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Fundamentals > Pharmacology: Drug Metabolism > Flashcards

Pharmacology: Drug Metabolism Flashcards

1
Q

What innate enzymes evolved to metabolize drugs?

A

Drugs are usually lipophilic molecules. They are metabolized by enzymes involved in cholesterol, steroid and bilirubin pathways

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2
Q

Why are drugs less absorbed in the stomach?

A

The drugs are basic and the stomach pH decreases the amount of drug pushed through the membrane.

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3
Q

What is it called when drugs are completely metabolized by the liver?

A

First pass metabolism. This happens when drugs are poorly absorbed by the GI tract. They have low bioavailability because of low absorption from the GI tract.

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4
Q

What is the usual route of metabolism of drugs in the liver?

A

Phase I enzymes metabolize the drug and metabolites are excreted in the urine.

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5
Q

What liver enzymes are typically rate limiting?

A

Phase I enzymes

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6
Q

What enzyme family is a family of mixed function oxidases (mono-oxygenases)?

A

Cytochrome P450 Family (CYP family)

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7
Q

What are the steps of CYP P450 in drug oxidation?

A
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8
Q

What is the role of NADPH cytochrome P450 reductase?

A

It reduces the oxidized drug complex to give a reduced product.

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9
Q

How did P450 get its name?

A

If you react the complex with CO, it absorbs under UV light at 450.

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10
Q

Where do CYP reactions take place?

A

Lipid bilayer of the endoplasmic reticulum

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11
Q

What is the center key element of P450?

A

Fe centered in a heme group

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12
Q

Why can the liver have such high metabolism by P450?

A

It has lots of endoplasmic reticulum

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13
Q

How does CYP P450 change drugs?

A

It changes lipophilic molecules to more hydrophilic molecules that are easier to excrete.

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14
Q

Where are GI P450s found?

A

The small intestine wall

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15
Q

40% of drugs metabolized by phase I are metabolized by these two enzymes.

A

CYP3A4 and CYP3A5

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16
Q

What major drugs are metabolized by CYP1A2?

A

Tylenol, caffeine, theophylline and warfarin

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17
Q

What major drugs are metabolized by CYP2A6?

A

Zidovudine and warfarin if CYP1A2 is not ready to metabolize it.

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18
Q

What major drugs are metabolized by CYP2C9?

A

Phenytoin, S-warfarin (active enantiomer), hexobarbital and ibuprofen

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19
Q

What major drugs are metabolized by CYP2C19

A

Diazepam, omeprazole and propranolol

20
Q

What major drugs are metabolized by CYP2D6?

A

Fluoxetine and codeine. This enzyme converts inactive drugs to active drugs.

21
Q

What major drugs are metabolized by CYP2E1?

A

Tylenol. This enzyme is induced by ethanol.

22
Q

What genetic variation in metabolism enzyme might a person who is resistant to codeine have?

A

CYP2D6

23
Q

What major drugs are metabolized by CYP3A4?

A

Steroids, Ca channel blockers, benzodiazepines, amiodarone, and erythromycin

24
Q

What other phase I enzymes catalyze oxidation?

A

Flavin monoxygenases, alcohol dehydrogenases and amine oxidases

25
Q

What other phase I enzymes catalyze hydrolysis?

A

Esterases and amidases

26
Q

What other phase I enzymes catalyze reduction?

A

Compounds that reduce Nitro and Azo compounds

27
Q

Why are phase II reactions called synthetic reactions?

A

Enzymes add a polar or charged hydrophilic group to the drug.

28
Q

What major reactions are carried out by phase II enzymes?

A

Glucuronidation, sulfation, acetylation, glutathione conjugation, glycine conjugation and methylation

29
Q

What are the major enzymes in phase II reactions?

A

UDP glucuronide transferases

30
Q

Glucuronidation

A
31
Q

Sulfation

A

Donates PAPS

32
Q

Acetylation

A
33
Q

What conjugation reaction plays a role in immune reactions?

A

Acetylation of histamine allows for its release.

34
Q

What is a consequence of decreased NAT2 enzyme?

A

Increase in toxic metabolite accumulation

35
Q

What drugs are activated by synthetic reactions (glucuronidation)?

A

Morphine on the 6’ site. If glucuronide is added on the 3 position it is inactivated. Minoxidil is converted to minoxidil sulfate.

36
Q

What is a major factor of CYP enzyme rate limitation?

A

NADPH. When enzymes are saturated, elimination becomes zero order and you put yourself at risk for toxicity because the liver is not taking drugs out of the blood as quickly.

37
Q

Why do people get drunk quicker after 4-5 beers?

A

They have saturated alcohol dehydrogenase and elimination decreases to zero order and blood alcohol is eliminated more slowly.

38
Q

What happens as a result of enzyme induction by a drug?

A

More enzymes are produced and can turn over more drug. However, this can increase toxicity or reduce drug efficacy because it is metabolized faster.

39
Q

How do drugs increase the rate of production of the enzyme that metabolizes them?

A
40
Q

What receptors do drugs act on to cause enzyme induction?

A

RXR, PXR, CAR and AHR receptors. Binding leads to overproduction of CYP P450 enzymes.

41
Q

Why shouldn’t you drink when taking tylenol?

A

Alcohol induces CYP2E1 and increases enzyme levels. Tylenol is metabolized by this enzyme and a very toxic metabolite is produced.

42
Q

How are CYP P450s commonly inhibited?

A

Inactivation of or competition with heme group or competition for NADPH.

43
Q

Major CYP Inhibitors

A

Macrolide antibiotics (erythromycin but not azithromycin), antifungals (ketoconozole), ritonavir, fluoxetine, nefazodone and cimetidine

44
Q

When should your ears perk up about considering drug interactions?

A

Low therapeutic index, high first pass metabolism, high plasma protein binding (could be released after addition of another drug), single route of elimination and polypharmacy.

45
Q

Drugs with high indexes of suspicion.

A

Anti-seizure, protease inhibitors, statins, warfarin,digoxin

46
Q

How does Tb treatment decrease effectiveness of ritanovir?

A

It induces CYP3A4. CYP3A4 metabolizes ritanovir out of the system. Additionally, ritanovir inhibits CP3A4 and results in rifampin toxicity.

47
Q

What other food can you eat to increase efficacy of statins?

A

Grapefruit juice because it has CYP3A4 inhibitors. Statins are metabolized rapidly in the liver and gut by CYP3A4. Grapefruit juice increases bioavailability.

Fundamentals (18 decks)

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