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pharm sci > distribution > Flashcards

distribution Flashcards

1
Q

drug factors affecting distribution

A

physiochemical properties

  1. solubility
  2. size of the molecule
  3. ionization
    - when an ionized species of drug accumulates in a particular tissue or organ because it cannot easily leave cells - ion trapping - ions can’t cross cell membranes without a transporter
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2
Q

physiologic factors affecting distribution

A
  1. protein binding of the drug
  2. lean to fat ratio of the patient
  3. blood flow to tissue (perfusion)
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3
Q

most well perfused tissues

A

kidney, heart, liver, brain. high rate of flow and extensive network of capillaries

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4
Q

why protien-bound drugs can’t leave capillaries

A
  1. paracellularly; too large (except liver)

2. transcellularly: too polar

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5
Q

2 main plasma binding protiens

A
  1. albumin: constant, hydrophobic and acidic drugs

2. alpha 1 acid glycoprotein: concentration can change due to stress (increase due to injury); basic drugs

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6
Q

high protein bound drugs

A
  1. won’t be able to cross filtration barrier in the kidneys (less excretion via urine)
  2. less free (unbound) drug in circulation and less to enter tissues
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7
Q

the amount of drug bound to a plasma protein is determined by (3)

A
  1. drug concentration
  2. number of available binding sites
  3. affinity of the drug for the protien
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8
Q

number of available binding sites

A
  1. protein binding reversible and saturable
  2. drugs compete for the same binding sites (results in more free molecules of both drugs)
  3. greatest effect observed with 90% protein bound or greater
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9
Q

hypoalbuminemia

A

low plasma levels, less drug bound to proteins. results in a higher free drug concentration in the plasma and possible toxic effects as more drug would be able to leave the plasma

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10
Q

TBW

A

total body water, 0.6 X kg = L

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11
Q

ECF

A

extracellular fluid, 0.2 x kg = L

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12
Q

ISF

A

interstitial fluid, 0.75 x .2 x kg = L (.15)

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13
Q

Plasma

A

.25 x .2 (0.05) x kg = L

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14
Q

ICF

A

intracellular fluid, .40 x kg = ICF

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15
Q

vd

A

dose/C- zero

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16
Q

C-Zero

A

theoretic drug concentration at the instant the dose is administered. often extrapolated value

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17
Q

Vd > 0.6 L/kg

A

indicates there is tissue binding of the drug. higher the number, greater degree of tissue binding

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18
Q

Vd between 0.2- 0.6

A

drug distributes in ECF and some in ICF. higher the number the more in the ICF

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19
Q

Vd 0.05-0.2

A

drug is freely distributed in ECF (plasma and interstitial)

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20
Q

Vd0.05 or less

A

drug confined to the plasma

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21
Q

why some only in plasma

A

big molecules, vascular, high protein bound, hydrophilic

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22
Q

why not in plasma

A

small, high lipophilicity

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23
Q

blood brain barrier

A

bain capillaries that protects the brain from dangerous molecules from entering into CNS

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24
Q

BBB capillaries

A

lined with a continuous layer of thin epithelial cells with tight junctions - lowest paracellular permeability in the body

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25
Q

astrocyte

A

in the brain. must cross astrocyte and the capillary endothelium before entering the brain

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26
Q

PgP

A

P-glycoprotein - present to help actively pump out drugs and other toxins from the brain

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27
Q

How do solutes distribute in the brain?

A

paracellular is impossible even for small solutes in BBB. transcellular transport and transcytosis are the only mechanisms for distribution of solutes in the brain. transcellular slowed from astrocyte sheath

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28
Q

what type of molecules can’t pass into the brain?

A

hydrophillic, polar, ionized, larger than 300 daltons

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29
Q

metabolism

A

collection of processes that alter a drug to produce a metabolite. metabolites usually have little to no biological activity except in prodrugs

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30
Q

excretion

A

removal of unchanged parent drug.

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31
Q

primary excretory organ

A

kidneys. can be eliminated through bile or pulmonary route

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32
Q

% undergoes metabolism. % undergoes elimination as unchanged molecules through bile and kidney

A

75, 25

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33
Q

most important metabolic organ

A

liver (100) ! then lungs (20), kidney (8), intestines (6)

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34
Q

biotransformation/metabolism serves to make drug molecules more_____

A

hydrophillic/polar and/or larger. makes them easier to eliminate from the body through the urine.

35
Q

phase 1

A

reactions which a reactive functional group is introduced or exposed in the drug molecule. increases polarity and preparation for phase 2. product is a “derivative”

36
Q

common phase 1 reactions

A

oxidation, reduction, hydrolysis, dealkylation, hydroxylaton. -OH, NH2, -COOH, -SH

sometimes it is polar enough to be excreted without subsequent phase 2 action. may undergo more than one phase 1 reactions.

37
Q

primary reactions in CYP450 enzymes

A

phase 1

38
Q

phase 2

A

reactions in which a molecule or large functional group provided by the body is added to the drug or a derivative to form a conjugate. increase water solubility for easier elimination out of the body.

drug may undergo more than 1 phase 2 reaction. doesn’t need to undergo phase 1 if already has a reactive roup

