Toxicology and Antidotes (RxPrep 2022)

*Antidote* for *anticoagulant* toxicity, specifically *apixaban and rivaroxaban*?

*Andexanet alfa* (Andexxa) Can use prothrombin complex concentrate *Kcentra* for factor Xa inhibitors, too

Uses for *andexanet alfa/Andexxa* as an antidote?

*Apixaban and rivaroxaban*

*Antidote* for *anticoagulant* toxicity, specifically *heparin and LMWH's*?

*Protamine* 1 mg protamine neutralizes 100 units UFH (dose based on amount of UFH given over the last 2 hours) 1 mg protamine neutralizes 1 mg enoxaparin (dose based on amount of enoxaparin given over the last 8-12 hours)

Symptoms of *organophosphate* overdose/poison? ***

OPs *block acetylcholinesterase* which *increases ACh levels* and causes cholinergic SLUDD symptoms: *salivation, lacrimation, urination, diarrhea/defecation* OPs include industrial insecticides (malathion) and nerve (warfare) gases like sarin

How to increase excretion of a drug that is a *weak base*?

*Acidify the urine*

When is *activated charcoal contraindicated*?

*Airway is unprotected* (patient is unconscious, cannot clear their throat, or cannot hold their head upright) *Intestinal obstruction* *Gastrointestinal tract is not intact or when there is reduced peristaslsis*

PRIOR to using activated charcoal, what must you ensure?

*Airway should be protected* (with intubation if needed) *to prevent aspiration* (Aspiration = inhalation of foreign material that can lead to resp failure or infection) *Certain compounds like hydrocarbons* (petroleum products like gasoline and paint thinner) can *increase the risk of aspiration*

How to increase excretion of a drug that is a *weak acid*?

*Alkalinize* the urine by giving an alkalinizing agent like *sodium bicarbonate*

Antidote for *scorpion stings*?

*Antivenin* immune FAB Centruroides (Anascorp) Scorpions with venom potent enough to cause clinically severe symptoms are found mainly in the southwest

Antidote for *snake bites*? *eastern coral snake, Texas coral snake, copperhead snake, rattlesnake)

*Crotalidae polyvalent immune VAG/CroFab* for copperhead and *rattlesnake* bites Cortalidae Immune F(ab')2 Anavip for rattlesnake bites, too *Do not use ice*, do NOT cut/suck out venom Transport pt to healthcare facility

Uses for *idarucizumab/Praxbind* as an antidote?

*Dabigatran* (Pradaxa)

Management of *iron and aluminum* overdose/poison? What antidotes/drugs are given?

*Deferoxamine* (Desferal) for BOTH iron and aluminum Deferiprone (Ferriprox) or deferasirox (Exjade, Jadenu) for iron overload from blood transfusions

How to *manage APAP toxicity*?

*Draw APAP level 4-24 hours after ingestion* Plot levels on *Rumack-Matthew nomogram* to determine risk of hepatotoxicity

Management of *toxic alcohols* (ethylene glycol/*antifreeze*, diethylene glycol, and *methanol*) overdose/poison? What antidotes/drugs are given?

*Fomepizole* = preferred agent Ethanol = 2nd line *Can cause increase in anion gap*

Management of *valproic acid or topiramate-induced hyperammonemia* overdose/poison? What antidotes/drugs are given?

*Levocarnitine* (Carnitor)

*Antidote* for *anticoagulant* toxicity, specifically *dabigatran*?

*Praxbind* aka *idarucizumab* (dabigatran = Pradaxa)

Antidote for *animal bites*?

*Rabies vaccine* (RabAvert, Imovax Rabies) *WITH human rabies immune globulin* (HyperRAB S/D, Imogam Rabies HT)

What are the most commonly ingested substances by adults based on 2019 American Association of Poison Control Centers (AAPCC) data?

Analgesics (both Rx and OTC) Sedative hypnotics Antipsychotics Antidepressants (overdoses can also occur in adults d/t reduced clearance of drug (renal or hepatic impairment), altered cognition, etc.)

Management of *hydrocarbons (petroleum products* like gasoline, kerosene, mineral oil, paint thinners) overdose/poison? What antidotes/drugs are given?

*DO NOT INDUCE VOMITING* *Keep patient NPO d/t aspiration risk*

Mechanism of APAP hepatotoxicity?

Dose-dependent adverse effect caused by increased metabolism of APAP by *CYP2E1* to N-acetyl-p-benzoquinone imine AKA *NAPQI* NAPQI can covalently bind to liver cell proteins and cause liver injury and ultimately liver failure *CYP2E1 is the route of metabolism ONLY with excessive doses* of APAP

Management of *paralytics* (like rocuronium bromide, vecuronium bromide, and pancuronium bromide) overdose/poison? What antidotes/drugs are given?

