topic 22 Flashcards
What are 4 forms of toxic RXNS?
- Local (irritant) effects
- Systemic effects
- Combination of both
- Affect substrate delivery or utilization
– Oxygen
– Glucose
- Free radical formation (toxic intermediary)
- Toxic metabolite formation (e.g., formic acid from methanol)
- Enzymatic deficiency revealed (G6PD)
- Affect metalloproteins
- Allergic reactions
- Hypersensitivity reactions
What is an antidote that can be used for a variety of toxicants such as CO? How is it used?
• Oxygen is an essential
“antidote” used for the
treatment of a variety of
toxicant exposures (e.g.
carbon monoxide).
• Oxygen usually applied
via high flow face mask
10-15 L/min.
What are some toxicants tha twill cause hypoglycemia? What are the effects? What is the antidote? How is it applied?
• Hypoglycemia is possible from several drugs
and toxicants such as insulin and oral
hypoglycemic agents (sulfonylureas) as well
as beta-blockers, alcohol, quinine and
salicylates.
• Inadequate cellular energy for normal
function, most acutely noticeable as impaired
brain function.
• Concentrated dextrose solution ( D50%,
D25%, D10%) treats hypoglycemia.
What is an example of a toxicant that effects transport of oxygen? How does it do so? What are the results?
• Carbon monoxide binds to hemoglobin with
much higher affinity than oxygen.
• This leads to a functional defect in forming
oxyhemoglobin and thus leads to decreased
oxygen delivery to the body.
- Hemoglobin cannot bind oxygen.
- Carbon monoxide also affects the cytochrome
oxidases, which contributes to lower energy
production by cells. The overall effect is
tissue hypoxia.
What are 2 examples of toxicants that effect the transport of oxygen?
CO, Methemoglobin formers
How do methemoglobin formers work?
- Methemoglobin is another example of a toxic effect on hemoglobin as a metalloprotein.
- Methemoglobin is hemoglobin in the oxidized ferric state (Fe3+) and cannot carry oxygen for cellular delivery.
- Normally, the iron or “heme” in hemoglobin is in the Fe2+ state which is capable of “picking up” oxygen to transport.
What is an example of a toxicant that releases free radicals or toxic electrophiles? How is it metabolized? What is the result of too much of it? How is it normally detoxified?
APAP (Acetaminophen)
• Electrophiles “love to attack” molecules with
abundant outer shell electrons.
- Metabolism of acetaminophen (APAP or acetyl-para-amino-phenol) occurs via glucuronidation, sulfation and hepatic cytochromes (mainly CYP 2E1).
- Overdose of APAP may result in excessive amounts of the reactive electrophile NAPQI
- Normally, any small amount of this reactive metabolite once formed is detoxified by endogenous (i.e., made in the body) glutathione.
• Its sulfhydryl group will bind many toxic
compounds including NAPQI.
What does G6PD do? Why is it necessary? What happens if its deficient?
• G-6-PD catalyzes the conversion of glucose-6-phosphate to phosphonolactone and thereby reducing NADP+ to NADPH.
• NADPH is required for glutathione production,
which is a natural antioxidant.
• If the patient with G-6-PD deficiency is exposed to
strong oxidant drugs (eg. sulfacetamide, dapsone) or chemicals (naphthalene, methylene blue) the sulfhydryl groups on RBC membranes are more susceptible to attack by reactive oxygen species.
• Hgb is damaged and precipitates as Heinz bodies – RBC membranes are deformed and cells hemolyze
What are two examples of toxicants that are metabolized to toxic products? What are the products? How is this treated?
- Methanol or ethylene glycol are metabolized to toxic products such as formic acid or glycolic acid by hepatic alcohol dehydrogenase (ADH).
- The key to toxicologic management is prevention of formation of these toxic metabolites.
- Competitive inhibition of ADH by ethanol is usually effective, but is largely replaced by a specific ADH inhibitor, 4-methylpyrazole, also known as, fomepizole (Antizol®).
What are some general principles to the organ system approach? What are the two most common history taking mistakes?
• First “Treat the Patient, not the Poison”
• A,B,C’s: Airway, Breathing, Circulation
• Obtain relevant history of exposure (type,
amount, duration, etc)
• Remember, the two most common mistakes that
can occur while obtaining history from patients
are when you:
- listen to the patient and believe everything
- don’t listen to everything the patient says
What are some side effects of isoniazid? How does it do this? What is the antidote?
Seizures, Metabolic acidosis
- INH also inhibits lactate dehydrogenase that converts lactate to pyruvate and thus lactic acidosis may develop
- INH poisoning will result in seizures.
- Lactic acid may also build up from the excessive muscular activity from seizures.
• Etiology of INH-induced seizures involves a
decrease in the availability of gamma-
aminobutyric acid (GABA).
• Isoniazid metabolites bind to pyridoxine and
inactivate it.
• Isoniazid and hydrazines also inhibit the
enzyme pyridoxine phosphokinase and thereby decreases conversion of pyridoxine (Vit B6) to active pyridoxal-5-phosphate.
• Because pyridoxal phosphate is an essential cofactor for glutamic acid decarboxylase, which converts glutamate to the inhibitory neurotransmitter GABA, any disruption of this metabolic pathway may result in decreased GABA, and consequently, increased chance of seizures.
Pyridoxine (Vit. B6) is the antidote…a benzo alone probably won’t get rid of the seizures
What neurological aspects of the body can be affected by toxins? How?
• Pharmaceuticals and toxins may affect:
– Central Nervous System
– Peripheral Nervous System
• Over 90% of all toxic effects on peripheral nerves are axonopathies (may be a board ?)
• Neuronopathies
• Myelinopathies
– Mixed CNS & PNS
How might CNS toxin effects manifest?
• CNS toxin effects may manifest as:
– Change in LOC or confusion
– Coma
– Seizures
• Many causes (see Goldfrank’s table)
What are some toxic causes of seizures? What is the most common cause?
– Cyclic antidepressant overdoses are certainly common causes for seizures
– Small children can also access camphor from
Camphophenique® and similar products and this can cause seizures
• But the most common cause of seizures from
toxins is actually withdrawal from alcohol.
- Cocaine-induced seizures are also common.
- Amphetamines including MDMA can cause seizures
- But isoniazid (INH) is a big one to remember especially with TB resurgence (also with INH remember pyridoxine or Vitamin B6 is antidote)
- Overdoses of many anticonvulsants may result in seizures.
What are some mechanisms by which toxins can cause seizures?
• Seizures from toxins can be caused by a variety of mechanisms:
– Sodium channel poisoning
– GABA-chloride channel poisoning
– NMDA receptor stimulation
– Metabolic causes • Hyponatremia • Hypoglycemia • Hypocalcemia • Hypomagnesemia • Hypophosphatemia
