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Pharm Chapter 23: Pharm of Cardiac Rhythm
The mechanical part of the blood pumps blood, and the electrical part controls the rhythm of the pump
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When the mechanical part is messed up, you get heart failure
When the electrical part gets messed up (arrhythmia) the heart cells don’t contract in unison,
decreasing pumping ability
Changes in membrane potential of heart cells directly affects rhythm, and most antiarrhythmic drugs act
by regulating the activity of ion channels in the membrane
The heart has 2 types of myocytes, those that can spontaneously initiate action potentials (pacemaker
cells) and those that can’t
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All pacemaker cells have automaticity, which is the ability to depolarize above a threshold
voltage in a rhythmic fashion
Automaticity results in the generation of spontaneous action potentials
Pacemaker cells are found in the SA node, AV node, and ventricular conducting system (bundle
of His, bundle branches, and Purkinje fibers)
The pacemaker cells make up the specialized conducting system that governs the electrical
activity of the heart
Nonpacemaker cells (heart muscle) can acquire automaticity in some pathologies, and act as
pacemaker cells
During normal conditions, pumps move potassium into cells and pump out sodium and calcium, creating
a chemical and electrical gradient across the cell membrane, forming the membrane potential
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The Nernst equilibrium potential for sodium, potassium, and calcium depends on the
concentrations of ions inside and outside the cell
o The Nernst potential for potassium is negative (-94 mV), and the potential for calcium
(+150mV) and sodium (+70 mV) is positive
The difference between an ion’s Nernst potential and the cell’s membrane potential determines
the driving force for ions into or out of the cell
When an ion channel opens, the membrane potential approaches the equilibrium potentnial for
that ion
o Ex: opening a potassium channels drives the membrane potential towards potassium’s
negative Nernst equilibrium potential (-94 mV)
o When sodium and calcium channels open, the membrane potential is moved towards
their positive equilibrium potentials
The final membrane potential depends on the # of channels of each type, their ability to let ions
through (conductance), and how long the channels are open
The resting membrane of a heart myocyte is permeable to potassium because some of its
potassium channels are open, but not to sodium or calcium
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So the resting membrane potential is close to the equilibrium potential for potassium,
so negative
Heart action potentials are longer than those for nerves for skeletal muscle
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This provides the sustained depolarization and contraction needed for the heart to empty its
chambers
SA node cells pace the heart at normal resting heart rates between 60-100bpm
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SA node cells fire spontaneously, in a cycle with 3 phases – page 403 graphs on right, and page
404 top table
o Phase 4 – has slow spontaneous depolarization that is caused by an inward pacemaker
current (If)
 This spontaneous depolarization causes the automaticity of the SA node
 The channels that carry the If current are activated during the repolarization
phase of the previous action potential
 If channels are nonselective cation channels, that let in sodium (mostly) and
calcium
o Phase 0 – more rapid depolarization mediated by selective voltage gated calcium
channels that, when open, drive the membrane potential towards calcium’s positive
equilibrium potential
 They’re opened once the influx through the If channels causes the membrane
potential to reach a threshold for calcium channel opening
o Phase 3 – calcium channels slowly close and potassium channels open, causing
membrane repolarization
 Once the membrane is repolarized to about -60 mV, the If channels open, and
the cycle starts over
Although the inward pacemaker current (If) is responsible for the slow spontaneous
depolarization in phase 4, the depolarization is regulated by voltage-gated sodium channels in
the SA node
o Myocytes in the borders of the SA node express more voltage gated sodium channels,
and cells in the center of the SA node express more If and calcium channels
Unlike the SA node, ventricle myocytes don’t depolarize spontaneously under normal conditions
o So the membrane potential of the resting ventricle myocyte remains negative until the
cell is stimulated by a wave of depolarization initiated by a pacemaker cell
o Phases of ventricle myoycte action potential – page 404 graphs and bottom table
 Phase 0 – increase in sodium influx through a voltage-gated sodium channel
causes an action potential upstroke of rapid depolarization
 This is different from the SA node, whose current was carried by
calcium, while ventricle current is carried by sodium
 The influx of sodium makes the membrane potential more positive
 The sodium channels then inactivate and close quickly
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Inactivation of the fast sodium channels causes a dramatic decrease in
influx of sodium current (INA)
 The time it takes for sodium channels to recover from their voltage and
time dependent inactivation is called the refractory period
o So the refractory period is the time where another action
potential can’t fire
o This protects to ensure the heart has enough time to eject
blood from its chambers
o The refractory period lasts from the initiation of the action
