Drugs Used In Cardiac Arrhythmias Flashcards
What cells/fibers are involved in creating a fast action potential?
Ventricular contractile cardiomyocytes
Atrial cardiomyocytes
Purkinje fibers
What cells are involved in creating a slow (pacemaker) action potential?
SA node cells
AV node cells
What ions, and in which direction, flux across the cell membrane in developing a fast action potential in the cardiac muscle? What do they open in response to (increase in voltage/membrane potential or collapse of membrane potential)?
Inward flux of Na+: increase in voltage
Inward flux of Ca++: increase in voltage
Outward flux of K+: collapse of voltage
How does a Phase 4 AP occur? What triggers its influx of ions?
There is Funny (If) “poorly-selective” ionic influx of Na+ and K+ that slowly approaches threshold potential. This influx is activated by hyperpolarization.
As membrane potential approaches the threshold potential, slow Ca++ influx (via T-type) occurs to draw even closer to threshold.
What is Phase 0 of the pacemaker AP?
“Upstroke of AP”
Ca++ influx through the relatively slow L-type (long-acting) Ca++ channels.
What is Phase 3 of the pacemaker AP?
Repolarization via inactivation of Ca++ channels due to increased K+ efflux.
What are 3 factors of the pacemaker AP that determines the firing rate of the heart?
- Rate of spontaneous depolarization in Phase 4: decreased slope would lead to a slower firing rate, as more time is needed to reach threshold.
- Threshold potential.
- Resting potential: if potential is less negative, less time is needed to reach threshold, so firing rate would increase.
What is the overall MOA of Class 1 drugs?
Block Na+ channels
1A drugs
Quinidine
Procainamide
Disopyramide
1B drugs
Lidocaine
Mexiletine
1C drugs
Flecainide
Propafenone
What is the general MOA for Class 2?
Beta-blockers
Class 2 drugs
Esmolol
Propranolol
What is the MOA for Class 3 drugs?
Block K+ channels
Class 3 drugs
Amiodarone
Sotalol
Dofetilide
Ibutilide
What is the MOA for Class 4 drugs?
Cardioactive Ca++ channel blockers
Class 4 drugs
Verapamil
Diltiazem
What is unique about Sotalol?
It is classified as a Class 3 drug because it has K+ channel-blocking activity, but also has some beta-blocking (Class 2) activity.
Which classes of anti-arrhythmic drugs interact w/ a G protein, rather than an ion channel directly?
Class 2 - beta-blockers
Misc. agents (Adenosine)
Na+ channels have distinct resting states, activated states and inactivated states. What happens in each state?
Resting - channel is closed but ready to generate an AP.
Activated - depolarization to the threshold opens m-gates and greatly increases Na+ permeability.
Inactivated state - h-gates are closed, inward Na+ influx is inhibited and the channel is not available for re-activation. It is the “refractory period”.
What is “state-dependent block”?
Most therapeutically useful drugs block the Na+ channels in which states?
The concept that drugs may have different affinities of the ion channel protein in certain states of the resting/activated/inactivated cycle of the Na+ channel.
They block the activated or inactivated states, with little affinity toward the resting state.
What is the significance of Class 1 drugs being positively charged?
There are 2 aromatic residues on Na+ channels and the cationic state of the drug allows for enhanced binding to the channel proteins.
What are “kinetics of dissociation”? How does it effect side effects?
It determines how quickly drugs dissociate from the channel.
If they are too fast, then no effect will be noted by taking the drug. If they are too slow, there will be progressive slowing of AP firing. Drugs with slower kinetics of dissociation tend to have more side effects for this reason.
Class 1A drugs MOA:
What state-dependent block is used?
What else do they block?
What happens to the cardiac action potential as a result of a Class 1A drug?
What does the graph of a pacemaker cell look like when treated w/ a Class 1A drug?
Block Na+ channels —> slow impulse conduction and reduce automatism of ectopic (latent) pacemakers.
Preferentially bind to open (activated) Na+ channels (ectopic pacemaker cells with faster rhythms are preferentially blocked).
K+ channels also blocked.
All of this results in a prolonged AP duration and a prolonged QRS and QT (ventricular depolarization) intervals in ECG.
The slope (depolarization) is not as rapid, the AP duration is longer, and the graph is shifted right.
Class 1B drugs MOA
What state-dependent block do they use? What cells do they preferentially bind?
What are their kinetics of dissociation?
Overall, what happens to conduction once treated w/ a Class 1B drug?
Block Na+ channels.
Bind to inactivated channels w/ preference to depolarized cells.
Dissociated from channel w/ fast kinetics, so there is no effect on conduction of normal tissues.
May shorten AP due to more specific action on Na+ channels. They do NOT block K+ channels and don’t prolong AP or QT on ECG.
What does the AP graph look like on a patient treated w/ a Class 1B drug in normal tissue and damaged (depolarized) tissue?
Normal: the AP is slightly shortened.
Damaged: the depolarization is prolonged and the duration of AP is shortened.
Which cells are preferentially targeted when treated w/ Class 1A?
Ectopic pacemaker cells w/ faster rhythms.
