Pharmacology of Antiarrhythmias Flashcards Preview

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Flashcards in Pharmacology of Antiarrhythmias Deck (36):
1

Transmembrane Potential

Resting membrane potential determined by concentrations of ions
Sodium (Na+), Potassium (K+), Calcium (Ca2+), Chloride (Cl-)

Ions unable to cross lipid membrane

Electrical gradient
-90 mV inside
0 mV outside

2

Gates in the Cell Membrane

Depolarization opens the activation (m) gates
If inactivation (h) gates have not already closed, the channels are open and activated
Opening brief; open (m) gates very quickly followed by closure of (h) gates and channel inactivation

M- you May come in
H- Heck no!

3

Cell Depolarization phases

Phase 0- rapid depolarization, abrupt increase in Na+ permeability

Phase 1- brieff repolarization, transient K+ efflux

Phase 2- plateau phase, Ca3+ influx ,balanced by K+ efflux

Phase 3- repolarization, continued K+ efflux

Phase 4- gradual depolarization, Na+ leak balanced by K+ efflux

4

Impulse Conduction

Heart rate reflects SA node
- Much faster rate of spontaneous firing

AV node much slower
- Ca2+ current

Bundle of His and Purkinje fibers fast
- Large Na+ current

P-wave: depolarization of atria

PR interval: AV nodal conduction time

QRS: depolarization of ventricles, conduction time of ventricles

QT interval: ventricular action potential duration

T-wave: repolarization of ventricles

5

Abnormal impulse generation

Disturbance of impulse formation

Interval between depolarizations = duration of action potential + duration of diastolic interval

Triggered automaticity:
- Early afterdepolarization – interrupts phase 3
- Delayed afterdepolarization – interrupts phase 4

6

Abnormal impulse conduction

Depressed conduction
- Simple block
- eg. AV nodal block, bundle branch block

Reentry
- Impulse reenters/excites areas of heart more than once
- Must be an obstacle – establishes a circuit
- Must be unidirectional block
- Conduction time must be long enough that retrograde impulse does not encounter refractory tissues

7

Antiarrhythmic drugs can:

Induce arrhythmias
- Must weigh benefits vs. risks

Depress autonomic properties of abnormal pacemaker cell
- Decrease slope of phase 4
- Elevate threshold potential

Alter conduction characteristics of reentrant loop
- Facilitate conduction (shorten refractoriness)
- Depress conduction (prolong refractoriness)

8

Class IA Na+ Channel Blockers

Disopyramide
Quinidine
Procainamide***


Proarrhythmic (TdP)
Use-dependence
- Open/inactivated channel binding
- Block tissues more frequently depolarized (tachycardia)
Intermediate kinetics

9

Procainamide

Slows upstroke of action potential, slows conduction, prolongs QRS, prolongs action potential duration
Extracardiac: ganglion-blocking

PK:
Metabolite N-acetylprocainamide (NAPA) with class III activity

Therapeutic Use:
Atrial and ventricular arrhythmias

ADRs:
Excessive APD prolongation, QT prolongation, reversible lupus erythematosus (~33%)

10

Class IB Na+ Channel Blockers

Lidocaine***
Tocainide
Mexiletine

Not for atrial arrhythmias
Activated and inactivated channel binding
Rapid kinetics

11

Lidocaine

Decreases action potential duration, shortens phase 3 repolarization

PK:
- Extensive first-pass metabolism (3% bioavailable), given IV
- Therapeutic levels: 2-6 mcg/mL

Therapeutic Use:
- DOC for termination of VT and prevention of VF after cardioversion in setting of acute ischemia

ADRs:
- Least cardiotoxic but associated with neurologic (paresthesias, tremor, nausea, lightheadedness)

12

Class IC Na+ Channel Blockers

Moricizine
Flecainide
Propafenone

High incidence of drug induced arrhythmias
Cannot be used in structural heart disease
Slow kinetics

13

Flecainide

Blocks both Na+ and K+ channels but does not prolong action potential or QT interval

