Drugs for Cardiac Arrhythmias (Konorev) Flashcards
1
Q
Excitation-contraction coupling
A
-Electrical activity controls the rhythm and rate of the heart pump
2
Q
Ions move in response to their
A
-concentration and electric gradients
3
Q
Ions move across the membrane at
A
specific times of the cardiac cycle when their specific ION CHANNELS are open
4
Q
Cardiac action potential
A
- sequence of ion fluxes through specific ion channels across the cell membrane (sarcolemma)
- 2 types: Fast and slow (pacemaker) action potential
5
Q
Fast AP
A
- Ventricular contractile cardiomyocytes
- Atrial cardiomyocytes
- Purkinje fibers
6
Q
Slow (pacemaker AP)
A
- SA node cells
- AV node cells
7
Q
Phase 0 in fast AP
A
-Voltage dependent fast Na+ channels open as a result of depolarization; Na+ enters the cells down its EC gradient
8
Q
Phase 1 in fast AP
A
-K+ cells exit down its gradient while fast Na+ channels close resulting in some repolarization
9
Q
Phase 2 in fast AP
A
-plateau phase results from K+ exiting cells offset by and Ca2+ entering through slow voltage-dependent Ca2+ channels
10
Q
Phase 3 in fast AP
A
-Ca2+ channels close and K+ begins to exit more rapidly resulting in repolarization
11
Q
Phase 4 in fast AP
A
-Resting membrane potential is gradually restored by Na/K+ ATPase and the Na+/ca2+ exchanger
12
Q
Depolarizing vs repolarization forces
A
- Depolarization by Na+ (fast) and Ca+ (slow to open and close)–voltage gated channels
- Repolarization by K+ (not just one type of K+ channel but many different types)
13
Q
Phase 4 in pacemaker AP (slow AP)
A
- Slow spontaneous depolarization
- Poorly selective ionic influx (Na+, K+) known as pacemaker current (funny current, If)–activated by HYPERPOLARIZATION
- Slow Ca2+ influx via T-type transient channels (opens and closes very quickly)
14
Q
Phase 0 in pacemaker AP (slow AP)
A
Upstroke of AP
-Ca2+ influx through the relative slow L-type (long acting) Ca2+ channels
15
Q
Phase 3 in in pacemaker AP (slow AP)
A
- Repolarization
- Inactivation of calcium channels with increased K+ efflux
16
Q
Factors that determine the firing rate or automaticity
A
- Rate of spontaneous depolarization in phase 4 (slow AP): decreased slope means decreased rate–need more time to reach threshold potential
- Threshold potential–the potential at which AP is triggered
- Resting potential- If potential is less negative, less time needed to reach the threshold–firing rate increases
17
Q
Antiarrythmic Drugs classification according to MOA–Class 1 drugs
A
-Sodium channel blocking drugs
18
Q
Class 1A drugs
A
- Quinidine
- Procainamide
- Disopyramide
19
Q
Class 1B drugs
A
- Lidocaine
- Mexiletine
20
Q
Class 1C drugs
A
- Flecainide
- Propafenone
21
Q
Class 2 drugs are
A
- Beta Blockers
- Esmolol
- Propranolol
22
Q
Class 3 drugs are
A
- Potassium channel blocking drugs
- Amidarone
- Dronedarone
- Sotalol
- Dofetilide
- Ibutilide
23
Q
Class 4 drugs
A
- Cardioactive CCBs
- Verapamil
- Diltiazem
24
Q
Miscellaneous agens
A
-Adenosine
25
When sodium channel is activated,
Na+ current occurs down electric and concentration gradients
26
Resting state of sodium channels
-the channel is closed but ready to generate AP (h gates are open but m gates closed)
27
Activated state of sodium channels
-depolarization to the threshold opens m gates, greatly increasing sodium permeability
28
Inactivated state of sodium channels
-h-gates are closed so inward sodium flux is inhibited; the channel is not available for reactivation--this state is responsible for the refractory period
29
State dependent block of sodium channels
drugs may have different affinities towards the ion channel protein while it shuttles through different states of the cycle
30
Most useful Class `1 drugs (Na-channel blockers) block which states of the Na channel?
-block open activated or inactivated Na+ channels with very little affinity towards channels in the resting state
31
Kinetics of dissociation
- determines how quickly drugs dissociate from the channel
| - Fast, intermediate or slow kinetics
32
If a drug dissociates quickly from the Na channel then how is conductivity of heart affected?
- Conductivity not significantly affected for drugs that dissociate quickly
- In contrast, drugs that dissociate slowly there is progression of inhibition of conductivity because as the next AP comes, some of the channels will still be blocked due to slow dissociation
33
Features of class 1A drugs
- Block sodium channels
| - reduce automatism of latent (ectopic) pacemakers
34
Class 1A drugs--use dependent block
- preferentially bind to OPEN (activated) sodium channels
| - Ectopic pacemaker cells with faster rhythms will be preferentially targeted
35
Class 1A dissociation kinetics
-dissociate from channel with INTERMEDIATE kinetics
36
In addition to blocking sodium channels, Class I A drugs
-Block potassium channels as well causing long QT
37
Effects of Class 1 A drugs on AP and ECG
- prolong AP duration (decreased slope of phase 0)
| - Prolong QRS and QT intervals of ECG (widened)
38
Class 1B drugs block what?
