Can the block help the beat? Beta blockers for ventricular fibrillation

Caleb J Stephenson, PharmD Department of Pharmacy, University Health System, San Antonio, TX

Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center,

University of Texas Health Science Center at San Antonio

March 6, 2015

Learning Objectives

1. Describe the presentation and management of ventricular fibrillation (VF) 2. Identify the potential cellular benefit of beta blockers during VF 3. Evaluate the evidence regarding beta blockers in VF 4. Formulate a recommendation based on the available literature

I. Ventricular Fibrillation (VF) A. Introduction 1,2

1. High-frequency and asynchronous contraction of the ventricles resulting in no cardiac output or blood pressure

2. Almost always fatal i. Approximately 92% of out-of-hospital cardiac arrest die ii. Tends to deteriorate into asystole over time

3. Most common arrhythmia in cardiac arrest 4. The initial rhythm in 65-85% of cardiac arrest patients

B. Epidemiology 2,3,4 1. VF accounts for approximately 100,000 deaths each year in the US

2. The incidence in the US is 0.1-0.2% C. Characteristics 5,6

1. Disorganized and totally random activation of ventricle 2. Electrical wavelet activity from multiple wandering locations

Figure 1. VF conduction6

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D. Presentation 1. VF patients all have similar presentations

i. Hemodynamic collapse ii. Lack of blood pressure iii. Absent heart sounds iv. Apnea or agonal breathing

2. Primary vs secondary 7 i. Primary

a. Independent of myocardial infarction damage ii. Secondary

a. Associated with heart failure or underlying cardiac issues

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Figure 2. Sinus rhythm evolving into VF on ECG 8

E. Risk Factors 4,9 1. Prior heart disease

i. Myocardial infarction (13.6/1000 person-years) ii. Heart failure (21.9/1000 person-years)

2. Premature ventricular contractions 3. Coronary artery disease 4. Family history of cardiac arrest

i. 2-fold increase with first degree relative

II. Management 10 A. Advanced cardiac life support (ACLS) overview (see Appendix A. for algorithm)

1. Builds on basic life support (BLS) i. Activation of emergency response system ii. High quality cardiopulmonary resuscitation (CPR) iii. Early defibrillation

a. First line treatment for VF and ventricular tachycardia b. Only rhythm-specific therapy proven to increase survival c. Biphasic (120-200 joules) or monophasic (360 joules)

2. ACLS team i. Leader ii. Compressions iii. Airway iv. Vitals and defibrillation v. Access and medication vi. Recorder

3. Airway management 4. Ventilation

i. Bag-mask ventilation 5. Medications

i. Help to facilitate and maintain spontaneous rhythm ii. Increased rates of return of spontaneous circulation (ROSC)

6. Treat reversible causes i. H & T’s

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Table 1. Reversible causes of cardiac arrest Reversible cause Treatment Hypovolemia Fluids Hypoxia Ventilation (advances airway) Hydrogen ion (acidosis) Ventilation, Sodium bicarbonate IV Hypo-/hyperkalemia Potassium / Sodium bicarbonate IV, Glucose + Insulin, Calcium IV Hypothermia Warming measures Tension pneumothorax Needle decompression Tamponade Pericardiocentesis Toxins Antidote or Reversing agent Thrombosis, pulmonary Fibrinolytic treatment Thrombosis, cardiac Percutaneous Coronary Intervention (PCI)

B. ACLS Medication 10

1. Epinephrine i. Endogenous catecholamine with both alpha and beta activity ii. 1 mg IV push every 3-5 minutes iii. Primary benefit is alpha receptor stimulation (vasoconstriction)

a. Increase coronary and cerebral perfusion pressure b. Found to improve ROSC

iv. Controversial effects with epinephrine a. Increased demand and decreased oxygen

