jami johnson's scheffe 2019 slides€¦ · tasteless gas why co binds tightly to hemoglobin...
TRANSCRIPT
10/8/2019
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Toxicology Take‐AwaysWalter P. Scheffe 2019 CPE Series
Jami Johnson, PharmD, DABATAssistant Director, Oklahoma Center for Poison & Drug Information
Assistant Adjunct Professor, OU College of Pharmacy
Financial Disclosure and ResolutionUnder guidelines established by the Accreditation Council for Pharmacy Education (ACPE), disclosure must be made regarding financial relationships with commercial interests within the last 12 months.
Jami Johnson
Commercial Interest
Nature of Relevant Financial Relationship
What was received? For what role?
Boston Scientific (BTG International, Inc.) Speaker Fee Speaker’s Bureau
The conflict was resolved by Dr. Johnson agreeing to refrain from making recommendations on topics in which the conflict exists and agreeing that the presentation will not include discussion of any products or services from the listed commercial interest. Presentation slides were reviewed for content validation and bias by the Continuing Education Administrator.
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At the completion of this activity, pharmacists will be able to:
1. Identify toxins known to cause serious adverse effects with small, inadvertent exposures
2. Recognize common substances not likely to cause serious adverse effects
3. Outline an appropriate management strategy for a patient exposed to a 'red flag' substance
4. Describe the mechanism of action of kratom
5. Identify the potential adverse effects from loperamide overdose
Learning Objectives
Pre‐Assessment Question #1
Which of the following substances may cause severe toxic effects following ingestion of just one tablet in a child?
A. Famotidine
B. Glipizide
C. Ibuprofen
D. Lisinopril
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Pre‐Assessment Question #2
Kratom has effects on which of the following receptors?
A. µ opioid receptors
B. D1 receptors
C. Κ opioid receptors
D. All of the above
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Non‐Toxic StuffNo worries
Very Toxic StuffWho
What
Why
What (to do‐immediate actions)
Opioids (I know)Kratom
Loperamide
Omeprazole + methadone
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OCPDI’s ‘Non‐Toxic’ List
OTC Medications• < 200 mg/kg acetaminophen/ibuprofen• melatonin• antacids• multivitamins• bulk‐forming laxatives• simethicone• calamine lotion• teething tablets• guaifenesin• homeopathy• < 10 mg/kg elemental iron
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OCPDI’s ‘Non‐Toxic’ List
• Prescription Medications
• birth control tablets
• cephalosporins
• corticosteroids
• levothyroxine
• montelukast
• penicillin/amoxicillin
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OCPDI’s ‘Non‐Toxic’ ListHousehold Products
• diaper rash ointment
• deodorant
• petroleum jelly
• art supplies (glues, pencils, pens, chalk)
• glow sticks
• Play‐Doh® (not home‐made)
• shampoo & conditioner
• candles
• make up
• lotions
• nail polish
• thermometers
• desiccants
• motor oil
• caulk/spackle 9
OCPDI’s ‘Red Flag’ List
calcium channel blockers (CCB)calcium channel blockers (CCB)
beta blockers (BB)
beta blockers (BB)
centrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanidecarbon monoxide
(CO)hydrogen sulfide
(H2S)
cyanidecarbon monoxide
(CO)hydrogen sulfide
(H2S)
Micotil® (tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
plants
mushrooms
plants
mushrooms
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Hydrocarbons
Who?Children (assume for all)
Self‐Harm (assume for all)
Workers
Intentional abusers
What?Carbon + Hydrogen +/‐ Halogen
• Fuels, lighter fluid, paint thinners, solvents, Freon
• Essential oils
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Hydrocarbons
Pulmonary Aspiration pneumonitis, disruption of surfactant
CNS General depressant (GABA agonists)
Cardiac ‘Sudden sniffing death’
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Immediate Actions
• Dermal
• Decontaminate with mild soap and water
• Aspiration• Call 911
• Inhalation Abuse• Avoid stress, call 911
• All exposures• Call OCPDI
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
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Hydrofluoric Acid
Who?Children
Workers (auto detailing, refineries)
Craftsmen
What?Hydrogen + Fluorine
Industry‐ High octane fuel, electroplating, cleaning, dissolves
silica
Household use‐ Glass etching, rust removers, wheel cleaners
Why?Fluorine‐most electronegative element
• Binds calcium, magnesium, manganese
Acid‐ coagulative necrosis, ocular burns, white discoloration
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Hydrofluoric Acid‐Immediate Actions
Dermal
1. Decontamination2. Apply calcium
10g carbonate tablets in20mL lubricating gel
3. Apply magnesiumIf no access to calcium
Exposure to highly concentrated (>~5%) product
Call 911
All exposures
Call OCPDI
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
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Micotil® (tilmicosin)
Who?Veterinarians
Ranchers/farmers
What?Veterinary antibiotic approved for metaphylaxis for Bovine Respiratory Disease
• Mannheimia haemolytica, Pasteurella multocida, Histophilus somni
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Micotil® (tilmicosin)
• Why?
