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
Class 1 Antiarrhythmics: Effect on Action Potential
class 1A, 1B, and 1C
26
Class 1A
* Mixed block: Na+ and K+ channels * Blocks open state * Moderate, incomplete dissociation * Widen QRS * Prolonged QT
27
Class 1B
* Na+ channel block * Blocks open & inactivated state * Rapid, complete dissociation * Slight narrowing of action potential * No clinically significant effect on ECG
28
Class 1C
* Strong Na+ channel block * Blocks open state * Very slow, incomplete dissociation * Widen QRS
29
Class 1 Antiarrhythmics: Drugs
class 1A: * Quinidine * Procainamide * Disopyramide class 1B: * Lidocaine * Tocainide * Mexiletine * Phenytoin class 1C: * Propafenone * Flecainide * Moricizine
30
Quinidine
*2-8% risk of Torsades de Pointes *Anti-muscarinic activity
31
Procainamide
*Lupus-like syndrome *Ganglionic blocker
32
Disopyramide
*Anti-muscarinic activity
33
Lidocaine
*IV only; not effective orally *Among top choices for rapid control of ventricular arrhythmias *only ventricular, not atrial
34
Mexiletine
*Orally available, similar to lidocaine in efficacy
35
Flecainide
*Ventricular and supraventricular *Orally available
36
Propafenone
*Ventricular and supraventricular *bAR blocking activity *Orally available
37
Class 3 Antiarrhythmics: Mechanism of Action
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
Class 3 Antiarrhythmics: Torsade de Pointes
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
Class 3 Antiarrhythmics: Drugs
amiodarone dronedarone ibutilide sotalol dofetilide
40
Amiodarone
*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
Dronedarone
* Amiodarone analog used for atrial fibrillation prevention * Reduced toxicity compared to amiodarone (iodine atoms removed)
42
Ibutilide
*2% incidence of TdP *Rapid conversion of atrial fibrillation/flutter to normal rhthym
43
Sotalol
*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
Dofetilide
* High (10%) risk of TdP, drug very restricted, used infrequently * Atrial arrhythmias
45
Class 3 Antiarrhythmics: Clinical Use
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
Acquired Long QT Syndrome
* Drug-induced * Electrolyte imbalances * Block of HERG channel (IKr potassium current) Genetic mutations (KCNQ1, KCNH2, SCN5A) cause LQTS
47
Drugs belonging to the following classes have been shown to have risk for TdP:
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
Drugs Affecting the Cardiac Action Potential
class 1, 2, 3, 4
49
Drugs Affecting the Cardiac Action Potential: Class 1
Na+ channel blocker: 1 a (moderate): Quinidine, Procainamide; 1b (weak): Lidocaine, Phenytoin; 1c (strong): flecainide, propafenone
50
Drugs Affecting the Cardiac Action Potential: Class 2
beta blocker: propranolol, metoprolol
51
Drugs Affecting the Cardiac Action Potential: Class 3
K+ channel blocker: amiodarone, sotalol
52
Drugs Affecting the Cardiac Action Potential: Class 4
Ca2+ channel blocker: verapamil, diltiazem
53
Misc. (Class V) Antiarrhythmic Drugs/Agents
digoxin, magnesium chloride, potassium chloride, adenosine
54
Digoxin
* Inhibition of AV node * Also increase intropy, used for CHF.
55
Magnesium chloride
* Inhibition of AV node * Also increase intropy, used for CHF.
56
Potassium chloride
* hypokalemia reduces Ikr current, which can prolong action potentials and be pro-arrhythmic
57
Adenosine
* similar to M2 muscarinic activation: depresses pacemaker cells * suppress atrial tachycardia * short half-life, given IV
58
Adenosine cont.
* 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.