Antiarrhythmic Agents

Indications
Paroxysmal supraventricular tachycardia (PSVT) Atrial fibrillation (Afib) Premature ventricular contractions (PVC)

Anatomy & Pathophysiology

Heart has both automaticity and conductivity Primary pacemaker = SinoAtrial Node Electrical waves start at the SA node
Depolarize across the atrium Through the AV node Down the Bundle of His Across the Purkinje fibers

Anatomy & Pathophysiology

Irregular rhythms/Arrhythmias
Occur when the primary pacemaker does not fire normally Other cell groups take the place of the SA node Action potential: difference in electric charge across myocardial cell membrane Depolarization: electrical impulse that comes before myocardial contraction Repolarization: recovery stage after contraction

Anatomy & Pathophysiology

Tachyarrhythmias
2 mechanisms
Increased automaticity, creating an ectopic focus
Treated with drugs that prolong the action potential

Reentry pathways
Treated with drugs that prolong the refractory period

Anatomy & Pathophysiology

PSVT
Applies to all tachycardias that are supraventricular
Except A-fib and A-flutter

Generally due to reentry

Atrioventricular nodal reentrant tachycardia (AVNRT)
HR of 130-250, 1:1 conduction, narrow QRS complex

Anatomy & Pathophysiology

A-fib is one of the most common arrhythmias
Risk factors: male, comorbid disease states, age Classified by duration
Paroxysmal: self-terminating episodes lasting 1-7 days Persistent: not self-terminating lasting over a week, requires cardioversion (assuming no clot present via TEE), warfarin and amiodarone therapy Permanent: lasts over a year, termination has not worked Lone: A-fib in patients with no underlying cause

Anatomy & Pathophysiology

PVCs are caused by increased automaticity
Classified by morphology and prevalence
Determine comorbid disease states
MI or ischemia

Risk factors: cardiac scarring, hypertrophy, LVD PVCs during QT interval can propagate V-fib

QRS Complex: simultaneous ventricular depolarization/Atrial repolarization

P wave: SA firing

T wave: Ventricular Repolarization

EKG Example & Ventricular AP

EKG showing SVT: narrow QRS complex with HR 179

Ventricular Action Potential, 5 phases Depolarization Phase 0: permeable membrane, increased Na influx Repolarization Phase 1: positive membrane potential due to Na Phase 2: slow influx of Ca and outflow of K Phase 3: Rapid outflow of K Resting Period Phase 4: active exchange of Na and K

Re-entry Circuit
Black Line: Normal conduction Red Line: Normal conduction hitting scarred cardiac muscle, propagation of impulse terminated Green Line: Reentry into circuit, preventing forward propagation of impulse

Assessment
Thorough health assessment
Drug sensitivity Cormorbidities Current drug therapy

Auscultation of the heart

Rate and rhythm
A-fib: irregular rhythm and rate PSVT: fast regular rate and rhythm PVC: premature ventricular beats with a pause

Assessment
Obtain lab studies
Exercise stress test, EKG, ECG, 24hr Holter monitor CBC, thyroid, lytes, renal and hepatic fxn

Antiarrhythmic Drugs
Class I Subclass IA Generic Quinidine Procainamide IB lidocaine mexilitine tocainide IC flecainide propafenone II Beta blockers propranolol metoprolol III amiodarone sotalol ibutilide dofetilide IV CCB, nondihydropyridines Procan SR Xylocaine Mexitil Tonocard Tambocor Rythmol Inderal Torpol Cordarone, Pacerone Betapace Corvert Tikosyn Brand

Mechanism of Action
All act to reduce electrical irregularities Class IA: lengthens AP
Depression of phase 0 by decreasing inward Na flux Prolong atrial and ventricular refraction and decreasing automaticity

Class IB: shortens AP Class IC: slows conduction of AP

Mechanism of Action
Class II (Beta Blockers)
Inhibit sympathetic stimulation Reduces rate of SA (or other foci) firing Prolongs refractory period of AV node

Class III
Prolong phase 3 repolarization by blocking K channels This lengthens QT interval
Increased risk of Torsades, excluding amiodarone

Class IV (Nondihydropyridines)

Treatment Principles
Cardiologist will generally begin treatment, PCP will do routine monitoring Digoxin and nondihydropyridines
Effective in controlling HR with recent onset A-fib