potential upstroke until the repolarization phase
 Sodium influx is the major thing determining the velocity of impulse
conduction throughout the ventricle
Phase 1 – rapid repolarization to about +20 mV, due to rapid inactivation of the
sodium channels, and the activation of potassium channels to have potassium
current (IK) move out of the cell
Phase 2 – plateau phase unique to heart cells
 The plateau is maintained by a balance between calcium coming in
through calcium channels, and potassium moving out through
potassium channels
 Only a few channels open to do this, so the total membrane
conductance is low
 The high membrane resistance during the plateau insulates the heart
cells electrically, allowing rapid propagation of the action potential with
little current dissipation
 There are 2 types of calcium channels used:
o Transient (T)-type calcium channels – “inactivate with time”
 T-type calcium channels are insensitive to block by
dihydropyridines like nifedipine
o Long-lasting (L)-type calcium channels – provide the domiant
calcium current (ICa) in almost all heart cells
 It’s activated at -30 mV, and inactivates slowly
 L-type calcium channels are sensitive to block by
dihydropyridines (nifedipine), benzothiazepines
(diltiazem), and phenylalkylamines (verapamil)
 L-type calcium channels are crucial for letting calcium in
to stimulate contraction of heart myocytes
Phase 3 – calcium channels close and potassium channels kick out potassium,
repolarizing the cell
 The potassium channels are activated during the plateau, and as the
time-dependent calcium influx inactivates, outward potassium current
(IK) moves potassium out and makes the membrane potential negative
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The IK channels inactivate though, so repolarization by them stops at -40
mV
Phase 4 – resting membrane potential is reestablished by activation of timeindependent potassium currents (IK1), which make it more negative to get back
to the resting potential
 Inward and outward currents are then equal
In medicine, you measure the electrical activity of the heart, not its ionic changes
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This is measured with an electrocardiogram (ECG or EKG), which measures the body surface
potentials induced by heart electrical activity
P wave – atrial depolarization, QRS complex – ventricular depolarization, T wave – ventricular
repolarization
P-R interval – from beginning of the P wave (initial depolarization fo the atria) to the beginning
of the Q wave (initial depolarization of the ventricles)
Q-T interval – from the beginning of the Q wave to the end fo the T wave, it represents the
entire interval of ventricular depolarization and repolarization
S-T segment – from the end of the S wave to the beginning of the T wave, it’s the period that the
ventricles are depolarized (the plateau of the action potential)
The conduction system of the heart is the SA node, AV node, bundle of His, and Purkinje system
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Each has their own intrinsic rate of firing
3 things determine rate of firing:
o As the rate of spontaneous depolarization in phase 4 increases, the rate of firing
increase because the threshold potential (potential needed to trigger an action
potential) is reached more quickly at the end of phase 4
o If the threshold potential becomes more negative, the rate of firing increase because
the threshold potential is reached more quickly at the end of phase 4
o If the max diastolic potential (resting membrane potential) gets more positive, the rate
of firing increases because less time is needed to repolarize the membrane fully at the
end of phase 3
The pacemakers with the fastest firing rate set the heart rate
o The SA node has the fastest intrinsic firing rate (60-100bpm), so it’s the native
pacemaker
o The cells of the AV node and bundle of His fire about 50-60 bpm
o The Purkinje system fire the slowest (30-40 bpm)
o So the cells of the AV node, bundle, and Purkinje system are called latent pacemakers,
because their intrinsic rhythm is overridden by the faster SA node
 This is called overdrive suppression
Problems with electrical dysfunction in the heart can be either from defects in impulse formation (SA
node is messed up), or defects in impulse conduction
Defects in impulse formation – problems at the SA node that affect its function or disturb overdrive
suppression can lead to impaired impulse formation
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Two things that often cause problems making impulses are changes in automaticity, and
triggered activity
Changes in automaticity:
o Some things that change the automaticity of the SA node are physiologic
 The autonomics regulate automaticity at the SA node
 Symps during exercise increase catecholamine release to activate β1adrenergic receptors
o Activating β1’s opens more pacemaker channels (If channels),
causing faster phase 4 depolarization
o Symps also open more calcium channels
o Opening both sodium & calcium channels ↑ the heart rate
 Parasymps from the vagus release acetylcholine at the SA node to
decrease pacemaker channel opening, decrease calcium channel
opening, and make resting membrane potential more negative by
increasing potassium channel opening
o Parasymps don’t innervate the ventricles well, so their affects
are mainly in the atria and SA and AV nodes
o When the SA node firing rate becomes slow, or conduction of the SA node impulse is
blocked, the latent pacemakers kick in as an escape beat
 A series of escape beats is called an escape rhythm, and happens from
prolonged SA node problems
o Ectopic beat happens when latent pacemaker cells develop a faster intrinsic firing rate
