Flashcards in Molecular Arrhythmias & Drugs Deck (25):
How are arrhythmias acquired?
MI, ischemia, acidosis, alkalosis, electrolyte abnormalities
Drug toxicity is common cause
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
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)
Torsades de pointes
Twisting of the points due to afterdepolarization occurring too early, can decay into ventricular fibrillation
NCX1 is responsible for what
Removing calcium from cytosol. Ca leave, Na enter.
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
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
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
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
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.
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!
Ca2+ entry during the prolonged QT interval triggers ___ via Ca2+ channel reactivation or ____ via NCX-dependent depolarization
Increased sympathetic tone increases the likelihood of ____ because Ca2+ influx is enhanced by B-adrenergic receptor activity
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
In many cases, arrhythmia is triggered by ___ but maintained by ____
Afterdepolarizations, maintained by re-entry
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
Example of important unclassified drug
Class III with class I action too
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)
Reduced upstroke velocity means there is ___ conduction velocity
reduced conduction velocity
Examples of Class IA drugs
Examples of Class IB drugs
2. Mexiletine (use if can't do electrotherapy)
Examples of Class IC drugs
- 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)