One Pill…Can
Kill
Steven J. Walsh, M.D.
Research Director, Division of Medical Toxicology
Clinical Instructor, Department of Emergency Medicine
Carolinas Medical Center
Outline
Chloroquine (Aralen)
Oral Hypoglycemics (Sulfonylureas)
Diphenoxylate and Atropine (Lomotil)
β-Blockers (Sustained-Release)
2+
Ca -Channel Blockers (SustainedRelease)
Opiates/Opioids (Long-Acting)
Chloroquine
Aminoquinoline
Hydroxychloroquine
Mefloquine
Primaquine
Prophylaxis/treatment
Malaria/Parasitic
Rheumatic disease
Chloroquine
 Mechanism of Toxicity
 Blocks DNA and RNA synthesis
 Vd = > 150 L/kg
 T1/2 = 2 months (terminal)
 New formulation (phosphate salt): 250 and 500
mg tabs
 Lowest reported lethal dose is 300 mg
Chloroquine
Clinical Presentation
GI upset
Seizures
Hematologic
Hemolysis
Methemoglobinemia
Chloroquine
Clinical Presentation
Cardiotoxicity
Depresses fast sodium channels (phase zero)
Reversibly blocks delayed rectifier (K+) currents
(phase 3)
Chloroquine
Sodium Channel Blockade
With QRS widening
QTc Prolongation
And Torsades
Chloroquine
Sodium Channel Blockade
Chloroquine
Quinidine-like Cardiotoxicity
Type 1a antidysrhythmic
QRS/QTc prolongation
Negative inotropy
Heart block, dysrhythmias
Chloroquine
 Treatment
 ABC’s
 Benzodiazepines for seizures
 Epinephrine for persistent hypotension
 Sodium bicarbonate for cardiotoxicity
Chloroquine
 Treatment
 Clinical evidence of successful treatment using
epinephrine, valium and intubation
 Protocol:
 Epinephrine 0.25 µg/kg/min (increase for SBP >100mmHg)
 RSI with ventilation and no chemical paralysis
 Diazepam 2 mg/kg over 30 minutes
 10/11 survived compared to 1/11 of retrospective controls
Riou B, et al: Treatment of severe chloroquine poisoning. N Engl J Med 1988, 318:1-6.
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Who is this? To what toxin was he exposed? What condition is this?
Toxicology in the News
Oral Hypoglycemics
Sulfonylureas
 First– and second–generation
Biguanides
 Metformin, phenformin
Thiazolidinediones
 Troglitazone, pioglitazone
α-Glucosidase inhibitors
 Acarbose
Sulfonylureas
Mechanisms of Hypoglycemic Actions
Stimulate endogenous insulin secretion from
pancreatic β cells
Enhance peripheral insulin sensitivity
Reduce glycogenolysis
Significant risk for severe/prolonged hypoglycemia
Sulfonylureas
Cellular Mechanisms
Bind and inactivate ATP-sensitive K+
channels, preventing K+ efflux
Depolarization activates voltage-sensitive
Ca2+ channels
Increased intracellular [Ca2+] causes β cells
to release insulin
Sulfonylureas –
Cellular Mechanism
Sulfonylureas
Agent
Onset (h)
Peak (h)
Duration (h)
Acetohexamide
2
4
12-24
Chlorpropamide
1
5
24-72
2.5
24
Glimepride
Glipizide
0.5
1
< 24
Glyburide
0.5
4
24
Tolazamide
1
5
18
Tolbutamide
1
6
6-12
Sulfonylureas
Clinical Presentation
Hypoglycemia
Tachycardia
Diaphoresis
Δ LOC
Seizures (focal)
Sulfonylureas
Treatment
ABC’s
Glucose with documented
hypoglycemia (not empirically)
D5-10W via peripheral line
Sulfonylureas
Treatment
Octreotide
Excessive dextrose requirements
Synthetic somatostatin analogue
Antagonizes pancreatic insulin release
Dose = 50 µg IV or SQ BID
 1-10/kg µg for children (based on wt)
Octreotide Mechanisms of Action
Octreotide inhibits
insulin release
Sulfonylureas
Treatment
Accu-cheks
Q2 hours while awake
Q1 hour while asleep
PRN signs/symptoms
Monitor 24 hours after last dextrose or
octreotide treatment
Lomotil
Diphenoxylate and Atropine combination
Potential for delayed/prolonged toxicity
Children especially sensitive
Lomotil
Diphenoxylate
Opioid analogue of meperidine
Metabolized to active metabolite (difenoxin)
Atropine
Anticholinergic agent
Both agents decrease GI motility
Lomotil
Clinical Presentation
Anticholinergic or
Opioid Syndrome
Lomotil
Anticholinergic Syndrome
Opioid Syndrome
Tachycardia
Mydriasis
Ileus
Hyperthermia
Agitation
Lethargy
Dry membranes
Apnea
Miosis
Coma
Illeus
Lomotil
Treatment
ABC’s
Naloxone for opioid antagonism
May require infusion (2/3 effective
response dose)
Lomotil
Treatment
Physostigmine
Reversible inhibitor of acetylcholinesterase
CNS penetration
0.5 – 2 mg slow IV push (0.02 mg/kg)
May cause cardiac dysrhythmias or seizures
Benefits often don’t justify risks
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What is the toxin? And with which disease is it associated?
