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CA1 concepts Flashcards

1
Q

Plasma is treated with _______

A

Anti-coagulants; fibrinogen present

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2
Q

Serum contains _______

A

coagulants; fibrinogen absent

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3
Q

Normally, fu is ______

A

a constant

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4
Q

Which ROA doesn’t have systemic absorption?

A

IV

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5
Q

How does the enterohepatic cycle work (which organs are involved)?

A

Bile –> gall bladder –> SI –> back into circulation

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6
Q

Elimination is reversible or irreversible?

A

irreversible

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7
Q

What is permeability rate limit absorption?

A

Dissolution&raquo_space; Absorption

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8
Q

What is dissolution rate limit absorption?

A

Absorption&raquo_space; Dissolution

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9
Q

Fick’s Law; CGI&raquo_space; CP to create ________

A

sink condition

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10
Q

Which properties of drug are favourable?

A
  • smaller and more lipophilic
  • paracellular <350g/mol
  • if too lipophilic, poorer aq solubility, greater propensity to bind to memb transporters
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11
Q

What is GER?

A

Controls onset along with rate of absorption

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12
Q

What is intestinal motility?

A

the residence time of dosage form in SI

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13
Q

How do we change GER for Permeability- rate limited absorption?

A

Slow down GER (decrease GER) to compensate poor permeability

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14
Q

How do we change GER for dissolution-rate limited absorption?

A

Slow down GER, to allow more time for complete dissolution

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15
Q

What happens to GER with food?

A

slow down, dec GER

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16
Q

What happens to GER with solutions/suspensions VS chunks of food?

A

soln/suspensions: faster GER

chunks: slower GER

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17
Q

Which drugs slows down GER?

A

Anti-cholinergic drugs, nacrotic analgesics

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18
Q

Which drugs increases GER?

A

Metoclopramide

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19
Q

Which units affects rate of abs?

A

Cmax, Tmax

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20
Q

Which units affects extent of abs?

A

Cmax, AUC

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21
Q

Location of apical memb

A

Towards lumen of gut

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22
Q

Location of basolateral memb

A

towards vilious blood

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23
Q

What is FF, FG, FH?

A

FF - enters intestinal tissue (gut lumen)
FG - enters portal vein (gut wall)
FH - reaches liver

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24
Q

Does systemic abs happens at IM and SC sites?

A

yes

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25
Q

Drugs abs in solution from IM and SC are what type of rate-limited?

A

Perfusion rate limited

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26
Q

What are the assumptions for C/Cb?

A
  • Binding to RBC is not saturated. If saturated, non-linear relationship btw C and Cb observed
  • Distribution equilibrium of the free drug in plasma and drug in RBC is established (KP rbc)
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27
Q

what should we take note of the pH-partition hypothesis?

A

only unbound and unionised drugs permeate the memb via passive transcellular pathway

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28
Q

What do we take note of passive facilitated diffusion?

A
  • they are equilibrating transporters
  • no ATP; unbound drug conc equal at equilibrium
  • maximum transport, substrate specificity and inhibition
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29
Q

What to take note for active transport?

A
  • they are concentrating transporters
  • ATP
  • influx and efflux transporters
  • at GIT, liver, kidney
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30
Q

Why do some drugs have low logP but BBB permeability is high?

A
  • substrates of uptake transporters

- relatively small molecule, low MW

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31
Q

Why do some drugs have high logP but BBB permeability is low?

A
  • substrates of efflux transporters (e.g. PGP)

- relatively large molecule, high MW

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32
Q

What are some factors affecting distribution?

A
  • Rate of distribution?
  • Perfusion rate limited
  • Permeability rate limited
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33
Q

What does higher KPB stands for?

A

takes more time for the drug to distribute a lot more into the fats to reach distribution equilibrium, despite KPB is higher

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34
Q

What are the assumptions we need to take note for extracellular water / volume of distribution?

