Antiarrhythmic Drugs Flashcards
What does it mean to say that pacemaker cells are physiologically depolarized?
they normally sit at a depolarized resting membrane potential compared to myocytes
Pacemaker cells exhibit action potentials that are dependent on what?
dependent on Ca2+ for the upstroke phase of the spike
Automaticity
the ability to generate action potentials regardless of input from outside of the cell (though outside influences certainly can change this automaticity)
How do ventricular myocytes differ from pacemaker cells?
- they are contractile cells
- they exhibit a more hyperpolarized resting membrane potential
- they exhibit much less automaticity
- the upstroke phase of the action potential is carried by sodium current passing through voltage gated sodium channels
Ventricular myocyte action potentials are dependent on what?
sodium current passing through voltage gated sodium channels
Describe Phase 0 of the SA node action potential
the “upstroke” of the action potential; mediated by L-type Ca2+ channels
Describe Phase 1 and 2 of the SA node action potential
not present in the SA node action potential
Where are Phase 1 and Phase 2 present?
present in Purkinje fiber and myocyte action potentials
Describe Phase 3 of the SA node action potential
repolarization; mediated by voltage gated K+ channels
Describe Phase 4 of the SA node action potential
diastolic depolarization or “pacemaker current”, where most automaticity mechanisms are found
What are the Phase 4 currents of the SA node action potential generated by?
“funny” currents i(f) are mediated by HCN channels
ACh-gated K+ channels mediate i(kAch)
i (f)
diastolic pacemaker current (phase 4) in SA node AP
i (K(Ach))
K+ current activated by vagus nerve (phase 4) in SA node AP
bAR stimulation results in
increased cAMP formation in SA node AP
What does increasing the activity of the HCN channels do?
increased depolarizing currents during phase 4 of the action potential and helps return the cell to firing threshold sooner
What does phosphorylation of the L-type voltage gated calcium channels do?
increases the amount of current these channels can pass, and also allows them to open at more negative membrane potentials
Which neurotransmitter acts on M1 receptors in the atrium and nodal cells?
Ach
What kind of channel is M1R
Gi-coupled
What do Gi-coupled channels do?
inhibit cAMP formation via Galpha and activates GIRK channels via Gbeta gamma
Why are GIRK channels odd K channels?
they conduct inward current better than outward current
GIRK inward K current is conducted at which membrane potentials
conducted at membrane potentials more negative than -90 mV
GIRK outward hyperpolarizing current are conducted at which membrane potentials?
conducted at membrane potentials more positive than -90 mV (which is most of the time in most cells)
Agonists that couple to GIRK channels
adenosine receptors or muscarinic receptors
Agonist activation of receptors that couple to GIRK channels increase what?
increases the otherwise small outward current through GIRK channels at potentials more positive than -90 mV
Inhibition of cAMP reduces?
HCN current (phase 4 depolarization), and reduces the amplitude of Ca2+ dependent spikes in nodal cells
Activating GIRK channels does what to the membrane potential?
hyperpolarized
Acetylcholine effects on atrium and SA/AV nodal cells?
decreased HCN and Ca2+ current
hyperpolarization (GIRK)
Describe phase 0 of the myocyte action potential
“upstroke” and involves a rapid increase in conductance due to opening of sodium channels
Describe phase 1 of the myocyte action potential
brief repolarization, often called the “notch”
current causing this feature is “transient outward”
Describe phase 2 of the myocyte action potential
plateau phase, involving many inward Ca2+ currents with some contribution from sodium and potassium as well
Ca2+ entry during phase 2 of the myocyte action potential is critical for?
permitting actual myocyte contraction
Describe phase 3 of the myocyte action potential
repolarization phase, where potassium current dominate and serve to return the membrane potential back to the resting membrane potential
Describe phase 4 of the myocyte action potential
the intervening time between action potentials, and there is slight depolarizing current during this time (though much less in nodal cells)
Which channels are key in mediating the phase 0 upstroke of myocyte cells?
voltage gated Na+ channels
What happens when voltage gated Na+ channels are depolarized?
they open, allowing rapid inward current that gives rise to phase 0 of the action potential
When do voltage gated Na+ channels inactivate?
a few msec after opening
What are the two voltage gated sodium channel gates called?
“m” gate and the “h” gate
When is the voltage gated sodium channel closed?
in the “closed” state at hyperpolarized resting membrane potentials, such as -80 mV
(“m” gate is closed and the “h” gate is open)
What happens when the voltage gated sodium channels are depolarized?
