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pharmacology > Metabolism and Biotransformation Lect 7 > Flashcards

Metabolism and Biotransformation Lect 7 Flashcards

1
Q

most pharmacologically active drugs have what qualities at physiological pH

A
  • lipid soluble
  • non-ionized
  • strongly bound to plasma proteins and other tissues
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2
Q

what is the biotransofrmation of drugs

A

converts lipid-solube, non-ionized compounds to water-soluble, ionized metabolites

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3
Q

where are most drugs metoblized

A

liver

* some occurs in GI tract

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4
Q

what molecular weight classifications determines if a drug is excreted by the kidney or in bile

A
  • MW < 350 is excreted by kidney
  • MW > 350 is excreted in bile
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5
Q

give an example of a drug that must be metabolized to be active

A

codeine (prodrug) -> morphine (active metabolite)

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6
Q

Name a drug in which its metabolites are more active than the parent drug

A

Diazepam (active drug) -> Nordiazepam -> Oxazepam (both active metabolites)

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7
Q

Name a drug that is metabolized to toxic metabolites

A

acetaminophen (active drug) -> N-acetyl-p-benzoquinone imine (toxic metabolite)

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8
Q

What happens during phase I of biotransformation reactions

A

modification of molecule

  • converts lipid-soluble, non-ionized compounds to more ionized, hydrophilic metabolites
    • some metabolites are inactive and readily excreted
    • other metabolites may undergo phase II conjugation
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9
Q

what happens during phase II biotransformation reactions

A

conjugation

  • adds an ionized, charged particle (peptide, protein) to a phase I metabolite to form a more polar and hydrophilic conjugate
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10
Q

in some cases, phase II (conjugation) occurs before phase I (modification). Give an example

A

isoniazid

  • acetylation (II) followed by hydrolysis (I)
  • results in toxic metabolites
  • high degree of genetic polymorphisms
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11
Q

what are the most common phase I reactions

A

oxidation

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12
Q

characteristics of phase I reactions

A
  1. not compound specific
  2. no specific enzymes metabolizing a particular drug
  3. enzymes attack functional groups or bonds of multiple drugs
  4. introduce or “unmask” chemical functional groups (OH, SH, NH2)
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13
Q

example of phase I reaction of a molcule that contains a benzene ring

A
  • benzene ring can be hydroxylated (adding OH group)
  • or an O-CH3 group can be de-methylated
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14
Q

what are cytochrome P450s (CPY450). What are their functions?

A

family of microsomal enzymes in the liver

  • function: oxidation (formation of OH) of mulitple drugs; acts as a handle for phase II conjugation
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15
Q

function of CYP450 subtype CYP3A4

A

metabolizes >50% drugs

* drugs metabolized by 3A4 have high degree of drug interactions

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16
Q

function of CYP450 subtype CYP2D6

A

polymorphism impairs codeine metabolism

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17
Q

function of CYP450 subtype CYP2E1

A

metbolizes, and is induced by alcohol

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18
Q

all phase I microsomal enzymes (CYP450s) are inducible except which one

A

2D6

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19
Q

which is the only phase II enzyme which is microsomal and inducible

A

glucuronyl transferase

20
Q

enzyme induction or inhibition can increase drug toxicity. In light of this, why do you not want to consume alcohol while taking acetaminophen?

A

ethanol induced CYP2E1 increasing acetaminophen metabolism and potential hepatotoxicity caused by metabolites

21
Q

smoking and chargrilled foods induces what CYP enzyme

A

1A2

22
Q

barbituates/phenobarbital, and St. John’s wort induce what CYP enzymes

A
  • 2A6
  • 2B6
  • 2C8
  • 2C9
  • 2C18
  • 3A4
23
Q

ehtanol induces what CYP enzyme

A

2E1

24
Q

grapefruit juice inhibits what CYP enzyme

A

3A4

25
Q

Quinidine inhibits what CYP enzyme

A

2D6

26
Q

function of monoamine oxidase (mitochondrial)

A

inactivates amines

27
Q

warfarin is inactivated by a reduction reaction (adding H+) by what CYP enzyme

A

CYP2A6

28
Q

hydrolytic reactions occur in plasma and in many tisues. Esterases and amidases are metabolized in this fashion by what enzyme

A

psuedocholinesterase

29
Q

Esterases, amidases, alcohol dehydrogenase, and monoamine oxidase these enzymes are involved in CYP450 independent oxidative reactions. What does this mean

A

these enzymes are not inducible

30
Q

where does the majority of phase II reactions (conjugation) occur. What are they mediated by

A
  • liver
  • glucuronidation and UGT (UDP glucuronyl transferase)
31
Q

characteristics of end products of phase II reactions

A
  • decreased lipid solubility
  • polar and inactive
  • have a large molecular weight
  • readily eliminated
32
Q

most common phase II conjugation

A

functional groups (OH, SH, NH2) conjugated with glucuronic acid

  • glucuronic acid is transferred to the substrate, forming a bond via UGT (UDP glucuronyl transferase)

** biliruben and adrenal corticosteroids are conjugated by this system

33
Q

sulfonamides, isoniazid, clonazepam, dapsone, and mescaline undergo what type of conjugation

A

acetylation

34
Q

CYP2D6 has a large degree of polymorphisms: inhertied autosomal recessive trait. what is usually affected

A
  • leads to poor metabolism of codeine to morphine
35
Q

why does alcohol flush reaction occur

A

a condition found in Asian populations in which the face and/or body experiences flushes after consuming alcohol. Caused by the accumulation of acetaldehyde due to a polymorphism that encodes the enzyme, acetaldehyde dehydrogenase which metabolizes acetaldehyde, a toxic product of the alcohol metabolism

36
Q

acetaminophen metablism can form toxic metabolites in chronic drinkers

A
  • acetminophen is a GSH (glutathione)-conjugated metabolite
  • increased production of free radicals may exhaust the supply and free radical molecules can then induce toxicity (oxidative stress)
37
Q

describe “Freeing” of drugs in enterohepatic circulation

A
  • The compounds secreted into the bile following liver metabolism are not always excreted but often go through the enterohepatic cycle and are reabsorbed
  • Some glucuronides that are secreted into the bile are cleaved by glucuronidases in the small intestine, “freeing” the parent drug for reabsorption. (conjugate is removed and drug is freed)
38
Q

what happens to half life of drugs that enter enterohepatic circulation

A

long half life

39
Q

excretion of drugs is enhanced by what

A
  • agents that bind drugs in the intestive (charcoal) increasing peristalsis
  • antibiotics that eliminate GI bacteria
40
Q

how does young age influence metabolism

A
  • organ maturation is incomplete
    • blood brain barrier is not fully developed
    • liver function and renal excretion is not developed
41
Q

how does being elderly influence metabolism

A
  • decreased renal function occurs first
  • decreased hepatic metabolism
  • slower gastric emptying and decreased gastric secretion
42
Q

how does liver cancer modify drug metabolism

A

patients have lower CYP450 enzymes resulting in slow metabolism of many drugs

43
Q

drugs differ in the rate at which they are excreted by the kidney. How do penicillin and diazepam differ.

A
  • PCN: cleared almost completely of a single transit through the kidney
  • Diazepam: is cleared very slowly.
44
Q

which is excreted more quickly: products of phase I and II metabolism or parent compound

A

products of phase I and II metabolism

45
Q

what are the 3 basic processes that accoun for differences in renal excretion

A
  1. glomerular filtration
  2. active tubular secretion or reabsorption
  3. passive diffusion across tubular epithelium

pharmacology (9 decks)

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