39
Q

6 types of phase 2 reactions

A
  1. glucuronidation: derivative of glucose is added to the molecule, large molecular weight, polar weak acids, ionized at pH. morphine, valproic acid, UGT enzymes catalyze glucuronidation
  2. sulfation: addition of a sulfate group
  3. glutathione conjugation: addition of glutathione, cysteine, glycene, tripeptide of glutamic acid (acetaminophen)
  4. amino acid conjugation: addition of glycine, glutamine, aspartate, serine
  5. acylation: primary alkyl and aromatic amines are conjugated with acetic acid to form an acetyl conjugate (CH3COO-) hydralazine, isoniazid
  6. methylation: addition of a CH3 group
40
Q

phase 2 reactions usually make it more water soluble except in _______

A

acetylation and methylation

41
Q

cytochrome P450 enzymes

A

superfamily of mixed-function, heme-containing oxidases for oxidation reactions and hydrolysis. involved in endogenous substrates, steroids, fatty acids prostaglandins, and bile acids. remove drugs, carcinogens, plant toxins, enviromental pollutants

42
Q

first number following CYP

A

family in which the enzymes share 40% amino acid homology

43
Q

first letter following CYP

A

subfamily which the enzymes share 55% or greater homology

44
Q

last number following CYP

A

gene product

45
Q
  • and number following the CYP
A

enzyme is in a different isoform

46
Q

CYP families 1, 2, 3

A

act upon drugs and other xenobiotics (substances outside the body)

47
Q

major enzymes in drug metabolism

A

CYP3A4,5

48
Q

major enzyme in alcohol metabolism

A

CYP2E1

49
Q

CYP families 4, 5, 8

A

fatty acids, prostaglandins, thromboxanes

50
Q

CYP families 7, 11, 17, 21, 24, 27

A

steroid hormones

51
Q

enterohepatic recycling and glucuronidation

A

drug gluceronides excreted in the bile and in the gut. hreabsorbed and go through cycle instead of being eliminated so it prolongs its action

52
Q

exposure induces CYP enzyme

A

metabolism by that enzyme will increase and the patient will need a higher dose

53
Q

smoking induces ____ so patients taking Zyprexa who are smokers will_____

A

CYP1A2, need a higher dose

54
Q

if exposure inhibits CYP enzyme

A

patient will have higher than normal plasma concentration due to less metabolism of a drug

55
Q

grapefruit juice inhibits ___. patient taking statin with grapefruit juice will need ____

A

CYP3A4, lower dose

56
Q

Paxil inhibits ____.

A

CYP2D6. metabolizes the prodrug codeine into active drug morphine. Tylenol-3 will not be an effective pain reliever for patients taking Paxil

57
Q

if a patient is taking more than one drug that is metabolized by the same enzyme

A

there will be a competition for that enzyme. translates into less of both drugs being metabolized and a higher plasma concentration

58
Q

amount of drug excreted from the body is determined by three processes

A
  1. filtration (sends blood to urine)
  2. reabsorption (sends drug back to the blood)
  3. secretion (sends drug back into the body)
59
Q

filtration

A

occurs at the glomerular capillary
larger the molecule, less of it that will be filtered out. anything larger than 5,000 daltons will not be filtered, protien-bound drugs will not be filtered (albumin is 67,000 daltons), hydrophillic polar and ionized drugs remain in the urine

60
Q

reabsorption

A

sends drug back to the blood
drug returns to the blood from the filtrate in the tubule via the paratubular capillaries
non-ionized, lipophilic molecules do this

61
Q

secretion

A

sends drug back to the body
drug leaves the paratubular capillaries and enters the tubular space
lipophillic molecules more likely as the process involves crossing multiple cell membranes

62
Q

amount excreted =

A

amount filtered - (amount reabsorbed + amount secreted)

63
Q

zero order equations

A 
Ct = C-zero - Kt
half-life = A / 2K (zero order is dose dependent)
64
Q

First order equations

A 
Ct= C-zero e ^ -Kt
half-life = 0.693 / k (independent of dose)
65
Q

volume of distribution equation

A

vd = dose/ c-zero (to normalize vd divide by the kg of the patients weight)

66
Q

decrease in plasma conc same from one hour to next

A

zero order

67
Q

decrease in plasma conc increases from one hour to next

A

first order

68
Q

zero order k units

A

amount per time, mg/h

69
Q

first order k units

A

inverse time, h^-1

70
Q

if you are given half-life with no description of it being related to the dose administered

A

first order

71
Q

the half life of a 300 mg dose of drug Y is 3 hours

A

zero order

72
Q

the half life of drug X is 3 hours

A

first order

73
Q

first order on graph paper

A

cartesian: curved line

log : straight line

74
Q

zero order on graph paper

A

cartesian: straight line

75
Q

nutrition factors influencing Activity and level of CYP enzymes

A

3A3,4 - grapefruit juice inhibits

76
Q

smoking factors influencing Activity and level of CYP enzymes

A

1A2 - smoking induces, olanzapine

77
Q

alcohol factors influencing Activity and level of CYP enzymes

A

2E1 - chronic alcohol induces

78
Q

Drug factors influencing Activity and level of CYP enzymes

A

2C, 2D6, 3A3,4,5 affects lots

79
Q

enviiroment factors influencing Activity and level of CYP enzymes

A

1A2, 2E1, 3A3, 4, 5

80
Q

genetic polymorphism factors influencing Activity and level of CYP enzymes

A

2C9, 19, 2D6

81
Q

what does the elimination rate constant tell us correlated to concentration

A

if K= 0.215 hr -1 then 20% of whatever the drug conc that’s how much is eliminated in one hour

82
Q

factors regarding the ability of a drug to undergo ion trapping (4)

A
  1. degree of plasma protein binding of the drug
  2. pKa of the drug
  3. whether the drug is an acid or a base
  4. pH of the environment in the tissue or the organ
83
Q

patients who express a non-functional allele of CyP2D6

A

should have a dose reduction on drugs that are metabolized by 2D6 or even avoid them completely

84
Q

if you solve for Ct of the first dose. What would be the C-zero of the second dose?

A

first dose Ct + C-zero of the first dose = C-zero of second dose

pharm sci (12 decks)

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