Therapeutic Use:
Supraventricular arrhythmia

ADRs:
Severe exacerbation of arrhythmia

Propafenone
Similar to flecainide + β-blocking activity

14

Class II β-Blockers

Propranolol
* Esmolol
* Metoprolol

Decrease automaticity
Prolong AV conduction
Decrease heart rate and contractility
Decrease O2 demand

15

Class II β-Blockers Therapeutic Use:

Tachyarrhythmias
Atrial flutter
Atrial fibrillation
AV nodal re-entrant tachycardia
Hypertension
Heart failure
Ischemic heart disease

16

Class II β-Blockers ADRs:

bradycardia**, heart block**, potential worsening of reactive airway disease (nonselective), cold extremities, fatigue, cardiac decompensation if heart relying on sympathetic drive (heart failure)

17

Metoprolol

B1-selective
PK:
Onset of action: 1-2 hours (oral), 20 minutes (IV); t1/2: 3-4 hours
Significant first pass effect: 50%, CYP2D6 metabolism
ADRs:
Similar to other B-blockers but with reduced risk of bronchospasm and diabetes

18

Esmolol

B1-selective, ultra-short-acting

PK:
Onset of action: 2-10 minutes; duration of effect: 10-30 minutes
Metabolized by red blood cell esterases

19

Class III K+ Channel Blockers

Amiodarone ***
Dofetilide
Sotalol

Diminish outward K+ during repolarization
Increase duration of action potential
Prolong effective refractory period

20

Amiodarone

Prolongs action potential duration (& QT interval), significantly blocks Na+ channels, weak adrenergic and calcium channel blockade; broad activity
Extracardiac effects: peripheral vasodilation

PK:
Bioavailability: 35-65%; hepatic metabolism, major active metabolite
t1/2: 3-10 days (rapid component 50%), several weeks (slower component)
Effect maintained 1-3 months after drug discontinued

ADRs:
Symptomatic bradycardia, heart block (those with preexisting AV node disease), accumulates in tissues, pulmonary toxicity (& fatal pulmonary fibrosis), abnormal LFTs, skin deposits, gray-blue skin discoloration

DDIs: MANY! CYP3A4 blockers (cimetidine) ↑ amiodarone levels; inducers (rifampin) ↓ amiodarone levels; reduce doses of warfarin, statins, digoxin…33-50%


21

Class IV Ca2+ Channel Blockers

Verapamil
Diltiazem

Decrease inward Ca2+ current
Decrease rate of phase 4 spontaneous depolarization
Slows conduction in Ca2+ dependent tissues (AV node)
Use dependent

22

Verapamil

Blocks activated and inactivated L-type Ca2+ channels, slows SA node by direct action, suppresses both early and delayed afterdepolarizations
Extracardiac effects: peripheral vasodilation

PK:
Bioavailability: 20% after oral administration
Extensively metabolized in the liver; t1/2: 7 hours

Therapeutic Use:
Supraventricular tachycardia, decreases ventricular rate in AFib and AF, angina, hypertension

ADRs:
Hypotension & VF if given to a patient with VT misdiagnosed as SVT; can induce AV block; constipation, lassitude, nervousness, peripheral edema


23

Adenosine

Nucleoside, activates inward rectifier K+ current and inhibits Ca2+ current resulting in marked hyperpolarization and increased refractory period

PK:
Metabolized in blood and tissue; t1/2: less than 10 seconds
Adenosine --> inosine --> adenosine monophosphate and hypoxanthine

Therapeutic Use:
DOC for conversion of paroxysmal SVT

ADRs:
Flushing, shortness of breath, chest burning, high grade AV block, atrial fibrillation, headache, hypotension, nausea, paresthesias

24

Atropine

Blocks actions of acetylcholine at parasympathetic sites, increases CO

PK:
30-50% excreted unchanged in the urine; t1/2: 2-3 hours

Therapeutic Use:
Bradycardia, neuromuscular blockade reversal, cholinergic poisoning

