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Physiology Part 2 > Lec 50 Pharmacokinetics > Flashcards

Lec 50 Pharmacokinetics Flashcards

1
Q

What is pharmacokinetics vs pharmacodynamics?

A 
pharmacokinetics = what body does to drug
pharmacodynamics = what drug does to bidy
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2
Q

What are the four processes of pharmacokinetics? mnemonic?

A

ADME

  • absorption
  • distribution
  • metabolism
  • excretion
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3
Q

What is definition absorption?

A

movement of drug from site of administration [GI tract] to systemic circulation

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4
Q

What is definition distribution?

A

movement of drug from systemic circulation to perfused tissue and between compartments

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5
Q

What is definition metabolism?

A

biotransformation of administered drug

mainly hepatic

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6
Q

What is definition excretion

A

removal drugs and their metabolites from body – mainly in urine or bile

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7
Q

What type of administration of drug bypasses the absorption process?

A

intravenous

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8
Q

What are 4 mechanisms of absorption?

A
  1. diffusion through membranes
  2. diffusion through aqueous intercellular spaces [capillary fenestrations]
  3. through membrane channels
  4. active transport via membrane carriers
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9
Q

What types of drugs can diffuse through membrane readily? which not?

A

small, non-polar, uncharged molec pass through easily

polar molec not as well

charged molec not at all

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10
Q

What happens to concentration of drug in systemic circulation for IV vs extravascular administration?

A

IV: will start high and decrease
extravascular: will start low as it is absorbing will increase to peak and then decrease

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11
Q

What is bioavailability [F] of a drug? What are its possible values?

A
  • fraction of dose that reaches systemic circulation

- ranges from 0 to 1

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12
Q

What factors can limit oral bioavailability?

A
  • incomplete absorption from GI tract

- first-past metabolism

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13
Q

Why would you get incomplete absorption from GI tract?

A
  • some of dose undergoes metabolism within intestinal epithelial cells
  • some of dose excreted in feces
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14
Q

What is first pass metabolism?

A
  • drug absorbed through GI enters portal circulation first and passes by liver before reaching the rest of systemic circulation
  • drug may be metabolized within liver so less bioavailability
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15
Q

Which types of administration have first pass metabolism?

A
  • only oral

- sublingual, intramuscular do not

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16
Q

What is CYP3A4?

A
  • enzyme in GI epithelial cell and in liver

- inactivates some percentage of drug that enters

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17
Q

How do you calculate bioavailability for time vs plasma concentration graph?

A

bioavailability can be calculated by area under the curve [AUC]

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18
Q

Is AUC for IV drug bigger smaller or same as for oral?

A

bigger AUC = higher bioavailability for IV drug

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19
Q

Where in the GI tract can drugs be absorbed?

A
  • can take place in all segments of GI tract
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20
Q

How does pH affect drug absorption?

A
  • many drugs are weak acids or weak bases

- those ionized in the stomach’s acidic environment will be poorly absorbed there

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21
Q

What is the major site of absorption for most oral drugs?

A

small intestine [particularly duodenum]

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22
Q

What 3 things determine why most drugs are absorbed in duodenum?

A
  • large surface area
  • longer transit time relative to stomach
  • pH in range that leaves week acids and bases mostly non-polarized so can pass through membranes
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23
Q

How do extended-release drugs affect their absorption?

A

often designed to be released from tablet at various location along GI

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24
Q

What 2 factors influence drug distribution?

A
  1. binding to plasma proteins

2. vascularity of tissue

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25
Q

What are the 2 most important plasma proteins for drug binding?

A
  • albumin

- a1-acid glycoprotein

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26
Q

How does binding to plasma proteins affect drug distribution?

A
  • almost all drugs bind plasma proteins [often 95-99% of total drug in plasma is bound]
  • only free fraction of drug is available for distribution
  • drug that binds protein more will have smaller Vd
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27
Q

How does vascularity of tissue affect drug distribution?

A
  • drugs distribute faster to highly perfused tissues [brain and heart]
  • distribution slower to muscle
  • slowest to adipose tissue and bone
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28
Q

What is redistribution?

A
  • drugs distribute between tissues, mediated by return to bloodstream
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29
Q

What does VRG stand for?

A

vessel-rich group = brain and heart

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30
Q

What is the volume of distribution?

A 
Vd = volume of distribution
Vd = A/C
A = amount of drug in body
C= plasma concentration of drug
Vd is the apparent volume = the volume of plasma you would need to hold the amount of drug administered
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31
Q

What is relationship between amount of drug accumulated in tissue and Vd?

A

more drug accumulated in tissue = bigger Vd

can often be much bigger than plasma volume

32
Q

What specific type of drugs in particular have large Vd?

A

lipophilic drugs that accumulate in adipose tissue

33
Q

What are two methods of drug elimination?

A
  • metabolism

- excretion

34
Q

What are the two major organs of elimination?

A
  • liver most important metabolizer, kidney also does some metabolizing
  • kidney plays role in drug elimination primarily by excreting unchanged drug
35
Q

What is difference elimination and excretion?

A
  • once drug undergoes metabolism it has been eliminated even if metabolites still present in body
  • excretion is elimination only when the excreted drug is unchanged
  • excretion of already metabolized drug by urine or bile is NOT elimination
36
Q

What is the rate of elimination?

A

amount of drug removed from body per unit time

37
Q

What is relationship rate of elimination and plasma drug concentration [C]? What order process?

