Exam 3: the end is near Flashcards
if a child presents with an altered level of consciousness, metabolic disturbances, neurologic dysfunction, cardiac/pulmonary distress: ___
it is important to include toxic exposures as part of differential
supportive care in peds tox includes:
-begins with airway stabilization
-early antidote admin (if indicated)
what lab values do we want to initially get in children who present with toxicities?
-alcohol ingestion –> serum osmolality
-BBs or CCBs –> electrocardiogram
-always serum concentrations of acetaminophen
Gastric decontamination in peds tox: AC
-activated charcoal (consider use within 1 hr in pts with a potentially toxic ingestion)
–> dose: 0.5 - 1 g/kg
-multiple dose activated charcoal: use to prevent prolonged absorption or enterohepatic recirculation
–> dose: LD of 1 g/kg followed by 0.5 g/kg every. 4-6 hrs for up to 24 hrs
Gastric decontamination in peds tox: whole bowel irrigation
-performed using polyethylene glycol AND electrolyte solution
–> consider in pts who have ingested: sustained- release, enteric coated, iron or other metals
(can be given orally but admin via NG tube is easier in kids)
–> dose: 0/5 L/hr (small kids) up to 1.2-2 L/hr in older kids and adults for 4-6 hrs
**do NOT use miralax
Acetaminophen in ped tox
toxic ingestion: > 200 mg/kg (oral) or >. 60 mg/kg (IV) in kids
-GI decontam: AC within 1 hr
-Antidote: NAC (use IV & to prevent hyponatremia in children, product should be diluted to a concentration of 40 mg/dL)
Ethylene Glycol in ped tox
-engine coolant - has a sweet taste so kids and pets love it
-give IV pyridoxine 100 mg/day + thiamine 100mg/day until ethylene glycol metabolites are eliminated
Antidote: ethanol or fomepizole
Methanol in peds tox
ex: solvents, antifreeze, fuels, windshield washer fluid
-formaldehyde and formic acid cause lead to metabolic acidosis and blindness
-give folic acid 1 mg/kg (max 50 mg) every 4-6 hours for 24 hrs
Antidote: ethanol or fomepizole
Ethylene Glycol + Methanol Antidotes: ethanol (10%)
- can be oral or IV
LD: 8 mL/kg over 1 hr
Infusion: 0.8 mL/kg/hr
–> want serum concentrations of 100-150
Disadvantages: - requires central venous catheter
-central nervous system depression
-respiratory depression
-therapeutic drug monitoring
Ethylene Glycol + Methanol Antidotes: Fomepizole
1st line therapy!!
-load: 15 mg/kg , then 10 mg/kg q 12 h x 4 doses, 15 mg/kg q 12 h until serum concentrations are < 25
Advantages: no alternation in consciousness, no effect on blood glucose or electrolytes, no need for central venous access, no need for intensive care unit monitoring
what to do with a foreign body ingestion
-manual removal if impaction suspected
-battery may become lodged in the esophagus + result in serious life threatening complications
Signs & symptoms: vomiting, diarrhea, abdominal pain, fever, refusal to eat or drink, dysphagia
cough and cold preparations in peds tox
-avoid them in 6 years and younger, most cases lead to death
-GI decontamination: AC
-symptomatic management: htn (labetalol, nicardipine), arrhythmias (amiodarone) and seizures (benzos)
Strategies for poison prevention
-child proof caps
-child proof containers
-storage location
-environmental precautions
-taking appropriate doses
**disposal of unused, expired drugs
-never mix household products (ammonia and bleach = toxic fumes)
valuable information to collect when faced with a potential poisoning
-age and weight
-health history
-time of exposure
-route of exposure
-present symptoms
-exact name of product
-estimate how much may have been ingested
-strength of product
-formulation of product
General tx approach of poisoned pt
1- assess the pt: level of exposure, amount, symptoms
2- self tx (at home)?
