Toxicology Exam 1

Ipecac

no longer recommended for home poisoning

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contraindicated if:

• seizures, coma, profound sleepiness

• patient has ingested caustics, aliphatic hydrocarbons or fast-acting agents that produce seizures/com

• time since ingestion is over an hour

methods of gastric decontamination

IPECAC, Gastric lavage, cathartics, activated charcoal

Methods of enhanced elimination

Whole Bowel irrigations, urine alkalinization, hemodialysis

Activated charcoal definition

Adsorbent tht binds to toxins in GI tract to reduce systemic absorption; optimal administration w/in 60 minutes of toxin ingestion

Activated charcoal contraindications

• Unconscious state,

• inability to otherwise protect airway w/o ET intubation,

• recent GI surgery

Situations where activated charcoal is not helpful (other than contraindications)

• Pesticide

• Hydrocarbons/heavy metals,

• Alcohols

• Iron

• Lithium

• Solvents

Hint: PHAILS

Activated Charcoal Complications

aspiration, accidental administration into lungs, emesis, constipation, gastric obstruction,

Whole bowel irrigation uses

wash out GI tract by administering osmotic PEG solution during life-threatening ingestion of meds with a long half-life, SR dosage, or EC forms.

Whole Bowel Irrigation Complications and Contraindications.

Complications: Anaphylaxis, angioedema of lips, aspiration, Mallory Weiss tear, esophageal perforation

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CI: Bowel obstruction, perforation, ileus, recent GI/Bowel surgery

Gastric lavage indications

• Presentation w/in 1-2 hrs

• Significant amount of toxin ingested that likely stay in stomach

• No specific antidote available

• Patient should be intubated

Gastric lavage contraindications

Craniofacial abnormalities, head trauma, unprotected airway, risk of aspiration or GI hemorrhage

Cathartics

decreases toxin adsorption and in combination w/ activated charcoal reduces constipating effects

ex: Mg citrate, sorbitol, mg sulfate, Na sulfate, Mg hydroxide,

Cathartics CIs

• Absent bowel sounds, recent GI surgery, intestinal perforation or obstruction,

• hypotension, electrolyte disturbances,

• renal insufficiency (Mg-based)

Acetylcysteine mechanism

supplies glutathione to aid in metabolism of the active metabolite of acetaminophen, protecting the liver from its toxic effects

Urine drug screens

Amphetamines, barbiturates, cocaine, opioids, pcp

Serum drug screens

APAP, salicylates, co-oximetry, ethanol, digoxin, iron, Lithium, phenobarbital, valproic acid, carbamazepine

Drug Screen: Amphetamine False positives

Selegiline, chloropromazine, trazodone, ranitidine, amantadine

Drug Screen: BZDs False positives

Sertraline

Drug Screen: Marijuana False positives

Ibuprofen, naproxen

Drug Screen: Cocaine False positives

"caine" anesthetics

Drug Screen: Opioid False positives

• Detection of synthetic opioids (may be limited or not detected)

• Rifampin

• Fluroquinolones

Drug Screen: PCP False positives

• dextromethorphan, diphenhydramine,

• Ketamine, venlafaxine,

• ibuprofen, meperidine, tramadol

Urine alkalinization

Improves toxin elimination by increasing urine pH with administration of Na bicarb or Na acetate (>7.5 pH). May be beneficial in salicylates, phenobarbital, chlorpropamide

Urine alkalinization complications & CIs

Complications: HypoK + Ca, hyperNa, cerebral vasoconstriction, coronary vasoconstriction

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CIs: Acute and chronic renal failure, preexisting HF owing to volume of fluid required for this strategy

When is hemodialysis beneficial overall?

