Toxicology

  • General Side Effects
  • Alpha-1 Antagonism (Norepinephrine)
    • Significant orthostatic hypotension/tachycardia
    • MC: Risperidone/Paliperidone, Clozapine, Thioridazine, Trazodone
  • Dopamine receptor antagonist
    • Metoclopramide
    • For nausea and vomiting, may have EPS
  • Histamine Antagonism (Histamine)
    • Sedation, appetite stimulation, weight gain
    • MC: Quetiapine (most sedating), Olanzapine (weight), Clozapine (weight), Thioridazine
  • Muscarinic Antagonism (Acetylcholine)
    • Anticholinergic – Delirium, fever, tachycardia, flushing, dry mucus membranes, constipation, Confusion and hallucinations
    • MC: Olanzapine, Clozapine, Thioridazine, Chlorpromazine
  • Side Effect Monitoring
    • EKG
    • Amitriptyline/TCAs
    • CBC
    • Clozapine (Agranulocytosis) weekly but not carbamazepine
    • Plasma levels
    • Lithium, valproate
    • Falls
    • TCAs and Benzos
    • Glucose
    • Clozapine after 6 months
    • Dextromethorphan (cough syrup)
    • Dissociative symptoms and hallucinations
    • Add Quetiapine to treat Pseudobulbar Affect
Antipsychotic Extrapyramidal Effects – "ADAPT" Pharmacotherapy
Acute Dystonia** (4 hours)**
- Sudden, sustained contraction of neck, mouth, tongue and eye muscles
- Benztropine
- Diphenhydramine
Akathisia** (Days to weeks)**
- Subjective inner restlessness, inability to sit still, wanting to walk off
- Dose dependent
- Benzodiazepine (Lorazepam)
- Low-Dose BB (Propranolol)
- Benztropine
Parkinsonism** (Weeks to months)**
- Gradual-onset tremor, rigidity and bradykinesia
- Benztropine≥
- Amantadine
- Trihexyphenidyl
Tardive dyskinesia** (4 months)**
- Gradual onset after prolonged therapy (≥6m): dyskinesia of mouth, face, trunk, extremities
- Valbenazine
- Deutetrabenazine
- Switch to Clozapine or Quetiapine
  • Acetaminophen Overdose
  • Gastroenteritis (non-specific) within hours, hepatoxicity within 1-2 days
    • Leading cause of hepatic failure in US
  • Treatment
    • Activated Charcoal and N-Acetylcysteine
    • Liver Transplant
  • Alcohol Intoxication
  • Slurred speech, incoordination, unsteady gait, attention/memory impairment, stupor, nystagmus
  • Alcohol/Methanol Overdose
  • Anion Gap Metabolic Acidosis
  • Fomepizole
    • Inhibits alcohol dehydrogenase
  • Alcohol Ketoacidosis
  • Slurred speech, unsteady gait, altered mentation
  • High Osmolar gap
  • Increased anion gap
  • Metabolic acidosis due to ketosis
  • Alcohol Withdrawal
  • Symptoms
    • Tachycardia, diaphoresis, anxiety, hallucinations, Seizures
    • Macrocytic anemia
    • Mild (6-24h) – anxiety, insomnia, tremors, diaphoresis, palpitations, GI upset, intact orientation
    • Seizures (12-48h) – single or multiple generalized tonic, clonic
    • Alcoholic hallucinosis (12-24h) – visual, auditory, or tactile; intact orientation
    • Delirium Tremens (48-96h) – unstable vitals, hallucinations, confusion
  • Withdrawal Prophylaxis
    • Chlordiazepoxide, Diazepam (medium-acting)
  • Treatment
    • IV Lorazepam ≥ Chlordiazepoxide
    • Especially in Liver disease
    • IVF, Thiamine, Folate
