Toxicology - Antihypertensives, Synthetic Cannabinoids, Aspirin/Salicylates, Digoxin, Sympathomimetics

Question 1

Bradycardia with hypotension

Answer 1

*Beta blockers
*Calcium channel blockers
Digoxin
Alpha-agonist (clonidine, guanfacine, methyldopa)

Don’t have the ability to have compensatory increased HR to to maintain cardiac output

CCBs
́ Alert initially, *elevated blood sugar
́ Sustained release may delay onset

BB
́ Decreased mental status
́ Sustained release may delay onset

Digoxin
́ Need AV conduction abnormality
́ Delay in onset (GI early)

Alpha-2 agonist
́ Decreased mental status, small pupils,
́ No delay in onset

Question 2

Pathophysiology of Overdose - CCBs (DHP + non-DHP) (just read 1-2 times)

Answer 2

Verapamil + diltiazem (non-dihydropyridines)
́ Decreased ventricular contractility
́ Negative inotrope (BP)
́ Sinus node depression
́ Negative chronotrope (HR)
́ AV node depression leads to various blocks

All calcium channel blockers (including dihydropyridines)
́ Vasodilation leads to hypotension

Question 3

Beta Blockers

Answer 3

Selective and non-selective
́ Membrane stabilizing activity
́ Inhibit fast sodium channels
́ CNS – depression & seizures
́ Negative inotropic effects

Pertinent Selective Beta-Blockers:
Bisoprolol
Esmolol
Atenolol
Metoprolol

Vasodilating agents:
Betaxolol Carvedilol Labetalol Nebivolol

Membrane stabilizing effects (sodium channel effect, may also widen QRS)
Acebutolol, Carvedilol, Betaxolol, Propranolol

Question 4

Beta Blockers Clinical Effect

Answer 4

Toxidrome - Bradycardia, hypotension
Cardiac - AV blocks and CHF
́ Sotalol - Torsades de Pointes
́ CNS - depressed LOC
́ Propranolol - seizures (crosses BBB more than other BB)

Question 5

CCB/BB Treatment (General)

Answer 5

GI decontamination
́ Activated charcoal
́ Whole bowel irrigation

́ Fluids
́ Atropine
́ Calcium
́ Glucagon? - ONLY BETA BLOCKERS
́ High dose Insulin and glucose
́ Vasopressors
́ Inotropes
́ Cardiac Pacing
́ Intralipid
́ ECMO

Question 6

Differentiation diagnostic between CCBs and BBs

Answer 6

Glucose elevation in CCB overdose

Question 7

CCB/BB Overdose Treatment

Answer 7

Fluids
́ Isotonic crystalloids
́ 0.9% normal saline, lactated ringers

Atropine
́ 0.5 - 1mg every 5 minutes for 3 doses
- if more is needed, would switch to longer acting agent

Calcium Chloride
́ 13.4 mEq/ca per 1 gram (this is 3x elemental calcium)
́ Sclerosing - more of a vesicant. Needs a larger vein or central vein to limit risk
́ Dose: 1-3g IV (adult)

Calcium Gluconate
́ 4.3mEq/ca per 1 gram
́ Veno-friendly (okay for peripheral administration)
́ Dose: 3-9g IV (adult)

Question 8

CCB/BB Overdose Treatment - Insulin and Glucose

Answer 8

Insulin and glucose (HIET – high dose insulin euglycemia therapy)
́ May shift cardiac energy from free fatty acids to carbohydrates
Dose:
́ 1 unit/kg bolus
́ 1-10 units/kg/hr
́ Glucose: administer to keep glucose > 100 mg/dL (loose target, don’t want hypo)
́ Potassium: replace as needed (goal 2.8 – 3.5) (lower end of normal because it’s just a redistribution of potassium)
́ Effects start 30-60 minutes after dosing

Question 9

CCB/BB Overdose Treatment part 2

Answer 9

Vasopressors
́ Norepinephrine, epinephrine

Inotropes
́ Dobutamine (beta agonist), milrinone (vasodilating, PDE inhibitor)

CardiacPacing

Intralipid
́ MOA: ‘lipid sink’ – pulls toxin off of a site of toxicity into intravascular space
́ MOA: modulator of myocardial energy – enhances fatty acid intracellular transport

VA-ECMO

Question 10

CCB/BB Overdose Treatment - Glucagon?