3- referral to hospital: if its moderate to severe exposure or intentional ingestions
ABCDEs of management of a poisoned pt
-airway
-breathing
-circulation
-dextrose/decontamination
-EKG/elimination
Activated charcoal in a poisoned pt
-absorbant: 1 g/kg
-time window: 1 hr
-substances that will NOT bind: ionized metals, alcohols, gasoline
ADrs: vomiting, black tarry stools; want pts to have a protected airway
whole bowel Irrigation in poisoned pts
-polythylene glycol + electrolytes (1-2 L/hr PO/NG until rectal effluent is clear
-goal is to minimize time in GI tract for absorption
-beneficial for XR products and body packets
Orogastric lavage in poisoned pts
“stomach pumping”
-potential to produce serious toxicity
-use when no antidote exists
-time window gives reason to believe agent may still be in stomach
Hemodialysis in poisoned pts
-use when other elimination strategies are not effective/contraindicated
-potential to produce serious toxicity
-agent able to be removed through filtration
Anticholinergic toxidrome
-delirious
- high HR, pupils, BP, RR, temp
-signs: blindness, confused, hot, dry membranes, urinary retention, redness/flushing, tachycardia, no bowel sounds + hypertensive
Antidote: physostigmine (unpopular tho)
sedative- hypnotic toxidrome
-diazepam/ ethanol
-can see dec HR, BP, RR, hyperflexia
S&S: unresponsive but has response to painful stimuli
Adrenergic/Sympathomimetic toxidrome
-methamphetamine/ cocaine
-all vital signs inc, tremors
-S&S: agitation, SWEATY and bowel sounds present
Opioid toxidrome
-heroin/morphine
-decrease in all vitals, hyperflexia
S&S: unresponsive, unresponsive to painful stimuli, low HR + RR, see pinpoint pupils, bowel sounds are absent
Cholinergic toxidrome
(pesticides)
-dec pupil size, BP, HR, inc bowel sounds
SLUDGE: salivation, lacrimation, urination, defecation, gastric cramps, emesis
KILLER B’S**: bradycardia, bronchorrhea, bronchospasm (these will kill you, focus tx on these)
cholinergic toxidrome antidote
1: Atropine: 1 mg IB- titrate to effect,
-Pralidoxime (2-PAM): not used too often, but mainly for nerve gas agents/chemical warfare
Opioid receptors
-MU receptor: central pain analgesia, respiratory depression
-Kappa receptor: spinal analgesia, miosis (small constricted pupils)
-Delta receptor: central and spinal analgesia, cough suppression
exs of opioid agonists
-codeine
-fentanyl
-heroin
-morphine
-hydrocodone
-oxycodone
ex of opioid partial agonist
-busprenorphine (still hits on the opioid receptors)
ex of opioid agonist-antagonist
-nalbuphine
-butorphanol
-pentazocine
ex of opioid antagonist
-naloxone (used to reverse the opioids)
-methylnaltrexone, naltrexone, alvimopan (all used for substance use disorders, opioid induced constipation etc)
Opioid clinical presentation & management
Prezzy: decreased mental status, pinpoint pupils, decreased bowel sounds, depressed respiration
-management: administer antidote (naloxone), #1: PROTECT AIRWAY!
Naloxone use in opioid overdose
-non- opioid dependent: IV 0.4 mg
-opioid dependent pt: IV 0.04 mg and titrate to effect (increase by 0.04 mg; want to avoid acute withdrawal)
-bystanders: IN 4 mg (narcan)
-continuous infusion: 1/2 initial bolus dose and 2/3 of new bolus dose per hour
SEs: runny nose, flash pulmonary edema –> associated with high doses of naloxone upfront (acute precipitated withdrawal)
Naloxone induced pulmonary edema
-adrenergic response: tachycardia, tachypnea, hypertension
-shift in blood volume into the pulmonary vasculature: pulmonary vasoconstriction, pulmonary HTN, fluid leakage into lungs
TX: diuretics
Prevention: smaller initial doses of naloxone
Loperamide (used for opioid overdose)
-OTC anti-diarrheal
-inhibits intestinal peristalsis through u-opioid receptor agonism
Clinical presentation: opioid overdose, severe cardiac arrhythmias (when ppl abuse this med for its opioid effects)
-BBB: P-glycoprotein: usually shunts it from the BBB but in high doses the opioid can inhibit this and get into the BBB
-co administration of PGP inhibitors can enhance effects
Loperamide overdose management
Respiratory depression: Naloxone
Cardiac disturbances:
–> IV magnesium (for long QT intervals)
–>sodium bicarbonate
–> IV isoproterenol
–> transcutaneous pacing
- and then CPR and ACLS
Benzo overdose: drugs
-benzos work on Cl channels, binding helps facilitate GABA binding, opens up Cl- channels + CL- will flow causing inhibition of the CNS
Drugs: alprazolam, chlordiazepoxide, diazepam, lorazepam, midazolam, oxazepam
Flumazenil (used in benzo overdose)
-dose: 0.2 mg IV over 15 secs (peds- 0.01 mg/kg IV)
-competitiive antagonist at benzo receptor site (kicks off the benzos)
-onset: 1-2 mins
duration: variable, may need re dosing
Benzo withdrawal symptoms
-severe sleep disturbances
-irritability
-increased tension and anxiety
-panic attacks
-sweating
-dry retching and nausea
-palpitations
-headache
-psychotic reaction
-seizures (can be lethal)
To use or not to use flumazenil?
-benzos protectant effect, relatively non-lethal component of toxicity (death is usually due to losing the airway)
-benzo reversal can potentially cause lethal seizures
What to do in a polysubstance overdose
-elimination: activated charcoal
-administer antidotes: NAC
-supportive care: benzos (SO if you give flumazenil, you could reverse any protective effects that the benzos might be giving - so the drug really is controversial)
when is it safe to use flumazenil?
1- procedural sedation: being put to sleep for a short period of time, use on pts if its safe + wont precipitate a benzo withdrawal. may not completely remove the respiratory depression but will perk them up
2- unintentional, pediatric exposure: use where you dont want to do a lot of work up in peds. peds are usually not benzo dependent
effects of THC
-THC is the main component of marijuana that is responsible for the major psychoactive effects
–> mood elevation, euphoria, relaxation, creative thinking, and increased sensory awareness
Cannabinoid receptors
CB1: high levels int he brain regions, lack of CB1 receptors in the brainstem also explains lack of coma and respiratory depression seen with cannabis use
CB2: high levels expressed in periphery, expressed on a number of immune cells, isolated agonism of CB2 receptors has been the target for novel pharmaceutical candidates as anti-inflammatory agents
Medical conditions that MJ can treat
-anorexia
-anxiety
-asthma
-depression
-epilepsy
-glaucoma
-head injury
-insomnia
-mograine headaches
-multiple sclerosis
-muscle spasticity and spasms
-N/V
-pain
-parkinsons
-tourette syndrome
Clinical effects of phytocannabinoids: wanted effects
-mood elevation
-euphoria
-relaxation
-creative thinking
-increased sensory awareness
-appetite stimulation
-nausea suppression
Clinical effects of phytocannabinoids: paradoxical effects
-short-term memory difficulties
-agitation
-feeling tense
-anxiety
-dizziness
-lightheadedness
-confusion
-loss of coordination
Synthetic Cannabinoids
-sold as different types of smokables, incents etc that ppl smoke to get high
-synthetic cannabinoids are full agonists: higher receptor affinity & longer half-lives
Clinical effects of synthetic cannabinoids: desired effects
-mood elevation
-euphoria
-relaxation
-creative thinking
-increased sensory awareness
Clinical effects of synthetic cannabinoids: unwanted effects
-tachy/bracdycardia
-agitation
-irritability
-nausea
-vomiting
-drowsiness
-lethargy
-confusion
-seizures
-chest pain
-AKI
-CNS depression
-tremors
SO MUCH MORE!
