LMP301 Lecture 17: Toxicology Flashcards

1
Q

define: mithridatism

A

taking poisons in small doses to develop tolerance

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2
Q

define: xenobiotics

A

pharmacologically active substance that is not produced in the body(e.g. drugs)

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3
Q

TDM

A

therapeutic drug monitoring

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4
Q

The difference between toxin and anecdote is…

A

dose

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5
Q

define: pharmacodynamics

A

how the drug affects your body

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6
Q

define: pharmacokinetics

A

what the body does to the drug

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7
Q

difference between pharmacodynamics and pharmacokinetics

A

what the drug does to the body vs. what the body does to the drug

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8
Q

absorption, distribution, metabolism of the drug is pharmacodynamics / pharmacokinetics?

A

pharmacokinetics

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9
Q

drug-receptor interaction is pharmacodynamics / pharmacokinetics?

A

pharmacodynamics

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10
Q

difference between toxicology & TDM

A

toxicology: harmful substance
TDM: medicine

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11
Q

define: biotransformation

A

converting fat soluble chemicals to hydrophilic chemicals to be excreted in the urine/bile

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12
Q

biotransformation alters the biological properties of xenobiotics so…

A

it become less toxic (detoxification)

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13
Q

what makes xenobiotics less toxic?

A

biotransformation

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14
Q

what happens in rare cases when biotransformation on xenobiotics don’t react as expected?

A

makes a more toxic metabolite (e.g. metabolism of alcohol)

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15
Q

enzymes that carry out biotransformation can be put into 4 categories… (main reactions that happen)

A
  1. hydrolysis
  2. reduction
  3. oxidation
  4. conjugation
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16
Q

examples of conjugation reactions

A
  • glucuronidation (add glucuronic acid / B-glucuronide)
  • sulfonation (add sulfate)
  • add glycine
  • add glutathione
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17
Q

define: glucuronidation

A

addition of glucuronic acid to a substrate

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18
Q

enzymes involved in biotransformation are usually ____, so activity differs among individuals

A

polymorphic

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19
Q

what limits exposure of orally ingested xenobiotics?

A

small intestines & liver

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20
Q

Phase I of toxin metabolism

A
  • activation/inactivation of compounds

- change pharmacological activity (make drug less toxic)

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21
Q

where does most of the phase I activities take place?

A

liver mitochondria

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22
Q

which enzyme is involved in phase I?

A

cytochrome P-450 system

  • oxidation
  • reduction
  • hydrolysis
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23
Q

how are drugs processed by the P450 class of enzymes? (slide 8)

A
  1. attached to P450-Fe3+
  2. Fe3+ gets reduced to Fe2+ (attached to P450-Fe2+)
  3. O2 is added = peroxide dianion
  4. 2H+ is added, which removes oxidized drug + water from P450-Fe3+
  5. P450-Fe3+ goes on to attach to more drugs
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24
Q

what reduces Fe3+ to Fe2+ in the P450 enzyme system?

A

reduced P450 reductase

reduced [P450 reductase] + [Fe3+] -> [P450 reductase] + [Fe2+]

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25
Q

what changes oxidized flavoprotein -> reduced flavoprotein?

A

NADPH

[NADPH] + [P450 reductase] -> [NADP+] + reduced [P450 reductase]

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26
Q

What element does the drug bind to on P450?

A

N

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27
Q

binding of the drug to P450 changes…

A

conformation of the enzyme, and exposes drug to other reactions

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28
Q

the active form of the drug is oxidated / reduced?

A

oxidated

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29
Q

Which is the oxidated state: Fe3+ or Fe2+?

A

Fe3+

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30
Q

steps of drug metabolism

A
  1. activation / inactivation
  2. conjugation products
  3. elimination
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31
Q

what is phase 2 of the drug metabolism pathway?

A

conjugation reactions

32
Q

where does phase 2 normally happen?

A

liver & kidneys

33
Q

purpose of conjugation

A

enhance excretion of drugs; facilitate excretion

34
Q

function of B-Glucuronidase

A

a-glucuronic acid -> B-glucouronide

35
Q

what catalyzes the reaction a-glucuronic acid -> B-glucouronide

A

B-Glucuronidase

36
Q

what transfers B-glucuronide to drugs?

A

UDP glucuronosyl transferase

37
Q

what is attached to drugs to make it more soluble?

A

B-glucuronide

38
Q

besides drugs like morphine, what else is glucuronidated?

A

bilirubin

39
Q

most important route of drug elimination is…

why?