Answer 10

? Because early tachyphylaxis —> will stop working. Still is a viable option

Does what beta receptor does to increase cAMP and increase contractility

́ Benefit after beta blockers (not CCB)
Dose:
́ Initial: 3-5mg (up to 10mg) bolus
́ Infusion: 3-5mg/hour

Side effects:
́Vomiting – limited use with altered mental status
(Use with anti-emetic)

Question 11

Other antihypertensives and treatment

Answer 11

́ Alpha-2 agonists
́ Alpha-1 antagonists
́ Vasodilators
́ ACEi/ARB

Supportive Care
Fluids
Atropine (if HR goes low)
Vasopressors

Won’t regularly go to insulin or other options in these overdoses

Question 12

Other Antihypertensives and Treatment - Clonidine

Answer 12

́ Transient hypertension and tachycardia
́ Bradycardia and hypotension
́ CNS depression
́ Respiratory depression

Treatment:
́ Naloxone 5-10mg bolus +/- infusion - very high dose, most providers not comfortable
́ May reverse respiratory depression
́ Supportive care

Question 13

Types of Cannabinoids

Answer 13

Phytocannabinoids - plant derived (CBD, THC, CBN, etc)
THC is the main component of marijuana that is responsible for the major psychoactive effects
́ THC partial agonism at CB1 receptors (this is why smoking marijuana has HIGH therapeutic index)
́ Mood elevation, euphoria, relaxation, creative thinking, and increased sensory awareness

Endocannabinoids - Brain-derived

Synthetic Cannabinoids - Chemically Engineered

All bind to endocannabinoid receptors CB1 and CB2

Marijuana is still illegal under federal law

Question 14

Endocannabinoids receptors functions

Answer 14

CB1 Receptors
́ CNS
́ GPCRs
́ Motor Activity
́ Thinking
́ Pain perception

CB2 Receptors
́ Periphery
́ GPCRs
́ Immune modulation
́ Anti-inflammatory

Question 15

Clinical Effects of Phytocannabinoids (just read 1-2 times)

Answer 15

Wanted Effects
• Mood elevation
• Euphoria
• Relaxation
• Creative thinking
• Increased sensory awareness
• Appetite stimulation
• Nausea suppression

Paradoxical Effects
• Short-term memory difficulties
• Agitation
• Feeling tense
• Anxiety
• Dizziness
• Lightheadedness
• Confusion
• Loss of coordination

Question 16

Street Names for Cannabinoids

Answer 16

“K2” or “Spice”

Question 17

Synthetic Cannabinoids

Answer 17

́ AB-CHIMINACA
́ AMB-FUBINACA
́ Naming system based on chemical structure
́ N-(1-Adamantyl)-1-Pentyl-1H-INdAzole-3- Carboxamide
́ APINACA

Structure-Activity relationship. Minor changes result in big effects

Synthetic cannabinoids are much more potent than phytocannabinoids and can have unpredictable effects

Question 18

Differences in Cannabinoids

Answer 18

Synthetic Cannabinoids
́ Full agonists
́ Higher receptor affinity
́ Longer half-lives

Ki = affinity. Lower # = higher affinity

Question 19

Clinical Presentation (idk that we’ll be asked this)

Answer 19

Signs and Symptoms
• CNS depression
• Disorientation
• Restlessness/agitation
• Hallucinations
• Seizures, generalized • Combativeness
• Anxiety
• Mydriasis
• Tachycardia
• Vomiting

Lab abnormalities
• ↓ Potassium
• ↑ Blood glucose
• ↑ Creatinine kinase
• ↑ White blood cells
• ↑ Creatinine

