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MLSCI 466 > Pharmacokinetics and Pharmacodynamics > Flashcards

Pharmacokinetics and Pharmacodynamics Flashcards

1
Q

What is pharmacokinetics

A

uses math to describe the fate of a drug with dosing schedule and route of administration

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2
Q

what is pharmacodynamics

A

the interaction of a drug on the body receptors

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3
Q

What is LADME

A

Liberation
Absorption
Distribution
Metaboilsm
Elimination

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4
Q

What is the concept of LADME

A

determine how rapid, in what concentration and how long the drug takes to reach the target organ

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5
Q

T/F - availability is a function of liberation and absorption

A

T

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6
Q

What factors affect absorption of drugs in the GI

A

food
pH
surface area
enzyme and microflora

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7
Q

what factors influences absorption

A

GI factors
physiochemical drug properties
transporters
route of administration

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8
Q

how do large charged molecules cross the lipid bilayer

A

active transport

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9
Q

How does the Henderson Hassel Balch predict the absorption capacity of a drug

A

calculate the pH to determine if pH of environemnt < pKa of drug. charged molecules = less absorbed

If pH< weak acid pKa = not ionized
If pH < weak base pKa = ionized

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10
Q

Is aspirin (pKa = 3.5) absorbed in the stomach or intestines more?

A

stomach - acidic nature turns aspirin neutral as pH < pKa = easier to absorb

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11
Q

What is the best indicator of total exposure to a dose of drug

A

Area Under the curve

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12
Q

What is bioavailability

A

amount of drug that reaches the circulation

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13
Q

How to calculate bioavailability?

A

ratio of AUC (alternative) / AUC (intravenous)

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14
Q

what is first pass metabolism

A

liver and intestine reduce administered drug bioavailability

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15
Q

What does a F =1 mean

A

complete absorption (intravenous)

F <1 = extra vascular

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16
Q

What is F and S in the effective dose calculation

A

S = chemical form = active form of drug salts
F = bioavailability factor = dose that reaches circulation

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17
Q

T/F - bioavailability estimates extent and rate of absorption

A

F - bioavailibity only estimates extent and NOT rate of absorption

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18
Q

what does a large volume of distribution mean (Vd)

A

concentration in tissues > concentration in plasma

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19
Q

what is the relationship of Vd and water solubility and plasma concentration

A

increase water solubility = increase plasma conc = DECREASE Vd

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20
Q

What is the relationship of plasma protein binding (PPB) and plasma concentration and Vd

A

low PPB = low plasma conc = INCREASE Vd

eg. liver cirrhosis = less albumin is made = high Vd for an albumin bound drug in the tissue than plasma

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21
Q

why is Vd important?

A
  1. determines if dialysis of a drug is benefitial
  2. estimates body burden of drug (amount)
  3. Calculates loading dose
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22
Q

how to calculate amount of drug

A

amount = Vd x weight x Cp (concentration of plasma)

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23
Q

what are the units of Vd

A

ug/L

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24
Q

ug to mg conversion

A

ug / 1000 = mg

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25
Q

what factors effect Vd (2)

A
  1. drug solubility
  2. plasma protein binding
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26
Q

clearance definition

A

volume of plasma (NOT VOLUME OF DRUG) cleared of drug per unit time through metabolism and excretion

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27
Q

what are the components in the clearance equation Cl= Vd x Kel

A

Vd = volume of distribtion
Kel = elimination constant

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28
Q

how to figure out Kel from graph

A

log of AUC elimination phase slope gives - Kel

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29
Q

how does half life relate to time to steady state

A

steady state is assumed to be reached in 5 half lives

time to acheive steady state influenced by half life

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30
Q

what is steady state concentration determined by

A

dose and frequency of dose

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31
Q

what must the time units be in steady state

A

mg/ minute

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32
Q

what is first order elimination

A

rate of drug clearance is proportional to drug concentration. the drug PERCENTAGE is removed at constant rate

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33
Q

what is zero order elimination

A

drug clearance is CONSTANT regardless of drug concentration

34
Q

when is zero order elimination seen

A

when drugs saturate elimination mechanism (enzymes/transporters)

eg. alcohol and aspirin

35
Q

what is used to sop up drugs that undergo enterohepatic circulation

A

activated charcoal

36
Q

what is enterohepatic recirculation

A

when the drug gets reabsorbed in the small intestine to the liver over and over again

37
Q

what are the two phases of hepatic elimination of drugs

A

phase 1 chemical reaction
phase 2 conjugate reaction

38
Q

process of renal elimination of drugs

A
  1. glomerular filtration - passive
  2. proximal tubular secretion - active
  3. distil tubular reabsorption - passive
39
Q

what factors affect renal excretion

A

PPB
urine pH
kidney function

40
Q

If a patient overdosed on amphetamines (basic), would you acidify or alkalinize the urine to clear the drug?

