14 anti-arrhythmics Flashcards
P wave represents
atrial contraction
The time between the P wave and the QRS complex indicates the purposefully ___ conduction through the AV node.
slowed
QRS complex represents
ventricular contraction
the QT interval is used as a measure of the time it takes the ventricular myocardium to ___
repolarize
T wave represents
ventricular repolarization
electrical condunction in the heart
1) ___ node fires
2) excitation spreads through ___ myocardium
3) ___ node fires
4) excitation spreads down ___
5) ___ fibers distribute excitation through ___ myocardium
1) SA
2) atrial
3) AV
4) AV bundle
5) purkinje, ventricular
antiarrhythmic drug pharmacology
- pacemaker cells express specific ion channels and receptors that give them significant ___ (ability to generate action potentials regardless of input from outside of the cell)
- but input from ___ and ___ can influence nodal firing
- hormones from SNS normally ___ the heart rate while increased activity of the PSNS nerve ___ the heart rate.
- automaticity
- SNS, PSNS
- increase, decrease
ECG
important ion channels in the heart
- ___ channels (voltage-gated, Nav1.5)
- ___ channels (N-type Cav2.2, T-type Cav3.x)
- ___ channels (Kir, Kv)
- ___ channel (HCN1, HCN4)
- ___ (KCNH2, KV11.1, an important channel to ___ being targeted when developing new drugs)
- Na
- Ca
- K
- HCN
- hERG, avoid
membrane potential
inside cell: ___ mV
- ___ mM [K]
- ___ mM [Na]
- < ___ mcM [Ca]
- ___ mM [Cl]
- -70
- 148
- 10
- 1
- 4
membrane potential
outside cell: ___ mV
- ___ mM [K]
- ___ mM [Na]
- ___ mM [Ca]
- ___ mM [Cl]
- 5
- 142
- 5
- 103
Action potential in myocytes
phase 0) depolarization
- Ca ___
- Na ___
phase 1) ___ channels close
phase 2)
- Ca ___
- K ___
phase 3) repolarization
- K ___
- ___ channels close
phase 4) resting potential
- leaky ___ channels
0
- increase
- increase
1
- Na
2
- increase
- decrease
3
- decrease
- Ca
4
- K
Ion Channels Mediating Cardiac Action Potentials
Pacemaker Cells: SA and AV
- Specialized, non- ___ cells
- physiologically ___
- high ___
- ** ___ dependent spikes**
- contractile
- depolarized
- automaticity
- Ca
Ion Channels Mediating Cardiac Action Potentials
Ventricular Myocytes
- ___ cells
- hyper ___
- low ___
- ___ +- dependent spikes
- contractile
- hyperpolarized
- automaticity
- Na
Pacemaker Action Potentials
- Phase 0 (iCa): the “upstroke” of the action potential, is mediated by L-type ___ channels
- Phase 3 (iK): repolarization, mediated by voltage-gated ___ channels
- Phase 4 (if and iKACh): diastolic ___ or “pacemaker current,” is where most ___ mechanisms are found
- “Funny” currents (if) are mediated by ___ channels
- iKACh - K current activated by ___
iKACh = ACh-gated K channels
- Ca
- K
- depolarization, automaticity
- HCN
- vagus
Ion Channel Signaling in Pacemaker Cells
- bAR stimulation results in increased ___ formation, which leads to activation of ___
- results in increased ___ currents during phase 4 of the action potential and helps return the cell to firing threshold ___
- also increases ___ activity, which increases phosphorylation of L-type voltage gated ___ channels
- This phosphorylation increases the amount of ___ these channels can pass, and also allows them to open at more ___ membrane potentials.
NE highest during fight or flight
- cAMP, HCN
- depolarizing, sooner
- PKA, Ca
- current, negative
- ACh acts on M1 receptors in the ___ and ___ cells. coupled to Gai, so it inhibits ___ formation and activates GIRK channels
- GIRK channels are odd K channels in that they conduct ___ current better than outward current. “Clamps” the membrane potential near the equilibrium potential for ___
- Membrane potential is ___ by activating GIRK channels.
