Pharmacology: Arrhythmias PC PHPP 515 (IT I) Fall JACOBS Wed, Dec. 03 4:00 5:50 PM

Transcription

1 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

2 Cardiac Conduction SA node generates action potential and delivers to the atria and AV node AV node receives impulse and delivers to Purkinje fibers Conduction also occurs between cardiomyocytes when adjacent cells are depolarized 2 Purkinje fibers conduct impulse to ventricles

3 Cardiac Conduction Nodal AP Phase 4: Pacemaker Potential Na + influx (i f ) Ca 2+ influx (i Ca(T) ) FUNNY Na + CURRENT TRANSIENT Ca 2+ CURRENT Phase 0: Upstroke (depolarization) Ca 2+ influx (i Ca(L) ) CALCIUM DEPOLARIZATION LONG Ca 2+ CURRENT Phase 3: Repolarization K + efflux (i K ) OUTWARD POTASSIUM CURRENTS 3

4 Ventricular AP Bundle of His Purkinje fibers Ventricular Myocytes Phase 0: Upstroke Na + influx (i Na ) FAST Na + CURRENT SODIUM DEPOLARIZATION Cardiac Conduction Phase 1: Partial Repolarization K + efflux (i Kto ) Phase 2: Plateu Ca 2+ influx (i Ca(L) ) K + efflux (i Ks ) TRANSIENT OUTWARD (TO) K + CURRENT Phase 3: Repolarization K + efflux (i Kr ) LONG Ca 2+ + SLOW K + CURRENTS Phase 4: Resting Potential (K + 1, K + ACh) INWARD RECTIFIER Effective refractory period DELAYED RECTIFIER Na + influx (i f ) FUNNY OR PACEMAKER CURRENT (HCN) 4

5 Myocyte Resting Potential Na + /K + ATPase 3 Na + Cardiac Conduction Inward Rectifier (K + channel) Na + HIGH OUT K + out 4mM Na + out 140 mm 0 mv 2 K + K mm K + in 10 mm Na + in 94 mv 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

6 Cardiac Conduction Myocyte Depolarization Fast Na+ Channels Three States: Open Inactivated Closed/Resting Recovery from (I) to (C) is voltage dependent (O) (I) (C) Ventricular Q Duration of Ventricular Depolarization Goldfrank's Toxicologic Emergencies T 6

7 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

8 Etiology of Arrhythmias: Arrhythmias Definition of Arrhythmias: Abnormal heart rhythm (irregular heart beat). Arises from abnormal impulse generation or conduction. Electrolyte imbalance (e.g. K +, Ca 2+, Mg 2+ ) Drugs, toxins Physical conditions: Mutation or genetic polymorphisms in ion channels (channelopathy) Nervous (sympathetic stimulation) Hormonal (hyperthyroidism) Cardiac ischemia Scarring, cardiomyopathies 8

9 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

10 By Location Arrhythmias Supraventricular If arrhythmia arises from SA node AV node Atrial foci Junctional Ventricular If arrhythmia arises from ventricles 10

11 By Mechanism Arrhythmias Abnormal Impulse Automaticity Triggered Rhythms Enhanced normal automaticity (sinus tachycardia) Abnormal Conduction Ectopic focus Early afterdepolarization Late afterdepolarization Today s main topics are in RED Heart Block Re entry 11

12 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

13 By Mechanism Arrhythmias Abnormal Conduction Re entry AFL 1. Atrial flutter (AFL) 2. Supraventricular tachycardia (AVNRT and AVRT) 3. Ventricular tachycardia (VT) AVNRT AVRT VT 13

14 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

15 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: Ca 2+ channel blocker Class V: Other Anti Bradycardia Drugs: agonists Anti muscarinics 15

16 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: Ca 2+ channel blockers Verapamil, Diltiazem Class V: Other Adenosine, Digoxin 16

17 Cardiac Re Entry How it Happens: Anti Arrhythmic Drugs 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 selfsustaining cycle is generated) 17