Clinical presentation of synthetic cannabinoid used: Signs & Symptoms
-CNS depression
-disorientation
-restlessness/agitation
-hallucinations
-seizures
-combativeness
-anxiety
-mydriasis
-tachycardia
-vomiting
Clinical presentation of synthetic cannabinoid used: lab abnormalities
-dec potassium
-inc blood glucose
-inc creatinine kinase
-inc white blood cells
-inc creatinine/ AKI
synthetic cannabinoid used management
supportive, symptomatic care
-fluid, electrolyte replacement
-anti-emetics
-benzos
-ketamine
-intubation
cannabinoids: hyperemesis syndrome
-dysregulation of endocannabinoid system: desensitization and downregulation of CB1 receptors that generally have antiemetic effects
Diagnosis: hx of regular cannabis use, cyclic nausea and vomiting, generalized, diffuse abdominal pain & compulsive hot showers with symptom improvement
Hyperemesis Syndrome stages
1- pre-emetic or prodromal phase: months - years, diffuse abdominal discomfort, feelings of agitation or stress, morning nausea and fear of vomiting, increased use of MJ to treat
2- hyper-emetic phase: 24-48 hrs, cyclic episodes of nausea and vomiting, diffuse, severe abdominal pain
3- recovery phase: upon total cessation of cannabis, bowel regimens, fluids, electrolyte replacement and full resolution may take ~ 1 month
Hyperemesis Syndrome: clinical management
-hot showers : activate TRPV1
-capsaicin topical cream: activate TRPV1
-haloperidol: anti- nausea
-IV benzos: inhibitory effect on medullary and vestibular nuclei associated with nausea and vomiting
-fluids and electrolytes: supportive care
What is a sympathetic?
-inhibition of norepinephrine and dopamine reuptake, or increased release of neurotransmitters “uppers:
alpha1: vasoconstriction, increased peripheral resistance, increased blood pressure, mydriasis, increased closure of internal sphincter of the bladder
beta1: tachycardia, increased lipolysis, increased myocardial contractility, increased release of renin
Sympathomimetic toxidrome
-increased: BP, HR, RR, temp, pupil size, bowel sounds, diaphoresis
–> agitated, hyperalert, tremors, seizures
General management of sympathomimetic toxicity
supportive care
-elimination strategies (AC)
-#1: benzos
-anti- hypertensives
-fluids
-anti-psychotics
-electrolyte management
-ice baths
-sodium bicarbonate
sympathomimetic toxicity : cocaine
-typical line = 20-30 mg, ingestion of 1 gram is likely to be fatal
-euphoria, seizures, dysrhythmias, hypertension, coronary artery spasm, MI
-can have adulterants like levamisole (causes neutropenia, vasculitis, purpura)
-body backers are at high risk
Management: high dose benzos, supportive care
sympathomimetic toxicity : amphetamines
-MOA: releases catecholamines
-similar effects to cocaine but longer lasting
-causes agitation, seizures, hyperthermia, HTN, delirium
Management: benzos, barbiturates, anti-hypertensives & supportive care
sympathomimetic toxicity: bath salts
synthetic cathinones that cause: agitation, tachycardia, insomnia, paranoia, seizures, violent, unpredictable behavior
management: supportive care
sympathomimetic toxicity: others
-pseudoephedrine
-nootropics: ppl use it to stimulate a creativity boost or improve cognitive function
sympathomimetic toxicity: supportive care
clinical effects: #1- benzos
airway protection: intubation
hyperthermia: ice packs, cool fluids, antipyretics, benzos (high dose)
dysrhythmias: sodium bicarbonate, lidocaine
rhabdomyolysis: fluids
Pharmacokinetics of aspirin
A: rapidly absorbed in the stomach in its nonionized form due the acidic pH
D: small volume of distribution (-0.2 L/kg) and hightly protein bound
M: metabolized via the liver; rapidly hydrolyzed to salicylic acid
E: excreted via the kidney (half life 2-3 hrs, half life at high doses: 12 hours)
Toxicokinetics of aspirin
-delayed absorption due to pylorospasm. and bezoar formation in the stomach
-peak concentrations may not be seen until 24 - 36 hrs after ingestion with enteric coated products
-decreased protein binding & larger volume of distribution (higher drug concentrations and low pH, larger amounts of free drug reach the tissue)
-prolonged half-life due to hepatic metabolism saturation (salicylate elimination changes from 1st order kinetics to 0 order kinetics)
Acute salicylic toxicity: signs and symptoms