Low MW, water soluble, small Vd, low protein binding

Qualitative lab tests

Only tests for PRESENCE of a substance. Not comprehensive, should tests if more agents present. If toxin known, quantitative drug screen may be used

Quantitative lab tests

Used to confirm EXACT amount of drug present

When to obtain APAP concentration

at least 4 hours after ingestion.

plot on RM nomogram to determine if there is a risk for hepatotoxicity

N-acetylcysteine oral dose

• Loading dose: 140 mg/kg

• Maintenance: 70 mg/kg every 4 hrs for 17 doses

N-acetylcysteine IV dose

Loading: 150 mg/kg (max 15 g) over 60 mins

Maintenance 1: 50 mg/kg (max 5 g) over 4 hrs

Maintenance 2: 100 mg/kg (max 10 g) over 16 hrs

NAC indications

1. Possible OR probably hepatotoxicity risk w/in 8-10 hrs post-ingestion

2. In addition to risk stratification on RM nomogram

i) Single ingestion of >150 mg/kg OR 7.5 g total in anyone

ii) Pt w/ unknown duration since ingestion

• Elevated ALT (3xs ULN)

• serum APAP >20 mcg/mL

• H/o ingestions (>4g/d) + elevated ALT

• (+/-) presenting >24-hrs post-ingestion w/ hepatotoxicity

NAC Moa

Sulfhydryl compound tht acts as substitute sulfate source to replenish hepatic glutathione stores by combining and inactivating reactive APAP metabolites

NAC early d/c

Serum APAP

APAP toxicity monitoring parameters

Markers of liver fxn (ALT, AST, total bili, INR, PT)

BUN, SCr

Serum electrolytes

Fulminant hepatic failure --> bicarb, Na, lactate, ABC, glucose, ammonia

CYP2E1 inducers

phenobarbital, carbamazempine, phenytoin, rifampin, EtOH, St. John's wort, opioids, zidovudine, TMP-SMX

Acute toxic APAP doses

• > 200 mg/kg in children <6 yrs

• 10 g or 200 mg/kg (whichever is less) for persons ≥6 yrs

APAP Toxicity phases

Phase I: 12-24 hrs

• GI upset: N/V anorexia, diaphoresis

• Sweating

Phase II: 1-3 d

• Latent, lessened sxs

• Asymptomatic rise in liver enzymes and bilirubin (hepatic injury onset)

Phase III: 3-5 d

• Symptomatic hepatic injury: abdominal tenderness, jaundice, hypoglycemia, encephalopathy, elevated LFTs, prolonged INR

• Severe liver damage: hepatic encephalopathy (coma), hepatorenal syndrome, death

Phase IV: >1 wk to 6 mths

• No residual functional or histologic abnormalities

APAP MOTox

1. Large APAP amts ingested in a short time --> increase metabolism via CYP2E1

2. glutathione (sulfate stores) depleted & normal NAPQI detox not possible

3. NAPQI interacts w/ other hepatocellular compounds = hepatic necrosis

4. severe hepatotoxicity --> impaired kidney fxn (oliguria --> AKI)

NAC: PO vs IV

IV rec'd if severe hepatic damage; used more often. PO lacks tolerability due to smell & taste (can improve w/ dilution by cola or juice or by covering cup)

ASA MOTox

1. Liver can't metabolize excess drug

2. interference w/ aerobic metabolism causes increased anaerobic metabolism & accumulation of lactate & pyruvate --> lactic acidosis

3. Glycogen depletion, gluconeogenesis, & FA breakdown --> glycemic manifestations

4. Direct respiratory center stimulation --> hyperventilation & respiratory alkalosis

ASA Toxicity sxs

• Hyperventilation

• Tinnitus

• GI irritation (N/V)

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Vary depending on serum conc

• Acute toxicities (30-50 mg/dL) associated w/ GI

• Chronic toxicities (>50 mg/dL) associated w/ CNS type sxs

ASA toxicity management path

1. Start w/ supportive care if profoundly acidotic move to

2. Serum Alkalinization w/ Na bicarb

3. Hemodialysis if indicated

ASA Toxicity supportive care path

1. Activated charcoal if indicated

2. Fluids to support kidney injury

3. Treat any active bleeding

4. Transfusion (if Hg <7 g/dL)

Sodium bicarbonate for ASA Toxicity

Dose: 1-2 mEq/kg

• 150 mEq in 1 Liter of D5W

• Administer at 150-200 mL/h

Hemodialysis indications for ASA toxicity

Altered mental status

Renal insufficiency

End-organ damage: pulmonary edema, seizure, rhabdomyolysis

Deterioration of clinical status

Acute ingestion & lvl > 90 mg/dL

Chronic ingestion & lvl > 60 mg/dL

ASA Toxicity Monitoring

Monitor for ≥24 hrs

Vitals to determine clinical status (RR specifically)

electrolytes: K & Ca

Serum pH: 7.45-7.55

Urine PH: 7.5-8.0

serum ASA lvl < 30 mg/dL

Resolution of clinical sxs

AC MOTox

competitively antagonizes ACh's effects at peripheral muscarinic (M1-M5) + central receptor