than the SA node
 A series of ectopic beats is called an ectopic rhythm, and can happen from
ischemia, electrolyte changes, or increased symps
o Tissue damage (like in MI) can change automaticity
 Tissue injury can disrupt the cell membrane, making them unable to maintain
ion gradients
 If the membrane potential then gets positive enough, nonpacemaker
cells can start to depolarize spontaneously
 Also, tissue injury causes loss of gap junctions, so connections to relay overdrive
suppression are lost, and the unsuppressed cells then initiate their own rhythm
Afterdepolarization happens a normal action potential triggers an extra abnormal depolarization
o The first (normal) action potential triggers additional oscillations of membrane
potential, which can lead to arrhythmia
o The 2 types of afterdepolarizations are early afterdepolarizations and delayed
afterdepolarizations
o Early afterdepolarization – if afterdepolarization happens during the causing action
potential
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Things that prolong the action potential tend to trigger early afterdepolarization
 Includes drugs that prolong the QT interval
 An early afterdepolarization can happen during the plateau (phase 2) or rapid
repolarization phase (phase 3, this one is more common) – page 407 top left pic
 During the plateau, since most of the sodium channels are inactivated,
calcium influx is what’s responsible for the early afterdepolarization
 During the rapid repolarization phase, sodium channels can bring in
sodium that adds to the early afterdepolarization
 If an early afterdepolarization is sustained, it can lead to a ventricular
arrhythmia called torsades de pointes, characterized by QRS complexes of
varying amplitudes that “twist” along the baseline
 This rhythm is a medical emergency that can lead to death if not treated
quick with antiarrhythmics and/or defibrillation
Delayed afterdepolarization – happens shortly after the completion of repolarization
 High cell calcium levels activates the sodium/calcium exchanger, causing sodium
influx, which triggers the delayed afterdepolarization – page 407 bottom left pic
Defects in impulse conduction – can be from re-entry, conduction block, &/or accessory tract pathways
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Normal heart conduction: SA nodeAV nodebundle of HisPurkinje systemmyocardium
The cell refractory period ensures that stimulated areas of the myocardium depolarize only once
during propagation of an impulse – page 407 bottom right top pic
Re-entry of an electrical impulse happens when a self-sustaining electrical circuit stimulates an
area of the myocardium repeatedly and rapidly – page 407 bottom right pic
o 2 conditions have to be present for a re-entrant electrical circuit to happen:
 Unidirectional block – anterograde conduction is prohibited, but retrograde
conduction is able to happen
 Slowed retrograde conduction velocity
o By the time the impulse gets back to its starting point, the cells already repolarized and
are stimulated again by the action potential, causing a tachyarrhythmia
Conduction block happens when an impulse can’t propagate because there is an area of heart
tissue that can’t be excited
o This tissue could be normal and just refractory, or it could be tissue damaged by trauma,
ischemia, or scarring
o This removes overdrive suppression by the SA node, so you get bradycardia from latent
pacemakers taking over
Some people have accessory electrical pathways that can bypass the AV node to travel between
the atria and ventricles
o Some people have a bundle of Kent that can transmit signals from the SA node to the
ventricles faster than it goes normally through the AV node – page 408
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The ventricles receive signals from both the bundle of Kent and normal AV node
delivery, so EKG shows a wider than normal QRS complex and an earlier than normal
ventricular upstroke
The bundle of Kent is faster, which can allow for a re-entrant loop, predisposing them
for tachyarrythmias
Common heart electrical disturbances:
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Effective refractory period – period during which an area of heart tissue can’t be excited by an
electrical impulse
Sinus tachycardia – SA node fires between 100-180 bpm, & ECG shows normal P waves & QRS’s
o Sinus tachycardia can be a normal physiologic response or pathologic
Paroxysmal supraventricular tachycardia (PSVT) – atrial firing rates of 140-250 bpm, that’s
usually transient and self-limited, and ususally caused by re-entry involving the AV node, SA
node, or atrial tissue
Atrial flutter – atrial rate from 280-300 bpm, and ECG shows rapid “saw-tooth” appearance of
atrial activity
o The AV node inhibits all these extra rates from going into the ventricles, so the ventricle
beat slower than the atria
o The ratio of atrial to ventricular firing is usually 2:1
Atrial fibrillation and ventricular fibrillation – chaotic, re-entrant impulse conduction through the
atrium or ventricle
o Vfib is fatal if not corrected, while afib can be tolerated for years
Ventricular tachycardia – series of 3 or more ventricular extrasystoles at rates of 100-250 bpm
Torsades de pointes – the QRS has varying amplitudes that looks like “twisting points” on the
baseline of the ECG
o Caused by afterdepolarizations in people with prolonged Q-T intervals
Antiarrythmic drugs are used to restore normal heart rhythm by targeting proarrhythmic parts of the
heart
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Drugs that affect heart rhythm work by changing:
o The max diastolic potential in pacemaker cells – so the resting membrane potential in