-N/V
-GI irritation
-tinnitus
-tachypnea/hypopnea
-respiratory alkalosis or respiratory acidosis
-metabolic acidosis (anoin gap or non-anoin gap)
-altered mental state/ hallucination
-coma/seizures
-hyper or hypo glycemia
-pulmonary edema
-hepatic injury
-coagulopathy *
-cerebral edema *
-acute respiratory distress syndrome *
-hyperthermia *
*these have the gravest clinical consequences
Acid-base stages in salicylic toxicity: early
-primary respiratory alkalosis, alkalemia and alkaluria
–> serum pH and urine pH are elevated
Acid-base stages in salicylic toxicity: intermediate
-mixed respiratory alkalosis and anoin gap metabolic acidosis, alkalemia and aciduria
–> elevated serum pH
–> low urine pH
Acid-base stages in salicylic toxicity: late
-metabolic acidosis with either a respiratory alkalosis or respiratory acidosis, acidemia and aciduria
–> serum and urine pH will be low
chronic salicylic toxicity: signs & symptoms
-nonspecific symptoms and often misdiagnosed
-severe toxicity is associated with serum concentrations > 60 mg/dl, altered mental status, and acid-base disturbances
-cerebral edema and acute lung injury may be present
acute salicylic toxicity characteristics
-younger
-intentional
-easily diagnosed
-suicidal ideation
-severely elevated serum concentrations
-death is uncommon
chronic salicylic toxicity characteristics
-older
-iatrogenic/unintentional
-underrecongnized as a diagnosis
-intermediate elevation in serum concentrations (can be missed)
-death is more common due to delayed recognition
Evaluation and diagnostic testing with serum salicylate levels
-toxicity is associated with serum concentrations > 30 mg/dL
-acute toxicity:
–> mild symptoms: > 150-200
–> severe symptoms: > 300-500 mg/kg
-chronic toxicity: > 100 mg/kg/day for several days
-blood gas and anion gap to classify acid-base disorder
Supportive therapies for salicylate toxicity
1: 0.5 - 1 gram/kg dextrose followed by additional bolus doses or a continuous infusion for severe salicylate toxicity
-multiple dose activated charcoal (MDAC): prevents absorption of unabsorbed salicylates, consider if pharmacobezoar or extended release preparation is suspected
-hypovolemia should be corrected with administration of crystalloids
Serum and urine alkalization in salicylate toxicity
-want to shift salicylate out of the brain and tissues into the serum to promote renal elimination
–> IV sodium bicarbonate is recommended for all symptomatic pts
-bolus dose: 1-2 mEq/kg
-continuous infusion: 150 mEq sodium bicarbonate in 1,000 mL of 5% dextrose at a rate of 1.5 to 2 times the maintenance rate
Hemodialysis in salicylate toxicity: when to recommend it
-serum salicylate level > 100 mg/dL
-serum salicylate level > 90 with impaired renal function OR failure of supportive therapies
-serum salicylate levels > 80 with impaired renal function AND failure of supportive therapies
-supplemental oxygen required due to altered mental status from hypoxemia
–> D/C hemodialysis when serum salicylate level is < 19 mg/dL and pt is clinically improving
Patient monitoring in salicylate toxicity
-serum salicylate concentrations ever 2-4 hours until patient is improving clinically with a low serum salicylate concentration and a normal or high serum pH
-urine pH
-serum pH
-more frequent monitoring may be needed in your critically ill patients
Summary of salicylate toxicity
-characterization of a salicylate overdose includes early onset nausea, vomiting, abdominal pain, tinnitus and lethargy while the gravest clinical consequences include coagulopathy, cerebral edema, and ARDS
-treatment of salicylate toxicity is aimed at preventing tissue injury by urinary arlkalinization to enhance elimination of salicylates through the kidney
-additional supportive therapies include MDAC to decrease absorption, crystalloids to correct hypovolemia, and dextrose to increase glucose concentrations in the CSF.
where is methanol usually found?
-model airplane and car fuel
-windshield washer fluids (> 60%)
-photocopying fluid
-colognes and perfumes
-gas line antifreeze
-hydraulic fracturing (“fracking”)
where is ethylene glycol found?
engine coolant (antifreeze) in car radiators
–> sweet taste, but aversive bittering agents have been added
where is isopropanol found?
