An Update on Uncommonly Used Antidotes

19 Pages·2014·3.92 MB·English

2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Objectives:
• Describe the statistics and characteristics of 
sulfonylurea poisonings.
• Explain the mechanisms of action of 
sulfonylureas and octreotide as an antidote.
Combating Sulfonylurea‐Induced  • Explain the mechanism of sulfonylurea‐induced 
recurrent hypoglycemia.
Hypoglycemia. Octreotide to the 
• Evaluate the clinical evidence behind the use of 
Rescue! octreotide as an antidote for sulfonylurea 
Patrick Dougherty, PharmD, BCPS poisoning.
Assistant Professor of Pharmacy Practice ‐Emergency Medicine
University of Maryland Eastern Shore School of Pharmacy & Health Professions • Create a medication therapy plan for managing a 
Princess Anne, MD patient with sulfonylurea‐induced hypoglycemia.
Background: Exposures of  Background: SFUs
Sulfonylureas
• American Association of Poison Control  • 1stgeneration: • 2nd/3rdgeneration:
Centers (AAPCC) 2012 Annual Report
• Acetohexamide • Glipizide
• 4,206 exposures involved sulfonylureas
• Chlorpropamide • Glyburide
• ≤ 5 years old –850 cases (20%)
• Tolazamide • Glimepiride
• 1,449 cases unintentional (34%)
• 66 adverse reactions • Tolbutamide
• 1,291 cases treated in a health care facility
• Included in 1 death
Mowry, et al. 2012 Annual Report of the AAPCC’s NPDS. Clinical Toxicology. 2013;949-1229. CPhaarrr mRa, ceot tahle. rO. c2t0re0o2t;i3d6e: 1fo7r2 S7-u3lf2o.nylurea-Induced Hypoglycemia Following Overdose. Ann
Background: SFUs Evidence of Toxicity:
• Times to peak: 1‐12 hours • 2‐year old girl found with father’s glipizide XL 10 mg
• Pediatrician: “observe for changes in behavior”
• Half‐lives: 3‐76 hours
• 4 hours later lethargy to emergency department (ED)
• Durations of action: 6‐60 hours
• Serum glucose concentration (SGC): 39 mg/dL
• Weakly active hepatic metabolites • 2 mL/kg D50W, food & juice
• Negligible fecal elimination • 1 hour later lethargy, 47 mg/dL
• Extended‐release formulations • Admission of 2 days
• Combination products
Carr R, et al. Octreotide for Sulfonylurea-Induced Hypoglycemia Following Overdose. Ann
Pharmacother. 2002;36:1727-32.
Glatstein M. et al. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology.
2012;795-804.
Harrigan RA, et al. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology,
Toxicity, and Treatment. Ann Emerg Med. 2001;38:68-78. L20itt0le5 ;G28L(,3 e):t3 a0l.5 A-1r0e. One or Two Dangerous? Sulfonylurea Exposure in Toddlers. J Emerg Med.
© 2014 American Society of Health-System Pharmacists 1
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Evidence of Toxicity: Pharmacology of SFUs
• Life‐threatening hypoglycemia in poisoning/overdose  • Agonize SFU‐receptor subunit on K+ channel
(OD) • Stimulate depolarization of pancreatic βcells
• 30% of pediatric exposures hypoglycemia • Prevent efflux of K+ through ATP‐mediated channel
• Changes in membrane potential influx of Ca++
• All potential SFU ingestions by young children 
• Ca++ activates enzymes for insulin production & secretion
refer to ED
• Regardless of plasma glucose concentration
• Toxicity from accidental or intentional ingestion;  • Greater pharmacologic effects, longer durations of 
hepatic or renal impairment; adverse effect action in OD
Bosse GM. Antidiabetics and Hypoglycemics. In: Nelson LS, et al, editors. Goldfrank’s Toxicologic
Glatstein M. et al. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology. Emergencies. 9thed. New York: McGraw-Hill;2011. chapter 48.
2012;795-804. Doyle ME, et al. Pharmacological Agents that Directly Modulate Insulin Secretion. Pharmacol Rev.