18 Approaches to Halt Re Entry 1. INCREASE the Effective Refractory Period 2. DECREASE Conduction Velocity

19 Approaches to Halt Re Entry 1. INCREASE the Effective Refractory Period e.g. K + channel blockers w/ drug, repolarization is slowed, so 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

20 Approaches to Halt Re Entry 2. DECREASE Conduction Velocity e.g. Na + channel blockers (some) Reduce the Phase 0 slope (rate of depolarization) 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

21 Atrial Flutter (AFL) and Atrial Fibrillation (AFib) Atrial flutter (AFL) Fast atrial reentry Atrial fibrillation (AFib) Disorganized electrical activity Rapid (ventricular) heart rate, depends upon: 1. Atrial firing rate 2. AV conduction ratio 21

22 Approaches to Treat AFL and AFib 1. RHYTHM CONTROL (Goal: Reduce Atrial Firing Rate) atrial firing rate = 400 AV conduction ratio = 2:1 ventricular rate = 200 AGENTS: Class Ia,c Class III atrial firing rate = 200 AV conduction ratio = 2:1 ventricular rate = 100 EFFECT: TREATS AFL/AFib SO FEWER IMPULSES ARE TRANSMITTED TO THE VENTRICLES 22

23 Approaches to Treat AFL and AFib 2. RATE CONTROL (Goal: Slow AV Node Conduction) atrial firing rate = 400 AV conduction (ratio = 2:1) ventricular rate = 200 atrial firing rate = 400 AV conduction (ratio = 4:1) ventricular rate = 100 AGENTS: EFFECT: Class II SLOWS VENTRICULAR RATE Class IV BUT PATIENT STAYS IN AFL/AFib Cardiac glycosides (digoxin) 23

24 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

25 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 i Kr (K + channels) so they prolong the action potential by slowing repolarization 25

26 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

27 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

28 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 Ca 2+ entry (not sodium) Class Icdrugs MAY AV node conduction (esp. high doses) Quinidine actually AV node conduction! 28

29 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 afterdepolarizations (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

30 Class I agents (Na + channel blockers) Class Ib SELECTIVELY act on ischemic (depolarized) tissues normal RP = 94 mv ischemic RP = 60 mv (partly depolarized) Infarct zone, High [K + ] out ERP in normal His Purkinje and ventricular myocyte ERP in ischemic tissues (myocardial infarct), WHY?? 30

31 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) (s) Act somewhat like Class Ia or Ic drugs in MI tissues! 31

32 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 = i Ca(L) Myocyte, His Purkinje depolarization = i Na 32

33 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 V d 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

34 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

35 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

36 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

37 Class Ia Anti Arrhythmic Drugs Quinidine Admin: IV, ORAL (usual route) as gluconate or sulfate forms Use: RARELY used: AFib, atrial flutter, sustained ventricular arrhythmias OTHER Pharmacology: a. i Kr 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 ( QT c interval = risk of TDP) Other arrhythmias can also occur: extrasystoles, ventricular tachycardia, flutter, and fibrillation. 37

38 Class Ia Anti Arrhythmic Drugs 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

39 Class Ia Anti Arrhythmic Drugs Quinidine DANGER SCENARIO: caused by AV conduction (anticholinergic) atrial firing rate = 450 AV conduction ratio = 3:1 atrial firing rate = 300 AV conduction (ratio = 1:1) SVT Untreated ventricular rate = Quinidine ventricular rate = 300 Ventricular Rate (flutter) 39

40 Class Ia Anti Arrhythmic Drugs Procainamide Admin: IV, IM Use: Atrial and ventricular arrhythmias OTHER Pharmacology: a. i Kr blocker: N acetylprocainamide (aka NAPA) (metabolite) Warning: Pro arrhythmic effect ( QT c 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

