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Year 4 - Toxicology > Lecture 1 - Toxicology & Biotransformation > Flashcards

Lecture 1 - Toxicology & Biotransformation Flashcards

1
Q

ADME

A

Absorption
Distribution
Metabolism
Excretion

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2
Q

Metabolism and Excretion make up ________

A

Elimination

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3
Q

What are the 2 types of kinetics involved in elimination?

A
  • Linear kinetics

- Capacity-limited kinetics

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4
Q

Bioavailability

A

The amount of drug that enters the circulation and is able to have an active effect

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5
Q

First-pass effect

A
  • the concentration of the drug is greatly reduced before it enters the circulation
  • drug heads to the liver first via the hepatic portal vein before entering circulation
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6
Q

Half-life

A

The time it takes for the drug to be reduced by 50%

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7
Q

AUC

A

area under the curve

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8
Q

Michaelis menten kinetics is an example of _____-____ kinetics

A

capacity-limited

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9
Q

Toxicokinetics vs. Pharmacokinetics:

The pharmacodynamic effect is _____

A

toxic

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10
Q

Toxicokinetics vs. Pharmacokinetics:

Dosing information is ?

A

lacking or inaccurate

**you don’t always know the dose, you just know it’s too much

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11
Q

Toxicokinetics vs. Pharmacokinetics:

PK and PD in these circumstances is usually ___ ____

A

not known

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12
Q

Toxicokinetics vs. Pharmacokinetics:

Drugs may be _______

A

illegal, unlicensed, untested compounds (street drugs)

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13
Q

Toxicokinetics vs. Pharmacokinetics:

Drugs may be used in ___ ___ ___ combinations

A

never studied before

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14
Q

It’s important to know ____ of admin for OD to think about absorption rates

A

ROUTE

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15
Q

What does absorption depend on?

A
  • rate and extent
  • route of admin
  • transport mechanism (MW, solubility, polarity, ionization, lipid solubility)
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16
Q

What are xenobiotic characteristics that affect GI absorption?

A
  • Physicochemical properties, dosage forms, dissolution profiles
  • Presystemic elimination
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17
Q

Xenobiotic

A

means that it’s foreign to the system

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18
Q

What are patient characteristics that affect GI absorption?

A
  • GI motility (gastric emptying time, GI transit time)
  • GI disease (achlorhydria, gastric ulcer, duodenal ulcer, Crohn’s disease)
  • Malnutrition (GI transit time, mucosal atrophy, altered flora)
  • Pregnancy
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19
Q

How does pregnancy affect absorption?

A
  • Increased gastric emptying time (30-50%)
  • Decreased intestinal motility
  • Increased intestinal blood flow (increases absorption)
  • Increased gastric pH and buffer capacity
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20
Q

Does pregnancy increase or decrease absorption?

A

Tendency towards increased absorption, therefore the pregnant woman may be at increased risk for xenobiotic toxicity; however, factors such as increased cardiac output can increase renal perfusion and thus clearance of some xenobiotics

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21
Q

How can we decrease bioavailability?

A
  • Gastric emptying (emesis, gastric lavage, increase in intestinal motility)
  • Administration of activated charcoal (direct intervention on absorption process)
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22
Q

When is gastric emptying useful?

A
  • only useful when we know for sure that the exposure is massive and the drug is still in the stomach
  • airways have to be protected
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23
Q

When is activated charcoal good?

A
  • used 1 hour after exposure
  • very effective, but only studied in healthy volunteers who have not taken that high of doses
  • relatively safe
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24
Q

What does a large Vd indicate?

A

that the xenobiotic resides outside the plasma compartment. in OD it can be used to estimate a max plasma concentration when the dose is known

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25
Q

Albumin primarily binds ____ compounds

A

acidic

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26
Q

Where is albumin

A

in plasma

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27
Q

alpha 1 acid glycoprotein primarily binds _____ compounds

A

basic

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28
Q

Anything that alters _____ will alter the free fraction available and can slow down or prevent absorption

A

binding

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29
Q

Normal range of albumin

A

35-50 g/L

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30
Q

Normal range of alpha-1 acid glycoprotein

A

0.4-1 g/L

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31
Q

What factors affect distribution?

