Cardiac Anti-Arrhythmic agents Flashcards
what happens when there is increased potassium permeability?
Vm close to Ek
strong repolarization
increased threshold
what happens when there is decreased potassium permeability?
Vm depolarized (toward ENa, ECa) decreased threshold
characteristics of a typical Fast AP
conduction velocity determined by phase ) slope
Fast Na channels cause the depolarization
slow ca channels are responsible for the plateau
characteristics of a typical slow AP
SA and AV nodal tissue
No fast Na channels (phase 0)
More Ca dependent
Spontaneous phase 4 depolarization due to funny Na and Ca channels
Action of Na channel blockers
decrease conduction velocity (phase 0)
suppress ventricular and atrial muscle firing
Action of K channel blocker
increase time for repolarization (phases 2 and 3)
prolongs AP duration , slows down
increases time to “reset” excitability (refractoriness)
Action of K channel stimulator
increases repolarizing influence (Ek)
decreases slope of phase 4
slows HR (Ach/PNS)
Action of Ca channel blocker
nodal cells: decreases slope of phase 4
decrease excitability of nodal cells
not as effective in Na-dependent cells
Spontaneous activity (phase 4) is under …
autonomic control
what prevents tetanus in cardiac muscle?
Refractory period
Absolute refractory period - another AP cannot fire, Na channels are inactive
Relative refractory period - late phase 3, Na channels are reactivated and another AP could fire
How are inactived Na channels reset?
by repolarization
What affinity contributes to Na channel efficacy?
blockers have a high affinity for O state (open) or inactive state of the Na channel
faster HR means more time in O or I, so more effective in a heart that is tachycardiac vs normal sinus rhythm
Cardiac ATP
75% of cardiac ATP is for the Na/K ATP pump
How does ischemia affect depolarization?
lowers ATP and increases intracellular NA so the cells are slightly depolarized because gradient not being closely maintained. There is less “reactivation” of fast Na channels, slower phase 0 upstroke and impulse conduction and may contribute to re-entry of impulses.
Need a negative potential to reactivate Na channels.
What is a strategy to decrease arrhythmias?
by increasing ERP
makes the cell less sensitive to stimulation
can slow the development/propagation of abnormal rhythms
K channel blocker
slows phase 3 repolarization
increases AP duration
delays “recovery” of Na channels
prolongs Effective repolarizing Potential and R (relative) RP
Na channel blocker
binds to and blocks inactive channels
reduces number of “recovered” channels
extends the ERP of atrial/ ventricular myocytes
Ca channel blocker
increase ERP and depress phase 4 slope in nodal tissue
bradyarrhythmias
SA node dysfunction
electronic pacemakers are t.o.c
atropine or isoproterenol
tachyarrhythmias
increased impulse generation (automaticity)
increased impulse conduction (propagation)
tx: primarily channel blockers
Triggered Activity
after depolarizations
occur “after” the normal AP depolarization
can trigger abnormal beat if threshold is reached and sufficient # of Na channels have recovered from inactivation
abnormal beat occurs before optimal diastolic filling
Delayed afterdepolarization (DAD)
often produced by too much calcium
occurs during phase 4
Early afterdepolarization (EAD)
can occur with excessive prolongation of AP
occurs during phase 3
3 simultaneous conditions for Premature excitation before next normal impulse
- area of depressed conduction/block
- block must be unidirectional
- impulse speed “around the block” must be slow enough to reenter healthy area AFTER the refractory period (sufficient Na channels have recovered and can be opened) this insures abnormal “retrograde” propagation
Circus movement
repetitive “circulation” of abnormal impulses can produce a sustained tachyarrhythmia independent of the SA node
Pharma approach to circus movement issues
make unidirectional block Bidirectional
further decrease conductance through injured region (block retrograde impulse)
Na channel blocker or Ca channel blocker (nodal tissue)
Increase ERP in tissues so impulse cannot be conducted -(k channel blockers can lengthen ERP, makes healthy tissue refractory to retrograde impulse, abnormal excitation dies out)
Class I drugs
Na channel blockers - decrease velocity of phase 0 Class 1A - (quinidine, procainamide, disopyramide) prolong AP duration, dissociate with intermediate kinetics class 1B -(lidocaine, mexiletine) shorten AP duration, rapid dissociation Class 1C - (Flecaindine, propafenone) - High affinity, minimal effect on AP duration, slow dissociation
what type of block will not work on Nodal tissue?
Na block
Class 2 drugs
Beta adrenergic blockers -> decrease in nodal automaticity and conduction
propranolol, non selective beta blocker (sotalol), metoprolol, esmolol, beta 1 blockers
Agents that prolong AP duration: K channel blockers
amiodarone - k channel blocker weak non selective beta blocker (Dronedarone - non iodinated amiodarone)
sotalol - K channel block and non selective beta blocker
dofetilide & ibultilide - k channel blockers
Ca channel blockers (hits SA and AV, non DHP)
verapamil, diltiazem- inhibit slow, inward calcium current
MOA of class 1 drugs
slower rate of phase 0 depolarization and decreased conduction velocity (primarily in non nodal tissue)
Threshold Vm for activation is also increased
greater depolarization is required to elicit a response
Use-dependent: bind to open or inactivated Na channels only. Reduce tachyarrhythmia, but little effect on normal sinus rhythm.