2. Vasopressin i. Nonadrenergic peripheral vasoconstrictor

a. V1 receptor activation ii. 40 units IV push for 1 dose

a. To replace 1st or 2nd epinephrine dose b. No difference in outcomes verses epinephrine

iii. Not affected by pH variation 3. Amiodarone

i. Antiarrhythmic agent a. Potassium, sodium, and calcium channel blocker b. Alpha and beta adrenergic blocking properties

ii. VF unresponsive to CPR, defibrillation, and vasopressor therapy iii. 300 mg IV push

a. Repeat 150 mg if needed iv. Termination of arrhythmias are improved

4. Lidocaine i. Class Ib antiarrhythmic

a. Sodium channel blocker ii. 1-1.5 mg/kg IV

a. Repeat 0.5-0.75 mg/kg if needed iii. No proven short- or long-term efficacy

a. Consider if amiodarone not available

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III. Cardiac action potential

Figure 3. Cardiac electrophysiology

Phase 0 Depolarization - Rapid Na+ channels Phase 1 Peak-L-type Ca++ channels Phase 2 Plateau- Rectifier K+ channels Phase 3 Repolarization- Ca++ channels close Phase 4 Resting membrane potential

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IV. Catecholamine effects on myocardium A. Catecholamines

1. Bind to G-protein coupled adrenergic receptors i. Intracellular enzyme activation

a. Cardiac and/or vascular response

Figure 4. Intracellular mechanism of action of catecholamines 11

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B. Positive effects 1. Essential for maintaining cardiovascular system 2. “Fight -or-flight” response 3. Life saving effects in hypotension and decreased cardiac output

C. Detrimental effects 12 1. Calcium overload

i. Hallmark of persistent catecholamine exposure ii. Change in mitochondrial membrane permeability iii. Sarcoplasmic reticulum dilation

2. Oxidative stress i. Hydrogen peroxide formation through catecholamine deamination ii. Superoxide anion radical formation iii. Aminochrome accumulation

a. Coronary vasoconstriction 3. Mitochondrial dysfunction

i. Opening of mitochondrial permeability transition pore

Figure 5. Effects of sustained catecholamine exposure 12

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V. Bench Research 13 A. Mann et al used cultures of adult cardiac muscle cells to evaluate norephinephrine

1. Determining norepinephrines effects on cardiac myocytes in vitro i. Cultured cells treated with adrenergic agonist, antagonist, chelating and calcium

channel blocking agents ii. Only lowest concentration producing effect reported iii. Response based on spontaneous beating

Table 2. Induction of spontaneous cardiac myocyte beating Treatment Beating of myocytes (%) Control 0 10-6 M norepinephrine 20.9 ± 2.5 10-5 M dideoxyadenosine + norepinephrine 0 10-6 M forskolin 12.5 ± 4.1 10-3 M dibutyryl cyclic AMP 20.5 ± 4.6 10-3 M ethylene glycol tetraacetic acid (EGTA) + norepinephrine 0 10-6 M verapamil + norepinephrine 0 10-2 M cobalt + norepinephrine 0 10-5 M lidocaine + norepinephrine 20.2 ± 3.4 10-5 M tetrodotoxin + norepinephrine 20.8 ± 3.1 10-3 M dibutyryl cyclic AMP + 10-6 verapamil 0

See appendix B for mechanisms

iv. Results a. Response blocked by removing calcium or blocking slow calcium channels

2. Effects of norepineprine on cAMP levels within stimulated cells

i. Cultured cells pretreated with propranolol or normal medium ii. Stimulation with norepinephrine for 1,5,15,and 30 minutes iii. Radioimmunoassay measured cAMP

Figure 6. cAMP levels with norepinephrine stimulation

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iv. Results a. 4 fold increase in cAMP with norepinephrine stimulation b. Propranolol blunted cAMP elevation

v. Beta blockers decrease cAMP levels, causing decreased calcium release

3. Effects of norepinephrine stimulation on calcium concentrations i. Cultured cells pretreated with propranolol, normal medium alone, or EGTA ii. Calcium concentrations measured directly with tetracarboxylate calcium indicator

fura-2 a. Emission of fluorescence measured

Figure 7. Calcium concentrations after norepinephrine stimulation

iii. Results a. Propranolol and EGTA significantly reduced calcium concentrations

iv. Beta blockers and chelating agents decrease calcium concentrations, limiting the overall effects norepinephrine