AC Toxicity causes

• TCAs, SSRIs,

• antiparkinson, antihistamines, antipsychotics, antispasmodics, antitussives, antiepileptics,

• inhaled bronchodilators,

• belladonna alkaloids, jimson weed, angels trumpet

ACs that can cause AC toxicity

atropine, scopolamine, glycopyrrolate, benztropine, trihexyphenidyl

Antihistamines tht can cause AC toxicity

cyproheptadine, doxylamine, hydroxyzine, diphenhydramine, meclizine

AC Toxicity Sxs

Peripheral: Dry mouth, blurred vision, photophobia, dry skin

Central: Delirium +/- hallucinations, confusion, agitation or seizures

Severe: seizure, cardiac conduction abnormalities +/- dysrhythmias, hypotension or rhabdomyolysis

May occur w/in 6 to 8 hrs after ingestion

AC Toxicity Signs

• Tachy,

• elevated body temp,

• absent or decreased bowel sounds,

• dilated pupils minimally reactive to light

• Hemodynamic instability may occur in meds w/ additional properties to AC effects (i.e quetiapine, TCAs)

AC Toxicity Dx workup

Labs: CK, serum electrolytes, SCr to assess for rhabdomyolysis & AKI; Serum APAP lvl (bc of combo products)

Dx Tests:

• ECG w/ continuous monitoring, pulse oximetry

• Bladder scan for detection of urinary retention

AC Toxicity Risk assessment

• Suspect when pts present w/ sx's

• 1st gen antihistamine exposures <7.5 mg/kg unlikely to cause significant toxicity

• In accidental ingestion of med w/ known toxic threshold, may allow asymptomatic pts to be monitored at home

• Consider SR products when evaluating sx onset

• Age, route, and home meds influence Atypical antipsychotic's toxic potential

• TCAs have narrow therapeutic index

Examples of how atypical antipsychotics toxicity potential fluctuates

Peds naive to med may feel toxicity at lower threshold than non-naive

Pts on chronic AAPs unlikely to incur toxicity at ingestions < 5xs typical single dose

AC Toxicity supportive management

Airway maintenance, adequate ventilation, IV line

May use BZDs for seizures or agitation tx

Can use sodium bicarb to reverse wide complex dysrhythmias

After baseline ECG, Pt's condition determines cardiac monitoring, pulse oximetry and supplemental oxygen

Atropine indications in toxicology

used in cases of organophosphates and carbamate anticholinesterase insecticide poisoning (including nerve agents)

Physostigmine

MOA: Carbamate acetylcholinesterase inhibitor; can reverse peripheral & central AC manifestations

ADEs: Bradycardia, bradydysrhythmia, seizures

Physostigmine indication

Severe AC toxicity management (manifested as agitation). AVOID in known or suspected TCA toxicity

AC Toxicity monitoring

Vital signs, blood gases, pulse oximetry

Serum electrolytes, serum glucose, kidney fxn, CPK, urine output for symptomatic pts

Bladder scans beneficial to assess urinary retention

If severe, pts likely to have peripheral and/or central effects w/in 6 hrs of ingestion (12—24 hrs if SR products)

Cholinergic MOTox

[acetyl]cholinesterase inhibition causes Ach accumulation overstimulating muscarinic & nicotinic receptor

Cholingeric Toxicity Causative agents

Carbamates, Arecholine, Pilocarpine, Urecholine (Betanechol), Carbachol, Choline, Metacholine, Mushrooms

