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

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.
2.
3.
4.
Describe the presentation and management of ventricular fibrillation (VF)
Identify the potential cellular benefit of beta blockers during VF
Evaluate the evidence regarding beta blockers in VF
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
http://www.washingtonhra.com
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
Phase 1
Phase 2
Phase 3
Phase 4
Depolarization - Rapid Na+ channels
Peak-L-type Ca++ channels
Plateau- Rectifier K+ channels
Repolarization- Ca++ channels close
Resting membrane potential
http://www.cvpharmacology.com
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
Control
10-6 M norepinephrine
10-5 M dideoxyadenosine + norepinephrine
10-6 M forskolin
10-3 M dibutyryl cyclic AMP
10-3 M ethylene glycol tetraacetic acid (EGTA) + norepinephrine
10-6 M verapamil + norepinephrine
10-2 M cobalt + norepinephrine
10-5 M lidocaine + norepinephrine
10-5 M tetrodotoxin + norepinephrine
10-3 M dibutyryl cyclic AMP + 10-6 verapamil
See appendix B for mechanisms
Beating of myocytes (%)
0
20.9 ± 2.5
0
12.5 ± 4.1
20.5 ± 4.6
0
0
0
20.2 ± 3.4
20.8 ± 3.1
0
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
CJStephenson 7
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
DBP 2 minutes post drug administration 32 ± 4.5
49.1 ± 6.9
CPP
19 ± 7.0
27.7 ± 5.3
ROSC
4
9
ROSC First Defibrillation
4
7
ROSC Second Defibrillation
0
2
p<0.05
p<0.05
p<0.05
p<0.05
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
Survival (p<0.05)
Mean number of shocks
Total CPR time (min)
Survivor CPR time (min)
Coronary perfusion pressure (mmHg)
Animals requiring dobutamine
Placebo (n=8)
3
10 ± 8
27 ± 15
9±8
15 ± 7
1/3
Esmolol (n=8)
7
5±4
13 ± 7
9±7
17 ± 7
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
CJStephenson 11
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
• No significant differences in any variables
o
Baseline
Characteristics
Primary Outcomes
Table 5. Characteristics of sympathetic blockade vs ACLS groups
Characteristics
Sympathetic blockade
ACLS (n=22) group 2
(n=27) group 1
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
12 ± 10
11 ± 12
(days)
K+ <3.5
4
3
• 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
Author’s
Conclusion
Strengths
Limitations
Conclusion
• Sympathetic blockade along with amiodarone improves survival of ES
•
•
•
•
•
•
Standard ACLS vs sympathetic blockade
Length of follow-up
Treatment was physician preference
Retrospective, Non-blinded
Sample size
ACLS guidelines contained lidocaine which is no longer first line
CJStephenson 12
Take Home Points
•
•
•
•
•
Sympathetic blockade was within 1 hour after stopping antiarrhythmics
Medications given during ACLS not specified for group 1
Esmolol dosing in mg not µg
Sympathetic blockade had better outcomes then ACLS alone
Unknown effects of sympathetic blockade without amiodarone
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
• 42 patients admitted to critical care center
Characteristics
• 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
CJStephenson 13
• 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)
Age (years)
60 ± 16
72 ± 11
Acute MI
8 (32%)
13 (76%)
Killip class (I/II/III/IV)
16/1/0/8
4/0/2/11
APACHE II score
15 ± 9
24 ± 11
pH
7.3 ± 0.1
7.2 ± 0.2
Hypertension
16 (64%)
16 (94%)
Assisted circulation device 5 (20%)
9 (53%)
IABP*
*Intra-aortic balloon pump
P value
0.01
0.01
0.02
0.01
0.007
0.03
0.04
•
•
•
•
•
Author’s
Conclusion
Strengths
Limitations
Take Home Points
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
When class III antiarrhythmics are ineffective landiolol should be considered for
possible ES refractory to antiarrhythmics.
• Landiolol used after traditional standards of care failed
• Initiated landiolol at very low dose
• Specific reassessment period after administration
• Clinical features used for evaluation
• 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
• 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
CJStephenson 14
Interventions
Baseline
Characteristics
Patient Outcomes
Author’s
Conclusion
Strengths
Limitations
• 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
Esmolol 500 mcg/kg load followed by infusion at 0-100 mcg/kg/min
Results
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 7
6
arrival (min)
Total pre-hospital
25 (18,29)
42 (25.5, 51)
time (min)(IQR)
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
5 (83.3)
3 (15.8)
catheterization from ED (%)
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
3 (50)
2 (10.5)
good neurologic outcome (%)
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
• Inclusion criteria defined exact number of defibrillations and doses of
medications needed
• Therapeutic hypothermia and catheterization was reported
• Retrospective
• Sample size
• Non-blinded, non-randomized
CJStephenson 15
•
Take Home Points
•
•
•
•
Different rates of therapeutic hypothermia and catheterization between the
groups
Descriptive statistics
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
CJStephenson 16
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CJStephenson 18
Appendix A. ACLS algorithm
Appendix B. Mechanism of action
Dideoxyadenosine
Forskolin
Dibutyryl cAMP
Ethylene glycol tetraacetic acid (EGTA)
Cobalt
Tetrodotoxin
Verapamil
Adanylate cyclase inhibitor
Direct action stimulates adenylate cyclase
cAMP analog
Chelating agent
Depresses oxygen uptake by the mitochondria
Block the pore of the Na+ channel
Non-dihydropyridine calcium channel blocker
CJStephenson 19