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

14 anti-arrhythmics Flashcards by Reagan Smith

P wave represents

atrial contraction

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The time between the P wave and the QRS complex indicates the purposefully ___ conduction through the AV node.

slowed

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QRS complex represents

ventricular contraction

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the QT interval is used as a measure of the time it takes the ventricular myocardium to ___

repolarize

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T wave represents

ventricular repolarization

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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

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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

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ECG

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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

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membrane potential

inside cell: ___ mV
- ___ mM [K]
- ___ mM [Na]
- < ___ mcM [Ca]
- ___ mM [Cl]

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membrane potential

outside cell: ___ mV
- ___ mM [K]
- ___ mM [Na]
- ___ mM [Ca]
- ___ mM [Cl]

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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

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Ion Channels Mediating Cardiac Action Potentials

Pacemaker Cells: SA and AV
- Specialized, non- ___ cells
- physiologically ___
- high ___
- ** ___ dependent spikes**

contractile
depolarized
automaticity
Ca

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Ion Channels Mediating Cardiac Action Potentials

Ventricular Myocytes
- ___ cells
- hyper ___
- low ___
- ___ +- dependent spikes

contractile
hyperpolarized
automaticity
Na

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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# 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 ## Footnote 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

14 anti-arrhythmics Flashcards

(64 cards)