Class 1A
intermediate binding, dissociation kinetics intermediate depression of phase 0
block K channels (increase ERP, APD)
increases the slope of phase 0
ex: quinidine
-moderate Na channel blockade, increase ERP
Class 1B
weaker binding, rapid dissociation
little depression of phase 0 (less than 1A)
pure Na channel blockers (no K channels)
ex: Lidocaine
-Weak Na channel blockade, decrease ERP
Class 1C
strong binding, slower dissociation
strong depression of conductance (phase 0)
little effect on ERP
ex: flecainide
-strong Na+ channel blockade, shift to right ERP
Quinidine class?
Class 1A
Quinidine
anti malarial drug - “opium of the heart”
Na and K blockade
tx: atrial and ventricular arrhythmia
Side effects of Quinidine
Cinchonism: tinnitus, blurred vision, HA
ventriculr arrhythmias/torsades de pointes (prolonged APD)
GI problems (N/V)
Anticholinergic/vagolytic
contaminant of online herbal preparations of cinchona bark
Procainamide class??
Class 1A
Procainamide
derived from procaine (local anesthetic)
Na and K channel blockade
Metabolic: N-acetylprocainamide (class III action, prolong APD) ~50% of americans are “rapid acetylators” and in these individuals [NAPA]>[procainamide]
Tx: atrial and ventricular arrhythmias
Procainamide side effects
lupus like autoimmune syndrome
ventricular arrhythmias and prolonged QT: torsades de pointes
Disopyramide class?
Class 1A
Disopyramide
similar to quinidine and procainamide in use but fewer side effects
Na and K chnnel blockade
Tx: atrial and ventricular arrhythmias
Disopyramide side effects
Anticholinergic effects (dry mouth, constipation, urinary retention)
Class 1A
Quinidine
Procainamide
Disopyramide
Lidocaine class?
class 1B
Lidocaine
local anesthetic with fast binding/dissociation kinetics
inactive orally
Mech: blockade of open or inactive Na channels, more effective for tachyarrhythmia or depolarized tissues
little effect on SA or AV node
Tx: hyper excitability, Life threatening ventricular arrhythmias, PVCs inhibited due to blocked Na channel
Lidocaine side effect
CNS effects: drowsiness, dizziness, confusion, High doses can produce seizures and convulsions
Epi helps what stay locally?
Lidocaine
Mexiletine class?
Class 1B
Mexiletine
analog of lidocaine (orally active version) , fast kinetics
Mech: similar to lidocaine
Orally effective - avoids first pass hepatic metabolism
Tx: life threatening ventricular arrhythmias, PVCs inhibited due to blocked Na channels
Treat chronicc pain -diabetic neuropathy
Mexiletine side effects
CNS effects: tremor, blurred vision
GI: nausea (lessened by food intake)
Class 1B drugs
Lidocaine
Mexiletine
Flecainide class?
Class 1C
Flecainide
derivation of procainamide with slow kinetics
Mech: strong inhibition of phase 0 and general cardiac excitability, weaker ability to block K channels can prolong APD slightly
slight ability to block Ca channels
Tx: supraventricular and ventricular tachy, PVCs, can slow nodal conduction (use in atrial fib)
Flecainide side effects
Proarrhythmic effect: potentially lethal ventricular tacyarrhythmia when given after MI, blurred vision, depression of LV performance
Propafenone class?
class 1C
Propafenone
structurally similar to propranolol
mech: strong inhibition of phase 0 and general cardiac excitability, weaker ability to block K channels can prolong APD slightly, slight ability to block Ca channels
Tx: supraventricular and ventricular tachy, PVC’s, can slow nodal conduction (use in atrial fibrillation)
Propafenone side effects
weak beta adrenergic blocking action (bronchospasm)
Class II agents
Anti-arrhythmic - beta blockers
Antagonize sympathetic stimulation of beta 1 adrenoceptors in the heart = decreases HR, contractility, and conduction
side effects: typical for beta blockers
Propranolol
Class II
non selective beta adrenergic antagonist
mech: inhibition of sympathetic stimulation of heart, inhibit NE activity, block Na channels at high doses
Tx: decreased AV conduction: suraventriculr arrhythmias, slow HR, Post-MI therapy: reduces mortality 2-3 years after MI by decreasing risk of ventricular arrhythmias
Propranolol side effects
beta adrenergic blocking action
Metoprolol and Esmolol
Class II
cardio-selective beta adrenergic antagonist
Mech: inhibition of sympathetic stimulation of the heart, preference for the beta 1 adrenoceptor
Tx: (similar to propranolol) decreased AV conduction: supraventricular arrhythmia, slow HR, post MI therapy
Metoprolol and Esmolol side effects
fewer side effects compared to propranolol
Peripheral beta 2 receptors left intact
Esmolol is very rapidly metabolized iv so is used for acute management of ventricular rate in atrial flutter/fibrillation
Class III agents
Anti-arrhythmic agents that Prolong APD AP duration and ERP are prolonged most class III drugs are K channel blockers phase 0 is not affected prolongation of AP can increase risk of torsades de pointes (polymorphic ventricular tachy)
Amiodarone
Class III
iodinated thyroxine derivative, exhibits class I, II, III and IV action.