VI. Animal Studies 15-17

A. Cammarata et al (2004) 1. To determine if short-acting beta1-selective blockade during CPR will improve initial and

post-resuscitation survival 2. Esmolol group (n=9): 300µg/kg bolus 3. Placebo group (n=9) 4. Methods

i. VF induced and left untreated for 6 minutes ii. Resuscitation

a. Precordial compressions and mechanical ventilation b. Defibrillation attempted up to 3 times c. Esmolol injected 2 minutes after precordial compression into right atrium

iii. ROSC: supraventricular rhythm with MAP 60 mmHg for 5 minute

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5. ROSC i. Esmolol 9/9 vs placebo 5/9 (p<0.05)

6. Postresuscitation survival prolonged in esmolol group (50 vs 20 hours)(p<0.05)

B. Bassiakou et al (2008) 1. Assess whether beta blockade will improve initial cardiopulmonary resuscitation success

in piglets 2. Group A (n=10): placebo (saline) + epinephrine 3. Group B (n=10): atenolol + epinephrine 4. Methods

i. VF was induced ii. Arrhythmia confirmed by electrocardiography and sudden drop in MAP iii. After induction of VF, mechanical ventilation was stopped and left untreated for 8

minutes iv. Resuscitation procedure

a. 100% oxygen and study drugs b. Mechanical chest compressions for 2 minutes c. Defibrillation attempted after 2 minutes d. Maximum of three cycles

v. End points: asystole, ROSC, or VF after 3 failed defibrillations 5. 4 animals in group A had ROSC, 9 in group B had ROSC (p< 0.05)

Table 3. Different parameter before defibrillation and ROSC after defibrillation

Epi + Placebo (n=10) Epi + Atenolol (n=10) SBP 2 minutes post drug administration 73 ± 11 90.5 ± 11.3 p<0.05 DBP 2 minutes post drug administration 32 ± 4.5 49.1 ± 6.9 p<0.05 CPP 19 ± 7.0 27.7 ± 5.3 p<0.05 ROSC 4 9 p<0.05

ROSC First Defibrillation 4 7 ROSC Second Defibrillation 0 2

6. Group A > group B postresuscitation heart rate (p<0.05)

C. Killingsworth et al (2004)

1. Part 1: Assess the levels of myocardial interstitial catecholamines at baseline, during 8 minutes of VF, after defibrillation, and during reperfusion

i. 8 mixed-breed pigs ii. Open chest with 2 microdialysis probes in lateral wall of LV iii. Catheters placed in aorta and coronary sinus (CS) iv. Interstitial fluid (ISF) from left ventricle collected v. VF induced and continued for 8 minutes vi. Defibrillation

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Figure 8. ISF norepinephrine and epinephrine during 8 minutes of VF

Figure 9. ISF and plasma norepinephrine and epinephrine from the aorta and CS

vii. Results a. Significant increase in both norepinephrine and epinephrine during VF b. Aortic and CS levels do not correlate to ISF levels

• Plasma levels peak earlier and higher • Decrease rapidly below ISF values

c. Longer sustained levels in ISF (p<0.05)

2. Part 2: Determine the effects of short-acting beta blockade on catecholamine surge and survival

i. Catheter placed at junction of superior vena cava and right atrium to measure coronary perfusion pressure and central venous pressure

ii. 8 minutes of VF iii. External defibrillation iv. 1 mg/kg esmolol (n=8) or placebo (saline) (n=8) intravenously after defibrillation

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v. ACLS performed in both groups a. Only epinephrine and dobutamine used

Table 4. Resuscitation data Placebo (n=8) Esmolol (n=8) Survival (p<0.05) 3 7 Mean number of shocks 10 ± 8 5 ± 4 Total CPR time (min) 27 ± 15 13 ± 7 Survivor CPR time (min) 9 ± 8 9 ± 7 Coronary perfusion pressure (mmHg) 15 ± 7 17 ± 7 Animals requiring dobutamine 1/3 2/7

vi. Esmolol improved ROSC

VII. Literature Review 18-20

Nademanee K et al. Treating electrical storm: sympathetic blockade verses advanced cardiac life support-guided therapy. Circulation. 2000;102:742-747.