L20itt0le5 ;G28L(,3 e):t3 a0l.5 A-1r0e. One or Two Dangerous? Sulfonylurea Exposure in Toddlers. J Emerg Med. 2003;55:105-31.
Spiller HA, et al. Prospective Multicenter Study of Sulfonylurea Ingestion in Children. J Pediatr. Harrigan RA, et al. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology, Toxicity, and
1997;131(1):141-6 Treatment. Ann Emerg Med. 2001;38:68-78.
Pharmacology of SFUs SFU‐Induced Recurrent 
Hypoglycemia (SIRH):
• MS: 68‐year old female
• Overdose of glyburide
• Lethargic & confused; SGC = 35 mg/dL
• What do you want to do for MS?  How do you 
want to monitor for its effectiveness?
• Dextrose!
• Serum glucose concentrations q hour!
Bosse GM. Antidiabetics and Hypoglycemics. In: Flomenbaum NE, et al, editors. Goldfrank’s
Toxicologic Emergencies. 8th ed. New York: McGraw-Hill; 2002. p.749-63.
SIRH Mechanism:
SFU‐Induced Recurrent 
Hypoglycemia:
• What do you want to do for MS?
• What are the pharmacologic options?
• Dextrose!
• Glucagon?
• Diazoxide?
© 2014 American Society of Health-System Pharmacists 2
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Octreotide: Octreotide:
• Long‐acting somatostatin analog • Mechanism of action as antidotal therapy:
• FDA approvals: • Agonist at somatostatin‐receptor on voltage‐
gated Ca++ channels at pancreatic βcells
• Acromegaly, metastatic carcinoid, vasoactive intestinal 
secreting tumors • Closing of Ca++ channels decrease influx of 
Ca++ decrease activation of enzymes for 
• Suppresses secretion of hormones:
insulin production & secretion
• Gastrin, Cholecystokinin, Growth Hormone, TSH, 
• “Downstream” of SFU agonism
Glucagon, Insulin
• AAPCC 2012 Annual Report:
• Administered in 356 cases (70% in ≥ adults) Glatstein M. et al. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology. 2012;795-
Harrigan RA, et al. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology, Toxicity, 804.
and Treatment. Ann Emerg Med. 2001;38:68-78. Harrigan RA, et al. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology, Toxicity,
Lheureux PE, et al. Bench-to-Bedside Review: Antidotal Treatment of Sulfonylurea-Induced and Treatment. Ann Emerg Med. 2001;38:68-78.
Hypoglycemia with Octreotide. Critical Care. 2005;9:543-9. Lheureux PE, et al. Bench-to-Bedside Review: Antidotal Treatment of Sulfonylurea-Induced
Mowry, et al. 2012 Annual Report of the AAPCC’s NPDS. Clinical Toxicology. 2013;949-1229. Hypoglycemia with Octreotide. Critical Care. 2005;9:543-9.
Mechanism of Octreotide:
Octreotide
Bosse GM. Antidiabetics and Hypoglycemics. In: Flomenbaum NE, et al, editors. Goldfrank’s
Toxicologic Emergencies. 8th ed. New York: McGraw-Hill; 2002. p.749-63.
Octreotide: Octreotide:
• Peak effect: 30 minutes (subcutaneous) • Antidotal use:
• Elimination half‐life: 1.5 hours • Treat recurrent hypoglycemia induced by SFUs & 
• Duration of action: 6‐12 hours subcutaneous, 4 hours  refractory to administration of intravenous 
IV dextrose
• Dosing: • Adverse effects:
• 50 mcg subcutaneously every 6 hours until resolution of 
hypoglycemia • Hyperglycemia…
• Pediatric: 4‐5 mcg/kg/d divided every 6 hours up to adult  • Nausea, abdominal pain, diarrhea, flatulence
dose (1 mcg/kg per dose)
• Bradycardia, prolonged QTc with long term use
• Can be increased to 100 mcg; wide therapeutic window
Glatstein M. et al. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology. Glatstein M. et al. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology.
2012;795-804. 2012;795-804.
