Antiarrhythmics

Question 1

Electrical conduction in the heart

Answer 1

1. SA node fires
2. Excitation spreads through atrial myocardium
3. AV node fires
4. Excitation spreads down AV bundle
5. Purkinje fibers distribute excitation through ventricular myocardium

Question 2

Antiarrhythmic Drug Pharmacology

Answer 2

• Pacemaker cells have automaticity.
• But input from the sympathetic and parasympathetic nervous systems can influence nodal firing.

Question 3

Important Ion Channels in the heart

Answer 3

Action potentials firing mediated by ion channels
Sodium channels (voltage-gated, Nav1.5)
Calcium channels (N-type Cav2.2, T-type Cav3.x) Potassium channels (Kir, Kv)
HCN channel (HCN1, HCN4)
hERG (KCNH2, KV11.1, an important channel to avoid being targeted when developing new drugs).
Many good drug leads were abandoned early during the development because of their interaction with hERG channels

Question 4

Membrane potential

Answer 4

inside the cell: -70 mV
outside the cell: 0 mV
potassium greater inside the cell; sodium, calcium, and chloride greater outside the cell
membrane potential affected by electrical gradient and concentration gradient

Question 5

Action potential in the myocytes

Answer 5

phase 0: depolarization - increase in Na and Ca; phase 1: Na channels close; phase 2: increase in Ca, decrease in K; phase 3: rapid repolarization: decrease in K, Ca channels close; phase 4 - resting potential, leaky K channels
absolute refractory period: a 2nd action potential cannot be initiated

Question 6

Ion Channels Mediating Cardiac Action Potentials

Answer 6

pacemaker cell (SA and AV node)
ventricualr myocyte

Question 7

Pacemaker cells

Answer 7

specialized, non-contractile cells; physiologically depolarized; high automaticity; Ca2+ dependent spikes

Question 8

Ventricular myocytes

Answer 8

contractile cells; hyperpolarized; low automaticity; Na+ dependent spikes

Question 9

Pacemaker Action Potentials

Answer 9

Currents important for pacemaker cell Action Potentials
* iCa – carries AP upstroke (phase 0)
* iK – repolarizing K+ current (phase 3)
* if – diastolic pacemaker current (phase 4)
* iK(ACh) – K+ current activated by vagus
(phase 4)

Question 10

Ion Channel Signaling in Pacemaker Cells - NE

Answer 10

NE highest during the fight or flight response; NE binds to betaAR and goes through signal cascade –> G-protein coupled receptor binds cAMP and PKA to activate the Ca2+ channel and cAMP activates the Na+ channel –> Na+ influx, more AP firing

Question 11

Ion Channel Signaling in Pacemaker Cells - ACh

Answer 11

slows down the heart; no activation of Na+ or Ca2+, Galphai inhibits the pathway; ACh binds to M1R –> activates the GIRK channel and opens the K+ channel

Question 12

Myocyte Action Potentials

Answer 12

Currents important for Myocyte Action Potentials
* iNa – carries AP upstroke (phase 0)
* iKto – “transient outward” repolarizing K+
current (phase 1)
* iCa(L) – plateau Ca2+ current critical for muscle contraction (phase 2)
* iK – repolarizing K+ current (phase 3)
* if – pacemaker current (phase 4; very
minimal)
neuronal APs (no calcium channel involved)

Question 13

Na+ Channel Inactivation & the Refractory Period

Answer 13

rest: Vm = -80 mV –> open: Vm = -20 Vm –> inactivated: Vm = -20 mV
recovery from activation: 20 msec to >10 sec

Question 14

The Refractory Period

Answer 14

Result of a 2nd stimulus on ability to elicit an AP is greater as you progress through the RRP (relative refractory period)

Question 15

Common Arrhythmias

Answer 15

1. Atrial sinus arrhythmia
2. Re-entry arrhythmias
3. Atrial fibrillation
4. Wolf-Parkinson White
5. Monomorphic ventricular tachycardia
6. AV nodal re-entrant tachycardia
7. Premature ventricular complexes

Question 16

Re-Entry Arrhythmia

Answer 16

Re-Entry Requirements:
1. Multiple parallel pathways
2. Unidirectional block
3. Conduction time greater than ERP
(effective refractory period)
one direction blockade: signals don’t cancel out, signal goes back up and triggers cells to fire again –> ischemic damage