A

kidneys

  • glomerular filtration
  • active tubular secretion
40
Q

less common drug excretion pathways

A
  • drug into bile (happens in intestine)
  • breath
  • breast milk
  • saliva
41
Q

why do we build up good drug tolerance if we continuously take small doses?

A

prime the elimination pathways to be very good at getting rid of toxin (esp. the less common elimination paths)

42
Q

normal metabolism of alcohol

A

ethanol -[ADH]-> acetaldehyde -[AcDH]-> acetate

acetate goes to TCA

43
Q

where does alcohol metabolism take place?

A
  1. cytosol (ethanol -> acetaldehyde)

2. mitochondria (acetaldehyde -> acetate)

44
Q

ADH

A

alcohol dehydrogenase

45
Q

AcDH

A

acetaldehyde dehydrogenase

46
Q

what is different when there is abnormal alcohol metabolism

A
  • not enough NAD+ to work with AcDH, so there is build up of acetaldehyde
  • not enough NAD+ to work with TCA, so build up of acetyl-CoA
  • pyruvate gets converted to lactate instead because it can’t enter TCA (metabolic acidosis)
  • no TCA = fatty acid metabolism favoured = fatty deposits in the liver
47
Q

what is the toxic metabolite of alcohol metabolism?

A

acetaldehyde

48
Q

what allows acetate to be used in the citric acid cycle?

A

Acetate + CoA = acetyl-CoA

49
Q

why will alcoholism lead to fatty liver?

A

build up of acetyl CoA in the liver stops liver cells from getting enough ATP through aerobic respiration.

fatty acid metabolism causes fatty deposits in liver.

50
Q

what is needed to convert pyruvate -> lactate?

A

NADH

51
Q

what contributes to hangover effects?

A
  • metabolic acidosis from lactic acid

- acetaldehyde build up

52
Q

effect of acetaldehyde build up

A
  1. damage / immunological response

2. necro-inflammation / apoptosis of hepatocytes

53
Q

what liver enzyme can be seen abnormally when there is acetaldehyde build up?

A

ALT

54
Q

effect of chronic alcohol ingestion on intestines (and effects that may have)

A
  1. increase permeability of intestines
  2. endotoxin release
  3. Kupffer cells take up endotoxins
  4. release cytokines
  5. cytokines activate stellate cells & cause hepatocyte apoptosis
  6. stellate cells secrete matrix proteins, which makes liver harder
55
Q

define: endotoxins

A

toxin that is present inside a bacterial cell and is released when the cell dies

56
Q

Another name of Ecstasy

A

MDMA

57
Q

define: diaphoretic

A

sweating a lot

58
Q

which race has the most toxic MDMA metabolite?

A

south(east) Asian girls

59
Q

MDMA is a derivative of…

A

methamphetamine

60
Q

metabolite of MDMA

A

MDA

61
Q

is the metabolite of MDMA active?

A

yes

62
Q

are MDMA & MDA products that can be found in the body naturally?

A

no, synthetic

63
Q

absorption & metabolism of MDMA

A

absorbed: intestines
metabolized: liver

64
Q

physical effects of MDMA

A
  • more awake
  • higher energy, endurance
  • less fatigue
65
Q

psychological effects of MDMA

A
  • euphoria
  • sharp sensory perception
  • more social
  • feel closer to others
66
Q

MDMA activation

A

MDMA -> MDA -> HHA

MDMA -> HHMA

67
Q

what is produced at the end of MDMA phase I?

A
  • HHA

- HHMA

68
Q

MDMA conjugation

A
  • HHA & HHMA can be conjugated (glucuronide / sulfate) & excreted in urine
  • HHA & HHMA can be further metabolized
  • metabolites conjugated with glutathione & excreted in urine
69
Q

what enzyme conjugates glutathione?

A

GST (Glutathione S-transferase)

70
Q

what is needed to conjugate MDMA metabolites?

A

nothing!

GST helps speed up process, but it is not necessary

71
Q

secretion of MDMA?

A

in urine after conjugation

72
Q

why do MDMA and tylenol not go well together?

A

MDMA metabolism uses glutathione for conjugation, and so does tylenol metabolism. Activated form of tylenol (NAPQI) is very toxic, but can’t be excreted if it can’t conjugate with glutathione.

73
Q

what complex is formed during glutathione conjugation?

A

Mesenheimer complex

74
Q

effect of decreased glutathione stores

A
  • influx of Ca into cell
  • changes in cell membrane
  • hepatocyte necrosis
75
Q

MDMA will initiate a(n) ___ response, which will cause…

A

immune

inflammation

76
Q

the negative effects of MDMA metabolism will cause…

A

VERY HIGH fever