- Inhibition of cAMP reduces ___ current (phase 4 ___ ), and reduces amplitude of ___ dependent spikes in nodal cells
- ACh will ___ HR
- atrium, nodal, cAMP
- inward, K
- hyperpolarized
- HCN, depolarization, Ca
- decrease
Myocyte Action Potentials
- Phase 0 (iNa) - “upstroke” and involves a rapid increase in conductance due to opening of ___ channels
- Phase 1 (iKto) - brief ___ , often called the “notch” (called transient ___ )
- Phase 2 (iCa) - ___ phase, involving mainly inward ___ currents. Entry during this phase is critical for permitting actual myocyte ___
- Phase 3 (iK) - ___ phase, where ___ currents dominate and serve to return back to the ___ membrane potential
- Phase 4 (if) - pacemaker current - intervening time ___ action potentials, and there is slight ___ current during this time, though much less than in nodal cells (very minimal)
- Na
- repolarization, outward
- plateau, Ca, contraction
- repolarization, K, resting
- between, depolarizing
Phase 0: Voltage-Gated Na+ Channels
- depolarization occurs, __ gate ___
- within a few msec, the ___ gate ___ = inactivated
- Voltage gated Na channel inactivation occurs during the ___ refractory period when the cell is ___
- recovery from inactivation occurrs during the ___ refractory period. Recovered channels are in the “ ___ ” state to allow another ___ to open those channels and depolarize the cell
- m, opens
- h, closes
- absolute, depolarized
- relative
- closed, depolarization
T or F:
Result of a 2nd stimulus on ability to elicit an AP is greater as you progress through the RRP (relative refractory period)
True
Phase 2: Voltage-Gated Ca2+ Channels
- At the same time that voltage gated Na channels are rapidly ___ in response to depolarization, two other channel types open but in a ___ manner
- Phase 2, the “ ___ phase” of the myocyte action potential, is mediated by opening of voltage gated ___ channels
- Voltage gated ___ channels are also opening at this time, and the ___ current they carry is roughly balanced by the inward current of the ___ channel, which is why the membrane potential is at a “ ___ ” during phase 2
- open, slower
- plateau, Ca
- K, outward, Ca, plateau
Phase 3: Voltage-Gated K+ Channels
- voltage gated ___ channel currents are declining and the voltage gated ___ currents are increasing
- ___ happens during phase 3 because the ___ channels are dominant and are relatively unopposed by ___ channels
Remember the ___ is hard at work this whole time re-establishing these gradients.
- Ca, K
- repolarization, K, Ca
- Na/K ATPase
Common Arrhythmias
Atrial sinus arrhythmia
Normal: SA node, atrial depolarization, pause at AV node, rapid transmission down HP fibers, ventricular depolarization, repolarization.
Normal features of the ECG
common arrhythmias
re-entry arrhythmias
normally APs will cancel out
unidirectional block
Unfortunately, the red wavefront can now travel around the non-conducting area and will be strong enough to sufficiently excite the ischemic region to allow conduction to go back up this area in a retrograde direction.
common rrhythmia
re-entry arrhythmias
Requirements:
1) Multiple parallel pathways
2) ___ block
3) Conduction time ___ than ERP
(effective refractory period)
“ectopic pacemaker” can manifest as PVCs or sustained V tach
PVC = premature ventricular contractions
unidirectional
greater
common arrhythmias
Afib
- Common, especially in elderly populations
- Disorganized activity in atria
- Rapid yet unpredictable (note that the rate changes rapidly from 60s to 130s)
- No discernible P wave, T wave is muddled
Atria don’t contract, so blood sits in there and can become coagulated, especially in untreated patients
common arrhythmias
wolf-parkinson white
- Rare, global re-entrant arrhythmia
- Conduction normal slows through the AV node
- The aberrant conduction pathway that creates WPW doesn’t have as much of this slowing.
common arrhythmias
Monomorphic ventricular tachycardia
- Suddenly, the ventricles begin to pace the heart.
