Toxicology

Question 1

Mechanism of methotrexate

Answer 1

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

Question 2

Effects of methotrexate overdose

Answer 2

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

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

Question 3

What is leucovorin?

Answer 3

= 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

Question 4

How to treat a methotrexate overdose

Answer 4

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

Question 5

Method of methotrexate elimination

Answer 5

MTX elimination = Renal

Question 6

What is the indication for the enzyme that inactivates methotrexate?

Answer 6

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

Question 7

Method of colchicine elimination

Answer 7

Colchicine elimination = 80% hepatic, 20% renal

Question 8

Colchicine

(a) Volume of distribution
(b) Therapeutic Index

Answer 8

Colchicine

(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

Question 9

Mechanism of colchicine

Answer 9

Colchicine = mitotic/spindle poison

-inhibits microtubule polymerization by binding to tubulin which is necessary for the mitotic spindle

Question 10

What is colchicine first line therapy for?

Answer 10

Gout

Question 11

Signs of colchicine overdose

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

Answer 13

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

Question 14

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

Answer 14

Aspirin levels in the brain is what causes death

Question 15

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

Answer 15

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

Question 16

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

Answer 16

(1) small molecule, MW

Question 17

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

Answer 17

Acetaminophen toxicity

Question 18

Describe acetaminophen breakdown, enzymes required?

Answer 18

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

Question 19

Mechanism of acetaminophen toxicity

Answer 19

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

Question 20

Histological findings of acetaminophen toxicity

Answer 20

Massive central necrosis

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

Question 21

Describe the impact of alcohol on acetaminophen toxicity

(a) Acute EtOH
(b) Chronic EtOH

Answer 21

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

Question 22

What is the antidote for a tylenol overdose?

(a) Mechanism

Answer 22

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

Question 23

What is the key to successful NAC treatment?

Answer 23

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

Question 24

What is the treatment for a colchicine overdose?

Answer 24

• largely supportive therapy

- experimental antibodies

Question 25

What enzyme bioactivates acetaminophen?

Answer 25

Cytochrome p450 2E1