Often the most prescribed anti-arrhythmic agent
DIRTY!!!!
Mech: K channel block to increase repolarization time (increase ERP), weak alpha and beta adrenergic receptor blocking effect and Ca channel antagnoism reduces automaticity, decreases phase 4 slope in pacemaker cells, decreases AV node conduction (can tx atrial fibrillation)
Tx: recurrent tachy or fibrillation resistant to other drugs, first line treatment for acute V tachy/fib
Amiodarone side effects
Thyroid: hyper or hypothyroidism blue skin discoloration (blue) pulmonary tox/ fibrosis corneal microdeposits peripheral neuropathy/ weakness hepatic dysfunction hypotension, esp. with IV administration QT prolongation, but risk for torsades de pointes is lower compared to other class III agents
Very lipophilic, requires high loading dose
Dronedarone
class III
Newer, non iodinated form of amiodarone
Mech: similar to amiodrone but slightly less effective
Dronedarone side effects
fewer compared to amiodarone
less thyroid, pulmonary and hepatic tox.
can increase mortality due to heart failure
Sotalol
class III non selective beta blocker that also blocks K channels Mech: blocks K channels to increase APD and ERP automaticity can also be decreased due to beta blockade, slows SA and AV node conduction
Tx: supraventricular and ventricular tachy, approved for PEDs
Sotalol side effects
risk of torsades de pointes necessitates inpatient monitoring
effect typically associated with beta adrenergic blockers
Dofetilide
class III pure K channel blocker (at clinical doses) Mech: blocks K channels to increase APD and ERP Tx: anti-fibrillatory effect in atria
Dofetilide side effects
life threatening ventricular arrhythmias can occur
restricted to physicians who have undergone manufacturers training
Ibutilide
class III pure K channel blocker (at clinical doses) Mech: blocks K channels to increase APD and ERP Tx: terminate atrial flutter/fib, iv admin required
side effects : QT prolongation/torsades de pointes
Class IV agents
Anti arrhythmic - Ca channel blockers
Block the “slow” inward Ca current
non-DHP (on T tubules) - more cardio-selective, DHPs are greater affinity for vascular ca channels
Target Ca-dependent cells: SA/AV nodes - slows conduction
decrease slope of phase 4 depolarization
Verapamil
Class IV
blocks voltage-sensitive Ca channels
Mech: decreases automaticity (depresses phase 4 slope) and afterdepolarization formation, slows conduction in SA and AV nodes and ventricular contractility can be decreased (phase 2)
Tx: primarily atrial tachyarrhytmias (protects ventriculars from this misfiring)
Verapamil side effects
Negative inotropic effect - limited use in patients with LV dysfunction
Hypotension - due to vasodilatory effect (reflex tachy)
bradycardia and AV block - lengthens PR interval
constipation - blocks SM ca channels
Diltiazem
Class IV
blocks voltage sensitive Ca channels
Mech: decreases automaticity (depresses slope of phase 4) and afterdepolarization, slows conduction in SA and Av nodes, ventricular contractility can be decreased (phase 2)
Tx: primarily atrial tachyarrhythmia
Diltiazem side effects
negative inotropic effet - limited use in pts with LV dysfunction
hypotension - due to vasodilatory effect
bradycardia and AV block
Adenosine
Non classified
endogenous nucleoside, rapid and transient depression “stops and resets the heart”
Mech: stimulates the ACh sensitive K current to decrease phase 4 slope and antagonizes the effects of cAMP to reduce calcium currents )increase nodal refractoriness and inhibit DADs) and rapid uptake and metabolism (deamination)
Tx: primarily for acute treatment of supraventricular tachy and produces transient ASYSTOLE (~5 seconds)
Adenosine side effects
limited because of very short duration of action
vasodilation - flushing, HA
bronchoconstriction
Digoxin
non classified
cardiac glycoside
Primary use: Positive inotropic effect
Mech: inhibit Na/K ATPase activity, vagotonic action - (inhibit ca current, increase ACh stimulated K current), increased AV node refractoriness/ lower conductance and increased calcium: higher tendency for DADs
Tx: control ventricular rate in atrial flutter/ fib, slow conduction in AV node
Digoxin side effects
low therapeutic index
ventricular arrhythmias (VT, PVC)
hypokalemia increases risk of arrhythmia
