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Anti Arrhythmic Drug Anti Arrhythmic Drug TherapyTherapy
Mordechai Muszkat, MD
Department of Internal Medicine
Clinical Pharmacology Unit
Anti Arrhythmic Drug TherapyAnti 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 TherapyAnti 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 TherapyAnti Arrhythmic Drug Therapy
Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoinIc- Flecainide, propafenone
II- beta-blockers
III- Amiodarone, bretylium, sotalol
IV- Calcium cannel blocking agents
Anti Arrhythmic Drug TherapyAnti 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 TherapyAnti Arrhythmic Drug Therapy proarrhythmia 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:Anti Arrhythmic Drug Therapy: Ia: Quinidine (1)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 1Case 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 CHADS2 score and risk of stroke in atrial fibrillationstroke in atrial fibrillation..
Heart Failure or Ejection Fraction ≤35% 1Hypertension 1Age>75 1Diabetes 1Stroke, 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 RiskAnnual Stroke Risk
CHADS2 Score Stroke Risk % 95%CI 0 1.9 1.2–3.01 2.8 2.0–3.82 4.0 3.1–5.13 5.9 4.6–7.34 8.5 6.3–11.15 12.5 8.2–17.56 18.2 10.5–27.4
Case 1- Cont’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.PulselessECG :
Diagnosis
Treatment
Diagnosis: QT prolongation precedes the fatal ventricular arrhythmia Torsade de pointes (polymorphic VT)
Treatment: electrical cardioversion, Mg, anti arrhythmic therapy
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug Therapy
Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoinIc- Flecainide, propafenone
II- beta-blockers
III- Amiodarone, bretylium, sotalol
IV- Calcium cannel blocking agents
Ia, Ic, III: Cardiac toxicityIa, Ic, III: Cardiac toxicity
Proarrhythmia:
Torsades des pointes-polymorphic VTPrior 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 Anti Arrhythmic Drug Therapy QTc prolongationQTc prolongation
1. Congenital2. Cardiac disease: Cardiomyopathy, ischemia, myocarditis3. Older age4. Female gender5. Bardycardia6. CNS disease: Trauma, hemorrhage, CVA7. Electrolite disturbances (hypo: K, Ca, Mg)
8. Drug induced:1. Antiarrhythmics- Ia, Ic, III2. Macrolide antibiotics3. Antifungal (ketokonazole, itraconazole,)4. Anti-psychotic (haloperidol, Chlorpromazine, thioridazine)5. Antidepressant (imipramine)6. Antihistamines (terfenadine, astemizole)7. Cisapride
Philpot EE, Brooker AE, Biegalski CS. Effects of Philpot EE, Brooker AE, Biegalski CS. Effects of sedating and nonsedating antihistamines on flying sedating and nonsedating antihistamines on flying
performance. Mil Med. 1993 Oct;158(10):654-60.performance. Mil Med. 1993 Oct;158(10):654-60.
The purpose of this double-blind study was to compare the effects on flyingperformance of a nonsedating antihistamine, (terfenadine), two sedatingantihistamines, (chlorpheniramine and diphenhydramine), and a placebo. TwelveUSAF pilots were tested at 1-month intervals with the above medications,administered during separate testing periods. Medication was given twice dailyfor 3 days. On the third day, each pilot performed three landing approaches in a C5-B flight simulator, followed by assessment with psychological andneuropsychological tests. Evaluation of the flight data showed no significantdifferences in flight performance among any of the pilots while on four differentmedications. Psychological and neuropsychological testing demonstrated nosignificant differences in performance with the exception of the SCL-90-R, where pilots reported psychological and physiological subjective symptoms withdiphenhydramine and chlorpheniramine, but not with terfenadine. While pilots wereon each medication, open-ended questionnaires corroborated the results of theSCL-90-R. Both the flight and neuropsychological testing data suggest thatterfenadine 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
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug Therapy
Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoinIc- Flecainide, propafenone
II- beta-blockers
III- Amiodarone, bretylium, sotalol
IV- Calcium cannel blocking agents
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug Therapy
Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoinIc- Flecainide, propafenone
II- beta-blockers
III- Amiodarone, bretylium, sotalol
IV- Calcium cannel blocking agents
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug Therapy
Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoinIc- Flecainide, propafenone
II- beta-blockers
III- Amiodarone, bretylium, sotalol
IV- Calcium cannel blocking agents
Quinidine: Non-cardiac toxicityQuinidine: 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 TherapyAnti Arrhythmic Drug TherapyClass Ia Procainamide:Class 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 TherapyAnti Arrhythmic Drug TherapyIa Procainamide toxicity:Ia 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 TherapyAnti Arrhythmic Drug TherapyIa Disopyramide:Ia 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 TherapyAnti Arrhythmic Drug TherapyLidocaine (Ib):Lidocaine (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 TherapyAnti Arrhythmic Drug TherapyMexiletine (Ib):Mexiletine (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 TherapyAnti Arrhythmic Drug TherapyPhenytoin (Ib):Phenytoin (Ib):
Used in the treatment of Digoxin toxicity
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug Therapy
Ic:Depress phase 0 of the action potential,
