Beta-Blocker and Calcium Channel Blocker

Overdose: Management and Unique Considerations

Najma Ansari, PharmD, PGY-1 Resident
Preceptor: Eve Anderson, PharmD, BCPS
Conflict of Interest

 I have no actual or potential conflict of interest in relation to this

presentation

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Learning Objectives
 Identify signs and symptoms of beta-blocker and calcium channel blocker overdose

 Discuss the use of High-dose Insulin euglycemia therapy for beta blocker and calcium channel
blocker toxicity

 Review pharmacological therapies for the management of beta blocker and calcium channel
blocker overdose

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Epidemiology
 American Association of Poison Control Centers: Beta Blockers (BB) and Calcium Channel
Blockers (CCB) account for 41% of all cardiovascular drug exposures reported
 67% of death as a result of cardiovascular drug exposures

 2019: 27,930 cases of BB poisoning and 15,176 cases of CCB poisoning in the US

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2019 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS)
Pathophysiology

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
Chakraborty RK. Calcium channel blocker toxicity. In:StatPearls.2021.
 Unique characteristics – Beta Blockers

Characteristic Drug Effect

Cardiac sodium channel blockade
Cardiac Potassium Channel
Blockade
Peripheral vasodilators
Acebutolol, Carvedilol, Pindolol, Bradycardia, hypotension, QRS
Propranolol widening
Acebutolol, Sotalol QTc prolongation, Torsades de
Pointes
Carvedilol, Labetalol, Nebivolol Hypotension

Lipophilic Propranolol, Labetalol, High volume of distribution

Metoprolol
Hydrophilic Atenolol, Sotalol Low volume of distribution, low
protein binding

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Agesen FN. Pharmacol Res Perspect. 2019;7(4):e00496.
 Unique characteristics - Calcium Channel Blockers
Class Drug (s) Effect
 IR and SR: peak plasma concentration within
30mins – 2h Dihydropyridines Nifedipine, Vasodilation,
 CR: peak effect in 5-7 hours Amlodipine hypotension,
reflex tachycardia
 Metabolism: Liver
 At higher doses clearance slows 1º  0º Phenylalkylamines Verapamil Bradycardia
Benzothiazepines Diltiazem Bradycardia,
 Excretion: Kidney vasodilation

IR: Immediate Release

SR: Sustained Release 7
CR: Controlled Release Br J Clin Pharmacol. 2016;81(3):453-461.
 Clinical Characteristics
Characteristics Beta Blocker Calcium Channel Blocker
Time to presentation Within 6 hours Symptoms can be delayed up to 16 hours

Cardiac Bradycardia, reduced contractility; little or no Negative inotropy, chronotropy, impaired glucose
effect on peripheral vasculature utilization by cardiac cells

Vascular smooth muscles Hypotension Systemic hypotension, coronary vasodilation

Conduction abnormalities First degree heart block, QTc widening Sinus bradycardia, PR interval prolongation
(verapamil)
CNS Drowsiness, confusion, dizziness Seizures, coma, hypoxia
Large doses: hallucinations, seizures, coma

Metabolic disturbances Hypoglycemia, hyperkalemia, hypothermia Insulin resistance and hyperglycemia, metabolic
acidosis, mild hypokalemia and hypocalcemia
Others Bronchospasm Non-cardiogenic pulmonary edema, MI, renal
failure, bowel infarction, ileus

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
Chobanian AV et al. JAMA.2003;289(19):2560-2571.
 Vasoplegic shock

• Vasodilation
• Warm skin

Cardiogenic shock

• Decreased contractility
Clinical Presentation • Bradycardia
• Cool skin

Mixed Presentation

• Loss of selectivity
• Bradycardia and hypotension
• Warm skin

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
Assessment Question #1
 Which of the following signs/symptoms are specific to beta blocker overdose?
a. Bradycardia and hypotension
b. Negative inotropy and hypotension
c. Bronchospasm and hypoglycemia
d. Negative inotropy and hyperglycemia

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Assessment Question #1
 Which of the following signs/symptoms are specific to beta blocker overdose?
a. Bradycardia and hypotension
b. Negative inotropy and hypotension
c. Bronchospasm and hypoglycemia
d. Negative inotropy and hyperglycemia

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 Time of ingestion and number of tablets ingested

