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Flashcards in Toxicology Deck (25)
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Mechanism of methotrexate

MTX = chemotherapy agent used to inhibit dividing cells by inhibiting dihydrofolate reductase used in folate synthesis (folate needed to make purines for RNA/DNA synthesis)

-basically MTX blocks folate production needed to DNA synthesis


Effects of methotrexate overdose

Areas of rapidly dividing cells are affected first => GI and buccal mucosa

-=> trouble eating (mouth sores), swollen and painful fingers


What is leucovorin?

= Folinic acid- used to reverse methotrexate overdose

-form of folic acid that allows some purine/pyrimiding synthesis to occur in the presence of a dihydrofolate reductase inhibitor
-replaces TH4 derivative created after that enzyme needed


How to treat a methotrexate overdose

IV fluids, bicarbonate to alkalinize urine, folinic acid (leucovorin)


Method of methotrexate elimination

MTX elimination = Renal


What is the indication for the enzyme that inactivates methotrexate?

Being a gillionaire...each dose of Voraxaze (inactivates MTX) is $27,000


Method of colchicine elimination

Colchicine elimination = 80% hepatic, 20% renal



(a) Volume of distribution
(b) Therapeutic Index


(a) High volume of distribution => a lot gets pushed into the tissues and binds to intracellular components
(b) Narrow therapeutic index => small difference btwn therapeutic dose and toxic dose


Mechanism of colchicine

Colchicine = mitotic/spindle poison
-inhibits microtubule polymerization by binding to tubulin which is necessary for the mitotic spindle


What is colchicine first line therapy for?



Signs of colchicine overdose

Skin sloughs off (cells can't divide), first GI phase, then multi-organ dysfunction if overdose continues for days


As pH of the serum falls, is more or less aspirin available to enter tissue?

Drugs only enter tissues as uncharged molecule => HA can cross biological membranes, but A- cannot.

When pH HA > A- => when pH decreases there is more HA available (which can cross membranes) => as pH lowers more is distributed into the tissues


Would more or less aspirin get into the brain if the serum is alkaloid, why?

Alkaloid serum: pH > pKa => unprotonated form predominates => A- > HA and A- is not able to cross biological membranes

=> less aspirin will get into the tissues if the serum is alkaloid b/c more aspirin is in the A- form which is unable to cross biological membranes


Aspirin levels in which organ are the cause of death in aspirin overdose?

Aspirin levels in the brain is what causes death


Would you want to acidify or alkalinize urine to treat an aspirin overdose? Explain

Aspirin = acid => want to alkalinize urine to treat overdose

-HA is in equilibrium btwn all 3 compartments (urine, plasma, and tissues) => drawing H+ A- out of urine by giving pt bicarbonate will drag HA first out of the plasma, then out of the tissues = out of the brain = prevent death


What are three key features of a dialyzable molecule (molecule that is a good candidate for dialysis)?

(1) small molecule, MW


What is the number 1 cause of fulminant hepatic failure in the US?

Acetaminophen toxicity


Describe acetaminophen breakdown, enzymes required?

Acetaminophen broken down my cytochrome p450 2E1 into NAPQI

W/ glutathione present NAPQI is converted into detoxified products

-but if glutathione is not present (saturated b/c of acetaminophen overdose), NAPQI builds up and causes cell injury


Mechanism of acetaminophen toxicity

Glutathione depletion/saturation => NAPQI builds up and causes cell injury

-mainly in the liver b/c that is where it comes in first and where cytp450 2E1 is present


Histological findings of acetaminophen toxicity

Massive central necrosis

Localized near central vein b/c that is where drug first comes in and where cytp450 is concentrated


Describe the impact of alcohol on acetaminophen toxicity

(a) Acute EtOH
(b) Chronic EtOH

EtOH and tylenol

(a) Acute alcohol intake is actually protective against acetaminophen overdose b/c acutely alcohol acts as a competitive inhibitor of cytp450 2E1 => less NAPQI produced

(b) Chronic alcohol intake and anticonvulsants are p450 inducers => more NAPQI made => clear worsening of tylenol toxicity


What is the antidote for a tylenol overdose?

(a) Mechanism

NAC = N-acetylcysteine = antidote for acetaminophen overdose

(a) NAC acts as a glutathione precursor and substitute => replaces glutathione activity to convert NAPQI and prevent cell injury


What is the key to successful NAC treatment?

When using NAC to reverse an acetaminophen overdose the key is timing- the sooner delivered the better

-effect of NAC diminishes w/ delay to therapy
-it is never too late, but there are clear diminishing returns


What is the treatment for a colchicine overdose?

-largely supportive therapy
-experimental antibodies


What enzyme bioactivates acetaminophen?

Cytochrome p450 2E1