Toxicology - Antihypertensives, Synthetic Cannabinoids, Aspirin/Salicylates, Digoxin, Sympathomimetics Flashcards
Bradycardia with hypotension
*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
Pathophysiology of Overdose - CCBs (DHP + non-DHP) (just read 1-2 times)
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
Beta Blockers
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
Beta Blockers Clinical Effect
Toxidrome - Bradycardia, hypotension
Cardiac - AV blocks and CHF
́ Sotalol - Torsades de Pointes
́ CNS - depressed LOC
́ Propranolol - seizures (crosses BBB more than other BB)
CCB/BB Treatment (General)
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
Differentiation diagnostic between CCBs and BBs
Glucose elevation in CCB overdose
CCB/BB Overdose Treatment
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)
CCB/BB Overdose Treatment - Insulin and Glucose
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
CCB/BB Overdose Treatment part 2
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
CCB/BB Overdose Treatment - Glucagon?
? 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)
Other antihypertensives and treatment
́ 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
Other Antihypertensives and Treatment - Clonidine
́ 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
Types of Cannabinoids
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
Endocannabinoids receptors functions
CB1 Receptors
́ CNS
́ GPCRs
́ Motor Activity
́ Thinking
́ Pain perception
CB2 Receptors
́ Periphery
́ GPCRs
́ Immune modulation
́ Anti-inflammatory
Clinical Effects of Phytocannabinoids (just read 1-2 times)
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
Street Names for Cannabinoids
“K2” or “Spice”
Synthetic Cannabinoids
́ 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
Differences in Cannabinoids
Synthetic Cannabinoids
́ Full agonists
́ Higher receptor affinity
́ Longer half-lives
Ki = affinity. Lower # = higher affinity
Clinical Presentation (idk that we’ll be asked this)
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
Management (most common sx) - Cannabinoids
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
Cannabinoids Hyperemesis Syndrome
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
Cannabinoids Hyperemesis Syndrome Phases
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
Cannabinoids Hyperemesis Syndrome Clinical Management
• 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
Sources of Salicylate
́ Various analgesics (OTC)
́ GI remedies
́ Pepto-bismol (9mg/ml)
́ Alka-seltzer (325mg)
́ Topical balms
́ Icy hot
́ Bengay
́ Oil of wintergreen (1440mg/ml)
- TOXIC DOSE * - Aspirin / Salicylates
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
Pharmacokinetics of Aspirin / Salicylates
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
Mechanism of Toxicity - Aspirin/Salicylates
Metabolic acidosis
́ Salicylic acid (minor)
́ Uncoupled oxidative phosphorylation (major)
Clinical Manifestations - Aspirin / Salicylates
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
Laboratory Manifestations - Aspirin/Salicylates
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
Chronic Overdose - Aspirin/Salicylates
́ 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
Management - Aspirin / Salicylates
́ 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
Bezoar
Concentrated lump of aspirin/Salicylates which slowly releases salicylates over time in the GI tract
Ion Trapping - Aspirin/Salicylates
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)
Management of Aspirin / Salicylate Overdoses
́ 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
Hemodialysis Indications - Aspirin/Salicylates
́ 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
Acute Digoxin Toxicity
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
Digoxin Toxicity - Hyperkalemia
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
Digoxin Toxicity
Cardiac
- Decreased conduction
- Enhanced automaticity
- Classic rhythms: PVC’s bidirectional ventricular tachycardia, atrial tachycardia with block
any rhythm except rapidly conducting SVT’s
Treatment for Digoxin Toxicity
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
Indications for Digifab Use
Potassium > 5 mEq/L
Level > 20 mcg/L
Progressing signs of toxicity
Chronic Digoxin Toxicity
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
What is a Sympathomimetic?
Inhibition of norepinephrine and dopamine reuptake, or increased release of neurotransmitters
“Uppers”
Types of Sympathomimetics and General Management
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
Cocaine
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
Amphetamines
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
Bath Salts
Syntheticcathinones
́ Agitation
́ Tachycardia
́ Insomnia
́ Paranoia
́ Seizures
́ Violent, unpredictable behavior
́ Management: Supportive are
Supportive Care - Sympathomimetics
Clinical Effects
• Benzodiazepines
Airway protection
• Intubation
Hyperthermia
• Ice packs
• Cool fluids
• Antipyretics (may or may not work)
• Benzodiazepines
Dysrhythmias
• Sodium bicarbonate
• Lidocaine
Rhabdomyolysis
• Fluids
