antiarrhythmics 63/64 Flashcards
Quinidine
Class 1A
inhibits Na+ channels but also K+ channels
used for variety of arrhythmias, but limited by SEs
increased used for vfib, Brugada syndrome (inherited ion channelopathy–>vfib): can also be stopped with cardioversion, and afib in short-QT syndrome
past: used to keep cardioverted a fib pts in the cardioverted state
Procainamide
Class 1A
quite similar to quinidine except K+ channels are inhibited by an *acetylated hepatic metabolite (NAPA)
only IV use
Lidocaine
Class 1B
rapidly interact with phase 0 Na channels, shortens phase 3 depolarization, dec. AP duration and ERP
inhibition of small population of late opening sodium channels still open during the AP plateau (opened more by ischemic conditions)
emergent ventricular arrhythmias, during MI
decrease slope phase 4
abolishes ventricular reentry
stops TdP because decreases AP duration
IV only (1st past effect: dec. action and increases toxic metabolites)
MOA: not always logical, can stop reentry via decreasing AP duration?
stop torsades by reducing EAD
Flecainide
Class 1C
reserved for severe cases resistant to other drugs for (FA: SVTs, including afib; only last resort in refractory VT)
block phase 0 Na+ the most, markedly suppresses phase 0 slope, slows conduction
inhibits some K+ channels, but no net effect as it blocks late Na+ channels as well
increases threshold for phase 0 and decrease slope of phase 4 (both reduce abnormal automaticity)
Propranolol
Class II
non-selective (B1, B2-block)
reduces adrenergic-driven arrhythmic death after MI
membrane stabilization at unacceptably high doses-not used this way
Acebutolol
Class II
B1-selectivity, less bronchospasm
partial agonist activity (ISA) may decrease risk of too much suppression of normal cardiac function
Esmolol
Class II
short duration of action (only IV)
acute arrhythmias during emergent situations, surgery
Amiodarone
Class III: block K+ channels
actions similar to I, II and IV, decrease cell-to-cell coupling, slows functional movement of AP, slows velocity of AP
severe and refractory (resistant) SVT and Vtach, combined with auto ICD (reduces how often shock must deliver shocks: “reduced tachyarrhythmic burden”)
severely limited by SEs
FA: afib, aflutter, vtach
fast IV, slow oral
may be used emergently when lidocaine not recommended
Dofetilide
Class III
inhibits only K+ channels (mimics NAPA) prolongs phase 3, no multiple mechanisms like amiodarone
mostly for SVTs, i.e. afib
corrects reentry phenomenon
Verapamil
Class IV
Diltiazem
Class IV
Adenosine
miscellaneous (not a class)
synthetic form, IV
used to tx emergent arrhythmias, short duration
stops acute PSVTs (paroxysmal) (due to WPW or AV nodal origin)
very short duration of action (less than 15s)
decreases conduction and abnormal AP formation in AV node by dec. Ca2+ influx and increasing ACh-sensitive phase 4 K+ current (hyper polarizing resting potential)
also prolongs AV node refractory period
Class I antiarrhythmics block
Na+ channels
Class II antiarrhythmics block..
Ca2+ channels
Class III antiarrhythmics block
K+ channels
APs occur in phases
Phase 0: upstroke: fast depolarization -85mV to 0mV
Phase 1: early-fast repolarization (we ignored this)
Phase 2: important plateau phase (drugs affect here)
Phase 3: repolarization phase back to resting
Phase 4: in between phase (resting, diastole)
AP phases travel from place to place in heart
start in SA node
also change shape based on location
threshold for phase 0
need something to get it to threshold, will get up the rest on on
some tissues can do this on own, i.e. SA node, AV node, purkinje: have automaticity
steepest slope, reaches AP 1st–>atria–>AV node–>Purkinje fibers–>rest of heart
before these tissues reach threshold on their own
when these other tissues reach threshold on own: pathological
channels for phase 0
1st reach threshold
then Na+ enters cell (also Ca2+) neutralize the internal negative charge: upstroke: goes from -85 mV to 0mV
very steep, much Na+ coming in
some Na+ channels may remain open, esp. during ischemia: late Na+ channels
Phase 1 channels
some K+ outflux, we mostly ignore
Phase 2 channes
Ca2+ comes in, keeps above 0 mV
then close! and K+ channels open, K+ flows out, some downward movement
Phase 3
more K+ flowing out, back down to resting potential
Phase 4
refractory to AP from phase 0-beginning phase 4
only digoxin acts here
leakage of Na+ and Ca2+ in, K+ out, can influence slope of phase 4 (if flat: no net change)
if more + charge in, may reach threshold, shows automaticity (pacemaker cells)
Na+/K+ ATPase (sodium pump) (Na+ out, K+ in)
Na+/Ca2++ exchanger (Ca2+ out, Na+ in)
Na+ channel blockers may ??