“m” gate opens; sodium rushes into the cell and further depolarizes it
Describe an inactivated voltage gated sodium channel
“m” gate is open, “h” gate is closed
“h” gate precludes the channel from conducting any more current; channels cannot open in response to depolarization
Voltage gated sodium channels inactivation occurs during which period?
absolute refractory period
Phase 2 (plateau phase) of the myocyte action potential is mediated by opening of?
voltage gated Ca2+ channels (L-type Ca2+ channels)
What balances the inward current of the L-type Ca2+ channel during the myocyte action potential?
outward current from the voltage-gated K+ channels;
why the membrane potential is at a “plateau” during phase 2
What happens with the channels during phase 3 of the myocyte AP
the voltage gated Ca2+ channel currents are declining and the voltage gated K+ current are increasing
Why does repolarization happen during phase 3? (myocyte AP)
because the K+ channels are the dominant channel and are relatively unopposed by Ca2+ channels
What would happen to the EKG if you decrease the activity of the L-type voltage gated Ca2+ channels in the AV node
increase the R-R interval
What would happen to the EKG if you block a minority of the voltage-gated Na+ channels in the ventricular myocardium?
decreased QRS amplitude
What would happen to the EKG if you slow the phase 3 of the ventricular myocyte AP?
increase the QT interval
When does torsades de pointe occur?
when ion channels (K+ channels) active during phase 3 of the myocyte action potential are blocked
Most common way that antiarrhythmic drugs are classified?
Vaugh Williams Singh scale
Vaugh Williams Singh scale is based on
electrophysiological effect the drug has
Briefly describe bAR signaling in pacemaker cells
bAR stimulation results in increased cAMP -> increases HCN activity -> increase depolarizing currents during phase 4 of action potential -> helps return cell to firing threshold sooner
bAR signaling and cAMP formation also increases?
protein kinase A activity -> increases phosphorylation of L-type voltage gated calcium channels -> increases amount of current these channels can pass -> allows them to open at more negative membrane potentials
Class 2 Antiarrhythmics summary
- bAR blockers
- slow pacemaker and Ca2+ currents in SA/AV node
- increase refractoriness of SA/AV node
- increase P-R interval
- Arrhythmias involving catecholamines
Class 4 Antiarrhythmics summary
- 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
- Acebutolol
- Propanolol
- Sotalol
Cardioselective beta blockers preferentially inhibit?
beta1 adrenergic receptors in the heart (NOT beta 2 or alpha receptors)
When are beta blockers often used as antiarrhythmics
often used when the underlying arrhythmia involves catecholamines, such as when there is an increase in sympathetic tone or when sensitivity to catecholamines has increased
Beta blockers have a large effect on which cells? What is the clinical significance of this?
large effect on pacemaker cells; they are often used in atrial arrhythmias to protect the ventricular rate
Esmolol
cardioselective (beta1 AR); very short half life; given IV
Acebutolol
cardioselective; weak partial agonist at beta1AR (sympathomimetic); weak Na+ channel blockade
Propanolol
non-selective; weak Na+ channel blockade
Clinical uses of betaAR blockers used as antiarrhythmics
- arrhythmias involving catecholamines
- atrial arrhythmias (protect ventricular rate)
- post-MI prevention of ventricular arrhytmias
- prophylaxis in long QT syndrome (catecholamine sensitive)
Ca2+ channel blockers used as antiarrhythmics
- Verapamil
2. Diltiazem
What kind of blockade do verapamil (and to a less extent) diltiazem exhibit
frequency-dependent blockade; meaning that these drugs only begin to block the channel as it is being opened
Which calcium channels are most susceptible to blockade by verapamil and diltiazem?
calcium channels that are opening and closing more often; includes calcium channels in the pacemaker cells
Verapamil and diltiazem blockade will accumulate in which tissue?
rapidly depolarizing tissue, such as heart tissue exhibiting tachycardia
Clinical uses of Ca2+ channel blockers used as antiarrhythmics
- block re-entrant arrhythmias involving AV node
2. protect ventricular rate in atrial flutter and atrial fibrillation
What happens when Ca2+ channel blockers increase the refractoriness of the AV node?
atrial arrhythmias cannot transmit as readily to the ventricles
Mechanism of action summary for verapamil and diltiazem?