Harrigan RA, et al. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology, Harrigan RA, et al. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology,
Toxicity, and Treatment. Ann Emerg Med. 2001;38:68-78. Toxicity, and Treatment. Ann Emerg Med. 2001;38:68-78.
Lheureux PE, et al. Bench-to-Bedside Review: Antidotal Treatment of Sulfonylurea-Induced Lheureux PE, et al. Bench-to-Bedside Review: Antidotal Treatment of Sulfonylurea-Induced
Hypoglycemia with Octreotide. Critical Care. 2005;9:543-9. Hypoglycemia with Octreotide. Critical Care. 2005;9:543-9.
© 2014 American Society of Health-System Pharmacists 3
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Octreotide: Patient Case:
• Available as solution for subcutaneous & IV  • MS: 68‐year old female
injection (100 mcg/mL) • Overdose of glyburide
• Presents to ED lethargic & confused; SGC = 35 mg/dL
• Long‐acting depot IM NOT for antidotal 
• What interventions are needed?
therapy
• IV dextrose & food!
• Inexpensive • Serum glucose concentrations every hour!
• Octreotide 50 mcg subcutaneously every 6 hours, if SIRH 
develops
Clinical Evidence Clinical Evidence
• Boyle PJ, et al. • FasanoCJ, et al.
• Volunteer crossover trial, 8 healthy subjects given glipizide 1.45  • Prospective, double‐blind, placebo‐controlled trial of adults 
mg/kg on 3 occasions with SGC’s < 60 mg/dLfrom SFU exposure
• Groups: dextrose‐only, dextrose & diazoxide, dextrose &  • N = 22 octreotide & dextrose group, N = 18 placebo & dextrose 
octreotide
group
• Results
• Recurrent hypoglycemia treated with 50% dextrose
• No difference in dextrose requirements with dextrose‐only 
vs diazoxide • Results:
• Significant less dextrose requirements for octreotide arm vs  • SGCs for octreotide patients higher than placebo patients for 
dextrose‐only & diazoxide first 8 hours  
• SGC’s remained significantly higher in octreotide arm vs  • SGCs after 8 hours did not differ between groups
dextrose‐only & diazoxide
• 4/8 volunteers required no supplemental dextrose after 
having been administered octreotide
Boyle PJ, et al. Octreotide Reverses Hyperinsulinemia and Prevents Hypoglycemia Induced by Fasano CJ, et al. Comparison of Octreotide and Standard Therapy versus Standard Therapy Alone for
Sulfonylurea Overdoses. J Clin Endocrinol Metab. 1993;76:752-756. the Treatment of Sulfonylurea-Induced Hypoglycemia Ann Emerg Med. 2008;51:400-406.
Clinical Evidence Clinical Evidence
• Glatstein M, et al. • Dougherty, et al.
• Retrospective chart review of the clinical features of pediatric  • Retrospective case series of pediatric (< 6 years old) SFU 
patients after SFU ingestion ingestions from national poison center data
• N = 10 (6 suspected, 4 confirmed); ages 1.5‐15 years old • Pretreatment & post‐treatment hypoglycemic episodes & SGCs, 
• Accidental & intentional exposures medical outcomes, adverse effects
• All patients received IV dextrose • Results:
• Toddlers received octreotide no further hypoglycemia • 121 cases
• Adolescents received only dextrose rebound hypoglycemia &  • 2 episodes vs 0 episodes before & after octreotide
higher dextrose requirements • Lowest SGC was significantly higher after octreotide 
• ~75% of children only received 1 dose of octreotide
• All children survived
• No adverse effects to octreotide documented
Glatstein M, et al. Sulfonylurea intoxication at a tertiary care paediatric hospital. Can J Clin Pharmacol. Dougherty PP, et al. Evaluation of the use and safety of octreotide as antidotal therapy for sulfonylurea
2010;17:51-6. overdose in children. Pediatr Emerg Care. 2013;29:292-5.
