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Kristen C. Sherlin, PharmD

Emergency Medicine Clinical Pharmacist

University of Louisville Hospital

Objectives

1. Identify medications known to cause toxicity in overdose situations

2. Review management principles of toxic overdoses

3. Demonstrate understanding through participation in active learning activity

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Resources Toxidromes

Acetaminophen Toxic Alcohols

Calcium Channel Blockers

Beta Blockers

Acetaminophen

Mechanism: prostaglandin inhibitor

Most common cause of acute hepatic failure 30% incidence in patients presenting 8

hours after ingestion

FDA maximum recommended dose: 4 grams daily

Ciejka. Clin Lab Med. 2016.

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Acetaminophen Metabolism

Ciejka. Clin Lab Med. 2016.

Acetaminophen Overdose Clinical Presentation

Ciejka. Clin Lab Med. 2016.

Acetaminophen Overdose Monitoring

Ciejka. Clin Lab Med. 2016.

Treatment of Acetaminophen Overdose N-acetylcysteine (NAC)

Nearly 100% effective if administered within 8 hours of ingestion

Available in oral and IV formulations ○ IV form should be used in severe cases

Common side effects:○ Nausea/vomiting○ Anaphylactoid reactions

Activated charcoal May administer if patient has stable mental

status and presents within 1 hour of ingestion

Ciejka. Clin Lab Med. 2016.

Treatment of Acetaminophen Overdose Administer NAC to acute APAP

overdose with either possible or probable risk for hepatotoxicity (level B) Ideally within 8-10 hours postingestion

Administer NAC to patients with hepatic failure thought to be due to APAP (level B)

Ciejka. Clin Lab Med. 2016.

Treatment of Acetaminophen Overdose

NAC

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Treatment of Acetaminophen Overdose

Oral IV

Loading dose: 140 mg/kg x 1 dose For treatment within 8 hours of ingestion: • Initial bolus: 150 mg/kg IV over 1 hour • Infusion: 50 mg/kg over 4 hours • Then: 100 mg/kg over 16 hours

Then: 70 mg/kg every 4 hours x 17 doses

For treatment > 8 hours after ingestion, chronic ingestion, or for those with hepatic failure:• Infusion: 12.5 mg/kg/hr over 48 hours

May be discontinued once the protocol is complete if: • Serum APAP level < 10 μg/mL

• No signs of ongoing hepatic injury

Acetadote [package insert]

Toxic Alcohols

Ethylene glycol

Methanol

Propylene glycol

Isopropanol

Mégarbane. Open Access Emerg Med. 2010;2:67-75.

Ethylene Glycol Mechanism of Toxicity

Mégarbane. Open Access Emerg Med. 2010;2:67-75.

Ethylene Glycol Clinical Presentation Early

Inebriation or altered mental status

Late Metabolic acidosis Hyperventilation Anion gap Oxalate crystalluria Renal failure Clinical hypocalcemia Life-threatening arrhythmias Coma Seizures Death

Mégarbane. Open Access Emerg Med. 2010;2:67-75.Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.

Ethylene Glycol Toxicity Diagnosis

Serum chemistry Blood gases

Plasma EG concentration

Osmolal gap Difference between the measured osmolality

and the calculated osmolality ○ Normal = < 10 mOsm/kg H20

Calculated Osmolality mOsm/L = 2(Na+) + BUN/2.8 + glucose/18

Mégarbane. Open Access Emerg Med. 2010;2:67-75.Gennari, et al. N Engl J Med. 1984;310(2):102-5.Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.

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Treatment of Ethylene Glycol Toxicity

Mégarbane. Open Access Emerg Med. 2010;2:67-75.

Treatment of Ethylene Glycol Toxicity

Criteria for Fomepizole

Documented recent history of ingestion of

a toxic amount of toxic alcohol and osmolal gap > 10

mOsmol/L

Documented plasma concentration ≥ 20

mg/dL

Suspected ingestion with at least 3 of the following criteria: • Arterial pH < 7.3• Serum bicarbonate

concentration < 20 mmol/L

• Osmolal gap > 10 mOsm/L

• Oxalate crystalluria

Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.

Treatment of Ethylene Glycol Toxicity Fomepizole Dosing

Loading dose: 15 mg/kg IV infused over 30 minutes

Followed by 10 mg/kg IV q12h x 4 doses Then 15 mg/kg q12h until ethylene

glycol concentration < 20 mg/dL and pH is normalized

Dose adjustment If patient requires concomitant hemodialysis

(HD)

Antizol [package insert]. April 2009.