Question 20

Management (most common sx) - Cannabinoids

Answer 20

Agitation
• IM/IV lorazepam 2-4mg (titrate to effect)
• IM/IV Midazolam 5-10mg (titrate to effect)
• IM/IV Haloperidol 2.5 – 10mg
• IM/IV Olanzapine 5 – 10mg
• IM/IV Droperidol 2.5mg – 10mg

Seizures
• IV lorazepam 2-4mg
• IM midazolam 5-10mg
• IV diazepam 5-10mg
• Antiepileptics – unclear role (because they don’t remove drug toxin, but not a hard no)

Nausea / Vomiting

Dehydration
• IV crystalloids

Hypertension / Tachycardia
• IM/IV Benzodiazepines
• IV antihypertensives as necessary

Question 21

Cannabinoids Hyperemesis Syndrome

Answer 21

Excessive vomiting due to chronic cannabinoid use
Pathophysiology
́ Dysregulation of endocannabinoid system
́ Desensitization and downregulation of CB1 receptors that generally have antiemetic effects
́ Alteration in TRPV1 receptor (transient receptor potential vanilloid subtype 1) after chronic cannabinoid use
Diagnosis
́ History of regular cannabis use
́ Cyclic nausea and vomiting
́ Generalized, diffuse abdominal pain
́ Compulsive hot showers with symptom improvement

Question 22

Cannabinoids Hyperemesis Syndrome Phases

Answer 22

Pre-emetic or Prodromal Phase
• Months to years
• Diffuse abdominal discomfort, feelings of agitation or stress, morning nausea, and fear of vomiting
• Increased use of marijuana to treat

Hyperemetic Phase
• 24 – 48 hours
• Cyclic episodes of nausea and vomiting
• Diffuse, severe abdominal pain

Recovery Phase
• Upon total cessation of cannabis
• Bowel regimens, fluids, electrolyte replacement
• Full resolution may take ~ 1 month

Question 23

Cannabinoids Hyperemesis Syndrome Clinical Management

Answer 23

• Hot showers
• Activate TRPV1
• Capsaicin topical cream (apply to abdomen)
• Activate TRPV1
• Anti-nausea (HaVOC Trial: Haloperidol was superior to ondansetron for improvement of nausea and abdominal pain at 120 minutes)
• Haloperidol
• Ondansetron
• Benzodiazepines
• Inhibitory effects on medullary and vestibular nuclei associated with nausea and vomiting
• Supportive care
• Fluids, electrolytes

Question 24

Sources of Salicylate

Answer 24

́ Various analgesics (OTC)
́ GI remedies
́ Pepto-bismol (9mg/ml)
́ Alka-seltzer (325mg)
́ Topical balms
́ Icy hot
́ Bengay
́ Oil of wintergreen (1440mg/ml)

Question 25

• TOXIC DOSE * - Aspirin / Salicylates

Answer 25

Acute overdose
́ Greater than 150mg/kg
́ Life threatening > 500mg/kg

Chronic overdose
́ Less clearly established
́ Greater toxicity at lower doses

́ Oil of wintergreen
́ 98% methyl salicylate
́ 98g/100ml
́ 20.4ml = 20g life threatening for 70kg adult
́ 5.1ml = 5g life threatening for 10kg child
́ 1.5ml = seek medical attention for 10kg child

Question 26

Pharmacokinetics of Aspirin / Salicylates

Answer 26

Absorption
́ Aspirin
́ Absorption can be delayed (pylorospasm, enteric coated, concretions/bezoars)
́ Other salicylates
́ Absorption varies according to the dosage form
́ Methyl salicylate will be absorbed quickly

Distribution
́ Protein binding 50-90% (decreased in OD)
́ Vd = 0.1-0.2 L/kg (small), larger in acidosis

Elimination
́ Hepatic and renal: normal half life 2-4 hours
Overdose
́ Michaelis-Menten kinetics
́ Half life extends
Significant overdose
́ Renal elimination plays a greater role

Question 27

Mechanism of Toxicity - Aspirin/Salicylates

Answer 27

Metabolic acidosis
́ Salicylic acid (minor)
́ Uncoupled oxidative phosphorylation (major)

