Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Prescription costs wikipedia , lookup
Pharmacognosy wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Dydrogesterone wikipedia , lookup
Psychopharmacology wikipedia , lookup
Antiarrhythmic Agents All you need to know Jacob S Koruth, MD Assistant Professor of Medicine Director, Experimental Laboratory Cardiac Arrhythmia Service The Mount Sinai Hospital New York , NY Pharmacodynamics • Ionic Channels – three states – Resting, open, inactivated – Drugs bind to channels preferentially in these states – Have differing rates of binding and unbinding • Use dependence- At ↑ HR: more pronounced effect- Class I drugs • Reverse use dependence- At ↓HR: potassium channels ↑ active- therefore ↑ pronounced effect- Class III drugs Vaughn Williams Classification • Simplistic- classifies drugs based on main action • Class 1- Sodium channel block- slow conduction • Class II- Beta blockers • Class III- Potassium channel • Class IV- Calcium channel blockers Class 1 • 1a- Moderate Na block – At rapid rates slow conduction, also block K • 1b- Weak Na block – Minimal block in resting tissue – Marked block in activated tissue – Dissociates rapidly- no use dependence • 1c- Strong Na block – Significant conduction slowing – Increase QRS duration – More effect at rapid rates- use dependent Quinidine- Ia • Na & K+ channel blockade – IKr , IKs, Ito • Alpha receptor blocker • Dose 600-1600 mg day BID or TID Clinical use • Refractory VT, often in combination with mexilitine (after other AA drugs fail) • Limited use for AF due to side effect profile • Very difficult to find VF prevention in patients with Brugada or early repolarization Procainamide- Ia • • • • • • Na blocker NAPA is K blocker Minimal negative ionotropic effect Only available IV in the US Load 10-14 mg/kg given slowly Maintenance 1-4 mg/min Procainamide- Clinical utility • Conversion of AF to NSR • Slow rate and convert preexcited AF • Unmask Brugada syndrome Disopyramide - Ia • • • • • Na channel blockade 400 to 800 mg/day given BID Potent Vagolytic/anticholinergic Negatively ionotropic Hepatic and renal excretion Disopyramide - Side effects • Anticholinergic – Dry eyes, urinary retention, constipation • Heart failure • Torsades • AF to rapid flutter (can enhance AV nodal conduction) Disopyramide - Summary • Disopyramide: – Vagal AF – HOCM (with AF) Lidocaine- Ib • Na channel block- minimal effect on atrium • Works most in depolarized tissues such as during ischemia • Only IV • Large boluses increase CNS toxicity Mexilitine- Ib • • • • • Na channel blockade Metabolized by CYP2D6 Renal clearance 450 to 750 mg/day given TID GI side effects Clinical use: Lidocaine/Mexilitine • Lidocaine– Ventricular tachycardia • Peri MI • Scar related • Mexilitine – Used in combination for refractory VT Propafenone- Ic • Na Channel block & Beta blocker • Slow onset and offset kinetics- use dependent • Slows conduction in fast response tissue • Dose 450-900 mg/day divided BID or TID • Hepatic metabolism and renal clearance Propafenone-Side effects • • • • Proarrhythmia Metallic taste Constipation, nausea Slight increase in pacing and defibrillation thresholds • Negative ionotrope Flecainide- Ic • Na blockade / IKr blockade • In atrial tissue, prolongs action potential in rapid rates: More active at faster rates • Purkinje tissue APD shortened (Na) • Ventricular tissue APD prolonged (K) Flecainide- Ic • • • • Dose 50 to 150 mg BID Long half life CYP2D6 metabolism and renal excretion Renal excretion usually rapid even for slow metabolizers Flecainide-Side effects • Proarrhythmia: Aflutter – 1:1 conduction • Must prescribe AV nodal agents even if pt has no h/o of flutter • Renal insufficiency can lead to toxic levels especially for slow metabolizers Clinical use of Ic • • • • Acute conversion of AF (60-70%) Maintenance of NSR (30-40%) Must be used with AV nodal blockers Consider stress testing- if QRS increases 25% consider termination Amiodarone • Class III but multiple effects • Prolongs APD and refractoriness in all cardiac tissues • Blocks all channels Amiodarone • Prolongs QT but Torsades uncommon • Large volume of distribution– Long elimination half life 16-180 days – 50% is eliminated within 3-10 days Amiodarone-Side effects • • • • • • IV - hypotension Pulmonary fibrosis Thyroid Gastrointestinal- nausea, anorexia, Hepatic- transient transaminitis common discontinue if 3 x normal or 2x levels at baseline if abnormal Ocular- keratopathy with corneal microdeposits in virtually all patients, 10% with halo vision/dry eyes Neurologic- 50%- peripheral neuropathy, paresthesia, malaise/fatigue, tremors, dizziness, HA, sleep disorder Photosensitivity- 15% - blue/gray tanning or burning • Bradycardia common • • Thyroid Effects • 37% iodine by weight • 30% pts have early laboratory abnormalities – T4 levels rise 20-40% in first month then return to high normal – T3 decreases by 30% in first few weeks then returns to low normal – TSH rises initially then returns to normal • 5-10% clinical effects- either hypo or hyper Pulmonary complications • • • • • 1-17% Rarely early- hypersensitivity pneumonitis Most with late interstitial fibrosis Reduced DLCO Probably dose related but some paradoxical with low dose • Annual CXR and PFT recommended, but efficacy not proven Amiodarone- Clinical uses • Conversion of AF – 25-30% acute success • Maintenance of NSR- highest of any AA drug – About 60% success at 1 year • Ventricular tachycardia • VF/polymorphic VT (ACLS) Sotalol • Ikr blocker + B blocker • QT prolongation at higher doses and increases linearly with dose • Avoid if Cr clearance ≤ 40 ml/min • 160 mg – 360 mg /day as BID dose • Reverse use dependence • ↓effective than amiodarone and ~Ic for AF • Ventricular tachycardia: ischemic heart disease, ARVC Sotalol-Side effects • B-blocker related • CHF 3.3% • Torsades 2.4% mostly in first week or after dose change – More common in • • • • • • • Women High dose CHF Recent DCCV Hypokalemia Bradycardia Renal insufficiency Ibutilide • Structurally similar to sotalol • Only IV • Watch QT interval Dofetilide • Pure IKr blocker • Prolongs action potential, both atrial and ventricular refractory periods • QT interval with dose related prolongation • Modestly reverse use dependent Dofetilide • Renally excreted- doing based on CrCl • 20% degree of metabolism by CYP3A4inhibitors use with caution • Half life of 10 hours • Contraindicated with verapamil- results in 40% increase in peak levels- also with drugs that inhibit cationic renal secretion • Uncorrected hypokalemia contraindicated • Diuretics to be used with caution Dofetilide • Can only be prescribed by authorized users • Initiation must be done as inpatient (3 days) • Contraindicated if baseline QTc greater than 440 msec or 500 msec in presence of BBB, delta wave, pacing Clinical use • 30% AF to NSR conversion rate • 40-50% maintenance of NSR • Safety in HF – DIAMOND CHF • 1518 patients with class III and IV CHF, EF<35% • No difference in total mortality, cardiovascular death, successful resuscitation • 25 episodes of Torsades Dronadarone • Multiple channel blocker • More Ikach blocking than amiodarone • Extensive first pass metabolism- 15% bioavailability • Metabolized by CYP3A4 • Can see 10-15% creatinine rise, not true decrease in GFR • One dose 400 mg BID Ivabradine • If inhibitor • Anti-anginal • Inappropriate sinus tachycardia