Drugs Used In Cardiac Arrhythmias

Question 1

What cells/fibers are involved in creating a fast action potential?

Answer 1

Ventricular contractile cardiomyocytes
Atrial cardiomyocytes
Purkinje fibers

Question 2

What cells are involved in creating a slow (pacemaker) action potential?

Answer 2

SA node cells

AV node cells

Question 3

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)?

Answer 3

Inward flux of Na+: increase in voltage

Inward flux of Ca++: increase in voltage

Outward flux of K+: collapse of voltage

Question 4

How does a Phase 4 AP occur? What triggers its influx of ions?

Answer 4

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.

Question 5

What is Phase 0 of the pacemaker AP?

Answer 5

“Upstroke of AP”

Ca++ influx through the relatively slow L-type (long-acting) Ca++ channels.

Question 6

What is Phase 3 of the pacemaker AP?

Answer 6

Repolarization via inactivation of Ca++ channels due to increased K+ efflux.

Question 7

What are 3 factors of the pacemaker AP that determines the firing rate of the heart?

Answer 7

1. Rate of spontaneous depolarization in Phase 4: decreased slope would lead to a slower firing rate, as more time is needed to reach threshold.
2. Threshold potential.
3. Resting potential: if potential is less negative, less time is needed to reach threshold, so firing rate would increase.

Question 8

What is the overall MOA of Class 1 drugs?

Answer 8

Block Na+ channels

Question 9

1A drugs

Answer 9

Quinidine
Procainamide
Disopyramide

Question 10

1B drugs

Answer 10

Lidocaine

Mexiletine

Question 11

1C drugs

Answer 11

Flecainide

Propafenone

Question 12

What is the general MOA for Class 2?

Answer 12

Beta-blockers

Question 13

Class 2 drugs

Answer 13

Esmolol

Propranolol

Question 14

What is the MOA for Class 3 drugs?

Answer 14

Block K+ channels

Question 15

Class 3 drugs

Answer 15

Amiodarone
Sotalol
Dofetilide
Ibutilide

Question 16

What is the MOA for Class 4 drugs?

Answer 16

Cardioactive Ca++ channel blockers

Question 17

Class 4 drugs

Answer 17

Verapamil

Diltiazem

Question 18

What is unique about Sotalol?

Answer 18

It is classified as a Class 3 drug because it has K+ channel-blocking activity, but also has some beta-blocking (Class 2) activity.

Question 19

Which classes of anti-arrhythmic drugs interact w/ a G protein, rather than an ion channel directly?

Answer 19

Class 2 - beta-blockers

Misc. agents (Adenosine)

Question 20

Na+ channels have distinct resting states, activated states and inactivated states. What happens in each state?

Answer 20

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”.

Question 21

What is “state-dependent block”?

Most therapeutically useful drugs block the Na+ channels in which states?

Answer 21

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.

Question 22

What is the significance of Class 1 drugs being positively charged?

Answer 22

There are 2 aromatic residues on Na+ channels and the cationic state of the drug allows for enhanced binding to the channel proteins.

Question 23

What are “kinetics of dissociation”? How does it effect side effects?

Answer 23

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.

Question 24

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?

Answer 24

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.

Question 25

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?

Answer 25

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.

Question 26

What does the AP graph look like on a patient treated w/ a Class 1B drug in normal tissue and damaged (depolarized) tissue?

Answer 26

Normal: the AP is slightly shortened. Damaged: the depolarization is prolonged and the duration of AP is shortened.

Question 27

Which cells are preferentially targeted when treated w/ Class 1A?

Answer 27

Ectopic pacemaker cells w/ faster rhythms.

Question 28

What is the ionic basis behind the longer AP duration in Class 1A drugs vs. the shorter duration in Class 1B?

Answer 28

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.

Question 29

In what circumstance is Lidocaine given?

Answer 29

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.

Question 30

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?

Answer 30

Block Na+ channels —> slow impulse conduction. Slow dissociation. Block certain K+ channels, but not ones involved in repolarization. Prolong QRS interval.

Question 31

What does the AP graph look like in a patient treated w/ a Class 1C drug?

Answer 31

Slower depolarization and AP length w/ normal repolarization.

Question 32

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?

Answer 32

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.

Question 33

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?

Answer 33

SA node - decreased HR (increased RR interval) AV node - decreased AV conductance (increased PR interval)

Question 34

What effect does a beta-blocker have on the pacemaker AP graph?

Answer 34

Decreased slope in phase 4 (due to effect on If and T-type channels) and increased threshold (due to effect on L-type channels).

Question 35

What are the gradients at play in K+ influx/efflux?

Answer 35

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.

Question 36

Inward (electrical) gradient is in equilibrium w/ the outward (concentration) gradient in the resting cell. In what state are inwardly rectifying K+ channels open?

Answer 36

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.

Question 37

Hypokalemia has what effect on membrane potential?

Answer 37

Partial hyperpolarization —> greater stimulus needed to fire AP

Question 38

Hyperkalemia has what effect on membrane potential?

Answer 38

Partial depolarization —> less of a stimulus is needed to fire an AP.

Question 39

Class 3 drugs MOA Effects on AP: Effects on ECG:

Answer 39

Block K+ channels. Prolong AP duration and refractory period. Prolong QT interval on ECG.

Question 40

Class 4 drugs MOA What cells are they active in? What are the effects on AP graph?

Answer 40

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.

Question 41

Adenosine MOA

Answer 41

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.

Question 42

QT interval represents: PR interval represents:

Answer 42

QT = ventricular depolarization —> repolarization PR = atrial depolarization —> ventricular depolarization

Question 43

Which classes prolong the QT interval?

Answer 43

Class 1A | Class 3

Question 44

Under what circumstances would the QRS complex widen?

Answer 44

If treated with a drug that inhibits Na+ channels

Question 45

The cardiac myocyte AP graph is used in which 2 classes?

Answer 45

Class I and Class III

Question 46

The SA/AV cell AP graph is used in which 2 classes?

Answer 46

Class II and Class IV

Question 47

Drugs that block K+ channels tend to:

Answer 47

Prolong the QT interval

Question 48

Drugs that black Na+ channels tend to:

Answer 48

Widen the QRS complex

Question 49

Class 1A Ions involved: Changes in ECG: Changes in AP and ERP length: Kinetics:

Answer 49

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

Question 50

Class 1B Ions involved: Changes in ECG: Changes in AP and ERP length: Kinetics:

Answer 50

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

Question 51

Class 1C Ions involved: Changes in ECG: Changes in AP and ERP length: Kinetics:

Answer 51

Ions involved: Na+ Changes in ECG: Increased QRS Changes in AP and ERP length: N/A Kinetics: very slow

Question 52

Class II drugs act on which cells? What changes occur to the AP graph? What changes happen on the ECG?

Answer 52

SA/AV nodal cells Decreased slope of phase 4 (If) and prolonged repolarization. Decreased HR and conduction velocity. Increased PR interval on ECG.

Question 53

What change occurs to the ECG when treated w/ a Class IV drug?

Answer 53

Increased PR interval