Question 28

Clinical Manifestations - Aspirin / Salicylates

Answer 28

Respiration
́ Potent stimulatory effects on respiratory drive
́ Tachypnea/hyperpnea
GI
́ Disrupts mucosal barrier
́ n/v, hemorrhagic gastritis, volume depletion
CNS
́ Neuronal energy depletion, hypoglycorrachia (neuroglycopenia) - decreased BG in CNS, but not necessarily in the bloodstream
́ Tinnitus, altered mental status, hyperpyrexia, tachycardia, fever, coma, seizures
Other
́ Non-cardiogenic pulmonary edema (chronic), renal and hepatic injury

Question 29

Laboratory Manifestations - Aspirin/Salicylates

Answer 29

Acid / Base
́ EARLY: respiratory alkalosis (direct stimulation)
́ MIDDLE: mixed metabolic acidosis and respiratory alkalosis
́ LATE/PRETERMINAL: metabolic and respiratory acidosis

Electrolytes
́ hypo or hyperglycemia, (CNS hypoglycemia)
́ increased fluid and electrolyte losses
́ increased anion gap (MUDPILERS. S = Salicylates)

Urine
́ urine ketones will be positive

Question 30

Chronic Overdose - Aspirin/Salicylates

Answer 30

́ Acute overdose may be present
́ Slower, more insidious onset
́ N/V, tinnitus, dyspnea, hyperthermia, neurologic manifestations
́ More common to be misdiagnosed
Delirium, dementia, encephalopathy
Pulmonary edema more common
Increased PT/LFTs
́ Lower levels will produce toxic effects
́ Enlarged volume of distribution

Question 31

Management - Aspirin / Salicylates

Answer 31

́ Airway, breathing, circulation - ABCs
́ maintain ventilation – do not intubate
́ Multiple serum salicylate levels
́ Enhance elimination
́ multiple doses of activated charcoal 1 g/kg (loss of 10:1 ratio)
́ urine alkalization (pH > 7.5)
́ hemodialysis
́ Treat adverse effects
́ seizures, cerebral edema, hypoglycemia, dysrhythmias

Question 32

Bezoar

Answer 32

Concentrated lump of aspirin/Salicylates which slowly releases salicylates over time in the GI tract

Question 33

Ion Trapping - Aspirin/Salicylates

Answer 33

Alkalize the urine to make H+A- cross to the urine, become ionized to attempt to neutralize it, and then the ions can’t cross back into the bloodstream

Significantly higher urinary clearance with increasing Urinary Alkylinization

Is a learning objective! (1 of 2 for the aspirin lecture)

Question 34

Management of Aspirin / Salicylate Overdoses

Answer 34

́ Give dextrose (even if normal glucose levels)
́ 0.5-1g/kg
́ Fluid maintenance
́ Serum pH 7.45 – 7.55
́ 150mEq SODIUM BICARBONATE in D5W at twice maintenance rate
́ Urine pH > 7.5
́ Maintain potassium
́ Monitor Mental status, urine and blood pH, salicylate levels, fluid and electrolytes q 2-4 hours

Question 35

Hemodialysis Indications - Aspirin/Salicylates

Answer 35

́ Serum level
́ Acute: > 100mg/dL
́ Lower threshold in impaired kidney function
́ Chronic > 60mg/dL
́ Neurologic deterioration
́ Seizures
́ Intractable acidosis
́ pH < 7.20
́ Renal failure
́ Pulmonary edema

Continue hemodialysis until:
-Clear improvement in patient
-Salicylate level < 19mg/dL
-HD completed for 4-6 hours and levels not obtainable

Question 36

Acute Digoxin Toxicity

Answer 36

Gastrointestinal system
- Nausea, vomiting, diarrhea
Central nervous system
- Headaches, confusion, delirium
- Visual (halos/colors)
Metabolic derangements
- Hyperkalemia