© 2014 American Society of Health-System Pharmacists 4
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Clinical Evidence Clinical Evidence
• Recent Case Reports ‐Adults • Recent Case Reports –Pediatrics
• Adverse effect of therapeutic use of SFU:  • Cerebral edema: 
• Arora A. Hypoglycaemia begets hypoglycaemia. BMJ.  • Llomado R, et al. Continuous octreotide infusion for 
2013;28:2013. sulfonylurea‐induced hypoglycemia in a toddler. J Emerg 
• Barkin JA, et al. Octreotide: a novel therapy for  Med. 2013;46:209‐13.
refractory sulfonylurea‐induced hypoglycemia. Pancreas.  • Delayed hypoglycemia: 
2013;42:722‐3. • Pelavin PI, et al. Extended‐release glipizide overdose 
• Gonzalez RR, et al. Octreotide therapy for recurrent  presenting with delayed hypoglycemia and treated with 
refractory hypoglycemia due to sulfonylurea in diabetes‐ subcutaneous octreotide. J Pediatr Endocrinol Metab. 
related kidney failure. Endocr Pract. 2007;13:417‐423. 2009;22:171‐5.
• Vallurupalli S. Safety of subcutaneous octreotide in 
patients with sulfonylurea‐induced hypoglycemia and 
congestive heart failure. Ann Pharmacother. 2010: 
44:387‐90
Clinical Evidence Objectives:
• Review articles • Describe the statistics and characteristics of 
• Dougherty PP, et al. 2010 sulfonylurea poisonings.
• Sufficient evidence to recommend the use of octreotide with  • Explain the mechanisms of action of 
supplemental dextrose for the treatment of sulfonylurea‐ sulfonylureas and octreotide as an antidote.
induced hypoglycemia. • Explain the mechanism of sulfonylurea‐induced 
• Glatstein M, et al. 2012 recurrent hypoglycemia.
• Limited, available data suggest that octreotide should be  • Evaluate the clinical evidence behind the use of 
considered first‐linetherapy in all cases (pediatric & adult) 
octreotide as an antidote for sulfonylurea 
of SFU poisoning with evidence of hypoglycemia.
poisoning.
• Octreotide may need to be re‐dosed to prevent recurrent 
hypoglycemia. • Create a medication therapy plan for managing a 
patient with sulfonylurea‐induced 
hypoglycemia.
Dougherty PP, et al. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med
Toxicol. 2010;6:199-206.
Glatstein M, et al. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology.
2012;50:795-804.
BN is a 24 year‐old female who intentionally 
ingested 20 tablets of glipizide 10 mg in a  Administer dextrose 25 g orally and re‐administer if she 
becomes hypoglycemic, along with an IV infusion of 5% 
suicidal gesture approximately 2 hours ago.  
dextrose.
She presents to the ED and is lethargic, 
Administer dextrose 25 g IV bolus and re‐administer if she 
diaphoretic, and tremulous.  Her serum glucose 
becomes hypoglycemic, along with an IV infusion of 5% 
concentration is found to be 30 mg/dL.  All of  dextrose.
her other laboratory values are unremarkable. Administer glucagon 1 mg IV for correction of her 
hypoglycemia, along with an IV infusion of 5% dextrose.
Which of the following medication therapy  Administer octreotide 50 mcg subcutaneously for correction 
plans is most appropriate to recommend for BN  of her hypoglycemia, along with an IV infusion of 5% 
at this time? dextrose.
© 2014 American Society of Health-System Pharmacists 5
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Despite your initial recommendation 
Administer dextrose 25 g orally and re‐administer if she 
becomes hypoglycemic, along with an IV infusion of 5%  & intervention, BN’s serum glucose 
dextrose. concentration decreases to 25 mg/dL 
Administer dextrose 25 g IV bolus and re‐administer if she 
one hour later and she is found to be 
becomes hypoglycemic, along with an IV infusion of 5% 
dextrose. lethargic and slow to respond.
Administer glucagon 1 mg IV for correction of her 
hypoglycemia, along with an IV infusion of 5% dextrose.
Which of the following medication 
Administer octreotide 50 mcg subcutaneously for correction 
of her hypoglycemia, along with an IV infusion of 5%  regimens is most appropriate to 
dextrose.
administer to BN at this time?
Administer dextrose 25 g orally along with octreotide 50 mcg  Administer dextrose 25 g orally along with octreotide 50 mcg 
subcutaneously followed by 3 more doses each 2 hours apart. subcutaneously followed by 3 more doses each 2 hours apart.
Administer dextrose 25 g IV along with glucagon 1 mg IV  Administer dextrose 25 g IV along with glucagon 1 mg IV 
followed by 3 more doses each 3 hours apart. followed by 3 more doses each 3 hours apart.
Administer dextrose 25 g IV along with 50 mcg of octreotide  Administer dextrose 25 g IV along with 50 mcg of octreotide 
subcutaneously followed by 3 more doses each 6 hours apart. subcutaneously followed by 3 more doses each 6 hours 
Administer dextrose 25 g orally along with glucagon 1 mg IV  apart.
followed by 3 more doses each 6 hours apart. Administer dextrose 25 g orally along with glucagon 1 mg IV 
followed by 3 more doses each 6 hours apart.
BN is admitted to the hospital for 
Monitor her SGCs every hour during treatment and gradually 
treatment of her overdose.  Which of  titrate down the 5% dextrose IV. 
the following set of instructions is  Monitor her SGCs every 3 hours during treatment and 
administer 25 g of 50% dextrose IV  if hypoglycemia recurs.
appropriate for how to manage the 
Monitor her SGCs every hour during treatment and 
care of BN? administer glucagon 1 mg IV if hypoglycemia recurs.
Monitor her SGCs only after she orally consumes dextrose‐
containing food and administer 25 g of 50% dextrose IV if 
hypoglycemia recurs.
© 2014 American Society of Health-System Pharmacists 6
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Key Takeaways
Monitor her SGCs every hour during treatment and 
gradually titrate down the 5% dextrose IV.  • Key Takeaway #1
Monitor her SGCs every 3 hours during treatment and  • Octreotide should be considered as antidotal therapy 
administer 25 g of 50% dextrose IV  if hypoglycemia recurs. for SFU‐induced hypoglycemia (for both therapeutic‐use 
or overdose) refractory to the administration of 
Monitor her SGCs every hour during treatment and  dextrose.
administer glucagon 1 mg IV if hypoglycemia recurs. •Perhaps even first‐line?
Monitor her SGCs only after she orally consumes dextrose‐ • Key Takeaway #2
containing food and administer 25 g of 50% dextrose IV if  • For patients with prolonged SFU‐induced hypoglycemia, 
hypoglycemia recurs. multiple doses of octreotide may be necessary.
• Key Takeaway #3
• Octreotide can be safely given to pediatric patients 
experiencing SFU‐induced hypoglycemia refractory to 
the administration of dextrose.
Combating Sulfonylurea‐Induced  “HIE” Dose Insulin for Calcium‐
Hypoglycemia. Octreotide to the  Channel Blocker Overdose
Rescue!
Patrick Dougherty, PharmD, BCPS Adrienne Perotti, Pharm D, BCPS
Email: [email protected],  Clinical Specialist in Emergency Medicine/Toxicology
Presence Saints Mary and Elizabeth Medical Center, Chicago, IL
[email protected] 
Objectives Case Report
• Define the morbidity and mortality of toxin  • 17 yoF PA is presenting to the ED 3 hours post ingestion of 
300 mg amlodipine tablets.
induced cardiogenic shock • Vitals: 
• Describe the pathophysiology of toxin induced  •HR 45, BP: 80/40, RR: 18, Wt: 55 kg
• Physical Exam:
cardiogenic shock due to calcium channel 
•She is awake but sleepy, diaphoretic with has active 
blocker (CCB) or Beta Blocker (BB) overdose. bowel sounds.  Her extremities are cold with slow 
capillary refill.
