Decontamination/Elimination/Antidotes Flashcards
What is decontamination?
stop ongoing exposure
-no longer in direct contact with the patient
to prevent absorption and thereby minimize systemic toxicity
decrease the possibility of transfer of the toxic substance
What are the principles of GI decontamination?
if a patient is already symptomatic, it means absorption has occurred and decontamination is unlikely to be benefit
-its efficacy decreases with time
prioritize airway protection and provide symptomatic and supportive care
risk vs benefit of GI decontamination is largely dependent on severity of potential toxicity
What is activated charcoals absorptivity attributed to?
its highly porous structure
What happens when toxicant and activated charcoal form a complex?
not systemically absorbed; therefore toxicant removed with AC upon bowel movement
Describe AC preparation.
derived from various organic materials
-e.g. coconut shells or peat
activated by heating at 600-900 C, then washing with inorganic acids and drying
creates highly developed internal pore structure
-small particle size with large surface area make it very adsorptive
allows for the adsorption of drugs and toxins through weak intermolecular forces
AC becomes less effective with use and have to be recharged or replaced
What are examples of agents that adsorb to AC?
acetaminophen
amitriptyline
amphetamines
chlordiazepoxide
cimetidine
codeine
diazepam
digoxin
salicylates
What are examples of agents that do not adsorb to AC?
boric acid
cyanide
ethanol
ethylene glycol
iron
lithium
malathion
methanol
petroleum distillates
What is sometimes added to AC to increase palatability?
sorbitol (sugar alcohol)
What is the dose of AC if the amount of toxicant ingested is known?
10-40x the dose of toxicant
When is AC more likely to reduce poison absorption?
if it is administered within 1 hour of ingestion
insufficient data to support or exclude the use of AC when more than 1 hour has passed since ingestion
When do we start AC method?
within 1 hour of ingestion (if feasible) but consider:
-bezoars
-MR products
-toxicants or co-ingestants that reduce GI motility/gastric emptying rate
-effect of volume ingested on gastric emptying rate
the above have benefits well beyond 1 hour
What are factors that increase AC appropriateness?
serious toxicity anticipated, no antidote
recent ingestion
alert, cooperative, intact airway
favourable stoichiometry
MR product
known to adsorb
no ileus/intestinal obstruction
opioids (can be given 2-3 hours after ingestion)
What are contraindications to AC?
toxicant known not to adsorb
unprotected airway (unconscious or trauma)
ingestion of hydrocarbons - risk of aspiration
risk of GI perforation (has ulcer, surgery, caustic agent)
endoscopy will be required (ex. corrosive)
What are examples of caustic agents?
drain cleaners
detergents
strong acids or alkali
What are complications of AC?
emesis
constipation/diarrhea
pulmonary aspiration
black stool/tongue/mucous membranes
pts with pre-existing motility disorders might be at greater risk
When is orogastric lavage considered?
ingested a potentially life-threatening amount of a poison and the procedure can be undertaken within 60 minutes of ingestion
What are practical indications for orogastric lavage?
toxicant likely to be life-threatening
OR obvious signs and symptoms of life-threatening toxicity
AND reason to believe significant amount in stomach
AND AC not an option
AND no spontaneous emesis
OR no highly effective antidote or alternative therapies pose high risk
What is whole bowel irrigation?
introduction of large amounts of fluid into GIT to expel intraluminary contents
rationale: cleanses bowel with large amounts of PEG solution to minimize drug absorption and expel intraluminal contents out of GIT; does not cause net change in ions, therefore no electrolyte imbalances
What are situations where WBI is an option?
expediting GI luminal clearance of:
-SR preparations
-toxic heavy metals
-packets of illicit drugs smuggled within the body
What is the evidence for WBI?
reported effective:
-decrease lithium concentrations
-98% success in body packers
-not effective for rapidly absorbed drugs
-may reduce hospital time, if successful
What are contraindications to WBI?
unprotected or compromised airways
GI compromises/hemorrhage
hemodynamically unstable
persistent vomiting
suspected leakage from drug packets or bowel obstruction or perforation
What are complications of WBI?
nausea/vomiting
abdominal cramping/bloating
aspiration/acute respiratory distress syndrome
hypo/hypernatremia
interreference with AC
What are some “other” methods of decontamination?
surgical removal
misc adsorbents
-Kayexalate
-cholestyramine
What is elimination?
