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LMP301 > LMP301 Lecture 17: Toxicology > Flashcards

LMP301 Lecture 17: Toxicology Flashcards

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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
what changes oxidized flavoprotein -> reduced flavoprotein?
NADPH [NADPH] + [P450 reductase] -> [NADP+] + reduced [P450 reductase]
26
What element does the drug bind to on P450?
N
27
binding of the drug to P450 changes...
conformation of the enzyme, and exposes drug to other reactions
28
the active form of the drug is oxidated / reduced?
oxidated
29
Which is the oxidated state: Fe3+ or Fe2+?
Fe3+
30
steps of drug metabolism
1. activation / inactivation 2. conjugation products 3. elimination
31
what is phase 2 of the drug metabolism pathway?
conjugation reactions
32
where does phase 2 normally happen?
liver & kidneys
33
purpose of conjugation
enhance excretion of drugs; facilitate excretion
34
function of B-Glucuronidase
a-glucuronic acid -> B-glucouronide
35
what catalyzes the reaction a-glucuronic acid -> B-glucouronide
B-Glucuronidase
36
what transfers B-glucuronide to drugs?
UDP glucuronosyl transferase
37
what is attached to drugs to make it more soluble?
B-glucuronide
38
besides drugs like morphine, what else is glucuronidated?
bilirubin
39
most important route of drug elimination is... | why?
kidneys - glomerular filtration - active tubular secretion
40
less common drug excretion pathways
- drug into bile (happens in intestine) - breath - breast milk - saliva
41
why do we build up good drug tolerance if we continuously take small doses?
prime the elimination pathways to be very good at getting rid of toxin (esp. the less common elimination paths)
42
normal metabolism of alcohol
ethanol -[ADH]-> acetaldehyde -[AcDH]-> acetate acetate goes to TCA
43
where does alcohol metabolism take place?
1. cytosol (ethanol -> acetaldehyde) | 2. mitochondria (acetaldehyde -> acetate)
44
ADH
alcohol dehydrogenase
45
AcDH
acetaldehyde dehydrogenase
46
what is different when there is abnormal alcohol metabolism
- 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
what is the toxic metabolite of alcohol metabolism?
acetaldehyde
48
what allows acetate to be used in the citric acid cycle?
Acetate + CoA = acetyl-CoA
49
why will alcoholism lead to fatty liver?
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
what is needed to convert pyruvate -> lactate?
NADH
51
what contributes to hangover effects?
- metabolic acidosis from lactic acid | - acetaldehyde build up
52
effect of acetaldehyde build up
1. damage / immunological response | 2. necro-inflammation / apoptosis of hepatocytes
53
what liver enzyme can be seen abnormally when there is acetaldehyde build up?
ALT
54
effect of chronic alcohol ingestion on intestines (and effects that may have)
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
define: endotoxins
toxin that is present inside a bacterial cell and is released when the cell dies
56
Another name of Ecstasy
MDMA
57
define: diaphoretic
sweating a lot
58
which race has the most toxic MDMA metabolite?
south(east) Asian girls
59
MDMA is a derivative of...
methamphetamine
60
metabolite of MDMA
MDA
61
is the metabolite of MDMA active?
yes
62
are MDMA & MDA products that can be found in the body naturally?
no, synthetic
63
absorption & metabolism of MDMA
absorbed: intestines metabolized: liver
64
physical effects of MDMA
- more awake - higher energy, endurance - less fatigue
65
psychological effects of MDMA
- euphoria - sharp sensory perception - more social - feel closer to others
66
MDMA activation
MDMA -> MDA -> HHA | MDMA -> HHMA
67
what is produced at the end of MDMA phase I?
- HHA | - HHMA
68
MDMA conjugation
- HHA & HHMA can be conjugated (glucuronide / sulfate) & excreted in urine - HHA & HHMA can be further metabolized - metabolites conjugated with glutathione & excreted in urine
69
what enzyme conjugates glutathione?
GST (Glutathione S-transferase)
70
what is needed to conjugate MDMA metabolites?
nothing! | GST helps speed up process, but it is not necessary
71
secretion of MDMA?
in urine after conjugation
72
why do MDMA and tylenol not go well together?
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
what complex is formed during glutathione conjugation?
Mesenheimer complex
74
effect of decreased glutathione stores
- influx of Ca into cell - changes in cell membrane - hepatocyte necrosis
75
MDMA will initiate a(n) ___ response, which will cause...
immune | inflammation
76
the negative effects of MDMA metabolism will cause...
VERY HIGH fever

LMP301 (18 decks)

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