- sodium channels only! (decreases slope of phase 0)
| - More specific action on sodium channels--do not block K channels!
39
Class 1B use dependent block (bind to what state of sodium channel?)
- bind to inactivated state
- preferentially bind to depolarized cells
- so only affects damaged cells like in ischemia leading to arrhythmias because damaged cells are usually partially depolarized--does NOT affect normal tissue!!!
40
Class 1B kinetics
-FAST dissociation kinetics--no effect on conduction in normal tissue
41
Effects of 1B drugs on AP and ECG
- may shorten AP
| - do NOT prolong QT duration or AP because potassium channel is not blocked
42
Class 1B useful in treating
-ventricular arrhythmias secondary to acute myocardial ischemia
43
Class 1C drugs block
- sodium channels, slow impulse conduction
| - also block CERTAIN K+ channels but not ones that repolarize!!
44
Class 1C drugs preferentially bind to
-open (activated) sodium channels
45
Class 1C drugs dissociation kinetics
-SLOW
46
Class 1C drugs effects on AP, and ECG changes
- Do NOT prolong AP and QT interval duration of ECG
| - Prolong QRS interval duration
47
what causes long QT syndrome by class 1A drugs?
-decreased outward K flux
48
Sympathetic innervation of pacemaker activity
- Pacemaker cells express B1 receptors
- B1 receptors are GPCRs that are coupled to Gs proteins
- Activates adenylyl cyclase leading to increase cAMP
- >Activates protein kinase A
- PKA phosphorylates Funny channel protein so that it opens faster
- PKA also phosphorylates T and L type Ca channels--which will make them open at a more negative AP inducing a stronger Ca2+ current (more Ca2+ flux into cell)
49
Sympathetic effect on the pacemaker AP
- Increased slope due to effects on If and T-type Ca channels--tachycardia
- Reduced threshold due to effect on L-type Ca channel (more robust flux of Ca ions)
50
Beta Blockers effect on slow AP
- Decreased slope due to effects on If and T-type Ca channels--slows HR
- -SA node--slows HR (increase RR interval)
- -AV node--decrease AV conductance (Increase PR interval)
- Increased threshold due to effect on L-type Ca channel
51
Beta Blockers effect on ventricular myocardium
-Decrease Ca2+ overload, prevent delated after depolarizations
52
Types of potassium channels
- Calcium activated--activated by Ca channel in cytosol; increase in Ca due to opening of Ca+ channel activates this channel will contribute to repolarization
- Inwardly rectifying
- Tandem pore domain
- Voltage gated--contributes to repolarization
53
Why is sodium channel considered "fast" while K channel is not?
- Because both the electrical and chemical gradient of sodium are in the same direction (out to in)
- In contrast, K+ is higher inside the cell so its chemical gradient wants to go outside but electrically, its positive so wants to go inside the negatively charged cell
54
Regulation of RESTING potential by Class 3 drugs (potassium blocking)--what kind of potassium channels??
- Inward (electric) gradient is in equilibrium with the outward (concentration) gradient in the resting cell
- Inwardly rectifying K+ channels are open in the resting state
- No current occurs in these channels because of this equilibrium
- If EC K+ concentration changes, membrane potential will have to readjust to reach new equilibrium
55
Regulation of AP by class 3 drugs
- VOLTAGE gated K+ channels contribute to the regulation of AP
- Repolarization of cell membanre during AP
- Limit fréquency of AP (regulate duration of REFRACTORY PERIOD)
56
Class 3 drugs effects on AP and ECG
- Block potassium channel
- So QT interval is prolonged and AP is prolonged as well
- Prolong REFRACTORY PERIOD
57
APD prolongation by class 3 drugs is
-RATE dependent with the most marked effect at SLOW heart rate
58
Class 4 drugs blocks ____ channels; what are the different staes of this channel?
- Ca channel
- Resting closed state
- Activated state (voltage dependent gate is open)
- Inactivated state
59
Mechanisms of Ca channel inactivation by class 4 drugs
- VDI--voltage dependent inactivation
- CDI--calcium dependent inactivation
**In cardiac tissue, Ca contributes to inactivation state by negative feedback; As Ca comes in and conc of Ca in cytosol builds up too much, Ca binds to Calmodulin and Ca-calmodulin complex binds to C-terminal domain of L-type Ca channel and blocks the Ca entry leading to the inactivated state
60
Class 4 drugs block what state of Ca channels?
- Both the activated and inactivated L type calcium channels
| - Active in slow response cells--decrease the slope of phase 0 depolarization
61
Class 4 drugs names, effects on AP, ECG
- Verapamil, Diltiazem
- Slow sinoatrial node depolarization, cause bradycardia
- Prolong AP duration and refractory period in AV node
- Prolong AV node conduction time
- May suppress delayed afterdepolarizations--may be effective in DAD-induced ventricular arrhythmias
