Anti Arrhythmic Drug Therapy

Anti Arrhythmic Drug Therapy Mordechai Muszkat, MD Department of Internal Medicine Clinical Pharmacology Unit

Anti Arrhythmic Drug Therapy • Diverse set of agents, wide range of adverse effects • Each drug has more than one electrophysiological (EP) action • Active metabolite may have different EP activity, different than the parent drug

Anti Arrhythmic Drug Therapy • I- Inhibit fast Na channels • II- beta-adrenergic antagonists • III- Inhibit K channels, prolong repolarization • IV- Ca channels antagonists

Anti Arrhythmic Drug Therapy Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoin Ic- Flecainide, propafenone II- beta-blockers III- Amiodarone, bretylium, sotalol IV- Calcium cannel blocking agents

Anti Arrhythmic Drug Therapy Class I- Inhibit fast Na channels (during phase 0 of action potential), local anasthetic and membrane stabilizing • Ia- prolong ventricular refractoriness and QT interval • Ib- shorten action potential duration and refractoriness • Ic- Slowing action potential, little effect on repolarization

Anti Arrhythmic Drug Therapy proarrhythmia • Ia, Ic, III class have the highest propensity for proarrhythmia. • Ia and Ic associated with increased mortality due to dysarrhythmia in patients with IHD and left ventricular dysfunction.

Anti Arrhythmic Drug Therapy:Ia: Quinidine (1) • Uses: Conversion of AF to sinus and preventing recurrence (& SVT) • Oral bio availability-Complete (IV associated with hypotension) • Increased t 1/2 –age, hepatic cardiac renal dysfunction

Case 1 A 77 years old female is admitted to ER because of palpitations and dyspnea. Background diseases: DM type II, HTN On examination: BP160/90, HR 150, irregular, lungs- clear, heart- no murmurs, abdomen- no organomegaly, mild lower limb edema

Diagnosis ? • Patient evaluation- underlying conditions • Approach (es) • Treatment ?

Diagnosis – atrial fibrillation • Patient evaluation- • stable vs unstable patient • underlying conditions: thyroid function, fever, anemia, infection, valvular disease…

Approach (es) : • cardioversion- electrical, medical • rate vs rhythm control • onset, anticoagulation • Treatment:rate control (BB), anticoagulation, medical cardioversion

CHADS2 score and risk of stroke in atrial fibrillation. Heart Failure or Ejection Fraction ≤35% 1 Hypertension 1 Age>75 1 Diabetes 1 Stroke, TIA or Systemic Emboli 2 • Warfarin anticoagulation (INR of 2.0-3.0) is recommended for a CHADS2 score ≥2 unless contraindicated (e.g., history of frequent falls, clinically significant bleeding, inability to obtain regular INR). • Warfarin / Aspirin - for CHADS2 score of 1 depending on physician discretion and patient preference. • Aspirin 325 mg daily - for the average patient with a CHADS2 score of 0.

Annual Stroke Risk CHADS2 Score Stroke Risk % 95%CI 0 1.9 1.2–3.0 1 2.8 2.0–3.8 2 4.0 3.1–5.1 3 5.9 4.6–7.3 4 8.5 6.3–11.1 5 12.5 8.2–17.5 6 18.2 10.5–27.4

Case 1- Cont’ • The patient is treated with betablocker (Atenolol, 50 mg/day), and anticoagulation with warfarin is initiated. • 3 weeks following ER visit: • Patient complains of palpitations • INR is therapeutic • heart rate is 60-70, however yet irregular. • Atiarrhythmic therapy with propaphenone (Rythmex) is initiated

2 weeks later… • The patient is found in the street unconscious. • Pulseless • ECG :

Diagnosis • Treatment

Diagnosis: QT prolongation precedes the fatal ventricular arrhythmia Torsade de pointes (polymorphic VT) • Treatment: electrical cardioversion, Mg, anti arrhythmic therapy

Ia, Ic, III: Cardiac toxicity • Proarrhythmia: Torsades des pointes-polymorphic VT Prior sign: QTc prolongation Stop if QT> 500ms or prolongs > 25% Ia Tachycardia: Enhanced AV nodal conduction (vagolytic effect, AV conduction should be slowed prior to treatment)