- QRS complexes become wide, disorganized, and rapid
- P waves may or may not be evident
- Typical cause: circus waveforms and re-entrant circuits
Common Arrhythmias
AV nodal re-entrant tachycardia
- After the 2nd QRS, you see a “premature” atrial complex or depolarization that initiates the re-entry circuit
- AV node starts to not only excite the HP fibers, but also the atria again
- Elimination of the P wave – all you see is the QRS and the T wave
- Rapid rate (130 to 250)
Common Arrhythmias
Premature ventricular complexes
After the T wave and before the next P wave, there is a depolarization of the myocardium initiated from an abnormal location in the heart muscle
Antiarrhythmic Drugs
Vaughan-Williams-Singh Scale
class 1) ___ channel blockers
class 2) ___ adrenergic antagonists
class 3) agents that prolong refractory period ( ___ channel blockers)
class 4) ___ channel blockers
1) Na
2) beta
3) K
4) Ca
Class 2 & 4 Antiarrhythmics: bAR reivew
bAR signaling in pacemaker cells
- bAR stimulation results in increased ___ formation, which increases the activity of ___
- increases ___ currents during phase 4 of the action potential and helps return the cell to firing theshold ___
- bAR stimulation and cAMP formation also increases ___ activity
- phosphorylation of L-type voltage gated ___ channels increases the amount of ___ these channels can pass, and also allows them to open at more ___ membrane potentials
- cAMP, HCN
- depolarizing, sooner
- PKA
- Ca, current, negative
Summary and Review: Class 2 and 4 Antiarrhythmics
Class 2: bAR blockers
- ___ pacemaker and Ca2+ currents in SA and AV node
- Increase ___ of SA and AV node
- Increase ___ interval
- Arrhythmias involving ___ (epinephrine, norepinephrine, etc…)
Class 4: Ca2+ channel blockers
- ___ dependent block
- Increase ___ of AV node and ___ interval
- Protect ___ rate from ___ tachycardia
- slow
- refractory period
- PR
- catecholamines
- frequency
- refractory period, PR
- ventricular, atrial
bAR Blockers used as Antiarrhythmics
esmolol
- cardioselective
- very ___ t1/2 (~9 min) due to plasma esterase hydrolysis
- given ___
- short
- IV
bAR Blockers used as Antiarrhythmics
acebutolol
- cardioselective
- weak partial agonist ( ___ )
- weak ___ channel blockade
propranolol
- ___ selective
- weak ___ channel blockade
ISA
Na
non-selective
Na
bAR blockers clinical uses
Clinical Uses:
- arrhythmias involving ___
- ___ arrhythmias (protect ___ rate)
- Post ___ prevention of ventricular arrhythmias
- Prophylaxis in Long ___ syndrome
- catecholamines
- atrial, ventricular
- MI
- QT
Ca2+ Channel Blockers used as Antiarrhythmics
MOA
- ___ dependent block of ___ channels
- selective block for channels ___ more ___
- accumulation of blockade in rapidly ___ tissue (tachycardia)
clinical uses
- block ___ arrhythmimas involving ___ node
- protect ___ rate in atrial flutter/Afib
- frequency, Cav 1.2
- open, frequently
- depolarizing
- re-entrant, AV
- ventricular
verapamil is more frequency dependent than diltiazem
Class 1 Antiarrhythmics: Effect on Action Potential
Class 1A
- Mixed block: ___ and ___channels
- Blocks ___ state
- Moderate, incomplete dissociation
- Widen ___
- Prolonged ___
- Na, K
- open
- QRS
- QT
Class 1 Antiarrhythmics: Effect on Action Potential
Class 1B
- pure ___ channel block
- Blocks ___ & ___ state
- Rapid, complete dissociation
- Slight ___ of action potential
- **No clinically significant effect on ___ **
Na
open, inactivated
narrowing
ECG
Class 1 Antiarrhythmics: Effect on Action Potential
Class 1C
- ___ Na+ channel block
- Blocks ___ state
- Very slow, incomplete dissociation
- Widen ___
- strong
- open
- QRS
Class 1A drugs (3)
- quinidine
- procainamide
- disopyramide
Class 1B drugs (4)
- lidocaine
- mexiletine
- tocainide
- phenytoin
Class 1C drugs (3)
- flecainide
- propafenone
- moricizine
Class 1 Antiarrhythmics: Drugs
Quinidine
- class 1 ___
- 2-8% risk of ___
- anti ___ activity
A
TDP
muscarinic
Class 1 Antiarrhythmics: Drugs
procainamide