enhances the removal of a toxicant that has already been systemically absorbed
removal from blood, therefore related to distribution or redistribution from tissues
When wont elimination methods have much effect?
if distribution is large
Vd > 1 L/kg considered large because it indicates that only a small portion of the total dose is in the plasma
What are the two types of elimination methods?
intracorporeal (occurring inside the body)
extracorporeal (occurring outside the body)
What is an example of an intracorporeal elimination method?
multiple dose activated charcoal
What are examples of extracorporeal elimination methods?
hemodialysis
hemofiltration
hemoperfusion
When does MDAC decrease absorption to tissues?
large amounts of xenobiotics are ingested, and dissolution is delayed (bezoars, SR, impaired GI motility)
when reabsorption can be prevented by lowering the concentration of free toxic substance in the intestinal lumen
How does MDAC work?
repeated administration of oral AC to enhance elimination to enhance elimination of drugs already absorbed into the body by functioning as an adsorbent “sink” at several sites in the gut
What is the dose for MDAC?
optimum dose unknown
dose and administration interval tailored to:
-amount and dosage form of xenobiotic ingested; severity of overdose; whether the patient is vomiting; potential lethality of xenobiotic; and tolerability
Which drugs have enhanced elimination from MDAC?
carbamazepine
dapsone
phenobarbital
quinine
theophylline
What are contraindications to MDAC?
patients with unprotected airways
if use is likely to increase risk and severity of aspiration
when threat of GI perforation or hemorrhage is high
when endoscopy is likely to be attempted
intestinal obstruction
when activated charcoal is known to not meaningfully adsorb the ingested toxin
if decreased peristalsis is likely to occur from the substance ingested
What are complications of MDAC?
constipation
bowel obstruction
emesis/aspiration
rectal ulcer/hemorrhage
reduction of therapeutically used xenobiotic
What are indications for MDAC?
life-threatening amount of CBZ, dapsone, phenobarbital, quinine, or theophylline
drugs with long t1/2, small Vd (<1L/kg), and those that undergo enterohepatic recirculation
Differentiate hemodialysis, hemofiltration, hemoperfusion, and hemodiafiltration.
hemodialysis:
-uses diffusion through a concentration gradient
hemofiltration:
-uses convection through a pressure gradient
-removes larger molecules
hemoperfusion:
-blood passes through adsorbent substance
-even larger molecules
-plasma removed, treated, and returned to body
hemodiafiltration:
-combines hemodialysis and hemofiltration
What are complications of hemodialysis?
hypotension
osmolar imbalance
hypoxemia
bleeding (have to anticoagulate)
rebound levels
air embolism
What must be the route of elimination for a drug if urine alkalinization is used?
kidneys
What is the mechanism of action of urine alkalinization?
ion trapping
-ionized drugs cannot cross lipid bilayer
helps clear weak acids by trapping the xenobiotics in the tubular lumen and not allowing it to be passively reabsorbed into the bloodstream
Which drugs are used for alkalinization and acidification?
alkalinization: sodium bicarbonate
acidification: ascorbic acid
done through IV
What are contraindications to urine alkalinization?
established/incipient renal failure
pre-existing heart failure (would be better suited for hemodialysis)
What are complications of urine alkalinization?
alkalemia
hypokalemia
hypernatremia
fluid overload
hypocalcemia
alkalotic tetany and hyperexcitability of nerves and muscles
When is urine alkalinization considered 1st line?
patients with moderately severe salicylate poisoning who do not meet criteria for hemodialysis
What are antidotes?
neutralize or counteract the toxin
prevents the development of, or reverses the signs and symptoms of toxicity
specifically counteracts the poison beyond a more general decontamination/elimination strategy
Are there lots of antidotes available?
few antidotes available
What must be done after treatment with an antidote?
patient must be monitored until toxic effects abate in absence of antidote
What are the types of antidotes?
receptor antagonists
-ex: atropine, vitamin K
chemical/chelator
-forms compound of lesser toxicity that is removed
-ex: deferoxamine, digoxin-specific antibody fragments, idarucizumab
dispositional
-alters toxicants ADME
-ex: ethanol, fomepizole
unclassified
-ex: intralipid
What is the use of atropine?
toxicity caused by acetyl-cholinesterase inhibitors
-donepezil, rivastigmine
pesticides
-organophosphates, carbametes
clitocybe or inocybe mushrooms
sometimes for digitalis through indirect MOA
What is the MOA of atropine?
