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Pharmacology: Arrhythmias PC
JACOBSTues, Dec. 024:00 – 5:50 PM
PHPP 515 (IT‐I)Fall 2015
Required Reading (via Access Pharmacy)• Katzung: Chapters 14
Recommended Reading (via Access Pharmacy)• Goodman and Gilman: Chapter 29
1
Cardiac Conduction
SA node generates action potential and delivers to the atria
and AV node
AV node receives impulse and delivers to Purkinje fibers
Purkinje fibers conduct impulse to ventricles
Conduction also occurs between cardiomyocyteswhen adjacent cells are
depolarized 2
Cardiac Conduction
Nodal AP
Phase 4: PacemakerPotentialNa+ influx (if) Ca2+ influx (iCa(T))
“FUNNY” Na+ CURRENTTRANSIENT Ca2+ CURRENT
Phase 3: RepolarizationK+ efflux (iK)
OUTWARDPOTASSIUMCURRENTS
Phase 0: Upstroke(depolarization)Ca2+ influx (iCa(L))
LONG Ca2+CURRENT
CALCIUM DEPOLARIZATION
3
Cardiac Conduction
4
Na+ influx (if)
“FUNNY” OR “PACEMAKER”CURRENT (HCN)
Phase 4:Resting Potential(K+1, K+ACh)
INWARD RECTIFIER
Phase 0: UpstrokeNa+ influx (iNa)
FAST Na+ CURRENT
SODIUMDEPOLARIZATION
Phase 1: Partial RepolarizationK+ efflux (iKto)
TRANSIENT OUTWARD (TO)K+ CURRENT
Phase 2: PlateuCa2+ influx (iCa(L))K+ efflux (iKs)
LONG Ca2++ SLOW K+CURRENTS
Phase 3: RepolarizationK+ efflux (iKr)
DELAYED RECTIFIER
Effectiverefractory period
Ventricular AP• Bundle of His• Purkinje fibers• Ventricular Myocytes
3 Na+
2 K+
Na+/K+ ATPase
K+
Inward Rectifier(K+ channel)
4 mM
150 mM
K+out
Na+inK+in
Na+out
10 mM
140 mM
K+ HIGH IN
Na+ HIGH OUT
0 mV
‐94 mV
Cardiac ConductionMyocyte Resting Potential
Na+/K+ ATPase makes cell more negative (below ‐90 mV)Inward rectifier allows for inward K+ flow
(b/c below ‐94 mV charge drive > concentration drive)This keeps the ‘resting’ cell near the Eq potential for K+
5
Cardiac ConductionMyocyte Depolarization
Duration ofVentricular Depolarization
Q T
Goldfrank's Toxicologic Emergencies
Ventricular
(O) (I) (C)
“Fast Na+ Channels”Three States:• Open• Inactivated• Closed/Resting
Recovery from (I) to (C)is voltage‐dependent
6
What an ECG tells you about cardiac function:• HR = SA node AUTOMATICITY• PR‐interval = AV node CONDUCTION TIME• QRS duration = Ventricular CONDUCTION TIME• QT interval = Ventricular AP DURATION
Cardiac Conduction
7
Etiology of Arrhythmias:• Electrolyte imbalance (e.g. K+, Ca2+, Mg2+)• Drugs, toxins• Physical conditions:
Mutation or genetic polymorphisms in ion channels (channelopathy)
Nervous (sympathetic stimulation) Hormonal (hyperthyroidism) Cardiac ischemia Scarring, cardiomyopathies
Definition of Arrhythmias:• Abnormal heart rhythm (irregular heart beat). • Arises from abnormal impulse generation or conduction.