Cholingeric Toxicity Sxs

1 hr: DUMBELLS

1—6 hrs: H/a confusion, coma, and seizure

Other: SLUDE, killer B's

DUMBELLS

Diarrhea

Urination

Miosis

Bradycarida, bronchospasms, bronchorrhea

Emesis

Lacrimation

Lethargy

Salivation

SLUDGE

Salivation

Lacrimation

Urination

Defecation

GI sxs

Emesis

Killer B's

bradycardia, bronchospasm, bronchorrhea

Cholingeric Toxicity Signs

• Bronchorrhea, tachypnea, rales, cyanosis w/in 1—6 hrs

• Muscle weakness, fasciculations, respiratory paralysis w/in 1—6 hrs

• Brady, atrial fibrillation, AV block, hypotension w/in 1—6 hrs

Cholingeric Toxicity Dx workup

Labs:

• Serum pseudocholinesterase activity (markedly depressed),

• ABG (Acidosis),

• serum electrolytes,

• BUN & SCr in response to respiratory distress/shock

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Dx Tests:

• CXR ,

• ECG (continuous monitoring), Pulse oximetry for complications from toxicity and hypoxia

Cholinergic Toxicity Risk Assessment

• Triad of 1) miosis 2) bronchorrhea and 3) muscle fasciculations suggests poisoning & warrants antidote trial

• In low-lvl exposure, if no signs w/in 6 hrs, low likelihood of toxicity

• Ingestions of concentrated form (agricultural product) can cause serious & life-threatening toxicity vs diluted house product (aerosol insecticide) would not produce serious toxic effects.

• Dx depends on h/o exposure & presence of typical sx's

Cholingeric Toxicity Managment Pathway

1. Decontaminate affected body surfaces + supportive care

2. Atropine

3. Pralidoxime if severe organophosphate poisonings

Cholingeric Toxicity: Decontamination based on affected body surfaces

Inhaled

• Get fresh air immediately, open doors & windows

On Skin

• Remove contaminated clothing, flood skin w/ water for 10 mins

• Wash gently w/ soap + water and rinse

• Alcohol wash may be useful (removes excess insecticide bc of lipophilic nature), surgical scrub

In Eye

• Flood open eye w/ lukewarm or cool water poured from a glass 2 or 3 in before flushing eye.

• Repeat for 10—15 mins continuously

• Remove contact lenses, avoid ocular drops

Cholingeric Toxicity Supportive care

Airway maintenance, adequate ventilation, establishing IV line

Prontopam

pralidoxime

Atropine clinical effects

• Improves bronchospasm and bronchorrhea

• No effect on inhibited enzyme.

• Little effect on muscle paralysis or respiratory failure in severe poisoning

Atropine

MOA: Competitively blocks ACh action on cholinergic & some CNS receptors

Dose: 0.05—0.1 mg/kg (<12 y/o) OR 2—5 mg (>12 y/o); can repeat Q5—10 mins until secretions or rales resolve

ADEs: coma, hallucinations, tachy

Pralidoxime indication

severe poisoning by organophosphate anticholinesterase insecticide or chem-bioterrorism nerve agent. Must administer w/in 36—72 hrs of exposure to avoid risk of "aging"

Pralidoxime

MOA: Regenerates enzyme activity by breaking covalent bond between cholinesterase & organophosphate

Dose: 25—50 mg/kg <1—2 gm IV over 5—20 mins; Can repeat after 1 hr, continuous infusion sometimes used

ADEs: dizziness, diplopia, tachy, h/a

Antidote for organophosphates

atropine

pralidoxime

What is the antidote for acetaminophen toxicity?

N-acetylcysteine (NAC)

Cholingeric Toxicity Monitoring

• Vital signs, blood gases, pulse oximetry

• Leukocyte count w/ differential to assess infection development (PNA)

• CXR to evaluate for pulmonary edema or pneumonitis

Opioid MOTox

Opioid analgesics bind to mu opioid receptors in CNS & PNS in an agonist manner

Opioid Toxicity: Drug Specific MOTox

• Nor-meperidine CNS excitation --> delirium, tremor, seizure

• Meperidine blocks serotonin reuptake --> serotonin syndrome

• Methadone blocks K efflux on myocardium --> TdP, syncope & sudden death

• Tapentadol & tramadol block NE + 5HT reuptake --> seizures

Opioid Toxidromes

Opiates: morphine, codeine

Synthetic opioids: fentanyl, methadone, meperidine

Semi-synthetic opiate derivatives: hydromorphone, hydrocodone, oxycodon

Tramadol, Heroin (Cl)