• Macrolide class of antibiotic, parenteral administration only
• Calcium channel antagonist in human cardiac muscle
• Hypotension, dysrhythmias expected following intravenous (IV) injection
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Micotil® (tilmicosin)
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• Immediate actions
• Dermal
• Decontaminate with soap and water
• Absorption poor
• Any parenteral exposure
• Call 911
• All exposures
• Call OCPDI
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphate & carbamates
organophosphate & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
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Organophosphates (OP) & carbamates
Who?
Agricultural workersVictims of chemical terrorism
What?
Nerve agents• soman, sarin, tabun, VX, Novichok agents
Pesticides• OPs‐parathion, diazinon, malathion (Spectracide®) dichlorvos (Hot Shot®)
• Carbamates‐aldicarb (Temik®), carbaryl (Sevin®)
Why?
Excess build‐up of acetylcholine by inhibition of acetylcholinesterase• Enzyme aging• + OP• ‐ carbamates
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Autonomic Nervous System
(Parasympathetic)
Acetylcholine Nicotinic cholinergic receptors
Muscarinic cholinergic receptors
NorepinephrineAlpha receptors
Beta receptors
End‐Organ
Parasympathetic Ganglion
CNSParasympathetic
stimulation
Acetylcholine nicotinic receptors
Acetylcholine muscarinic receptors
Acetylcholine nicotinic receptors
Norepinephrine alpha/beta receptors
acetylcholinesterase
Breaks down acetylcholine to
acetic acid & choline
OPs & carbamates
acetylcholinesterase
Breaks down acetylcholine to
acetic acid & choline
Excess Acetylcholine
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Cholinergic Toxidrome
• D• Diarrhea
• U• Urination
• M• Miosis (small pupils)
• B• BRADYCARDIA• BRONCHORRHEA/BRONCHOSPASM
• E• Emesis
• L• Lacrimation
• S• Salivation
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Cholinergic Toxidrome
• M• Mydriasis (dilated pupils)
• T• Tachycardia
• W• Weakness
• tH• Hypertension
• F• Fasciculations
organophosphates & carbamates• Immediate Actions
• Dermal
• Decontaminate with soap and water
• May have significant absorption
• Any respiratory symptoms or seizures
• Call 911
• All exposures
• Call OCPDI
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
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Cyanide• Who?
• Fire victims, industrial accidents, laboratory workers
• What?• Inorganic salts‐ plastic manufacturing, fumigation, mining• Closed space fires‐ victims and rescuers• Plants‐Prunus species• Miscellaneous‐ sodium nitroprusside, homicide, laboratory exposures
• Why?• Inhibition of multiple enzymes‐primarily cytochrome oxidase
• Enzyme responsible for oxidative phosphorylation• The last step of the electron transport chain• Cells cannot utilize oxygen, hydrogen ions begin to accumulate
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Carbon Monoxide (CO)
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Who
Occupational
Environmental
Fire
What
Formed during incomplete combustion of carbon‐containing compounds
• Odorless, colorless, tasteless gas
Why
CO binds tightly to hemoglobin decreasing offloading of oxygen
CO binds to mitochondrial cytochrome oxidase
Hydrogen Sulfide (H2S)
• Workplace exposures
• Sulfur decay (sewers/manholes/lagoons), oil & gas, natural gas drilling
• Environmental disasters
• Volcanoes, caves, sulfur springs, natural gas deposits
Who?
