Toxicology

Anticholinergic

• Blind as a bat (pupils dilated - mydriasis)
• mad as a hatter (confusion)
• red as a beet  (flushed red appearance)
• hot as a hare (hot, flushed, dry)
• dry as a bone
• The bowel and bladder lose their tone, and the heart runs alone (brady).

Cholinergic

• Substances that may cause this:
  • Four "anti"s of antihistamines, antipsychotics, antidepressants, and antiparkinsonian drugs
  • Also: atropine, benztropine, datura, and scopolamine. 
• SLUDGE
  • Salivation
  • Lacrimation
  • Urination
  • Diarrhea
  • Gastrointestinal distress
  • Emesis

Opioid

• Opioids are potent respiratory depressors.
• Opioid intoxication:
  • Miosis
  • Encephalopathy
  • Hypotension
  • Hypothermia
  • Hyporeflexia
• Exams: Think alternative diagnosis if do not respond to total of 10mg naloxone (mean half-life 1 hour), continuous infusion may be needed.  (In practice can start with 0.1-0.4mg naloxone)
  • Naloxone lasts ~30min-60min
  • If naloxone is effective, set up a drip - effective dose given hourly (titrate to resp rate >9 or agitation)
• Opioid intoxication does not require intubation, usually can be managed with naloxone.
• Chronic opioid users receiving naloxone should be watched for withdrawal:
  • Opioid withdrawal symptoms:
    • Delirium
    • Agitation
    • Diaphoresis
    • Tremulousness
    • Hypertension
    • Fever
    • Seizures

Sympathomimetic

• Shared findings:
  • ↑ HR, ↑ BP, ↑ temp,
  • diaphoresis, mydriasis, agitation,
  • seizure, ↑ CK, ↑ liver chemistry studies
  • ↑ Cr

• Benzodiazepines are first line for agitation

• Avoid β-blockers for hypertension

• NOTE: Haloperidol may worsen hyperthermia

Methanol

• Metabolized by Alcohol Dehydrogenase
• No ethanol odor
• Metabolites:
  • Formic Acid (mitochondrial toxin - inhibits cytochrome oxidase)
    • Most susceptible are retina, optic nerve, and basal ganglia
  • Lactate (production of NADH)
• Poisoning:
  • Early toxicity: 6 hours post-ingestion (inebriation like alcohol)
  • Late signs: 6-24hrs  (scotoma, blurry vision, complete blindness, depressed consciousness, coma, seizures)
• Treatment: (Same as ethylene glycol)
  • Fomepizole
  • Dialysis (esp if visual impairment)
  • Sodium bicarb to keep pH > 7.3 (to keep methanol in neutral state (protonated), which decreases tissue penetration)
    •  Crit Care Clin. 2012 Oct;28(4):661-711. doi: 10.1016/j.ccc.2012.07.002.    

Ethyelene Glycol

• Component of solvents and antifreeze
• Metabolized by alcohol dehydrogenase to acids to oxalic acid (also glycolic acid, formic acid), precipitates in the kidneys causing AKI.
• No ethanol odor (odorless)
• Poisoning
  • Neurologic impairment (similar to ethanol)
  • Seizures, coma.
  • If untreated:  non-cardiogenic pulmonary edema, shock, hypotension. 
  • 24-48hrs later can develop flank pain and kiney failure
  • Renal Failure (metabolized to oxacic acid -->  crystallization in tubules causing AKI)
• Urine will show calcium oxalate crystals (envelope-shaped crystals)
• Osmolar gap metabolic acidosis
• Metabolytes:
  • Glycolic Acid (creates anion gap)
  • Lactate (through NADH production) - elevates serum lactate
  • Oxalic Acid (anion gap, final metabolite - can crystallize in urine, cause renal failure)
• Management:
  • IV Fomepezole (EtOH dehydrogenase inhibitor)
    • 4 hours after ingestion, 15 mg/kg IV bolus + 10mg/kg q12h x48hrs until ethyl glycol level is 25mEq/L
    • Decreases metabolism of ethylene glycol (metabolites are toxic).
      AND!:
  • Hemodialysis
    • Indications: pH < 7.1, evidence of end orga damage (continue fomepizole q4h)
  • Sodium Biarb to keep pH > 7.3 (minimizes tissue penetration)
    • Crit Care Clin. 2012 Oct;28(4):661-711. doi: 10.1016/j.ccc.2012.07.002.
  • NOTE: Use of fomepezole alone is not sufficient, usually need both. 
  • Previously used IV ethanol, but no longer needed.

