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49th Annual Meeting Disclosure

• I do not have a vested interest in or affiliation with any corporate organization offering financial Prescription Drug Overdose Emergencies support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially Daniel Yousef, Pharm.D., BCPS Clinical Hospital Pharmacist, Emergency Medicine bias my presentation Jackson Memorial Hospital

OWNING CHANGE: Taking Charge of Your Profession

Objectives Assessment Questions

1. Sodium Bicarbonate drips for TCA overdose should be • Pharmacist Objectives:  1. List prescription drugs commonly identified in lethal overdoses, either accidental or compounded: intentional  A. ½ NS with 3 amps of sodium bicarbonate  2. Explore the use of fat emulsions to reverse acute drug toxicity  3. Examine the pearls of high-dose insulin therapy for acute beta-blocker toxicity  B. 1L NS with 3 amps of sodium bicarbonate and calcium channel blocker toxicity  C. 1L D5W with 3 amps of sodium bicarbonate  D. Use hypertonic saline first line not sodium bicarbonate • Technician Objectives:

• 1. List common medications identified in intentional and accidental 2. True of False: Ethanol dosing in toxic alcohol ingestions overdoses is based on a 10% solution for IV and 20% solution for • 2. Describe the risks of compounding high-dose insulin therapy for acute drug toxicity oral 3. True of False: Lipid emulsion boluses can be programmed in a standard infusion pump

Ingestions Associated with High Mortality Opioid Overdoses

• Opioids • One most common overdoses in emergency rooms

• Toxic Alcohols • In many cases treated easily with the opioid antagonist • Tri Cyclic Antidepressants naloxone • Beta-Blockers & Calcium Channel blockers • Goal of giving naloxone is to maintain a patient airway and respiratory rate greater than 8 breath/min

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Concerns with Naloxone Naloxone Dosing

• Most cited concern is precipitating withdrawal • Dose range 0.04 mg to 2 mg repeat every 2-3  This should be the least concern in patients with respiratory minutes as needed keep respiratory rate >8 rates <6 breaths/min breaths/min

• Non-cardiogenic pulmonary edema from catecholamine  How do you decide to give 0.04mg or 2 mg? surge • Prepare 0.04 mg dose diluting 0.4 mg with 9 mL of  Best avoided by bagging patient before and during normal saline

naloxone administration  Labeling and logistical concerns

• Case reports describe hypertension, cardiac • Incident in California dosing naloxone at 0.04 mg dysrhythmias, and acute lung injury  Case reports make it difficult to attribute such complications to naloxone alone

Tri-Cyclic Antidepressant (TCA) Naloxone Drip Overdoses

• Recommendation is to give 2/3 of effective dose as • Acute ingestions of 10-20 mg/kg cause significant starting dose for the drip cardiovascular and CNS toxicity

 Poison center recommends: Multiplying the effective dose by • Patients are typically sedated, confused, delirious and 6.6, placing that amount in 1L and running at 100 mL/hr or hallucinating  Example: Patient responds after 3 mg of naloxone  6.6 x 3= 19.8 mg, place in 1L normal saline and run at 100 • Cardiac conduction delays, arrhythmias, hypotension mL/hr= 2mg/hr and anticholinergic toxicity (hyperthermia, flushing,  Pharmacy issues include compounding a non-standard dilated pupils) are common concentration and programing pump • Ultimately die from refractory hypotension due to myocardial depression

Sodium Bicarbonate Therapy for TCA Deciding When to Treat TCA Overdose Overdoses

• No seizures or dysrhythmias have occurred with • Bolus 1-2 mEq/kg and repeat every 5 minutes while patients with QRS <100 ms running continuous 12-lead ECG  Literature mentions hypertonic sodium bicarbonate • QRS >100 ms associated serious toxicity, including  Refers to the bristojets/ampules, drip should not be made coma, intubation, and hypotension. hypertonic

• 50% incidence ventricular dysrhythmias with • Drip 3 amps 1L D5W@ 250 ml/hr or 2-3 mL/kg/hr • QRS >160 ms • Goal pH around 7.5

• As QRS narrows decrease drip 25% per hour over 4 hours

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A Word about Hypertonic Saline Ethylene Glycol (EG) Toxicity