• Colorless, dense gas
• ‘rotten egg’ smellWhat?
• Inhibition of cytochrome oxidase > interrupt oxidative phosphorylationWhy?
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Cyanide/CO/H2S
• Immediate Actions
• Environmental
• Remove patient from poison
• Any known exposure (non‐prunus related)• Call 911
• All exposures• Call OCPDI
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
32
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Sulfonylureas
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Who?Children!!
Therapeutic errors
What?glipizide (Glucotrol®)
glyburide (Diabeta®, Micronase®)
glimepiride (Amaryl®)
Why?Hypoglycemia
• Delayed/prolonged
glucose
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glucose
ATP ↑↑ K+
depol
↑↑Ca2+
insulin exocytosis
sulfonylureas
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Immediate Actions
• Hypoglycemia
• Oral glucose supplementation if safe
• Glucagon not recommended
• All exposure in naïve patients• Refer to emergency department
• All exposures• Call OCPDI
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10/8/2019
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
37
Tricyclic Antidepressants
38
Who?Suicidal patients (recent initiators)
Accidental ingestions (pain, children, etc.)
What?
Tertiary‐ imipramine, amitriptyline, clomipramine, doxepin, trimipramine
Secondary‐ amoxapine, desipramine, nortriptyline, protriptyline, maprotiline
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Tricyclic Antidepressants‐ why?
Serotonin & norepinephrine reuptake inhibitors
Anticholinergic activity
Alpha blocking activity
Sodium channel blocking activity
Seizure activity (multifactorial)
Immediate Actions
40
All intentional exposures
Call 911 or take to nearest emergency department
All exposures
Call OCPDI
10/8/2019
21
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
41
colchicine
42
• Who?• Therapeutic errors (pain)• Accidental exposures• Suicidal ingestions
• What?• Colchicum autumnale‐Autumn crocus, naked lady• Gloriosa superba‐Glory lily• Colchicine‐ utilized for gout
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colchicine
• Why?
• Inhibitor of microtubule formation/function
• Interferes with cellular mitosis, intracellular transport mechanisms, maintenance of cell structures and shape
• Cell dysfunction & death
43
Immediate Actions
• Immediate Actions
• Any intentional exposure• Call 911• Early intervention
• All exposures• Call OCPDI
10/8/2019
23
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
45
The Therapeutic Error
46
• TID IR > Daily XR• Bupropion ER 450 mg tablets
• Initial thoughts?
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Bupropion
• Who?
• All‐comers
• What?
• Mechanism of action (MOA) not well understood
• Noradrenergic or dopamine activity
• Minimal effects on monoamine oxidase or serotonin uptake
• Why?
• Metabolite hydroxybupropion
• Cathinone‐sympathomimetic and alpha agonist properties
• Seizures, conduction disturbances
47
• Retrospective Review
• 4 poison centers
• 2000‐2006
• Children < 6 years
• 407 bupropion exposures
• Clinical findings
• Seizure (0.7%)
• Sinus tachycardia (12.3%)
• Author Conclusions
• Mean dose (ST)= 24 mg/kg (11‐64)
• Mean dose (seizure)= 39 mg/kg (34‐44)
• Max dose (no effects)= 10 mg/kg (SD +/‐ 7.9)
• Versus 18.6 mg/kg (SD +/‐ 13.4), p<0.05
48
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• Retrospective Review• TESS database (2000‐2003)
• 476 bupropion therapeutic errors• Age: 13‐92 years (SD 40 +/‐ 16 years)
• 354 (74.4%) female
• 412 (86.6%) sustained release formulation
• Author Findings• Mean dose= 300 mg (75‐1,500 mg)
• All seizures= < 450 mg
• Moderate/major effects in >10%
• Clinical Findings (mild)• N/V (6.7%), drowsiness (6.1%)
• Clinical Findings (moderate)• Tachycardia (5.5%)
• Tremor (7.1%)
• Dizziness (7.4%)
• Clinical Findings (major)• Agitation (8.2%)
• Seizures (0.8%)
• Hallucinations (0.4%) 49
50
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Immediate Actions
Therapeutic Errors
• Refer all long acting formulations
Any intentional exposures
• Call 911 or take to nearest ED if safe
All exposures
• Call OCPDI
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
52
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27
Opioids
53
• Who?• Anyone with access
• What?• Prescription medications• Illicit substances‐heroin, fentanyl derivatives• Miscellaneous sources‐ loperamide, kratom• Buprenorphine & diphenoxylate
• Why?• CNS/respiratory depression• Cardiac/CNS toxicity
Immediate Actions
• Administer antidote
• Naloxone
• Any CNS or respiratory depression• Call 911
• All exposures• Call OCPDI
54
10/8/2019
28
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
55
Antiarrhythmics & antimalarials
• Who?
• Therapeutic errors
• Inadvertent ingestions
• What?
• Antiarrhythmic‐ procainamide, disopyramide, flecainide, propafenone, dofetilide, amiodarone, dronedarone, sotalol
• Antimalarials‐ quinidine, chloroquine, hydroxychloroquine
• Why?
• Narrow therapeutic window
• Toxicity‐Extension of therapeutic effects
• Chloroquine cardiac toxicity >>> hydroxychloroquine
56
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29
57
• Immediate Actions
• Any intentional exposure• Call 911 or take to nearest ED if safe
• All exposures• Call OCPDI
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
58
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30
Stimulants
59
Who?
• Inadvertent exposures, abuse/misuse
What?
• Pharmaceuticals‐ amphetamine salts, phentermine, ephedrine, pseudoephedrine, theophylline, vasopressors (norepinephrine, epinephrine, phenylephrine), ketamine, caffeine
• Drugs of abuse‐methamphetamine, MDMA, synthetic cannabinoids, synthetic cathinones, cocaine, PCP & derivatives, nicotine
Why?
• Alterations in neurotransmitters > end‐organ dysfunction
• CNS, cardiac, renal, autonomic dysfunction
• Immediate Actions
• Therapeutic errors• Dependent upon agent and age/clinical picture
• Any parenteral exposure• Call 911 or take to nearest ED
• All exposures• Call OCPDI
10/8/2019
31
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
61
Calcium Channel Blockers (CCB) and Beta Blockers (BB)
• Who?
• Inadvertent ingestions
• Suicidal patients
• What?
• BB‐ bisoprolol, atenolol, nebivolol, metoprolol, acebutolol, nadolol, carvedilol, labetalol, penbutolol, propranolol
• CCB‐ diltiazem, verapamil, amlodipine, nicardipine, nimodipine, nifedipine, felodipine, nisoldipine, isradipine
• Why?
• Narrow therapeutic index
• Toxicity‐extension of therapeutic effects
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32
• Immediate Actions
• Therapeutic errors• Dependent upon medication and situation
• Any intentional exposure• Call 911
• All exposures• Call OCPDI
63
Toy Hall of Shame
Aquadots® and Bindeez®
• Beads coated with 1,4‐butanediol
64
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33
65
Sciencelab.com
10/8/2019
34
Daphne (1.2 mg)‐
15 minutes‐ ‘Don’t care one bit about the 9‐5 stuff that I was worrying about 15 minutes ago’
25 minutes‐ ‘Starting to ramp up a bit, feeling nauseous, getting dizzier’
35 minutes‐ ‘*very* dizzy’‘I kind of like the body‐high: legs feel wobbly and kind of vibrating”
Kamack (1.6 mL)‐
‘Take at cocktail hour for general relaxation & stimulation of growth hormone. Also take ¾ dose before exercise to increase endurance.’