Fomepizole

Adverse reactions Headache Nausea Dizziness Drowsiness Metallic taste

Food interactions Ethanol decreases the rate of fomepizole

elimination by ~ 50% Fomepizole decreases rate of elimination of

ethanol by ~ 40%

Antizol [package insert]. April 2009.

Hemodialysis Indications

Arterial pH < 7.0

Drop in arterial pH > 0.05 resulting in an

abnormal pH despite bicarbonate

infusion

Inability to maintain arterial pH > 7.3

despite bicarbonate therapy

Decrease in bicarbonate

concentration> 5 mmol/L despite

bicarbonate therapy

Renal failure

Deteriorating vital signs despite

intensive supportive care

Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.

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Other Treatment Principles for Ethylene Glycol Toxicity

Gastric lavage, activated charcoal, or ipecac syrup are not recommended

Asymptomatic inhalation exposures can be managed out-of-hospital

Unintentional, asymptomatic ingestions > 24h since exposure without alcohol co-ingestion do not need medical treatment

Sodium bicarbonate should be administered if pH < 7.3

Calcium is only recommended if hypocalcemia significantly contributes to symptoms

Pyridoxine and thiamine

Mégarbane. Open Access Emerg Med. 2010;2:67-75.Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.

Alternative Treatments??

Treatment of Ethylene Glycol Toxicity

Treatment of Ethylene Glycol Toxicity

Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.Rietjens, et al. Neth J Med, 2014;72(2):73-9.

Fomepizole

Advantages

Higher affinity for ADH

Minimal adverse effects

Monitoring not necessary

Certain patients may not need

dialysis

Disadvantages

Expensive

Limited shelf life

Less experience

Ethanol

Advantages

Inexpensive

Available in most medical centers

Traditional antidote

Disadvantages

Significant adverse effects

Requires ICU hospitalization

Intensive monitoring

Rietjens, et al. Neth J Med, 2014;72(2):73-9.

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Calcium Channel Blockers (CCBs): Pharmacology

Dihydropyridines: antagonism of L-type calcium channels in the peripheral vasculature Produce potent vasodilation, have minimal effect on

cardiac contractility Ex: Amlodipine, nicardipine, nimodipine

Non-dihydropyridines: antagonism of L-type calcium channels in the myocardium Produce a reduction in cardiac contractility, heart

rate Ex: diltiazem, verapamil

Dewitt CR. Toxicol Rev. 2004;23(4):223-38.

Mowry JB. Clin Toxicol (Phila). 2015;53(10):962-1147.

Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

Calcium Channel Blocker: Clinical Presentation Cardiovascular effects

Hypotension

Bradycardia○ Most commonly with non-

dihydropyridine overdoses

Tachycardia○ Most commonly with

dihydropyridine overdoses

Signs of heart failure○ Pulmonary edema

○ Jugular venous distention

Endocrine effects Hyperglycemia

Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

Image: De león DD. Nat Clin Pract Endocrinol Metab. 2007;3(1):57-68.

Beta Blockers: Pharmacology

Antagonism of beta-1 and beta-2 receptors

Receptor activity Beta-1: primarily located in cardiac tissue, increased

inotrophy/chronotrophy

Beta-2: most prominent in vascular smooth muscle and bronchioles, leads to vasodilation and bronchodilation

Mowry JB. Clin Toxicol (Phila). 2015;53(10):962-1147.

Image: Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

Beta Blocker Overdose: Clinical Presentation Cardiovascular

Hypotension

Bradycardia

Signs of cardiogenic shock

○ Pulmonary edema

○ Jugular venous distention

1st degree heart block

Pulmonary Bronchospasm

Neurologic Delirium

Coma

Seizures

Endocrine Hypoglycemia

Image: Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

Beta Blockers: Pharmacology

Lipophilicity of a beta blocker is a major determinant of central nervous system penetration and effects of beta blocker overdose May potentiate seizures, delirium, coma

Lipophilic beta blockers Propranolol

Nebivolol

Carvedilol

Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

Reith DM. J Toxicol Clin Toxicol. 1996;34(3):273-8.

Overdose TreatmentCalcium Glucagon Catecholamines

Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.

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Calcium Preparations

Calcium gluconate Calcium chloride

10 mL of 10% solution

4.5 mEq of Ca2+

10 mL of 10%

13.6 mEq of Ca2+

• Must be administered via central venous access• Adjust infusion based on ionized calcium

• Calcium is contraindicated in concurrent digoxin toxicity

Calcium gluconate. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH.Calcium chloride. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH.