41 Class Ia Anti Arrhythmic Drugs 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

42 Class Ia Anti Arrhythmic Drugs Disopyramide Admin: ORAL Use: Life threatening ventricular arrhythmias, paroxysmal SVT OTHER Pharmacology: a. i Kr 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

43 Class Ia Anti Arrhythmic Drugs 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

44 Class Ib Anti Arrhythmic Drugs 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

45 Class Ib Anti Arrhythmic Drugs Lidocaine Oral Bioavailability: 35% (HIGH first pass ORAL not used) Half life: 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

46 Class Ib Anti Arrhythmic Drugs 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

47 Class Ic Anti Arrhythmic Drugs 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

48 Class Ic Anti Arrhythmic Drugs 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: hr Metabolism: Hepatic by CYP2D6 (inhibitors of either will increase flecainide levels) 48

49 Class Ic Anti Arrhythmic Drugs 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

50 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

51 Class II agents ( blockers) NE, EPI Na + Ca 2+ i f (aka i h ) and i Ca(T) pacemaker currents 1 Gs Na + Ca 2+ AC ATP camp PKA Result: Increased Automaticity 51

52 Class II agents ( blockers) Automaticity (firing rate) of AV Node (by blocking catecholamine stimulation of i f and i Ca ) AV Node AP Effect on AV Node is > than effect on Purkinje fibers or Myocyte automaticity 52

53 Class II agents ( blockers) Anti Arrhythmic Drugs AV Node AP Reduce risk of arrhythmias in patients with MI A. The Ca 2+ that enters the cell in phase 0 has to be pumped back out to maintain ion homeostasis. C. In ischemic (ATP depleted) cells, the ATPase does not pump as much Ca 2+ out, so this enhances AV node automaticity (firing rate). B. In the AV node, a Ca 2+ ATPase pumps it back out. Ca 2+ ADP ATP D. blockers lower automaticity by blocking i Ca(T) transient inward calcium currents, raising time between spontaneous firing. 53

54 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

55 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

56 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 Ca 2+ 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

57 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

58 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

59 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

60 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

61 Class III agents (K + channel blockers) MOA: Block the potassium delayed rectifier (i Kr ) 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

62 Class III agents (K + channel blockers) Requirements for Cardiac Re entry 1. Multiple conduction pathways 2. Unidirectional conduction block 3. Conduction time > ERP unidirectional conduction block 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) 62

63 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

64 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. Ca 2+ 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

65 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: days (LONG!) Metabolism: Hepatic CYP2C8 and CYP3A4 Major metabolite = desethylamiodarone (may be active) Excretion: Fecal (metabolites) 65

66 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

67 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

68 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

69 Class IV agents (Ca 2+ 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 i Ca(L) currents, Class IV agents SLOW the firing (conduction) of the AV node = RATE CONTROL 69

70 Class IV agents (Ca 2+ 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

71 Class IV agents (Ca 2+ channel blockers) Verapamil (Calan, Isoptin, Verelan ) Pharmacology: 1. Ca 2+ 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

72 Class V agents (Other) Adenosine (Adenocard ) Ado Na + Ca 2+ i f (aka i h ) and i Ca(T) pacemaker currents A 1 Gi Na + Ca 2+ Result: Decreased Automaticity AC ATP camp PKA Signaling path is: OPPOSITE to EPI and NE, and SAME as ACh 72

73 Class V agents (Other) Adenosine (Adenocard ) Use: Drug induced CARDIOCONVERSION of acute AV node reentry (back to normal sinus rhythm) Pharmacology: 1. A 1 receptor agonist Effect is VERY SHORT LIVED (t 1/2 = 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

74 Class V agents (Other) Adenosine Admin: IV bolus Oral Bioavailability: 0% Half life: seconds Anti Arrhythmic Drugs 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

75 Class V agents (Other) Digoxin POSITIVE INOTROPIC EFFECT Intracellular calcium levels (and SR stores) are increased (indirectly by stimulating the Na + /Ca 2+ 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