Question 17

Antiarrhythmic Drugs

Answer 17

Vaughan-Williams-Singh Scale
Class 1- Na+ channel blockers
Class 2- Beta adrenergic antagonists
Class 3- Agents that prolong refractory period (K+ channel blockers)
Class 4- Ca2+ channel blockers
(miscellaneous antiarrhythmic agents)

Question 18

Class 2 & 4 Antiarrhythmics

Answer 18

betaAR blockade (class 2): effect on Ca2+ channel is less, so no decrease in peak; change the slope; create shift of timing; slow down pacemaker call and heartbeat
Ca2+ channel blockade (class 4): slope remains unchanged; reduce the peak; shift timing

Question 19

Class 2

Answer 19

• bAR blockers
• Slow pacemaker and Ca2+ currents in SA, AV node
• Increase refractoriness of SA, AV node
• Increase P-R interval
• Arrhythmias involving catecholamines (epinephrine, norepinephrine,
  etc…)

Question 20

Class 4

Answer 20

• Ca2+ channel blockers
• Frequency-dependent block
• Increase refractoriness of AV node and P-R interval
• Protect ventricular rate from atrial tachycardia

Question 21

bAR Blockers used as Antiarrhythmics

Answer 21

1. Esmolol
   * cardioselective (b1 AR)
   * very short half-life (~9 min) due to plasma esterase hydrolysis
   * given IV
2. Acebutolol
   * cardioselective
   * weak partial agonist at b1AR
   (sympathomimetic)
   * weak Na+ channel blockade
3. Propranolol
   * non-selective
   * weak Na+ channel blockade

Question 22

BetaAR blockers clinical uses

Answer 22

• arrhythmias involving catecholamines
• atrial arrhythmias (protect ventricular rate)
• Post-MI prevention of ventricular arrhythmias
• Prophylaxis in Long QT syndrome (catechol.-sens)

Question 23

Ca2+ Channel Blockers used as Antiarrhythmics

Answer 23

verapamil and diltiazem
Mechanism of Action:
* Frequency-dependent block of Cav1.2 channels
* Selective block for channels opening more
frequently
* Accumulation of blockade in rapidly depolarizing
tissue (i.e. tachycardia)

Question 24

Ca2+ channel blockers clinical uses

Answer 24

Clinical Uses:
* Block re-entrant arrhythmias involving AV node
* Protect ventricular rate in atrial flutter and atrial
fibrillation

Question 25

Class 1 Antiarrhythmics: Effect on Action Potential

Answer 25

class 1A, 1B, and 1C

Question 26

Class 1A

Answer 26

* Mixed block: Na+ and K+ channels * Blocks open state * Moderate, incomplete dissociation * Widen QRS * Prolonged QT

Question 27

Class 1B

Answer 27

* Na+ channel block * Blocks open & inactivated state * Rapid, complete dissociation * Slight narrowing of action potential * No clinically significant effect on ECG

Question 28

Class 1C

Answer 28

* Strong Na+ channel block * Blocks open state * Very slow, incomplete dissociation * Widen QRS

Question 29

Class 1 Antiarrhythmics: Drugs

Answer 29

class 1A: * Quinidine * Procainamide * Disopyramide class 1B: * Lidocaine * Tocainide * Mexiletine * Phenytoin class 1C: * Propafenone * Flecainide * Moricizine

Question 30

Quinidine

Answer 30

*2-8% risk of Torsades de Pointes *Anti-muscarinic activity

Question 31

Procainamide

Answer 31

*Lupus-like syndrome *Ganglionic blocker

Question 32

Disopyramide

Answer 32

*Anti-muscarinic activity

Question 33

Lidocaine

Answer 33

*IV only; not effective orally *Among top choices for rapid control of ventricular arrhythmias *only ventricular, not atrial

Question 34

Mexiletine

Answer 34

*Orally available, similar to lidocaine in efficacy

Question 35

Flecainide

Answer 35

*Ventricular and supraventricular *Orally available

Question 36

Propafenone

Answer 36

*Ventricular and supraventricular *bAR blocking activity *Orally available

Question 37

Class 3 Antiarrhythmics: Mechanism of Action

Answer 37

Class 3 Antiarrhythmics: * Block IKr, prolong action potential duration and Q-T interval * Increases effective refractory period (ERP) * In re-entrant circuit, increased ERP above conduction time around circuit will terminate re-entry