Isopropyl Alcohol

• Present intoxicated with an elevated osmolar gap, but NO ANION GAP!

Amphetamines

• Increase central catecholamine activity --> anorexia, tachycardia, hypertension, hyperthermia, psychomotor agitation.
• Organ Toxicity:
  • Myocardial ischemia / Infarction
  • Strokes
  • Seizures
  • AKI
  • Fulminant hepatic failure
  • Psychosis
• Ecstasy or 3,4-methylenedioxy-methamphetamine (MDMA)
  • Can cause bruxism (sometimes severe dental damage w/ chronic use)
  • Hyponatremia resulting in cerebral edema.
• Management:
  • Benzodiazepines + supportive measures.
  • Fluid repletion
  • Nutrition

Cocaine

• Potent stimulant
• Inhaled, Oral, IV, Transmucosal
• Classic sympathomimetic:
  • Tachycardia, hypertension, hyperthermia, psychomotor agitation.
• Organ Toxicity:
  • Myocardia Ischemia / MI
  • Atrial/Ventricular Arrhythmias
  • Aortic Dissection / Rupture (from acute HTN0
  • Neuro: Seizures, Strokes, Bronchospasm
  • Pulmonary Edema / Alveolar Hemorrhage
  • Rhabdomyolysis.
• Management:
  • Benzodiazepines for sympathomimetic symptoms.
  • CCB are considered safe + effective in lowering BP + HR.
  • Labetalol (for Hypertension) because it is non-selective alpha+beta blocker
    • Many experts caution against using Beta-Blockers --> can cause unapposed alpha-vasoconstriction --> more severe HTN. (claim not evidence based)
  • Myocardial Ischemia --> Nitroglycerin + ASA.
    • Plaque rupture / thrombosis possible, always rule out (consider angiography)

Acetaminophen

• Toxic dose: 7.5g in 8h period.  (nomogram available for serum levels at 4h mark).
• Effect:
  • Acute hepatitis  --> fulminant hepatic failure.
• Treatment:
  • N-Acetylcysteine (oral or IV)!!!
  • Charcoal (if <4hrs of ingestion)
  • If fulminant hepatic failure (see fulminant hepatic failure)
    • ---> Contact hepatology for transplant consideration ASAP!

      Chronic Acetaminophen Use:

• If malnourished and get 4g/day of acetaminophen, can get toxic (target <2g/day)
• Pyroglutamic acid
• Treatment:
  • D/C acetaminophen
  • isotonic NS
  • NAC can be delivered 

Benzodiazepines

• Toxic dose is variable.
• Flumazenil can reverse resp depression in benzo overdose, but rarely given due to risk of seizures in chronic benzo users.
• Benzo overdose usually does not cause life-threatening respiratory depression without co-ingestion of other drugs (i.e. narcotics).
• Management:
  • Monitor, airway/hemodynamic support if needed.
  • Antitode: Flumazenil (but rarely used: risk of seizures in those that chronically abuse benzodiazepines)