ventricular cells
o The rate of phase 4 depolarization
o The threshold potential
o Action potential duration
Channel blockers work by whatever effect their channel would normally have
o Sodium and calcium channel blockers alter the threshold the potential
o Potassium channel blockers prolong the action potential duration
o Blockers usually block the pore from inside the cell, and they get there either from going
through the pore or diffusion through the membrane
State-dependent ion channel block:
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Ion channels can change their conformational state, which changes the permeability of
the membrane to that ion
o Antiarrhythmic drugs often have different affinities for different conformational states
of the ion channel, they bind to one conformation of the channel with higher affinity
than they do the other conformations, called state-dependent binding
o The sodium channel has 3 major state changes: open, closed, and inactivated
 During the upstroke of the action potential, the sodium channel is in the open
conformation
 The sodium channel gets inactivated during the plateau, and changes to closed
(resting) conformation as the membrane is repolarized to its resting potential
 Most sodium channel blockers prefer to bind to the open and inactivated states
fo the sodium channel, not the closed state
 So the sodium channel blockers block the channel during the action potential
(systole), and dissociate from the channels during diastole
o The dissociation rate (unblocking rate) of the sodium channel blockers is important in
determining the steady-state block of sodium channels
 When heart rate increases, the time available for unblocking (dissociation of the
drug from its binding site on the channel) decreases, and the degree of steadystate sodium channel block increases
 Sodium channels depress sodium conduction in ischemic tissue way more than
in normal tissue
 In ischemic tissue, heart myocytes are depolarized for a longer period of
time
 This increase in action potential duration prolongs the inactivation state
fo the sodium channels, making the inactivated sodium channels
accessible to sodium channel blockers for a longer period of time
 The rate of channel recovery from block is also decreased in depolarized
ischemic myocytes because of the prolonged action potential
 So the higher affinity of sodium channel blockers for open and
inactivated states of the channel allows them to act preferentially on
ischemic tissue, and block an arrhythmic focus at its source
o Antiarrhythmic drugs are often complicated by the fact they can also cause arrhythmia
 Ex: trying to treat re-entry – if the retrograde impulse int eh re-entrant circuit is
completely gotten rid of by the antiarrhythmic drug, then you stopped the cycle
 If the drug doesn’t get rid of it completely though, then you slowed the
impulse & conduction, which can actually induce a re-entry arrhythmia
Antiarrhythmic drugs are organized into 4 classes based on their mechanism of action
o Class 1 antiarrhythmics – sodium channel blockers
o Class 2 antiarrhythmics – β-adrenergic receptor antagonists
o Class 3 antiarrhythmics – potassium channel blockers
o Class 4 antiarrhythmics – calcium channel blockers
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Many antiarrhythmics aren’t entirely selective blockers of one channel though, and
often they block more than one channel
Class 1 antiarrhythmic agents – fast sodium channel blockers
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Sodium channel blockers decrease automaticity in the SA node cells by shifting the threshold to
be a more positive potential, and decreases how fast the phase 4 depolarization is – page 410
The block of sodium channels leaves less channels available to open in response to membrane
depolarization, therefore raising the threshold for action potential firing and slowing the rate of
depolarization
o Both effects extend the duration of phase 4, so they decrease heart rate
The shift in threshold potential means that in patients with implanted defibrillators who are
treated with sodium channel blockers, a higher voltage is needed to defibrillate the heart
Sodium channel blockers also act on ventricular myocytes to decrease re-entry, by decreasing
the upstroke velocity of phase 0, & some sodium channel blockers by prolonging repolarization
o By decreasing phase 0 upstroke velocity, sodium channel blockers decrease the
conduction velocity through the heart tissue
o Ideally, the conduction velocity is decreased enough to extinguish the impulse before it
restimulates the myocyte in the re-entry pathway
o If conduction velocity isn’t decreased enough though, the impulse isn’t extinguished,
and the slowed impulse is now more prone to cause re-entry, causing arrhythmia
o All subclasses of class 1 antiarrhythmics block the sodium channel to some degree
 Class 1A do a moderate sodium channel block – page 411 – graph of each type
 Class 1B rapidly bind and block, then dissociate and unblock rapidly
 Class 1C do a strong sodium channel block
Class 1A sodium channel blockers also prolong repolarization, which increases the refractory
period, so that the cells in the circuit can’t be depolarized by the re-entrant action potential
So sodium channel blockers decrease the likelihood of re-entry to prevent arrhythmia, by
decreasing conduction velocity, and increasing the refractory period of the ventricle myocytes
Class 1A antiarrhythmics – do a moderate block on sodium channels and prolong the
repolarization of both SA node cells and ventricle myocytes
o Class 1A’s prefer open sodium channels
o By blocking the sodium channels, they decrease the phase 0 upstroke velocity, which