What is the ionic basis behind the longer AP duration in Class 1A drugs vs. the shorter duration in Class 1B?
Class 1A blocks both Na+ and K+ channels which allows for a longer AP.
Class 1B only block Na+, so repolarization can occur per usual.
In what circumstance is Lidocaine given?
Acute MI w/ Vtach. It is a Class 1B drug and preferentially binds to energy deficient depolarized cells, so its use in Vtach is appropriate.
Class 1C drugs MOA
What state-dependent block do they use?
What is their dissociation kinetics?
What else can they block?
What effect do they have on ECG?
Block Na+ channels —> slow impulse conduction.
Slow dissociation.
Block certain K+ channels, but not ones involved in repolarization.
Prolong QRS interval.
What does the AP graph look like in a patient treated w/ a Class 1C drug?
Slower depolarization and AP length w/ normal repolarization.
What is the effect of sympathetic activation on SA node cells?
What channels does it bind?
What effect does it have on the pacemaker action potential graph?
Binds beta-1 receptor (Gs) which increases cAMP levels. Normally, cAMP will increase concentration of PKA which can activate channels, but in this case cAMP can directly have an effect on the protein channels itself.
Binds If, T- (slow) and L-type (long) channels.
Increased slope due to effects on If and T-type Ca++ channels AND a reduced threshold due to the effect on L-type Ca++ channels.
Affecting the SA and/or the AV node with beta-blockers can slow the action potential. When they are antagonized, what is the outcome of each?
SA node - decreased HR (increased RR interval)
AV node - decreased AV conductance (increased PR interval)
What effect does a beta-blocker have on the pacemaker AP graph?
Decreased slope in phase 4 (due to effect on If and T-type channels) and increased threshold (due to effect on L-type channels).
What are the gradients at play in K+ influx/efflux?
The electrical gradient wants to bring K+ inside the cell, while the concentration gradient wants to keep K+ outside of the cell.
Both gradients work in favor of Na+ to enter the cell, so that’s why depolarization occurs much more quickly.
Inward (electrical) gradient is in equilibrium w/ the outward (concentration) gradient in the resting cell. In what state are inwardly rectifying K+ channels open?
In the resting state when all other channels are closed; however, no current occurs in these channels in a steady state due to the equilibrium. When concentrations of K+ in the body change, so must equilibrium potential.
Hypokalemia has what effect on membrane potential?
Partial hyperpolarization —> greater stimulus needed to fire AP
Hyperkalemia has what effect on membrane potential?
Partial depolarization —> less of a stimulus is needed to fire an AP.
Class 3 drugs MOA
Effects on AP:
Effects on ECG:
Block K+ channels.
Prolong AP duration and refractory period.
Prolong QT interval on ECG.
Class 4 drugs MOA
What cells are they active in? What are the effects on AP graph?
Block both activated and inactivated L-type Ca++ channels.
They are active in pacemaker (slow response) cells (SA and AV nodes):
- Decreased slope of phase 0 depolarization.
- Increased L-type Ca++ channel threshold potential at SA node (slows the SA node’s depolarization —> bradycardia).
- Prolong AP duration and refractory period in AV node.
Adenosine MOA
Binds to its A1 adenosine receptor (Gi pathway) and activates K+ current and inhibits Ca++ and Funny currents (via decrease of cAMP) —> hyperpolarization and suppression of APs in slow (pacemaker) cells.
Inhibits AV conduction and increases nodal refractory period.
QT interval represents:
PR interval represents:
QT = ventricular depolarization —> repolarization
PR = atrial depolarization —> ventricular depolarization
Which classes prolong the QT interval?
Class 1A
Class 3
Under what circumstances would the QRS complex widen?
If treated with a drug that inhibits Na+ channels
The cardiac myocyte AP graph is used in which 2 classes?
Class I and Class III
The SA/AV cell AP graph is used in which 2 classes?
Class II and Class IV
Drugs that block K+ channels tend to:
Prolong the QT interval
Drugs that black Na+ channels tend to:
Widen the QRS complex
Class 1A
Ions involved:
Changes in ECG:
Changes in AP and ERP length:
Kinetics:
Ions involved: Na+ and K+
Changes in ECG: Increase QRS and QT
Changes in AP and ERP length: Increase AP and ERP length
Kinetics: slow
Class 1B
Ions involved:
Changes in ECG:
Changes in AP and ERP length:
Kinetics:
Ions involved: Na+
Changes in ECG: Decreased QT (due to targeting depolarized cells)
Changes in AP and ERP length: Decreased AP and ERP length
Kinetics: fast
Class 1C
Ions involved:
Changes in ECG:
Changes in AP and ERP length:
Kinetics:
Ions involved: Na+
Changes in ECG: Increased QRS
Changes in AP and ERP length: N/A
Kinetics: very slow
Class II drugs act on which cells?
What changes occur to the AP graph?
What changes happen on the ECG?
SA/AV nodal cells
Decreased slope of phase 4 (If) and prolonged repolarization.
Decreased HR and conduction velocity.
Increased PR interval on ECG.
What change occurs to the ECG when treated w/ a Class IV drug?
Increased PR interval