competitive antagonist of acetylcholine
common binding site on muscarinic receptors but nicotinic receptors
What is the use of atropine in surgery?
reduce saliva and fluid in the respiratory tract during surgery
What is the reversal for atropine?
physostigmine
What are precautions against atropine?
tachyarrhythmias, CHF, CAD, hyperthyroid
obstructive diseases of GIT
What is the use of deferoxamine?
used in iron/aluminum toxicity
What is the MOA of deferoxamine?
acts as a chelator and binds free Fe to form ferrioxamine, which is renally excreted (brown urine results)
What is severe iron toxicity?
serum levels > 90 umol/L
clinical signs of significant toxicity
What should deferoxamine be accompanied with?
GI decontamination and supportive measures
What are complications of deferoxamine?
rapid IV admin can cause flushing, urticaria, hypotension, shock
Fe-ferrioxamine complex: hypotension, accumulation if renal disease, reddish urine
-may need hemodialysis if renal impairment to remove complex
What is the use of DigiFab?
used in severe, life-threatening digoxin toxicity
What is the MOA of DigiFab?
antibody fragments bind to digoxin = renally excreted
How many vials of DigiFab are needed for acute toxicity? What about chronic toxicity?
acute: 10
chronic: 6
What are complications of DigiFab?
very few
-monitor for deterioration of cardiac function
-hypokalemia
no contraindications
What is the brand name of idarucizumab?
Praxbind
What is the use of Praxbind?
reversing dabigatran-induced anticoagulation
What is the MOA of Praxbind?
antibody fragments bind to dabigatran
complex renally excreted
What are precautions to Praxbind?
thrombosis
hypersensitivity
hereditary fructose intolerance
-idarucizumab contains 4g sorbitol as excipient
What is the MOA of ethanol?
competitively blocks the formation of toxic metabolites in toxic alcohol ingestion by having a higher affinity for ADH
What is the application of ethanol?
methanol and ethylene glycol ingestion
-now regarded as second choice antidote in countries that have access to fomepizole
What is the lethal dose of ethylene glycol?
1.4 ml/kg
What is the lethal dose of methanol?
1-2 ml/kg
How are toxic alcohols metabolized?
by ADH and ALDH –> toxic organic acids (no rapid elimination pathway = accumulation) –> metabolic acidosis
How much higher is the affinity of ethanol for ADH compared to methanol?
15.5 x
What is the metabolite of methanol that results in toxicity?
formic acid and formaldehyde
What is the mechanism of ethylene glycol toxicity?
ethylene glycol is metabolized to ketoadipate and glycine using thiamine and pyridoxine as cofactors
How much higher is the affinity of ethanol for ADH compared to ethylene glycol?
67 x
When might hemodialysis need to be used for methanol or ethylene glycol toxicity after ADH has been blocked?
degree of end-organ damage has occurred
how well the body can eliminate the parent compound by itself
to extent to which toxic metabolites are already present
What are the complications of ethanol?
CNS depression
toxicities: hepatitis, pancreatitis, hypoglycemia, dehydration
What is the preferred alternative to ethanol?
fomepizole
What is the use of fomepizole?
treat ethylene glycol or methanol poisoning
What is the preferred antidote for methanol and ethylene glycol toxicity?
fomepizole
What is the MOA of fomepizole?
complete inhibition of ADH
even greater affinity to ADH than ethanol (80,000x greater than methanol/ethylene glycol, 8,000x greater than ethanol)
What is the use of intravenous lipid emulsion (Intralipid)?
current recommended treatment for local anesthetic systemic toxicity
What are precautions to Intralipid?
allergies
-soy, eggs
medical conditions
-ARDS, pancreatitis, fat metabolism disorder
What are the toxicant properties that make use of Intralipid more successful?
lipophilic
cardiotoxic
What is the MOA of Intralipid?
modulation of intracellular metabolism
-ILE overcomes blocked or inhibited enzymes by providing fatty acids as energy source for myocytes
lipid sink
-lipophilic drugs have high Vd, ILE expands the plasma lipid phase allowing toxicant to move from tissue to plasma lipid phase
activation of ion channels
-either or both Ca2+ or Na+ channels of mycotes
-increased intracellular Ca2+ = improved contractility
What are complications of Intralipid?
pancreatitis
fat emboli syndrome
lipemic serum
decreases effect of other therapies?