decreases conduction velocity through the myocardium
o Class 1A antiarrhythmics also block potassium channels, decreasing potassium outflux
that would normally cause repolarization of the membrane
o The prolonged repolarization increases the refractory period of the cells
o Together, the decreased conduction velocity and increased refractory period, decrease
re-entry
o Class 1A sodium channel blockers include quinidine, procainamide, and disopyramide
o Quinidine
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Quinidine is the protypical Class 1A sodium channel blocker, but is being used
less due to its adverse effects
Quinidine does everything the 1A sodium channel blockers do, plus it has an
anticholinergic (antivagal) effect, since it blocks potassium channels that would
be opened by vagal stimulation of M2 muscarinic receptors in the AV node
 This anticholinergic effect is important because it can increase the
conduction velocity through the AV node
 This would be bad on someone with atrial flutter, whose atria are
contracting at 280-300 bpm
o Most of these impulses get to the AV node while its still
refractory, so most of them don’t get transmitted to the
ventricles
o So the atria fire faster than the ventricles usually at a 2:1-4:1
ratio of atria:ventricles
o If you give quinidine to people with atrial flutter, it decreases
atrial firing rate by slowing conduction velocity through the
myocardium, but it also increases AV node conduction velocity
by its antivagal effects
o The increase in AV node conduction velocity creates a 1:1 ratio
of atrial to ventricular firing rates
o So if they were firing at 300:150, a person can handle that, but
then you give them quinidine and you get 200:200, which is too
fast for ventricular pumping
o This is why quinidine should be taken with something that slows
AV node conduction, like a β-antagonist or verapamil
The most common adverse effects of quinidine are diarrhea, nausea, headache,
and dizziness
 These make it tough to take quinidine chronically
Quinidine is contraindicated in patients with prolonged QT intervals, or taking
another drug that predisposes to prolonged QT intervals, because it increases
the risk of torsades de pointes
Relative contraindications to quinidine include sick sinus syndrome, bundle
branch block, myasthenia gravis, and liver failure
Quinidine is given orally & metabolized by cytochrome P450’s (CYP’s) in the liver
Quinidine increases plasma levels of digoxin (an inotropic agent), by competing
for the P450’s, so quinidine caused digoxin toxicity is common
You need to watch plasma potassium in people taking quinidine, because
hypokalemia will decrease the effectiveness of quinidine, make worse QT
prolongation, and predispose to torsades de pointes
 Torsades de pointes is thought to be the cause for quinidine caused
fainting
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Because of all these adverse effects and contraindications, quinidine has been
largely replaced by class 3 antiarrhythmics, like ibutilide and amiodarone, to fix
atrial flutter or afib back to normal sinus rhythm
o Procainamide – class 1A antiarrhythmic drug, used often to convert new-onset afib to
normal sinus rhythm
 Procainamide isn’t as effective at this ibutilide
 Procainamide can be used safely to decrease the likelihood of re-entrant
arrhythmias in acute MI
 Procainamide can be given IV for acute ventricular tachycardia
 Unlike quinidine, procainamide doesn’t have much of an anticholinergic effect
and doesn’t effect plasma levels of digoxin
 Procainamide can cause peripheral vasodilation by inhibiting transmission at
symps
 Chronic use of procainamide cause almost all patients to develop a lupus-like
syndrome and antinuclear antibodies
 Stopping procainamide gets rid of these problems
 Procainamide is converted int eh liver into N-acetyl-procainamide (NAPA), which
prolongs the refractory period and lengthens the QT interval
 NAPA won’t cause the lupus-like effects procainamide does
o Disopyramide – Class 1A antiarrythmic that’s similar to quinidine, and only differs in its
adverse effects
 Disopyramide causes fewer GI problems, but has even more strong
anticholinergic effects than quinidine, causing adverse effects like urinary
retention and dry mouth
 This is because disopyramide is an antagonist of muscarinic
acetylcholine receptors
 Disopyramide is contraindicated in patients with obstructive uropathy,
glaucoma, patients with conduction block between the atria and ventricles, and
in patients with SA node dysfunction
 Disopyramide depresses heart contractility, so it can be used to treat
hypertrophic obstructive cardiomyopathy and neurocardiogenic syncope
 Because of its negative inotropic effects, disopyramide is absolutely
contraindicated in people with decompensated heart failure
 Oral disopyramide is approved only for treating life-threatening ventricular
arrhythmias
 Oral or IV disopyramide is sometimes used to convert supraventricular
tachycardia to normal sinus rhythm
 Life threatening arrhythmias though are usually treated with a class 3
anitarrhythmic, not class 1’s
Class 1B antiarrythmics – alter the ventricular action potential by blocking sodium channels, and
sometimes by shortening repolarization
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Repolarization is shortened because class 1B’s block the few sodium channels that
inactivate late during phase 2 of the heart action potential
Class 1B antiarrhythmics are lidocaine, mexiletine, and phenytoin
Class 1B’s bind to both open and inactivated sodium channels
 So the more time the sodium channels spend in the open or inactivated state,
the more blockage the class 1B’s can exert