suppress slope of Phase 0, may depress rate of depolarization
abnormal AP can spontaneously arise from cardiac sites other than the SA node (sometimes called ectopic sites) if ??
K+ too high or too low (e-lyte imbalance) ischemia acidosis scar tissue drugs abnormal cardiac anatomy (WPW) abnormal automatic nerve activity
abnormal AP formation: steep slope in phase 4
(also abnormal conduction)
abnormal AP formation
EADs and DADs
triggered by a previous AP
early after depolarizations (EADs) that “pop out” of phase 3
should be refractory!
esp. in Purkinje and Ventricles
can be due to ischemic conditions or if duration of AP is lengthened, slow HR, low EC K+ and certain AP-prolonging drugs
if happen earlier, involve Ca2+ current, if later, involve both Na+ and Ca2+ current
delayed after depolarizations (DAD)
happen after phase 3, beginning of phase 4 (NOT abnormal automaticity)
intracellular Ca2+ overload from:
too much SNS (adrenergic stress)
digoxin toxicity
ischemic conditions
more likely if HR is rapid, upstroke may involve nonspecific mix of cations
both EADs and DADs are due to
ion fluctuations
inhibiting these channels may prevent abnormalities
suppress EADs by decreasing AP duration
suppress DADs by correcting Ca2+ overload (or cause)
drugs can suppress both upstrokes by blocking influx of Na+/Ca2+
how to stop abnormal automaticity
suppress slope of phase 4 diastolic depolarization by inhibiting Na+, Ca2+ channels that are allowing influx
some drugs increase threshold to reach AP in phase 0
delay recovery phase by decrease AP, delays phase 4, delays abnormal pacemaker activity
can hyperpolarize cell (lower negative voltage) will take more time to reach threshold: makes diastolic resting membrane potential more negative (impacts diastolic K+ channel)
abnormal AP conduction
purkinje fibers bifucate, AP goes in both directions, spreads throughout ventricles
ischemia, scar tissue may slow down one pathway (impulse block), AP may REENTER normal pathway and produce another AP producing an abnormal rhythm (“circus phenomenon”)
mechanisms to tx abnormal AP conduction
- drugs that slow conduction
decrease slope of phase 0
will not slow down already slowed pathway, will slow pathologic pathway
-both traveling slow now may cancel each other out (bidirectional block) may stop reentry phenomenon - extend refractory period (phase 4) can’t get another reentry
many arrhythmias can start
in atria and travel through AV node
drugs: may slow through AV node stop them from reaching ventricle
B-blockers, CCBs
supraventricular arrhythmias
a flutter
afib
WPW
PSVT
atrial flutter
single ectopic site in atria, abnormal automaticity
HR: 250-350 bpm but regular
about 50% impulses reach ventricle
atrial fibrillation
multiple ectopic sites, abnormal automaticity or reentry phenomenon
HR: 400 bpm and irregular! ventricles beat from 100-200/min
“multifocal atrial tachycardia”
WPW
anatomical situation
familial (autosomal dominant)
bypass of AV conduction pathway: abnormal pathway that connects atria and ventricles (“Bundle of Kent”)–> reentry phenomenon: normal impulses may be transferred back to atria by
retrograde conduction through the bypass tract (Bundle of Kent)
also, abnormal atrial impulses may travel directly from atria to ventricles down the bypass tract (WPW + afib)
names: ventricular arrhythmia, PSVT, or atriventricular reciprocating tachycardia (AVRT)
paroxysmal supra-ventricular tachycardia
abrupt start/stop
most likely site is AV node
reentry phenomenon (may have automaticity)
ventricular arrhythmias
Torsades De Pointes (TdP) PVC Vtach Vfib ventricular circus phenomenon
Torsades De Pointes
collation of EADs
atypical ventricular tachycardia APs abnormally prolonged by drugs/ischemia
long QT intervals
one form: “pause-dependent TdP”
premature ventricular contraction (PVC)
single ectopic abnormal ventricular discharge, abnormal automaticity, DADs, reentry phenomena
1 extra beat
may be seen with drug toxicity (digitalis)
unifocal, multifocal, or paired
ventricular tachycardia
more PVCs, i.e. 3-4, fire quite regularly
extra beats
HR may be 150-250 bpm +
dangerous if sustained, may progress to vfib
ventricular fibrillation
several ectopic sites, non-synchronous irregular ventricular impulses
any/all arrhythmic mechs may be involved
“whole bunch” of PVCs/extra beats
fatal if not corrected by defib/cardioversion
Class I drugs
selectivity: mainly Na+ channels, also some K+ (quinidine)
use-dependence: many are capable of only inhibiting channels that are in USE, not when resting, largely attack abnormal APs (good!) don’t interfere much with normal channels
subdivisions: A, B, C:
* various currents that are affected* and speed of interation with channels (not as important) , secondary action on recovery phase
ALL INCREASE THRESHOLD FOR PHASE 0 can stop arrhythmias from abnormal automaticity
All 3 Class I drugs inhibit ??