-rubbing alcohol
-solvent used in household products, cosmetics and topical pharmaceuticals
Toxicokinetic of alcohols: absorption
–> ingestion: rapidly absorbed, gastric alcohol dehydrogenase and first pass hepatic metabolism, oral bioavailability = 92-100%
–> inhalation: occupation or intentional inhalation of methanol, ethylene glycol inhalation does not cause poisoning
–> transdermal: isopropanol and methanol penetrate skin better than ethylene glycol
Toxicokinetic of alcohols: distribution
-rapidly to total body water
-0.5 - 0.77 L/kg
Toxicokinetic of alcohols: metabolism and elimination
-AHD and/or aldehyde dehydrogenase coupled to the reduction of NAD+ to NADH
-ethylene glycol is eliminated via the kidney unchanged
-methanol eliminated as a vapor in expired air
Clinical manifestations of alcohol toxicity: CNS
-inebriation is dependent on dose and molecular- weight
-absence of inebriation does not exclude ingestion
Clinical manifestations of alcohol toxicity: metabolic acidosis
-toxic alcohols are metabolized to toxic organic acids (methanol –> formic acid; ethylene glycol –> glycolic acid) which cause a high anion gap metabolic acidosis
-exception = isopropanol
(metabolite = acetone which causes ketosis without acidosis
Clinical manifestations of alcohol toxicity: methanol
-retinal toxicity: blurry vision to complete blindness which can be asymmetric
-neurotoxicity: basal ganglia lesions bilaterally which can lead to Parkinsonism
-acute kidney injury
-pancreatitis
Clinical manifestations of alcohol toxicity: ethylene glycol
-nephrotoxicity: oxalic acid + calcium = calcium oxalate, monohydrate crystals which deposit in renal tubules
-this precipitation can cause hypocalcemia
Clinical manifestations of alcohol toxicity: Isopropanol
hemorrhagic gastritis
Diagnostic testing for alcohol toxicity
-serum concentrations: methanol, formate, ethylene glycol, and isopropanol
–> prolonged time from ingestion? formate levels can be helpful
-serum and urine oxalate concentrations are usually not clinically relevant
-toxic concentrations of methanol and ethylene glycol > 25 mg/dL
(obtain electrolytes, calcium, BUN, Cr, UA, VBG or ABG, lactate, measured serum osmolality and serum ethanol concentration
anion gap in alcohol toxicity
-high anion gap metabolic acidosis of unknown etiology
–> lack of high anion gap metabolic acidosis can be seen with recent ingestion of toxic alcohol
osmol gap in alcohol toxicity
-extremely elevated osmol gap ( > 50 mOsm/L)
-normal osmol gap ranges from -14 to +10 (baseline is needed to compare)
-serum ethanol concentration can prevent metabolism to the organic acid and is considered protective
-elevated lactate levels can be seen with methanol and ethylene glycol poisoning
Management of alcohol toxicity
–> resuscitation (fluid admin, BP support with vasopressors if needed)
–> inhibition of ADH: used for METHANOL AND ETHYLENE GLYCOL
1) fomepizole
2) IV ethanol 10 % continuous infusion (not really used in the US)
–> renal replacement therapy but we like hemodialysis better :)
Fomepizole in methanol and ethylene glycol toxicity
-competitive inhibition of ADH
-initial bolus: 15 mg/kg IN piggyback over 30 mins
-maintenance dose: 10 mg/kg IB piggyback every 12 hrs x 4 doses then increase to 15 mg/kg IV piggyback q 12 hrs
–> continue until serum toxic alcohol concentrations is < 20 mg/dL + asymptomatic with normal serum pH
AEs: hypotension and bradycardia
Adjunctive therapy for methanol toxicity
1- folic acid: enhances formate elimination
2- methylprednisolone: 1 gram IV every 24 hours for 3 days may improve the amount of vision loss experiences
3-sodium bicarbonate continuous infusion: shifts formic acid to formate and causes ion trapping in the urine : goal serum pH > 7.2
Adjunctive therapy for ethylene glycol toxicity
1- thiamine: promotes conversion of ethylene glycol to ketoadipate
2- pyridoxine: promotes conversion of glycine to hippuric acid
3- sodium bicarbonate continuous infusion can be considered in pts with pH < 7.15
Summary of alcohol toxicity
-understand time of ingestion and time of presentation to the hospital
–> early signs of toxic alcohol poisoning = inebriation
–> metabolism of toxic alcohols cause metabolic acidosis and end-organ effects (methanol and ethylene glycol)
-anion gap and osmol gap can be used to initiate treatment while awaiting results for serum concentration
-treatment include fomepizole with adjunctive therapy which can include bicarbonate, folic acid, pyridoxine, and thiamine
-severe toxicity will require hemodialysis
Pharmacology of TCAs
-classified as tertiary and secondary amines
-inhibit presynaptic reuptake of NE and serotonin, increasing the amount at the CNS receptor
-competitive antagonists of the muscarinic acetylcholine receptors
-peripheral alpha1 adrenergic receptor antagonist
-cardiac sodium channel binders
-inhibit peripheral and central postsynaptic histamine receptors
-interfere with chloride conductance
Pharmacokinetics of TCAs
A: completely & rapidly absorbed in the GI tract, peak concentration at 2-8 hrs
D: 10-40 L/kg; large and variable: lipophilic, rapidly distributed to heart, brain, liver and kidney
M: demethylation, aromatic hydroxylation and glucuronide conjugation of hydroxy metabolites
E: t1/2 = 7-58 hrs
Toxicokinetic of TCAs
-delayed absorption due to decreased gastric motility (anticholinergic effects and ionization in gastric acid
-severe overdose lead to low blood pH increasing the amount of free drug
-saturable metabolisms cause prolonged half-life
-clinical toxicity is rapid and unpredictable, presenting initially with no signs or symptoms of toxicity, quickly developing cardiovascular and CNS toxicity
–> therapeutic dose = 2-4 mg/kg/day, concentration 50-300 ng/mL
Acute ingestion causing cardiotoxicity and CNS toxicity of TCAs
dose: 10-20 mg/kg
concentration: > 300-1000 ng/mL
Patho of TCAs: ECG findings & sinus tachycardia
ECG: prolonged QRS complex, right bundle branch block pattern
ST: antimuscarinic, vasodilatory, and sympathomimetic effects
Patho of TCAs: hypotension
-direct myocardial depression from alternations in the function of sodium channels
-alpha1-adernergic blockage causing peripheral vasodilation
Patho of TCAs: others
-TCAs are weak bases and therefore in an acidic environment become increasingly ionized
-increasing the pH via alkalinization decreases ionization, decreasing the sodium channel binding and moving the TCA into the lipid member
-agitation, delirium, and depressed sensorium
-seizures
Clinical manifestations of TCA toxicity: acute
-hypotension and ventricular dysrhythmia including sinus tachycardia and wide-complex tachycardia
-prolonged PR interval, QRS complex, and QT interval
-delirium, agitation, psychotic behaviors with hallucinations, seizures, lethargy and coma
-anticholinergic: dilated pupils that are minimally responsive to light, dry mouth, drug flushed skin, urinary retention and ileus
-acute respiratory distress syndrome, aspiration pneumonitis, and multi system organ failure
Clinical Manifestations of TCA toxicity: chronic
-not life threatening
-sedation and sinus tachycardia
Diagnostic testing for TCA toxicity
-ECG: see R waves and prolonged QRS duration
-TCA serum concentrations
-electrolytes
-glucose
-venous or arterial blood gas
Management of TCA toxicity
-GI decontamination: AC is recommended in all pts within 2 hrs of ingestion with a normal mental status but protected airway
-serum alkalization and sodium loading : membrane-stabilizing effect (sodium bi carbonate)
-control arrhythmias, hypotension and seizures
-IV lipid emulsion: SALVAGE therapy when cardiovascular therapy is refractory to standard therapy
–> only effective for lipophilic drugs (amitriptyline & clomipramine)
–> AEs: ARDS and pancreatitis
What is is membrane stabilizing effect?