Arrhythmias
8
Different ways to classify Arrhythmias:• Heart Rate:
Normal Sinus Rhythm Tachycardia (fast HR) Bradycardia (slow HR)
• Location: Supraventricular (atria, SA node or AV node) Ventricular Junctional
• Mechanism: Abnormal impulse Abnormal conduction Both (impulse and conduction)
Arrhythmias
9
Arrhythmias
SupraventricularIf arrhythmia arises from
• SA node • AV node• Atrial foci
VentricularIf arrhythmia arises fromventricles
Junctional
By Location
10
ArrhythmiasBy Mechanism
Abnormal Impulse
Enhanced normalautomaticity
(sinus tachycardia)
Ectopicfocus
Heart Block Re‐entry
Automaticity Triggered Rhythms
Early after‐depolarization
Late after‐depolarization
Abnormal Conduction
11
Today’s main topics are in RED
12
ArrhythmiasBy Mechanism
Automaticity
Abnormal Impulse
Ectopicfocus Atrial or Ventricular Ectopic Pacemakers
Cause: Heart cells other than those of the SA node (at a specific site, or ‘focus’) depolarize faster than the SA node, and take over as the cardiac pacemaker.Example: multifocal atrial tachycardia (MAT), common in patients with COPD
13
Abnormal Conduction
Re‐entry
ArrhythmiasBy Mechanism
1. Atrial flutter (AFL)2. Supraventricular tachycardia (AVNRT and AVRT)
3. Ventricular tachycardia (VT)
AFL
AVRTAVNRT
VT
Anti‐Arrhythmic DrugsAnti‐arrhythmic drugs work in one of two ways:• Block specific ion channels• Alter autonomic function
Major goals to drug therapy:• Halt an ongoing arrhythmia• Prevent future arrhythmias
14
Anti‐Arrhythmic DrugsClasses of Anti‐Arrhythmics:
Vaughan‐Williams classification (1970)• Class I: Na+ channel blocker
(aka local anesthetics)• Class II: ‐blockers• Class III: K+ channel blocker• Class IV: Ca2+ channel blocker• Class V: Other
Anti‐Bradycardia Drugs:• ‐agonists• Anti‐muscarinics
15
16
Class I: Na+ channel blockersIa: Quinidine, Procainamide, Disopyramide (Norpace®)Ib: Lidocaine, Mexiletine (Mexitil®)Ic: Flecainide (Tambocor®), Propafenone (Rythmol®)
Class II: ‐blockersPropranolol, Atenolol, Metoprolol
Class III: K+ channel blockersAmiodarone, Dronedarone, Sotalol (Betapace AF®), Ibutilide (Corvert®)Dofetilide (Tikosyn®)
Class IV: Ca2+ channel blockersVerapamil, Diltiazem
Class V: OtherAdenosine, Digoxin
Anti‐Arrhythmic Drug List
17
Anti‐Arrhythmic DrugsCardiac Re‐EntryHow it Happens:
1. Multiple conduction pathways (branching point, marked with a star in the diagram)
2. Unidirectional conduction block (allows retrograde conduction of a cardiac impulse)
3. Retrograde conduction time > ERP: The time it takes for the impulse to back to the branch point must be greater than the ERP at branch point (but it is also typically faster than a new arriving impulse from above, meaning a local self‐sustaining cycle is generated)
Anti‐Arrhythmic DrugsApproaches to Halt Re‐Entry
18
1. INCREASE the Effective Refractory Period
1.
2. DECREASE Conduction Velocity
2.
Anti‐Arrhythmic Drugs
BLACK = w/o drugRED = w/drug
e.g. K+ channelblockers
1. INCREASE the Effective Refractory Period
19
w/ drug, repolarization is slowed, soNa+ channels are slower to reactivate,so the refractory period is prolonged
Approaches to Halt Re‐Entry
By prolonging the refractory period: the retrograde impulse is less likely to cause reentry, because the tissue at the branch‐point will still be in a refractory state
Anti‐Arrhythmic Drugs
20
2. DECREASE Conduction Velocitye.g. Na+ channelblockers(some)
Reduce the Phase 0 slope(rate of depolarization)
Approaches to Halt Re‐Entry
By decreasing conduction velocity: the retrograde impulse can be slowed enough to eventually “decay”. This can effectively “cut‐off” reentry.However, in some cases it may actually WORSEN re‐entry (depending on the type of arrhythmia) b/c “retrograde conduction time > ERP” is one of the contributing factors to re‐entry in the first place!
