Pharmacology: Arrhythmias PC PHPP 515 (IT‐I) Fall 2014
JACOBS Wed, Dec. 03 4:00 –5:50 PM Required Reading (via Access Pharmacy) • Katzung: Chapters 14 Recommended Reading (via Access Pharmacy) • Goodman and Gilman: Chapter 29 1 Cardiac Conduction
SA node generates AV node receives action potential and impulse and delivers delivers to the atria to Purkinje fibers and AV node
Conduction also occurs between cardiomyocytes Purkinje fibers conduct when adjacent cells are impulse to ventricles depolarized 2 Cardiac Conduction
Nodal AP Phase 0: CALCIUM DEPOLARIZATION Upstroke LONG Ca2+ (depolarization) CURRENT 2+ Phase 3: Ca influx (iCa(L)) Repolarization + K efflux (iK) OUTWARD POTASSIUM Phase 4: CURRENTS Pacemaker Potential + Na influx (if) 2+ Ca influx (iCa(T)) “FUNNY” Na+ CURRENT TRANSIENT Ca2+ CURRENT
3 Cardiac Conduction Ventricular AP Phase 1: Partial TRANSIENT • Bundle of His Repolarization OUTWARD (TO) • Purkinje fibers + K+ CURRENT K efflux (iKto) • Ventricular Myocytes
Phase 0: Phase 2: Plateu LONG Ca2+ 2+ + Upstroke Ca influx (iCa(L)) + SLOW K + + K efflux (iKs) CURRENTS Na influx (iNa) FAST Na+ CURRENT SODIUM Phase 3: Repolarization DEPOLARIZATION + K efflux (iKr)
Phase 4: DELAYED RECTIFIER Resting Potential + + Effective (K 1, K ACh) Na+ influx (i ) refractory period f INWARD RECTIFIER “FUNNY” OR “PACEMAKER” CURRENT (HCN)4 Cardiac Conduction Myocyte Resting Potential Na+ HIGH OUT Na+/K+ ATPase 3 Na+ Inward Rectifier K+ Na+ (K+ channel) out out 4mM 140 mM 0 mV
150 mM 10 mM ‐94 mV 2 K+ + + + K K in Na in
K+ HIGH IN 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 Conduction Myocyte Depolarization Recovery from (I) to (C) is voltage‐dependent “Fast Na+ Channels” Three States: • Open • Inactivated • Closed/Resting (O) (I) (C)
Ventricular
Goldfrank's Toxicologic Emergencies Duration of QTVentricular
Depolarization 6 Cardiac Conduction 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
7 Arrhythmias Definition of Arrhythmias: • Abnormal heart rhythm (irregular heart beat). • Arises from abnormal impulse generation or conduction.
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
8 Arrhythmias 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)
9 By Location Arrhythmias
Supraventricular If arrhythmia arises from • SA node • AV node Junctional • Atrial foci
Ventricular If arrhythmia arises from ventricles 10 By Mechanism Arrhythmias Abnormal Impulse
Automaticity Triggered Rhythms
Enhanced normal Ectopic Early after‐ Late after‐ automaticity focus depolarization depolarization (sinus tachycardia) Today’s main topics are in RED Abnormal Conduction
Heart Block Re‐entry 11 By Mechanism Arrhythmias
Abnormal Impulse
Automaticity
Ectopic focus 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
12 By Mechanism Arrhythmias
Abnormal Conduction AFL Re‐entry
1. Atrial flutter (AFL) 2. Supraventricular tachycardia (AVNRT and AVRT) AVNRT AVRT 3. Ventricular tachycardia (VT)
VT
13 Anti‐Arrhythmic Drugs Anti‐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 Drugs Classes 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 Anti‐Arrhythmic Drug List Class I: Na+ channel blockers Ia: Quinidine, Procainamide, Disopyramide (Norpace®) Ib: Lidocaine, Mexiletine (Mexitil®) Ic: Flecainide (Tambocor®), Propafenone (Rythmol®) Class II: ‐blockers Propranolol, Atenolol, Metoprolol Class III: K+ channel blockers Amiodarone, Dronedarone, Sotalol (Betapace AF®), Ibutilide (Corvert®) Class IV: Ca2+ channel blockers Verapamil, Diltiazem Class V: Other Adenosine, Digoxin
16 Anti‐Arrhythmic Drugs Cardiac Re‐Entry How 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)
17 Anti‐Arrhythmic Drugs Approaches to Halt Re‐Entry 1. INCREASE the Effective Refractory Period 2. DECREASE Conduction Velocity
1. 2.