Aspirin

• Hyperventilation, dehydration, severe intoxication can cause seizures, hypoglycemia, etc...
• 10-30g can cause toxicity
• Presentation:
  • Tinnitus, Confusion, low-grade fever, N/V
  • Respiratory alkalosis (ASA stimulates respiratory center)
  • If Severe: Metabolic Acidosis (NOT osmolar gap)
• Labs:
  • Produces both anion gap metabolic acidosis + respiratory alkalosis (central stimulation of resp center)
  • Nomograms useful for estimated dose ingested (if time of ingestion is known)
  • Careful if sustained release! (can underestimate dose ingested).
  • If chronic and severe:
    • can impair vitamin K metabolism in liver --> rises INR
• CAUTION: Must hyperventilate to maintain high pH, which keeps ASA from entering CNS and allows clearance.
• CAUTION: If you try to intubate, the short period of apnea will remove respiratory alkalosis, causing ASA-incuded metabolic acidosis to dominate.  Causes ASA penetration to CNS --> DEATH!!!
  • Avoid intubating ASA overdose patients!
• Treatment:
  • IV Fluids
  • Sodium bicarb infusion (achieve urine pH > 8.0 [some say 7.5-8.0 target], and >2 mL/kg/h) --> ASA diuresis.
    • Follow lytes, ASA levels q2h to ensure resolving. 
  • Supportive Care:
    • Trend clinical signs, electrolytes, blood gasses q2h
    • Avoid hypokalemia (hypokalemia causes ASA reabsorption in distal tubules)
    • If impaired mentation --> give IV glucose (to avoid ASA-induced neuroglycopenia)
      • -> EVEN IF GLUCOSE NORMAL
  • Indications for hemodialysis:

    • ASA level >80 mg/dL (5.8 mmol/L),

    • Altered mentation

    • Pulmonary edema

    • Advanced Kidney Disease (cannot excrete)

    • Clinical status worsens depiste medical therapy

       

Digoxin Toxicity

• Clinical Features:
  • Look for new onset renal failure or dehydration that can cause it to ac
• Toxicity:
  • CNS: visual disturbances (diplopia, photophobia, etc... many) confusion, weakness
  • GI: diarrhea
  • Renal: AKI
  • Cardiac: ANY cardiac arrhythmia (with exception of rapidly conducted atrial arrhythmias)
• Labs:
  • Digoxin level >2.6 nmol/L = toxic, but correlates poorly with toxicity (use symptoms!)
    • Best to do it 6hrs post ingestion (earlier can be falsely elevated, has not distributed yet)
  • Hyperkalemia - does not cause death!
    • Treatment with insulin/dextrose/bicarb does not improve mortality
  • AKI - Elevated creatinine
• Treatment:
  • If within 1-2 hours of ingesting Digoxin --> Activated charcoal (1 g/kg - maximum 50 g)
    • Patient must be awake, alert, protecting airway.
  • Digoxin-specific antibody (very expensive!)
    • Careful! --> exacerbates hypokalemia (monitor lytes).
  • Do not treat hyperkalemia.
    • Do not give Calcium (intracellular concentrations of calcium is high, associated with mortality but dating back to 1933).  currently effect unknown and is not recommended.
  • Be careful with hypokalemia --> correct if K+ is low.

Beta Blocker

• Generally slows down SA and AV nodes, negative inotropy.
• Treatment:
  • 1st line:
    • Atropine 0.5mg as per ACLS
    • Fluids (to improve BP)
    • (Glucagon 3-5mg (if response --> 3-5mg/hr IV infusion))
      • Careful: glucagon causes lots of NAUSEA!!! (use gravol, not ondansetron)
    • Insulin + D50 shown has benefit
      • High dose 1 unit/kg/hr with D10 drip  (DKA dose is only 0.1 u/kg/hr)
  • 2nd line:
    • Calcium (chloride or gluconate, but twice more available Ca in chloride than gluconate)
      • (i.e. 1amp has 1g of CaCl OR 2g of CaGluconate)
    • Inotropes/Chronotropes
      • Isoproterenol (B1 agonist)  + add a1 agent such as norepinephrine.
      • Dopamine (2.5-10 mcg/kg/min)
      • Dobutamine + a1 agent such as norepinephrine.
  • May need pacing (transcutaneous or transvenous).
  • Lipophilic B-blockers are dialyzable (carvedilol, labetalol, propranolol)

Other Drug Overdose

Therapeutic Drug Toxicities, Antidotes, and Management

Source: MKSAP 16