21
Anti‐Arrhythmic Drugs
Atrial flutter (AFL)
Atrial Flutter (AFL) and Atrial Fibrillation (AFib)
Fast atrial reentry Disorganized electrical activityAtrial fibrillation (AFib)
Rapid (ventricular) heart rate, depends upon:1. Atrial firing rate2. AV conduction ratio
1. RHYTHM CONTROL (Goal: Reduce Atrial Firing Rate)
atrial firingrate = 400
AV conductionratio = 2:1
ventricularrate = 200
Anti‐Arrhythmic DrugsApproaches to Treat AFL and AFib
AGENTS:• Class Ia,c• Class III
EFFECT:TREATS AFL/AFib SO FEWERIMPULSES ARE TRANSMITTED TO THE VENTRICLES
atrial firingrate = 200
ventricularrate = 100
22
AV conductionratio = 2:1
2. RATE CONTROL (Goal: Slow AV Node Conduction)
atrial firingrate = 400
AV conduction(ratio = 2:1)
ventricularrate = 200
Anti‐Arrhythmic Drugs
atrial firingrate = 400
EFFECT:SLOWS VENTRICULAR RATEBUT PATIENT STAYS IN AFL/AFib
AGENTS:• Class II• Class IV• Cardiac glycosides
(digoxin)
ventricularrate = 100
AV conduction(ratio = 4:1)
23
Approaches to Treat AFL and AFib
Because they bind ONLY to Open (O) or Inactivated (I) Na+ channels, these drugs are more effective when the heart is beating faster (tachycardia)
Drug
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
MOA: Bind ONLY to Open (O) or Inactivated (I) Na+ channelsPrevent recovery (to the closed/resting state)
Stuck in these statesuntil drug dissociated
24
Classified by Effects on the Action Potential
Note: These are NOT the only effect of these drugs
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
Class Ia ALSO block the delayed rectifier iKr (K+ channels) so they prolong the action potential by slowing repolarization
Slower drug dissociation = Slower depolarization (slope of Phase 0)Slower depolarization = Slower myocyte conduction (for Ia and Ic)
25
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
INCREASE AP DURATION
Caused by K+ channel blockade(an “off‐target” effect of Class Ia)
• Slower repolarization• QT interval• Risk of TDP• “Class III effect”
26
EFFECTS on Myocyte Action Potentials: Class Ia ONLY
27
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
EFFECTS on Myocyte Action Potentials: Class Ia and Ic ONLY
The more you can slow the depolarization of one cell (as shown in the myocyteaction potential), the slower the impulse propagatesthrough the cardiac tissue
Class Ia and Ic drugs slowdepolarization, so they alsoslow myocyte conduction rates
SLOW MYOCYTE CONDUCTION
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
SLOW MYOCYTE CONDUCTION
28
Blocking Na+ channels has MORE EFFECT ON MYOCYTE CONDUCTION and less effect on AV node conduction. Why? b/c AV Node depolarization is caused by Ca2+ entry (not sodium!)• Class Ic drugs MAY AV node conduction (esp. high doses) • Quinidine actually AV node conduction!
Conduction rate (in any tissue) is determined mainly by the Rate of depolarization
EFFECTS on Myocyte Action Potentials: Class Ia and Ic ONLY
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
Na+ channel recovery time constants: state (I) to state (C)• NO DRUG = 0.02 sec (normal recovery time)• CLASS Ia = 3.0 sec (quinidine) = 150x longer• CLASS Ib = 0.10 sec (lidocaine) = 5x longer• CLASS Ic = 11.0 sec (flecainide) = 550x longer
29
EFFECTS on Myocyte Action Potentials: Class Ia, Ib, Ic
DECREASE AUTOMATICITY ( ectopic pacemaker firing)w/o drug, Na+ channels are mostlyback in the (C) state and can be opened again
w/ drug, Na+ channels are stuck in the(O) or (I) states until later – this preventsopening and prevents early after‐depolarizations (EAD)
Class Ib
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
SELECTIVELY act on ischemic (depolarized) tissues
‐‐ ERP in normal His‐Purkinje and ventricular myocyte ERP in ischemic tissues (myocardial infarct), WHY??
Infarctzone,High [K+]out
ischemic RP = ‐60 mV(partly depolarized)normal RP
= ‐94 mV
30
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
These drugs (e.g. Lidocaine) ARE:• USE‐DEPENDENT: the more action potentials there are, the
more Na+ channels they inhibit• VOLTAGE‐DEPENDENT: means affinity for Na+ channels is higher
at depolarized potentials (bind better at ‐60 mV than ‐94 mV). Result = time constant for channel recovery‐94 mV, = 0.10s (FAST recovery) ‐60 mV, = 20.0s (VERY SLOW recovery)
(s)
Act somewhat like Class Ia or Icdrugs in MI tissues!
