Harvey: Anti-arrhythmics Flashcards
Explain the phases of the fast response ventricular action potential
Phase 0: activation of Na+ channels, deactivation of K+ channels
Phase 1: Inactivation of Na+ channels, activation of K+ channels
Phase 2: activation of Ca++ channels (Ca++ influx balances K+ efflux)
Phase 3: inactivation of Ca++ channels, activation of delayed rectifier K+ channels
Phase 4: deactivation of delayed rectifier K+ channels, reactivation of inward rectifier K+ channels
Explain the phases of the slow response ventricular action potential
Phase 0: activation of Ca++ channels, Na+ channels permanently inactivated
Phase 3: inactivation of Ca++ channels, activation of delayed rectifier K+ channels
Phase 4: deactivation of delayed rectifier K+ channels, activation of pacemaker channels
- *no Na+ involved
- *the slope in phase 4 determines the HR
What is the effective refractory period?
the time when a new action potential cannot be generated (phases 0, 1, 2, and part of 3)
**During the ERP, stimulation of the cell by an adjacent cell undergoing depolarization does not produce new, propagated action potentials. The ERP acts as a protective mechanism in the heart by preventing multiple, compounded action potentials from occurring
What is the relative refractory period?
the period shortly after the firing of a nerve fiber when partial repolarization has occurred and a greater than normal stimulus can stimulate a second response
**occurs in last half of phase 3
disruption of rate, rhythm, or pattern of electrical activity
cardiac arryhythmias
(blank) % of patients who suffer an MI have a cardiac arrhythmia
(blank) % of patient who undergo anesthesia have a cardiac arrhythmia
80%;
50%
Why do arrhythmias occur?
disturb the conduction of electrical activity
or
disturb the electrical impulse formation (automaticity)
What are some types of cardiac arrhythmias?
sinus tachycardia sinus bradycardia atrial tachycardia atrial fibrillation ventricular tachycardia ventricular fibrillation
Two examples of disturbances in impulse formation
bradycardia: sick sinus syndrome, excessive parasympathetic tone
tachycardia - excessive sympathetic tone
Impulses originate at the SA node at varying rates
sinus arrhythmia
**increased firing rate during inspiration, decreased during expiration
What are two disturbances in impulse formation, which causes impulses to be generated in the atrial or ventricular myocardium?
early after-depolarizations (EADs)
delayed after-depolarizations (DADs)
What causes an early after-depolarization?
prolonged ventricular action potention
longer QT
some Na+ channels begin to recover and are available to be reactivated
What do early after-depolarizations do the QT interval?
prolong the QT interval
Early after-depolarizations can lead to (blank)
torsade de pointes (V tach)
List 6 risk factors for Torsades de pointes
think about things that increase the QT interval
pharmacologic - acquired long QT syndrome
genetic - inherited long QT syndrome (gain of function of Na+/Ca++ channels or loss of function of K+ channels)
electrolyte imbalances: hypokalemia
female gender (fewer K+ channels)
bradycardia (decrease HR, longer AP)
sympathetic stimulation
What causes delayed after-depolarizations?
excess Ca++ in the sarcoplasmic reticulum causes spontaneous release into the cytoplasm
then Ca++ goes across the Na/Ca++ exchanger and brings Na+ into the cell causing another depolarization
**essentially caused by too much Ca++ in the SR
What 5 things can cause delayed after-depolarizations?
digoxin (increases Ca++) catecholamines hypercalcemia increased heart rate genetic defects
Two gene defects that can cause DADs?
gain of function mutation in the gene for the ryanodine receptor - can lead to spontaneous release of Ca++
loss of function mutation in the calsequestrin gene (binds Ca++ and buffers it)
You can also have disturbances in the conduction of electrical activity across the AV node. If you have 1st degree slowed conduction & AV node dysfunction, what will happen?
If you have 2nd degree slowed conduction & AV node dysfunction, what will happen?
Third degree?
1st degree – prolonged PR interval
2nd degree – intermittent failure of AV conduction (intermittent skipped ventricular beat - no QRS)
3rd degree – complete failure of AV impulse conduction (atria and ventricle firing is not synchronous)
You can also get slowed conduction with REENTRY, which can be atrial, ventricular, or at the AV node. What are some examples of slowed conduction with reentry?
premature contractions (PVCs)
tachycardia - sustained and nonsustained
fibrillation (atrial and ventricular)
Mechanism responsible for the majority of clinically significant arrhythmias, including premature contractions, tachycardia, and fibrillation
slowed conduction with reentry
unidirectional block, which can come around from other side and re-activate some Na+ channels if they have had enough time to recover
What are the requirements for reentry? There are 3
- multiple parallel conduction pathways
- area of unidirectional block
- slowed conduction (allows enough time for Na+ channels to become ready to open again)
What does ischemia do to the resting membrane potential?
it depolarizes it!
well within minutes, coronary block will decrease O2, so no ATP will be generated; this will mess with the Na/K ATPase, which will disturb the balance of Na+ and K+. K+ will leak out of cells. Increase in extracellular K+ will depolarize the resting membrane potential (resting membrane potential will be lower on the X axis - less negative); in addition, it will slow the recovery of Na+ channels from inactivation and prevent some from recovering at all!