*Neostigmine methylsulfate* (Bloxiverz): rocuronium, vecuronium, and pancuronium *Sugammadex* (Bridion): rocuronium and vecuronium These are for reversal of the effects of neuromuscular blockade in adults undergoing surgery

Managing mixed overdoses involves matching symptoms to the toxin and then selecting appropriate antidote. Match the following symptoms: *somnolence, shallow labored breathing, pintpoint pupils*

*Opioid overdose* --> *Naloxone* should be administered *NOTE that if opioids and acetaminophen were both ingested --> naloxone given first*

PO vs IV use of *NAC*? ***

*PO NAC* (injectable or inhalation solution): high dose given for one dose then lower dose for 17 doses, *repeat dose if emesis occurs w/in 1 hr of admin* *IV NAC*: 3 infusions over a total of 21 hours

Where are organophosphates found? ***

*Pesticides* (malathion) - *people working on farms are at risk* *Nerve/warfare* gases like *sarin*

What are the 4 phases of *APAP* toxicity/overdose?

*Phase 1 (1-24 hours)*: commonly asymptomatic, or nonspecific SX like N/V *Phase 2 (24-48 hours)*: hepatotoxicity evident w/ labs (elevated INR, AST/ALT), any SX from phase 1 subside *Phase 3 (48-96 hours)*: *fulminant hepatic failure* (jaundice, coagulopathy, *renal failure*, and/or *death*) *Phase 4 (> 96 hours)*: pt *recovers or receives liver transplant*

*Antidote* for *anticoagulant* toxicity, specifically *warfarin*?

*Phytonadione (vitamin K)* (only if severe/major bleeding or if INR > 10) *Prothrombin complex concentrate, Kcentra* available, too

Management of *neostigmine, pyridostigmine* overdose/poison? What antidotes/drugs are given?

*Pralidoxime* counteracts muscle weakness and/or resp depression secondary to overdose of acetylcholinesterase medications used to treat myasthenia gravis Others: *atropine or glycopyrrolate* can be given to prevent bradycardia from neostigmine

Management of *isoniazid* overdose/poison? What antidotes/drugs are given?

*Pyridoxine or vitamin B6*, benzodiazepines, and/or barbiturates For acute neurotoxicity (seizures, coma), administer IV pyridoxine Oral pyridoxine 10-50 mg is used daily with isoniazid to prevent neuropathies

*Symptoms* of *anticholinergic overdose*? (Atropine, diphenhydramine, dimenhydrinate, scopolamine, Atropa belladonna aka deadly nightshade, jimson weed)

*Red as a beet* (flushing) *Dry as a bone* (*Dry skin* and mucous membranes) *Blind as a bat* (*mydriasis w/ double or blurry* vision) *Mad as a hatter* (altered mental status) *Hot as a hare* (fever)

Management of *salicylates* overdose/poison? What antidotes/drugs are given?

*Salicylates are acidic* so *sodium bicarbonate (alkalinizing agent)* given to alkalinize the urine and *reduce drug reabsorption and increase the excretion* of salicylates and other weak acids

Management of *tricyclic antidepressant (TCA)* overdose/poison? What antidotes/drugs are given?

*Sodium bicarbonate* given to *reduce a widened QRS complex* b/c overdose can quickly cause *fatal arrhythmias* *Benzodiazepines* (supportive care for agitation or seizures if present) *Vasopressors* may be needed for hypotension

Management of *nicotine* (including e-cigarette) overdose/poison? What antidotes/drugs are given?

*Supportive care* - *atropine* for symptomatic bradycardia and *benzodiazepines* for seizures Early symptoms include abdominal pain, nausea, diaphoresis, tachycardia, and tremors Later symptoms include bradycardia, dyspnea, lethargy, coma, seizures

What resources are available to evaluate for toxicology and antidotes?

*ASHP* *CDC* Emergency Preparedness and Response *POISONDEX* in Micromedex *Lexi-Tox* in Lexi-Comp

*How to manage a mixed overdose*?

*Always treat the most life-threatening overdose first* (the substance that is causing impaired CABs - circulation, airway, breathing)

Antidote for *Black Widow spider bites*?