Class Ib
31
Anti‐Arrhythmic DrugsClass I agents (Na+ channel blockers)
Class Ia and Ic: Ventricular and Supraventricular arrhythmiasClass Ib: Ventricular arrhythmias ONLY ... WHY?
Also, Class I drugs have MORE effect on myocytes vs. nodes• Nodal depolarization = iCa(L)• Myocyte, His‐Purkinje depolarization = iNa
Because Class Ib drugs onlybind to (I) state channels
and atrial Na+ channelsspend much less timein the (I) state than Purkinje fibers andventricular myocytes
32
Anti‐Arrhythmic Drugs
WARNINGS:1. ALL Class I agents (Ia, Ib, Ic) have a NEGATIVE INOTROPIC effect
(decrease cardiac contractility) Disopyramide = worstThis effect can precipitate heart failure.
2. ALL Class I agents (Ia, Ib, Ic) can have PRO‐ARRHYTHMIC effects(exacerbation in 10‐15% of life‐threatening arrhythmias)
3. DANGEROUS INTERACTION: Quinidine + DigoxinQuinidine binds to the same sites in tissuesas digoxin. This lowers the apparent Vd of digoxin,raising its plasma concentrations to toxic levels.DOSE REDUCTION of digoxin is necessary!
This is dangerous, but not stated in all electronic resources!
Class I agents (Na+ channel blockers)
33
Anti‐Arrhythmic Drugs
COMPARISON OF CLASSESClass Ia: Quinidine, Procainamide, Disopyramide (Norpace®)
Binding preference: OPENRecovery rate (recovery) = 1‐10 sec (SLOW)
= time for 63% recovery (1‐1/e)Effects:
Ectopic Pacemaker Firing (Automaticity)Myocyte Conduction Effective Refractory Period (ERP)
ECG: QRS (widened) QT interval (risk of TDP)
Class I agents (Na+ channel blockers)
34
Anti‐Arrhythmic Drugs
COMPARISON OF CLASSESClass Ib: Lidocaine, Mexiletine (Mexitil®)
Binding preference: INACTIVERecovery rate (recovery) < 1 sec (VERY FAST)
= time for 63% recovery (1‐1/e)Effects:
Ectopic Pacemaker Firing (Automaticity)‐‐ Myocyte Conduction‐‐ ERP in normal His‐Purkinje and ventricular myocytes, but ERP in ischemic tissues (i.e. myocardial infarct)
ECG: minor effect
Class I agents (Na+ channel blockers)
35
Anti‐Arrhythmic Drugs
COMPARISON OF CLASSESClass Ic: Flecainide (Tambocor®), Propafenone (Rythmol®)
Binding preference: OPENRecovery rate (recovery) > 10 sec (VERY SLOW)
= time for 63% recovery (1‐1/e)Effects:
Ectopic Pacemaker Firing (Automaticity)Myocyte Conduction ERP
ECG: QRS (widened, effect is > than Ia drugs)
(average QRS increase = 25%, but may be up to 150%)‐‐ QT interval, minor or no effect
Class I agents (Na+ channel blockers)
36
Anti‐Arrhythmic DrugsClass Ia
QuinidineAdmin: IV, ORAL (usual route) as gluconate or sulfate formsUse: RARELY used: AFib, atrial flutter, sustained ventricular
arrhythmiasOTHER Pharmacology:
a. iKr blockerb. Anticholinergic (Stimulates AV Node)
Inhibition of mACh receptors ERP in AV node (allows faster AV node conduction rates!)
c. Alpha‐blocker (hypotension + sinus tachycardia)Warning: Pro‐arrhythmic effect ( QTc interval = risk of TDP)
Other arrhythmias can also occur: extrasystoles, ventricular tachycardia, flutter, and fibrillation.