• Hypertonic saline has been used in patients with • Odorless and sweet tasting ongoing dysrhythmias and high serum pH • Found in antifreeze, de-icers, & industrial solvents • One case report describes use of 7.5% hypertonic  Blue or green fluorescent dye added most products contain saline ethylene glycol  Explains positive urinary fluorescence under wood lamp  Administered 256.5 mEq • Weak toxin by itself • Suggest using 23.4% (4 mEq/mL) saline and  Metabolites that are toxic administering 60 mL (240 mEq)

Primary Treatment- Methanol Methanol Toxicity and EG

• Colorless, and odorless, bitter tasting & volatile • Treatments are very similar

• Found in paint removers, duplicator fluid, gas-line • Involve inhibiting formation of toxic metabolites antifreeze, windshield washing fluid, & solid canned • Treatment involves inhibiting alcohol dehydrogenase fuel

• Weak toxin • Fomepizole favored over ethanol  Metabolites that are toxic  Less blood monitoring  Does not exacerbate the inebriated state

• Dialysis indicated in certain situations even in conjunction with fomepizole

Introduction Fomepizole Fomepizole Dosing

• Competitive inhibitor ADH • 15 mg/kg IV loading dose over 30 min  Prevents/slows formation of toxic metabolites • Maintenance dose of 10 mg/kg IV q12h over 30 min • Most effective when given early on before toxic  For 4 doses or 48 hrs metabolites have formed • After 48 hrs, if patient still requires therapy  Dependent on time of treatment initiation, and amount of toxic metabolite already formed  Increase dose to 15 mg/kg q12h

 Less dependent on amount of toxic alcohol ingested • Fomepizole levels still remain high up to 24 hrs after last dose • Primary evidence from two retrospective case series • Consult packaging HD dosing, most patients can be managed by HD alone

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Discontinuing Fomepizole Ethanol Blame it on the Aaantizol

• Published recommendations based on experience rather • Competes for binding to ADH than evidence • Can be given orally or IV • Typically stopped when serum levels of methanol or EG • Some protocols suggest titrating to legal limit fall <20 mg/dL • NOT aggressive enough- goal maintain serum level 100- • Since fomepizole levels last well beyond 24 hrs after 200 mg/dL last dose this recommendation has been questioned • Loading dose 0.06 g/kg ethanol IV followed by • Still recommend wait until <20 mg/dL AND patient is infusion of 66mg/kg/hr for non-alcoholics and 154 asymptomatic with improving organ function mg/kg/hr for alcoholic patients

• Poison control has recommended until levels are • Double infusion rate in patients on HD undetectable

Logistic of Preparing Ethanol Clinical Presentation- Beta Blockers and Calcium Channel Blockers

• Oral dosing based on 20% solution • Typically symptomatic within 2 hours of ingestion with  If choose carry whiskey or vodka that’s 80 proof or 40% Beta blockers (BB), up to 6 hrs with Calcium Channel  Suggest carrying vodka since whiskey is an acquired taste and Blockers (CCB) patients need drink a lot  All symptoms typically develop within 6-8 hours  Work with poison center find out if there dosing volume  Exception delayed release products and sotalol can take recommendation based on 20% or 40% up to 24 hrs

• Intravenous dosing based on 10% solution • Cardiac:  Commercially available as 98.5% solution in 5 mL  Hypotension (cardiac depression) and bradycardia  Need have lot of vials on hand to make a drip-40 vials minimum  Ventricular arrhythmias from agents with MSA

Treatment BB/CCB Overdose- Vasopressor Support in BB/CCB Cardiac Support Overdoses

• IV crystalloids (10-20 mL/kg) as bolus • Poor outcomes are documented in humans and animals with vasopressor monotherapy • Atropine best choice initially (3 mg max) • Need give either glucagon or high dose insulin therapy • Literature has used the following agents:

 Dopamine, dobutamine, milrinone, epinephrine & • Catecholamines exert positive inotropic & chronotropic isoproterenol activity thru adrenergic receptors

• Caution with dobutamine and milrinone because of  High doses needed > increase risk of arrhythmias hypotension

• Historically dopamine> either epinephrine or isoproterenol infusions

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Glucagon Mechanism of Action in Dosing and Administering Glucagon for Overdose BB/CCB Overdoses

• Glucagon bypasses B-receptors and acts directly on G • First give bolus- 5 mg proteins  Administer very fast  Stimulates conversion ATP to cAMP  Give ondansetron 8 mg IVP beforehand  If do not respond to first 5 mg give another 5 mg in 3-5 • Particularly useful in BB overdose vs. CCB minutes • Shown have positive inotropic and chronotropic effects • Start IV drip at dose of the bolus that generated a despite beta receptor blockade in animal and human response- 5mg/hr or 10 mg/hr reports  Drip concentration 20 mg/200 mL D5W  Reconstitute vial using normal saline not diluent to avoid phenol toxicity