*Antivenin* for Latrodectus mactans Black Widows found in Southern and western states, children and elderly at highest risk for severe injury Primary treatment = supportive are (opioids for pain management and BZDs for muscle spasms) Antivenin made by injecting a small amount of venom into an animal and then collecting and purifying the antibodies that animal produces

Management of *organophosphate* (including *industrial insecticides* like malathion, and nerve (warfare) gases like sarin) overdose/poison? What antidotes/drugs are given? ***

*Atropine* (anticholinergic that blocks the effects of ACH to reduce cholinergic SLUDD symptoms) *Pralidoxime* (Protopam) (treats muscle weakness and *relieves paralysis of respiratory muscles by reactivating cholinesterase* that was inactivated by exposure to OPs) *Atropine and pralidoxime may be given in combo* (DuoDote)

Management of *mushroom (amatoxin-containing* overdose/poison? What antidotes/drugs are given?

*Atropine* to treat muscarinic symptoms like bradycardia

Management of *stimulant* (amphetamines, including *ADHD and weight loss drugs*, cocaine, ephedrine, caffeine, theophylline, MDMA/ecstasy) overdose/poison? What antidotes/drugs are given?

*Benzodiazepines* Supportive care for agitation and seizures

If patient is unconscious, what are the principles of BLS?

*Call 911* *CABs* = circulation, airway, breathing (If pulseless, immediately start CPR/cardiopulmonary resuscitation)

How to manage APAP toxicity?

*Check APAP level* and use *Rumack-Matthew nomogram* to determine if NAC should be given

Management of *insulin or other hypoglycemics* overdose/poison? What antidotes/drugs are given?

*Dextrose* injection or drip/infusion Oral glucose (but DON'T give if the patient is unconscious *Glucagon when IV or PO dextrose can't be administered* Octreotide for sulfonylurea-induced hypoglycemia

*Ipecac syrup*?

No longer recommended (previously lused to induce emesis for certain exposures)

*Treatment* of *anticholinergic* overdose? (Atropine, diphenhydramine, dimenhydrinate, scopolamine, Atropa belladonna aka deadly nightshade, jimson weed)

Primarily supportive care *Rarely physostigmine given* - inhibits acetylcholinesterase (normally breaks down acetylcholine/ACh) to increase ACh and reduce anticholinergic toxicity

Management of *antipsychotic* overdose/poison? What antidotes/drugs are given?

Primarily supportive, *benztropine* can be given for dystonias and bicarbonate can be given if there is QRS-interval widening

How to use *NAC* (N-acetylcysteine) for APAP toxicity? ***

NAC (Acetadote) = free radical scavenger and precursor to glutathione (GSH) that ultimately increases GSH (which metabolizes NAPQI to non-toxic metabolites) GSH converts NAPQI to mercapturic acid which can be safely excreted

*Antidote for opioids*?

Naloxone This *reverses* the depressant effects of opioids with minimal to no adverse effects for those who didn't ingest any opioids (so no harm in giving it even if you're unsure of opioid overdose)

Initial management of ocular exposure to a toxin?

Remove contact lenses and rinse eye(s) w/ gentle water stream for > 15 min

Initial management of topical exposure to a toxin?

Remove contaminated clothing and wash skin w/ soap and water x 10 minutes

Management of *digoxin* (or oleander, foxglove) overdose/poison? What antidotes/drugs are given?

*Digoxin immune Fab (DigiFab)* Each 40 mg vial of Digifab binds ~0.5 mg digoxin When the amount ingested or digoxin level is unknown, max adult dose is 20 vials NOTE that it interferes w/ digoxin levels after it has been given

Management of *benzodiazepine* overdose/poison? What antidotes/drugs are given?

*Flumazenil* NOTE that it *can cause seizures when used in patients on benzodiazepines chronically* - sometimes used off-label for non-benzodiazepine hypnotic overdose (zolpidem) but not routinely recommended

Management of *beta-blocker* overdose/poison? What antidotes/drugs are given?

*Glucagon if unresponsive to symptomatic treatment* High-dose insulin WITH GLUCOSE may be used in pt refractory to glucagon Lipid emulsion to enhance elimination of some lipophilic drugs

Dangers of *acetaminophen* toxicity? How to prevent?

*Hepatotoxicity* (most common cause of drug-induced liver injury) *Limit APAP from all sources to < 4,000 mg/day* (for most patients, others max 2000 mg/day like heavy alcohol drinkers, liver impairment, etc.)

Management of *cyanide* overdose/poison? What antidotes/drugs are given? Could be from smoke inhalation of *nitroprusside in high doses/long duration/renal impairment*

*Hydroxocobalamin (Cyanokit* Sodium thiosulfate + sodium nitrite (Nithiodote) is an alternative

Management of *methotrexate* overdose/poison? What antidotes/drugs are given?