Jason (5 mL)‐
0 min: 3mL‐ no effect
30 min: + 1 mL‐ ‘Remember, you can always take more drugs, but once you take too much, you’re f***ed’
60 min: + 1mL‐ ‘Feel like going for a walk’
~2 hours: ‘having a slightlyharder time keeping my balance walking around, but that's alright as I don't really have to go anywhere’
~6 hours: ‘My stomach is upset’
~8 hours: ‘I crash’
https://www.erowid.org/experiences/subs/exp_14Butanediol.shtml
https://www.erowid.org/experiences/exp.php?ID=29274https://www.google.com/search?q=sceptical+meme&rlz=1C1EODB enUS595US595&espv=2&biw=1280&bih=899&source=lnms&tbm=isch&sa=X&ved=0CAYQ AUoAWoVChMI2I 7wZ66xwIVhB8eCh0oQQrs#imgrc= YyF6QfuAUx xM%3A
Chromodynamix‐
“I am a qualified Pharmacologist, so I ‘should’ have known better…On a Sunday afternoon, I decided to have a ‘nap’. Instead of measuring the amount into some grapefruit juice, I ‘estimated’ the amount…BAD MOVE! …Next thing I remember were paramedics checking me out and coming round in emergency resuscitation. I had already had a brain scan as they suspected a stroke and I had been intubated. They started discussing doing a lumbar puncture and possible ‘brain surgery,’ and all this time I am trying to explain I was a qualified Pharmacologist and I was not in any danger.
Addendum‐ I mentioned mixing the 1,4‐Butanedoil with grapefruit juice. There are many drug ‘interactions’ with grapefruit juice, which inhibits an enzyme Cytochrome P 450 in the intestinal wall. This can cause much higher concentrations of a drug to get to the blood stream with dangerous results. I am convinced this led to the ‘OD reaction.’”
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Pharmacology‐Pharmacology‐ Schep, et al. Clin Tox. 2012; 50: 458‐470.
OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting
alpha‐2 agonists
centrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
70
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Centrally acting alpha2 agonists
• Who?
• Children, therapeutic errors, intentional ingestions, malicious intent
• What?
• Clonidine, tizanidine, guanfacine, dexmedetomidine, tetrahydrozoline, oxymetazoline
• Why?
• Act on alpha‐2 receptors in the CNS to decrease sympathetic tone
• CNS/respiratory depression, hypotension, bradycardia
71
Immediate Action
• Immediate Actions
• Therapeutic errors• Dependent upon medication and situation
• Any intentional exposure• Call 911
• All exposures• Call OCPDI
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
73
Oil of Wintergreen
• Methyl salicylate• 100% is most common formulation• 5mL (1 mouthful) = 5g methyl salicylate• 1.5g aspirin equivalents per 1g methyl salicylate
• 7.5g aspirin (equivalent) per 5mL• For a 30lb child (13.6kg)
• 551.5 mg/kg• Threshold for referral is 150 mg/kg
74
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OCPDI’s ‘Red Flag’ List
calcium channel blockers
calcium channel blockers
beta blockersbeta blockerscentrally acting alpha‐2 agonistscentrally acting alpha‐2 agonists
stimulantsstimulants antiarrhythmicsantiarrhythmics antimalarialsantimalarials
bupropionbupropion colchicinecolchicine opioidsopioidstricyclic
antidepressantstricyclic
antidepressantssulfonylureassulfonylureas toxic alcoholstoxic alcohols
black widow bites
black widow bites
organophosphates & carbamates
organophosphates & carbamates
cyanide/CO/H2Scyanide/CO/H2SMicotil®
(tilmicosin)Micotil®
(tilmicosin)hydrocarbonshydrocarbons snake bitessnake bites
button batteriesbutton batterieshydrofluoric
acidhydrofluoric
acidoil of
wintergreenoil of
wintergreenchlorfenapyrchlorfenapyr local anestheticslocal anesthetics
Plants
Mushrooms
Plants
Mushrooms
75
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The U.S. Opioid Epidemic
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Prescription opioids
Alternative Prescription Opioids
Traditional illicit opioids
Non‐Traditional illicit opioids
Opioid alternatives
The ‘Roots’ of Kratom
• Family: Rubiaciae
• Genus: Mitragyna
• Species: speciosa
Indigenous to:• Southeast Asia• The Philippines• New Guinea
White CM. Am J Health Syst Pharm. 2018; 75(5): 261‐267.Kaye et al. Best Pract Res Clin Anaesthesiol. 2018; 32(2): 125‐136.
