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Pharm 2024 > PPT 4 > Flashcards

PPT 4 Flashcards

1
Q

What is the primary biotransformation organ?

A

Liver - hepatocytes

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2
Q

Describe the first-pass effect of oral medications

A

Hepatic portal system
GI → local veins (intestinal capillaries) → hepatic portal vein (combines with splenic vein)→ Sinusoids (very leaky capillaries) → Hepatic vein → Vena cava → Systemic Circulation

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3
Q

Describe the route an IV medication takes in regards to hepatic blood flow

A

Systemic Circulation → hepatic artery → Sinusoids → Hepatic vein → Vena cava → Systemic Circulation

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4
Q

Hepatic portal vein and hepatic arteries combine to form ________

A

sinusoids

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5
Q

Describe the oxygenation of the blood in the sinusoids

A

Mixture of deoxygenated blood from heaptic portal vein and oxygenated blood from hepatic artery
Lower oxygen environment, lower than systemic circulation

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6
Q

________ are the cells that absorb a drug from leaky sinusoids, where biotransformation takes place

A

Hepatocytes

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7
Q

What are the reactions the liver uses to complete biotransformation?

A

Phase I and phase II reactions - help with clearance or excretion of drug

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8
Q

Differentiate between phase I and phase II reactions

A

Phase I - make drug more polar
- add or unmask a functional group on an enzyme (small)
Phase II - conjugation reactions, often detoxifying
- adding bigger molecules on drug (glucuronidation)

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9
Q

What are the 4 phase I reactions?

A

Oxidation, reduction, dehydrogenation, and hydrolysis

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10
Q

The vast majority of drugs are modified by _______ in phase I reactions

A

oxidation

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11
Q

Describe the steps to cytochrome P450 oxidation

A
  1. Drug binds to CYP
  2. CYP is reduced by flavoprotein (P450 reductase)
    - Flavoprotein is reduced by NADPH
  3. Oxygen attaches to CYP
  4. Oxygen attached to drug, CYP is oxidized
  5. Oxidized drug is released (more hydrophobic with -OH instead of -H)
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12
Q

30% of drugs undergoing phase I reactions are oxidized by ________

A

CYP3A4 - substrate specificity low
- 50% of oxidation reactions

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13
Q

What are the 3 most important cytochrome P450 types?

A

CYP3A4, CYP2D6, and CYP2B6
2B6 < 2D6 < 3A4
B less than D, 2’s less than 3

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14
Q

Cytochrome 450 enzymes are _________

A

oxidases

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15
Q

Cytochrome p450 oxidation occurs in the ________ of the hepatocyte

A

Sarcoplasmic endoplasmic reticulum

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16
Q

How is the WT indicated?

A

*1 - most commonly seen in population
- everything else is mutant

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17
Q

Polymorphic variants

A

mutations from the WT that can have greater, less, or the same amount of activity of the WT (*1)

18
Q

Drugs that increase cytochrome P450 activity

A

induction

19
Q

Drugs that decrease or irreversibly inhibit cytochrome P450 activity

A

inhibition

20
Q

Cytochrome P450 induction causes a decreased drug effect – IF metabolism ________ drug

A

deactivates

21
Q

Cytochrome P450 induction causes an increased drug effect – IF metabolism ________ drug

A

activates

22
Q

Cytochrome P450 inhibition causes an increased drug effect – IF metabolism ________ drug

A

inactivates

23
Q

Cytochrome P450 inhibition causes a decreased drug effect – IF metabolism ________ drug

A

activates

24
Q

If a patient who is on warfarin eats a lot of Brussel sprouts, what effect would they have on the medication? (Brussel sprouts are an inducer of CYP1A2 and warfarin is inactivated by CYP1A2)

A

A lot more inactivation of warfarin - less effect of medication

25
Q

What are the 7 types of conjugation?

A

glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfation, methylation, and water conjugation

26
Q

What is the most important type of conjugation?

A

glucuronidation

27
Q

How do uridine diphosphate glucuronyltransferases (UGTs) glucuronidate a drug?

A

Uridine diphosphate (carrier molecule) adds glucuronic acid to drug

28
Q

Glucuronidation and Glutathione-S-transferase (GST) make a drug more _______ and increase _______

A

Water soluble, urinary excretion

29
Q

How does Glutathione-S-transferase (GST) work?

A

Adds glutathione to a xenobiotic (drug) to make it more water-soluble (detoxification)

30
Q

What is a therapeutic dose?

A

Normal detox pathways functional – no toxic byproducts

31
Q

What is overdose?

A

Overwhelm normal pathways, alternative pathways activated – toxic by-products

32
Q

How does a Tylenol overdose occur?

A
  • occurs when limited amount of glutathione exhausted
  • nucleophilic toxic intermediate binds to cell macromolecules (proteins, cell membrane, carbohydrates) and inactivates them.
  • leads to liver cell death
33
Q

What are the normal pathways for Tylenol metabolism?

A

Normal pathways: Phase 2 - glucuronidation and sulfation, creating nontoxic byproducts.

34
Q

What occurs when Tylenol is given in toxic doses?

A
  • Phase 1 - CYP2E1 and CYP3A4, creates reactive toxic intermediates
  • Phase 2: glutathione conjugation- binds to nucleophilic intermediate to neutralize (backup to toxic pathway)
35
Q

What are the 3 examples of personalized medicine?

A

6-MP - TPMT mutations, warfarin - CYP2C9, herceptin - HER2 overexpression

36
Q

The Goal of Personalized Medicine

A
  • The Right Dose of
  • The Right Drug for
  • The Right Indication for
  • The Right Patient at
  • The Right Time
37
Q

Alternative forms of a gene which occur at the same locus

A

Allele
All of the variant forms of a gene that are found in a population

38
Q

Genetic testing is _______ for herceptin treatment of breast cancer

A

required

39
Q

Genetic testing is _______ for warfarin treatment

A

recommended

40
Q

Describe the variations in drug response based on pharmacogenomics for 6-MP

A
  1. WT - normal metabolism
  2. Heterozygous mutant - metabolize drug slower
  3. Homozygous mutant - extra slow metabolizer (TPMT deficient); can be fatal
41
Q

Describe the pharmacogenomics for Warfarin - CYP2C9

A

Racemic mixture - (S) much more potent than (R)
- (S) metabolized by CYP2C9
- If mutation in CYP2C9, warfarin won’t work very well
- WT, heterozygous mutant, homozygous mutant
- mutants have reduced metabolism and higher warfarin concentrations → more likely to bleed out
- (R) metabolized by CYP2C19

42
Q

How does herceptin work in treating breast cancer?

A

Herceptin aka trastuzumab is a monoclonal antibody that binds to and shuts down the HER2 receptor
- If patient not HER2+, herceptin won’t do anything

Pharm 2024 (13 decks)

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