Predistribution
- Nausea, vomiting
- Hyperkalemia

Post-distribution
- Hypotension
- Bradycardia
- Dysrhythmias
- Death

Question 37

Digoxin Toxicity - Hyperkalemia

Answer 37

Acute, single ingestions
Normal organ function
K+ > 5.5mEq/dL = all died
K+ < 5.0mEq/dL = all survived
K+ 5.0 - 5.5mEq/dL = mixed

Digoxin Cardiac ECG
- Prolonged PR interval
- Salvador Dali’s mustache

Question 38

Digoxin Toxicity

Answer 38

Cardiac
- Decreased conduction
- Enhanced automaticity
- Classic rhythms: PVC’s bidirectional ventricular tachycardia, atrial tachycardia with block
any rhythm except rapidly conducting SVT’s

Question 39

Treatment for Digoxin Toxicity

Answer 39

Gastrointestinal decontamination
- Activated charcoal, repeat doses in renal failure
Hyperkalemia
- Digoxin specific FAB fragments ; Temporizing measures

Digoxin specific FAB fragments (Digifab)
- Derived from sheep ; Digoxin-specific antibody formed
- Fc fraction (antigenic) cleaved
- Increased volume of distribution
- Less allergy

Digifab dose: 1 vial binds 0.5mg digoxin ingested. Unknown amount? —> 10 vials Digifab
In Practice…
- Give 2 vials and titrate to effect
- Give Q1 hour if no response seen

Without digibind – phenytoin is the antidysrhythmic classically of choice

Question 40

Indications for Digifab Use

Answer 40

Potassium > 5 mEq/L

Level > 20 mcg/L

Progressing signs of toxicity

Question 41

Chronic Digoxin Toxicity

Answer 41

Less common to present with typical manifestation and potassium is unhelpful

Digifab indications are soft and include:
- Post-distribution level of > 6 mcg/L (~6 after last ingestion)
- Progressing or severe signs of toxicity

Unknown digoxin dose (#Digifab vials):
- 5 in adults
- 3 in children

In practice…
Give 1-2 vials and titrate to effect
Give Q1 hour if no response seen

Question 42

What is a Sympathomimetic?

Answer 42

Inhibition of norepinephrine and dopamine reuptake, or increased release of neurotransmitters

“Uppers”

Question 43

Types of Sympathomimetics and General Management

Answer 43

Cocaine, Amphetamines, Bath Salts, Pseudoephedrine, Nootropics (said to promote intelligence)

NO ANTIDOTE

Supportive Care
• Elimination strategies (i.e. activated charcoal)
• Benzodiazepines
• Anti-hypertensives
• Fluids
• Anti-psychotics (if agitated or combative - haloperidol or olanzapine)
• Electrolyte management
• Ice baths (Temp too high—> Cool them down quickly
• Sodium bicarbonate (if acidosis present)

Bupropion and Pseudoephedrine have similar chemical structures

Question 44

Cocaine

Answer 44

Sympathomimetic

Typical Line = 20-30 mg
́ Ingestion of 1 gram is likely to be fatal
́ Euphoria, seizures, dysrhythmias, hypertension
́ Coronary artery spasm myocardial infarction
́ Adulterants
́ Levimasole: neutropenia, vasculitis, purpura
́ Body Packers
́ Management: Benzodiazepines, supportive care

Question 45

Amphetamines

Answer 45

Mechanism of action: releases catecholamines
́ Clinical manifestations: adrenergic
́ Similar to cocaine though longer lasting
́ Agitation, seizures, hyperthermia, hypertension, delirium
́ Management: benzodiazepines, barbituates, anti- hypertensives
́ Supportive care

Question 46

Bath Salts

Answer 46

Syntheticcathinones
́ Agitation
́ Tachycardia
́ Insomnia
́ Paranoia
́ Seizures
́ Violent, unpredictable behavior
́ Management: Supportive are

Question 47

Supportive Care - Sympathomimetics

Answer 47

Clinical Effects
• Benzodiazepines

Airway protection
• Intubation

Hyperthermia
• Ice packs
• Cool fluids
• Antipyretics (may or may not work)
• Benzodiazepines

Dysrhythmias
• Sodium bicarbonate
• Lidocaine

Rhabdomyolysis
• Fluids