37
Anti‐Arrhythmic Drugs
QuinidineAdverse Effects:
Diarrhea (most common)Cinchonism (quinidine overdose = HA, dizziness, tinnitus)
Oral Bioavailability: 70‐80%Half‐life: 6‐8 hrMetabolism: CYP3A4
CYP3A4 inhibitors increase quinidine levelsCYP3A4 inducers decrease quinidine levels
Inhibits: CYP2D6Quinidine increases CYP2D6 substrates (e.g. thioridazine)Quinidine reduces the activation of CYP2D6‐metabolized
prodrugs (e.g. codeine, tamoxifen)
Class Ia
38
Anti‐Arrhythmic DrugsClass Ia
QuinidineDANGER SCENARIO: caused by AV conduction (anticholinergic)
SVT Untreated
atrial firingrate = 450
AV conductionratio = 3:1
ventricularrate = 150
VentricularRate (flutter)
+ Quinidine
atrial firingrate = 300
AV conduction(ratio = 1:1)
ventricularrate = 300
39
Anti‐Arrhythmic DrugsClass Ia
ProcainamideAdmin: IV, IMUse: Atrial and ventricular arrhythmiasOTHER Pharmacology:
a. iKr blocker: N‐acetylprocainamide (aka NAPA)(metabolite)
Warning: Pro‐arrhythmic effect ( QTc interval = risk of TDP)• Some patients rapidly acetylate procainamide to develop
high levels of NAPA (= higher risk of TDP)• NAPA is eliminated by the kidneys
(renal failure = higher risk of TDP)
40
ProcainamideAdverse Effects:
Lupus‐like syndrome (ANA titer common after long‐term use, >1 year = 25% of patients)
Oral Bioavailability: 85% (oral route NOT in US)Half‐life: 2‐5 hr (NAPA: 6‐8 hr, longer w/ renal failure)Metabolism: Two major pathways
1. Hepatic acetylation (N‐acetyltranferase)(use with caution in fast acetylators)
2. Hepatic oxidation by CYP2D6CYP2D6 inhibitors may increase procainamide levels (but effect is minor b/c acetylation pathway stays active)
Anti‐Arrhythmic DrugsClass Ia
41
Anti‐Arrhythmic DrugsClass Ia
DisopyramideAdmin: ORALUse: Life‐threatening ventricular arrhythmias, paroxysmal SVTOTHER Pharmacology:
a. iKr blocker: parent drugb. Anticholinergic: N‐dealkyldisopyramide (MND)
(metabolite) – but unlike quinidine, itdoes NOT affect AV conduction ratesAdverse effects of MND:• Precipitation of glaucoma• Constipation• Dry mouth• Urinary retention
42
DisopyramideAdverse Effects:
Anticholinergic (caused by MNDmetabolite)Oral Bioavailability: good (% not reported)Half‐life: 4‐10 hrMetabolism: Hepatic dealkylation by CYP3A4
(to major metabolite, MND)Caution with strong CYP3A4 inhibitors or inducers
Anti‐Arrhythmic DrugsClass Ia
43
Class IbAnti‐Arrhythmic Drugs
LidocaineAdmin: IV, IMUse: VENTRICULAR arrhythmias (post‐MI)
NOT effective against SVTWarning:• Some patients have hypersensitive to amide‐based
local anesthetics (like lidocaine)Overdose toxicity:• Light‐headedness• Tinnitus• Metallic taste• Numbness (around the lips)• Twitching, convulsions (effect on CNS motor control)
44
LidocaineOral Bioavailability: 35% (HIGH first pass – ORAL not used)Half‐life: 1.5‐2 hrMetabolism: Hepatic N‐dealkylation by CYP1A2
Two active metabolites:• monoethylglycinexylidide (MEGX)• glycinexylidide (GX)
Excretion: Renal (90% as metabolites)MGEX and GX may accumulate in renal failure and cause the toxicities shown on previous slide
Class IbAnti‐Arrhythmic Drugs
45
Class IbAnti‐Arrhythmic Drugs
MexiletineAdmin: ORALUse: Ventricular arrhythmias (post‐MI)
NOT effective against SVTWarning:• Some patients have hypersensitive to amide‐based
local anesthetics (like lidocaine)Overdose toxicity: same as lidocaineBioavailability: 80‐95% (LOW first pass effect)Metabolism: CYP1A2 and CYP2D6
(inhibitors of either will mexilitine levels)
46
Class IcAnti‐Arrhythmic Drugs
FlecainideAdmin: ORALUse: SVT in patients w/no history of MIWarning:• Flecainide SLOWS AV node conduction and can cause
first‐degree AV block or other conduction blocks• May cause sinus bradycardia, sinus pause or sinus arrest
(sick sinus syndrome). Although effect is use‐dependent,it can be overcome at high trough plasma levels.