Overview Objective To determine the efficacy of sympathetic blockade in treatment of electrical storm

(ES) patients and compare their outcomes with ES patients treated according to ACLS guidelines

Trial Design Retrospective observational analysis, non-randomized, non-blinded Inclusion Criteria • Recent myocardial infarct (MI) with ES.

o ES: ≥20 ventricular tachycardia (VT)/VF episodes per day or ≥ 4 VT/VF episodes per hour

o Recent MI: occurring within 72 hours to 3 months before the onset of ES

Exclusion Criteria • Onset of MI was <72 hours • Acute pulmonary edema • Previous treatment with intravenous amiodarone • Acute respiratory failure • Acquired or congenital long QT syndrome • Recent coronary revascularization (<1 week before the onset of ES)

Outcomes • Termination of ES • Determine short-term and long term effects of treatment

Interventions Sympathetic blockade treatment within 1 hour after all ACLS antiarrhythmic medications were discontinued Sympathetic blockade treatments: • Left stellate ganglionic blockade

o 10-20 mL 1% xylocaine injected millimeters anterior to lateral process of spine until Horner’s syndrome developed (miosis, partial ptosis)

o Repeat with 10 mL 0.25% marcaine or xylocaine if needed • Esmolol 300-500 mg/kg load followed by 25-50 mg/kg/min infusion

o Infusion titrated every 5-10 minutes up to 250 mg/kg/min • Propranolol 0.15 mg/kg followed by 3-5 mg dose every 6 hours • ACLS Protocol

o Lidocaine 1 mg/kg IV bolus was first antiarrhythmic

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o Repeated once and continuous infusion started at 1-4 mg/min for persistent VF

o Procainamide 100 mg bolus was given if no sinus rhythm every 5 minutes up to 500-1000 mg then 2-4 mg/min continuous infusion

o Procainamide alternative was bretylium tosylate 5 mg/kg every 5 minutes up to 25 mg/kg

Results Baseline Characteristics

• No significant differences in any variables Table 5. Characteristics of sympathetic blockade vs ACLS groups

Characteristics Sympathetic blockade (n=27) group 1

ACLS (n=22) group 2

Age (years) 59 ± 11 56 ± 9 Men/women 23/4 19/3 Ejection Fraction (%) 31 ± 9 34 ± 6 Calcium antagonist 19 17 Beta blocker 6 3 ACE inhibitor 11 15 Onset of VF after MI (days)

12 ± 10 11 ± 12

K+ <3.5 4 3

Primary Outcomes • 1-week mortality rate, n=6 (22%) group 1 vs n=18 (82%) group 2 (p<0.0001) • Overall survival to 1 year: 67% group 1 vs 5% group 2 (p<0.0001) Figure 10. Kaplan-Meier survival cure of sympathetic blockade and ACLS group

Conclusion Author’s Conclusion

• Sympathetic blockade along with amiodarone improves survival of ES

Strengths • Standard ACLS vs sympathetic blockade • Length of follow-up

Limitations • Treatment was physician preference • Retrospective, Non-blinded • Sample size • ACLS guidelines contained lidocaine which is no longer first line

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Miwa Y et al. Effects of landiolol, an ultra-short-acting β1-selective blocker, on electrical storm refractory to class III antiarrhythmic drugs. Circulation. 2010;75:856-863.