The major characteristic of Class 1B antiarrythmics is their fast dissociation from sodium
channels
 Because sodium channels recover quickly from the block, 1B’s are most
effective in blocking depolarized or rapidly driven tissues, which are times there
is a higher likelihood of the sodium channels being open or inactivated
 So class 1B antiarrythmics show use-dependent block in diseased myocardium,
where the cells have a tendency to fire more often, and have very little effect on
normal heart tissue
Ischemic tissue increases proton concentration, which activates membrane pumps that
increase the ECF potassium
 This shifts the cell to a more depolarized (positive) potential than before
 The changed potassium gradient provides a smaller driving force for potassium
to leave the cells, and depolarization of the membrane leads to a higher
likelihood of action potential firing
 Because ischemic heart myocytes tend to fire more often, the sodium channels
spend more time in the open or inactivated state, serving as a better target for
block by class 1B antiarrhythmics
Lidocaine – class 1B antiarrhythmic commonly used IV to treat ventricular arrhythmias
in emergency situations
 Lidocaine doesn’t work for supraventricular arrhythmias
 If they’re hemodynamically stable, lidocaine is reserved for treating ventricular
tachyarrhythmias or frequent premature ventricular contractions that are
bothersome or significant
 Lidocaine has a short half-life of about 20 minutes, & is metabolized in the liver
 So people with decreased liver blood flow or P450 activity, you need a
lower dose of lidocaine
 For those whose P450’s are induced by drugs like barbiturates,
phenytoin, or rifampin, you need to increase the dose of lidocaine
 Lidocaine shortens repolarization, so it doesn’t prolong the QT interval, and is
afe to use in patients with prolonged QT syndrome
 Lidocaine also blocks sodium channels in the CNS though, so it can cause
adverse effects like confusion, dizziness, and seizures
 Lidocaine is also used as a local anesthetic
Mexiletine – lidocaine analog taken orally
 Mexiletine does not prolong the QT interval and lacks vagolytic effects
 Mexiletine also doesn’t depress hemodynamics much
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The main indication for mexiletine is life-threatening ventricular arrhythmia
Mexiletine is often used though with other antiarrhythmics
 Mexiletine is used in combo with amiodarone in patients with recurrent
ventricular tachycardia
 Mexiletine is also used in combo with quindine or sotalol to increase
antiarrhythmic effect, while reducing adverse effects
 Major adverse effects of mexiletine are nausea and trauma, which can be
reduced by taking it with food
 Mexiletine is metabolized in the liver, so its levels are decreased when you’re
also taking P450 inducers like phenytoin and rifampin
o Phenytoin – usually an antiepileptic drug, but it also acts as a class 1B antiarrhythmic
drug on the heart myocardium
 Its use is limited mainly to ventricular tachycardia (vtac) in kids and treating
congenital prolonged QT syndrome when β-antagonist treatment isn’t working
 Phenytoin induces liver P450 enzymes, so it effects plasma levels of other
antiarrhythmics, like quinidine, lidocaine, and mexiletine
Class 1C antiarrhythmics – the most potent sodium channel blockers
o 1C’s have little or no effect on action potential duration
o By greatly decreasing the rate of the phase 0 upstroke of ventricular cells, class 1C
antiarrythmics also prevent paroxysmal supraventricular tachycardia and afib
o Class 1C antiarrhythmics have marked depressive effects on heart function, so use with
discretion
o Class 1C antiarrhythmics can cause arrhythmia
o Class 1C antiarrhythmics are flecainide, encainide, moricizine, and propafenone
o When flecainide is given to patients with preexisting ventricular tachyarrhythmias or
people with history of MI, it can worsen the arrhythmia
 So flecainide is approved for use only in life-threatening situations, like when
paroxysmal arrhythmias aren’t responding to other treatments
 Flecainide is eliminated slowly from the body, and has a half life up to 30 hours
 Since flecainide strongly blocks sodium channels and suppresses heart function,
it causes adverse effects like SA node dysfunction, decrease in conduction
velocity, and conduction block
Class 2 antiarrhythmic drugs – β-adrenergic antagonists (aka β-blockers)
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β-blockers inhibit symp input to the pacing regions fo the heart
The heart can beat on its own without any help from the autonomics, but symps and parasymps
innervate the Sa node and AV node to affect their rate of automaticity
Symp stimulation releases norepinephrine, which binds to β1-adrenergic receptors, which are
the receptors preferentially expressed in heart tissue
o Activation of β1’s in the SA node triggers an increase in the pacemaker current (If), which
increases the rate of phase 4 depolarization, causing the SA node to fire more frequently
o
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Stimulation of β1’s in the AV node increases calcium and potassium currents, increasing
the conduction velocity and decreasing the refractory period of the AV node
β1-antagonists block the symp stimulation of β1’s in the SA node and AV nodes
o The AV node is more sensitive than the SA node to the effects of β1-blockers
o β1-antagonists affect the action potentials of the SA and AV nodal cells by decreasing the
rate of phase 4 depolarization, and prolonging repolarization – page 413
 decreasing the rate of phase 4 depolarization decreases automaticity, which
decrease myocardial oxygen demand