47
Class IcAnti‐Arrhythmic Drugs
Flecainide
Note: For Class Ic drugs the length of the QRS complex is increased but the QT interval is NOT increased.
Therefore TDP is less likely than Class Ia drugs.
Oral Bioavailability: 95%Half‐life: 12‐27 hrMetabolism: Hepatic by CYP2D6
(inhibitors of either will increase flecainide levels)
48
Class IcAnti‐Arrhythmic Drugs
PropafenoneAdmin: ORALUse: SVT in patients w/no history of MIOTHER Pharmacology:
a. ‐blocker (both the parent drug and N‐dealkylatedmetabolite are structurally similar to ‐blockers)
Warning:• Propafenone slows AV conduction and can cause
first‐degree AV block or other conduction blocks• ‐blocker effect can worsen heart function in CHF patients
Oral Bioavailability: LOW (3‐21%) due to HIGH first passHalf‐life: 2‐10 hr
49
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
MOA: Prevent or terminate tachycardia caused by:1. Elevated sympathetic tone2. Elevated local or circulating catecholamines3. Elevated responsiveness to catecholamines
1NE = EPI
Chronotropy (HR)
Inotropy (Contraction)
Dromotropy (Conduction)
‐blockers Effects
50
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
1
NE, EPI
Gs
ACATP
cAMP PKA
Ca2+
Ca2+
Na+
Na+if (aka ih) and iCa(T)
“pacemaker currents”
Result: IncreasedAutomaticity
51
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
Automaticity (firing rate) of AV Node(by blocking catecholamine stimulation of if and iCa(T))
AV Node AP
Effect on AV Node is > thaneffect on Purkinje fibersor Myocyte automaticity
52
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
AV Node AP
A. The Ca2+ that enters the cell inphase 0 has to be pumped backout to maintain ion homeostasis.
Ca2+ATP
ADP
B. In the AV node, a Ca2+ ATPase pumpsit back out.
C. In ischemic (ATP‐depleted) cells,the ATPase does not pump as much Ca2+ out, so this enhances AV node automaticity (firing rate).
D. ‐blockers lower automaticity by blocking iCa(T) transient inward calcium currents, raising time between spontaneous firing.
Reduce risk of arrhythmiasin patients with MI
53
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
Use: • RATE CONTROL (reduce conduction through AV node) in SVT• Warnings
FOR ALL ‐blockers:• Abrupt discontinuation can cause angina (in some cases, MI)• May exacerbate CHF (sympathetic tone can be
compensating HF – take that away and it worsens)• May “mask” some signs of hypoglycemia
FOR NONSPECIFIC ‐blockers:• Bronchospasm (2 effect)‐may be dangerous in patients
with emphysema or asthma
54
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
Contraindications (FOR ALL ‐blockers):• Cardiogenic shock• Sinus bradycardia• Greater than first degree block• Bronchial asthma• Some patients are hypersensitive to ‐blockers
(and EPI is not very useful in treating hypersensitivity!)