A
  • membrane diffusion principles
  • affinity for plasma and tissue proteins
  • acid-base status of the patient
  • physiological barriers
  • patient characteristics (obesity, age, pregnancy, disease)
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32
Q

How does obesity affect lipophilic drugs?

A
  • increased Vd
  • serum levels will decrease
  • may decrease toxicity
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33
Q

How does obesity affect hydrophilic drugs?

A
  • decreased Vd
  • serum levels will increase
  • may increase toxicity
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34
Q

How does increase in body fat affect Vd?

A

increases Vd for lipophilic drugs (ex. diazepam)

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35
Q

How does decrease in total body water affect Vd?

A

decreases Vd for hydrophilic drugs (ex. aminoglycosides)

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36
Q

How does a decrease in plasma albumin affect binding?

A

decrease in binding = increase in free fraction of drug = increase in toxicity

(ex. phenytoin)

37
Q

Pregnancy:

How does hypoalbuminemia affect binding?

A

decreases binding of acidic drugs (salicylic acid, sulphonamides, phenytoin)

38
Q

Pregnancy:

How does increase in plasma volume affect Vd?

A

increase in Vd for many drugs (ex. increase dose for aminoglycosides)

39
Q

Pregnancy:

How does increased cardiac output affect clearance?

A

increase renal perfusion and output which increases clearance for some drugs

40
Q

Does pregnancy affect hepatic blood flow?

A

nope

41
Q

Hypoalbuminemia decreases binding of _____ drugs

A

acidic

ex. naproxen (hypoalbuminemia increases Vd and t1/2)

42
Q

How does hypoalbuminemia affect phenytoin?

A

phenytoin fraction unbound increases 2-3 fold partly due to decreased binding sites (phenytoin doses must be adjusted)

43
Q

Do phenytoin doses need to be adjusted for hypoalbuminemia?

A

Yes

44
Q

How can we alter distribution of drugs??

A
  • Manipulation of pH (salicylates)
  • Chelators (deferoxamine)
  • Use of antibody fragments (digoxin)
45
Q

What are the clearance organs?

A

liver, kidney, lungs

46
Q

Define clearance

A

unit of volume per unit of time (ex. mL/min)

47
Q

What is the formula for clearance?

A

Cl = Q x ER

Q = blood flow
ER = extraction ratio
48
Q

Formula for extraction ratio

A

ER = (Cin-Cout)/Cin

49
Q

What factors affect elimination?

A

1) Environmental/social (smoking, alcohol, diet)
2) Age (ex. renal fcn decreases w old age)
3) Gender (ex. metabolic capacity differences)
4) Disease
5) Pregnancy
6) Genetics

50
Q

Smoking induces what isoenzymes?

A

cytochrome P450

51
Q

How does smoking affect Theophylline?

A
  • Clearance increases
  • Half life decreases
  • Serum levels fall leading to therapeutic failure
  • *Smoking makes theophylline ineffective
52
Q

Is second-hand smoke enough to induce enzymes?

A

Yes - common in children of smokers

53
Q

How does smoking affect NABQI (formed from acetaminophen) ?

A

May exceed glutathione stores

54
Q

What does Smoking + Malnutrition + Alcohol = ?

A

Increased acetaminophen toxicity

55
Q

What are the acute effects of alcohol?

A

Inhibition of oxidative metabolism immediately after ingestion.

**In acute situations, the risk of toxicity is not that high chronic alcohol consumption is what leads to toxicity.

56
Q

Describe chronic effects of alcohol

A

Enzyme induction - “metabolic tolerance” which means that the clearance of drugs such as warfarin, meprobamate and phenytoin increases

57
Q

Describe cirrhosis and alcohol

A

may decrease clearance, however, because of enzyme induction no changes may be seen until shunting occurs

58
Q

Describe shunting and alcohol

A

hepatic damage leads to obstruction of normal blood flow

59
Q

How does age influence hepatic function?