Benzene
AML
β – Blocker Actions
Background
Catecholamines bind at b-adrenergic
receptors
G-protein activation of second messenger
cAMP
Results with increased cytosolic [Ca2+]
β – Adrenergic Receptors
b1
Myocardium
Increased
inotropy/chronotropy
b2
Smooth muscle
(pancreas, liver, adipose)
Muscular relaxation in
vessels, lungs,
intestines
Insulin release,
lipolysis
β – Blocking Agents
Selective b1- Adrenergic Antagonists
Acebutolol
Atenolol
Betaxolol
Bisoprolol
Esmolol
Metoprolol
β – Blocking Agents
 Nonselective b - Adrenergic Antagonists
Carvedilol
Labetalol
Nadolol
Pindolol
Propranolol
Timolol
β – Blocker Kinetics
Well-absorbed via GI tract and IV
Peak serum level within 1 - 4 hours (regular
release)
Delayed effects with extended release
New preparations provide relatively
constant rates of delivery over 24 hours
β – Blocking Agents
Extended-release b - Adrenergic
Antagonists
Metoprolol (Toprol XL)
Propranolol (Inderal ER)
β – Blocker Effects
Decreased inotropy/chronotropy
Decreased peripheral resistance
CNS inhibition (propranolol)
Prevention of response to pressors
Na+ channel blockade (prolonged
QRS)
β – Blocker Specifics
Propranolol
Most reported b-blocker in poisonings
Produces significant QRS prolongation (via
Na+ channel blockade)
Lipophilic (crosses BBB)
Coma/seizures
β – Blocker Specifics
Pindolol
Partial agonist
Tachycardia
Nadolol
T1/2 is shortened by repeat AC
β – Blockers
Clinical Toxicity
Hypotension
Bradycardia/Blocks
QRS prolongation
Hypoglycemia
Coma/Seizures
Bronchospasm
Calcium – Channel Blockers
Inhibit entry of calcium into cardiac and
smooth muscle cells (not skeletal muscle)
Inhibit slow Ca2+ channels in SA and AV
nodes
Inhibit α-adrenergic receptors at high
concentrations
CCB Kinetics
Well-absorbed GI Tract
Highly protein-bound
Metabolized in liver
Available in long-acting and extendedrelease preparations
Ca2+ – Channel Antagonists
Sustained-release Ca2+ Channel
Antagonists
Dihydropyridines
Felodipine
Isradipine
Nicardipine
Nifedipine
Nisoldipine
Ca2+ – Channel Antagonists
Sustained-release Ca2+ Channel
Antagonists
Benzothiazepines
Diltiazem
Phenylalkylamine
Verapamil
CCB Specifics
Dihydropyridines
Smooth muscle effect >> nodal effect
No effect at AV node, minimal at SA
Reflex tachycardia with induced SVR
depression
More likely to induce seizures and decrease
LOC
CCB Specifics
Benzothiazepines
 Moderate negative chronotropic effect
Phenylalkylamines
 Profound chronotropic, inotropic and SVR
depression
 Most toxic CCB, widely reported in serious
poisonings
Signs/Symptoms of CCB Toxicity
Hypotension
Nausea / Vomiting
Bradycardia
Hyperglycemia
Tachycardia
Hypokalemia
Pulmonary Edema
Lethargy
Respiratory Depression
Coma
Seizures
Cellular Effects of β– and Ca2+ Channel Blockers
β–
Blockers
Ca2+ – Channel Blockers
Treatment for βB and CCB Toxicity
 ABC’s
