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The Medicine Y3 Semester 1 - Drug disposition > Renal Elimination > Flashcards

Renal Elimination Flashcards

1
Q

Importance of renal excretion?

A
  • A major elimination mechanism for many drugs e.g. metformin, acyclovir, digoxin
  • Important for elimination of many metabolites formed in the liver
  • Important for elimination of many metabolites formed in the liver
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2
Q

Changes in dosage regimen may be required in:

A
  • Patients with renal impairment
  • Elderly – reduced GFR
  • Children – physiological differences
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3
Q

Structure of kidney:

A

Medulla, capsule, cortex, ureter

  • Perfusion of kidneys – receive 20% of cardiac output!

Distinct regional differences in:

  • blood and tubular fluid flows
  • transport functions and permeability to water and salts
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4
Q

Mechanisms of renal drug excretion:

A

1) Glomerular filtration
GFR = 120 ml/min

2) Reabsorption -– moves drug back to systemic circulation
3) Active secretion – also facilitate excretion (excretion = filtration - reabsorption + secretion

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5
Q

Rate of excretion =

A

CLR·C

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6
Q

Renal clearance=

A

CLR = Rate of Urinary Excretion /C plasma

Units = L/h

Higher plasma conc, higher rate of excretion

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7
Q

Components of Renal Clearance:

A

Rate of Excretion= [Rate of
Filtration + rate of secretion] x [1-fraction reabsorbed]

CLR = (CLRF + CLRS)(1- FR)

CLRF – renal filtration clearance
CLRS – renal secretion clearance
FR - fraction of filtered and secreted drug reabsorbed

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8
Q

Glomerular filtration is:

A
  • A passive process, only plasma water containing unbound drug (Cu) is filtered! using passive diffusion simply following conc gradient
  • Only unbound drug is going to be filtered and any small molecules will be filtered
CLRF = fu x GFR
(fu = fraction unbound in plasma)
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9
Q

If you have highly bound drug, GFR will be fairly _____.

A

Low

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10
Q

How is GFR determined?

A

Determined using inulin (large molecular carbohydrate NOT insulin) or creatinine*
Good markers because (not bound to plasma proteins, fu=1; not secreted or reabsorbed)

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11
Q

Renal clearance (GFR) =

A

CLR = fu •GFR

e.g. 1 x GFR

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12
Q

GFR depends on:

A
  • Body size, gender and age
  • Men (20 yr) – 120 ml/min
  • Women (20 yr) – 110 ml/min

GFR decreases by 1% per year after age 20

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13
Q

GFR marker, highly correlated with:

A

inulin clearance

HOWEVER: Creatinine CLR > GFR
Net CLR,sec ≈ on average 9% of CLR

Detect/ monitor/ diagnose acute kidney injury or chronic kidney disease.

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14
Q

Active tubular secretion facilitates:

A

excretion, because it adds drug to tubular fluid.

Transporters exist for basic and acidic drugs
Dissociation of plasma drug-protein complex as unbound drug is transported

  • It is a Saturable process, competition (multiple drugs competing due to similar substrate specificities)
    If no reabsorption occurs, all drug presented to the kidney may be excreted in the urine
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15
Q

Transporters and metabolic enzymes expressed in the kidney proximal tubule. Organic anion transporter (OAT1):

A
  • Role in uptake of small organic ANIONIC drugs

- OAT1 substrates - adefovir, oseltamivir carboxylate, methotrexate, penicillin G

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16
Q

Transporters and metabolic enzymes expressed in the kidney proximal tubule.
Organic cation transporter (OCT2):

A
  • Transport of hydrophilic, low molecular weight organic CATIONS
  • Role in excretion of metformin, amaliplatin, pindolol
17
Q

Clinical relevance of renal transporters (penicillin G)

A
  • Penicillin G is rapidly eliminated via renal excretion (80% excreted in urine within 3 h).
  • Co-administration with probenecid increases plasma concentrations of penicillin G.
  • Pencillin is a substrate for OAT1
    Probenecid inhbits OAT1 – so less penicillin be taken up by renal transporter therefore staying in plasma and increasing conc.
18
Q

Excretion rate and plasma drug conc graph:

A

Excretion: carries on increasing because it is driven by filtration which isn’t saturable.

Secretion= linear relationship between plasma drug conc and excretion rate (Tm) so plateus when it reaches Tm

Filtration= Filtration process = non saturable process due to passive diffusion and simply driven by concentration gradient

19
Q

Renal excretion is a NET effect of 3 processes:

A

1) Glomerular filtration
GFR = 120 ml/min
2) Reabsorption – important as GFR is a lot faster than urine flow
3) Active secretion

20
Q

Consideration of water reabsorption. Approx. 65% of GFR ____ at proximal tubule

A

Reabsorbed

Variable in segments like collecting duct in response to hormones.

