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PHRM 845 Module #1 > Antiarrhythmics > Flashcards

Antiarrhythmics Flashcards

1
Q

Electrical conduction in the heart

A
  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
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2
Q

Antiarrhythmic Drug Pharmacology

A
  • Pacemaker cells have automaticity.
  • But input from the sympathetic and parasympathetic nervous systems can influence nodal firing.
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3
Q

Important Ion Channels in the heart

A

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

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4
Q

Membrane potential

A

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

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5
Q

Action potential in the myocytes

A

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

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6
Q

Ion Channels Mediating Cardiac Action Potentials

A

pacemaker cell (SA and AV node)
ventricualr myocyte

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7
Q

Pacemaker cells

A

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

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8
Q

Ventricular myocytes

A

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

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9
Q

Pacemaker Action Potentials

A

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)

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10
Q

Ion Channel Signaling in Pacemaker Cells - NE

A

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

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11
Q

Ion Channel Signaling in Pacemaker Cells - ACh

A

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

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12
Q

Myocyte Action Potentials

A

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)

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13
Q

Na+ Channel Inactivation & the Refractory Period

A

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

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14
Q

The Refractory Period

A

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

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15
Q

Common Arrhythmias

A
  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
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16
Q

Re-Entry Arrhythmia

A

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

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17
Q

Antiarrhythmic Drugs

A

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)

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18
Q

Class 2 & 4 Antiarrhythmics

A

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

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19
Q

Class 2

A
  • 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…)
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20
Q

Class 4

A
  • Ca2+ channel blockers
  • Frequency-dependent block
  • Increase refractoriness of AV node and P-R interval
  • Protect ventricular rate from atrial tachycardia
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21
Q

bAR Blockers used as Antiarrhythmics

A
  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
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22
Q

BetaAR blockers clinical uses

A
  • arrhythmias involving catecholamines
  • atrial arrhythmias (protect ventricular rate)
  • Post-MI prevention of ventricular arrhythmias
  • Prophylaxis in Long QT syndrome (catechol.-sens)
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23
Q

Ca2+ Channel Blockers used as Antiarrhythmics

A

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)

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24
Q

Ca2+ channel blockers clinical uses

A

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

25
Q

Class 1 Antiarrhythmics: Effect on Action Potential

A

class 1A, 1B, and 1C

26
Q

Class 1A

A
  • Mixed block: Na+ and K+ channels
  • Blocks open state
  • Moderate, incomplete
    dissociation
  • Widen QRS
  • Prolonged QT
27
Q

Class 1B

A
  • Na+ channel block
  • Blocks open &
    inactivated state
  • Rapid, complete
    dissociation
  • Slight narrowing of
    action potential
  • No clinically significant effect on ECG
28
Q

Class 1C

A
  • Strong Na+ channel block
  • Blocks open state
  • Very slow, incomplete
    dissociation
  • Widen QRS
29
Q

Class 1 Antiarrhythmics: Drugs

A

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

30
Q

Quinidine

A

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

31
Q

Procainamide

A

*Lupus-like syndrome *Ganglionic
blocker

32
Q

Disopyramide

A

*Anti-muscarinic activity

33
Q

Lidocaine

A

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

34
Q

Mexiletine

A

*Orally available, similar to lidocaine in efficacy

35
Q

Flecainide

A

*Ventricular and supraventricular
*Orally available

36
Q

Propafenone

A

*Ventricular and supraventricular
*bAR blocking activity
*Orally available

37
Q

Class 3 Antiarrhythmics: Mechanism of Action

A

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

38
Q

Class 3 Antiarrhythmics: Torsade de Pointes

A

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

39
Q

Class 3 Antiarrhythmics: Drugs

A

amiodarone
dronedarone
ibutilide
sotalol
dofetilide

40
Q

Amiodarone

A

*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

41
Q

Dronedarone

A
  • Amiodarone analog used for atrial fibrillation prevention
  • Reduced toxicity compared to amiodarone (iodine atoms removed)
42
Q

Ibutilide

A

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

43
Q

Sotalol

A

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

44
Q

Dofetilide

A
  • High (10%) risk of TdP, drug very restricted, used infrequently
  • Atrial arrhythmias
45
Q

Class 3 Antiarrhythmics: Clinical Use

A

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

46
Q

Acquired Long QT Syndrome

A
  • Drug-induced
  • Electrolyte imbalances
  • Block of HERG channel (IKr potassium current)
    Genetic mutations (KCNQ1, KCNH2, SCN5A) cause LQTS
47
Q

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

A

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

48
Q

Drugs Affecting the Cardiac Action Potential

A

class 1, 2, 3, 4

49
Q

Drugs Affecting the Cardiac Action Potential: Class 1

A

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

50
Q

Drugs Affecting the Cardiac Action Potential: Class 2

A

beta blocker: propranolol, metoprolol

51
Q

Drugs Affecting the Cardiac Action Potential: Class 3

A

K+ channel blocker: amiodarone, sotalol

52
Q

Drugs Affecting the Cardiac Action Potential: Class 4

A

Ca2+ channel blocker: verapamil, diltiazem

53
Q

Misc. (Class V) Antiarrhythmic Drugs/Agents

A

digoxin, magnesium chloride, potassium chloride, adenosine

54
Q

Digoxin

A
  • Inhibition of AV node
  • Also increase intropy, used for CHF.
55
Q

Magnesium chloride

A
  • Inhibition of AV node
  • Also increase intropy, used for CHF.
56
Q

Potassium chloride

A
  • hypokalemia reduces Ikr current, which can prolong action potentials and be pro-arrhythmic
57
Q

Adenosine

A
  • similar to M2 muscarinic activation: depresses pacemaker cells
  • suppress atrial tachycardia
  • short half-life, given IV
58
Q

Adenosine cont.

A
  • 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.

PHRM 845 Module #1 (50 decks)

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