EvaluationE
Type of drug ingested, formulation, concomitant ingestion
with other drugs/alcohol/illicit drugs

Vital signs
Evaluation
Baseline EKG

Blood gas analysis

Serum electrolytes, creatinine, and bedside fingerstick

glucose test

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
 Goals of Therapy

1 2 3 4
Limit the absorption of Promote Provide hemodynamic Restore normal
drug(s) metabolism/excretion support until the cardiovascular status
of drug(s) ingested agents are
metabolized and
eliminated

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 Management Overview

Gastric Decontamination • Gastric lavage

• Activated charcoal
• Whole bowel irrigation
Reversal of cardiovascular effects • Atropine
• Calcium
• Glucagon
• Vasopressors
Hemodynamic support • High-dose Insulin Euglycemic Therapy
• Intralipids
• Methylene Blue
Refractory hypotension • Angiotensin II

Treatment refractory cardiovascular toxicity • Hemodialysis

• ECMO

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 Within 1 hour of presentation
• Orogastric lavage

Gastrointestinal Within 4 hours of presentation

Decontamination • Activated charcoal: 1g/kg

Large ingestion of Sustained Release

products
• Whole bowel irrigation

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
 Indication: CCB toxicity with suspected
hypotension from cardiogenic shock
and/or vasodilatory shock
• Calcium gluconate (peripheral IV access)
• Bolus: 3g/100mL over 5-10 minutes
Calcium • Calcium chloride (central IV access)
• 1g over 2-5 minutes

MOA: Improves cardiac output due to

improved contractility by increasing
calcium release

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
 Indication: Hypotension and severe
bradycardia
• Norepinephrine, Epinephrine

MOA: Increases contractility, heart rate,

and systemic venous resistance
Catecholamines • Increased cardiac output and blood pressure

Titrate up to a MAP >65 mmHg

• No max dose

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
 Indication: Bradycardia in Beta Blocker overdose

MOA: Directly stimulates conversion of ATP to

cAMP

Dose: 3 to 5 mg (50-150 mcg/kg) IV bolus slowly

Glucagon over 1-2 minutes
• May repeat at increased dose of 4-10 mg in 5 minutes if no effect
• Continuous infusion: 5mg/h (Max 10mg/h)

ADE: Nausea, vomiting

• Premedication with anti-emetic

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
 Indication: Vasoplegic shock with normal or
depressed cardiac function

MOA: Increased intracellular glucose

transport, increased inotropy and vascular
High-dose Insulin dilatation
Euglycemic Therapy • Onset: 15-60 mins
(HIET)
Bolus: 0.5–1 units/kg as IV push
Continuous infusion: Initiated at 0.5–1 units/kg/h
and titrated up to as high as 10 units/kg/h

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
Efficacy of High-Dose Insulin (HDI)
 Holger et al: HDI (10 units/kg/h) vs vasopressin + epinephrine in porcine model of
propranolol poisoning
 Insulin group: Decreased SVR while maintaining goal MAP and increased cardiac
output
 Vasopressin/epinephrine group: Increased MAP and SVR initially steady decline
until death. Steady decline in cardiac output and heart rate
 Survival rate: 5/5 in HDI vs 0/5 in vasopressin/epinephrine
 Engebretsen et al: Mixed beta blocker/calcium channel blocker overdose treated with
HDI
 Insulin rate titrated to 16.7 units/kg/h
 Single episode of hypoglycemia
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Engrebretsen et al. Clinical Toxicology. 2011;49(4):277-283.
  34 YOF with PMH of HTN and renal failure ingested 12 ER tablets of
amlodipine 2.5mg
 48 YOM with PMH of HTN, COPD, CHF, and depression ingested an unknown
amount of diltiazem
 Hypotension, bradycardia
 Calcium, IV Fluids, glucagon and vasopressors; no change in vitals
 HIET initiated at 0.5 units/kg/h rapidly reversed cardiovascular collapse in
Case 6h

Reports  59 YOF unknown PMH ingested 5.76g of diltiazem ER

 Hypotension and bradycardia
 IV Fluids, vasopressors, and standard insulin dose; remained hypotensive
 Insulin dose increased to 25 units/h + D50
⎻MAP increased to 80mmHg in 30 mins
⎻All vasoactive agents discontinued in 60 mins