 prolonged repolarization at the AV node increases the refractory period, which
decreases re-entry
β1- antagonists are the most often used drugs for treating arrhythmias caused by symps
β1- antagonists reduce mortality after MI, even when the patient has some contraindications to
them
Since β1- antagonists are used for so many things and are safe, they’re the most used
antiarrhythmics
First generation β- antagonists are nonselective β- antagonists that antagonize both β1’s and β2’s
o The main 1st generation β- antagonist is propranolol
o Propranolol is widely used to treat tachyarrhythmias caused by catecholamine
stimulation during exercise or emotional stress
o Propranolol doesn’t prolong repolarization in ventricles, so it can be used in patients
with long QT syndrome
Second generation β- antagonists are selective β1- antagonists at low doses
o 2nd generation β1- antagonists are atenolol, metoprolol, acebutolol, and bisoprolol
Third generation β- antagonists are β1- antagonists that also cause vasodilation
o Labetalol and carvedilol induce vasodilation by also antagonizing α-adrenergic receptor
caused vasoconstriction
o Pindolol is a partial agonist at the β2 adrenergic receptor
o Nebivolol stimulates endothelial making of NO
Adverse effects of β-blockers:
o Antagonizing the β2’s causes smooth muscle spasm, leading to bronchospasm, cold
extremities, and impotence
 These are more commonly caused by the non-selective β- antagonists
(propranolol)
 Excessive antagonism of β1’s can cause excessive negative inotropic effects,
heart block, and bradycardia
 β-blockers can get into the CNS and cause insomnia and depression
Class 3 antiarrhythmic agents – potassium channel blockers that inhibit repolarization
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2 types of currents determine how long the plateau of the heart action potential is: influx of
calcium that depolarizes, and outflux of potassium that hyperpolarizes
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In a normal action potential, the hyperpolarizing potassium currents eventually dominate,
returning the membrane potential to more negative values
Larger hyperpolarizing potassium currents shorten how long the plateau is, returning the
membrane potential to its resting value more quickly
Smaller hyperpolarizing potassium currents lengthen how long the plateau is, and delay return
of the membrane potential to its resting value
When potassium channels are blocked, a smaller hyperpolarizing potassium current is generated
o So K+ channel blockers cause a longer plateau and prolong repolarization – page 414
The ability of the potassium channel blocker to lengthen the plateau is mainly how its used and
responsible for its adverse effects
o Prolonged plateau increases the refractory period, which decreases re-entry
o But prolonged plateau increases the likelihood of developing early afterdepolarizations
and torsades de pointes
All the potassium channel blockers, except amiodarone, also show reverse use-dependency,
where action potential prolongation is most pronounced at slow rates (undesirable) and least
pronounced at fast rates (desirable)
Class 3 antiarrhythmic potassium channel blockers are ibutilide, dofetilide, sotalol, bretylium,
amiodarone, and dronedarone
Ibutilide- potassium channel blocker that prolongs repolarization by inhibiting the K+ outflux
o Ibutilide also enhances slow sodium influx, which further prolongs repolarization
o Ibutilide is used to stop afib and atrial flutter
o The major adverse effect of ibutilide is it prolongs the QT interval, which can cause
torsades de pointes in almost 2% of people taking ibutilide
 So don’t ibutilide to people with prolonged QT interval
Dofetilide – class 3 potassium channel blocker that inhibits the rapid part of potassium influx,
and has no effect on sodium flow
o Can only be taken orally
o Dofetilide increases how long the action potential is and prolongs the QT interval
o So since dofetilide can cause ventricular arrhythmias, it’s reserved for people with very
symptomatic afib and/or atrial flutter, to get them back to sinus rhythm
o Dofetilide has no negative inotropic effects, so it can be used for patients with
decreased ejection function
o The major adverse effect of dofetilide is also torsades de pointes
o Dofetilide is excreted by the kidneys, so people with kidney issues should get a smaller
dose
Sotalol – mixed class 2 and class 3 antiarrhythmic drug that nonselectively antagonizes βadrenergic receptors, and also increases how long the action potential is by blocking K+ channels
o Sotalol has two isomer forms, which are both equally as good at blocking potassium
channels, but the L-isomer is a more potent β- antagonist
o Sotalol is used to treat severe ventricular arrhythmias, especially in people who can’t
tolerate the adverse effects of amiodarone
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Sotalol is also used to prevent recurrent atrial flutter or afib and maintain normal sinus
rhythym
o Like other β- antagonists, Sotalol can cause fatigue and bradycardia
o Like other potassium channel blockers, Sotalol can induce torsades de pointes
Bretylium – drug that acts as both a class 3 potassium channel blocker, and an antihypertensive
o Bretylium is concentrated in the vesicles of the terminals of symp neurons, causing
initial release of norepinephrine, but then inhibiting further release of norep, decreasing
blood pressure
 So like other drugs like this, Bretylium can cause hypotension
o Bretylium also increases how long the action potential is
 It mainly does this at the Purkinje fibers, and somewhat in ventricle myocytes
 Bretylium has no effect on the atria
o Bretylium is used for recurrent vtac or vfib after lidocaine and defibrillation have failed
