Molecular Arrhythmias & Drugs

Question 1

How are arrhythmias acquired?

Answer 1

MI, ischemia, acidosis, alkalosis, electrolyte abnormalities

Drug toxicity is common cause

Question 2

Drugs:

1. Are useful in treating ___ arrhythmias
2. Are used with ICDs to ___ frequency of arrhythmic episodes, ____ battery life, ___ number of unpleasant ICD discharges
3. Would be more useful if we understood __ and __

Answer 2

1. some arrhythmias (supraventricular)
2. Decrease frequency, increase battery life, decrease unpleasant episodes
3. mechanism of action and molecular targets

Question 3

What are the 4 primary targets of antiarrhythmic drugs

Answer 3

Mneumonic: “Some Block Potassium Channels”

1. Na channels (Class I)
2. B-adrenergic receptors (Class II)
3. K channels (Class III)
4. Ca channels (Class IV)

Question 4

Torsades de pointes

Answer 4

Twisting of the points due to afterdepolarization occurring too early, can decay into ventricular fibrillation

Question 5

NCX1 is responsible for what

Answer 5

Removing calcium from cytosol. Ca leave, Na enter.

Question 6

Explain how you end up getting a LQT with K+ issues

Answer 6

Mutations in K+ channels result in decreased expression of K+ channels, which reduces the size of the K+ channel which normally ends Phase 2 of contraction. Phase 3 is delayed and you get LQT

Question 7

Explain how you end up getting a LQT with Na+ issues

Answer 7

Mutation sin Na channel frequency prevent the Na channels from inactivating completely… even if it’s 95% inactivated, there’s still enough Na to continue flowing and prolonging Phase 2. Get LQT

Question 8

Brugada Syndrome

Answer 8

AKA “Sudden Unexplained Death Syndrome”

> 30 mutations in cardiac Na+ channel (Nav1.5)
–> Reduce peak inward Na+ current in ventricular myocytes

Some patients have mutations (A39V, G490R) in the principle subunit Cav1.2
§ Appear to cause a large reduction in the magnitude of the L-type Ca2+ current which may be a consequence of impaired membrane trafficking
–> less calcium coming in –> Significantly shortened QT interval indicative of a shortened ventricular AP

• note: more brief plateau phase 2 than Timothy syndrome
• Note: Ventricular fibrillation -> survival rate of 40% by 5 years old

Question 9

Finnish familial arrhythmia

Answer 9

Protein yotiao binds protein kinase A, cardiac Ca2+, and K+ channels

Yotiao anchors kinase to both Ca and Iks channels

Result: during increased sympathetic activity, not enough repolarizing K+ current to match increasing depolarizing Ca2+ current

Phase 2 is prolonged, cytosolic Ca2+ levels rise, triggering afterdeoplarizations and death

Question 10

Inappropriate impulse initiation sources

Answer 10

1. Ectopic foci - SA node is abnormally slow or fast. Note that infarcts can also trigger this

2. Triggered afterdepolarizations: triggered by APs
Early afterdepolarizations (EADs): appear during late phase 2 and phase 3, dependent upon re-activation of Ca2+  channels.

Question 11

Re-entrant arrhythmias require 2 conditions

Answer 11

1. uni-directional conduction block in a functional circuit
2. Conduction time around circuit > refractory period.

For treatment, attack these!

Question 12

Ca2+ entry during the prolonged QT interval triggers ___ via Ca2+ channel reactivation or ____ via NCX-dependent depolarization

Answer 12

EAD

DAD

Question 13

Increased sympathetic tone increases the likelihood of ____ because Ca2+ influx is enhanced by B-adrenergic receptor activity

Answer 13

Triggered afterdepolarizations

Question 14

What initiates re-entry?

What can re-entry result in?

Answer 14

Reentry occurs when there is a unidirectional block and slowed conduction through the reentry pathway

EAD or DAD, and re-entry can result in torsades de pointes

Question 15

In many cases, arrhythmia is triggered by ___ but maintained by ____

Answer 15

Afterdepolarizations, maintained by re-entry

Question 16

4 classes of drugs

Answer 16

1. Class 1: blockers of V-G cardiac Na+ channels
2. Class II: B-adrenergic receptor blockers
3. Class III: drugs that prolong fast response phase 2 by delaying repolarization
4. Class IV: blockers of V-G cardiac Ca 2+ channels

Question 17

Example of important unclassified drug

Answer 17

Adenosine

Question 18

Amiodarone class?

Answer 18

Class III with class I action too

Question 19

Class I drugs __ upstroke
Class Ib drugs ___ upstroke and ___ AP duration
Class Ia ___ phase ___ via ___ block

Answer 19

Class I drugs slow upstroke (all block Na)
Class Ib drugs show pure class 1 action: slow upstroke (phase 0), decrease AP duration (only block Na)
Class Ia  and Ic delay phase 3 onset via K+ channel block (block Na- lots for IC and K - very minimally for IC)

Question 20

Reduced upstroke velocity means there is ___ conduction velocity

Answer 20

reduced conduction velocity

Question 21

Examples of Class IA drugs

Answer 21

1. quinidine
2. procainamide
3. disopyramide

Question 22

Examples of Class IB drugs

Answer 22

1. lidocaine
2. Mexiletine (use if can’t do electrotherapy)
3. phenytoin

Question 23

Examples of Class IC drugs

Answer 23

1. Propafenone
2. Flecainide
3. Encainide

Question 24

Timothy syndrome

Answer 24

• Debilitating genetic disorder resulting in syncope, cardiac arrhythmias and sudden death.

Linked to de novo mutations in Cav1.2 (Recall that Cav1.2 is the principle subunit of the L-type Calcium Channel)

• TS2 mutations profoundly suppress voltage-dependent inactivation of the calcium current
  § Because the current can’t be quickly inactivated, phase 2 of the AP is prolonged
  § Result = Prolonged QT syndrome (opposite of Brugada)

Question 25

Prolongation of QT intervals can lead to __________ which triggers arrythmias

Answer 25

afterdepolarizations → triggers arrhythmias→ maintained by re-reentry