Mechanism of Action High Dose Insulin Preparing for High Dose Insulin Therapy Therapy

• Promotes uptake and use of carbohydrates as energy • Dosing 1-2 units/kg bolus followed by infusion of 1-2 source units/kg/hr  Patients need have blood sugar >300 mg/dL before give • Promotes anti-inflammatory effect that corrects bolus problems caused of inefficient energy production  Patients need potassium >2.5 mEq/L before give bolus • Increased potassium may help prolong repolarization • Best prepare drip as a bigger bag not more allowing calcium channels stay open longer concentrated drip

• Shown have positive inotropic effect  Insulin drip 500 units/500 mL not 500 units/100 mL

• Patients need dextrose at rate 0.5-1g/kg/hr  100 kg patient at 0.5g/kg/hr of 10% dextrose- 500 mL/hr

What about Lipid Emulsion Therapy IVFE What is It?

• Becoming a very popular option • 10-30% soybean oil as major lipid  Especially for lipophilic drugs like propranolol and verapamil • Egg yolk phospholipid and glycerin as minor source of • Decision to use intravenous fat emulsion therapy (IVFE) & lipids and phospholipids specific dosing recommendations based on clinical judgment • Distributes primarily to muscle and subcutaneous tissues

• FDA indicated for: • Excreted by kidneys when given in high doses 1. Provision of free fatty acids in total parenteral nutrition 2. Drug delivery vehicle for highly lipid soluble drugs • 30 min serum half life parent compound

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Mechanism of Action of IVFE in How to Use IVFE Therapy Overdoses

• Lipid Sink Theory • In cases of cardiovascular collapse  Redistribution of lipid soluble drugs away from target tissues  Pull trigger and give this before patients get to this point  Ingested drug partitions into plasma-lipid phase  Administer if pulseless after >3 cycles of ACLS

 Tissue drug concentration decreases • Dosing:

• Metabolic effect  IV bolus of 20% emulsion at 1.5 mL/kg over 1 min  Direct inotrope effect independent of drug re-distribution  Start infusion at 15 mL/kg/hr = 0.25 mL/kg/min via lipid sink  After 5 min if patient still coding give another bolus and  Improve fatty acid metabolism to restore myocardial double infusion rate contractility  Max 12 mL/kg in first 30 minutes  Continue infusion for at least 10 minutes after stable circulation achieved

Assessment Questions References

1. Sodium Bicarbonate drips for TCA overdose should be • Boyer EW. Management of Opioid Analgesic Overdose. N Engl J Med. 2012; 367; 146-155

compounded: • Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001; 18:236.  A. ½ NS with 3 amps of sodium bicarbonate • Liebelt EL. Chapter 73: Cyclic antidepressants. In: Goldfrank's Toxicologic Emergencies, 9th, Nelson LS, et al. (Ed), McGraw-Hill, New York 2011.  B. 1L NS with 3 amps of sodium bicarbonate • Brent J. Current Management of Ethylene Glycol Poisoning. Drugs 2001; 61(7) 979-988.

 C. 1L D5W with 3 amps of sodium bicarbonate • Brent J. Fomepizole for Ethylene Glycol and Methanol Posioning. N Engl J Med. 2009; 360: 2216-33

 D. Use hypertonic saline first line not sodium bicarbonate • Shepard G. Treatment of Poisoning Caused by Beta-adrenergic and Calcium Channel Blockers. Am J Health-Sys Pharm 2006; 63:1828-35

2. True of False: Ethanol dosing in toxic alcohol ingestions • Newton CR, Delgado JH, Gomez HF. Calcium and Beta Receptor Anatagonist Overdose: A Review and is based on a 10% solution for IV and 20% solution for Update of Pharmacological Principles and Management. Semin Respir Crit Care Med. 2002; 23: 19-25. • Waring WS. Intravenous lipid administration for drug-induced toxicity: a critical review of existing data. oral Expert Rev Clin Pharmacol 2012;5(4):437-444.

• Turner-Lawrence DE, Kerns II W. Intravenous fat emulsion: A potential novel antidote. J Med Toxicol 3. True of False: Lipid emulsion boluses can be 2008;4(2):109-14. programmed in a standard infusion pump

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