Overview Objective Evaluate the effects of landiolol on electrical storm (ES) refractory to class III

antiarrhythmics Trial Design Prospective, observational Inclusion Criteria • Patient had ES

o ES: sustained VT/VF twice or more per hour or 3 times or more over 6 hours

o Class III antiarrhythmics administered to all patients prior to inclusion • Difficult to treat following established guidelines

o CPR, electric cardioversion, antiarrhythmic drugs Exclusion Criteria • Cardiac arrest at time of arrival

• Antiarrhythmic drugs before arrival • Renal failure ( SCr >2.0 mg/dL) • Hemodynamically stable VT

Outcomes Inhibition of ES, survival, and discharge from hospital Interventions • Landiolol initiated at 2.5µg/kg/min; starting maintenance 10-40µg/kg/min

o Effects assessed 10 minutes after administration o Titration using doubling protocol (2.5-5-10-20 etc.) o Maximum dose of 80 µg/kg/min

• Severe bradycardia or hypotension in landiolol effective treatment patients o Temporal pacemaker or catecholamines were used as needed o Treatment was discontinued if landiolol treatment was difficult to

maintain with supportive treatment • Inhibition of ES

o Completely resolved VT/VF for 12 hours after maintenance dose administered

o Oral carvedilol or bisoprolol given concomitantly at 2.5 and 1.25 mg/day for landiolol responsive patients

Results Baseline Characteristics

• 42 patients admitted to critical care center • All had ES and were difficult to treat following established guidelines • 60% had ischemic heart disease • 21 (50%) patients had an acute MI • Mean left ventricular ejection fraction 39 ± 15% • Killip class III and IV in 21(50%) patients • Mean APACHE II score 19 ± 10 • Number of shocks was 5 ± 13 • 17(40%) patients had assisted circulation devices

Primary Outcomes • Landiolol inhibited ES in 33 (79%) patients

• Sympathetic blockade was within 1 hour after stopping antiarrhythmics • Medications given during ACLS not specified for group 1 • Esmolol dosing in mg not µg

Take Home Points • Sympathetic blockade had better outcomes then ACLS alone • Unknown effects of sympathetic blockade without amiodarone

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• 25 (60%) patients survived and were discharged • Significant differences were found between survivors and non-survivors Table 6. Significant differences between survivors and non-survivors

Survivors (n=25) Non-survivors (n-17) P value Age (years) 60 ± 16 72 ± 11 0.01 Acute MI 8 (32%) 13 (76%) 0.01 Killip class (I/II/III/IV) 16/1/0/8 4/0/2/11 0.02 APACHE II score 15 ± 9 24 ± 11 0.01 pH 7.3 ± 0.1 7.2 ± 0.2 0.007 Hypertension 16 (64%) 16 (94%) 0.03 Assisted circulation device

IABP* 5 (20%) 9 (53%) 0.04

*Intra-aortic balloon pump

• Mean duration of landilol treatment was 29 ± 31 hours • Mean dose was 7.5 ± 12.2 µg/kg/min • Landiolol reduced heart rate (HR) (p<0.0001) • No changes noted in blood pressure (BP) • 21(64%) patients received carvedilol and 12(36%) received bisoprolol

Conclusion Author’s Conclusion

When class III antiarrhythmics are ineffective landiolol should be considered for possible ES refractory to antiarrhythmics.

Strengths • Landiolol used after traditional standards of care failed • Initiated landiolol at very low dose • Specific reassessment period after administration • Clinical features used for evaluation

Limitations • Lack of control • Differences in baseline characteristics between survivors and non-survivors • Sample size • Treatment for patients experiencing MI was only noted for 1 patient

Take Home Points • Landiolol was effective at inhibiting ES in the majority of patients • Non-survivors had significantly different clinical feature than survivors

Driver BE et al. Use of esmolol after failure or standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. Resuscitation. 2014;85:1337-1341.