Anti Arrhythmic Drug Therapy QTc prolongation • Congenital • Cardiac disease: Cardiomyopathy, ischemia, myocarditis • Older age • Female gender • Bardycardia • CNS disease: Trauma, hemorrhage, CVA • Electrolite disturbances (hypo: K, Ca, Mg) • Drug induced: • Antiarrhythmics- Ia, Ic, III • Macrolide antibiotics • Antifungal (ketokonazole, itraconazole,) • Anti-psychotic (haloperidol, Chlorpromazine, thioridazine) • Antidepressant (imipramine) • Antihistamines (terfenadine, astemizole) • Cisapride

Philpot EE, Brooker AE, Biegalski CS. Effects of sedating and nonsedating antihistamines on flying performance. Mil Med. 1993 Oct;158(10):654-60. The purpose of this double-blind study was to compare the effects on flying performance of a nonsedating antihistamine, (terfenadine), two sedating antihistamines, (chlorpheniramine and diphenhydramine), and a placebo. Twelve USAF pilots were tested at 1-month intervals with the above medications, administered during separate testing periods. Medication was given twice daily for 3 days. On the third day, each pilot performed three landing approaches in a C5-B flight simulator, followed by assessment with psychological and neuropsychological tests. Evaluation of the flight data showed no significant differences in flight performance among any of the pilots while on four different medications. Psychological and neuropsychological testing demonstrated no significant differences in performance with the exception of the SCL-90-R, where pilots reported psychological and physiological subjective symptoms with diphenhydramine and chlorpheniramine, but not with terfenadine. While pilots were on each medication, open-ended questionnaires corroborated the results of the SCL-90-R. Both the flight and neuropsychological testing data suggest that terfenadine has no detectable effects on overall flying performance.

From 1990-2005 the Civil Aerospace Medical Institute (CAMI) reported that antihistamines were found in 338 of 5383 pilot fatalities. It was felt that antihistamines were a factor in or the cause of 50 and 13 cases, respectively. The prevalence of antihistamine use among fatal crashes increased from 4% to 11% over this time span, indicating a worrisome trend.27

Quinidine: Non-cardiac toxicity • CNS (Cinchonism: tinitus, hearing and visual disturbances, confusion, psychosis) • GI (Nausea, vomiting, diarrhea, abdominal pain) • Immune: Fever, rash, hematological: immune - thrombocytopenia, hemolytic anemia

Anti Arrhythmic Drug TherapyClass Ia Procainamide: • Uses: as of quinidine (IV is effective as lidocaine in terminating VT) • Hepatic and renal excretion • Variable acetylaton in the liver • Active metabolite: N-Acetyl Procaineamide (NAPA), has class III action, excreted by the kidney

Anti Arrhythmic Drug TherapyIa Procainamide toxicity: • Lupus like syndrome (30%): • fever, pleuropericarditis, arthralgia, hepatomegaly, • kidney involvement is rare • Resolves with D/C of drug • More in slow acetylators • ANA (75%), may appear without the clinical syndrome, anti-histones • (other drugs: hydralazine, isoniazide, quinidine) • Agranulocytosis • Proarrhythmia • Hypotension (IV)

Anti Arrhythmic Drug TherapyIa Disopyramide: • Uses: like quinidine and procainamide • Renal and hepatic excretion • Toxicity: • Worsening of HF • Anticholinergic effect (dry mouth urinary retention, constripation, exacerbation of glaucoma) • Hypoglycemia/ masking of hypoglycemia • Proarrhythmia (like quinidine and procainamide)

Anti Arrhythmic Drug TherapyLidocaine (Ib): • Uses: VT, VT in MI • IV administration (Emergency- no IV: endotracheal/IM) • Hepatic excretion,“flow limited”: 50% Dose reduction in: HF, shock, hepatic dysfunction, age> 70, other drugs (propranolol, cimetidine) • Toxicity: • CNS (convulsions, confusion, respiratory arrest) • Worsening HF • Proarrhythmia: Sinus arrest, AV block, Augmentation of AV conduction in Afib/Aflut