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Boyer EW et al. N Engl J Med. 2001;344(22):1721-1722.
Min L. Crit Care Resusc. 2004;6(1):28-30.
 The safety of high-dose insulin euglycemia therapy in
toxin-induced cardiac toxicity
Objective To investigate the safety of high-dose insulin in toxin induced (BB and CCB)
cardiac toxicity

Methods Retrospective case review (N = 22)

Demographics • 22 patients (12 females)
• Median age: 57 years

Parameters assessed • Clinical effects, serum glucose, electrolytes

• Rate of insulin administration

Outcomes • Adverse effects of insulin administration

• Hypoglycemia during and after insulin administration
• Hypokalemia, hypomagnesemia, hypophosphatemia
• Cardiac arrhythmias

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Page CB et al. Clin Toxicol (Phila). 2018;56(6):389-396.
 The safety of high-dose insulin euglycemia therapy in
toxin-induced cardiac toxicity

Results • Hypoglycemia during treatment: 16 patients (7- mild 45-61 mg/dL; 9- severe <45 mg/dL)
• Hypoglycemia after Insulin was stopped: 15 patients (median glucose 47 mg/dL)
• Hypokalemia: 18 patients (Mild in 16 patients 2.5-3.4 mEq/L)
• Hypomagnesemia: 16 patients (Mild in 10 patients 1.2–1.68 mg/dl and severe in 6 patients
< 1.2 mg/dl)
• Hypophosphatemia: 15 patients (Severe in 7 patients <0.99 mg/dL)

Other outcomes • Median LOS: 4.2 days

• Median Insulin initiation time: 3.5h
• Median LD: 80 units or 1 unit/kg
• Median maximum infusion rate: 150 units/h
• Median duration of Insulin infusion: 21h
• Median duration of glucose administration: 18h after ceasing Insulin

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Page CB et al. Clin Toxicol (Phila).2018;56(6):389-396.

 The safety of high-dose insulin euglycemia therapy in
toxin-induced cardiac toxicity

Limitations • Small descriptive study without confirmatory drug concentrations

• No standard protocol for glucose or electrolyte replacement
Conclusion • HD-Insulin therapy has a significant effect on glucose and electrolyte
homeostasis
• Large doses of Insulin cause a prolonged requirement for glucose
• No relationship between increased insulin dose and increasing/worsening
adverse effects
• Suggests that HD-Insulin therapy with Insulin infusion rates up to
10units/kg/h is as safe as low dose Insulin therapy (1-2 units/kg/h)

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Page CB et al. Clin Toxicol (Phila). 2018;56(6):389-396.
 HIET – Unique Considerations
 Maintaining Euglycemia  Electrolyte imbalance
 Monitor serum glucose Q15-20 mins, once  Baseline potassium and recheck Q1H while
stable check hourly titrating insulin, once stable check Q6H
 Keep serum glucose 100-250 mg/dL  Replace K+ if <3.2mmol/L before initiation
 Dextrose (0.5g/kg bolus and 0.5g/kg/h of and during HIET
continuous infusion) titrated to blood
glucose >100 mg/dL  Magnesium and Phosphorus replacement

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
Assessment #2
 What would be an appropriate bolus dose of HD-Insulin for a person weighing 64kg?
a. 8 units
b. 16 units
c. 32 units
d. 80 units

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Assessment #2
 What would be an appropriate bolus dose of HD-Insulin for a person weighing 64kg?
a. 8 units
b. 16 units
c. 32 units (0.5 units/kg)
d. 80 units

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IU Health High-dose Insulin Orderset
Beta-adrenergic Blocker and Calcium Channel Blocker Overdose

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Intravenous Lipid Emulsions
 Indication: Refractory cardiogenic or vasodilatory shock due to
lipophilic agents
 MOA: Cardiac fatty acid metabolism, alters sodium or calcium channel
function, draws lipophilic substances into ‘lipid sink’ enhancing
elimination
 Improves BP, perfusion and heart rate
 Not recommended if planning ECMO
 Dose:
 LD: 1.5mL/kg 20% lipid emulsion
 Infusion: 0.25mL/kg/min for 30 min
 ADEs: Pancreatitis, blood hyper viscosity, pulmonary edema

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Walter E et al. J Intensive Care Soc. 2018;19(1):50-55.
 Indication: Refractory vasodilatory shock due to Calcium
Channel Blockers