18 Anti‐Arrhythmic Drugs Approaches to Halt Re‐Entry 1. INCREASE the Effective Refractory Period e.g. K+ channel w/ drug, repolarization is slowed, so blockers Na+ channels are slower to reactivate, so the refractory period is prolonged
BLACK = w/o drug RED = w/drug
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
19 Anti‐Arrhythmic Drugs Approaches to Halt Re‐Entry 2. DECREASE Conduction Velocity e.g. Reduce the Phase 0 slope Na+ channel (rate of depolarization) blockers (some)
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! 20 Anti‐Arrhythmic Drugs Atrial Flutter (AFL) and Atrial Fibrillation (AFib)
Atrial flutter (AFL) Atrial fibrillation (AFib) Fast atrial reentry Disorganized electrical activity Rapid (ventricular) heart rate, depends upon: 1. Atrial firing rate 2. AV conduction ratio
21 Anti‐Arrhythmic Drugs Approaches to Treat AFL and AFib 1. RHYTHM CONTROL (Goal: Reduce Atrial Firing Rate) atrial firing atrial firing rate = 400 rate = 200 AV conduction AV conduction ratio = 2:1 ratio = 2:1
ventricular ventricular rate = 200 rate = 100
AGENTS: EFFECT: • Class Ia,c TREATS AFL/AFib SO FEWER • Class III IMPULSES ARE TRANSMITTED TO THE VENTRICLES 22 Anti‐Arrhythmic Drugs Approaches to Treat AFL and AFib 2. RATE CONTROL (Goal: Slow AV Node Conduction) atrial firing atrial firing rate = 400 rate = 400 AV conduction AV conduction (ratio = 2:1) (ratio = 4:1)
ventricular ventricular rate = 200 rate = 100
AGENTS: EFFECT: • Class II SLOWS VENTRICULAR RATE • Class IV BUT PATIENT STAYS IN AFL/AFib • Cardiac glycosides (digoxin) 23 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) MOA: Bind ONLY to Open (O) or Inactivated (I) Na+ channels Prevent recovery (to the closed/resting state)
Drug
Stuck in these states until drug dissociated
Because they bind ONLY to Open (O) or Inactivated (I) Na+ channels, these drugs are more effective when
the heart is beating faster (tachycardia) 24 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers)
Classified by Effects on the Action Potential
Note: These are NOT the only effect of these drugs
Slower drug dissociation = Slower depolarization (slope of Phase 0) Slower depolarization = Slower myocyte conduction (for Iaand Ic)
+ Class Ia ALSO block the delayed rectifier iKr (K channels) so they prolong the action potential by slowing repolarization 25 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) EFFECTS on Myocyte Action Potentials: Class IaONLY
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 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) EFFECTS on Myocyte Action Potentials: Class IaandIcONLY SLOW MYOCYTE CONDUCTION The more you can slow the depolarization of one cell (as shown in the myocyte action potential), the slower the impulse propagates through the cardiac tissue
Class Ia and Ic drugs slow depolarization, so they also slow myocyte conduction rates
27 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) EFFECTS on Myocyte Action Potentials: Class IaandIcONLY SLOW MYOCYTE CONDUCTION Conduction rate (in any tissue) is determined mainly by the Rate of depolarization
Blocking Na+ channels has MORE EFFECT ON MYOCYTE CONDUCTION and less effect on AV node conduction. Why? AV Node depolarization is caused by Ca2+ entry (not sodium) Class Icdrugs MAY AV node conduction (esp. high doses) Quinidine actually AV node conduction!
28 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) EFFECTS on Myocyte Action Potentials: Class Ia, Ib, Ic DECREASE AUTOMATICITY ( ectopic pacemaker firing) w/o drug, Na+ channels are mostly back in the (C) state and can be opened again
w/ drug, Na+ channels are stuck in the (O) or (I) states until later –this prevents opening and prevents early after‐ depolarizations (EAD) 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 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) Class Ib SELECTIVELY act on ischemic (depolarized) tissues
ischemic RP = ‐60 mV normal RP (partly depolarized) = ‐94 mV Infarct zone, + High [K ]out
‐‐ ERP in normal His‐Purkinje and ventricular myocyte ERP in ischemic tissues (myocardial infarct), WHY??
