Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Drug Disposition > Renal Elimination > Flashcards

Renal Elimination Flashcards

1
Q

Importance of renal excretion in pharmacokinetics?

A
  • makes up 32% of renal elimination in top prescribed drugs
  • many new compounds are metabolically stable
  • major elimination mechanism for many drugs e.g. metformin, acyclovir, digoxin
  • important for elimination of many metaboites formed in liver
  • evidence of clinically relevant renal transporter DDIs
  • changes in dosage regiment may be required in renal impairment, elderly, children
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Perfusion of the kidneys?

A

20% of cardiac output

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What regional differences occur in the kidneys?

A
  • blood and tubular fluid flows
  • transport functions and permeability to water and salts

vary throughout the different areas of the kidney/nephron

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Mechanisms of renal drug excretion?

A

Filtration, reabsorption, active secretion, excretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Equation for total renal excretion?

A

filtration - reabsorption + secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Equation for rate of excretion?

A

CLr • C plasma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Units of flow for excretion?

A

L/h

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Equation for CLr using rate of filtration etc?

A

CLr = (CLrf + CLrs)(1-Fr)

CLrf is rate of filtration
CLrs is rate of secretion
Fr is fraction reabsorbed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What happens in golmerular filtration?

A

Only plasma water containing unbound drug is filtered - passive process

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

How to work our CLrf?

A

fraction unbound • GFR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is GFR usually independent of?

A

Renal blood flow - usually constant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What value can renal clearance not exceed?

A

GFR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How is GFR determined?

A

using inulin or creatinine

not bound to plasma proteins, Fu = 1, not secreted or reabsorbed. renal clearance is therefore equal to the GFR

Creatinine is actually actively secreted and overestimates GFR, but very easy to use clinically

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Average GFRs for a 20 year old?

A

120mL/min men
110mL/min women

1% decline per year after 20

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Role of active tubular secretion?

A
  • Facilitates excretion, adds drug to tubular fluid
  • transporters exist for basic and acidic drugs - dissociation of plasma drug-protein complex as unbound drug is transported (equilibrium)
  • saturable process
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Relationship between secretion and renal blood flow?

A

Secretion can occur very rapidly, so can lead to perfusion limited elimination

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Which transporters are involved in tubular secretion?

A
  • uptake into renal cell but OAT1/3, OCT2, OATP4C1
  • efflux into urine by MRP2/4, MATEs, P-gp

ENT1/2, OAT4 uptake and efflux at both sides, URAT1, PEPT1/2 uptake from urine, OCTN1/2 uptake and efflux

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Pairing of uptake and efflux transporters?

A

OAT1/3 uptakes anions from blood, MRP2/4 would efflux these molecuels

Cations taken up by OCT2, paired with MATEs which would efflux

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What happens when drug accumulates in proximal tubule?

A

nephrotoxicity

can be a result of the transporters

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What else can proximal tubule cells express?

A

Metabolising enzymes e.g. mycophenolic acid is extensively metabolised in the kidney by glucuronidation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Role of OAT1 transporters in the proximal tubule?

A
  • uptake of small organic anionic drugs

- substrates include adefovir, oseltamivir carboxylate, methotrexate, penicillin G

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Role of OCT2 transporters in the proximal tubule?

A
  • transport of hydrophilic, low MW organic cations

- role in excretion of metformin, amaliplatin, pindolol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What can transporters be sensitive to?

A

pH - MATE sensitive to urine pH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Penicillin G rapidly eliminated by renal excretion - co-admin of G and probenecid led to increased concentrations of Penciliin G. Why?

A

Penicillin G is secreted by OAT1 in the kidney. Probenecid inhibits OAT1, which prevents the active secretion of penicillin G into the urine, so increased plasma conc

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Probenecid and cidofovir DDI? Why is this actually desirable?

A
  • probenecid inihibts cidofovir uptake by OAT1
  • high concentrations of cidofovir in proximal tubule cells is nephrotoxic, so co-administration reduces the toxicity as slows the uptake
26
Q

Cimetidine and metformin DDI in the kidney?

A

Cimetidine inhibits OCT2, so renal clearance of metformin is reduced in coadministration

27
Q

Relationship between plasma drug concentration and rare of secretion?

A

Much like enzyme kinetics, gets saturated at a certain conc and rate will not increase further

28
Q

Relationship between plasma drug concnetration and rate of filtration?

A

Positive relationship consistently - not saturable

29
Q

Typical urine pH?

A

4.5-7.6

30
Q

Typical urine flow?

A

1-2mL/min

31
Q

General points about water reabsorption in the kidney?

A
  • approx 65% of golmerular filtrate is reabsorbed at proximal tubule
  • variable in segments like collecting duct in response to hormones
32
Q

How does concentration inside the tubule change along the nephron?

A

Working down through the regions, tubule becomes up to 120x more concentrated than blood (assuming no solute reabsorption) in the collecting duct

33
Q

What affects passive reabsorption of molecules in the kidney?

