Antiarrhythmics Flashcards
Electrical conduction in the heart
- SA node fires
- Excitation spreads through atrial myocardium
- AV node fires
- Excitation spreads down AV bundle
- Purkinje fibers distribute excitation through ventricular myocardium
Antiarrhythmic Drug Pharmacology
- Pacemaker cells have automaticity.
- But input from the sympathetic and parasympathetic nervous systems can influence nodal firing.
Important Ion Channels in the heart
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
Membrane potential
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
Action potential in the myocytes
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
Ion Channels Mediating Cardiac Action Potentials
pacemaker cell (SA and AV node)
ventricualr myocyte
Pacemaker cells
specialized, non-contractile cells; physiologically depolarized; high automaticity; Ca2+ dependent spikes
Ventricular myocytes
contractile cells; hyperpolarized; low automaticity; Na+ dependent spikes
Pacemaker Action Potentials
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)
Ion Channel Signaling in Pacemaker Cells - NE
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
Ion Channel Signaling in Pacemaker Cells - ACh
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
Myocyte Action Potentials
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)
Na+ Channel Inactivation & the Refractory Period
rest: Vm = -80 mV –> open: Vm = -20 Vm –> inactivated: Vm = -20 mV
recovery from activation: 20 msec to >10 sec
The Refractory Period
Result of a 2nd stimulus on ability to elicit an AP is greater as you progress through the RRP (relative refractory period)
Common Arrhythmias
- Atrial sinus arrhythmia
- Re-entry arrhythmias
- Atrial fibrillation
- Wolf-Parkinson White
- Monomorphic ventricular tachycardia
- AV nodal re-entrant tachycardia
- Premature ventricular complexes
Re-Entry Arrhythmia
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
Antiarrhythmic Drugs
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)
Class 2 & 4 Antiarrhythmics
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
Class 2
- 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…)
Class 4
- Ca2+ channel blockers
- Frequency-dependent block
- Increase refractoriness of AV node and P-R interval
- Protect ventricular rate from atrial tachycardia
bAR Blockers used as Antiarrhythmics
- Esmolol
* cardioselective (b1 AR)
* very short half-life (~9 min) due to plasma esterase hydrolysis
* given IV - Acebutolol
* cardioselective
* weak partial agonist at b1AR
(sympathomimetic)
* weak Na+ channel blockade - Propranolol
* non-selective
* weak Na+ channel blockade
BetaAR blockers clinical uses
- arrhythmias involving catecholamines
- atrial arrhythmias (protect ventricular rate)
- Post-MI prevention of ventricular arrhythmias
- Prophylaxis in Long QT syndrome (catechol.-sens)
Ca2+ Channel Blockers used as Antiarrhythmics
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)
Ca2+ channel blockers clinical uses
Clinical Uses:
* Block re-entrant arrhythmias involving AV node
* Protect ventricular rate in atrial flutter and atrial
fibrillation
Class 1 Antiarrhythmics: Effect on Action Potential
class 1A, 1B, and 1C
Class 1A
- Mixed block: Na+ and K+ channels
- Blocks open state
- Moderate, incomplete
dissociation - Widen QRS
- Prolonged QT
Class 1B
- Na+ channel block
- Blocks open &
inactivated state - Rapid, complete
dissociation - Slight narrowing of
action potential - No clinically significant effect on ECG
Class 1C
- Strong Na+ channel block
- Blocks open state
- Very slow, incomplete
dissociation - Widen QRS
Class 1 Antiarrhythmics: Drugs
class 1A:
* Quinidine
* Procainamide
* Disopyramide
class 1B:
* Lidocaine
* Tocainide
* Mexiletine
* Phenytoin
class 1C:
* Propafenone
* Flecainide
* Moricizine
Quinidine
*2-8% risk of Torsades de Pointes
*Anti-muscarinic activity
Procainamide
*Lupus-like syndrome *Ganglionic
blocker
Disopyramide
*Anti-muscarinic activity
Lidocaine
*IV only; not effective orally *Among top choices for rapid
control of ventricular
arrhythmias
*only ventricular, not atrial
Mexiletine
*Orally available, similar to lidocaine in efficacy
Flecainide
*Ventricular and supraventricular
*Orally available
Propafenone
*Ventricular and supraventricular
*bAR blocking activity
*Orally available
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
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
Class 3 Antiarrhythmics: Drugs
amiodarone
dronedarone
ibutilide
sotalol
dofetilide
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
Dronedarone
- Amiodarone analog used for atrial fibrillation prevention
- Reduced toxicity compared to amiodarone (iodine atoms removed)
Ibutilide
*2% incidence of TdP
*Rapid conversion of atrial fibrillation/flutter to normal rhthym
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
Dofetilide
- High (10%) risk of TdP, drug very restricted, used infrequently
- Atrial arrhythmias
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
Acquired Long QT Syndrome
- Drug-induced
- Electrolyte imbalances
- Block of HERG channel (IKr potassium current)
Genetic mutations (KCNQ1, KCNH2, SCN5A) cause LQTS
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
Drugs Affecting the Cardiac Action Potential
class 1, 2, 3, 4
Drugs Affecting the Cardiac Action Potential: Class 1
Na+ channel blocker: 1 a (moderate): Quinidine, Procainamide; 1b (weak):
Lidocaine, Phenytoin; 1c (strong): flecainide, propafenone
Drugs Affecting the Cardiac Action Potential: Class 2
beta blocker: propranolol, metoprolol
Drugs Affecting the Cardiac Action Potential: Class 3
K+ channel blocker: amiodarone, sotalol
Drugs Affecting the Cardiac Action Potential: Class 4
Ca2+ channel blocker: verapamil, diltiazem
Misc. (Class V) Antiarrhythmic Drugs/Agents
digoxin, magnesium chloride, potassium chloride, adenosine
Digoxin
- Inhibition of AV node
- Also increase intropy, used for CHF.
Magnesium chloride
- Inhibition of AV node
- Also increase intropy, used for CHF.
Potassium chloride
- hypokalemia reduces Ikr current, which can prolong action potentials and be pro-arrhythmic
Adenosine
- similar to M2 muscarinic activation: depresses pacemaker cells
- suppress atrial tachycardia
- short half-life, given IV
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.