-in the presence of TCAs the sodium channel is altered slowing the rate of rise of action potential
-increasing the sodium gradient across the affected sodium channel speeds the rate of the action potential –> drug induced effects are counteracted, increasing the pH removed TCAs from the binding site on the sodium channel
Serum arlkalinization & sodium loading in TCA toxicity
-effective for wide-complex dysrhythmias (QRS complex duration > 100 ms) with conduction delays and hypotension
Preferred: sodium bicarbonate
–> boluses or rapid infusion over several mins: 1-2 mEq/kg, additional boluses every 3-5 mins until QRS duration narrows and hypotension improves (target pH: 7.5-7.55)
Alternative: hypertonic saline
–> 1-2 mEq/kg bolus, only used with arlkalinization when sodium bicarbonate administration is not possible or contraindicated
Antidysrhythmic therapy in TCA toxicity
-lidocaine: class 1B, indicated for ventricular dysrhythmias not responsive to sodium bicarbonate therapy
-magnesium sulfate: consider after alkalization, sodium loading, and a trial of lidocaine fails
-CI: procainanmide, flecainide, amiodarone and sotalol
Hypotension tx in TCA toxicity
-0.9% sodium chloride or sodium bicarbonate
-hypotension despite volume resuscitation: NE, vasopressin can be added if needed
-extracorporeal membrane oxygenation
Seizure tx in TCA toxicity
first line: benzos (lorazampan IV push)
second line: propofol or barbiturate
-seizures cause an acute increase in serum lactate levels decreasing serum pH, increasing the risk of cardiac toxicity, bradycardia and asystole
what drugs are contraindicated in seizure tx in TCA toxicity?
-phenytoin: fails to terminate seizures, enhances cardiovascular toxicity
-Flumazenil: induces seizures
-Physostigmine: induces seizures
TCA toxicity summary
-TCA overdose can cause cardiovascular toxicity (mild conduction abnormalities to wide- complex tachycardia, hypotension, and asystole) and CNS toxicity (delirium, lethargy, seizures, and coma)
-cardiovascular toxicity can be managed with alkalization and sodium loading (membrane-stabilizing effect)
-other complications can induce dysrhythmias refractory to alkalinization, hypotension, and seizures and these should be managed appropriately
onset of action of digoxin (PO & IV)
PO- 1.5 - 6 hrs
IV: 5 - 30 mins
maximal effect of digoxin (PO & IV)
PO: 4-6 hrs
IV: 1.5 - 3 hrs
Toxicokinetic of digoxin
-elevated serum concentrations of digoxin result in greater renal clearance before distribution to the tissues causing the apparent half-life to decrease to 13-15 hrs
-hypokalemia and hypomagnesemia enhances the effects on the myocardium leading to toxicity at lower serum concentrations: decreases the sodium-potassium-ATPase activity
-toxicity can be seen with changes in liver, kidney or heart function, along with drug-drug interactions including quinidine, verapamil, carvedilol, aminodarone and spironolactone
Mechanism of action of digoxin toxicity
-digoxin and other pharmacological CAS inhibit the sodium-potassium-ATPase causing an increase in the intracellular sodium concentration, preventing the antiporter from expelling calcium –> increase in intracellular calcium and enhanced inotropy
-excessive elevations in calcium increases the resting potential leading to dysrhythmias
Electrophysiologic effects of CAS on the myocardium
-cardioactive steroids increase automacity and shorten repolarization intervals of the atria + ventricles and also decrease in the conduction of the SA and AV nodes
Toxicity = increased dysrhythmias and myocardial irritability
Signs and symptoms of digoxin toxicity: acute
-asymptomatic period of minutes to several hours
-nausea, vomiting, abdominal pain, lethargy, confusion and weakness
Signs & symptoms of digoxin toxicity: chronic
-difficult to diagnose
-loss of appetite, weakness, anorexia, nausea, vomiting, abdominal pain, weight loss, delirium, confusion, drowsiness, headache, hallucinations, visual disturbances, and rarely seizures
Signs & symptoms of digoxin toxicity: general
-electrolyte abnormalities: hyperkalemia (important prognostic implications)
-cardiac dysrhythmias including ventricular tachydyshythmias and bradydysrhythmias due to sensitized myocardium and depressed AV node
Diagnostic tests for digoxin toxicity
must wait 6 hrs after ingestion to ensure accurate serum concentrations after the alpha distribution phase has been completed (therapeutic range = 0.5 to 2 ng/mL)
-basic metabolic panel plus calcium and magnesium
-blood gas to assess for metabolic abnormalities and hypoxemia
-electrocardiogram
-thyroid function tests
-review medication list for potential drug-drug interactions
Management of digoxin toxicity
-GI decontamination: AC 1 g/kg q 2-4 hours up to 4 doses (use in pts if definitive therapy with Digifab is not immediately available or if acute kidney injury)
-electrolyte therapy:
–> hyper/hypokalemia: DO NOT administer ca, could exaggerate cardiac effects leading to “stone heart”
–> hypomagnesemia: magnesium sulfate 2 grams IV over 20 mins followed by 1-2 grams/hr if needed
-digoxin-specific antibody fragments
**indications for digoxin specific antibody fragment tx
-life threatening dysrhythmia regardless of digoxin concentration (ventricular tachycardia, ventricular fib, atropine-resistant bradydysrhythmias, or 2nd or 3rd degree heart block)
-potassium concentrations more than 5 mEq/L in the setting of acute digoxin toxicity
-chronic elevations of serum digoxin concentrations with dysrhythmias, GI symptoms, or altered mental status
-serum digoxin concentrations
–> measured at anytime after ingestion: > 15
–> measured 6 hrs after ingestion: > 10
-acute ingestion of 10 mg of digoxin in an adult
DigiFab MOA
-prepared from the blood of healthy sheep who are immunized with a digoxin derivative DDMA
-free digoxin in the intravascular and interstitial space is bound by the antigen-binding fragments
-movement of free intracellular and dissociated digoxin into the interstitial or intravascular space due to the concentration gradient which is established
-immediate decline in free digoxin concentrations
-increases renal clearance
-decreases serum potassium concentrations
**DigiFab Vial dosing: empiric therapy
empiric for chronic toxicity: 3-6 vials
empiric for acute toxicity: 10 vials
**DigiFab vial dosing for Digoxin-specific Fab dosing
-known digoxin serum concentrations:
–> (serum digoxin concentration * pt weight) / 100 = # of vials
-known amount ingested:
–> (amount ingested (mg) / 0.5 (mg/vial) * 80% bioavailability = # of vials
*round up to the nearest whole vial
other cardiac therapies to consider with digoxin toxicity
-atropine (early bradydysrhythmias) 0.5 mg IV push repeated every 5 mins
-Phenytoin & lidocaine (ventricular tachydysrhythmias) –> rarely used
-pace maker
-cardioversion
Digoxin toxicity summary
-digoxin has a narrow therapeutic window
-signs & symptoms of digoxin toxicity include nausea, vomiting, weakness, altered mental status, hyperkalemia and dysrhythmias including bradycardia, and atrial and ventricular ecotype with block
-digoxin toxicity can be managed with administration of activated charcoal, DigiFab, correcting electrolyte and providing other supportive therapies
beta blocker pharmacology
-decrease the chronotropic and inotropic effects by competitively antagonizing the effects of catecholamines at the beta adrenergic receptors
-decrease atrial, AV node, and SA node discharge and inhibit ectopic pacemakers
Beta1: inonotrophy and chronotropy
Beta2: contractility and chronotropy
Beta3: metabolic regulators in adipose tissue
CCB Pharmacology
-antagonizes the L-type or long action voltage gate calcium channels located in the myocardium and vascular smooth muscle
-NDCCB: inhibit the SA and AV node, used for rate control, HTN, and to reduce myocardial oxygen demand
-DCCB: little effect directly on the myocardium, peripheral vasodilators, used for migraine headache, HTN, and post-intracranial hemorrhage associated vasospasm to reduce vascular tone
Beta blocker pharmacokinetic
A: dependent on the BB ingested, ranges from 25-100%
D: lipid soluble BB have large volume of distribution and are highly protein bound while water soluble BB have smaller volume of distribution
M: hepatic metabolism
E: kidney and red blood cell esterase
calcium channel blocker pharmacokinetic
A: good absoprtion, but low bioavailability due to hepatic first-pass metabolism
D: highly protein bound; volume of distribution can be large or small
M: hepatic metabolism including CYP3A4 to primarily inactive metabolites
E: primarily excreted by the kidney
Clinical Manifestations: beta blocker toxicity
-hypotension
-bradycardia
-dysrhthymias: prolonged QRS and QTc intervals
-hypoglycemia
-seizures
-respiratory depression and apnea
-coma
Clinical manifestations of CCB toxicity
-hallmark symptom: hypotension and bradycardia
-lack of perfusion to the central nervous system can cause fatigue, dizziness and lightheadedness
-hyperglycemia
-severe overdose can cause syncope, coma, sudden death, and acute respiratory distress syndrome
Diagnostic tests for BB and CCB toxicity
- 12 lead ECG
-continuous cardiac and hemodynamic monitoring
-chest x-ray and oxygen saturation
-basic metabolic panel including serum glucose, magnesium and calcium
-digoxin levels
-thyroid function tests
-cardiac enzymes
-lactate
Management of BB & CCB overdose
-GI decontamination: AC
-hypotensive: cyrstalloid fluid: 10-20 mL/kg
-bradycardia: atropine
-IV lipid emulsion - salvage therapy
Management of CCB overdose
-calcium: calcium chloride 10% 10-20 mL or calcium gluconate 30-60mL over 10 mins administered every 10 mins for 2 doses and then every 20-60 mins as needed
**do NOT give if digoxin toxicity is suspected/confirmed
Management of BB overdose
glucagon (commonly avoided due to side effects: vomit & hypoglycemia)