slow conduction
Flecainide, Propafenone
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug TherapyIc: FlecainideIc: 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 TherapyAnti Arrhythmic Drug TherapyIc: FlecainideIc: 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 TherapyAnti Arrhythmic Drug TherapyIc: PropafenoneIc: Propafenone
Has both type Ic and beta-adrenergic antagonism
Clinical utility similar to flecainideNo relation between plasma level and effectBioavailability increases with doseRenal elimination of the drug and
metabolites
Case 2Case 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 2Case 2
Differential diagnosis:
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug TherapyIc: PropafenoneIc: 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 TherapyAnti Arrhythmic Drug TherapyClass II: beta-adrenergic antagonistsClass 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 TherapyAnti Arrhythmic Drug TherapyClass II: beta-adrenergic antagonistsClass 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 TherapyAnti Arrhythmic Drug TherapyClass III: K cannels, prolong repolarizationClass III: K cannels, prolong repolarization
AmiodaroneAmiodarone 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 TherapyAnti Arrhythmic Drug TherapyClass III: AmiodaroneClass 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 TherapyAnti Arrhythmic Drug TherapyAmiodarone toxicities (1): Amiodarone toxicities (1):
Dose dependent75% of patients treated with high doses for 5 yearsIn 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 TherapyAnti Arrhythmic Drug TherapyAmiodarone toxicities (2): Amiodarone 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 TherapyAnti Arrhythmic Drug TherapyAmiodarone toxicities (3): Amiodarone toxicities (3):
Nausea, anorexia Photosensitivity: Blue gray discoloration, does nor
resolve completely in discontinuation Corneal microdeposits: all patients, dose
dependent, halos around light; optic neuritis Drug interactions: reduce warfarin & digoxin dose
Despite it’s toxicity:Despite it’s toxicity:
Amiodarone is one of the most effective antiarrhythmic agents- even in cases when other drugs have failed (Such as atrial fibrillation with large LA)
DronedaroneDronedarone
Developed from amiodarone. No iodine: probably less ADE in eyes, lungs, thyroid
For the treatment of AF
Less effective than amiodarone for 2nd prevention of AF
Increased mortality in NYHA IV and unstable clases II and III CHF
Prolongs QT
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug Therapy
Class III: sotalolClass III: sotalol Uses:
– VT (Decrease frequency & duration of non-sustained VT 40%, prevent recurrence of sustained VT 70%)
– Afib prevent recurrence
Excreted in the urine Toxicities: Cardiac:
– Proarrhythmia- TDP; avoid other QT prolonging agents– Beta- blocker (bradyarrhythmia, bronchospasm, HF)
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug TherapyClass III: BretyliumClass III: Bretylium
Direct EP effects, interaction with sympathetic system , NE release, then blocks reuptake
Uses:– VT, VF
Excreted in the urine Toxicities: Cardiac:
– Proarrhythmia– Transient hypertension & tachycardia, then
hypotension
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug TherapyClass IV: Ca channels blockersClass IV: Ca channels blockers
Verapamil, diltiazem, Uses:
– SVT abolish– Afib slow
Liver metabolism Toxicities:
– Hypotension– Bradycardia, AV block– Worsening HF– Constipation
Case 3Case 3
A 22 year old women presents to the ER with 7 hour history of feeling that her heart has been beating rapidly.
This has occurred previously, but has always stopped by itself. No other significant past history.
Pulse is over 200/min, BP 125/75, no distress
Case 3-ECGCase 3-ECG
Differential diagnosis
Treatment
Differential diagnosis:
– SVT– Sinus tachycardia– Atrial fibrillation– Atrial flutter
Treatment
Case 3Case 3
Adenosine is given, and the following rhythm strip is recorded.
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug TherapyOthers: AdenosineOthers: Adenosine
Inhibition of SAN, AVN Uses:
– SVT abolish– Not effective in : Afib, A flut,
Only IV. Half life 4-8 sec Toxicities:
– AV block – Facial flushing– Dyspnea– Chest pressure
Case 3 ECG IICase 3 ECG II
??
Case 3Case 3
Sawtooth
Adenosine not effective in atrial flutter or fibrillation, but blocks transmission to the ventricles- uncover atrial activity (flutter)
Anti Arrhythmic Drug TherapyAnti Arrhythmic Drug TherapyOthers: DigitalisOthers: Digitalis
Uses:– Slow ventricular rate in : Afib, A flut,
Loading (1-1.5 mg/8-24 hours) Renal excretion
Toxicity– Also in therapeutic Levels (0.8-1.5, but different ranges
may be used)
Digitalis toxicityDigitalis toxicity
Cardiovascular- AV blocks, ventricular tachycardia, (atrial tachycardion)
CNS-blured/ yellow vision, headache weakness, dizziness, apathy, delirium
Dermatologic- maculopapular, pruritusGI- nausea, vomitting, diarrhea, abdominal
pain
Digitalis toxicity- Digitalis toxicity- predisposing factorspredisposing factors
Acute MI/ischemia Electrical cardioversion Advanced age Renal failure Metabolic (Hypothyroidism-decreased Vd, Hypoxemia Electrolyte [hypo-K- increased distribution to heart and
muscle (also hyper Na), hypo-Mg, hyper-Ca] Drug interactions (quinidine, propafenone, verapamil,
amiodarone, propranolol, diltiazem, tetracycline, erythromycin, clarythromycin, cyclosporine, spironolactone)- CLrenal+non-renal ,Vd
QuestionsQuestions
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Three weeks later….Three weeks later….