Question 38

Class 3 Antiarrhythmics: Torsade de Pointes

Answer 38

Torsade de Pointes: “twisting of the points” * IKr block induces EADs and triggered upstrokes * Multifocal/polymorphic ventricular tachycardia * Can degenerate into ventricular fibrillation drug binds to HERG channel, decrease Ikr --> normal action potential --> slowing of repolarization rate and increase in APD --> EAD --> one or more triggered beats --> prolonged QT --> triggered beats causing Torsades de pointes

Question 39

Class 3 Antiarrhythmics: Drugs

Answer 39

amiodarone dronedarone ibutilide sotalol dofetilide

Question 40

Amiodarone

Answer 40

*Activity like all 4 antiarrhythmic drug classes, but IKr block most important *Commonly used to suppress emergency ventricular and atrial arrhythmias *Prevention of atrial fibrillation *Very long half life (weeks) *Adverse: hypothyroidism, pulmonary fibrosis, photosensitization

Question 41

Dronedarone

Answer 41

* Amiodarone analog used for atrial fibrillation prevention * Reduced toxicity compared to amiodarone (iodine atoms removed)

Question 42

Ibutilide

Answer 42

*2% incidence of TdP *Rapid conversion of atrial fibrillation/flutter to normal rhthym

Question 43

Sotalol

Answer 43

*2% incidence of TdP *One isomer has bAR blocking activity *Life-threatening ventricular arrhythmias or maintenance of normal sinus rhythm after atrial fibrillation/flutter

Question 44

Dofetilide

Answer 44

* High (10%) risk of TdP, drug very restricted, used infrequently * Atrial arrhythmias

Question 45

Class 3 Antiarrhythmics: Clinical Use

Answer 45

Amiodarone – top choice for rate control in A-fib, suppression of post-MI Ventricular Arrhythmias Dronedarone – A-fib Sotalol – prevent A-fib re-occurrence Ibutilide – convert A-fib to sinus rhythm

Question 46

Acquired Long QT Syndrome

Answer 46

* Drug-induced * Electrolyte imbalances * Block of HERG channel (IKr potassium current) Genetic mutations (KCNQ1, KCNH2, SCN5A) cause LQTS

Question 47

Drugs belonging to the following classes have been shown to have risk for TdP:

Answer 47

been shown to have risk for TdP: * Antiarrhythmics * Antibiotics * Antiemetics * Antineoplastics * Ca2+channelblockers * Gastric pro-motility * Opiates * Antihistamines * Antipsychotics * Antidepressants * Diuretics * Most drugs known to precipitate TdP should be avoided in patients with diagnosed congenital LQTS

Question 48

Drugs Affecting the Cardiac Action Potential

Answer 48

class 1, 2, 3, 4

Question 49

Drugs Affecting the Cardiac Action Potential: Class 1

Answer 49

Na+ channel blocker: 1 a (moderate): Quinidine, Procainamide; 1b (weak): Lidocaine, Phenytoin; 1c (strong): flecainide, propafenone

Question 50

Drugs Affecting the Cardiac Action Potential: Class 2

Answer 50

beta blocker: propranolol, metoprolol

Question 51

Drugs Affecting the Cardiac Action Potential: Class 3

Answer 51

K+ channel blocker: amiodarone, sotalol

Question 52

Drugs Affecting the Cardiac Action Potential: Class 4

Answer 52

Ca2+ channel blocker: verapamil, diltiazem

Question 53

Misc. (Class V) Antiarrhythmic Drugs/Agents

Answer 53

digoxin, magnesium chloride, potassium chloride, adenosine

Question 54

Digoxin

Answer 54

* Inhibition of AV node * Also increase intropy, used for CHF.

Question 55

Magnesium chloride

Answer 55

* Inhibition of AV node * Also increase intropy, used for CHF.

Question 56

Potassium chloride

Answer 56

* hypokalemia reduces Ikr current, which can prolong action potentials and be pro-arrhythmic

Question 57

Adenosine

Answer 57

* similar to M2 muscarinic activation: depresses pacemaker cells * suppress atrial tachycardia * short half-life, given IV

Question 58

Adenosine cont.

Answer 58

* Adenosine has multiple effects on different cells in the heart. * Its half-life in the blood is very short. * Leads a brief but potent slowing of the heart.