CA1 concepts Flashcards
(91 cards)
1
Q
Plasma is treated with _______
A
Anti-coagulants; fibrinogen present
2
Q
Serum contains _______
A
coagulants; fibrinogen absent
3
Q
Normally, fu is ______
A
a constant
4
Q
Which ROA doesn’t have systemic absorption?
A
IV
5
Q
How does the enterohepatic cycle work (which organs are involved)?
A
Bile –> gall bladder –> SI –> back into circulation
6
Q
Elimination is reversible or irreversible?
A
irreversible
7
Q
What is permeability rate limit absorption?
A
Dissolution»_space; Absorption
8
Q
What is dissolution rate limit absorption?
A
Absorption»_space; Dissolution
9
Q
Fick’s Law; CGI»_space; CP to create ________
A
sink condition
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
11
Q
What is GER?
A
Controls onset along with rate of absorption
12
Q
What is intestinal motility?
A
the residence time of dosage form in SI
13
Q
How do we change GER for Permeability- rate limited absorption?
A
Slow down GER (decrease GER) to compensate poor permeability
14
Q
How do we change GER for dissolution-rate limited absorption?
A
Slow down GER, to allow more time for complete dissolution
15
Q
What happens to GER with food?
A
slow down, dec GER
16
Q
What happens to GER with solutions/suspensions VS chunks of food?
A
soln/suspensions: faster GER
chunks: slower GER
17
Q
Which drugs slows down GER?
A
Anti-cholinergic drugs, nacrotic analgesics
18
Q
Which drugs increases GER?
A
Metoclopramide
19
Q
Which units affects rate of abs?
A
Cmax, Tmax
20
Q
Which units affects extent of abs?
A
Cmax, AUC
21
Q
Location of apical memb
A
Towards lumen of gut
22
Q
Location of basolateral memb
A
towards vilious blood
23
Q
What is FF, FG, FH?
A
FF - enters intestinal tissue (gut lumen)
FG - enters portal vein (gut wall)
FH - reaches liver
24
Q
Does systemic abs happens at IM and SC sites?
A
yes
25
Drugs abs in solution from IM and SC are what type of rate-limited?
Perfusion rate limited
26
What are the assumptions for C/Cb?
- 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)
27
what should we take note of the pH-partition hypothesis?
only unbound and unionised drugs permeate the memb via passive transcellular pathway
28
What do we take note of passive facilitated diffusion?
- they are equilibrating transporters
- no ATP; unbound drug conc equal at equilibrium
- maximum transport, substrate specificity and inhibition
29
What to take note for active transport?
- they are concentrating transporters
- ATP
- influx and efflux transporters
- at GIT, liver, kidney
30
Why do some drugs have low logP but BBB permeability is high?
- substrates of uptake transporters
| - relatively small molecule, low MW
31
Why do some drugs have high logP but BBB permeability is low?
- substrates of efflux transporters (e.g. PGP)
| - relatively large molecule, high MW
32
What are some factors affecting distribution?
- Rate of distribution?
- Perfusion rate limited
- Permeability rate limited
33
What does higher KPB stands for?
takes more time for the drug to distribute a lot more into the fats to reach distribution equilibrium, despite KPB is higher
34
What are the assumptions we need to take note for extracellular water / volume of distribution?
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
35
Properties of acidic drugs:
- bind to albumin (high affinity) and low binding affinity for tissue proteins
- tend to have small V <1L/kg
36
Properties of basic drugs:
- bind to a1-AGP; albumin; lipoproteins
- extensive tissue protein binding and other sequestration mechanisms
- high V >1L/kg
37
When V is small =< 0.2L/kg,
changes in fu only causes minimal change in V
38
When V is large > 1L/kg,
changes in fu causes proportionate change in V
39
What to take note for Gibaldi and McNamara Model?
- 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
What to take note for Oie and Tozer Model?
- applies to BOTH large and small V
- Preferrable for antibiotics, acidic drugs (NSAIDs), therapeutic proteins
- purely passive diffusion
- VR = 27L for 70kg man
41
Why when fu increases, Cu remains constant but total conc C decreases?
Which kind of drug shows such properties?
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
Normally for clearance, what type of rate-limited it is?
Perfusion-rate limited or flow-limited
43
When E is large,
limited by blood flow Q; CLb ~ Q
44
When E is small,
independent on blood flow Q
45
When E is intermediate,
CLb limited by both elimination efficiency E and Blood flow Q
46
What is the renal blood flow?