• Discuss the use of high dose insulin‐ • Current Treatments:
euglycemia(HIE) in toxin induced cardiogenic  •2L NS fluid bolus given with 3rdL infusing
shock due to CCB or BB overdose •3 mg atropine given IV
•2 gmof IV calcium chloride given
• List the use of (HIE) in other toxins  •Norepinephrine IV infusion was started and is 
currently running at 10mcg/min  
© 2014 American Society of Health-System Pharmacists 7
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Introduction Mechanism of Toxicity
• NPDS 2012 data
Calcium Channel Blockers Beta Blockers
• Cardiovascular drug exposures account for  • Bind to L‐type voltage  • Antagonize beta‐adrenergic 
103,922/yr sensitive calcium channels and  receptors which disrupt calcium 
prevent the transport of Ca2+ channel influx into cell and release 
• 2ndlargest cause of overdose fatalities into cell from the sarcoplasmic reticulum
• Decreases chronotropic • Decreases chronotropicand 
•Majority due to Beta‐blockers (BBs) 
and inotropic effects in the  inotropic effects in the 
and Calcium channel blockers (CCBs) myocardium myocardium
• 3rdlargest increase since last year • Disrupts peripheral  • Disrupts peripheral vascular 
vascular resistance and  resistance and regulation
regulation • Prevents gluconeogenesis and 
• Block insulin release in β‐ glycogenolysis
islet cells
MowryJB, et al. Clinical Toxicology(2013), 51:949‐1229. Kerns W. EmergMed ClinN Am(2007), 25:309‐331.
Clinical Presentation
• Severity of symptoms is dependent on the 
patient and the amount of drug ingested
• Elderly 
• Children
• Multiple co‐morbidities
•Hxof CHF, MI, myocardial dysfunction
• Multiple medications ingested
• Immediate release versus Sustained 
Release
Shepherd G. Am J Health‐SystPharm.2006;63:1828‐35. Shepherd G. Am J Health‐SystPharm.2006;63:1828‐35.
Clinical Presentation What is the most common presentation 
of a CCB & BB toxicity?
CCBs BBs Tachycardia/Hypertension
• Bradycardia • Bradycardia Bradycardia/Hypertension
• Dysrhythmias • Dysrhythmias Tachycardia/Hypotension
• Hypotension • Hypotension
Bradycardia/Hypotension
• Hyperglycemia • Hypoglycemia
• Pulmonary Edema • Bronchospasm
• Cardiogenic Shock • Cardiogenic Shock
• Cardiac Arrest • Seizures
Shepherd G. Am J Health‐SystPharm.2006;63:1828‐35.
© 2014 American Society of Health-System Pharmacists 8
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
Traditional Therapy Traditional Therapy
• Supportive care • Calcium
• Fluids • Competes to override the voltage gated calcium 
channels to increase intracellular calcium
•Often effective in treating mild toxicity
• Shown to reverse bradycardiaand hypotension
•10‐40 ml/kg bolus; repeat if necessary
• Dosing: 13‐25 mEqbolus with continuous infusion 
•Caution in patients with CHF, renal  of 0.5mEq/kg/h
dysfunction or signs of pulmonary edema • Issues
• Atropine •Often short lived and cannot overcome blockade 
•Blocks parasympathetic pathway in severe overdose
•0.5‐1mg q2‐3 min; max 3 mg •Careful monitoring of serum calcium and 
phosphorous levels
•Clinically ineffective in severe cases
DeRoosFJ. Calcium Channel Blockers.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:884‐892. DeRoosFJ. Calcium Channel Blockers.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:884‐892.
BrubacherJR. β‐Adrenergic Antagonistss.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:896‐909. BrubacherJR. β‐Adrenergic Antagonistss.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:896‐909.
Traditional Therapy Traditional Therapy
• Vasopressors/Inotropes • Glucagon
• Beta‐Adrenergic agonists can facilitate cyclic  • Stimulates cAMPthrough a separate G‐
AMP and increase calcium channel opening
coupled protein receptor
• Alpha‐Adrenergic agonist peripherally can also 
activate receptor‐activated calcium channels •Creates positive inotropic and 
• PhosphodiesteraseInhibitors can prevent the  chronotropiceffects
degredationof cyclic AMP •Bolus of 50‐150 mcg/kg followed by 
• Conflicting data on effectiveness infusion of 1‐10 mg/hr
• May actually depress cardiac output by increasing  • Nausea and vomiting occurs at the higher 
oxygen demand and systemic vascular resistance
doses
• Increased risk of tissue ischemia
• Case reports of ineffectiveness
DeRoosFJ. Calcium Channel Blockers.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:884‐892. DeRoosFJ. Calcium Channel Blockers.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:884‐892.