frequency-dependent block of Cav1.2 channels; selective block for channels opening more frequently; accumulation of blockade in rapidly depolarizing tissue (i.e. tachycardia)
List the Vaughan-Williams-Singh Scale classes
Class 1 - Na+ channel blockers
Class 2 - Beta adrenergic antagonists
Class 3 - K+ channel blockers (agents that prolong refractory period)
Class 4 - Ca2+ channel blockers
Describe class 1A antiarrhythmics
mixed block: Na+ and K+ channels; blocks open state; moderate to slow dissociation (secs); widens QRS and prolongs QT interval
Describe class 1B antiarrhythmics
pure Na+ channel block; blocks open and inactivated state; rapid dissociation (milisecs); narrows the AP due to block of persistent sodium current
Describe class 1C antiarrhythmics
strong Na+ channel block; only blocks the open state; very slow dissociation (>10 sec); marked widening of the QRS complex
Class 1A antiarrhythmic drugs
quinidine; procainamide; disopyramide
Class 1B antiarrhythmic drugs
lidocaine; tocainide; mexilitine
Class 1C antiarrhythmic drugs
propafenone; flecainide
Quinidine
2-8% risk of Torsades de pointes
anti-muscarinic activity
Procainamide
Lupus-like syndrome
ganglionic blocker
Disopyramide
anti-muscarinic activity
Lidocaine
IV only; top choice 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 block
potassium channels and have a significant effect on i (Kr), the rapid component of the delayed rectifier potassium current that is responsible for repolarization
What do class 3 agents do to the AP?
prolong the AP, making the cell dwell a little longer at voltages that favor sodium channel inactivation; prolongs the effective refractory period of the cell
When are re-entry circuits possible?
when the conduction time around the circuit is slower than the effective refractory period of any one cell in the circuit
How do class 3 antiarrhythmics terminate a re-entry circuit/the arrhythmias that arose from it?
increased effective refractory period greater than conduction time around circuit
Two ways that Torsades de pointes can arise?
- due to administration of class 3 agents
2. severe toxicity reaction that can occur for other drugs that also block the HERG potassium channel
What is the HERG potassium channel?
the major voltage gated potassium channel that gives rise to the rapid component of the delayed rectifier potassium current i (Kr) that is responsible for the phase 3 repolarization during the cardiac AP
Class 3 drugs block which channel
HERG channel - can therefore slow repolarization and prolong the AP duration
What happens in a cell that dwells too long in the depolarized range and if the inward currents start to be greater than outward potassium currents?
an early after depolarization (EAD) can develop
EADs are capable of giving rise to?
triggered upstrokes and ectopic action potentials, potentially setting up a re-entry arrhythmia
What kind of arrhythmia is TdP characterized as?
polymorphic ventricular tachycardia
Class 3 antiarrhythmics drugs
- Amiodarone
- Dronedarone
- Ibutilide
- Sotalol
- Dofetilide
“Shotgun” drug because it has class 3, but also class 1, 2, and 4 activity
Amiodarone
Amiodarone used to
suppress emergency ventricular and atrial arrhythmias; prevention of atrial fibrillation
Adverse effects of amiodarone
hypothyroidism, pulmonary fibrosis, photosensitization
Dronedarone
amiodarone analog used for atrial fibrillation prevention; reduced toxicity and shorter half life
Ibutilide
2% incidence of TdP; rapid conversion of atrial fibrillation/flutter to normal rhythm
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; very restricted and used infrequently; atrial arrhythmias
Acquired LQTS
drug-induced; electrolyte imbalances; block of HERG channel
Which drugs should you not give to patients with congenital LQTS?
drugs known to precipitate TdP
Drugs that have a risk for TdP
antiarrhythmics, antibiotics, antiemetics, antineoplastics, Ca2+ channel blockers, gastric pro-motility, opiates, antihistamines, antipsychotics, antidepressants, diuretics
Clinical use of amiodarone
top choice for rate control in A-fib, suppression of post-MI ventricular arrhythmias
Clinical use of dronedarone
A-fib
Clinical use of sotalol
prevent A-fib reoccurance
Clinical use of ibutilide
convert A-fib to sinus rhythm
Misc. antiarrhythmics drugs/agents
- digoxin
- magnesium chloride
- potassium chloride
- adenosine
Digoxin
direct inhibition of AV node
Magnesium chloride
treat hypomagnesemia; convert TdP; prevent MI and digoxin associated arrhythmias
Potassium chloride
hypokalemia reduces i (Kr) 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
What does hypokalemia do in regards to arrhythmias?
reduce i (Kr), delays repolarization and lengthens APD, thereby causing it to be proarrhythmic
First-line for promptly stopping paroxysmal AV nodal reentrant tachycardia
adenosine
Best choice drug for normalizing sinus bradycardia rate without initiating any other arrhythmias?
atropine