Amiodarone – drug that mainly acts as a class 3 antiarrhythmic, but also acts as a class 1, 2, and
4 antiarrhythmic
o Amiodarone changes the lipid membrane holding the ion receptors
o In all heart tissues, amiodarone lengthens the refractory period by inhibiting the
potassium channels, which prolongs how long the action potential is
o Amiodarone also has class 1 effects to block sodium ahnnels, which decreases the rate
of firing in pacemaker cells, and shows use-dependent sodium channel block by binding
preferentially to channels in the inactivated conformation
o Amiodarone has class 2 effects by antagonizing α and β adrenergic receptors
o Amiodarone has class 4 effects to cause AV node block and bradycardia
o Amiodarone is low risk for torsades de pointes
o High dose amiodarone is toxic, so you reserve it for people with unstable vtac or vfib
after other antiarrhythmics have failed
o At lower doses, amiodarone is one of the most effective drugs for preventing ventricular
arrhythmias in people with heart failure or history of recent MI
o Amiodarone is also good at preventing recurrent paroxysmal afib and atrial flutter
o Adverse effects of amiodarone – page 415 top table
 Heart – amiodarone can decrease AV or SA node function by blocking calcium
channels, cause hypotension by being an α-blocker, and have negative inotropic
effects as a β-blocker
 Lungs – high doses of amiodarone can cause pneumonitis leading to pulmonary
fibrosis, but this is rare with low doses
 Thyroid – amiodarone is structurally similar to thyroxine, so it inhibits
conversion of thyroxine (T4) to triiodothyronine (T3), causing either
hyperthyroidism or hypothyroidism
 Liver – up to 1/5 of people taking amiodarone get high liver enzymes
 Neuro – peripheral neuropathy, headache, ataxia, and tremors
o Amiodarone is contraindicated in people with cardiogenic shock, 2nd or 3rd degree heart
block, and severe SA node problems with sinus bradycardia or syncope
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Dronedarone – class 3 potassium channel blocker that’s structurally similar to amiodarone
o Compared to amiodarone, dronedarone is less lipophilic, giving it a shorter half-life, and
lacks iodine, so it no longer messes with the thyroid
o Dronedarone helps recurrent afib with few adverse effects, but increases mortality in
systolic heart failure, and also rarely causes severe liver toxicity
Class 4 antiarrhythmic drugs – calcium channel blockers
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Drugs that block heart calcium channels act preferentially on SA and AV node tissues, because
these pacemaker tissues depend on calcium for the depolarization phase of the action potential
Calcium channel blockers have little effect on fast sodium channel-dependent tissues, like
Purkinje fibers and atrial and ventricular muscle
The major reason to use calcium channel blockers is to slow the action potential upstroke in AV
nodal cells, leading to slowed conduction velocity through the AV node – p. 415 bottom graph
o This also blocks re-entrant arrhythmias that involve the AV node
Since different tissues have different subclasses of calcium channels, and different calcium
channel blockers prefer different channel subtypes, different calcium channel blockers prefer
different tissues
Dihydropyridines like nifedipine work more on the calcium channels for vascular smooth muscle
Verapamil and diltiazem are more effective calcium channel blockers at the heart
o Verapamil and diltiazim are used to treat re-entrant paroxysmal supraventricular
tachycardias, because this is an arrhythmia that usually involves the AV node
o The only time you use verapamil and diltiazem for a vtac is idiopathic right ventricular
outflow tract tachycardia, and fascicular tachycardias
o Verapamil is used to treat hypertension and vasospastic (Prinzmetal’s) angina
2+
Ca channel blockers can cause AV node block by excessively decreasing conduction velocity
Giving IV verapamil to people taking β-blockers can cause heart failure
Verapamil and diltiazem increase plasma digoxin by competing with it for kidney excretion
Other antiarrhythmics:
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Adenosine – nucleoside used to treat arrhythmias with problems with AV node conduction
o Adenosine stimulates the P1 purinergic receptors to open G protein coupled potassium
channels (IKACh) to inhibit SA nodal, atrial, and AV nodal conduction
 The AV node is more sensitive to adenosine effects than the SA node
o Adenosine also inhibits cAMP suppress calcium dependent action potentials
o Adenosine has a half-life of 10 seconds, is used as a first line agent for converting
narrow-complex paroxysmal supraventricular tachycardia to normal sinus rhythm
o Adverse effects of adenosine are transient, and include headache, flushing, chest pain,
and excessive AV or SA node inhibition, and bronchoconstriction in people with asthma
o In over half of people, a transient new arrhythmia happens when you first give them
adenosine
Potassium – both hypokalemia and hyperkalemia can cause arrhythmias
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Hypokalemia can cause afterdepolarizations and ectopic beats in nonpacemaker cells
Hyperkalemia can cause slowed conduction velocity, because it decreases potassium
outflux and therefore depolarizes the cell
 The life threatening effects of hyperkalemia are the main reason why you give
someone with kidney failure dialysis
o Fixing the potassium levels can fix some arrhythmias
Ranolazine – drug that inhibits late sodium influx to treat chronic stable angina
o It improves exercise capacity and ↓ angina events in people with chronic stable angina