A
  • drug lipophilicity and degree of ionisation affect the rate and extent of reabsorption
  • unbound and uinionised form of the drug will cross the membrane, unionised form must be lipophilic enough to cross the membrane
  • urine flow
34
Q

When is CLr urine pH sensitive?

A

Weak acids - pKa 3-7.5
Weak bases - pKa 6-12
lipophilic and in unionised form

35
Q

What types of molecules are minimally reabsorbed and not pH sensitive?

A

pKa <3, strong acids as they are mostly ionised

pKa >12, strong bases as they are mostly ionised

36
Q

Effect of urine pH on elimination of weak acids?

A

CLr increases as pH increases (more reabsorption when molecule is unionised at low pH)
increased ionisation
decreased reabsorption
increased excretion

37
Q

What types of molecules are very well reabsorbed and not pH sensitive?

A

Very weak acids pKa >7.5, mostly unionised over pH range

Very weak bases, pKa <6

38
Q

Effect of urine pH on elimination of weak bases?

A

CLr increases as pH decreases - molecule becomes more ionised so less reabsorption

39
Q

What type of drug is amphetamine, and how does its CLr change with pH?

A

Weak base
pH 6.3 (normal) has urine recovery 40%
pH 5.3 has recovery 70%
pH 7.3 has recovery 3%

40
Q

Effect of urine flow on passive reabsorption in the kidney?

A

Flow dependent CLr if equilibrium is achieved between plasma and tubular fluid (urine) i.e. in substantial reabsorption

More flow will lead to more drug in urine (higher CLr)

41
Q

Effect of forced alkalined diuresis on phenobarbitone?

A

weak acid so CLr increases with pH

also urine flow dependent so increasing urine flow and increasing pH maximises rate of excretion

application: drug overdose

42
Q

Under what conditions is forced diuresis effective?

A

If renal excretion of the drug is significant under normal conditions (and the drug CLr is urine pH sensitive)

43
Q

Assumptions if CLr = Fu • GFR

A

no reabsorption or secretion

or reabsorption = secretion

44
Q

What does it mean when CLr > Fu • GFR

A

Net secretion (movement out of the blood into tubular fluid) - many acids and bases

45
Q

What does it mean when CLr < Fu • GFR

A

Net reabsorption (movement from tubular fluid into blood) - generally lipophilic molecules

46
Q

Where in the kidney is CYP3A5 located?

A

Cortex and medulla

47
Q

Where in the kidney is CYP2D6 located?

A

Cortex > medulla

highest in proximal tubule and loop of henle

48
Q

Where in the kidney is UGT1A9 located?

A

proximal tubule, distal tubule, loop of henle, collecting duct

49
Q

Where in the kidney is UGT2B7 located?

A

proximal tubule, distal tubule, loop of henle, collecting duct

50
Q

Where in the kidney are carboxylesterases located?

A

Proximal tubule, Bowman’s capsule

51
Q

Role of renal glucuronidation?

A

Important for certain drug molecules

endogenous molecules e.g. arachidonic acids, prostaglandins

52
Q

What relating to NSAIDs is linked to renal toxicity?

A

Acyl-glucuronides

53
Q

Effect on glucuroninidation enzymes as a result of kidney tumours?

A

Significant variability in expression and activity of enzymes, especially UGT1A6 and 2B7

leads to reduced renal glucuronidation in tumours

54
Q

Impact of renal disease/impairment on drug dosage regimen?

A

leads to increased plasma concentrations, risk of toxicity

55
Q

When is dose adjustment needed in renal impairment?

A
  • If the fraction excreted unchanged is >50%
  • narrow therapeutic window e.g. digoxin
  • active metabolites e.g. morphine 6-glucuronide
  • impaired metabolism e.g. polymorphic enzyme CYP2D56
56
Q

Which physiological changes occur in the kidney in CKD?

A
  • reduced CLr
  • reduced blood flow and kidney weight
  • decreased GFR
  • possible changes in tubular surface area
  • decreased tubular secretion (reduced transporter expression/activity, inhibitory effect of uremic solutes, proximal tubule cell numbers reduced)
  • reduced renal metabolism, thought to be reduced UGT
57
Q

Which physiological changes occur in the liver in CKD?

A

Reduced clearance of drugs that are not renally cleared

  • downregulation or inhibition of CYPs
  • reduced OATP activity
  • reduced UGT1A9 and 2B7
58
Q

Which physiological changes occur in the GI tract in CKD?

A
  • increased gastric emptying time (delayed)
  • increased intestinal pH
  • possible change in expression of CYPs
59
Q

Effect of CKD on albumin and haematocrit?

A

both are reduced compared to healthy subjects

60
Q

What other factors can affect protein binding in CKD?

A
  • competition for binding sites by uremic solutes

- limited data suggests elevated alpha-acid glycoprotein

Drug Disposition (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions