Toxicity and Drug Overdose (ADR)

Quick review of the 3 Beta receptors...

Beta 1: primarily in heart muscle Activation: increase HR and contractility, AV conduction and decrease in AV node refractioriness Beta 2: present in heart but primarily in bronchial and peripheral smooth muscle. Activation = vasodilation and bronchodilation Beta 3: found in adipose tissue and the heart Activation = catecholamine induced thermogenesis and may reduce cardiac contractility

elemental iron percentages for each formulation... sulfate, gluconate and fumurate?

ferrous sulfate 20% ferrous gluconate 12% ferrous fumarate 33%

Iron toxicity treatment agent(s)

serum level > 500 mcg/dl systemic symptoms *Deferoxamine* (chelation therapy) -all other agents (charcoal, ipecac are poor choice)

In what case or type of drug is activated charcoal good for?

* Low volumes of distribution*, drugs with... - Vd < 11/kg (not sure what that means, unit are missing) - low plasma binding - biliary or gastric secretion active circulating metabolites

TCAD toxidrome: PE

*mad as a hatter, red as a beet, blind as a bat, full as a flask and dry as a bone* ADD seizures on top of that

Ipecac C/I, go...

*must know for exam and boards* 1. CHILDREN under 6 months 2. PTs with no gag-reflex 3. Ingestion of: caustics, corrosives, bleach, ammonia, or sharp objects 4. Any of the following type of patients - lethargic - comatose - convulsing - expected to become unresponsive w/i 30 mins

TCAD toxicity treatment...

*sodium bicarb* is the single most important intervention lidocaine for arrhythmias and Mag for TdP Physostigmine-> possibility but not used in clinical practice

APAP poisoning: 0.5 - 24 hr

- Anorexia, nausea, vomiting, malaise OR patient may feel "ok" - APAP level elevated (duh)

BB Overdose tx:

- Atropine for emergent bradycardia 0.5 mg to 1 mg every three to five minutes for total of 0.03 to 0.04 mg/kg dose - Arrhythmia treatments (sodium bicarbonate, magnesium, ACLS) - Lipid emulsion therapy Glucagon IV calcium salts Vasopressors High dose insulin and glucose infusions Additional therapies

Dosing of activated charcoal, go...

- Children < 1 year-> 1 g/kg - Children 1-2 years 25-50 g - Adult 50-100 g *comes in 50 g tubes, so usually 1 tube in kids and 1-2 in adults*

Complications from gastric lavage, go....

- aspiration pneumonia - laryngospasm - esophageal and stomach injury - hypothermia -fluid/electrolyte imbalance - cannot use large enough tube in children <12 y/o

When/for what is activated charcoal ineffective for?

- enteric coatings - iron, lead, lithium - simple alcohols - corrosives

APAP poisoning: 24-48 hr

- hepatic necrosis, RUQ pain and possible ARF (acute renal failure) - elevated INR, increased LFTs and TBIL

How fast does Ipecac work and in what time frame do you want to administer it?

- works in 15-30 minutes - administer within 1 hour

Manifestation of CN toxicity?

-Can begin within seconds of exposure - Burning mouth and throat, agitation, syncope, N/V, headache, diaphoresis, dyspnea, tachycardia, HTN. - Bitter almond odor may be detected on breath - Progress to coma, convulsions, CV shock, death

Mechanism of Iron Toxicity

-GI irritant (can result in hemorrhage and perforation) - mitochondrial poison - metabolic ACIDOSIS - CV side effects *SHOCK*

Key parts to BB toxidrome?

-bradycardia -hypotension -mental status changes(delirium, seizure, coma) -bronchospasm -hypoglycemia

Worst case CN blood level?

0.25-0.3 mg/dl: coma > 0.3 mg/dl: death

What are some compounds and their drug names that contain salicylates?

1. ASA- aspirin 2. choline magnesium tirsalicylate- Trilisate 3. choline salicylate- Arthopan 4.Magnesium salicylate- Doan's

What treatment methods are "approved" in salicylate toxicity?

1. Activated charcoal (not that effective in EC aspirin) 2. Saline diuresis and urinary alkalization (monitor for fluid retention and pulmonary edema *Gastric levage and whole bowel irrigation are C/I in GI bleeding*

TCAD manifestations-> (hint think cardiac and anti-cholinergic)

1. Cardiac: Prolong QRS complex leading to arrhythmias 2. HYPOtension-> from blocking of vascular alpha adrenergic receptors by vasodilation 3. normal Anticholinergic- *mad as a hatter, red as a beet, blind as a bat, full as a flask and dry as a bone*

2 key adrenergic components in BB overdose

1. Competitive antagonism at B1 receptors-> (most importantly) leads to decreased myocardial contractility 2. Nonselective blockade-> Bronchoconstriction, impaired gluconeogenesis, decreased insulin release

What are the major results from salicylate toxicity? (4)

1. Direct irritation of the GI tract 2. Direct stimulation of the CNS respiratory center 3. Stimulation of the metabolic rate, which causes lipid and carbohydrate metabolism disturbances 4. Interference of hemostasis

What are 2 metabolic signs of salicylate toxicity? (Hint: has to do with 4 major results from toxicity)

1. Increase in respiratory center leads to tachypnea and lack of effective CO2 exchange-> *respiratory alkalosis* 2. no normal aerobic metabolism ->*increase in pyruvate and lactic acid-> metabolic acidosis*

C/I to gastric lavage, go...

1. Ingestion of corrosives, hydrocarbons 2. seizures 3. unprotected airways

What happens when the uncoupling of mitochondrial oxidative phosphorylation occurs? (2)

1. No generation of high energy phosphates 2. Increase in rate of metabolism ( O2 consumption, glucose utilization and CO2 and heat production)

Toxi doses/range for APAP:

1. acute, child 140 mg/kg 2. Adults (non-intentional overdose - General- never exceed 4 g/day -hepatotoxicity also seen with 5-8 g/day over 2 month period - 7.5 g can deplete glutathione over 4 days - 10-15 g can deplete glutathione in 1 day

Odds and ends of Salicylate toxidrome? (mental status and PE)

1. agitation, lethargy and coma 2. Diaphoresis and tender abdomen

*Progression* of manifestations of salicylate toxicity (5 main ones)

1. anion-gap *metabolic acidosis* 2. HYPERnatermia 3. HYPOkalemia 4. *HYPOglycemia* 5. Prolonged INR

Key points about TCAD toxicokinetics: (5)

1. anticholinergic, alpha-adrenergic blockade and adrenergic reuptake inhibition 2. rapidly and complete GI *absorption* 3. *C_max 2-8 hrs* post ingestions and prolonged *t1/2* in overdose -> 24-76 hr 4. undergo hepatic recirculation 5. *Large Vd* (10-20 L/kg) *highly protein bound*

APAP metabolism: What are 2 way you get into trouble with too much APAP

1. malnourished: so you don't have adequate enzyme systems for metabolism 2. taking too much parent drug

TCAD toxidrome: Lab

1. prolonged QRS 2. cardiac dysrhythmia

*Initial* manifestations of salicylate toxicity... (5 main ones)

1. tachycardia 2. hyperpnea 3. *tinnitus* 4. respiratory alkalosis 5. *alkaline urine*

What are the supportive measures in treatment of salicylate toxicity?

1. treat acidosis with bicarb 2. treat electrolyte abnormality with fluids 3. Seizures (BZDs) 4. MISC: O2, dextrose and Vit K 5. cooling blankets (for hyperthermia)

TCAD blood levels risk assessment?

<300 ng/mL therapeutic *>1000 ng/mL severe*

Iron Toxicity risk assessment...worse case?

> 60 mg/kg of ELEMENTAL IRON severe or lethal *>500 mcg/dL is HIGH* -> severe

what level is chronic intoxication of salicylates defined at?

>100 mg/kg/day for > 2-3 days (but always obtain serum salicylate levels)

HD in aspirin toxicity (self study or from the reading)

Adults: Consider hemodialysis (based on symptoms; salicylate level of 100 mg per dL or more in acute toxicity or 60 mg per dL or more in chronic toxicity; or if patient requires intubation) Children: Consider hemodialysis (based on symptoms; salicylate level of 80 mg per dL or more; or if patient requires intubation)

increase in pulse? Cholinergic or Anticholinergic

Anticholinergic (+/- in cholinergic)

Increase in pupil size: Cholinergic or Anticholinergic

Anticholinergic (Cholinergic may or may not change)

increase in temp? Cholinergic or Anticholinrgic

Anticholinergic (that's it, simple for once)

antidote/ Drug indicated for? glucagon/ ?

BB or CCB overdose

antidote/ Drug indicated for? Flumazenil/ ?

BZDs (benzo's you crazy)

Why does NAPQI cause liver toxicity so readily?

Binds *covalently* to liver protein/tissue

What is worse for the patient ACUTE or CHRONIC acetaminophen toxicity?

CHORNIC- much worse prognosis

What is the short way to describe cyanide toxicity's mechanism?

CN blocks mitochondrial cytochrome oxidase-> prevents ETC processes

antidote/ Drug indicated for? Oxygen/ ?

CO (carbon monoxide)

APAP metabolism: what enzyme is specific to EtOH and APAP metabolism?

CYP2E1 (so if you drink and take APAP, the enzyme will be split between metabolizing both- doesn't end well)

APAP metabolism: Binge drinking causes an increase in what enzyme?

CYP2E1 (you didn't think you would see that twice, oops)

Mental status is NL or depressed? Cholinergic or Anticholinergic

Cholinergic (in Anticholinergic you see delirium)

Increase in peristalsis? Cholinergic or Anticholinergic

Cholinergic (opposite in Anticholinergic)

Increase is diaphoresis? Cholinergic or Anticholinergic

Cholinergic (opposite in Anticholinergic)

TCAD toxidrome: Mental status

Confusion, lethargy and dizziness. may progress to coma

these agents have slowed elimination due to toxin-induced hypothermia

EtOH and propranolol

these agents cause slowed elimination due to saturation of biotransformation pathways

EtOH, phenytoin, aspirin, theophylline, APAP

T or F: NAC can be given PO or IV

FALSE- IV formulation exists, ACetadote, but PO NAC cannot be given IV because of pyrogenicity

T or F: in a TCAD overdose, you see a prolonged period of time from symptoms to life threatening cardiotoxicity or seizures?

FALSE- can go from no symptoms to life threatening symptoms very very quickly *DEATH can occur in 1 hour*

T or F: Ipecac is currently recommended for home use?

FALSE- it was but in his words " fell out of favor"

What is preferred over using ipecac or when it is C/I?

Gastric levage (aka stomach pumping) - use w/i 1 hour of ingestion

Ipecac dosing recommendations, go...

HA- don't need to know

antidote/ Drug indicated for? Dimercaprol or penicillamine / ?

Heavy metal poisons

antidote/ Drug indicated for? Digoxin/ ?

Immune Fab (???? not sure about what he did here)

APAP poisoning: Acetadote dosing

LD: 150 mg/kg over 15 minutes MD: 50 mg/kg over 4 hours then 100 mg/kg over 16 hours

Why are TCADs so dangerous

LOW pill burden for harm *(for example,10 x 100 mg tablets can be fatal)*

antidote/ Drug indicated for? Ca-EDTA or succimer

Lead poisoning

antidote/ Drug indicated for? fomepizole or EtOH

MeOH or ethylene glycol

APAP poisoning: antidote name and dose

NAC- N-acetylcysteine Initial: 140 mg/kg PO (diluted in juice or soda Follow up: 70 mg/kg q4 h for 17 doses

What is the most common cause of Cyanide toxicity?

Nitrate containing drugs!!! *free CN represent 44% of nitroprusside by weight*

antidote/ Drug indicated for? Naloxone/ ?

Opioids

Phase 1 or Phase 2 metabolism: oxidizes compounds or demethylation by CYP450

Phase 1

Phase 1 or Phase 2 metabolism: makes compounds more polar or water soluble

Phase 2

Why is cardiotoxicity hard to detect in TCAD overdose?

Sinus tachycardia may predominate with anticholinergic symptoms but hard to distinguish from VT with widened QRS

these agents slow absorption in overdose due to slow GI motility

TCADs and anticholinergics

T or F: ALWAYS give a APAP overdose agent regardless of time frame?

TRUE- especially because time frame is not always known

T or F: the more lipophilic a BB tends to be the worse the overdose?

TRUE: highly lipid soluble rapidly cross blood brain barrier into the CNS

What is hydroxocobalamin and what is role in cyanide poisoning treatment? Describe dosing and mechanism of action

The cobalt ion in hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin. One mole of hydroxocobalamin binds 1 mole of CN. Given the molecular weights of each, 52 g of hyroxocobalamin are needed to bind 1 g of cyanide.

what is there besides ipecac, lavage and activated charcoal for overdose treatment?

Whole bowel irrigation - preferred if ingestion was several hours after arrival to hospital - drugs not well adsorbed by activated charcoal (SR or EC) - in the case of those silly drug mules! C/I bowel perforations, obstruction and GI bleed

What is the danger in BB overdose (counter intuitive)

You can get proarrhythmic activity

What is the most common cause for acute APAP toxicity? chronic APAP toxicity?

acute- intentional overdose chronic- "polypharmacy" with OTC products that all contain APAP

Cholinergic toxidrome examples

altered mental status bradycardia meiosis diarrhea/defecation urination GI cramps and emesis bronchorrhea

Tx of CN toxicity (agents only)

amyl nitrite, sodium nitrite, sodium thiosulfate, & oxygen

antidote/ Drug indicated for? Atropine/ ?

anticholinesterases

this agent causes an increased volume of distribution

aspirin

These agents slow the absorption in their own incidence of overdose

aspirin, lithium, phenytoin,and theophylline-SR

APAP poisoning: 48-96 hr

cont. hepatic necrosis (jaundice, coagulapothy, hepatic encephalopathy)

Anticholinergic toxidrome examples

delirium hyperthermia ileus mydriasis tachycardia urinary retention warm, dry skin think * mad as a hatter, red as a beet, blind as a bat, full as a flask and dry as a bone*

TCADs inhibit what physiologic entity that leads to cardiotoxicity?

inhibit FAST sodium channels -> leads to QRS/QTc prolongation -> leads to VT, VFib and TdP

intoxication/poisoning/overdose: symptoms of toxicity associated with a chemical substance:

intoxication

these agents all cause decrease serum protein binding

lidocaine, salicylates, valproate, phenytoin

What is the most common cause of liver transplants (in the UK)?

liver toxicity from APAP

these agents have prolonged toxicity due to longer acting metabolites

meperidine, carbamazepine, dapsone and gluthemide

increase in BP? Cholinergic or Anticholinergic

mostly anticholinergic (his chart is confusing, usually increase in anti- but is +/- in cholinergic)

increase is respirations? Cholinergic or Anticholinergic

mostly cholinergic (tricky again, +/- with Anti and sometimes cholinergic)

intoxication/poisoning/overdose: an exposure intended to cause self injury

overdose

intoxication/poisoning/overdose: AEs on the body from a chemical taken in excessive amounts secondary to exposure

poisoning

this agent slow absorption due to hypoperfusion from the toxins

procainamide

TCAD toxidrome: VS->

tachycardia *HYPOtension* HYPERthermia

These are the examples of some drugs that just one mouthful can be fatal to a child?

theophylline, colchicine, clonidine

What accumulates in CN toxicity when there is renal impairment?

thiocyanate-> causes neurotoxic syndrome *if thiocyanate level is > 20 mg/dL then D/C or hold CN containing drug*

What is the rate that a healthy person can eliminate CN from the body?

~ 2 mcg/kg/min (hepatic elimination) *hepatic or renal impairment predisposes a patient to CN toxicity*