What does ischemia do to Na+ conductance?
ischemia slows Na+ channel recovery after inactivation - makes less Na+ channels available, and prevents some channels from recovering at all
this ultimately makes the resting membrane potential less negative
Again, what are the 3 requirements for slowed conduction with REENTRY?
- you have multiple parallel pathways
- you have a unidirectional block
- slowed conduction
So, recap what happens when ischemia occurs
ischemia reduces cellular ATP, which reduces the activity of the Na/K pump and activates ATP sensitive K+ channels
extracellular K+ rises within minutes of coronary occlusion
increased extracellular K+ depolarizes the resting membrane potential
depolarization of the RMP slows Na+ channel recovery from inactivation and increases the refractory period, creating areas of unidirectional block; it also partially inactivates Na+ channels slowing the upstroke velocity and the conduction velocity
ischemia reduces cellular ATP, which reduces the activity of the (blank) and activates ATP sensitive K+ channels
extracellular (blank) rises within minutes of coronary occlusion
increased extracellular K+ (blank) the resting membrane potential
depolarization of the RMP slows (blank) recovery from inactivation and increases the refractory period, creating areas of unidirectional block; it also partially inactivates Na+ channels slowing the upstroke velocity and the conduction velocity
Na/K pump
K+
depolarizes
Na+ channel
What is a premature ventricular contraction?
an R wave that occurs between two normal R waves; due to a single impulse originating at the ventricular pacemaker
**these are due to reentry excitation, but are usu a one time event and are not a problem
What is ventricular tachycardia? What will you see on the ECG?
wide irregular QRS complexes
due to ectopic impulses firing from ventricular pacemaker
What is ventricular fibrillation? What will you see on the ECG?
rapid, wide irregular ventricular complexes due to chaotic ventricular depolarization
What is atrial flutter? What will you see on an ECG?
atrial flutter occurs when re-entrant impulses travel in circles around the atria due to a variable block in conduction; you will see rapid flutter waves (sawtooth appearance) and irregular ventricular responses
What is atrial fibrillation? What will you see on an ECG?
atrial fib is when impulses have chaotic, random pathways in the atria; on ECG, you will see baseline irregular firing and irregular ventricular responses
When should you treat cardiac arrhythmias?
- if the arrhythmia decreases CO
- if the arrhythmia is likely to precipitate a more serious arrhythmia
- if the arrhythmia is likely to precipitate an embolism
What are some therapeutic modalities for treating arrhythmias?
drug therapy correct electrolyte imbalances DC cardioversion (implantable device) pacemaker carotid sinus massage surgical or catheter mediated ablation of ectopic foci life style modification
How do most antiarrhythmic drugs work?
they directly block or alter the kinetics of cardiac ion channels
**many of these agents interact with ion channels in a state-dependent manner, meaning they have higher affinity for channels that are open/inactivated vs. resting
Why do antiarrhythmic agents preferentially target ion channels in an open or inactivated state?
bc conditions that cause arrythmias often affect the state of the ion channels - so if you target the open or inactivated channels, you can prevent them from being pathologically activated
Although antiarrhythmic agents may preferentially target areas of abnormal electrical activity, they can also affect ion channels in normal tissue, and may be (blank).
pro-arrhythmic
Class 1a Na+ channel blockers that increase action potential duration
procainamide
quinidine
Class 1b Na+ channel blockers that slightly decrease action potential duraction
lidocaine
Class 1c Na+ channel blockers that don’t change the action potential duration
flecainide
B-blockers that are class II anti-arrhythmics?
metoprolol
propranolol
K+ channel blockers that increase action potential duration and are class III anti-arrhythmics
amiodarone
Class 4 anti-arrhythmics that are L-type Ca++ channel blockers
verapamil
Two miscellaneous drugs that can be used to treat arrhythmias
adenosine
digoxin (parasympathomimetic)
What do class 1a Na+ blockers do to the action potential duration, the QT interval and the upstroke velocity?
What do class 1b Na+ blockers do to the action potential duration, the QT interval and the upstroke velocity?
What do class 1c Na+ blockers do to the action potential duration, the QT interval and the upstroke velocity?
1a increases APD
increases QT
slows upstroke velocity (widens QRS)
1b decrease APD
decreases QT
do not affect upstroke velocity
1c doesn’t affect APD
QT stays the same
slows upstroke velocity (widens QRS)
What is the mechanism of action of class 1 Na+ channel blockers?
they reduce the excitability of ectopic pacemakers by decreasing available Na+ channels, which increases the threshold for firing
more importantly, they increase effective refractory period by blocking recovery of Na+ channels, so block re-entry of impulse
in this way, they convert unidirectional blocks to bidirectional blocks
**The effect that is most beneficial is there ability to affect reentry – if you use a Na+ channel blocker this will prevent the tissue from having enough time to recover enough Na+ channels to reactivate – so by the time the impulse comes back around, the cells are still non-excitable
What is the K+ channel that may be blocked leading to arrhythmias?