30 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) Class Ib 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)
Act somewhat (s) like Class Ia or Ic drugs in MI tissues!
31 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) Class IaandIc: Ventricular and Supraventricular arrhythmias Class Ib: Ventricular arrhythmias ONLY ... WHY? Because Class Ib drugs only bind to (I) state channels
and atrial Na+ channels spend much less time in the (I) state than Purkinje fibers and ventricular myocytes
Also, Class I drugs have MORE effect on myocytes vs. nodes
• Nodal depolarization = iCa(L) • Myocyte, His‐Purkinje depolarization = iNa 32 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) WARNINGS: 1. ALL Class I agents (Ia, Ib, Ic) have a NEGATIVE INOTROPIC effect (decrease cardiac contractility) Disopyramide = worst This 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 + Digoxin Quinidine binds to the same sites in tissues
as 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! 33 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) COMPARISON OF CLASSES Class Ia: Quinidine, Procainamide, Disopyramide (Norpace®) Binding preference: OPEN
Recovery 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 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) COMPARISON OF CLASSES Class Ib: Lidocaine, Mexiletine (Mexitil®) Binding preference: INACTIVE
Recovery 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
35 Anti‐Arrhythmic Drugs Class I agents (Na+ channel blockers) COMPARISON OF CLASSES Class Ic: Flecainide (Tambocor®), Propafenone (Rythmol®) Binding preference: OPEN
Recovery 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 Iadrugs) (average QRS increase = 25%, but may be up to 150%) ‐‐ QT interval, minor or no effect 36 Anti‐Arrhythmic Drugs Class Ia Quinidine Admin: IV, ORAL (usual route) as gluconate or sulfate forms Use: RARELY used: AFib, atrial flutter, sustained ventricular arrhythmias OTHER Pharmacology:
a. iKr blocker b. 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 Class Ia Quinidine Adverse Effects: Diarrhea (most common) Cinchonism (quinidine overdose = HA, dizziness, tinnitus) Oral Bioavailability: 70‐80% Half‐life: 6‐8 hr Metabolism: CYP3A4 CYP3A4 inhibitors increase quinidine levels CYP3A4 inducers decrease quinidine levels Inhibits: CYP2D6 Quinidine increases CYP2D6 substrates (e.g. thioridazine) Quinidine reduces the activation of CYP2D6‐metabolized prodrugs (e.g. codeine, tamoxifen) 38 Anti‐Arrhythmic Drugs Class Ia Quinidine DANGER SCENARIO: caused by AV conduction (anticholinergic) atrial firing atrial firing rate = 450 rate = 300 AV conduction AV conduction ratio = 3:1 (ratio = 1:1)
ventricular ventricular rate = 150 rate = 300 SVT Untreated + Quinidine
Ventricular Rate (flutter) 39 Anti‐Arrhythmic Drugs Class Ia Procainamide Admin: IV, IM Use: Atrial and ventricular arrhythmias OTHER 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 Anti‐Arrhythmic Drugs Class Ia Procainamide Adverse 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 CYP2D6 CYP2D6 inhibitors may increase procainamide levels (but effect is minor b/c acetylation pathway stays active) 41 Anti‐Arrhythmic Drugs Class Ia Disopyramide Admin: ORAL Use: Life‐threatening ventricular arrhythmias, paroxysmal SVT OTHER Pharmacology:
a. iKr blocker: parent drug b. Anticholinergic: N‐dealkyldisopyramide (MND) (metabolite) – but unlike quinidine, it does NOT affect AV conduction rates Adverse effects of MND: • Precipitation of glaucoma • Constipation • Dry mouth • Urinary retention 42 Anti‐Arrhythmic Drugs Class Ia Disopyramide Adverse Effects: Anticholinergic (caused by MND metabolite) Oral Bioavailability: good (% not reported) Half‐life: 4‐10 hr Metabolism: Hepatic dealkylation by CYP3A4 (to major metabolite, MND) Caution with strong CYP3A4 inhibitors or inducers
43 Anti‐Arrhythmic Drugs Class Ib Lidocaine Admin: IV, IM Use: VENTRICULAR arrhythmias (post‐MI) NOT effective against SVT Warning: • 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 Anti‐Arrhythmic Drugs Class Ib Lidocaine Oral Bioavailability: 35% (HIGH first pass –ORAL not used) Half‐life: 1.5‐2 hr Metabolism: 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 Anti‐Arrhythmic Drugs Class Ib Mexiletine Admin: ORAL Use: Ventricular arrhythmias (post‐MI) NOT effective against SVT Warning: • Some patients have hypersensitive to amide‐based local anesthetics (like lidocaine) Overdose toxicity: same as lidocaine Bioavailability: 80‐95% (LOW first pass effect) Metabolism: CYP1A2 and CYP2D6 (inhibitors of either will mexilitine levels)
46 Anti‐Arrhythmic Drugs Class Ic Flecainide Admin: ORAL Use: SVT in patients w/no history of MI Warning: • 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 Anti‐Arrhythmic Drugs Class Ic Flecainide Note: For Class Icdrugs the length of the QRS complex is increased but the QT interval is NOT increased. Therefore TDP is less likely than Class Iadrugs.
