or cardiac arrest in the first 14 days of therapy **[Class II]** Decreases rate of depolarization (beta) B-adrenergic blocking effects - **esmolol (BREVIBLOC)** - A short and rapid-acting beta-adrenergic competitive antagonist - Highly selective for 𝛽~1~ & devoid of intrinsic sympathomimetic activity - Indicated for control of heart rate (& BP) - MOA: competitively & cardio-selectively\* blocks 𝛽-1 adrenergic receptors in cardiac muscle - *\*in large doses may have* 𝛽*-2 effects* - 55% protein bound; Metabolized rapidly and extensively metabolized via esterases (probably arylesterase), principally in the cytosol of erythrocytes, the metabolite is ASL 8123, & renally excreted - Onset 1-2 min; half-life 9 min. - Dose: bolus 0.5 mg/kg IV, infusion 50-300 mcg/kg/min (some sources say 200 mcg/kg/min MAX) - No *PO equivalent* - Caution for use in high SVR (high sympathetic activity), *must be used with vasodilator drug to avoid fulminant pulmonary edema* - *Use in AV block and heart failure may be associated with pulmonary edema\** - *\*Avoid in individuals with atrioventricular block & heart failure without tachycardia* - **propranolol (INDERAL)** - A synthetic, ***noncardioselective***, competitive 𝛽-antagonist with antianginal, antiarrhythmic, and antihypertensive properties - A racemic mixture of 2 enantiomers where the S(-)-enantiomer has approximately 100 times the binding affinity for bet- adrenergic receptors (𝛽~1~: 𝛽~2~ affinity is equal) - Effective in hypertrophic obstructive cardiomyopathies (HOCM) - Drug effects are most pronounced during exercise or stress - 90% protein bound - Hepatic metabolism\* with 12 different metabolite-some active (ex. 4- hydroxypropranonol) & renal excretion - *\*Prolongs half-life of amide local anesthetics* - Used (Hemangiol) for treatment of infantile (5 weeks to 5 months) hemangiomas in EU - Dosing IV: 1--3 mg (may repeat once after 5 minutes if needed) MAX IV bolus 10 mg IV - Increased in divided doses until resting heart rate 55-60 beats per min. - **labetalol (NORMODYNE)** - An α~1~ selective- and nonselective β1- and β2-adrenergic antagonist - β to α blocking potency ratio is 3:1 for oral labetalol and ***7β:1α for IV labetalol*.** - Preserves presynaptic α~2~ receptors to create a negative feedback mechanism\...***has intrinsic sympathomimetic activity or ISA output will remain unchanged*** - Labetalol α~1~ are one-fifth to one-tenth as potent as phentolamine - β1- and β2-adrenergic antagonism is one-fourth to one-third as potent as propranolol - Metabolism: Hepatic conjugation of glucuronic acid with 5% of the drug recovered unchanged in urine - Utilized in hypertensive emergencies & catecholamine release r/t surgical stimulation - Dosing: 0.1-0.5 mg/kg IV (MAX effect noted at 5-10 min.); infusion 0.5-2 mg/min (MAX 10 mg/min) - Used to create "controlled hypotension" with intermittent injections of 10mg IV - Orthostatic hypotension (IV half-life is \~5.5 hrs.), bronchospasm in susceptible pts.(\>risk with larger doses), and CHF/Heart block/pulmonary edema - **acebutolol (SECTRAL)** - ***Cardioselective*** 𝛽-antagonist with little effect on the bronchial receptors. - The drug has stabilizing and quinidine-like effects on cardiac rhythm - Intrinsic sympathomimetic activity (ISA) - Dose (200-1200 mg PO, **no IV equivalent**) - 26% protein bound - Extensive first-pass hepatic biotransformation; renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. [BETA BLOCKER OVERDOSE] - Symptoms of overdose include hypotension, restlessness, euphoria, insomnia & hypoglycemic seizure (extreme) - Patients with asthma may develop bronchospasm (status asthmaticus) - Treat hypotension with intravenous fluids, bradycardia with atropine, isoproterenol & epinephrine for bronchospasm - If patients do not respond to intravenous fluids, follow up with glucagon 50-150 µg/kg intravenously, then 1-5mg/hour, followed by catecholamine - Dialysis will not be useful as beta blockers are highly protein bound **[CLASS III]** Inhibit potassium ion channels Prolongs repolarization (blocks potassium channels) - **amiodarone (PACERONE)** - Iodinated benzofuran derivative - Effective in treatment & prevention of refractory supraventricular^++^ & ventricular tachyarrhythmia\*^++^ - Associated with decreased mortality after myocardial infarction - Widely used for the treatment of Wolff-Parkinson-White syndrome^++^ - *\*Recommended for ventricular tachycardias resistant to electrical defibrillation* - MOA: inhibits adrenergic stimulation (alpha- and beta-blocking properties), affects sodium, potassium, and calcium channels; prolongs action potential and refractory period in myocardial tissue; decreases AV conduction & sinus node function - 96% protein bound; hepatic metabolism with biliary excretion - [Dosing:] - Pulseless ventricular tachycardia (pVT)/VF resistant to electrical defibrillation (ACLS): 300 mg IV push (may repeat 150 mg dose) - IV infusion for VF/VT or rate control after AF conversion 0.5 mg/min IV - Treatment of non-life-threatening arrhythmias is 5 mg/kg over 2-5 min. (duration of action 4 hrs.) or 150 mg over 10 min followed by 1mg/min for 6 hrs. then 0.5 mg/min for 18 hrs. - [Toxicity:] - Cardiotoxicity, hypotension, bradycardia, and prolonged QTc (Torsades de pointes-TdP) - TdP tendency is related to prolonged QTc (potassium channel blockade) and subsequent afterdepolarizations - Long term treatment is associated with pulmonary toxicity\* (interstitial pneumonitis, eosinophilic pneumonia, pulmonary nodules, acute respiratory distress syndrome (ARDS) - ***Restrict FiO~2~ in general anesthetics for those under chronic treatment*** - **\***Obtain a baseline chest X-ray and pulmonary function tests prior to long-term therapy - ***Thyroid dysfunction*** (hypothyroidism and hyperthyroidism) - ***Hepatotoxicity***, requires baseline and periodic transaminase levels - Optic neuropathy, associated with optic nerve injury, unilateral or bilateral visual loss - **dronedarone (MULTAQ)** - A noniodinated (modified deiodinated amiodarone molecule) antiarrhythmic agent structurally related to amiodarone exhibiting properties of all ***4**-*antiarrhythmic classes - Oral agent only - Utilized in treatment of atrial fibrillation & atrial flutter *after* chemical or direct current cardioversion (DCCV) returns to NSR - MOA: inhibits sodium (INa) and potassium (Ikr, IkS, Ik1, and Ik- ACh) channels resulting in prolongation of the action potential and refractory period in myocardial tissue without reverse-use dependent effects - High risk for symptomatic bradycardia, also QTc prolongation, torsades de pointes VT (rare) - 99.7% protein bound; hepatic metabolism\* & fecal excretion - \*associated with risk for hepatotoxicity - **Sotalol (BETAPACE)** - Long-acting, non-cardioselective 𝛽-blocking drug at low dose & higher doses prolongs cardiac action potential of ventricles, atrias and accessory bypass tracts - Racemic mixture (L/D) isomers: L isomer is effective betablocker, while D isomer may be proarrhythmogenic - Indicated for treatment of atrial arrhythmias^++^, SVT^+^, or life- threatening ventricular arrhythmias, including sustained VT^+^ - Dosing: IV: 10 mg over 1--2 minutes - MOA: competitive inhibitor of the rapid potassium channel, lengthening duration of action potentials & the refractory period in the atria & ventricles - 0% protein binding; sotalol is not metabolized, but renally excreted - **ibutilide (CORVERT)** - A \'pure\' class III antiarrhythmic drug - Indicated in the conversion of recent onset atrial fibrillation or flutter to NSR - Dosing: IV: For patients ≥ 60 kg, 1 mg infusion or, for patients \< 60 kg, 0.01 mg/kg over 10 minutes, with dose repeated after 10 minutes if the first infusion is unsuccessful - MOA: induction of a persistent Na+ current sensitive to dihydropyridine Ca^2+^ channel blockers and potent inhibition of the cardiac rapid delayed rectifier K^+^ current, by binding within potassium channel pores. - Torsades de pointes VT occurs in 2% of patients during loading dose and prolonged infusion - 40% protein bound; hepatic metabolism with renal & fecal elimination - Polymorphic VT w/wo QTc prolongation may occur (especially with preexisting prolonged QTc impaired LV function, hypokalemia/hypomagnesemia) - **dofetilide (TIKOSYN)** - 'pure' potent potassium channel-blocking drug - Indicated for chemical cardioversion & maintenance of NSR from atrial fibrillation and flutter - ![](media/image39.jpeg)Oral agent only. - MOA: Blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. - Results in a prolongation of action potential duration and the effective refractory period of accessory pathways - 70% protein binding; limited hepatic metabolism & 80% of drug eliminated unchanged in urine - QTc prolongation is significant during induction-high risk for torsades de points VT(pts. must be admitted & monitored for 3 days) - Avoid with calcium channel blockers-proarrhythmic - **bretylium** *\*RECENTLY REINTRODUCED AFTER 8-YEAR DISCONTINUATION* - Largely replaced by amiodarone (a more effective alternative) - Indication includes: increases VF threshold and lowers electrical defibrillation threshold-chemical cardioverter (takes 20 min) - Dosing: IV: Initially, 5 mg/kg, followed by 1--2 mg/minute as a constant infusion - Accumulates in presynaptic adrenal nerve endings leading to catecholamine discharge (transient hypertension \~30 min) & then blocks those presynaptic nerve endings (orthostatic hypotension) - MOA: prolongs the duration of the action potential and effective refractory period in Purkinje fibers and ventricular tissue - 0% protein binding; no metabolism, renal excretion of active drug (small fraction is excreted in bile) **[Class IV]** Inhibit slow calcium channels Calcium channel-blocking effects - **verapamil (CALAN)** - A racemic mixture containing equal amounts of the *S*- and *R*- enantiomer (*S*- is 20x more potent than *R*-, but metabolized faster) - Indications include terminating paroxysmal SVT & controlling ventricular rate in atrial fibrillation/flutter - Dosing: IV: 5--15 mg over 10 minutes - May cause sympathetic system activation and improve dromotropic activity - MOA: inhibition of flux of calcium ions decreasing the rate of spontaneous phase 4 depolarization - 94% protein bound; hepatic metabolism with 75% renal excretion & remainder biliary excretion - AV block may occur; dosing may lead to hypotension - Do not use with heart failure, EF \

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