Draw the chemical structure for Acetaminophen
What cytochrome P450 member enzyme is responsible for converting approximately 5% of acetominophen molecules into N-Acetyl-benzoquinonemine (NAPQI), a Hepatotoxin?
What role does Glutathione play in the inactivation of acetaminophen?
Glutathione deactivates NAPQI, rendering it harmless to the liver.
What process is responsible for the deactivation of 95% of acetaminophen?
Glucuronidation, generally deactivates drugs in a phase II rxn
Give a brief description of how the inactivation of acetaminophen changes during an overdose of the drug.
During an overdose, only ~70% of acetaminophen will go directly through the glucuronidation deactivation process, leaving ~30% of the drug to be converted into the hepatotoxin NAPQI by CYP2E1. Glutathione can’t keep up with the increased demand, resulting in massive liver damage.
Draw the chemical structure for aspirin
The half-life of aspirin (Acetylsalicylic acid) is only 1 hr, however, aspirin is recommended to be taken every 4 hrs. How do you explain the discrepancy?
Acetylsalicylic acid is converted into salicylic acid in the primary rxn. Salicylic acid is just as active as acetylsalicylic acid and has a half life of 3 hrs. Sou you add the half lives, you get 4 hrs.
Why is the metabolic scheme for the anti-anxiety drug Diazepam (valium) so dangerous?
Diazepam has a very long half life at 24 hours, this can be a good thing, however, its subsequent stages also are active and also have realtively long half lives meaning that overall the drug is active for ~42 hrs. Thus, if the patient is not careful the drug may build up in their system.
What is the consequences of benzodiazepine accumulation? What is the best way to prevent this?
Oversedation, confusion, and memory impairment. To prevent this, prescribe short-acting benzodiazepine without active metabolites.
Why might Diazepam (valium) be even more dangerous for older individuals?
B/c as we age some drugs are metabolized more slowly. Diazepam is one of these drugs and the approximate half life for Valium increases from ~24 hrs to ~85 hrs for an 80 yr old.
What does it mean if a drug is a prodrug?
Prodrugs are initially inactive but are converted to an active form during metabolism.
What cytochrome P450 enzyme is responsible for the conversion of the prodrug codeine (found in tylenol #3) into morphine?
The prodrug Terfenadine (Seldane) is an antihistamine drug that must be converted to its active form, Fexofenadine (Allegra), by CYP3A4. What are 3 common CYP3A4 enzyme inhibitors that can cause a build-up of the inactive Terfenadine?
Grape Fruit Juice
What is the consequence of a build up of the antihistamine prodrug Terfenadine (Seldane)?
If CYP3A4 is inhibited and terfenadane concentration increases, serious cardiac arrhythmias may result, such as Torsade’s de pointes.
What was the effect on Simvastatin concentration following 3 glasses of water vs 3 glasses of grapefruit juice per day? What may result?
Simvastatin (Zocor), which is metabolized by CYP3A4, was found to be at 5X concentration levels after drinking grapefruit juice instead of water. This increase in simvastatin may result in muscle aches and Rhabdomyolosis, a process by which skeletal muscle breaks down, overwhelming your kidneys and resulting in renal failure.
What was the effect on midazolam, a drug used as a premedication for sedation, which is metabolized by CYP3A4, concentration when taken with a placebo vs erythromycin?
The concentration of midazolam was 3X what it should have been when taken jointly with erythromycin vs the placebo. This overaccumulation of midazolam can result in prolonged and over-sedation, which could be fatal, especially in children, if protective reflexes are lost and airways close.
Quinidine, paroxetine, fluoxetine, and sertraline are all inhibitors of what cytochrome P450 enzyme?
CYP2D6. Note that all of these drugs end in
“-ine” and are generally antiarrythmics or antidepressants.
What is Rifampin’s effect on the enzyme CYP2C9 and its substrates?
Rifampin activates CYP2C9 causing a shortage of the drug substrate w/in the body
What is St. John’s wort’s affect on oral contraceptive?
St. John’s wort is an activator of the CYP3A4 enzyme. When CYP3A4 is overly activated it causes a premature degradation of estrogen & progestins resulting in the oral contraceptive only being affective for 12 hrs/day instead of the usual 24 hrs.
With age, what 2 factors will result in decreased biotransformation rates?
- As we age pre-hepatic and hepatic enzymes for certain drugs decrease, which may lead to drug accumulation. We saw this with diazepam (Valium).
- With Liver damage (cirrhosis) will decrease metabolism of many drugs