A
  • influences hepatic function - hepatic blood flow decreases 0.5 - 1.5% per year after age 25
  • the effect on drug metabolism is unclear, however the metabolism of high extraction drugs has been shown to decrease (e.g. propranolol)
  • if a drug decreases then you increase risk for poisoning
60
Q

Renal blood flow and function ____ with age

A

decrease

61
Q

Creatinine clearance decreases with ___

A

age

62
Q

Pregnancy:

Increased _____ levels may exaggerate sex differences

A

estrogen/progesterone

63
Q

Pregnancy:

What does estrogen do?

A

inhibits oxidative metabolism

64
Q

Pregnancy:

Estrogen has _____ effects (a risk for cholecystitis in pregnancy - impaired hepatic elimination of biliary excreted drugs)

A

cholestatic

65
Q

Pregnancy:

Progesterone induces microsomal enzymes, and thus may increase ______ of some drugs

A

clearance

66
Q

Pregnancy:

Renal blood flow is ______

A

increased

*therefore renal clearance is increased

67
Q

Pregnancy:

Caffeine metabolism may be ______

A

decreased

68
Q

Pregnancy:

Diazepam metabolism may be _____

A

decreased

69
Q

Pregnancy:

Metoprolol metabolism may be ______ with an increase in half-life

A

decreased

70
Q

Describe the oxidative reaction of P450

A

SH + NADPH + H+ + O2 = SOH + NADP+ + H2O

71
Q

What enzyme is involved in the following drug substrates:

  • Analgesics (codeine)
  • Antiarrhythmics
  • Antipsychotics
  • B-blockers
  • SSRI’s
  • TCAs
A

CYP 2D6

72
Q

What enzyme is involved in the following drug substrates:

  • Antidiabetic agents
  • Warfarin
  • Phenytoin
  • NSAIDs, Celecoxib
A

CYP 2C9

73
Q

What enzyme is involved in the following drug substrates:

  • Antidepressants
  • Clopidogrel
  • Diazepam
A

CYP 2C19

74
Q

What enzyme is involved in the following drug substrates:

  • Cyclophosphamide
  • Efavirenz
A

CYP 2B6

75
Q

What enzyme is involved in the following drug substrates:

  • Cisplatin
  • Acetaminophen
A

Glutathione S-transferase

76
Q

What enzyme is involved in the following drug substrates:

  • Azathioprine
  • Mercaptopurine
A

Thiopurine S-methyltransferase

77
Q

What enzyme is involved in the following drug substrates:

  • Isoniazid
  • Sulfonamides
A

N-acetyltransferase

78
Q

What enzyme is involved in the following drug substrates:

-Irinotecan

A

Glucuronosyltransferases

79
Q

Give an example of inducing metabolism

A

increasing the metabolic elimination of a poison (ex. rifampin is an inducer of P450)

80
Q

Give an example of inhibiting metabolism

A

decreasing the production of a toxic metabolite (ex. cimetidine is an inhibitor of P450)

81
Q

Why is altering metabolism not a very effective intervention in an acute OD ?

A

because it takes some time to work

82
Q

What is the treatment of acetaminophen OD ?

A

1) Give SH groups (i.e. N-Acetyl-Cysteine)

2) Slow the rate of NABQI formation: P450 inhibitor (ex. cimetidine)

83
Q

Describe the parts of renal excretion

A
  • Glomerular filtration (non-saturable process)
  • Tubular secretion (saturable)
  • Passive tubular reabsorption (non-charged, lipid soluble compounds)
84
Q

What is a normal CrCl?

A

> 90 mL/min

85
Q

How can we alter excretion?

A
  • Manipulation of pH (ion trapping or salicylates)
  • Chelators (deferoxamine)
  • Multiple-dose activated charcoal
  • Extracorporeal devices (ex. dialysis)
86
Q

How does excretion into breast milk occur?

A

occurs by simple diffusion

87
Q

Excretion in breast milk: pH of ____ ion trap for basic compounds

A

6.5

88
Q

What affects excretion in breast milk?

A

differences in affinity to serum proteins vs. milk proteins

89
Q

Drugs with _____ half-life will have greater opportunity to be excreted in milk

A

longer

Year 4 - Toxicology (24 decks)

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