Treatment Principles
PSVT prophylaxis
Beta blockade or digoxin Verapamil Ablation of scar tissue or accessory path

Treatment Principles
Atrial Fibrillation
Control rapid ventricular response (RVR) with beta or calcium blockade
Possible IV admin in acute settings to control slow RVR IV Digoxin or amiodarone in patients with a-fib and HF without accessory paths Anticoagulation Amiodarone for cardioversion and/or maintenance

Monitoring
Goal of therapy
Not to completely eliminate arrhythmia Prevention of potentially fatal patterns

Monitor for toxicity

Digoxin Quinidine
Persistent CBC, hepatic and renal function tests

Monitoring
Dofetilide (Tikosyn)
Therapy initiated inpatient
Prolonged QT intervals

Propafenone (Rythmol)
Taste changes, n/v, headache, fatigue, gi CHF, bradycardia, heart block, ventricular arrhythmias, torsades

Amiodarone (Cordarone)
Loading dose: 800-1600 mg/d for 1-3 weeks
Numerous baseline tests, EKG monitoring for prolonged QT

Maintenance: 200-400 mg/d Half-life 107 days Substrate of CYP 3A4 and 2C8
Moderate inhibitor of 3A4 als

Amiodarone Side Effects

Optic neuropathy, vision loss CNS effects: tremor, fatigue, tremor Thyroid function changes Pulmonary toxicity Heart block, bradycardia, ventricular arrhythmias, torsades N/V, constipation, anorexia Peripheral neuropathy Blue-gray skin discoloration, photosensitivity

Anticoagulants
Prevent or treat
Venous thromboembolism,
Deep vein thrombosis (DVT)

Peripheral arterial thrombosis

Pulmonary emboli (PE) Arterial ischemic events

Ischemic stroke & Transient ischemic attacks (TIA) Acute myocardial infarction Intermittent atrial fibrillation

Therapeutic Overview
Balance between fluidity and ability to clot
Intrinsic clotting pathway Extrinsic clotting pathway

These merge in the final common pathway

Conversion of fibrinogen to a fibrin clot

Most drugs are used to prevent or treat clots that may lead to thromboembolic events

Risk Factors for Thromboembolism

40+ years of age General anesthesia (> 30 minutes) Cancer Oral contraceptive pills Varicose veins, obesity Trauma Venous stasis, bed rest, immobility Chronic heart failure

Drug Categories
Heparin group
Heparin LMWH: enoxaparin (Lovenox) Heparinoids: fondaparinux Direct thrombin inhibitors

Oral anticoagulants
Warfarin (Coumadin)

Drug Categories
Platelet Inhibitors
Traditional - aspirin; dipyridamole ADP-induced inhibitors clopidogrel (Plavix)

GPIIb/IIIa inhibitors abciximab, eptifibatide, tirofiban

PDEIII inhibitors cilostazol (Pletal) Thrombolytic agents Hemorheologic agents pentoxifylline (Trental)

Coagulation and Fibrinogen Systems

(abridged version)

Intrinsic Pathway
Factor X

Extrinsic Pathway

Thrombin Fibrinogen Fibrin Clot Fibrin

Common Pathway

Heparin Group
Used to prevent venous thromboembolism
Major abdominothoracic surgery Treatment of PE and atrial fibrillation Diagnosis of acute and chronic DIC Prevent clotting in aterial and hear surgery Treatment of peripheral aterial embolism Anticoagulant in transfusions and dialysis

Not recommended for ischemic stroke

Heparin Group
LMWH enoxaparin (Lovenox)
Enoxaparin
40mg qd prophylaxis 1mg/kg q12h active treatment

Prevent venous thromboembolisms in patients undergoing major surgery and in medically ill patients
Treat pulmonary embolism and acute coronary syndrome Therapy for anticoagulated patients, postoperatively and in post percutaneous intervention Revascularization therapy Patients on recently-initiated warfarin
Subtherapeutic INR

Heparin Mechanism of Action

No effect on existing clots Prevents formation of new thrombi Two functions in the clot formation pathway
Neutralizes factor Xa with a direct effect reducing factor X Decreases conversion of prothrombin to thrombin
Reducing fibrin production

Adverse Effects
Patient education is VERY IMPORTANT!
Bleeding can be difficult to control while using anticoagulants

Heparin
Easily bruised, nosebleed, hematuria, tarry stool

LMWH - Enoxaparin (Lovenox)

Increased risk with spinal or neuraxial anesthesia

Warfarin (Coumadin)
Bleeding and hemorrhage
Reported in 20% of all patients

Hepatic disorders: hepatitis, jaundice, elevated liver enzyme activity Edema, abdominal pain, nausea, dizziness, cold intolerance

Oral Anticoagulants
Used to treat venous thromboembolism
High-risk surgery prophylaxis

Short-term treatment of DVT, PE, systemic embolism Heart valve replacement in valvular heart disease
Mechanical Tissue

Cardiomyopathy, acute MI Cardiodiversion in atrial fibrillation

Warfarin
Warfarin 5mg qd initially, titrate to INR
International Normalized Ratio
Test to establish the degree of anticoagulation against a normal population

Monitoring
Vitamin K-dependent factors during warfarin use Protein life span and activity
Varies with time of warfarin therapy

Full anti-coagulation is not achieved for at least 7 days of therapy

Do not bolus

Warfarin does not reverse damage or break up established clots

Warfarin Mechanism of Action

Warfarin
Prevent extension of existing thrombi Prevent formation of new thrombi Competitively blocks vitamin K binding sites Inhibits the synthesis of vitamin K-dependent coagulation factors
Factor II (50hr), VII (6hr), IX (24hr), X (36hr) Protein C (8hr) and S (30hr)

Warfarin Mechanism of Action

Vitamin K-dependent clotting factor synthesis
Occurs in the liver Reduced by as much as 50%
Metabolized by CYP 2C9 and VKORC1
Numerous drug interactions

Platelet Inhibitor MoA

Aspirin: 81mg qd (prophylaxis), 325mg qd (treatment)
Prevents platelet aggregation
Influencing the synthesis of thromboxane A2 prostacyclin
These compounds are platelet aggregators and vasoconstrictors.

Dipyridamole
Vasodilator, especially in coronary arteries

Clopidogrel (Plavix): 75mg qd

Inhibits platelet aggregation
Irreversible for the life of the platelet

GPIIb/IIIa inhibitors
Used to decrease ischemic events especially during balloon angioplasty

Agrenilide & cilostazol: still under investigation

Thrombolytic Agents MoA

Fibrinolytics
Dissolve clots at site of intravascular injury

Hemorheologic Agents
Pentoxifylline (Trental)
Decreases blood viscosity Improves red blood cell flexibility Increases white blood cell deformability Inhibits neutrophil adhesion & activation

Increased use of clopidogrel and ticlopidine replacing pentoxifylline.

Adverse Effects
Dipyridamole
Purpurea, dizziness, anemia

Clopidogrel (Plavix)
Hemorrhage, bleeding, abdominal pain, rash, gastritis, constipation, diarrhea

Cilostazol (Pletal)
Headache, palpitations, tachycardia, abdominal pain, dyspepsia, nausea, edema, myalgia, vertigo, cough

Pentoxifylline (Trental)
Nausea, dyspepsia, bloating, diarrhea, flatulence, dizziness, headache, angina, agitation, blurred vision

Patient Categories
Pediatrics
Oral anticoagulation in children not well documented Unknown safety of heparin, thrombolytics, clopidogrel and pentoxifylline

Aspirin should not be used unsupervised because of possible Reyes syndrome in children under age 18 Pregnancy and lactation
Heparin does not cross placenta and is the drug of choice Warfarin is not recommended for use during pregnancy Aspirin should not be taken in the last trimester

Patient Categories
Geriatrics
Heparin may be ineffective Warfarin
Subcutaneous bleeding is common May require a decreased dose based on liver functionality

Thrombolytics
Increased bleed risk in 75+ y.o.

Clopidogrel
Does not require dose adjustment

Pentoxifylline
Decreased renal function may delay excretion

Treatment Principles
Identify drugs used in prevention
Acute treatment or maintenance therapy

Monitor therapy to achieve desired level of anti-coagulation Education

Counseling on diet, activity, regularly scheduled evaluation and laboratory assessments

Use of aspirin alone should be discouraged