55
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
Adverse Effects: • NEGATIVE INOTROPIC EFFECT• Bradycardia• Exacerbation of CHF (at higher doses)• Worsening of AV block• Hypotension, Dizziness, Paresthesias
Interactions (FOR ALL and blockers): • Combination with Ca2+ Channel blockers can
cause bradycardia or heart block• Epinephrine (e.g. bee sting kits) may cause high BP
if used in patients taking ‐blockers• ‐blockers can decrease the hepatic metabolism of
lidocaine and increase lidocaine toxicity. This is because‐blockers reduce hepatic perfusion (blood flow) 56
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
PropranololPharmacology: Non‐selective 1 and 2 blockerAdmin: ORAL, IVOral Bioavailability: 25% (HIGH first pass)Half‐life: about 4 hrMetabolism: Hepatic by CYP1A2 and CYP2D6
Active metabolite: 4‐hydroxypropranololExcretion: Urine (>99% metabolites)
NO Dose reduction is necessary in renal impairment
57
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
AtenololPharmacology: Selective 1 (i.e. more cardio‐selective)Admin: ORALOral Bioavailability: 40‐50% (poor absorption)Half‐life: 6‐7 hrMetabolism: MINIMAL (<10% is metabolized)Excretion: Urine (unchanged drug)
Dose reduction necessary in renal impairment
58
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
MetoprololPharmacology: Selective 1 (i.e. more cardio‐selective)Admin: ORALOral Bioavailability: 50% (HIGH first pass)Half‐life: 6‐7 hrMetabolism: Hepatic CYP2D6
CYP2D6 poor metabolizers have reduced drug clearanceExcretion: Urine (metabolites)
NO Dose reduction is necessary in renal impairment
59
1. Some ‐blockers reverse cardiac remodeling caused by chronic elevation of sympathetic tone in patients with systolic heart failure. Ejection fraction typically increases significantly after several months of low dose beta blocker therapy.(bisoprolol, carvedilol, metorpolol ER)
2. ‐blockers are also useful for diastolic heart failure (heart failure with normal ejection fraction). This is because reducing HR can help increase diastolic filing.
Anti‐Arrhythmic DrugsClass II agents (‐blockers)
They are also useful for CHF:
60
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
MOA: Block the potassium delayed rectifier (iKr) currentEffect: Slower repolarization = Longer action potential
AP Duration
Prolonged action potential duration = Longer refractory period
(since the Nav1.5 inactivation gate blocks Na+current as long as the cell remains depolarized)
Prolonged AP= Longer QTc= Risk of TDP (except amiodarone)
61
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Requirements for Cardiac Re‐entry1. Multiple conduction pathways2. Unidirectional conduction block 3. Conduction time > ERP
Class III drugs:• Increase ERP (refractory period)
so it becomes > conduction time(i.e. NO MORE RE‐ENTRY)NO effect on conduction time (for a “pure” K+ channel blocker)
unidirectionalconduction block
62
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)Different from the Class I drugs:
Class III drugs produce LESS EFFECTon ischemic tissue vs. normal tissue(for multiple reasons)
But, they ARE effective in preventing re‐entry becausethey the ERP of normal tissue.
When the re‐entrant impulsearrives at this point, it is ‘cut‐off’because the cells are still refractory.
63
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Uses: • RHYTHM CONTROL (prolonging the action potential reduces
atrial firing rate) in SVT• Ventricular reentrant tachycardiasAmioradone (Cordarone®)Pharmacology:
1. K+ channel blockerAlso:
2. Na+ channel blocker (Class I effect)3. Ca2+ channel blocker (Class IV effect)4. Non‐selective ‐blocker (Class II effects)5. Thyroid hormone‐like effects (feedback‐like
effect on thyroid gland causes inhibition of T3 and T4 synthesis – may explain some effects)
64
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Amioradone• Although it is used for RHYTHM CONTROL
it ALSO has some RATE CONTROL effects (Class II and IV)
• Has LESS RISK OF TDP than other K+ channel blockers
Admin: ORAL, IVOral Bioavailability: 35‐65% (increased by food)Half‐life: 40‐55 days (LONG!)Metabolism: Hepatic CYP2C8 and CYP3A4
Major metabolite = desethylamiodarone (may be active)Excretion: Fecal (metabolites)
65
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Amioradone (Cordarone®)Other notable effects:• Peripheral vasodilation (esp. w/IV admin)• Interstitial Lung Disease (ILD) and risk of pulmonary
fibrosis with prolonged use (esp. at high doses that are now avoided)
• Hypothyroidism (inhibits T3 and T4 synthesis) Dronedarone is an analog that lacks iodone and does NOT have the thyroid effects of amiodarone
• Photodermatitis (deposition of drug in skin – turns gray when exposed to sunlight)
• Corneal microdeposits of drug (common but benign)
66
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Sotalol (Betapace AF®) – racemic (R,S)Pharmacology:
1. K+ channel blocker: R‐sotalol2. Nonselective ‐blockers: R‐sotalol, S‐sotalol
(Class II effect)Admin: ORAL, IVOral Bioavailability: 95%Half‐life: 12 hrMetabolism: NONEExcretion: Renal (unchanged)
Dose reduction necessary in renal impairmentWarning: SIGNIFICANT RISK of TDP (2%)
67
Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Ibutilide (Corvert®)Use: • Acute CARDIOCONVERSION of RECENT ONSET SVT
(conversion back to normal sinus rhythm)Pharmacology: “PURE” Class III
1. K+ channel blockerAdmin: IVHalf‐life: 6 hrMetabolism: HepaticExcretion: Renal (metabolites)Warning: SIGNIFICANT RISK of TDP (at high doses)
68
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Anti‐Arrhythmic DrugsClass III agents (K+ channel blockers)
Dofetilide (Tikosyn®)Use (restricted access)• Maintenance of normal sinus rhythm in patients with
recurrent atrial flutter/fibrillation following cardioversionPharmacology: “PURE” Class III