Oral Bioavailability: 95% Half‐life: 12‐27 hr Metabolism: Hepatic by CYP2D6 (inhibitors of either will increase flecainide levels)
48 Anti‐Arrhythmic Drugs Class Ic Propafenone Admin: ORAL Use: SVT in patients w/no history of MI OTHER Pharmacology: a. ‐blocker (both the parent drug and N‐dealkylated metabolite 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 pass Half‐life: 2‐10 hr
49 Anti‐Arrhythmic Drugs Class II agents (‐blockers)
MOA: Prevent or terminate tachycardia caused by: 1. Elevated sympathetic tone 2. Elevated local or circulating catecholamines 3. Elevated responsiveness to catecholamines
‐blockers Effects Chronotropy (HR)
NE = EPI 1 Inotropy (Contraction)
Dromotropy (Conduction)
50 Anti‐Arrhythmic Drugs Class II agents (‐blockers)
NE, EPI Na+ Ca2+ if (aka ih) and iCa(T) “pacemaker currents”
1 Gs Na+ Ca2+
Result: Increased ATP Automaticity AC cAMP PKA
51 Anti‐Arrhythmic Drugs Class II agents (‐blockers)
Automaticity (firing rate) of AV Node
(by blocking catecholamine stimulation of if and iCa)
AV Node AP
Effect on AV Node is > than effect on Purkinje fibers or Myocyte automaticity
52 Anti‐Arrhythmic Drugs Class II agents (‐blockers) Reduce risk of arrhythmias AV Node AP in patients with MI
A. The Ca2+ that enters the cell in phase 0 has to be pumped back out to maintain ion homeostasis.
B. In the AV node, a Ca2+ ATPase pumps ADP it back out. ATP Ca2+ C. In ischemic (ATP‐depleted) cells, the ATPase does not pump as much D. ‐blockers lower automaticity 2+ Ca out, so this enhances AV node by blocking iCa(T) transient inward automaticity (firing rate). calcium currents, raising time between spontaneous firing.
53 Anti‐Arrhythmic Drugs Class 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 Drugs Class 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 Drugs Class 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 Drugs Class II agents (‐blockers) Propranolol
Pharmacology: Non‐selective 1 and 2 blocker Admin: ORAL, IV Oral Bioavailability: 25% (HIGH first pass) Half‐life: about 4 hr Metabolism: Hepatic by CYP1A2 and CYP2D6 Active metabolite: 4‐hydroxypropranolol Excretion: Urine (>99% metabolites) NO Dose reduction is necessary in renal impairment
57 Anti‐Arrhythmic Drugs Class II agents (‐blockers) Atenolol
Pharmacology: Selective 1 (i.e. more cardio‐selective) Admin: ORAL Oral Bioavailability: 40‐50% (poor absorption) Half‐life: 6‐7 hr Metabolism: MINIMAL (<10% is metabolized) Excretion: Urine (unchanged drug) Dose reduction necessary in renal impairment
58 Anti‐Arrhythmic Drugs Class II agents (‐blockers) Metoprolol
Pharmacology: Selective 1 (i.e. more cardio‐selective) Admin: ORAL Oral Bioavailability: 50% (HIGH first pass) Half‐life: 6‐7 hr Metabolism: Hepatic CYP2D6 CYP2D6 poor metabolizers have reduced drug clearance Excretion: Urine (metabolites) NO Dose reduction is necessary in renal impairment
59 Anti‐Arrhythmic Drugs Class II agents (‐blockers) They are also useful for CHF: 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.