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The ‘Roots’ of Kratom
• Thai kratom extract composition:
• Mitragynine (66%)
• Paynantheine (9%)
• Hydroxymitragynine (2%)
• Speciogynine (7%)
• Speciociliatine (1%)
• 40 structurally related alkaloids, also flavonoids, terpenoid saponins, polyphenols and glycosides
White CM. Am J Health Syst Pharm. 2018; 75(5): 261‐267.Kaye et al. Best Pract Res Clin Anaesthesiol. 2018; 32(2): 125‐136.Feng et al. J Food Drug Anal. 2017; 25(3): 461‐471.
The ‘Roots’ of Kratom
• Ketum
• Kakuam
• Ithang
• Thom
• Mambog
Kaye et al. Best Pract Res Clin Anaesthesiol. 2018; 32(2): 125‐136.
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Kratom Use
• Fresh or dried leaves• Chewed• Made into a tea
• Traditional Uses• Improve productivity• Fight fatigue• Religious ceremonies
• Modern Uses• Opioid dependence• Opioid substitute• “Enhancer”• 4x100 (kratom, cough syrup, Coca‐Cola, ice)
White CM. Am J Health Syst Pharm. 2018; 75(5): 261‐267.Kaye et al. Best Pract Res Clin Anaesthesiol. 2018; 32(2): 125‐136.
1943 Prohibited in Thailand
1952 Prohibited in Malaysia
2011 Controlled in Denmark, Poland, Sweden, Latvia and Romania
2014 FDA banned importation & manufacturing (Schedule I status‐ did not stick)
2015 Australia & New Zealand
Considered a narcotic
2016 UK prohibited sale, import and export
2017 Schedule I substance in Republic of Ireland
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Mitragynine
Active at δ, μ, and κ opioid receptors
No structural similarity to morphine
Broad binding capacity
dopaminergic, serotonergic, gabaminergicand adrenergic pathways, COX inhibition
Ponglux, et al. Planta Medica. 1994; 60(6): 580–581. Horie, et al. Planta Medica. 2005; 71(3): 231–236. Takayama, et al. Chemical and Pharm Bulletin. 2004; 52(8): 916– 928.
7‐hydroxymitragynine
Active at μ, and κ opioid receptors and alpha‐2 receptors
No structural similarity to morphine
Broad binding capacity
dopaminergic, serotonergic, gabaminergic and adrenergic pathways, COX inhibition
Consideration for standardizationPonglux, et al. Planta Medica. 1994; 60(6): 580–581. Horie, et al. Planta Medica. 2005; 71(3): 231–236. Takayama, et al. Chemical and Pharm Bulletin. 2004; 52(8): 916– 928.
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Speciociliatine
Active at μ and κ opioid receptors
Not inhibited by naloxone
Takayama, et al. Chemical and Pharm Bulletin. 2004; 52(8): 916– 928.
Mild stimulant effects
• Similar to caffeine/nicotine
Opioid‐like effects
• Analgesia
• Sedation
• Respiratory depression
5‐15 m
g (m
oderate/high dose)
1‐5 m
g (low/m
oderate
dosin
g)
White CM. Am J Health Syst Pharm. 2018; 75(5): 261‐267.Kaye et al. Best Pract Res Clin Anaesthesiol. 2018; 32(2): 125‐136.
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• Bitter taste
• Feeling hot/sweaty
• Itchiness
• Hangover (similar to alcohol)
• Mild depressed mood
• Desire to repeat use
• Difficulty controlling use
• Building tolerance quickly
• Empathy• Euphoria• ‘Nodding’• ↓ opioid withdrawal symptoms
• Aphrodisiac• Increased sociability • Increased talkativeness
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White CM. Am J Health Syst Pharm. 2018; 75(5): 261‐267.Kaye et al. Best Pract Res Clin Anaesthesiol. 2018; 32(2): 125‐136.