A

this assumption is when V = 42 L

  • no binding of drug to plasma and tissue proteins
  • drugs are not a substrate of influx and efflux transporters
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35
Q

Properties of acidic drugs:

A
  • bind to albumin (high affinity) and low binding affinity for tissue proteins
  • tend to have small V <1L/kg
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36
Q

Properties of basic drugs:

A
  • bind to a1-AGP; albumin; lipoproteins
  • extensive tissue protein binding and other sequestration mechanisms
  • high V >1L/kg
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37
Q

When V is small =< 0.2L/kg,

A

changes in fu only causes minimal change in V

38
Q

When V is large > 1L/kg,

A

changes in fu causes proportionate change in V

39
Q

What to take note for Gibaldi and McNamara Model?

A
  • applies to large V
  • Vp = 3L
  • TBW = 42 L
  • VT = 39L (when it can access the TBW; cannot access TBW, VT can be <39L)
  • no active transport process involved
40
Q

What to take note for Oie and Tozer Model?

A
  • applies to BOTH large and small V
  • Preferrable for antibiotics, acidic drugs (NSAIDs), therapeutic proteins
  • purely passive diffusion
  • VR = 27L for 70kg man
41
Q

Why when fu increases, Cu remains constant but total conc C decreases?

Which kind of drug shows such properties?

A

Cu remains constant as it is insensitive to change in plasma protein binding

drugs with high V and low E

V of higher V drug is more sensitive to changes in fu

Cl of low E is more sensitive to the change in fu

When there is an inc in fu, both V and CL increases. Both these increases normalise the Cu of the drug over time. Hence, Cu is unchanged while C decreases

fu = Cu/C

42
Q

Normally for clearance, what type of rate-limited it is?

A

Perfusion-rate limited or flow-limited

43
Q

When E is large,

A

limited by blood flow Q; CLb ~ Q

44
Q

When E is small,

A

independent on blood flow Q

45
Q

When E is intermediate,

A

CLb limited by both elimination efficiency E and Blood flow Q

46
Q

What is the renal blood flow?

A

1.1L/min

47
Q

What is the hepatic blood flow

A

1.35L/min

48
Q

How does blood and bile flows?

A

opposite directions

49
Q

Distribution into the hepatocytes are what type of rate-limited?

A

perfusion rate limited

but if polarity is an issue, permeability-rate limited

50
Q

Sinusoidal transporters is located at which side of the memb?

A

Basolateral memb

51
Q

Properties of sinusoidal transporters?

A
  • uptake transporter = inc clearance

- efflux transporter = dec CL

52
Q

Canalicular transporters are located at which side of the memb?

A

Apical memb

53
Q

Properties of Canalicular transporters?

A
  • efflux transporter = inc CL via biliary route
54
Q

Which CYP has the highest contribution to drug metabolism?

A

2D6, despite being in low abundance

55
Q

Elimination via secretion of bile (excretion) + Elimination via metabolism (metabolism) =

A

Instrinsic CL

56
Q

What does the velocity Michaelis-Menten Model stand for?

A

rate of formation of metabolite per unit time per amount of enzyme

57
Q

How to find Km?

A

50% of Vmax

58
Q

When a drug has higher EH, what is the drug efficiency?

A
  • High efficiency in partitioning out of blood cells;
  • dissociate from plasma proteins,
  • permeate through hepatic memb,
  • metabolised by hepatic enzymes and
  • biliary excretion into bile
59
Q

High EH, what does it mean for CL? CL is sensitive to?

A

QH but relatively insensitive to changes in plasma protein binding or hepatocelluar eliminating activity (NOT sensitive to CLint)

CLb and EH are minimally affected by fu changes

Elimination becomes rate-limited by perfusion

60
Q

What is high EH?

A

> 0.7

61
Q

What is low EH?

A

<0.3

62
Q

When a drug has lower EH, what is the drug efficiency?

A

Poor efficiency; drug is a poor substrate for elimination process;
drug is polar and insufficient lipophilicity to permeate readily into hepatocytes
drug is substrate of efflux transporter along sinusoidal (basolateral) memb

63
Q

Low EH, what does it mean for CL? CL is sensitive to?

A

Changes in plasma protein binding or heptatocellular eliminating activity, (CLint may not have much change , not as sensitive as plasma protein binding)
Insensitive to QH

CLH depends on fu as only unbound drug permeates the hepatocytes for elimination

64
Q

Moderate EH, what does it mean for CL? CL is sensitive to?