HERG channel - K+ rectifier channel
What are the Class Ia sodium channel blockers? When are they used?
quinidine and procainamide
used for most atrial and ventricular arryhythmias in patients without a history of ischemic heart disease
**procainamide is the drug of 2nd or 3rd choice for treatment of sustained ventricular arrhythmias following myocardial infarction (amiodarone & lidocaine are preferred)
What is the class 1b sodium channel blocker? When is it used?
lidocaine
drug of 2nd choice for terminating ventricular tachycardia and preventing Vfib after DC cardioversion (amiodarone is first)
What is the class 1c sodium channel blocker? When is it used?
Flecainide
for supraventricular arrhythmias without a history of ischemic heart disease
Are sodium channel blockers effective in prevention of cardiac arrhythmias and sudden cardiac death post MI?
no!!!
How can Na+ channel blockers become proarrhythmic?
say you had some subtle loss of Na+ channel activity due to ischemia but not a full on unidirectional block… well, when you use Na+ channel blockers you can block enough Na+ channels to actually induce a unidirectional block in conduction and cause an arrhythmia
What are some adverse effects of Quinidine (class 1a)?
cinchonism (headache, dizziness, tinnitus)
adverse GI effects
anticholinergic effects
What are some adverse effects of procainamide (class 1a)?
anticholinergic effects
reversible lupus-like syndrome
What are some adverse effects of lidocaine (class 1b)?
local anesthetic effects
What are some adverse effects of flecainide (class 1c)?
torsade de pointes
Only class of antiarrhythmics documented to reduce mortality in MI survivors
Class II agents - beta blockers!
What do beta blockers do to decrease arrhythmias?
block sympathetic tone and tissue super-sensitivity to catecholamines following an MI
reduce pacemaker automaticity
reduce DADs
slows conduction thru the AV node (prevents supraventricular tachyarrhythmias from spreading to the ventricles.
Which beta blockers should we know for this lecture? What is the difference between the two?
propranolol - non selective
metoprolol - selective for B1
Potential side effects of beta blockers?
bradycardia
hypotension
AV node block
bronchospasm (propranolol)
This is Class III K+ channel blocker
Amiodarone
What is amiodarone used for?
post MI ventricular arrhythmias
prevent recurrent Vtach in post MI patients
adjuvant drug used to reduce shocks in post-MI patients with ICD
conversion of atrial fibrillation to normal sinus rhythm (NSR)
maintain NSR (rhythm control) in atrial fibrillation
How to K+ channel blockers work to decrease post MI arrhythmias?
block K+ channels (repolarization), increase AP duration and effective refractory period - they convert a unidirection block to a bidirectional block and block re-entry
What is one unfortunate side of amiodarone?
it’s non-selective, so it also blocks Na+ channels, Ca++ channels, and alpha and beta receptors
What is one potentially serious extra-cardiac effect of amiodarone?
pulmonary fibrosis
What are the Class 4 Ca++ channel blockers that we should know?
verapamil
How can Ca++ channel blockers decrease arrhythmias? What can they be used for?
slow AV node conduction
increase AV node refractory period duration
used to control ventricular firing rate in pts with a fib or flutter (slow conduction thru AV node)
can convert paroxysmal supraventricular tachycardia to sinus rhythm
What should Ca++ channel blockers NOT be used to treat?
ventricular arrhythmias (ectopic firing of the ventricles is Na+ dependent)
don’t use them in patients with heart failure bc they will decrease contractility
Digoxin can also be used to treat arrhythmias. How does it work?
positive inotropic agent in heart failure (increase contractility)
decrease conductance thru AV node, which prolongs the PR interval
**preferred over class 2 and 4 agents in heart failure patients
What is one concern with digoxin?
can cause life threatening arrhythmias by triggering DADs (too much Ca++)
Adenosine can also be used to treat arrhythmias. How does it work?
A1 adenosine receptor agonist, acts like ACh to slow SA nodal firing rate and AV nodal conduction - inhibits AV node reentry
What is adenosine used for?
paroxysmal supraventricular tachycardia
most common cardiac arrhythmia – affects more than 2 million Americans
atrial fibrillation
What does A fib due to the heart?
causes electrical remodeling of the atria, so usually progresses from paroxysmal to persistent to permanent
What are some symptoms of A fib?
palpitations dyspnea fatigue exercise intolerance chest pain
What are some complications of A fib?
thromboembolism, V tach, tachy induced heart failure, ventricular bradycardia
What are three different ways you can approach treatment of A fib?
- control rate: allow the arrhythmia to occur, but control ventricular rate
- rhythm control: eliminate the atrial arrhythmia and convert to normal sinus rhythm **reduces risk of stroke and improves exercise tolerance
- anticoagulant therapy
How would you aim to control the rate of SA nodal firing in A fib?
class II beta blockers (slow AV nodal conduction)
class 4 Ca++ channel blockers (AV conduction)
digoxin (AV conduction)
pacemaker!
How would you aim to control the rhythm in A fib?
cardioversion & maintenance of NSR:
direct current first
class 1c flecainide
Class 3 amiodarone