ALL 3 INHIBIT Na+ CHANNELS (upstroke and diastolic: stops both by direct suppression of slope
(gradations)
Class 1A
delay recovery, slope comes out, increase AP duration and duration of refractory period via inhibiting phase 3 K+ channels, inhibit ions responsible for recovery phase (+ charge flowing out) (some drugs only do this-later)
can stop reentry arrhythmias
FA: increase AP duration, inc. ERP in ventricular AP, increase QT interval
FA: used in both atrial and ventricular arrythmias, esp. reentry and ectopic SVT and VT
Class 1B
DECREASE duration of refractory period (counterintuitive?)
inhibit the late Na+ channels that contribute to plateau, decrease AP duration
MORE late Na+ channels open during ischemia (lidocaine, see later)
less inhibition of phase 0 Na+ currents, have less slowing effect on rate of rise of phase 0 than Class 1A drugs
FA: preferentially affect ischemic or depolarized Prukinje and ventricular tissue
FA: uses: acute ventricular arrhythmias (esp. postMI), dig-induced arrhythmias
Class 1C
curve travels close to control curve, does not effect recovery phase as much
still influence channels: inhibit late open Na+ channels or K+ channels (balance out, don’t see shift)
little to no net effect on AP duration or ERP
inhibits phase 3 K+ channels, prolong recovery phase (NOT diastolic K+ channels), delay AP duration, stop reentry arrhythmias
inhibit phase 0 Na+ currents, depress rate of phase 0 rise: slows conduction velocity much more than Classes 1A and 1B
*may increase likelihood of AEDs (tosades), but don’t see too much; other mechs stop this (increase threshold for phase 0)
most of these drug preps
IV and oral
Quinidine SEs
can cause other arrhythmias (i.e. TdP) due to prolonging ventricular AP duration (long QT)
GI probs (N/V/D)
cinchonism (ear ringing)-more serious
dec. BP and inc. regular sinus rate via a-block and “atropine-like” actions
can increase blood digoxin
Procainamide SEs
lupus syndrome (common but less for *rapid acetylators)
CNS (confusion)
GI problems
a-block/atropine actions and risk of TdP
less than quinidine
Lidocaine SEs
good things: (wide toxic to therapeutic ratio, little negative inotropic effect)
CNS effects (convulsions, slurred sleep, drowsiness, confusion) *may be pro-arrhythmic by mainly in presence of hyperkalemia*
Flecainide SEs
negative inotropic effects (aggravate CHF)
significant pro-arrhythimc effects, aggravate pre-existing arrhythmias, exacerbate vtach (amplified by hyperkalemia)
FA: contraindicated in structural and ischemic heart disease
CNS (dizziness, ha, nausea, blurred vision)
increase mortality
Amiodarone SEs
may continue after drug stopped
pulmonary fibrosis (fatal)
hyper/hypothyroid
iodine problems (amIODarone): blue skin, iodine sensitivity
TdP can occur due to inc. APDs in ventricular tissues but rare compared to other APD-proloning drugs
dizziness
FA: also has hepatotoxicity, CNS effects, constipation, CV effects check PFTs, LFTs, TFTs
FYI: cataracts (acts as a hapten), optic nerve damage, slow down HepC drugs
FYI new Class III drugs
Dronedarone: no iodine probs, high mort in CHF pts (black box)
Vernakalant: not out yet, some saying too dangerous in afib
Dofetilide SEs
TdP, especially due to high IV does, due to EADs
more than amiodarone
FYI: black box warning: hospitalize pt with defib. ready
FYI: Sotalol
blocks B-receptors as well as K+ channels, prevent arrhythmia recurrence (like amiodarone for pts ICD)
SEs: like B-blockers, TdP
Class IV drugs (CCBs: Verapamil, Diltiazem)