Optimum Calcium Dosing

Failure of human cases are probably under resuscitated

Animal models suggest need for high doses

• 8-20 mg/kg (0.4-1 mEq/kg) Bolus

• 36-300 mg/kg/hr (1.8-15 mEq/kg/hr)Infusion

• 1.5-2 x [Ca2+] associated with improved cardiodynamicsEndpoint

Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.

Calcium Guidelines

20 mg/kg Ca2+

bolus (0.2 ml/kg CaCl2)

Favorable hemodynamic

response

20-50 mg/kg/hrCa2+ continuous infusion (0.2-0.5 ml/kg/hr CaCl2)

No hemodynamic changes

Alternate therapy

Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.

Calcium Adverse Effects

Hypokalemia

Hypotension

Bradycardia

Dysrhythmia

Tissue extravasation

CCB Treatment Guideline

47St-onge M. Crit Care Med. 2016;10.

Glucagon Evidence Highest level in beta-blocker overdose

Successes and failures in calcium channel blockers

Indications Hypotension

Bradycardia

Dose Bolus: 2-5 mg IV

Infusion: 1-10 mg/hr

Calcium gluconate. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH.Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.

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Glucagon Limitations

Cost Glucagon 1 mg = $205.92

Availability Survey of 47 hospitals in Washington DC

○ 30 mg in 26%

○ 50 mg in 15%

Nausea and vomiting

Transient response

Glucagon. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OHLove, Jeffrey N et al. AEM. 1993;22(2):267-268.

High Dose Insulin and Glucose Infusion Rationale

Promotes carbohydrate metabolism in stressed myocardium○ Positive inotrophy and chronotrophy

Administration Initial insulin bolus: 0.5-1 unit/kg IV

0.5-1 unit/kg IV infusion, titrated to mean arterial pressure (MAP)

Dextrose infusion: 0.5 gm/kg/hr to maintain serum glucose levels

Aggressive potassium replacement

50Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

St-onge M. Clin Toxicol (Phila). 2014;52(9):926-44.

St-onge M. Crit Care Med. 2016;10.

Vasopressor Therapy

Norepinephrine is typically first choice High doses and multiple agents may be necessary

Dobutamine may be added for confirmed cardiogenic shock

Avoid Dopamine

Vasopressin as monotherapy

51Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

St-onge M. Clin Toxicol (Phila). 2014;52(9):926-44.

St-onge M. Crit Care Med. 2016;10.

Methylene Blue

Mechanism Inhibitor of guanylate cyclase

Decreased levels of cGMP

Scavenger of NO

Reduces vasodilation, counteracts calcium channel blocker mechanism of action

52Aggarwal N. BMJ Case Rep. 2013;2013

Intravenous Lipid Emulsion (ILE) Therapy Infusion of parenteral nutrition lipid formulation as a therapy

for overdoses Initially studied in local anesthetic overdoses

Now studied in wide range of overdoses

Mechanism theories “Lipid sink”

Free fatty acid source of energy for myocardium

Administration 1 to 1.5 ml/kg IV boluses of 20% solution over 1 minute

○ Repeat up to 3 times

0.25 to 0.5 ml/kg/min infusion until hemodynamic stability occurs

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Intravenous Lipid Emulsion Therapy Adverse Effects

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Hypertriglyceridemia

Fat embolism

Infection

Hypersensitivity reactions

Venous thromboembolism

Acute kidney injury

Pancreatitis

Lipid dose of a 70 kg patient Bolus dose: 14-21 gm

Continuous infusion: 3.5-7 gm/min

Palatnick W. Emerg Med Pract. 2014;16(2):1-19.

Hayes BD. Clin Toxicol (Phila). 2016;54(5):365-404.

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BB Lipophilicity and ILE Efficacy

Lipid sink mechanism of action for ILE may limit usefulness in non-lipophilic drugs Less partitioning of the drug molecules into the infused

lipid reservoir from tissues

55Samuels TL. Anaesthesia. 2011;66(3):221-2.

Beta Blocker

Lipid Solubility Coefficient (log

P)

Relative Lipid Solubility

Carvedilol 3.29 High

Propranolol 2.8 High

Metoprolol 1.35 Low to moderate

Atenolol 0.56 Low

Browne A. J Med Toxicol. 2010;6(4):373-8.

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