    • Thiamine prior to glucose
  • Anticholinergic Poisoning
  • Treatment
    • Physostigmine (cholinesterase inhibitors)
  • Arsenic Poisoning
  • Mechanism
    • Binds to sulfhydryl groups
    • Disrupts cellular respiration and gluconeogenesis
  • Sources
    • Pesticides, insecticides
    • Contaminated water, often from wells
    • Pressure-treated wood
    • Miners, smelters
  • Clinical
    • Acute: Garlic breath, vomiting, watery diarrhea, QTc prolongation
    • Dehydration secondary to vomiting and diarrhea
    • Seizure, delirium, coma, torsades de pointes
    • Acute tubular necrosis
    • Painful paresthesia, ascending weakness
    • Chronic: Pigmentation, hyperkeratosis, stocking-glove neuropathy
    • Cancer: Skin, bladder, kidney, and/or lung
    • Mees Lines (Leukonychia striata) on the nails (hypo/hyperpigmented)
  • Diagnosis: Elevated urine Arsenic Levels
  • Treatment
    • IM Dimercaprol (British anti-Lewisite)
    • DMSA (meso-2,3-dimercaptosuccinic acid, Succimer)
  • Barbiturate Overdose
  • Phenobarbital
  • Weak Acids
  • Treatment
    • Secure airway
    • Enhance elimination with Sodium Bicarbonate
    • Alkalinization of the urine
  • Benzodiazepine Overdose
  • Only Benzos = CNS depression with normal vitals
    • Altered LOC, ataxia, slurred speech
  • Benzos + Alcohol = CNS depression with abnormal vitals
    • Alcohol will cause bradycardia, hypotension, respiratory depression, hyporeflexia
  • Treatment
    • RR Normal (12-20)
    • Supportive Treatment
    • Emesis, Lavage, Charcoal
    • 1 Time Acute Overdose
    • Flumazenil
      • Avoid Flumazenil if chronic benzo user
      • Partial agonist, may precipitate withdrawal/seizures
      • Fixes CNS depression, less effective for respiratory
      • SE: Re-sedation, hypotension, hypertension, seizures in long term users, arrhythmias, angina
  • Beta Blocker Overdose
  • Bradycardia, AV block, and diffuse wheezing in a CAD patient
  • Drowsiness, fatigue, depression, Bradycardia, Torsade de points, worsening HF, hypertriglyceridemia, bronchoconstriction, ED, Weight gain
  • Treatment
    • Hypotension: IV Glucagon
    • Atropine, IV fluids
  • Carbon Monoxide Poisoning
  • Treatment
    • 100% O2
    • Hyperbaric Oxygen if CO is ≥25-40%
    • Lower if pregnant
  • Cocaine Toxicity
  • Inhibits norepinephrine reuptake into the sympathetic neuron (potentiating sympathomimetic actions)
    • Alpha and beta receptor stimulation results in coronary vasoconstriction and increased HR, Systemic BP, and Myocardial O2 demand
    • Enhances thrombus formation by promoting platelet activation and aggregation
  • Age \<30 w/o FH, severe or malignant hypertension, resistant hypertension, sudden rise in BP
  • Sympathetic hyperactivity
  • Symptoms
    • Personality/mood changes, sleep loss, weight loss, financial difficulties
    • Chest pain, epistaxis, rhinitis, headaches
    • Cocaine-related Chest Pain (CRCP)
      • Can occur due to non-cardiac causes (hemorrhagic alveolitis, pneumothorax)
    • Hypertension, tachycardia, dilated pupils, psychomotor agitation, tremors
  • Complications
