New York University
Department of Emergency
Medicine/Medical Toxicology
Antidotes for cardiovascular drug
poisoning
David H. Jang
Assistant Professor
Masters of Science Degree in Clinical Investigation (K30)
Clinical and Translational Science Institute (CTSI)
*Funded by the American Academy of Clinical Toxicology Junior Investigator Research Grant and also
supported in part by grant 1UL1RR029893 from the National Center for Research Resources,
National Institutes of Health.
Case

44 year-old man
presents with a
“overdose” after an
argument with his
mother

Patient obtained these
medications from his
mother who he still
lives with in her
basement
Case

Vitals on presentation:





Blood pressure: 140/90
mmHG
Heart rate: 90 BPM
Respiratory rate: 12
Temperature: 98.6
Oxygen saturation:
100% RA
Case
6 hours later…
Case

Repeat Vitals:





Blood pressure: 85/40
mmHG
Heart rate: 40 BPM
Respiratory rate: 20
Temperature: 98.6
Oxygen saturation:
100% RA
Case

Intubated

Hemodynamic support




On norepinephrine
On dopamine
On epinephrine
Still hypotensive…
Options?
Antidotes for cardiovascular
drug poisoning
Cardiovascular drug class

Antihypertensives
 Imidazolines
 Beta-blockers
 Calcium channel
blockers
 ACE-Is and ARBs

Cardioactive steroids
 Digoxin

Antidysrhythmics
 Flecainide
Cardiovascular drug class

Antihypertensives
 Imidazolines
 Beta-blockers
 Calcium channel
blockers
 ACE-Is and ARBs

Cardioactive steroids
 Digoxin

Antidysrhythmics
 Flecainide
Not all things are created
equal…
Beta-blockers

Non-selective


B1-selective



Carvedilol
Atenolol
Esmolol
Intrinsic
sympathomimetic

Pindolol
Beta-blockers

Potassium channel
blockers


Sotalol
Membrane-stabilizing

Propanolol
Calcium channel blockers

Phenylalkylamine


Benzothiazepine


Verapamil
Diltiazem
Dihydropyridines



Nifedipine
Amlodipine
Nicardipine
Epidemiology
Epidemiology
Epidemiology
Epidemiology
Beta and calcium channel
blocker poisoning

Clinical Features



Bradycardia
Hypotension
Management





Isotonic fluids
Glucagon
Inotropes/Pressors
High-insulin
Lipid emulsion
Beta and calcium channel
blocker poisoning

Clinical Features



Bradycardia
Hypotension
Management





Isotonic fluids
Glucagon
Inotropes/Pressors
High-insulin
Lipid emulsion
Beta and calcium channel
blocker poisoning

Clinical Features



Bradycardia
Hypotension
Management





Isotonic fluids
Glucagon
Inotropes/Pressors
High-insulin
Lipid emulsion
High insulin-euglycemic
therapy (HIE)
Historical use

Glucose-insulinpotassium (GIK)

Acute myocardial
infarction

Heart failure
Myocardium
Background

Hallmark of BB and
CCB poisoning

Bradycardia

Vasodilation

Decreased contractility
Background

Altered myocardial
physiology

Hyperglycemia
(pancreas/liver)

Altered myocardial
substrate use

Inhibition of lactate
oxidation
Mechanism of action

Alters ions
homeostasis
(potassium/calcium/so
dium)

Metabolic support

Increase lactate uptake

Epi and glucagon
promote FFA use
(increase energy)
Experimental evidence
Experimental evidence
Groups
1. Control: (0/6)
2. Epi: (4/6)(2/4)
3. HIE: (6/6)(6/6)
4. Glucagon: (3/6)(0/3)
Experimental evidence
Groups
1. Control: (0/6)
2. Epi: (4/6)(2/4)
3. HIE: (6/6)(6/6)
4. Glucagon: (3/6)(0/3)
Clinical experience
Clinical experience
Adverse events

Hypoglycemia

Hypokalemia
Treatment guidelines
Intralipid
Background



Triglycerides and
phospholipids
Primary triglycerides
composed of linoleic,
linolenic, and stearic
acid
pH 8, isotonic, various
concentrations
availiable (20% is
primarily used)
Mechanism of action
1. Modulation of
intracellular
metabolism
2. Lipid sink
3. Activation of ion
channels
Experimental evidence
Experimental evidence
Clinical experience
Adverse events
Adverse events
Treatment guidelines
www.lipidrescue.org
Treatment guidelines
Summary

Consider HIE early for
suspected CCB
poisoning

Consider lipid emulsion
when a patient is
perimortem with
suspected lipid-soluble
medication
Methylene blue (MB)
Methylene blue

Sentinel node
detection

Acquired
methemoglobinemia

Vasodilatory shock


Anaphylaxis
Sepsis
Nitric oxide synthase
Physiology of vascular
tone
The evidence for MB
Mechanism of action
Vasodilatory shock from
overdose?
Why calcium channel
blockers?
Why calcium channel
blockers?
Mechanism of action
So to test this…
Methods

Design:


Controlled, blinded
animal design
Subjects:


Adult Sprague-Dawley
rats (300-600 grams)
Preparation
(Instrumentation/sedation)

Protocol:


Phase 1: Dose-finding
Phase 2: Methylene
blue
Protocol summary and
timeline
Phase 1: Amlodipine dose determination
4 mg/kg: Incrementally increase dose 50% and decrease 50%
(5 rats per group – 1, 2, 4, 6, 8 mg/kg)
End-point: Decrease of mean arterial pressure
to10% of baseline
Amlodipine dose
Protocol summary and
timeline
Group 1: AmlodipineNormal saline (Control group)
Group 2: AmlodipineMethylene Blue (Treatment group)
Protocol summary and
timeline
Group 1: AmlodipineNormal saline (Control group)
Group 2: AmlodipineMethylene Blue (Treatment group)
Phase 2: Methylene blue treatment
Baseline Amlodipine
15 min
MB (2 mg/kg)
or saline
3-hours or until death
5 min
0 mins
180 mins
Results
Methylene blue-Pending
Normal Saline-Pending
Questions?