MOA: Inhibits NO synthase; blocks formation of cGMP

Methylene Blue
Dose: 1-2 mg/kg over 20-60 minutes x1

ADEs: Blue discoloration of skin and secretions, hemolysis,

methemoglobinemia, hypertension and tachycardia (serotonin
syndrome)

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Graudins A et al. Br J Clin Pharmacol. 2016;81(3):453-461.
Aggarwal N. BMJ Case Rep. 2013;2013:bcr2012007402.
 Indication: Treatment refractory hypotension

MOA: AT-II receptor on vascular smooth muscles causing

contraction and increase in systemic venous pressure

Angiotensin II Dosing: Initiate with 20ng/kg/min via continuous infusion

• Titrate Q5mins by 15ng/kg/min to achieve target BP
• t ½ 1 min

ADEs: DVT, thromboembolic disorder

• Thromboembolism prophylaxis

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Khanna A et al. N Engl J Med. 2017;377(5):419-430.
Angiotensin II: A new tool in the management of
refractory antihypertensive overdose?

 50 YOM with h/o HTN, HLD, borderline DM, depression c/o reported OD of amlodipine and
metoprolol.
 Bradycardic, hypotensive, warm extremities, and unresponsive
 Vitals: T 98ºF, BP 81/45mmHg (MAP 57 mmHg), HR 45, RR 16, SPO2 98% on RA
 Intubated with ketamine and resuscitation initiated with 1L NS bolus and infusions of both
norepinephrine at 20mcg/min and epinephrine at 10mcg/min
 High-dose Insulin was initiated early on at 1unit/kg/h
 After 1 hour, despite adequate volume resuscitation and escalating norepinephrine and
epinephrine infusion to 50mcg/min each and HD-Insulin at 3units/kg/h, pt remained
bradycardic with MAP below goal of 65 mmHg
 What additional agent(s) could be considered in this patient with distributive shock?

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Murray BP, Carpenter JE. ACEP Toxicology Section. March 2019
Assessment #3
 45 YOM is brought to the ED c/o respiratory failure and shock after ingesting an unknown
amount of amlodipine. Time of ingestion is not known. On examination, skin appears warm and
flushed with BP 80/44mmHg, HR 52, RR 10, T 98.8F. Pt is started on 1L NS, bolus of 3g/100mL
calcium gluconate, and continuous infusions of both norepinephrine and epinephrine. MAP is
still <50mmHg. What is the next best therapeutic agent in this patient?
a. Angiotensin II
b. High-dose Insulin
c. Glucagon
d. Intralipid emulsion

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Assessment #3
 45 YOM is brought to the ED c/o respiratory failure and shock after ingesting an unknown
amount of amlodipine. Time of ingestion is not known. On examination, skin appears warm and
flushed with BP 80/44mmHg, HR 52, RR 10, T 98.8F. Pt is started on 1L NS, bolus of 3g/100mL
calcium gluconate, and continuous infusions of both norepinephrine and epinephrine. MAP is
still <50mmHg. What is the next best therapeutic agent in this patient?
a. Angiotensin II
b. High-dose Insulin
c. Glucagon
d. Intralipid emulsion

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Additional Treatment Considerations
 Symptomatic Bradycardia  Cardiac rhythm abnormalities
 Atropine sulfate  Sodium bicarbonate for QRS widening or ventricular
⎻0.5–1 mg IV dysrhythmias
 Hypotension ⎻Dose: 1-2 mEq/kg IV bolus
 Fluids  Prolonged QT: Correct Potassium, magnesium, calcium,
lidocaine
⎻10-20 mL/kg bolus
⎻IV crystalloids
 Monitor: Serial ECGs
 Monitor:  Seizures
⎻ECHO
 Benzodiazepines
 Bronchospasm
 Related to beta-2 antagonism
 Rx: Inhaled Beta-2 agonists
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 Summary

Gastric Decontamination • Gastric lavage

• Activated charcoal
• Whole bowel irrigation
Reversal of cardiovascular effects • Atropine
• Calcium
• Glucagon
• Vasopressors
Hemodynamic support • High-dose Insulin Euglycemic Therapy
• Intralipids
• Methylene Blue
Refractory hypotension • Angiotensin II

Treatment refractory cardiovascular toxicity • Hemodialysis

• ECMO

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Accessing CE

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