 Treat SYMPTOMATIC bradycardia
 MS Δ , acidemia, oliguria, shock
 Sodium bicarbonate
 QRS Prolongation (propranolol)
 Atropine
 Pacing
Treatment for βB and CCB Toxicity
Glucagon
Increase cAMP via separate receptor
Calcium
Increase [cytosolic Ca2+]
Treatment for βB and CCB Toxicity
β–Agonists
 Overcome adrenergic blockade
Phosphodiesterase inhibition
 Prolong cAMP activity
 Insulin
 Augment cardiac carbohydrate metabolism
 Improve lactic acidosis
Treatment for βB and CCB Toxicity
Catecholamines
Isoproterenol
Norepinephrine
Dopamine
Epinephrine
Phenylephrine
Vasopressin
Treatment for βB and CCB Toxicity
Calcium
More effective with CCBs
Inotrope
Calcium chloride > gluconate
10% Chloride 5-10mL (0.1-0.2 mL/kg)
10% Gluconate 10-20mL (0.2-0.3 mL/kg)
Repeat Q5-10 min
Avoid with digoxin
Treatment for βB and CCB Toxicity
Glucagon
Best with βBs
Increases cAMP via separate receptor
Inotrope and chronotrope
5 – 10 mg bolus then 2 – 5 mg/hr gtt
(children: 0.15mg/kg IV, 0.1mg/kg/h)
Phenol toxicity with use of provided diluent
Treatment for βB and CCB Toxicity
Phosphodiesterase Inhibitors
Inhibit metabolism of cAMP
Inotrope
Atropine
Safe and ineffective
Treatment for βB and CCB Toxicity
Cardiac Pacing
Difficult to achieve capture
Often doesn’t increase cardiac output (SBP)
Optimal rate = 60 bpm
Insulin
Euglycemia increases survival (in dogs)
Opiates/Opioids
Natural/synthetic analgesics
Variety of routes of administration
Act at G-protein-coupled receptors
Opiates/Opioids
Act at four distinct receptors:
OP1 (δ)
?
OP2 (κ)
Predominately spinal
OP3 (µ)
Named for morphine
Mostly supraspinal
NOP (nociceptin/orphanin)
Anxiolysis
Opiates/Opioids
Major adverse effect is respiratory
depression
µ2 effect
Diminish sensitivity of medullary
chemoreceptors to hypercapnea
Depress ventilatory response to hypoxia
Opiates/Opioids
Long-acting formulations most
dangerous
Methadone
QTc prolongation
Long-acting morphine sulfate (Kadian)
Long-acting opioids (OxyContin, etc.)
Opioid Management
Naloxone
0.02 – 0.4 mg IV, repeated PRN
Infusion may be necessary
2/3 “response dose”/h gtt
Opiate/Opioid Miscellany
Rapid bedside drugs of abuse screen is
not reliable
“Opiates” screen is specific for morphine
Will not reliably detect most opioids
DXM: positive PCP screen
Opiate/Opioid Miscellany
 Seizure:
 Tramadol (therapeutic doses, ?naloxone as
precipitant)
 Propoxyphene (?naloxone as antidote)
 Meperidine
 Serotonin Syndrome:
 Dextromethorphan
 Acute lung injury:
 ?naloxone reversal
Pearls
Chloroquine
Na+ blockade
K+ efflux blockade
Seizures
Sulfonylureas
Prolonged hypoglycemia
Octreotide
Pearls
Lomotil
Opioid toxicity (CPR)
Anticholinergic
Delayed/prolonged
Pearls
CCB/βB
XL/SR very long acting
Tx symptomatic bradycardia/hypotension
Treatments
Glucagon
Calcium
Vasopressors
Pearls
Opiates/opioids
Delayed/prolonged
Esoteric effects
Naloxone