Toxicology - Opioid,Benzodiazepine,Antidepressant,Toxic Alcohols Overdose

Question 1

Opioids Toxidrome and Clinical Presentation

Answer 1

Toxidrome:
Opioid

Clinical Presentation:
-Decreased mental status
-Pinpoint pupils
-Decreased bowel sounds
-Depressed respiration

Question 2

Opioid Management and Antidote

Answer 2

Administer antidote (Naloxone)

Protect airway

Question 3

Naloxone doses and routes of administration

Answer 3

IV, IM, IN
Non-opioid dependent: IV 0.4mg
Opioid dependent patient (heroin, oxycodone, etc. daily): IV 0.04mg and titrate to effect
Bystanders: IN 4mg (Narcan®)
Continuous Infusion: 1⁄2 initial effective bolus dose and 2/3 of effective dose per hour

Goal: Maintain respirations
Side effects: runny nose, flash pulmonary edema, [acute precipitated withdrawal]

Question 4

Naloxone Induced Pulmonary Edema

Answer 4

Proposed mechanism: Adrenergic response, catecholamine surge
-Tachycardia, tachypnea, hypertension
Shift in blood volume into the pulmonary vasculature
-Pulmonary vasoconstriction, pulmonary hypertension, fluid leakage into lungs

Treatment: Nitroglycerin, diuretics, positive pressure ventilation

Prevention? Smaller initial doses of naloxone

Question 5

Loperamide

Answer 5

Imodium - OTC anti-diarrheal. Inhibits intestinal peristalsis through μ-opioid receptor agonism
Toxidrome: Opioid
Clinical presentation: Opioid overdose, severe cardiac arrhythmias
Blood brain barrier: P-glycoprotein. Co-administration of PGP inhibitor enhances effects
Doses:
Therapeutic: 2 – 4mg PRN (max: 16mg/day)
Recreational: 30mg – 200mg (+)

Question 6

Loperamide Management

Answer 6

Respiratory Depression: Naloxone

Cardiac disturbances:
-IV Magnesium
-Sodium Bicarbonate
-Intravenous Isoproterenol
-Transcutaneous Pacing

CPR and ACLS

Question 7

Benzodiazepine Overdose

Answer 7

Facilitate GABA binding
Toxidrome: Sedative-Hypnotic

CNS depression
Drowsiness
Stable vital signs
-Mildly depressed respiratory drive

Treatment: Monitoring, supportive care

High therapeutic index

Lethality rare, would be from respiratory depression (like opioids)

Question 8

Benzodiazepine Withdrawal

Answer 8

Symptoms:
́ Severe sleep disturbance
́ Irritability
́ Increased tension and anxiety
́ Panic attacks
́ Sweating
́ Difficulty in concentration
́ Dry retching and nausea
́ Palpitations
́ Headache
́ Psychotic reaction
́ Seizures
́ Death

Precipitated withdrawal is a concern in these patients! Lethal even more than opioid comparison

Question 9

Benzodiazepine Antidote

Answer 9

Flumazenil
Dose: 0.2 mg IV over 15 seconds
Peds: 0.01mg/kg IV

Competitive antagonist at benzodiazepine receptor site
Onset: 1-2 minutes
Variable duration, redoing may be required

Use or not use? Benzo protectant effect, relatively non lethal component of toxicity. Precipitated withdrawal and potentially lethal seizures possible

Flumazenil does not completely or consistently reverse benzodiazepine-induced respiratory depression and may require using other supportive measures (e.g. Bag-valve mask ventilation, endotracheal intubation, etc.)

Question 10

Polysubstance Overdose

Answer 10

Elimination (ex. activated charcoal)
Administer antidote (ex. N-Acetylcysteine)
Supportive Care (ex. Benzodizepines)

Question 11

Safest Times to Use Flumazenil

Answer 11

1. Procedural Sedation
   - Known PMH
   - Iatrogenic benzodiazepine sedation
2. Unintentional, pediatric exposure
   - Relative confidence on non-benzodiazepine dependent child
   - Minimizes extensive work up

Other proposed uses (None routinely recommended):
Hepatic encephalopathy
Z-drug overdose (e.g. Zolpidem)
Ethanol intoxication

Question 12

Top 2 Antidepressant Classes/Agents for Overdose

Answer 12

Probably not a question for exam purposes
1. Bupropion
2. TCA

Question 13

Tricyclic Antidepressant Agents (Reminder slide)

Answer 13

Amitriptyline
Nortriptyline
Doxepin
Imipramine
Desipramine

Question 14

Tricyclic Antidepressant Toxicity - Toxidrome and Effects

Answer 14

Toxidrome: Anticholinergic
Catechol reuptake inhibitor and Alpha adrenergic blocker = Hypotension
GABA antagonist = seizures
Sodium channel blocker = dysrhythmias

