Molecular Arrhythmias & Drugs Flashcards Preview

CV wk1 and wk2 > Molecular Arrhythmias & Drugs > Flashcards

Flashcards in Molecular Arrhythmias & Drugs Deck (25):
1

How are arrhythmias acquired?

MI, ischemia, acidosis, alkalosis, electrolyte abnormalities

Drug toxicity is common cause

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 __

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

3

What are the 4 primary targets of antiarrhythmic drugs

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)

4

Torsades de pointes

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

5

NCX1 is responsible for what

Removing calcium from cytosol. Ca leave, Na enter.

6

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

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

7

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

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

8

Brugada Syndrome

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

9

Finnish familial arrhythmia

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

10

Inappropriate impulse initiation sources

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.

11

Re-entrant arrhythmias require 2 conditions

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

For treatment, attack these!

12

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

EAD
DAD

13

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

Triggered afterdepolarizations

14

What initiates re-entry?
What can re-entry result in?

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

15

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

Afterdepolarizations, maintained by re-entry

16

4 classes of drugs

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

17

Example of important unclassified drug

Adenosine

18

Amiodarone class?

Class III with class I action too

19

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

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)

20

Reduced upstroke velocity means there is ___ conduction velocity

reduced conduction velocity

21

Examples of Class IA drugs

1. quinidine
2. procainamide
3. disopyramide

22

Examples of Class IB drugs

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

23

Examples of Class IC drugs

1. Propafenone
2. Flecainide
3. Encainide

24

Timothy syndrome

- 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)

25

Prolongation of QT intervals can lead to __________ which triggers arrythmias

afterdepolarizations → triggers arrhythmias→ maintained by re-reentry