PHPP 515 (IT I) Fall 2015 JACOBS Dec. 02 · Required Reading (via Access Pharmacy) • Katzung:...

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


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


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


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


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



22


2. RATE CONTROL (Goal: Slow AV Node Conduction)


AV conduction(ratio = 2:1)




EFFECT:SLOWS VENTRICULAR RATEBUT PATIENT STAYS IN AFL/AFib

AGENTS:• Class II• Class IV• Cardiac glycosides

(digoxin)



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


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


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


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


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


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


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


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


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


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


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)


34


COMPARISON OF CLASSESClass Ib: Lidocaine, Mexiletine (Mexitil®)

Binding preference: INACTIVERecovery rate (recovery) < 1 sec (VERY FAST)


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


35


COMPARISON OF CLASSESClass Ic: Flecainide (Tambocor®), Propafenone (Rythmol®)

Binding preference: OPENRecovery rate (recovery) > 10 sec (VERY SLOW)


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


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


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


QuinidineDANGER SCENARIO: caused by AV conduction (anticholinergic)

SVT Untreated




VentricularRate (flutter)

+ Quinidine




39


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)


41


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


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


45


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


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


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


1

NE, EPI

Gs

ACATP

cAMP PKA

Ca2+

Ca2+

Na+

Na+if (aka ih) and iCa(T)

“pacemaker currents”

Result: IncreasedAutomaticity

51


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


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


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


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


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


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


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


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.


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


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


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


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


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


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


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

69


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

70


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!

71


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)

72

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


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

74


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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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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PHPP 515 (IT I) Fall 2015 JACOBS Dec. 02 · Required Reading (via Access Pharmacy) • Katzung:...

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