    • Seizures, Acute MI, Aortic Dissection, Intracranial hemorrhage
  • Diagnosis: Urine Drug Screen
  • Treatment of NSTEMI/Chest Pain:
    • Benzodiazepines for BP and Anxiety and O2 (lorazepam, diazepam)
    • Reduce sympathetic outflow (alleviate tachycardia, hypertension)
    • ± Phentolamine if above doesn't work
    • Aspirin
    • Nitroglycerin and CCBs for pain
    • Beta blockers are contraindicated
    • Would worsen coronary vasoconstriction (unopposed alpha-adrenergic stimulation)
    • No fibrinolytics
    • ± Immediate Cardiac Catheterization
  • Cyanide Accumulation and Cyanide Toxicity
  • Cyanide is a potent inhibitor of cytochrome oxidase-a3 in the mitochondrial ETC
    • Inhibits cellular respiration

  • RF: Smoke inhalation (Mc toxicity in house fires)

    • Up to 90% of pts in house fires, only 35% have CO poisoning
    • Sodium Nitroprusside for hypertensive emergency
    • Prolonged use can lead to toxicity
    • More common in patients with renal insufficiency, signs of CHF
    • Onset is ~14-24 hours
    • Symptoms
    • Skin: Flushing before cyanosis
    • CNS: HA, AMS, seizures, coma, confusion, agitation
    • CV: Arrhythmias
    • Resp: Tachypnea followed by respiratory depression, Pulmonary edema
    • BP instability
    • GI: Pain, nausea, vomiting
    • "Almond like" odor to the breath
    • Renal: Metabolic acidosis (lactic acidosis), Renal failure
    • Bright red venous blood (elevated ventral venous oxyhemoglobin saturation
    • Treatment
    • Decontamination
    • Dermal
      • Remove clothing
    • Ingestion
      • Activated charcoal
    • Antidotes
      • 1) Hydroxocobalamin
      • Removes cyanide from mitochondrial respiratory system
      • 2) Sodium Thiosulphate
      • Slower onset, can't be given with #1 or through the same catheter
      • 3) Sodium Nitrite
      • Only if ingested
      • Can't be used in house fire victims due to synergistic effect with CO
    • Respiratory
    • No mouth-to-mouth resuscitation
    • Use supplemental O2/intubation
    • Digitalis Toxicity
    • Blocks na/k ATPase in myocardial cells
    • Leading to influx of calcium, increased contractility, increased SV
    • Prolongs refractory period reducing ventricular rate
    • Features
    • Characteristic ST depression with concave-up morphology "hockey stick"
    • AKI w/hyperkalemia and increased creatinine
    • Pain, nausea, vomiting
    • Confusion
    • Yellow halos around light, scotomas, blindness
    • Ethylene Glycol Ingestion
    • Symptoms
    • Flank Pain, hematuria, oliguria, cranial nerve palsies, tetany
    • Labs
    • High Osmolar gap
    • Increased anion gap
    • Metabolic acidosis
    • Calcium oxalate crystals in the urine
    • Treatment
    • Fomepizole or Ethanol
    • Heparin
    • Treatment
    • Protamine
    • Isopropyl Alcohol Ingestion
    • CNS depression, deconjugate gaze, absent ciliary reflex
    • High Osmolar gap
    • No Increased Anion Gap
    • No Metabolic acidosis
    • Treatment
    • Supportive Care
    • Malignant Hypertension (Hypertensive Crisis)
    • Binds to RYR1R causing CA2+ release.