- class 1 ___
- ___ like syndrome
- ___ blocker
- A
- lupus
- ganglionic
Class 1 Antiarrhythmics: Drugs
disopyramide
- class 1 ___
- anti ___ activity
- A
- muscarinic
Class 1 Antiarrhythmics: Drugs
lidocaine
- class 1 ___
- ___ only
- Among top choices for rapid control of ___ arrhythmias
- B
- IV
- ventricular
Class 1 Antiarrhythmics: Drugs
mexiletine
- class 1 ___
- ___ available
- similar to lidocaine in efficacy
- B
- PO
Class 1 Antiarrhythmics: Drugs
flecainide
- class 1 ___
- ventricular and supraventricular
- ___ available
C
PO
Class 1 Antiarrhythmics: Drugs
propafenone
- Class 1 ___
- Ventricular and supraventricular
- ___ blocking activity
- ___ available
- C
- beta
- PO
Class 3 Antiarrhythmics: Mechanism of Action
- Block ___ , prolong ___ duration and ___ interval
- Increases ___ (ERP)
- In re-entrant circuit, increased ERP above ___ time around circuit will ___ re-entry
- IKr, AP, QT
- effective refractory period
- conduction, terminate
class 3 can induce ___
- ___ block induces EADs and triggered ___
- Multifocal/polymorphic ventricular ___
- Can degenerate into ventricular ___
TDP
- IKr, upstrokes
- tachycardia
- fibrilation
Class 3 Antiarrhythmics: Drugs (5)
- amiodarone
- dronedarone
- ibutilide
- sotalol
- dofetilide
Class 3 Antiarrhythmics: Drugs
amiodarone
- Activity like all 4 antiarrhythmic drug classes, but ___ block most important
- Commonly used to suppress emergency ___ and ___ arrhythmias
- Prevention of ___ fibrillation
- Very long half life
- Adverse: hypothyroidism, pulmonary ___ , photosensitization
IKr
artial, ventricular
atrial
fibrosis
Class 3 Antiarrhythmics: Drugs
dronedarone
- ___ analog used for ___ fibrilation prevention
- reduced toxicity compared to amiodarone ( ___ atoms removed)
- amiodarone, atrial
- iodine
Class 3 Antiarrhythmics: Drugs
Ibutilide
- 2% incidence of ___
- rapid conversion of ___ fib/flutter to ___ rhythm
TDP
atrial, normal
Class 3 Antiarrhythmics: Drugs
sotalol
- 2% incidence of ___
- One isomer has ___ blocking activity
- Life-threatening ___ arrhythmias or maintenance of normal sinus rhythm after ___ fibrillation/flutter
- TDP
- beta
- ventricular, atrial
Class 3 Antiarrhythmics: Drugs
dofetilide
- High (10%) risk of ___ , drug very restricted, used infrequently
- ___ arrhythmias
- TDP
- atrial
Class 3 Antiarrhythmics: Drugs
___ – top choice for rate control in A-fib, suppression of post-MI Ventricular Arrhythmias
___ – A-fib
___ – prevent A-fib re-occurrence
___ – convert A-fib to sinus rhythm
- amiodarone
- dronedarone
- sotalol
- ibutilide
Acquired Long QT Syndrome
- Drug-induced
- Electrolyte imbalances
- Block of ___ channel (IKr potassium current)
Most drugs known to precipitate ___ should be avoided in patients with diagnosed congenital LQTS
HERG
TDP
review
class 1 ( ___ ) acts at phase ___
class 2 ( ___ ) acts at phase ___
class 3 ( ___ )acts at phase ___
class ( ___ )4 acts at phase ___
Na, 0
BB, 4
IKr, 3
CCB, 2
Misc. (Class V) Antiarrhythmic Drugs/Agents
Digoxin
- Inhibition of ___ node
- inhibits the ___ , leads to increased ___
- Also increase intropy, used for CHF
Magnesium chloride
- treat hypomagnesemia
- convert ___
- prevent MI and ___ associated arrhythmias
Potassium Chloride
- hypokalemia reduces ___ current, which can ___ AP and be pro-arrhythmic
Adenosine
- similar to M2 muscarinic activation: depresses ___ cells
- suppress ___ tachycardia
- ___ half-life, given ___
- AV, Na/K pump, Ca
- TDP, digoxin
- IKr, prolongs
- pacemaker, atrial, short, IV
Adenosine
- multiple effects on different cells in the heart
- half-life in the blood is very short
- brief but potent slowing of the heart
increases ___ in vascular smooth muscle = ___ through PKA activity
decreases ___ in nodal cells, inhibits HCN channel and Ca channels, ___ the heart
- cAMP, relaxation
- cAMP, slows
What drugs/conditions can cause the following changes?
A) widen QRS
- Class 1A and 1C
B) increase PR
- BB, CCB
C) Lengthen QT
- Class 1A, K channel
D) no change