*Leucovorin* (folinic acid) and *levoleucovorin* (Fusilev) *Glucardipase* (Voraxaze) For rescue after high dose cancer treatment, after an accidental overdose, or to reduce toxicity and counteract effects of impaired elimination

Management of *methemoglobinemia from topical benzocaine (in OraGel or teething products), dapsone, nitrates, or sulfonamides* overdose/poison? What antidotes/drugs are given?

*Methylene blue* (ProvayBlue) NOTE that *methylene blue is contraindicated in patients with G6PD deficiency* and you must avoid admin with SSRIs or SNRIs

What is the *antidote to APAP*?

*NAC aka N-acetylcysteine Can be given *PO or IV* *NAC is a glutathione precursor* NOTE that CYP2E1 metabolism ONLY occurs with excessive doses of APAP

Managing mixed overdoses involves matching symptoms to the toxin and then selecting appropriate antidote. Match the following symptoms: *QT prolongation*

Can be caused by *TCAs* --> check ECG and *given sodium bicarbonate if QRS is widened*

Managing mixed overdoses involves matching symptoms to the toxin and then selecting appropriate antidote. Match the following symptoms: *Hypoglycemia symptoms*

Check glucose level and if hypoglycemic given dextrose injection or glucagon (if family member provides) Oral carbohydrates can be given if alert and conscious (careful with alpha glucosidase inhibitors like acarbose and miglitol - must give pure glucose)

How to reduce accidental poisoning in children?

Child-resistant containers: screw caps, unit-dose packaging, safety packaging (Exception: *NTG SL tablets*)

What are the most commonly ingested substances by pediatrics based on 2019 American Association of Poison Control Centers (AAPCC) data?

Cosmetic products Cleaning substances Analgesics Dietary/Herbal supplements

Managing mixed overdoses involves matching symptoms to the toxin and then selecting appropriate antidote. Match the following symptoms: *Tachycardia, seizures, or severe agitation*

Could be from multiple causes Give *benzodiazepines*

Management of *heavy metal* overdose/poison? What antidotes/drugs are given? Think: arsenic, copper, gold, lead, mercury, thallium

For *arsenic, gold, and mercury: dimercaprol* For *lead*: dimercaprol + xalcium disodium edetate (CaNa2 EDTA) or *succimer* (Chemet) + dimercaptosuccinic acid (DMSA) For *thallium*: ferric hexacyanoferrate (Prussian blue, Radiogardase) For *copper: penicillamine*

Managing *animal bites* with *rabies vaccine and human rabies immune globulin*?

High-risk animal bites or exposure with NO previous rabies vaccination: given vaccine AND human rabies immune globulin (note that human rabies immune globulin is not useful after day 7 of vaccine or in previously immunized individuals) Vaccine given 1 mL IM in deltoid or thigh on days 0, 3, 7, 14, and immune globulin given day 0, infiltrated around wound site and a location separate from vaccine site Clean wound with soap and water *Tetanus shot* required if > 10 yr since last booster

Management of *local anesthetics* (bupivacaine, mepivacaine, orpivacaine) and other lipophilic drug overdose/poison? What antidotes/drugs are given?

IV lipid emulsion 20% Symptomatic treatment for seizures w/ benzodiazepines

Management of *ethanol* (think: alcoholic drinks) overdose/poison? What antidotes/drugs are given?

If suspected chronic alcohol user, administer *thiamine (Vitamin B12)* to *prevent Wernicke's encephalopathy* (neurological damage) *Can cause increase in anion gap*

Management of *naphthalene from mothballs* overdose/poison? What antidotes/drugs are given?

Methylene blue (ProvayBlue)

Management of *calcium-channel blocker* overdose/poison? What antidotes/drugs are given?

Same as beta-blockers - *Glucagon* (if unresponsive to symptomatic treatment, sometimes high-dose insulin w/ glucose, or lipid emulsion) *PLUS* *CALCIUM* (chloride or gluconate) - administered IV only, avoid fast infusion, monitor ECG, do NOT infuse Ca in the same line as phosphate-containing solutions

Uses for *protamine* as an antidote?

UFH, LMWH

Management of *5-fluorouracil (5-FU), capecitabine* overdose/poison? What antidotes/drugs are given?

Uridine triacetate (Vistogard, Xuriden)

Use of *activated charcoal*?

Used for *certain orally ingested drugs* *Most effective when used w/in 1 hour of ingestion* *Charcoal adsorbs the drug* to prevent GI absorption and systemic toxicity *Dose = 1 g/kg*

Uses for *phytonadione (vitamin K)* as an antidote?

Warfarin

Uses for *prothrombin complex concentrate (Kcentra)* as an antidote?

Warfarin, factor Xa inhibitors