BrubacherJR. β‐Adrenergic Antagonistss.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:896‐909. BrubacherJR. β‐Adrenergic Antagonistss.  In Goldfrank’sToxicologicEmergencies‐9thEdition., 2011:896‐909.
1 Ca++ Ca++ 2 EPI 3
Ca++
Ca++ Ca++ β1 Glucagon Back to our Case
Gs
AC ATP • PA is now in the PICU.  We are 10 hours post ingestion.  PA 
is currently on BIPAP for pulmonary edema and respiratory 
PDE distress.
PKA cAMP Amrinone • Current vitals:  HR 55, BP: 85/45 mmHg, RR 30 and pt. is 
Sarcoplasmic reticulum 4 currently altered and nauseous and retching 
Ca++ Ca++ • Current medications:
Ca++CaC++a++ CCaa++++ Ca+C+aC++a+C+a++ ••VNaosroepprinesespinh rIiVn ein IfVu siniofuns aiot n0 .a4t  u3n0i tms/cmg/inmin
Troponin
•Phenylephrine IV infusion at 150 mcg/min
•Hydrocortisone 100 mg IVP q8h
•9 L NS total has been given and is currently on 150 
Glucose Aerobic ml/hrNS infusion
Metabolism
Glucose •Glucagon IV infusion is at 10 mg/hrafter a 10 mg 
Glucose bolus
Glucose
© 2014 American Society of Health-System Pharmacists 9
2014 Midyear Clinical Meeting
An Update on Uncommonly Used Antidotes
What would you do in this  High Dose Insulin/Euglycemia(HIE)
scenario?
• Mechanism of Action
Increase phenylephrine drip to 200 mcg/min • Provides intracellular transport of glucose 
Increase glucagon to 15 mg/hr to cardiac and skeletal muscle
Add dobutamineat 1 mcg/kg/min •Preferred energy source in stressed 
myocardium
Call local poison center for HIE protocol
• Enhances inotropic effects
• Enhances endothelial nitric oxide synthase 
causing vascular dilation
•Enhances microvascularperfusion
EngebretsenKm, et al. Clinical Toxicology(2011), 49:277‐283
Efficacy of HIE
Kline JA, et al. 1993 Kerns W 2nd, et al. 1997
• Canine model • Porcine model
• Verapamil toxicity • Propranolol toxicity
• Compared saline, 
epinephrine, glucagon,  • Compared vasopressin 
calcium, or HIE with epinephrine, or HIE
• Results (Survival) • Results (Survival)
• Saline: 0/6 • Vasopressin/epinephrine
• Epinephrine: 4/6
•0/5
• Glucagon: 3/6
• HIE: 5/5
• Calcium: 3/6
• HIE: 6/6
Shepherd G. Am J Health‐SystPharm.2006;63:1828‐35. Kline JA, TomaszewskiCA, Schroeder JD, Raymond RM. J PharmcolExpTher(1993), 267:744‐750.
Kerns W 2ndet al.  Ann EmergMed (1997), 29:748‐757.
Efficacy of HIE Efficacy of HIE
• Yuan TH, et al. 1999 • Greene SL, et al. 2007
• Case Series (N=5 patients)
•4 verapamil • Prospective observational study of an HIE 
•1 amlodipine/atenolol protocol (N=7)
• Survival: 5
•CCB with SBP <90 mmHg despite other 
•Average insulin dose: 0.5 units/kg/h
•All had improved blood pressure and heart rate  traditional therapies
within 1 hour of therapy
•Loading dose: 25 gm dextrose IV 
• Adverse Events
•Transient hypoglycemia: 4 followed by 1 unit/kg short‐acting 
•Hypokalemia: 3 insulin IV
•Hypomagnesemia: 3
•Hypophosphatemia: 3 •Maintenance dose: 0.5‐2.0 units/kg/hr
Yuan TH, et al. Clinical Toxicology (1999), 37:463‐474. Greene SL, et al.  Intensive Care Med (2007), 33:2019‐2024.
© 2014 American Society of Health-System Pharmacists 10