60 Anti‐Arrhythmic Drugs Class III agents (K+ channel blockers)
MOA: Block the potassium delayed rectifier (iKr) current Effect: Slower repolarization = Longer action potential AP Duration Prolonged AP = Longer QTc = Risk of TDP (except amiodarone)
Prolonged action potential duration = Longer refractory period (since the Nav1.5 inactivation gate blocks Na+ current as long as the cell remains depolarized)
61 Anti‐Arrhythmic Drugs Class III agents (K+ channel blockers) Requirements for Cardiac Re‐entry 1. Multiple conduction pathways 2. 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 unidirectional + conduction block (for a “pure” K channel blocker)
62 Anti‐Arrhythmic Drugs Class III agents (K+ channel blockers) Different from the Class I drugs: Class III drugs produce LESS EFFECT on ischemic tissue vs. normal tissue (for multiple reasons)
But, they ARE effective in preventing re‐entry because they the ERP of normal tissue. When the re‐entrant impulse arrives at this point, it is ‘cut‐off’ because the cells are still refractory.
63 Anti‐Arrhythmic Drugs Class III agents (K+ channel blockers) Uses: • RHYTHM CONTROL (prolonging the action potential reduces atrial firing rate) in SVT • Ventricular reentrant tachycardias Amioradone (Cordarone®) Pharmacology: 1. K+ channel blocker Also: 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 Drugs Class 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, IV Oral 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 Drugs Class 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 Drugs Class III agents (K+ channel blockers) Sotalol (Betapace AF®) –racemic (R,S) Pharmacology: 1. K+ channel blocker: R‐sotalol 2. Nonselective ‐blockers: R‐sotalol, S‐sotalol (Class II effect) Admin: ORAL, IV Oral Bioavailability: 95% Half‐life: 12 hr Metabolism: NONE Excretion: Renal (unchanged) Dose reduction necessary in renal impairment Warning: SIGNIFICANT RISK of TDP (2%) 67 Anti‐Arrhythmic Drugs Class 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 blocker Admin: IV Half‐life: 6 hr Metabolism: Hepatic Excretion: Renal (metabolites) Warning: SIGNIFICANT RISK of TDP (at high doses)
68 Anti‐Arrhythmic Drugs Class IV agents (Ca2+ channel blockers) MOA: Block the L‐type calcium channels Effect: Raise threshold for depolarization
AV Node AP Opening of L‐type calcium channels is what causes depolarization in the AV node
By blocking iCa(L) currents, Class IV agents SLOW the firing (conduction) of the AV node = RATE CONTROL
69 Anti‐Arrhythmic Drugs Class IV agents (Ca2+ channel blockers) Use: • RATE CONTROL (slow AV node conduction in SVT) • Suppression of AV reentrant arrhythmias Adverse effects: • NEGATIVE INOTROPIC EFFECT • Constipation (common with verapamil) • Hypotension • Bradycardia • AV conduction block Interactions • Combination with ‐blockers can cause BRADYCARDIA or HEART BLOCK
70 Anti‐Arrhythmic Drugs Class IV agents (Ca2+ channel blockers) Verapamil (Calan®, Isoptin®, Verelan®) Pharmacology: 1. Ca2+ channel blocker (at a different site than nifedipine or diltiazem) Admin: ORAL, IV Oral Bioavailability: 20‐35% (HIGH first pass) Half‐life: 3‐8 hr Metabolism: Hepatic (extensive, by several P450 isozymes) Excretion: Renal (metabolites)
Other Class IV drug: Diltiazem (similar efficacy)
71 Anti‐Arrhythmic Drugs Class V agents (Other) Adenosine (Adenocard®)
Ado Na+ Ca2+ if (aka ih) and iCa(T) “pacemaker currents”
A1 Gi Result: Decreased Na+ Ca2+ Automaticity Signaling path is: OPPOSITE to ATP EPI and NE, and AC SAME as ACh cAMP PKA
72 Anti‐Arrhythmic Drugs Class 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
73 Anti‐Arrhythmic Drugs Class V agents (Other) Adenosine Admin: IV bolus Oral Bioavailability: 0% Half‐life: seconds Metabolism: in blood and tissue to inosine, then to AMP, then to hypoxanthine Adverse effects: • Arrhythmias (common, >50% of patients) • Bronchoconstriction (use with caution in patients with asthma or COPD) • Heart block
74 Anti‐Arrhythmic Drugs Class V agents (Other) Digoxin POSITIVE INOTROPIC EFFECT Intracellular 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
75