A

acidify - it ionizes the drug to promote elimination

(if it was alkalinized, the nonionized drug will get reabsorbed)

41
Q

what factors affects pharmacokineteic properties

A
  1. AGE
  2. gender
  3. pregnancy
  4. disease
42
Q

what are xenobiotics

A

organic compounds foreign to the body

eg drugs, pesticides, pollutant, toxins

43
Q

what is the goal of xenobiotic metabolism

A

harmful molecules can be lipophilic = reabsorbed in the body. We want to excrete these molecules

44
Q

How can xenobiotics be metabolized

A

biotransformation = enzymatic transformation by functionalization (phase 1) and conjugation (phase 2) into water soluble

45
Q

functionalization (phase 1) process

A
  1. introduction
  2. exposure or modification (eg oxidation reduction)
  3. (optional) conjugation in phase 2
46
Q

T/F - increase polarity / hydrophilicity dissolves xenobiotics in urine for elimination

A

T

47
Q

Process of acetaminophen metabolism

A

CYP2R1 converts APAP into NAPQI

NAPQI destroys liver cells unless bound to glutathione

glutathione removed = damage to liver

48
Q

Where can biotransformation occur

A

Major = liver

but all tissues can metabolize

49
Q

what enzymes are used for biotransformation

A

cytosolic enzyme or membrane anchored enzymes in ER

50
Q

what are CYP enzymes structural components and function

A
  1. hemoprotein - oxygen binding due to protoporphyrin IX containing heme
  2. flavoprotein - cofactor NADPH
  3. heat stable lipid component - holds everything together
51
Q

where did the name CYPP450 come from

A

P = red liver pigment

450 = max light absorption

52
Q

what is CYP450 used for

A

detoxify, generate energy, create hormones, abosorption/digestion

53
Q

How can host factors modify metabolism

A

can inhibit or induce CYP metabolism based on diet and disease

54
Q

How do brassica (brocoli) affect CYP1A2

A

increase activity

55
Q

how do apiaceous (celery /carrots) affect CYP1A2

A

decrease activiity

56
Q

how does grapefruit juice affect CYP3A4

A

stops actvitiy

57
Q

how does aging affect CYP

A

slight decrease activity

58
Q

Define pharmacogentics

A

study of genetically determined variation in drug metabolism

59
Q

What are extensive metabolizers (EM)

A

person who metabolizes a drug at similar rate as to the population

60
Q

what are poor metabolizers (PM) and what is the consequence?

A

person who responses drug at a slower rate than population

lack response = inability to convert drug into active form = toxic side effects of prodrug accumulation

61
Q

what are ultra rapid metabolizers (URM) and what are the consequences

A

person who metabolizes drugs rapidly due to multiple copies of CYP2D6 gene

fail to respond to normal doses of drug = need very high doses for effects

62
Q

How does the CYP2D6 impact codeine metabolism

A

Fluoxetine is a codeine drug that uses CYP2D6 to turn into morphine

63
Q

URM mother breastfeeding complications without CYP2D6 mutation

A

Taking codeine at higher dose for effect. CYP2D6 converts all into morphine (hydrophobic/nonpolar) and leaks into breastmilk. Baby drinks all the morphine

64
Q

Does CYP2C9 metabolize S or R warfarin

A

CYP2C9 metabolizes S-warfarin (5x stronger than R-warfarin)

65
Q

What are the allelic variants of warfarin metabolism and what do they mean

A

CYP2C91 = wildtype
CYP2C92 and CYP2C9*3 = slow metabolism

66
Q

how does warfarin get metabolized

A

S warfarin utilizes CYP2C9 to metabolize

or

inihibtion on K for activation of clotting factors for efficient warfarin clotting

67
Q

how to resolve excess warfarin?

A

give more vit K

68
Q

T/F Clopidogrel is a prodrug

A

T - Clopidogrel is a prodrug as it has to be metabolised into its active form

69
Q

What gene impacts codeine metabolism

A

CYP2D6

70
Q

what gene impacts warfarin metabolism

A

CYP2C9

71
Q

what gene impacts clopidogrel metabolism

A

CYP2C19

72
Q

How does the CYP2C19 gene impact clopidogrel metabolism

A

No gene = wt
detection of gene = altered enzymatic activity and slow clopidogrel metabolism

73
Q

how does enzyme induction work

A

increase CYP enzyme expression by increasing synthesis and decreasing degradation

74
Q

what process is seen in ethanol abuse in acetaminophen metabolism

A

enzyme induction

75
Q

What happens when ethanol abuse occurs with acvetaminophen

A
  • ethanol induces CYP2E1 enzyme which increases acetaminophen metabolism of NAPQI (toxic)
  • ethanol depletes glutathione stores
76
Q

3 Types of inhibition from drugs or xenobiotics

A
  1. substrate (reversible)
  2. non substrate (reversible)
  3. metabolite inhibition (irreversible / suicide)
77
Q

What happens when terfenadine is administered with an inhibitor

A

cardiac arrest

78
Q

3 types of immunosuppressants

A

cyclosporin
tacrolimus
sirolimus

79
Q

how does cyclosporin work

A
  • based from fungi amino acids (tolypocladium inflatum)
  • used as first line immunosuppressant
  • inhibiting calcineurin to block NFAT-mediated transcription of IL-2
80
Q

how does sirolimus work (rapamycin)

A
  • binds FKBP12 to inhibit mTOR = block signaling of IL-2
  • used with cyclosporin
81
Q

how does Tacrolimus work (FK506)

A
  • isolated from bacterium (streptomyces tsukubaensis)
  • 100x more potent than cyclosporin
  • inhibits calcinerurin
  • current first line immunosuppressant drug in US
82
Q

Which families of CYPP450 are the most important for metabolism

A

11, 17, 21

MLSCI 466 (8 decks)

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