ADRs:
Arrhythmia, tachycardia, dizziness, constipation, urinary retention

25

Digoxin

Inhibits Na+/K+ ATPase, results in positive inotropy, increased intracellular Na+, decreased Ca2+ expulsion, increased free Ca2+. Decreased HR, increased refractory period, decreased conduction velocity

PK:
65-80% absorbed after oral administration
Not extensively metabolized, ~66% excreted unchanged by the kidneys. Must be dose adjusted in renal impairment
t1/2: 36-40 hours

Therapeutic Use:
AFib, supraventricular tachycardia, heart failure

ADRs:
Nausea, vomiting, diarrhea, disorientation, visual disturbances, aberration of color perception, delayed afterdepolarization

26

Supraventricular Arrhythmias

originate above the Bundle of His; characterized by normal QRS complexes
Sinus bradycardia
Sinus tachycardia
Paroxysmal supraventricular tachycardia
Atrial flutter
Atrial fibrillation
Wolff-Parkinson-White
Premature atrial contractions

27

Ventricular Arrhythmias

originate below the Bundle of His
Premature ventricular contractions
Ventricular tachycardia
Ventricular fibrillation

28

Conduction Blocks

based on their level or location
Supraventricular: 1st, 2nd, or 3rd degree AV block
Ventricular: right or left bundle branch block

29

Atrial Fibrillation - description and appropriate drugs

Depolarization from ectopic focus or re-entrant circuit impact atria. No single pacemaker in control. “Irregularly irregular”

Acute: IV CCB, BB, or digoxin
B-blockers (propranolol, metoprolol, esmolol) 1st choice in high catecholamine states. Should not be used acutely in systolic heart failure.
Non-DHP CCB’s (verapamil, diltiazem) IV produce rapid effects 4-5 min.
Digoxin has much slower onset (max effect 6-8 hours), less effective than BB/CCB in increased sympathetic tone.

Chronic: oral BB, CCB
Digoxin if intolerable adverse effects to others

30

Atrial Fibrillation Long-term strategy:

Rate control > rhythm control +/- anticoagulation (CHA2DS2-VASc score)
Rhythm control indications – continued symptoms with adequate rate control, rate not adequately controlled, or intolerable adverse effects

31

Atrial Fibrillation Chemical vs. electrical cardioversion

Direct current cardioversion most effective
Chemical options: ibutilide IV, propafenone PO, flecainide PO, amiodarone PO/IV, dofetilide PO

32

Atrial Fibrillation Maintenance of NSR:

FDA indication – flecainide, dofetilide*, dronedarone
Others – propafenone, amiodarone*
*safe to use in patients with HF

33

Paroxysmal Supraventricular Tachycardia (PSVT) - descripation and appropriate drugs

AV nodal re-entry

Valsalva maneuver

Acute treatment: IV adenosine (DOC), verapamil, or diltiazem
Alternative – BB or digoxin if others fail

Chronic: radiofrequency catheter ablation potentially curative
Drugs – verapamil, diltiazem, BB, or digoxin

34

Premature Ventricular Contractions (PVCs)- description and appropriate drugs

Ventricular arrhythmias arise from irritable foci within ventricular myocardium

Asymptomatic: do not use class Ic agents
CAST trial associated with ↑ mortality

B-blockers within first 24 hours after MI if no contraindications (improves survival)

35

Sustained Ventricular Tachycardia- description and appropriate drugs

Hemodynamic instability: synchronous cardioversion

Stable VT patients: procainamide, sotalol, amiodarone

Implantable cardioverter/defibrillator for:
Survivors of cardiac arrest caused by VF or hemodynamically unstable sustained VT
LVEF less than/ = 35%, prior MI at least 40 days after event and NYHA Class II or III
LVEF less than/ = 30%, prior MI at least 40 days after event and NYHA Class I
After ICD, prophylactic ablation or adjunctive anti-arrhythmic drugs may be necessary depending on number of discharges

36

Torsades De Pointes

Hemodynamic compromise: electrical cardioversion

Hemodynamically stable: MgSO4
Alternative: class Ib agents