Anti Arrhythmic Drug TherapyMexiletine (Ib): • Similar to lidocaine in structure and EP effects • Uses (in combination with Ia): VT, VT in MI • Oral administration • Hepatic excretion • Toxicity: • CNS (tremor dizziness, blurred vision, confusion, diplopia, nystagmus) • Nausea, vomiting • Proarrhythmia: less than Ia and III

Anti Arrhythmic Drug TherapyPhenytoin (Ib): • Used in the treatment of Digoxin toxicity

Anti Arrhythmic Drug Therapy Ic: • Depress phase 0 of the action potential, slow conduction • Flecainide, Propafenone

Anti Arrhythmic Drug TherapyIc: Flecainide • More effective than other class I agents in the management of SVT, Afib, Aflut • Toxicities: • Conduction- prolong PR, QRS • Proarrythmia: up to 5%, higher with IHD, CHF • Increase AVN conduction (in AFib, AVN blocking agent should be added) • Increase pacing threshold

Anti Arrhythmic Drug TherapyIc: Flecainide • Non-cardiac toxicities: • Confusion, irritability, blurred vision, dizziness, nausea • Drug interactions: • Levels of flec & propranolol increase when administered together, amiodarone increase flec levels

Anti Arrhythmic Drug TherapyIc: Propafenone • Has both type Ic and beta-adrenergic antagonism • Clinical utility similar to flecainide • No relation between plasma level and effect • Bioavailability increases with dose • Renal elimination of the drug and metabolites

Case 2 • 72 yo male, Atrial fibrillation • Background diseases: • Asthma- treated with beta agonists, and corticosteroid inhalations, recurrent admissions • CHF- s/p MI • Started treatment with propafenone • 1 month later: Admitted to ER because of Severe Dyspnea • Differential diagnosis (?)

Case 2 • Differential diagnosis:

Anti Arrhythmic Drug TherapyIc: Propafenone Toxicities: • Cardiac: As of flecainide, Worsen HF • Non-cardiac • Bronchospasm • Dizziness, disturbance of taste, blurred vision, nausea Drug interaction: • Increased plasma concentration of digoxin, • Increased effect of beta adrenergic antagonists, warfarin

Anti Arrhythmic Drug TherapyClass II: beta-adrenergic antagonists • Effects: • Preventing AV reentrant arrhythmia • Decreasing ventricular arrhythmogenesis Uses: • post MI-reduces sudden death • Sinus tachycardia: Thyrotoxicosis, emotional stress • SVT • Atrial fibrillation • Congenital long QT sybdrome • Neurocardiogenic syncope

Anti Arrhythmic Drug TherapyClass II: beta-adrenergic antagonists Cardiac toxicities: • Neg. Inotropic effect-:Worsen HF • Neg. Chronotropic effects: sinus bradycardia (AVN conduction abnormalities) • Discontinuation- gradual Non-cardiac toxicities

Anti Arrhythmic Drug TherapyClass III: K cannels, prolong repolarizationAmiodarone • Slow sinus rate, prolong AV conduction • Alpha and beta adrenergic antagonistic effect • May reduce blood pressure (IV) Effective in: • VT, VF: prevention of recurrence (60%), Latency to effect 2-6wks • Afib, slow vent response, convert to sinus rhythm

Anti Arrhythmic Drug TherapyClass III: Amiodarone Elimination: • Hepatic excretion into bile • Slow uptake and release from reservior- multiphasic elimination: • 50% decrease in first 3-5 days, • Subsequently: half life 26-107 days

Anti Arrhythmic Drug TherapyAmiodarone toxicities (1): Dose dependent 75% of patients treated with high doses for 5 years In 5-10% per year requires discontinuation • Pulmonary: • 1-15%, less likely when dose<300mg/day • Dry cough, dyspnea, rales, pulmonary infiltrate • Reversible in early phases. If drug not discontinued- 10% mortality • CxR, PFT every 6 months

Anti Arrhythmic Drug TherapyAmiodarone toxicities (2): • Hepatic: increase in liver enzymes. Discontinue if more than 3-fold • Cardiovascular: bradycardia, AV block, prolonged QTc (TDP is rare), avoid other QT prolonging agents • Hyper/Hypo- Thyroidism: 2-5% per year. Thyroid functions be monitored annually. If hypo, consider Levothyroxin treatment

Anti Arrhythmic Drug Therapy