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Chapter 4, Drug Metabolism
Learning Objectives
1.
What are two important non-P450 oxidative enzymes?
 Alcohol dehydrogenase and monoamine oxidase (MAO) are important oxidative enzymes
i. Ex) Methanol =alcohol dehydrogenase=> formaldehyde
2.
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Outline the steps of P450 action (6):
P450-drug complex forms
NADPH donates electrons to flavoprotein reductase component
Oxygen joins the complex
more NADPH donates electrons to activate the P450-drug-O complex
Iron is oxidized with the creation of water
Oxidized drug is formed
3. At which step does hydrolysis fall in the metabolism of drugs?
 Hydrolysis is a step II reaction, more similar to conjugation than step I reactions
i. Leaves an –OH group, making the compound more soluble
4.
What drug can treat kernicterus?
 Use phenobarbital, which up-regulates the expression of UDPGT and so reduces serum
unconjugated bilirubin
i. 450 nm light works too
5.
What transporter moves drugs like digoxin and HIV-1 protease inhibitors into the intestinal
lumen?
 The multidrug resistance protein (MDR1 or P-glycoprotein) kicks drugs back into the lumen
6.
What do organic anion transporting polypeptide (OATP) and the organic cation transporter
(OCT) families do to HMG-CoA reductase inhibitors?
 OATP and OCT transport statins into hepatocytes
i. OATP and OCT are responsible for the “first pass effect” of the liver
7.
What does the organic anion tranporter (OAT) family move? Where?
 The OAT family secretes B-lactam antibiotics and NSAIDS from the kidneys
[oat => out!]
8.
What drug in the text increases its own metabolism by inducing P450 3A4 (tolerance)? What
else induces P450 3A4 (2 more)?
 Antiepileptics (carbamazepine) -- less effective (lower conc.) over time
 Rifamycins (rifampin)
 St John’s Wort
9. CYP3A4 inhibitors:
 Ketoconazole
 grapefruit juice
 Anti-HIV drugs (Saquinavir & Ritonavir) can be used to therapeutically inhibit CYP3A4

Macrolide antibiotics (Erythromycin)
10. Name three drugs that are metabolized into their active forms:
 Tamoxifen, losartan, and especially mitomycin C need to be metaboized to become active
i. mitomycin C is actually used to kill cancer cells which contain lots of P450
11. What are three drugs that are variably metabolized? What are the detrimental results?
 Succinylcholine – respiratory paralysis in slow metabolizers
 Isoniazid – elevated levels and additional drug reactions in slow acetylators (blacks and
northern europeans) – reduced efficacy in fast acetylators (asians and inuits)
 Clopidogrel (antiplatelet) – re-stenosis/thrombosis in fast metabolizers (2C19 polymorphism)
[variable metabolism will make you SIC]
12. Who has the highest frequency of reduced P450 2D6 activity? What drug uses this isozyme?
 Blacks (?%) and whites (8%) frequently have a broken P450 2D6, while asians have only a 1%
prevalance rate
 codeine => morphine slowed
13. What drug combination causes a ridiculous decrease in mortality in blacks?
 The vasodilator combo Isosorbide dinitrate and hydralazine (BiDil) works wonders for blacks
in heart failure
14. Why don’t we treat infants with chloramphenicol for H. influenzae anymore? [ch. 33 crossover]
 Chloramphenicol produces a metabolite that is toxic if not conjugated right away
i. Gray baby syndrome is the result
15. Which antibiotic makes birth control stop working?
 Rifampin causes estrogen-based contraception to be ineffective
16. What non-pharmacologic factor modifies the effectiveness of many drugs, such as lidocaine
and morphine?
 Blood flow compromise, such as in heart failure, can alter the rate of metabolism of many
drugs