A
  • first order process [linear]
  • rate of elimination directly related to plasma drug concentration [C]
    rate of elim = C* Cl
38
Q

What is pharmacokinetic definition of clearance [Cl]?

A
  • Clearance [Cl] is the constant that relates the rate of elimination to plasma concentration
  • vol of plasma from which drug eliminated per unit time [plasma volume/time - L/hr]
39
Q

How does clearance [Cl] change as drug administered or eliminated?

A
  • it does not

- clearance is constant, provides single value to characterize the drug’s elimination

40
Q

What is equation for Cl?

A

Cl = Rate of elimination / Concentration [C]

41
Q

What puts max limit on clearance?

A
  • limited by plasma perfusion

- Cl cannot exceed volume that passes through that organ

42
Q

What is max value for clearance of a drug by combined hepatic and renal elimination?

A

1600 mL/min

96 L/hr

43
Q

How does plasma kidney perfusion differ from GFR?

A
  • clearance by filtration limited to GFR

- renal secretion and metabolism combined with this allow kidney to have higher clearance

44
Q

What is extraction ratio [E] of organ?

A
  • E is an index of its efficiency in eliminating drug
  • fraction of plasma cleared of drug during each pass through organ
  • ranges from 0 [no elimination] to 1 [removes all drug from plasma in single pass]
45
Q

What is equation for E [extraction ratio]?

A

E = (Cin - Cout) / Cin

Cin and Cout = drug concentration in plasma as it enters and leaves organ respectively

46
Q

What does E=0 mean?

A

no elimination by the organ

47
Q

What does E = 1 mean?

A

all drug eliminated from plasma in single pass through the organ

48
Q

What is equation for specific organ clearance?

A 
Cl = Q*E
Cl = clearance
Q = plasma flow
E = extraction ratio
49
Q

What is renal clearance?

A

Cl = QE = (UV)/P

50
Q

What is another equation for the extraction ratio of kidney?

A

E = U/P

51
Q

What is a high extraction drug?

A

drug with E >= 0.7

52
Q

What is limiting factor of clearance of high-extraction drugs?

A

= flow limited

- sensitive to perfusion rate of organ since efficiency of organ already very high

53
Q

How is it possible that even some highly protein-bound drugs can have high extraction ratios?

A

as free drug eliminated within organ, bound drug dissociates and can be eliminated

54
Q

What is relationship high extraction and oral availability?

A

high extraction = low oral bioavalaibility because 70%+ of drug metabolized during first pass elimination

55
Q

What is a low extraction drug?

A
  • drug with E < = 0.3
56
Q

How does clearance of low extraction drug change with perfusion rate?

A
  • low extraction drug relatively insensitive to perfusion rate
  • reduced perfusion –> increases extraction ratio by giving elimination more time to act on drug
57
Q

What is limiting factor of clearance of low extraction drugs?

A
  • capacity-limited

- sensitive to enzyme regulation [induction or inhibition]

58
Q

What is equation for total clearance of drug?

A

Cl tot = Cl hepatic + Cl renal + Cl other

59
Q

What are phase I drug metabolism rxns?

A
  • oxidation/reduction rxns that add or expose active group of drug
  • produce more polar molec
60
Q

What is consequence of phase 1 rxn?

A
  • metabolite less active than parent drug [often no activity]
  • polar mole more likely to be excreted by kidney
  • active group provides substrate for phase II conjugation rxns
61
Q

What type of enzymes catalyzes most phase I rxns?

A

CYP450s

62
Q

What enzyme in GI works to limit drug absorption?

A

CYP3A4 [a type of CYP450]

63
Q

What is relationship rifampin and CYP450?

A

rifampin is a drug induces CYP450 so increases elimination of many other drugs

64
Q

What is an relationship CYP3A4 and grapefruit juice?

A

grapefruit juice inhibits CYP3A4 in guit

- increases absorption of CYP3A4 substrates

65
Q

Are phase I or phase II rxns catalyzed by CYP450 enzymes?

A

phase I

66
Q

What are phase II metabolic rxn?

A
  • conjugation endogenous metabolite [glucoronic acid, acetic acid, etc] to active group of drug
67
Q

Are conjugated [phase II products] active or inactive? Whats an example of an active one?

A
  • usually inactive

- exception: morphine glucoronide is active analgeisc

68
Q

Does phase II rxn require phase I rxn already complete?

A

No - some drugs already have active group present so don’t need phase I rxn

69
Q

What drugs mainly excreted in hepatobiliary excretion?

A
  • mainly high molecular weight drugs and metabolites
70
Q

What types of drugs are excreted via glomerular filtration?

A
  • only unbound drugs

- clearance limited by GFR

71
Q

What limits clearance of drugs excreted via glomerulus?

A
  • limited by GFR
72
Q

What is path of drug renal excretion?

A
  • glomerular filtration or secretion [active transport in PT]
  • then either excreted or reabsorped in PT/DT via passive diffusion or active transport
73
Q

What is fraction excreted unchanged [FEU]?

A
  • fraction of drugs excreted unchanged in urine

- represents net outcome filtration, reabsorption, secretion

74
Q

What is equation for renal clearance of drug [excluding renal metabolism]?

A

Cl renal = FEU * Cl total

75
Q

What is ion trapping?

A
  • due to pH difference between urine and plasma, ionization of drug in urine can reduce drug reabsorption [and increase excretion]
  • only uncharged species can be reabsorbed by diffusion
76
Q

What is the henderson hassleback equations?

A

pH = pKa + log [unprotonated]/[protonated]

= pKa + log [A]/[HA]

Physiology Part 2 (19 decks)

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