3-5 mg IV over 1-2 mins, may repeat with 4-10mg after 5 mins with no improvement in hemodynamics
High dose insulin in BB and CCB toxicity
-impairs sodium-calcium antiporter resulting in an increase of intracellular calcium which increases the calcium in the sarcoplasmic reticulum increasing cardiac contractility
-tx of choice but does have a delayed onset (so give with other things)
Bolus infusion: 1 unit/kg IV push with 0.5 g/kg of dextrose unless blood glucose is greater than 300 mg/dL
Continuous infusion: 1 unit/kg/hr titrated to effect in combo with dextrose infusion at 0.5 g/kg/dL
monitoring & SE for high dose Insulin
-monitor blood glucose every 30 mins for the first 4 hours and then every hour
-more frequent monitoring of blood glucose is necessary in the presence of renal failure
AEs: hypoglycemia and hypokalemia
Adjunctive hemodynamic support for BB/CCB toxicity
-inotropes and vasopressors
-cardiac pacing
-intraaortic balloon pump
-extracorporeal membrane oxygenation
Summary of BB and CCB toxicity
-hallmarks of BB and CCB include hypotension and bradydysrhythmias
–> BB: hypoglycemia
–> CCB: hyperglycemia
-tx icludes GI decontamination, crystalloid fluids, atropine, calcium, glucagon and HDI in addition to vasopressors and inotropes
most common toxins in pediatric toxicology?
analgesics, cosmetics & household cleaning substances
what clinical effects of IV lorazepam would need to be considered?
-IV lorazepam may cause respiratory depression in large doses and an intubation tray should be kept close to the bedside
-propylene glycol toxicity has been associated with IV lorazepam infusions
what could you educate the team about dosing of benzos in a sympathomimetic overdose?
higher doses than expected may be necessary, and as the patient is intubated, respiratory depression is less of a concern
what effects of synthetic cannabinoids are more unpredictable than their phytocannabinoids counter parts?
-are full agonists
-have higher receptor affinities
-have longer half lives
pt cames on w/ complaint of cyclic vomiting due to smoking mj, hot showers have helped but she wants more help. what is the most appropriate therapy to initiate in this patient?
capsaicin 0.025% cream applied topically to the abdomen
MN is a 22 y/o male who presented to the emergency department as an opioid overdose. EMS tells you that he responded well to 4 mg of IV naloxone and tells you he took a bunch of methadone. Then, one of his friends told him about these opioid smoothies he makes, in which he pours a bottle of loperamide into a blender with some orange juice and yogurt and drinks this to get high; so, he also had a glass or two of this. PMH: Polysubstance abuse Medications: Unknown Allergies: Unknown FH: Unknown SH: Unknown Based on the information in the case, what will we need to monitor MN for while he is in the emergency department? (SATA)
A: Intracranial hemorrhage
B: Respiratory depression
C: Cardiac arrythmias
D: Pneumonia E: Diarrhea
-respiratory depression
-cardiac arrythmias
After MN has been in the emergency department for one hour, he starts getting drowsier and his respiratory rate is now 8 breaths per minute. Based on the amount of naloxone that worked well for MN, given by EMS, what naloxone therapy should we start at this point in time? (responded well to 4mg IV via the paramedics)
A: Naloxone Bolus: 2 mg, with an infusion rate of 4 mg/hr
B: Naloxone Bolus: 2 mg, with an infusion rate of 1.3mg/hr
C: Naloxone Bolus: None, with an infusion rate of 4 mg/hr
D: Naloxone Bolus: 4 mg, with an infusion rate of 4mg/hr
E: Naloxone Bolus: None, with an infusion rate of 2 mg/hr
B: Naloxone Bolus: 2 mg, with an infusion rate of 1.3mg/hr –> (1/2 initial bolus and then 2/3 of new bolus/hr)
what signs and symptoms would you expect a pt to have if they overdosed on hydroxyzine?
-dry mouth
-increased temp
(anticholinergic things)
what drug levels should always be obtained in an overdose?
-salicylates
-acetaminophen
what is usually used for beta-blocker toxicity?
-insulin 1 unit/kg/hr IV infusion + dextrose IV infusion
what acid-base disturbance is most frequently seen in acute aspirin toxicity?
a respiratory alkalosis followed by metabolic acidosis
what symptoms result from the ingestion of windshield wiper fluids?
-inebriation
-blurry or hazy vision
-high anoin gap
(can give pt fomepizole)
findings persist upon arrival and the emergency team is suspicious of a nortriptyline overdose but it is determined that we are outside the window for GI decontamination. What is the first line agent that should be used in this patient?
sodium bicarbonate
Which of the following agents are the preferred treatment for seizures due to TCA toxicity
lorazepam
Which symptoms should you monitor for in Charles that are consistent with an overdose of diphenhydramine?
-increase in blood pressure
-increase in heart rate
-increase in temp