Opioid Toxicity Sxs

Lethargy progressing to coma, flaccid extremities,

seizures (meperidine & tramadol)

acute muscular rigidity (w/ rapid fentanyl inj),

deafness in some OD

Opioid Toxicity Signs

• Depressed respiratory depth + rate --> apnea, pinpoint pupils, unresponsiveness and depressed reflexes

• mild hypotension/brady (worsens w/ increasing hypoxia)

• absent bowel sounds,

• hypothermia (if cold conditions),

• frothy pink sputum & shortness of breath several hrs post exposure (pulmonary edema)

• QT prolongation TdP on ECG (methadone)

• "needle tracks" or skin infections if IVDU

Opioid Toxicity DX Workup

Labs:

ABG (Acidosis), serum electrolytes in response to hypoxia, serum glucose conc, serum APAP if combo drug ingested

Dx Tests:

• Pulse oximetry, continuous ECG monitoring

• CXR & physical sxs to monitor for pulmonary complications

• Monitor for rhabdomyolysis (CK, electrolytes) and AKI (BUN, SCr) if immobile for several hours

Opioid Toxicity Risk Assessment

Sxs, presence of drugs or paraphernalia at scene can be helpful indicators of risk

Triad of 1) depressed respirations (< 12 bpm) 2) coma and 3) pinpoint pupils strongly suggest opioid poisoning & warrant antidote

Clonidine & certain AAPs may present similarly

Don't delay therapy (antidote) pending lab confirmation of an opioid in a routine drug screen

Opioid Toxicity Mangement Pathway

Adequate respiratory support and naloxone administration

Naloxone MOA

Competitive opioid receptor antagonist that reverses toxic effects of opioids

IV Naloxone Approach

1. 0.04 to 0.05 mg (0.01 mg/kg pedi)

2. If no respiration improvement w/in 2 mins, administer 0.5 mg IV to adults & kids

3. At 2 min intervals, can increase dose to 2 --> 4 --> 10 --> 15 mg until adequate respirations achieved

4. 4) If no response at 15 mg, consider other causes or confounding variables

5. If repeated doses needed for respirations, consider continuous infusion 2/3 of single-dose that produced response, run at hourly rate

Opioid toxicity monitoring

• Vital signs, blood gases, pulse oximetry

• CXR for presence of pulmonary edema

• Monitor for rhabdomyolysis, AKI or seizures

• Serum APAP lvl to rule out combo product ingestion

Opioid toxicity timing/severity dependent on

Route of exposure (IV > fume inhalation > inhalation of particles, powder or solutions)

Form of drug product

Potency of total opioid dose received

Concurrent drugs

Coexisting conditions

Pharmacogenetic characteristics

Cholingeric toxicity timing/severity dependent on

Route of exposure (IV > inhalation > skin contact)

agent's Potency

Total dose received

Sympathomimetic toxidromes

• Caffeine, Cocaine, Amphetamines, Methamphetamines, Ritalin

• LSD, MDMA

• Theophylline, Pseudoephedrine

Sympathomimetic MOTox

increases sympathetic tone via cathecholamine release, reuptake inhibition (by direct receptor stimulation), and alts in NT metabolism

Sympathomimetic Toxicity Key Clinical Signs

HTN, tacycardia

Tachypnea

Hyperthermia

Mydriasis,

Increased bowel sounds

Diaphoresis

Sedative-Hypnotic Toxidromes

Anti-anxiety agents, BZDs, Antiepileptics

Muscle relaxants, Pre-anesthetic agents

Barbiturates

EtOH

Sedative-Hypnotic MOTox

inhibits GABA receptor Cl channel by modifying frequency or duration of channel opening, may decrease glutamate transmission, and/or interact w/ NMDA receptors

Sedative-Hypnotic Toxicity Key Clinical Signs

Hypotension, bradycardia

Bradypnea

Hypothermia

No change in pupils, nystagmus, double vision

No bowel sounds, loss of bladder control

Anhidrosis

Discoordination (ataxia)

Confusion, amnesia, slurred speech

Cholinergic Toxicity Key Clinical Signs

Bradycardia, Pinpoint pupils (miosis), increased bowel sounds, diaphoresis