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Transcript
Antiarrhythmic Drugs Drug/MOA Class IA Quinidine Alpha-blocker Blocks Na AND K channels. Disopyramide Na blocker Procainamide Na (primary) and K (secondary) blockade Class IB Lidocaine Fast on-off block of Na channels Class IC Flecainide Na channel block Fluorinated congener of procainamide Propafenone Na channel block Beta blocking Effects/Facts Adverse Effects (proarrhythmia is common) -Direct vasorelaxant -May cause orthostasis and reflex sinus tachycardia -No negative inotropic effect, even w/ left ventricular dysfunction. -Most common – diarrhea -Most lethal – torsades de pointes -Cinchonism – headache, dizziness, tinnitus -Significant anticholinergic effect -Significant negative inotropic effect -Effective drug for vagally mediated AF -Effective drug for AF in hypertrophic cardiomyopathy -Decreases both contractility and obstruction in the ventricle! -Slows CV and pacemaker rate b/c of Na blockade -Prolongs APD -Direct depressant effects on SA and AV nodes Clinical Applications: -Most atrial and ventricular arrhythmias -2nd DOC for sustained ventricular arrhythmias associated w/ MI -DOC in pre-excited atrial fibrillation w/ rapid ventricular response. PK: IV, IM, eliminated by hepatic metabolism to NAPA and renal elimination Fast and slow acetylator phenotypes exist and are genetically determined. -NAPA implicated in torsades de pointes in pts w/ renal failure -Lupus-related symptoms w/ long term therapy (arthralgias, myalgias, serositis, pulm infiltrates, hepatomegaly) (less common w/ rapid acetylators) -Hypotension w/ IV dosing due to ganglion blocking properties -Worsening of CHF in 10 % -GI (25 %), rash, Raynaud phenomenon, agrnulocytosis, neuromuscular effects in pts w/ myasthenia gravis, depression, ANA in 80%, Histone Ab in 2/3 -Shortens APD duration -Lidocaine and oral congener (Mexilitene) act largely by slowing conduction -Second line therapies for refractory ventricular arrhythmias Mainly neurological -Significant negative inotropic effect esp at higher doses -Proarrhythmia (VT and SVT) -Positive use dependence: More effective at higher HR, due to slow unbinding kinetics (check graph in ppt to understand) -Levels elevated by amio -Don’t use in LV dysfunction or CHF -Plasma half life 13-19 hrs/ 2/3rd metabolized in liver -FDA approval for tx of SVT -Usually used w/ AV nodal blocking agent -Similar antiarrhythmic profile to flecainide -Drug rapidly absorbed w/ bioavailability of 50 %, elimination half-life being 2-10 hrs in normal subjects and 12-32 hours in poor metabolizers Metabolism: CYP2D6 -Extensive metabolizers: less parent drug = less beta blocker effect -Poor metabolizers: more parent drug = more beta blocker effect Neuro and GI Class II - Beta Blockers (check ppts for MOAs) -Esmolol onset is within seconds! Propranalol -Check powerpoint for all facts – we’ve learned most of these already. Esmolol -Multiple drug interactions -Nausea, dizziness, metallic taste, blurry vision, paresthesias, liver test abnormalities, exacerbation of asthma -Strongly inhibited by quinidine Class III FOR ALL: prolong QT, no effect on CV (predominant effect is through prolonging repolarization) -Initiated or re-initiated in hospital Dofetilide K channel block Sotalol K channel block Ibutilide K channel block Amiodarone K channel block Dronedarone CI: A LOT of drugs – know ketoconazole, azithromycin, -Dose should be adjusted based on renal function (how its excreted) fluoroquinolones -Drugs used for maintaining sinus rhythm in pts w/ paroxysmal AF and CHF? DOFETILIDE AND AMIODARONE!!!!!!!!! -Initiated or re-initiated in hospital w/ EKG monitoring -Dose