Drug Interactions
Stimulants
Sedatives
Hypnotics
Disease Interactions
Depression
Addiction
Liver disease
White CM. Am J Health Syst Pharm. 2018; 75(5): 261‐267.
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Loperamide‐ 'poor man's methadone'
Binds to mu opioid receptors on the intestinal wall > decrease peristalsis
Maximum daily dose 16mg Available OTC
Lee et al. Clin Toxicol. 2018. Epub ahead of print: doi 10.1080/15563650.2018. 1510128
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Loperamide
• Pharmacokinetics
• Low oral bioavailability (<1%)
• High first pass metabolism
• Metabolized via CYP3A4
• Poor penetration into the CNS • P‐glycoprotein efflux
Lee et al. Clin Toxicol. 2018. Epub ahead of print: doi 10.1080/15563650.2018. 1510128Wu et al. Ann Emerg Med. 2017; 70(2): 245‐252.
Crafty Chemists
Add CYP 3A4 inhibitors to increase serum concentration
Grapefruit juice
Cimetidine
Inhibit P‐glycoprotein to improve blood brain barrier penetration
Omeprazole
Ingestion of supratherapeutic doses
25‐800mg daily
Lee et al. Clin Toxicol. 2018. Epub ahead of print: doi 10.1080/15563650.2018. 1510128Wu et al. Ann Emerg Med. 2017; 70(2): 245‐252.
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Loperamide abuse & misuse
• Initially used as opioid alternative for euphoria
• Followed by reports of arrhythmias
• More commonly used for withdrawal symptoms
Loperamide abuse & misuse
• Loperamide= $0.09/mg• 200mg= $18.00/day
• Oxycodone= $1.00/mg
• Heroin= $0.02‐$0.40/mg
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Clinical Effects
Opioid Toxidrome
CNS & respiratory depression, miosis, constipation
Sodium Channel Blockade
Prolonged QRS interval, dysrhythmias
Potassium Channel Blockade
Prolonged QT interval, dysrhythmiasMacdonald et al. BMJ Case Rep. 2015.
Eggleston et al. Annals of Emergency Medicine. 2017; 69(1): 83‐86. Wu et al. Ann Emerg Med. 2017; 70(2): 245‐252.
Methadone Kinetics
Orally administered racemic mixture
Lipophilic, basic drug
Predominantly absorbed in small intestine
Oral bioavailability: 41‐99%
N‐demethylation via CYP450 to inactive metabolites
3A4, 2B6, 2C19, 2C9, 2D6
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“Anecdotal “Evidence”
“Well I took one omeprazole (whatever the regular dose is, 20 mg i think) about an hour before taking methadone. I only took 10 mg, and it's still kicking in, but already it feels more like I took 15 mg. Not a huge difference, and it's still within the realm of possible placebo effect, but I actually believe there is some definite potentiation going on here.”
‐ Indy
“ … prolongs the duration of action of methadone very well.”
‐t1rex
Omeprazole Thefts Spark Change
“More than $3,500 worth of Prilosec OTC was stolen from a Suffolk Walmart.” –WVEC
2010
“Wanted: Battery and retail theft of Prilosec OTC Jewl‐Osco on Roselle Rd, Hoffman Estates” – The Cardinal
2011
“Over‐the‐counter theft receives police attention in Boone, NC” – Charlotte Criminal Lawyer Blog
2013
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Post‐Assessment Question #1
Which of the following substances may cause severe toxic effects following ingestion of just one tablet in a child?
A. Famotidine
B. Glipizide
C. Ibuprofen
D. Lisinopril
103
Post‐Assessment Question #2
Kratom has effects on which of the following receptors?
A. µ opioid receptors
B. D1 receptors
C. Κ opioid receptors
D. All of the above
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Toxicology Take‐AwaysWalter P. Scheffe 2019 CPE Series
Jami Johnson, PharmD, DABATAssistant Director, Oklahoma Center for Poison & Drug Information
Assistant Adjunct Professor, OU College of Pharmacy