    • MAOI + tyramine or stimulant
    • Prevents breakdown of tyramine in gut
    • Enhances peripheral NE effects increasing BP
    • Symptoms
    • Headache following a meal (tyramine)
    • Hypertension, sweating, HA, vomiting
    • Sympathomimetic effect (hypertension)
    • Labs
    • Increased BUN
    • Complications: Stroke, intracranial bleeding, death, rhabdomyolysis
    • Treatment
    • Stop agent
    • IV phentolamine
    • Dantrolene
    • Nifedipine can be helpful
    • Thyroxine (T4) is treated with IV thyroxine for myxedema
    • Coma required more
    • Methanol Ingestion
    • Visual Blurring, central scotomata, afferent pupillary defect, altered mentation, epigastric pain, hyperemic optic disc
    • High Osmolar gap
    • Increased anion gap
    • Metabolic acidosis
    • Treatment
    • Fomepizole (inhibits the alcohol dehydrogenase that converts methanol to formaldehyde)
    • Ethanol
    • Methemoglobinemia
    • Formed by the oxidation of ferrous to ferric iron in hemoglobin
    • Left shirt in the O2 curve because ferric iron cannot bind oxygen and this o2 binds tighter to ferrous iron in hemoglobin
    • Functional anemia
    • Causes: Dapsone, nitrates, topical/local anesthetics
    • Treatment
    • Methylene Blue
    • Neuroleptic Malignant Syndrome (NMS)
    • Antagonism of Dopamine (D2) receptors in the nigrostriatal pathway
    • Can occur with every class of antipsychotics
    • Symptoms
    • Slow onset, clouding of consciousness (over 1-3 days w/delirium being the 1st symptom)
    • Fever ≥104F, confusion, delirium or catatonia
    • Muscle rigidity (Lead-pipe), General muscle rigidity
    • Autonomic instability (Tachypnea, hypertension, tachycardia, dysrhythmia)
    • Abnormal vitals, sweating, mydriasis
    • Labs
    • Increased CPK, LFTs, WBCs
    • Myoglobin in urine
    • Treatment
    • Stop antipsychotics or restart dopamine agents
    • Antipsychotic meds
    • May have increases Creatine Kinase and WBCs
    • IV fluids, supportive care; ICU
    • Benzodiazepines
    • Dantrolene (skeletal muscle relaxant) or bromocriptine (dopamine agonist), amantadine (dopamine agonist) if refractory
    • Opioids
    • Treatment
    • Buprenorphine
    • Partial mu agonist, kappa antagonist
    • Treats withdrawal and chronic pain
    • Combined with naloxone (blocks receptor)
    • Naltrexone
    • Treats dependence, not withdrawal
    • Methadone
    • Treats withdrawl
    • Organophosphate Toxicity
    • Excessive salivation, miosis, lacrimation, diarrhea, emesis, urination, bronchospasm
    • Bradycardia, heart block, prolonged QTc
    • Treatment
    • Pralidoxime
    • Reverses muscle paralysis (nicotinic effects)
    • Atropine
    • Phencyclidine (PCP) Overdose
    • NMDA and Ach Antagonism
    • Particularly in the hippocampus and limbic system
    • Dopamine, norepinephrine, and serotonin receptor activation
    • Sigma receptor complex activation causing psychotic and anticholinergic effects
    • Lasts \<8 hours
    • PCP withdrawal
    • Depression
    • Ketamine is shorter acting
    • Vertical or horizontal nystagmus, ataxia, violent behavior, hyperthermia, disorientation, delusions, muscle rigidity
    • Treatment
    • Psychomotor Agitation: Parenteral Benzodiazepines (lorazepam, diazepam) ≥ Haloperidol unless seizure disorder is present
    • B52 – Haloperidol, diphenhydramine, and benzodiazepine
    • Phenytoin Toxicity
    • Vertical Nystagmus
    • Cerebellar-vestibular system affected
    • Sedation, hypotension, arrhythmias, GI disturbances
    • Gingival hyperplasia and hirsutism if long-term use
    • 2nd line anticonvulsant (after lorazepam) in treating status epilepticus
    • Decreases repetitive firing of neuronal action potentials by slowing the rate of recovery of voltage gated sodium channels from inactivation