should be adjusted based on renal function (how its excreted) -Blocks rapid component of delayed rectifier current (Ikr) -Most significant: incidence of TdP – 4 % -Lower concentrations drug also activates inward sodium current -2 % require cardioversion -Increases APD and ERP, thus increasing QT and QTc intervals -In almost all pts, onset of arrhythmia was within 40 mins of -Acute prolongation of atrial ERP leading to rapid termination of AF and AFL commencement of drug infusion -Only IV drug approved by FDA to convert AF or AFL of recent onset EFFECTS: Additive effect w/ beta blockers and CCB Metabolism – slow absorption from GI tract Dosage need not be adjusted in renal failure SIDE EFFECTS: 1. Frequency of hypotension low 2. Pulmonary (5-15 %) – dyspnea, cough, fever, pleuritic CP, CXR findings Acute – Subacute – Chronic (look at ppt for details) Pathology – inflammatory cell infiltrate, fibrosis, macrophages, etc.) 3. Hepatic (15-50 %) 4. Thyroid (2-24 %) – Hypo – Worff-Chaikoff Effect – block of thyroid gland iodine uptake and thyroid hormone biosynthesis Hyper -Thyrotoxicosis incidence 2-12 % -Type I amiodarone-induced thyrotoxicosis – unmasking of prior thyroid abnormality; pts w/ nodular goiter, nodules, or graves’ -Type II amiodarone-induced thyrotoxicosis – follicle cytotox w/ inflammation, IL-6 levels markedly elevated Tx: stop amio vs. medical and/or surgical therapy 5. Photosensitivity (25-75 %) - discoloration 6. Blue skin (<10 %) 7. Corneal microdeposits (>90 %) – reversible 8. Ocular Toxicity: halo vision, bilateral loss w/ gradual onset due to optic neuritis Pathology – intracytoplasmic lamellar bodies in corneal epithelium, opacities in anterior subscapscaular region of lens (irreversible), disk edema leading to optic neuropathy Dx: slit lamp exam, acuity testing Tx: stop drug if possible for vision loss CI: Increases digoxin, Coumadin, and cyclosporine 9. Neuro: symptoms include tremor, gait, peripheral neuropathy Pathology: accumulation in myelinated and unmyelinated axons w/ inclusions Dx: EMG, clinical syndrome Tx: responds well to dosage reduction -Neuro tox most common at higher doses and in elderly, can usually be ameliorated w/ doses reduction. K channel block; Young Padawan; DON’T GIVE TO PEOPLE W/ CHF Class IV Verapamil Diltiazem L-type Ca channel OTHERS: Adenosine Activation of outward K current in atria, SA, and AV nodes (not ventricles) Digoxin Central and peripheral actions to increase vagal activity Ranolazine Na channel block AND repol phase Ivabradine Inhibits If current -Decreases phase 0 depolarization – so sinus node automaticity is slowed -Increase AV nodal refractory periods – thus decreasing number of impulses that travel through AV node -Used for rate control in AF and AFL -DON’T USE IN PATIENTS WITH HEART FAILURE -AV node – drug depresses nodal action potential -SA node – sinus rate slows -Proarrythmias (tosades, faster AF, new AF) -Diagnostic uses (WPW, AVNRT) -Therapeutic uses – rapid termination of most narrow complex tachycardias -DON’T GIVE TO HEART TRANSPLANT PATIENTS -AV – delay in conduction and increase in ERP, which slows ventricular response in AF and AFL -No direct anti-fibrillatory actions of drug -Used largely for control of ventricular response in AF -Renally excreted -Not useful for rate control of AF in ambulatory state -Approved for angina. -Utilized w/ very food effects to treat ventricular arrhythmias. -Acts on both depol and repol stage -Creates uniform level of repolarization – good for rhythm control -FUNNY current -Used to treat sinus tachycardia -Effective in treatment of angina pectoris and in tx of heart failure CI: dipyridamole, theophylline