anti arrhythmic drug therapy

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


I- Inhibit fast Na channels

II- beta-adrenergic antagonists

III- Inhibit K channels, prolong repolarization

IV- Ca channels antagonists


Ia- Quinidine, procaineaide, disopyramide, Ib- lidocaine, mexiletine, phenytoinIc- Flecainide, propafenone

II- beta-blockers

III- Amiodarone, bretylium, sotalol

IV- Calcium cannel blocking agents


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



II- beta-blockers



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



II- beta-blockers



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


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


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


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


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

Thank you !

Three weeks later….Three weeks later….

anti arrhythmic drug therapy

Documents

contthe patient

patient preference

average patient

weeks laterthe patient

fast na channels

ventricular dysfunction

action potential duration

risk of stroke