Question 15

Tricyclic Antidepressant Toxicity - Clinical Effects

Answer 15

Increased BP (initially) -> Decreased BP
Increased HR
Increased temperature
Normal to decreased HR
Rapid decline in mental status

Question 16

EKG Interpretation- TCA Toxicity

Answer 16

Sensitivity 100%, specificity 98%
Terminal 40 msec rightward axis deviation in frontal plane (R wave in aVR)

QRS widening and increasing R wave amplitude
-higher/wider = higher risk of seizures

Question 17

TCA Toxicity Treatment/Antidote

Answer 17

Sodium Channel Blockade is lethal component
Sodium alone may be effective (Hypertonic Sodium)
Alkalinization alone may be effective (Hyperventilation)

Sodium + Alkalinization

Hypertonic sodium bicarbonate
-Provides sodium for sodium channel blockade
-Alkalinization reduces TCA binding to its receptor in myocardium
Dose: 1-2 mEq/kg boluses
150 mEq in 1 L D5W at twice maintenance rate (~150-200 ml/hour)

Endpoints: QRS narrowing and Blood pH not >7.55

Question 18

TCA Toxicity Other Treatments

Answer 18

Treat Anticholinergic effects: No treatment, tachycardia may be protective (because BP may lower, this preserves cardiac output)
Dysrhythmias: Magnesium, Lidocaine
Hypotension: Norepinephrine, Epinephrine, Vasopressin, Phenylephrine also Methylene Blue, Lipid Emulsion, High Dose Insulin
Seizures: Benzodiazepines, Barbiturates
Not Phenytoin (is a sodium channel blocker) - Increase frequency and duration of VT in TCA poisoned dogs
Not Flumazenil - Possible uncontrolled seizures and decreased ability to treat seizure

Question 19

Physostigmine

Answer 19

Anticholinergic Toxidrome treatment

Case reports of asystole following administration in TCA overdoses

Bottom line: Do not use in TCA overdose!!

Question 20

Bupropion (Wellbutrin, Zyban)

Answer 20

Toxidrome: Sympathomimetic

Unclear toxicology
-Delayed seizures in overdose setting (up to 24 hours s/p ingestion)
-Seizure risk doses >/ 600mg/day (hence MDD < 450mg/day)
-Wide complex dysrhythmias (widened QRS) - normally means sodium channel blockade, but not in this case because Not responsive to sodium bicarbonate

Decontamination
• Orogastric Lavage ; Activated Charcoal ; Whole bowel irrigation
Treatment: Supportive Care (seizure? hypertensive? —> Benzodiazepine), lipid emulsion, ECMO

Cases of
•Sympathomimetic crisis
•Cardiogenic shock
•Status epilepticus
•Lazarus effect (come back from dead)
•Death

Question 21

SSRIs

Answer 21

Serotonergic features
-Altered mental status, tachycardia, myoclonus, tremors, diarrhea, seizures

Treatment: Supportive Care, Monitoring

(Es)Citalopram most likely to cause seizures
-ECG abnormalities may be delayed up to 24 hours
-May also widen QTc and QRS

Question 22

Serotonin Syndrome

Answer 22

Causes:
-Polypharmacy
-Drug interaction
-Overdose of multiple serotonergic agents
-Most specific to 5HT2A and possibly 5HT1A

Clinical effects:
Spontaneous clonus, agitation, diaphoresis, hyperthermia, tremor, hyperreflexia, diarrhea, mental status changes, incoordination

Treatment:
- Supportive care: decreasing core temperature
- Antidote – Cyproheptadine 12mg PO followed by 4-8mg PO Q6H maintenance
-Is an antihistamine, antiserotonergic agent with anticholinergic burden potential
-Use is kind of controversial
- Other: **Benzodiazepines (mainstay therapy), propranolol

Question 23

Anion Gap Calculation and Normal Range

Answer 23

Anion Gap = Na+ - (Cl- + HCO3-)
Normal gap ~ 4 - 12 (up to 16 if including K+)

Question 24

MUDPILERS Acronym - What do these contribute to?

Answer 24

Increased Anion Gap Metabolic Acidosis

[which acid is contributing]

M - Methanol [Formic Acid]
U – Uremia [Urea]
D – DKA,SKA,AKA [Ketoacids]
P – Phenformin (metformin), Paraldehyde [Lactate]
I – Isoniazid, INH [Lactate]
L – Lactate, CO, CN, MetHb [Lactate]
E – Ethylene Glycol [Glycolic Acid]
R - Rhabdomyolysis
S – Salicylates [Ketoacids / Lactate]

Question 25

Clinical Presentation - Toxic Alcohols

Answer 25

Altered mental status
-Inebriation b/c alcohol still in the formulation
Gastrointestinal distress

Early:
Possible GI distress/inebriation
Methanol (0-24 hours), ethylene glycol
Osmol gap spikes early! (see graph in slides)
Lactate/ketone/renal function measurement spikes early