1. K+ channel blocker – no effect on other channels at clinically relevant concentrations.
Admin: ORAL (capsules), Bioavailability: >90%Half‐life: 10 hrExcretion: Renal (parent drug) – MONITOR CrCl!BOXED Warning: SIGNIFICANT RISK of Ventricular Arrhythmias (QTc prolongation) and sudden death. MONITOR patients closely when (re‐)initiating therapy
Anti‐Arrhythmic DrugsClass IV agents (Ca2+ channel blockers)
AV Node AP
MOA: Block the L‐type calcium channels
Opening of L‐type calcium channels is what causes depolarization in the AV node
Effect: Raise threshold for depolarization
By blocking iCa(L) currents, Class IV agents SLOW the firing (conduction) of the AV node = RATE CONTROL
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Anti‐Arrhythmic DrugsClass IV agents (Ca2+ channel blockers)
Use: • RATE CONTROL (slow AV node conduction in SVT)• Suppression of AV reentrant arrhythmiasAdverse effects: • NEGATIVE INOTROPIC EFFECT• Constipation (common with verapamil)• Hypotension• Bradycardia• AV conduction block
Interactions• Combination with ‐blockers can
cause BRADYCARDIA or HEART BLOCK!
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Anti‐Arrhythmic DrugsClass IV agents (Ca2+ channel blockers)
Verapamil (Calan®, Isoptin®, Verelan®)Pharmacology:
1. Ca2+ channel blocker (at a different site than nifedipine or diltiazem)
Admin: ORAL, IVOral Bioavailability: 20‐35% (HIGH first pass)Half‐life: 3‐8 hrMetabolism: Hepatic (extensive, by several P450 isozymes)Excretion: Renal (metabolites)
Other Class IV drug: Diltiazem (similar efficacy)
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Anti‐Arrhythmic DrugsClass V agents (Other)
Adenosine (Adenocard®)
A1
Ado
PKA
Ca2+
Ca2+
Na+
Na+if (aka ih) and iCa(T)
“pacemaker currents”
Result: DecreasedAutomaticitySignaling path is:OPPOSITE toEPI and NE, andSAME as ACh
Gi
ACATP
cAMP73
Anti‐Arrhythmic DrugsClass V agents (Other)
Adenosine (Adenocard®)Use: • Drug‐induced CARDIOCONVERSION of acute AV node reentry
(back to normal sinus rhythm)Pharmacology:
1. A1 receptor agonist• Effect is VERY SHORT LIVED (t1/2 = seconds)• Effect on AV Node is SAME AS ACh• Effect on AV conduction is SAME as Class II drugs
(‐blockers) but the effect of Ado is MORE ACUTE
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Anti‐Arrhythmic Drugs
AdenosineAdmin: IV bolusOral Bioavailability: 0%Half‐life: secondsMetabolism: in blood and tissue to inosine, then to AMP,
then to hypoxanthineAdverse effects:• Arrhythmias (common, >50% of patients)• Bronchoconstriction (use with caution in patients
with asthma or COPD)• Heart block
Class V agents (Other)
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Anti‐Arrhythmic DrugsClass V agents (Other)
Digoxin
POSITIVE INOTROPIC EFFECTIntracellular calcium levels (and SR stores) are increased(indirectly by stimulating the Na+/Ca2+ exchanger)
BUT WHY IS IT “ANTI‐ARRHYTHMIC”?Because it INCREASES VAGAL TONE (ACh)(various mechanisms unrelated to inotropic effect)
USEFUL for RATE CONTROL (slowing AV Conduction)esp. for patients with systolic HF
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