1.1L/min
47
What is the hepatic blood flow
1.35L/min
48
How does blood and bile flows?
opposite directions
49
Distribution into the hepatocytes are what type of rate-limited?
perfusion rate limited
| but if polarity is an issue, permeability-rate limited
50
Sinusoidal transporters is located at which side of the memb?
Basolateral memb
51
Properties of sinusoidal transporters?
- uptake transporter = inc clearance
| - efflux transporter = dec CL
52
Canalicular transporters are located at which side of the memb?
Apical memb
53
Properties of Canalicular transporters?
- efflux transporter = inc CL via biliary route
54
Which CYP has the highest contribution to drug metabolism?
2D6, despite being in low abundance
55
Elimination via secretion of bile (excretion) + Elimination via metabolism (metabolism) =
Instrinsic CL
56
What does the velocity Michaelis-Menten Model stand for?
rate of formation of metabolite per unit time per amount of enzyme
57
How to find Km?
50% of Vmax
58
When a drug has higher EH, what is the drug efficiency?
- 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
High EH, what does it mean for CL? CL is sensitive to?
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
What is high EH?
>0.7
61
What is low EH?
<0.3
62
When a drug has lower EH, what is the drug efficiency?
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
Low EH, what does it mean for CL? CL is sensitive to?
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
Moderate EH, what does it mean for CL? CL is sensitive to?
CL affected by both QH and plasma protein binding and CLint
65
Properties of biliary excretion through active transport:
- polar
- >350g/mol
- specific transport mechanisms (anions, cations, neutral organic compounds)
- hepatic disease (decrease biliary excretion)
66
What is the bile flow?
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
Glomerulus filtration rate
120ml/min
68
Urine flow
1-2ml/min
69
Urine formation and renal CL are dependent on:
- glomerular filtration
- tubular reabs
- tubular secretion
70
CL changes for passive filtration, active secretion and passive reabs
Passive filtration = inc CL
Active secretion = inc CL
Passive reabs = dec CL
71
What type of transporters are there in tubular secretion?
Apical memb: efflux transporters
| Basolateral memb: efflux transporters + highly fenestrated
72
CLR > fu x GFR (CLf) is active secretion or tubular reabs?
active secretion
73
CLR < fu x GFR (CLf) is active secretion or tubular reabs?
tubular reabs
74
At the proximal tubule, what is your apical and basolateral memb?
Basolateral: uptake
Apical: efflux
75
When drugs with high ER, what happens to protein binding?
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
When drugs with low ER, what happens to protein binding?
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
Endogenous compounds go through what kind of process transport?
Active reabs
| e.g. electrolytes, vitamins, glucose, amino acids
78
Exogenous compounds go through what kind of process transport?
Passive diffusion
| e.g. drugs
79
Urin pH range
4.4-7.0 (avg: 6.4)
80
CL of acidic drugs will be affected to a larger extent at ___ pH
lower
81
CL of basic drugs will be affected to a larger extent at ___ pH
higher
82
What is the effect of Urine pH on CLR of bases for polar basic drugs?
Unionised form not reabs (unless active transport)
| CLR is independent on urine pH
83
What is the effect of Urine pH on CLR of bases for VERY weakly non-polar basic drugs (with low pKa)?
Drugs with low pKa is extensively reabs; CLR is low
| CLR is independent on urine pH
84
What is the effect of Urine pH on CLR of bases for non-polar basic drugs (with moderate to high pKa)?
High pKa
Variable reabs, depending on pH
CLR is dependent on urine pH
85
What is the effect of Urine pH on CLR of ACIDS for polar acidic drugs?
Unionised form not reabs (unless active transport)
| CLR is independent on urine pH
86
What is the effect of Urine pH on CLR of acids for VERY weakly non-polar acidic drugs?
Drugs with high pKa is extensively reabs; CLR is low
| CLR is independent on urine pH
87
What is the effect of Urine pH on CLR of acids for non-polar acidic drugs?
moderate to low pKa
Variable reabs, depending on pH
CLR is dependent on urine pH
88
So when acidic non-polar drug is in basic pH, clearance __
increases (more ionised form)
89
When acidic non-polar drugs are in acidic pH (pka > ph), more are reabs, thus CLR _______
decreases (more unionised)
90
CLR changed by urine flow is dependent when _______
the drug is extensively of reabsorbed (CLR increases when urine flow increases; less time for reabsorption)
91
Acids and bases that show pH-sensitive reabs generally show what type of rate?
flow-rate dependence