Overview Objective To compare the outcomes of patients who received esmolol to those who did not

receive esmolol during refractory ventricular fibrillation. Trial Design Retrospective observational analysis, non-randomized, non-blinded Inclusion Criteria • Initial rhythm was VF or VT

• Cardiac arrest (CA) in the emergency department (ED) or had CA pre-hospital and remained in arrest upon ED arrival

• Received at least 3 defibrillation attempts, 300 mg of amiodarone, and 3 mg of adrenaline

Exclusion Criteria • Received esmolol before CA or after sustained ROSC Outcomes Not defined

Data collected

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• Pre-hospital and ED rhythms • Medications administered • CA management • Presence of ST-elevation myocardial infarction (STEMI) • Timing of ROSC • Patient outcomes Definitions • Temporary ROSC - non-fleeting return of restored circulation lasting more than

30 s, but less than 20 min • Sustained ROSC - 20 min of spontaneous circulation without recurrence of CA

Interventions Esmolol 500 mcg/kg load followed by infusion at 0-100 mcg/kg/min Results

Baseline Characteristics

Table 7. Characteristics of esmolol verses no esmolol Characteristics Esmolol (n=6) No esmolol (n=19) Age (yrs) 54.5 56 Male gender (%) 6 (100) 18 (94.7) Initial rhythm VF(%) 5 (83.3) 18 (94.7) Witnessed arrest (%) 5 (83.8) 16 (84.2) Bystander CPR (%) 3/4 (75) 14/18 (77.8) Time from call to EMS arrival (min)

7 6

Total pre-hospital time (min)(IQR)

25 (18,29) 42 (25.5, 51)

Patient Outcomes Table 8. Patient outcomes from esmolol verses no esmolol Esmolol (n=6) No esmolol (n=19) Total ED CPR time (min) 39.5 16 Total CPR time (min) 63 57 Temporary ROSC (%) 4 (66.7) 8 (42.1) Sustained ROSC (%) 4 (66.7) 6 (31.6) STEMI (%) 3/5 (60) 1/7 (14.3) Emergency cardiac catheterization from ED (%)

5 (83.3) 3 (15.8)

Survival to ICU admission (%) 4 (66.7) 6 (31.6) Therapeutic hypothermia (%) 4 (66.7) 5 (26.3) Survival to hospital discharge (%)

3 (50) 3 (15.8)

Survival to discharge with good neurologic outcome (%)

3 (50) 2 (10.5)

Conclusion Author’s Conclusion

• Prospective studies of beta-blockers in CA are warranted • Beta-blockers should be considered in patients with RVF once standard therapy

has been performed Strengths • Inclusion criteria defined exact number of defibrillations and doses of

medications needed • Therapeutic hypothermia and catheterization was reported

Limitations • Retrospective • Sample size • Non-blinded, non-randomized

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• Different rates of therapeutic hypothermia and catheterization between the groups

• Descriptive statistics Take Home Points • Improvement in mortality was seen with esmolol although not significant

• The different rates of therapeutic hypothermia and catheterization may have effected the survival rate

• Favorable neurologic outcomes are possible with prolonged CPR

VIII. Summary of evidence A. Bench research

1. Demonstrates the effects of norepinephrine on cardiac myocytes 2. Use of a beta blocker, calcium channel blocker, or calcium chelator decrease the response

to norepinephrine B. Animal studies

1. Use of beta blockers improved ROSC and postresuscitation survival 2. Quantified the levels of catecholamines during VF and CPR in various compartments

C. Literature 1. Beta blockers along with antiarrhythmic medication has a positive effect on ROSC in

patients with prolonged or recurrent VF 2. Beta blockers alone have not been studied in the setting of VF

IX. Conclusion

A. Limited evidence for beta blockers in VF B. Current evidence suggests the beta blockers may benefit patient refractory to the current

established guidelines. C. Recommendations

1. Beta blockers may be considered after antiarrhythmic administration and all reversible causes have been ruled out.

i. After ACLS performed ii. Continued VF iii. Esmolol 500 mcg/kg followed by 25-50 mcg/kg/min

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Appendix A. ACLS algorithm

Appendix B. Mechanism of action

Dideoxyadenosine Adanylate cyclase inhibitor Forskolin Direct action stimulates adenylate cyclase Dibutyryl cAMP cAMP analog Ethylene glycol tetraacetic acid (EGTA) Chelating agent Cobalt Depresses oxygen uptake by the mitochondria Tetrodotoxin Block the pore of the Na+ channel Verapamil Non-dihydropyridine calcium channel blocker

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