block CARDIAC voltage-sensitive L-type Ca2+ channels
mostly AV node (Ca2+-rich)
*phase 4: inhibits automaticity from influx of Ca2+ in AV node
*phase 0: Ca2+ influx for depolarization in heart (vs. Na+), suppress phase 0 slope, suppress conduction velocity, slow AP in AV node where most currents go thru, stop abnormal APs coming thru atria–>ventricle (SA node impulse will still get through-stronger)
phase 2 Ca2+ channels
extension of refractory period in phase 3: how? : secondary/indirect inhibition of late Ca2+-activated K+channels (less + charge flowing out)
more Class IV
error in BOARD books: will list Na+ in place of Ca2+ for AV node: wrong! AV node (also SA node) is Ca2+ dependent
FYI: why is voltage-sensitive important? (esp. phase 2): channels open up due to charges
FA: decrease conduction velocity, increase ERP, increase PR interval
Class IV uses
non-dihydr. CCBs
work well on AV nodal Ca2+currents
can stop atrial and AV nodal arrhythmias from reaching ventricles (SVTs>Varrhythmias)
also stop DAD formation even in ventricles
avoid if WPW accompanied by afib IV use
WPW may have reentry circuits that go from ventricle–>atria–>AV node–>back to ventricle
works for pure WPW to stop accessory pathway
works for pure afib
both: afib will go through ectopic node from atria–>ventricle if WPW and add class IV
FA: uses: prevention of nodal arrhythmias (SVT) rate control in afib
Class IV SEs
non-dihydr. CCBs
can decrease normal cardiac functions too much
negative inotropic action
don’t combo with B-blockers
FA: constipation, flushing, edema, CV effects (FA, AV block, sinus node depression)
Class II: B-blockers
similar to CCB actions (slow conduction thru AV node)
stop arrhythmias caused by high SNA and or high circulating catecholamines (pheochromocytoma)
FA: decrease SA and AV nodal activity by dec. cAMP–>dec. Ca2+ currents, suppress abnormal pacemakers by dec. slope of phase 4
diminish phase 4 depolarization, depress automaticity (nodal tissue), decrease phase 0 slope (slow conduction)
increase AP duration and ERP
aflutter, afib, AV nodal reentry tachycardia, prevent SVTs, suppress adrenergic-induced DADs
Class II SEs
B-blocker SEs
avoid combo w/ CCBs (too much suppression)
FA: Impotence, exacerbation of COPD and asthma, CV effects (bradycardia, AV block, HF), CNS effects (sedation, sleep alterations). May mask the signs of hypoglycemia.
Metoprolol can cause dyslipidemia.
Propranolol can exacerbate vasospasm in Prinzmetal angina.
β-blockers cause unopposed α1-agonism if given alone for pheochromocytoma or cocaine toxicity.
Treat β-blocker overdose with saline, atropine, glucagon.
MISCELLANEOUS antiarrhythmics
Digoxin
Adenosine
Magnesium
digoxin
may also cause arrhythmias (including TdP) as well as tx them
lidocaine IV used to stop digoxin ventricular arrhythmias
increases K+ current through Ca2+‐activated potassium channels due to the increased intracellular Ca++ caused by decreased Na/K‐ATPase activity: shortens AP duration and ERP but LENGTHENS ERP and DECREASES conduction velocity in AV node and purkinje fibers
protects ventricular rates in afib/flutter
Adenosine SEs
flushing, hypotension (FA)
SOB, related chest pain (bronchospasm, not cardiac)
get sense of impending doom! (remember Marshall)
FA: effects blunted by theophylline and caffeine (adenosine rec. antagonists)
Magnesium for…
Torsades de Point
FA: TdP and digoxin toxicity
future agents
stop ventricles from going thru anatomical changes that may cause arrhythmias:
ACE-inhibitors
ARBS