A

CL affected by both QH and plasma protein binding and CLint

65
Q

Properties of biliary excretion through active transport:

A
  • polar
  • > 350g/mol
  • specific transport mechanisms (anions, cations, neutral organic compounds)
  • hepatic disease (decrease biliary excretion)
66
Q

What is the bile flow?

A

0.5-0.8ml/min
drug is highly conc in bile –> high biliary CL
Bile is not a product of filtration but is the secretion of bile acids and other solutes (Drugs/metabolites)
Biliary transport may be saturated/ comp inhibited

67
Q

Glomerulus filtration rate

A

120ml/min

68
Q

Urine flow

A

1-2ml/min

69
Q

Urine formation and renal CL are dependent on:

A
  • glomerular filtration
  • tubular reabs
  • tubular secretion
70
Q

CL changes for passive filtration, active secretion and passive reabs

A

Passive filtration = inc CL
Active secretion = inc CL
Passive reabs = dec CL

71
Q

What type of transporters are there in tubular secretion?

A

Apical memb: efflux transporters

Basolateral memb: efflux transporters + highly fenestrated

72
Q

CLR > fu x GFR (CLf) is active secretion or tubular reabs?

A

active secretion

73
Q

CLR < fu x GFR (CLf) is active secretion or tubular reabs?

A

tubular reabs

74
Q

At the proximal tubule, what is your apical and basolateral memb?

A

Basolateral: uptake
Apical: efflux

75
Q

When drugs with high ER, what happens to protein binding?

A

CLs is less dependent on fu and relatively dependent on perfusion

CLb,R ~ close to QR

Drugs are rarely extracted by kidneys as most drugs are lipophilic (they are highly reabs); thus more drugs eliminated in liver than kidney

76
Q

When drugs with low ER, what happens to protein binding?

A

Depend on efficiency of transporter-mediated process (intrinsic CL) and contact time at secretory sites along proximal tubule
CLs dependent on fu; relatively independent on perfusion
CLf is dependent on fu as CLf = fu x GFR

77
Q

Endogenous compounds go through what kind of process transport?

A

Active reabs

e.g. electrolytes, vitamins, glucose, amino acids

78
Q

Exogenous compounds go through what kind of process transport?

A

Passive diffusion

e.g. drugs

79
Q

Urin pH range

A

4.4-7.0 (avg: 6.4)

80
Q

CL of acidic drugs will be affected to a larger extent at ___ pH

A

lower

81
Q

CL of basic drugs will be affected to a larger extent at ___ pH

A

higher

82
Q

What is the effect of Urine pH on CLR of bases for polar basic drugs?

A

Unionised form not reabs (unless active transport)

CLR is independent on urine pH

83
Q

What is the effect of Urine pH on CLR of bases for VERY weakly non-polar basic drugs (with low pKa)?

A

Drugs with low pKa is extensively reabs; CLR is low

CLR is independent on urine pH

84
Q

What is the effect of Urine pH on CLR of bases for non-polar basic drugs (with moderate to high pKa)?

A

High pKa
Variable reabs, depending on pH
CLR is dependent on urine pH

85
Q

What is the effect of Urine pH on CLR of ACIDS for polar acidic drugs?

A

Unionised form not reabs (unless active transport)

CLR is independent on urine pH

86
Q

What is the effect of Urine pH on CLR of acids for VERY weakly non-polar acidic drugs?

A

Drugs with high pKa is extensively reabs; CLR is low

CLR is independent on urine pH

87
Q

What is the effect of Urine pH on CLR of acids for non-polar acidic drugs?

A

moderate to low pKa
Variable reabs, depending on pH
CLR is dependent on urine pH

88
Q

So when acidic non-polar drug is in basic pH, clearance __

A

increases (more ionised form)

89
Q

When acidic non-polar drugs are in acidic pH (pka > ph), more are reabs, thus CLR _______

A

decreases (more unionised)

90
Q

CLR changed by urine flow is dependent when _______

A

the drug is extensively of reabsorbed (CLR increases when urine flow increases; less time for reabsorption)

91
Q

Acids and bases that show pH-sensitive reabs generally show what type of rate?

A

flow-rate dependence

PK (6 decks)

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