21
Q

Passive reabsorption:

A
  • Drug lipophilicity and degree of ionization affect the rate and extent of reabsorption
  • UNBOUND and NONIONISED form of the drug crosses the membrane.
  • Nonionised form needs to be lipophilic enough to be reabsorbed

Cu+ Cu0 Cur0 Cur+

22
Q

Urine pH varies:

A

4.5 – 7.6 depending on physical activity, diet etc.

23
Q

Weak acids - CLR is urine pH-sensitive if:

A

pKa = 3 – 7.5 and
lipophilic in nonionised form in order to be sensitive/to be reabsorbed

pKa < 3 strong acids, mostly ionised – minimal reabsorption

pKa > 7.5 very weak acids, mostly nonionised over urine pH range – more reabsorption and less renal elimination

24
Q

Effect of urine pH on elimination of weak acids?

A

As urine pH increases, sulpha. becomes more ionized, therefore less reabsorption and more drug cleared

Increased ionization
Decreaed reabsorption
Incresed excretion

25
Q

Passive reabsorption – effect of urine pH.

Weak bases - CLR is urine pH-sensitive if:

A

pKa = 6 – 12 and
lipophilic in nonionised form

pKa < 6 - mostly nonionised over urine pH range
pKa > 12 - mostly ionised – minimal reabsorption

26
Q

Effect of urine pH on urinary excretion elimination of weak bases – e.g., amphetamine

A

(urine recovery = how much molecule exctreted in 24 hours)

Urine pH –> Urinary recovery
Normal 40%
Acidic 70%
Alkaline 3%

27
Q

Passive reabsorption – effect of urine flow

A

Flow-dependent CLR occurs when drug is reabsorbed

If equilibrium is achieved – a higher urine volume means a higher amount of drug in urine and higher CLR

CLR = Rate of excretion /Cplasma
= Urine Flow x Urine conc /Cplasma

28
Q

At equilibrium: Cu = Urine Conc. CLR=

A

CLR = fu (fraction unbound) x Urine Flow

29
Q

Effect of forced alkalined diuresis – e.g., phenobarbitone

A
  • Drug overdose- forced diuresis and altered pH may be used to increase elimination of the drug
  • Only effective if renal excretion of the drug is significant under normal conditions!
30
Q

Reabsorption - summary

A
  • Passive process, dependent on drug properties
  • CLR is urine pH-sensitive only for weak acids and bases
  • CLR for very strong/ v. weak acids and bases is not dependent on urine pH
  • If reabsorption tends to equilibrium, CLR is urine flow dependent
31
Q

Identifying mechanism of renal elimination:

A

CLR = fu • GFR
Neither reabsorption nor secretion; or reabsorption = secretion

CLR > fu • GFR 	  
Net secretion (many acids, bases)
CLR < fu • GFR 	    
Net reabsorption(generally lipophilic molecules)
32
Q

Kidney as a metabolising organ :

A

CYP3A5 –> Cortex and medulla

CYP2D6 –> Paediatric; adult expression possibly low; Cortex > Medulla, Highest in PT and Loop of Henle

UGT1A9–> PT, DT, LoH, CD

Carboxylesterases –>
PT, Bowman’s capsule

33
Q

Changes in physiological parameters in chronic kidney disease. Kidney:

A

Decreased QR and kidney weight

Decreased GFR
Stages 1-5: ≥ 90 to <15 mL/min/1.73m2

Changes in tubular surface area?

Decreased tubular secretion

  • decreased Transporter expression/activity
  • Inhibitory effect of uremic solutes
  • Decreased Proximal tubule cell number
  • Decreased Renal metabolism
34
Q

Changes in physiological parameters in chronic kidney disease. Liver:

A
  • Decreased CLH for nonrenally cleared drugs
  • Downregulation or inhibition of CYPs
  • Decreased activity OATP (SN-38)
  • Decreased UGT1A9, -2B7
35
Q

Changes in physiological parameters in chronic kidney disease. GI:

A
  • Increased Gastric emptying time
  • Increased pH
  • Expression of CYPs?
36
Q

Other factors that may affect protein binding:

A
  • Competition for binding sites by uremic solutes

- Limited data suggest elevated -acid glycoprotein

37
Q

Impact of renal disease/impairment on drug dosage regimen:

A

Leads to increased plasma concentrations – risk of
toxicity:

Dose adjustment needed if:

  • Fraction of drug excreted unchanged (via kidneys) is > 50%
  • Narrow therapeutic window
  • Active metabolites – e.g., morphine 6-glucuronide
  • Impaired metabolism - e.g., polymorphic enzyme - CYP2D6

The Medicine Y3 Semester 1 - Drug disposition (14 decks)

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