    • SE: SJS
    • Salicylate Poisoning
    • Treatment
    • Gastric Lavage, Activated charcoal, alkalinization of the urine, diuresis, dialysis
    • Serotonin Discontinuation Syndrome
    • RF: SSRIs with short half-life and no active metabolites
    • MC with short half-life SSRIs (paroxetine ≥ venlafaxine)
    • Onset within 3 days of discontinuation, resolution within 1-2 weeks
    • Fatigue, insomnia, myalgias from abrupt discontinuation in 20%
    • Headaches, anxiety, agitation
    • "Weird" sensations along arms and legs, "electric-shock-like" sensations in head/neck, "rushing" sensations in the head
    • Vertigo, tremor, ataxia
    • Treatment
    • Restart drug and taper gradually over several weeks (6-8 weeks)
    • If persistent, switch to Fluoxetine
    • Serotonin Syndrome (SS)
    • General
    • Over stimulation of 5-HT receptors in the central grey nuclei and the medulla
    • MC with stopping sertraline and fluvoxamine
    • Fluoxetine has a long half-life, must be quit 5 weeks prior to MAOI, but doesn't need to be tapered
      • Tramadol (Ultram)
      • Serotonergic analgesic + SSRIs
    • Symptoms
    • Activity (hyperactivity, hyperreflexia, hypertonia, tremor, seizure)
    • Myoclonus, Lower extremity rigidity, tremor
    • Autonomic (hyperthermia, diaphoresis, diarrhea, mydriasis)
    • Flushing, Tachycardia, hypertension
    • Agitation (Need AMS)
    • Anxiety, confusion, hypomania, coma
    • Headaches, N/V/D, dizziness and fatigue when suddenly stopping
    • Exam
    • Hyperreflexia and myoclonus
    • Diaphoresis, hypertension, tachycardia
    • Fever/Hyperthermia, cardiovascular collapse
    • Labs
    • No CPK or liver enzyme changes
    • Treatment
    • Discontinue serotonergic meds, supportive, benzodiazepines, cyproheptadine
    • Cyclobenzaprine
    • Cyproheptadine (H1 receptor antagonist)
    • Weakly cholinergic hypotension
    • Steroids
    • Glucocorticoids/Prednisone (Asthma/Lupus)
    • Delusions/hallucinations. Alert and cognitively intact
    • Anxiety, depression, psychosis, mania rarely
    • Usually occur during the first week but may occur at any time
    • Tardive Dyskinesia
    • 98% get worse with acute cessation of antipsychotic
    • D2 receptor upregulation and super sensitivity
    • Chronic blockade of dopamine receptors causes this
    • Treatment
    • Switch from risperidone to clozapine (atypical antipsychotic)
    • VMAT2 Inhibitors
    • Blocks presynaptic dopamine release
      • May cause depletion of dopamine in synaptic cleft causing depression
    • Deutetrabenazine (Austedo)
      • TD and Huntington's
    • Valbenazine (Ingrezza)
    • Reserpine
    • TCA (Tricarboxylic Acid) Overdose
    • Features
    • Antihistamine Effects
    • Drowsiness, delirium, coma, seizures, respiratory depression
    • Anticholinergic Effects
    • Dry mouth, blurred vision, mydriasis, urinary retention
    • Flushing, hyperthermia
    • Hypotension, sinus tachycardia, prolonged PR/QRS/QT, Arrythmias
    • QRS ≥ 100ms is MC EKG abnormality
    • 1500mg for ≥4 hours = death
    • Treatment
    • O2 and intubation, EKG monitoring
    • IV fluids
    • Activated charcoal if within 2 hours of ingestion (unless ileus present)
    • Seizures: Benzodiazepines
    • QRS ≥100: IV Sodium Bicarbonate
    • Therapy for QRS widening or ventricular arrythmia
    • QRS ≥ 100msec is associated with increased risk of arrhythmias and/or seizures
    • Cardioprotective and helps metabolic acidosis
    • Theophylline Toxicity
    • Toxic form reduced clearance or decreased metabolism in the liver
    • CNS Stimulation (headache, insomnia, seizures), GI (Nausea, vomiting), and cardiac toxicity (arrhythmia)
    • Measure theophylline levels
    • tPA
    • Treatment
    • Aminocaproic Acid
    • Warfarin
    • Treatment
    • Vitamin K, FFP