Antiarrythmics

Question 1

Classes of antiarrythmics

Answer 1

a. Class I: Fast Sodium Channel Blockers
b. Class II: Beta-Adrenergic Antagonists
c. Class III: Inhibitors of Repolarization
d. Class IV: Calcium Channel Blockers
e. Other: (adenosine, digitalis, etc.)

Question 2

Phases of cardiac cycle

Answer 2

Phase 0 rapid depolarization (fast sodium channels open; fast inward flow of Na+ )
Phase 1 begin repolarization (sodium channels close)
Phase 2 plateau (slow calcium channels open; slow inward flow of Ca2+)
Phase 3 repolarization (calcium channels close; potassium channels open; slow outward K+ current)
Phase 4 pacemaker potential; return to resting membrane potentials
Refractory period (phases 1-3)
	(periods of repolarization)

Question 3

Sympathetic stimulation effects

Answer 3

(ß1 receptors activated)
Increases catecholamines 
Increased heart rate (positive chronotropic effect) 
Increased automaticity 
Facilitation of conduction of AV node

Question 4

Parasympathetic system effects

Answer 4

(M2 muscarinic receptors)
Decreases heart rate
Inhibits AV conduction

Question 5

Classification of arrythmias

Answer 5

Site of origin of abnormality (atrial/ junctional / ventricular)
Complexes on ECG (narrow/broad)
Heart rhythm (regular/irregular)
Heart rate is increased or decreased

Question 6

Mechanisms of Arrhythmia Production

Answer 6

Altered automaticity - latent pacemaker cells take over the SA node’s role; escape beats
Delayed after-depolarization - normal action potential of cardiac cell triggers a train of abnormal depolarizations
Re-entry - refractory tissue reactivated repeatedly and rapidly due to unidirectional block, which causes abnormal continuous circuit
Conduction block – impulse fail to propagate in non-conducting tissue

Question 7

Reasons for arrythmias

Answer 7

Arterial hypoxemia
Electrolyte imbalance
Acid-base abnormalities
Myocardial ischemia
Altered sympathetic nervous system activity
Bradycardia
Administration of certain drugs
Enlargement of a failing ventricle

Question 8

Class I agents

Answer 8

Block sodium channels which depresses Phase O in depolarization of the cardiac action potential with resultant decreases in action potential propagation (decrease in depolarization rate) and slowing of conduction velocity

Question 9

Class IA

Answer 9

Quinidine - Class IA Prototype
Procainamide
Disopyramide
Moricizine

Intermediate Na+ channel blocker (intermediate dissociation)
Decreased depolarization rate (phase 0)
Decreased conduction velocity
Prolonged repolarization
Increased AP duration

Question 10

Disopyramide

Answer 10

Suppresses atrial and ventricular tachyarrhythmias
Oral agent
Has significant myocardial depressant effects and can precipitate congestive heart failure and hypotension

Question 11

Class IB Agents

Answer 11

Lidocaine - Class IB Prototype
Mexiletine
Tocainide
Phenytoin

Fast Na+ channel blocker (fast dissociation)
Alters the action potential by inhibiting sodium ion influx via rapidly binding to and blocking sodium channels (fast)
Produces little effect on maximum velocity depolarization rate, but shortens AP duration and shortens refractory period
Decreases automaticity

Question 12

Lidocaine

Answer 12

Class IB Antiarrhythmic Drug- Prototype
Sodium channel blocker (fast)
Used in acute treatment and prevention of ventricular dysrhythmias in immediate aftermath of MI
Ventricular tachycardia, fibrillation, PVCs, especially associated with ischemia; Pulseless VT and VF

Question 13

Pharmacokinetics: Lidocaine

Answer 13

Elimination half-time (h) 1.4-8.0
Therapeutic plasma concentration 1-5 ug/mL
Dose: 1-1.5 mg/kg IV, infusion 1-4 mg/min (max dose 3 mg/kg)
50% protein binding
Hepatic metabolism
Active metabolite, which prolongs elimination half-time.
Metabolism may be impaired by drugs such as cimetidine and propanolol, or physiologic altering conditions such CHF, acute MI, liver dysfunctioin, GA; or can be induced by drugs like barbiturates, phenytoin, or rifampin
10% renal elimination

Question 14

Adverse effects: Lidocaine

Answer 14

hypotension, bradycardia, seizures, CNS depression, drowsiness, dizziness, lightheadedness, tinnitus, confusion, apnea, myocardial depression, sinus arrest, heart block, ventilatory depression, cardiac arrest and can augment preexisting neuromuscular blockade

Question 15

Mexiletine

Answer 15

Chronic suppression of ventricular cardiac tachyarrhymias

Oral agent

Question 16

Class IC Agents

Answer 16

Flecainide - Class IC Prototype
Propafenone
Slow Na+ channel blocker (slow dissociation), so does not vary much during the cardiac cycle
Potent decrease of depolarization rate phase 0 and decreased conduction rate, with increased AP
Markedly inhibit conduction through the His-Purkinje system

Question 17

Flecainide

Answer 17

Effective in the treatment of suppressing ventricular PVCs and ventricular tachycardia; also atrial tachyarrhythmias; Wolff-Parkinson-White syndrome (reentry rhythm)
Oral agent
Has proarrhythmic side effects

Question 18

Propafenone

Answer 18

Suppression of ventricular and atrial tachyarrhythmias
Oral agent
Has proarrhythmic side effects

Question 19

Class II Agents

Answer 19

Propanolol – Prototype
Metoprolol
Esmolol
Labetolol (off-label use)
Class II drugs - Beta-adrenergic antagonists. Depress spontaneous phase 4 depolarization resulting in SA node discharge decrease
Drug-induced slowing of heart rate with resulting decreases in myocardial oxygen requirements is desirable in patients with CAD
Slow speed of conduction of cardiac impulses through atrial tissues and AV node resulting in prolongation of the P-R interval on ECG, increased duration of the action potential in atria
Decreased automaticity

Question 20

Class II agent used for?

Answer 20

Used to treat SVT, atrial and ventricular arrhythmias
Used to suppress and treat ventricular dysrhythmias during MI and reperfusion
To treat tachyarrhythmias secondary to digoxin toxicity, and SVT (atrial fibrillation or flutter).
Prevents catecholamine binding to beta receptors
Slowing of heart rate
Decrease myocardial oxygen requirements

Question 21

Propranolol

Answer 21

Class II Antiarrhythmic Drug- Prototype
Beta-adrenergic antagonist (nonselective)
Used to prevent reoccurrence of tachyarrhythmias, both supraventricular and ventricular precipitated by sympathetic stimulation

Question 22

Pharmacokinetics: Propranolol

Answer 22

Dose: 1 mg/min (total dose of 3-6 mg) IV or 10-80 mg po
Onset: 2-5 minutes
Peak effect 10-15 minutes, duration 3-4 hours
Elimination half-time 2-4 hours
Cardiac effects: decreased HR, contractility, CO; increased PVR, coronary vascular resistance; however, oxygen demand lowered
Highly protein bound 90-95%
Hepatic metabolism, with weak metabolite
Therapeutic plasma level 10-30 ng/mL
Side effects: bradycardia, hypotension, myocardial depression, fatigue, and worsening bronchospasm, drug fever, rash, nausea, worsening Raynauds, interferency with glucose metabolism
Caution with reactive airway disease, hypovolemia, CHF, AV block

Question 23

Metoprolol

Answer 23

Class II Antiarrhythmic Drug- Prototype
Beta-adrenergic antagonist (selective B1)
Dose: Dose 5 mg IV over 5 minutes; max dose 15 mg over 20 min.
Onset: 2.5 min.
Duration: Half-life 3-4 hours
Metabolized by liver
Can be used in mild CHF

Question 24

Esmolol

Answer 24

Class II Antiarrhythmic Drug
Beta-adrenergic antagonist (selective B1)
Dose: 0.5 mg/kg IV bolus over 1 min, then 50-300 mcg/kg/min
Duration <15 mins
Effects HR without decreasing BP significantly in small doses
Rapidly hydrolyzed by plasma esterases
Not the same esterases as cholinesterases responsible for metabolism of sux, therefore no effect on sux metabolism

Question 25

Class III agents

Answer 25

Amiodarone – Class III Prototype Dronedarone Sotalol Class III drugs block potassium ion channels resulting in prolongation of cardiac depolarization and increasing action potential duration, and lengthening repolarization. Decrease the proportion of the cardiac cycle during which myocardial cells are excitable and thus susceptible to a triggering event Used to treat supraventricular and ventricular arrhythmias Prophylaxis in cardiac surgery patients r/t high incidence of Afib Preventative therapy in patients who have survived sudden cardiac death who are not candidates for ICD Control rhythm in Afib

Question 26

Amiodarone

Answer 26

Class III Antiarrhythmic Drug - Prototype also has Class I, II, and IV antiarrhythmic properties Potassium/ sodium/ calcium channel blocker, alpha and beta adrenergic antagonist Used for prophylaxis or acute treatment in the treatment of atrial and ventricular arrhythmias (refractory SVT, refractory VT/ VF, AF) 1st line drug VT/ VF when resistant to electrical defibrillation

Question 27

Amiodarone Pharmacokinetics

Answer 27

Dose: Bolus 150-300 mg IV over 2-5 minutes, up to 5 mg/kg, then 1 mg/hr x 6 hrs, then 0.5 mg/hr x 18 hrs Prolonged elimination half-life (29 days) Hepatic metabolism, active metabolite Biliary/ intestinal excretion Therapeutic plasma level 1.0-3.5 ug/mL Extensive protein binding 96% Large volume of distribution