Later:
High anion gap metabolic acidosis
Methanol: Visual changes
Ethylene glycol: nephrotoxicity, hypocalcemia
Anion gap spikes late (see graph in slides)

Question 26

Methanol

Answer 26

See pediatrics cards for more, reiterating important parts

High Volatility

Methanol —> Formaldehyde —> Formic Acid (can cause metabolic acidosis) <—> Formate - (Folic Acid) -> CO2 + H2O

Ethanol or Fomepizole inhibit alcohol dehydrogenase which converts methanol to formaldehyde

Question 27

Ethylene Glycol

Answer 27

See pediatrics card for more, highlighting important info

Low volatility

Ethylene Glycol -(alcohol dehydrogenase)-> glycoaldehyde -(aldehyde dehydrogenase)-> Glycolic Acid -(another enzyme)-> Glyoxylic Acid —> Oxalic Acid or other products if given Thiamine (B1) or Magnesium, Pyridoxine (B6)

Question 28

Initial Management for Toxic Alcohols

Answer 28

GI decontamination? (Activated charcoal doesn’t work for these)
Electrolytes and arterial blood gas
Ethanol level (need to know because it may already be at a level treating the patient!)
Methanol and ethylene glycol level - delayed
Measured osmolality
Consider ADH inhibition

Question 29

Ethanol vs. Fomepizole

Answer 29

Both ADHs (Alcohol Dehydrogenase Inhibitors)

Ethanol: Dose: 1g/kg
- IV: 10% solution
- PO: 4 shots patron
Maintenance
- BAC ~ 100mg/dL (legal limit 80mg/dL)
Inexpensive
Difficult to dose, titrate, and prepare (especially oral)
Hypotonic
Adverse effects: CNS inebriation, thrombophlebitis, GI symptoms
Availability (IV version hard to get)

Fomepizole: Adverse effects: Headache, nausea, dizziness, minor allergic reactions
Dose:
- Load–15mg/kg
- 2nd phase – 10mg/kg Q12H x 4 doses
- Maintenance–15mg/kg Q12H (dose increase to combat auto induction)
Diluted in NS or D5W and infused over 30 minutes
Dose increased during hemodialysis
Expensive
Easy to dose quickly
Minimal adverse effects

Question 30

Sodium Bicarbonate and Hemodialysis as Toxic Alcohol Treatments

Answer 30

Sodium Bicarbonate corrects acidosis for both methanol and ethylene glycol and also reduces ratio of formic acid to formate for methanol

Hemodialysis used only considered in the following scenarios:
- Methanol or ethylene glycol level of 25 mg/dL – 50mg/dL
- High osmol gap without another cause
- End organ manifestations of toxicity
- Severe metabolic acidosis

Question 31

Osmol Gap Calculation and Reason for Use

Answer 31

2Na + BUN/2.8 + Glucose/18 + Alcohol/N = Osmolality
N = 4.6 (ethanol)
N = 3.2 (methanol)
N = 6.2 (ethylene glycol)

Measured osmolality – calculated osmolality = osmol gap
Unaccounted for osmols (Similar concept to anion gap)

Normal osmol gap = Useless
- Such variability in normal osmol gap may equate to dialyzable level that appears normal

High osmol gap … Without other causes = very useful

Question 32

Metabolic Acidosis Decision Pathway

Answer 32

Metabolic Acidosis

Increased Anion Gap

Obtain ketone, lactate, and renal function labs

Increased Ketones?
• DKA, SKA, AKA
• Salicylates

Increased Lactate?
Medical Causes
• Seizures, sepsis
Toxin Causes
• Phen(met)formin
• INH
• Salicylates

Worsened Renal Function?
• Consider Uremia

None of the above? Consider non-measurable exogenous acids
• Formic acid
• Glycolic acid

Question 33

Propylene Glycol

Answer 33

Environmentally safe antifreeze
Drug diluent
- Lorazepam, diazepam, phenytoin
Metabolized to lactic acid

Question 34

Isopropyl Alcohol

Answer 34

Isopropanol -(alcohol dehydrogenase)-> Acetone (which is breathed off)

́ Very inebriating
́ Very irritating
́ Metabolized to acetone
- “ketosis without acidosis”
Would just monitor GI tract in these patients

Question 35

Summary Points - Toxic Alcohols (just read over)

Answer 35

Toxic alcohol suspected?
́ ADH inhibition (fomepizole)
́ Consider hemodialysis
́ Give adjunctive therapies:
́ Sodium bicarbonate (acidosis, ion trapping)
́ Folic Acid (methanol)
́ Magnesium (ethylene glycol)
́ Thiamine (ethylene glycol)
́ Pyridoxine [B6] (ethylene glycol)

The osmol gap can help rule in a toxic alcohol ingestion but may not be able to rule one out

Both ethanol and fomepizole preferentially block other toxic alcohols from being metabolized

Isopropyl alcohol produces a “ketosis without acidosis” that is not as toxic as other toxic alcohols