Question 28

Amiodarone Adverse Effects

Answer 28

``` Pulmonary toxicity Pulmonary edema ARDS Photosensitive rashes Grey/blue discolouration of skin Thyroid abnormalities 2% Corneal deposits CNS/GI disturbance Pro-arrhythmic effects (torsades de pointes) Heart block Hypotension Nightmares 25% Abnormal LFT 20% Inhibits hepatic P450 ```

Question 29

Class IV

Answer 29

``` Calcium channel blockers Verapamil – Class IV Prototype Diltiazem * Block slow calcium channels *primary site AV node Block slow calcium channels, which decreases conduction through AV node and shortens Phase 2 (the plateau) of the action potential in ventricular myocytes Contractility of the heart decreases Used in the treatment of SVT and ventricular rate control in Afib and Aflutter Used to prevent reoccurrence of SVT Not used in ventricular arrhythmias ```

Question 30

Verapamil

Answer 30

Class IV Antiarrhythmic Drug - Prototype Calcium channel blocker Dose 2.5-10 mg IV over 1-3 minutes (max dose 20 mg) Continuous infusion 5 ug/kg/minute Do not use IV verapamil with ß- blocker (heart block) T1/2 6-8 hours Highly protein bound Hepatic metabolism, with active metabolite Excreted in the urine, and bile Side effects: myocardial depression, hypotension, constipation, bradycardia, nausea, prolongs effects of neuromuscular blockers

Question 31

Caution with Verapamil

Answer 31

Caution: Myocardial depression and vasodilation with inhalational agents Can potentiate neuromuscular blockers Can increase risk of local anesthetic toxicity Together with Dantrolene can cause hyperkalemia Causes decreased clearance of Digoxin

Question 32

Diltiazem

Answer 32

``` Class IV Antiarrhythmic Drug Calcium channel blocker Dose: 5-20 mg IV (0.25-0.35mg/kg) over 2 min. Continuous infusion 10 mg/hour T1/2 4-6 hours Highly protein bound Hepatic metabolism Excreted in the urine Side effects: myocardial depression, hypotension, constipation, bradycardia, nausea, prolongs effects of neuromuscular blockers ```

Question 33

Other class V agents

Answer 33

Adenosine Digoxin Phenytoin Atropine

Question 34

Adenosine

Answer 34

Not in Vaughan Williams class Binds to A1 purine nucleotide receptors (activates adenosine receptors to open K+ channels and increase K+ currents) Slows AV nodal conduction Used for acute Rx only Used for termination of SVT/ diagnosis of VT Dose 6mg IV, rapid bolus Repeated if necessary after 3 minutes, 6-12 mg IV T1/2 < 10 seconds Eliminated by plasma and vascular endothelial cell enzymes Side effects: excessive AV or SA nodal inhibition, facial flushing, headache, dyspnea, chest discomfort, nausea, bronchospasm Contraindicated in asthma, heart block

Question 35

Digoxin

Answer 35

Not in Vaughan Williams class Cardiac glycoside Increases vagal activity, thus decreasing activity of SA node and prolongs conduction of impulses thru the AV node Decreases HR, preload and afterload Slows AV conduction by increasing AV node refractory period Positive inotrope- used to treat CHF

Question 36

Digoxin Pharmacokinetics

Answer 36

``` Used for the management of atrial fibrillation or flutter (controls ventricular rate), especially with impaired heart function Dose: 0.5-1 mg in divided doses over 12-24 hrs Onset of action 30-60 minutes T1/2 36 hours Narrow therapeutic index Therapeutic levels 0.5-1.2 ng/mL Weak protein binding 90% Excreted by kidneys Reduce dose in elderly/renal impairment ```

Question 37

Digoxin Adverse Effects

Answer 37

Arrhythmias, heart block, anorexia, nausea, diarrhea, confusion, agitation potentiated by hypokalemia and hypomagnesaemia Toxicity treatment Phenytoin for ventricular arrhythmias Pacing Atropine Antidote: digoxin immune Fab

Question 38

Phenytoin, class, use, and route

Answer 38

Effects resemble Lidocaine Class IA agent Used in suppression of ventricular arrhythmias associated with digitalis toxicity Can also be used other ventricular tachycardias or torsades de pointes Given IV (can precipitate in D5W; mix in NS) Can cause pain or thrombosis when given in peripheral IV Dose: 1.5 mg/kg IV every 5 min. up to 10-15 mg/kg Therapeutic blood levels 10-18 mcg/mL

Question 39

Phenytoin Metabolization and Elimination, adverse effects

Answer 39

Metabolized by liver Excreted in urine Elimination ½ time @24 hours Adverse effects: CNS disturbances, partially inhibits insulin secretion, bone marrow depression, nausea

Question 40

Atropine Dose, Route, Receptor, Use

Answer 40

``` Muscarinic receptor antagonist Used to treat unstable bradyarrhythmias Option for asystolic patients; PEA 0.4 to 1.0 mg IV and repeat as necessary Onset less 1 min; duration 30-60 minutes Metabolized by liver Caution dosing less than 0.4 mg Potential to evoking a paradoxical response Penetrates the BBB, CNS effects ```