Drug Dosing in Renal Failure.pdf

An insight into certain concepts pertinent to dosing adjustments in CKD and/or renal disorders.

1. Drug Dosing in Renal Failure

3. The conc. of the drug in the urine is the net result of
filtration + secretion (minus the reabsorption).

Rate of excretion = Filtration rate + Secretion rate –
Reabsorption rate

A
c = (A
filt + A
sec) – A
reabs

Cl
R = A
c / C

•where, A
c = amt. of drug ‘cleared’ or excreted by the
kidneys
•C = plasma drug conc.; Cl
R = Renal clearance

Overall Cl = renal Cl + non-renal Cl

4. Factors affecting Cl
R
•Physico-chemical props. of the drug
•Plasma conc. of the drug
•Urine pH
•Blood flow to the kidneys
•Biological factors
•Drug interactions
•Drug states

5. Disease states
Renal dysfunction: Impairs drug elimination (mainly
those drugs excreted primarily through urine);
Uremia: characterized by impaired GFR; impaired Cl
R;
accumulation of fluids and proteins in the plasma;


Renal function determination
•By estimating the GFR
•Exogenous and endogenous markers have been used
for this purpose;
•The marker should be entirely excreted unchanged in
the urine; must be physiologically and p’cologically
inert.

6. •Rate at which these markers are excreted in the urine
reflect the status of GFR (possibility of renal
dysfunction or not).
•Inulin (exogenous fructose polysacch.) and Creatinine
Inulin Cl provides accurate estimate of GFR, but the
process is tedious;

Creatinine Clearance (CrCl or Cl
cr)
•Creatinine: Endogenous amine produced by muscle
catabolism; excreted unchanged by GF only
•Cl
cr can be correlated to the steady state conc. (Css or
C
ss) of creatinine in plasma;
•Depends on: age, gender, weight, disease state among
other factors

8. Direct method: determine amt. of creatinine excreted
in urine over a 24 hr. period; and mean of S
cr from
blood samples taken before and after urine collection







 Normal Cl
cr value = 120 – 130 ml/min.
Cl
cr = 20 – 50 ml/min. (moderate renal
impairment)
Cl
cr = < 10 ml/min. (severe renal impairment)

9. Renal Function is calculated by:

10. Chronic Kidney Disease
Definition:
A CKD patient has abnormalities of kidney function or
structure present for > 3 months.
The definition of CKD includes…
•all individuals with markers of kidney damage, or
•those with an eGFR of < 60 ml/min/1.73m
2
on at least
2 occasions 90 days apart (with or without markers of
kidney damage).

11. Markers of kidney disease:
•Albuminuria (ACR > 3 mg/mmol),
•Haematuria (or presumed or confirmed renal origin),
•Electrolyte abnormalities due to tubular disorders,
•Renal histological abnormalities,
•Structural abnormalities detected by imaging (e.g.
polycystic kidneys, reflux nephropathy)
•H/o kidney transplantation.

13. CKD Classification
Based on the eGFR and the level of proteinuria and helps to
risk-stratify patients.
Patients are classified as…
•G1-G5 (based on the eGFR), and
•A1-A3 (based on the ACR which is albumin:creatinine ratio)

E.g.,
•A person with an eGFR of 25 ml/min/1.73 m
2
and an ACR of 15
mg/mmol has CKD G4A2.
•A person with an eGFR of 50 ml/min/1.73 m
2
and an ACR of 35
mg/mmol has CKD G3aA3.

14. CKD Classification (contd’.)

Patients with an eGFR of >60 ml/min/1.73m
2
should
not be classified as having CKD unless they have
other markers of kidney disease.

GFR category G2 may be over-diagnosed by eGFR
because sometimes equations used to estimate GFR
may give falsely low results in people with near-normal
function.

15. P’cokinetic considerations in Uremic Patients
May exhibit p’cokinetic alterations in BA, V
d, and Cl.
↓ed oral BA (probable) of a drugs in severe uremia due to
disease-related changes in GI motility and pH (↓ed oral BA
caused by nausea, vomiting, and diarrhea).
Mesenteric blood flow may also be altered.
↑ed Oral BA (probable) of drugs which have a high first-pass
effect (e.g., propranolol ) in patients with renal impairment due
to ↓ in first-pass hepatic metabolism.
The apparent V
d depends largely on drug-plasma protein
binding in tissues and total body water.

16. P’cokinetic considerations in Uremic Patients (contd’.)

Renal impairment may alter the drug distribution due
to changes in fluid balance, drug-protein binding,
among other factors.
↓ed PP binding of weak acidic drugs in uremic patients;
PP binding of weak basic drugs are less affected.


•↓ed drug-protein binding results in a larger fraction of free drug
and an increase in V
d.

17. P’cokinetic considerations in Uremic Patients (contd’.)

↑ed net elimination t
1/2 (generally) due to the dominant
effect of reduced glomerular filtration.

Drug-protein binding may be further compromised due
to the accumulation of drug metabolites and various
biochemical metabolites (FFAs and urea), which may
compete for the protein-binding sites for the active
drug.

18. P’cokinetic considerations in Uremic Patients (contd’.)
↓ed total body clearance of drugs by….
•↓ in GFR, or
•↓ed hepatic clearance (Cl
H)
•active tubular secretion

The appropriate drug dosage regimen in uremic
patients is based on estimation of the remaining
renal function of the patient and a prediction of the
total body clearance.

Drug protein binding in uremic patients is also
dependent on accumulation of urea, nitrogenous
wastes, and drug metabolites.

19. P’cokinetic considerations in Uremic Patients (contd’.)


A complete pharmacokinetic analysis of the drug in the
uremic patients is not possible.
The patient's uremic condition may not be stable and may
be changing too rapidly for pharmacokinetic analysis.

20. Dose adjustment in RF patients
Drugs in pts. with RF have altered p’cokinetic profile:
•↓ed Cl
r and elimination rate; ↑ed elimination t
1/2;
altered apparent V
d;

Dose adjustment for drugs in uremic or renally
impaired patients should be made in accordance with
p’codynamic and p’cokinetic changes of the drug in
each individual patient.

Active metabolites of the drug may also be formed and
must be considered for additional pharmacologic effects
when adjusting dose.

21. Dose adjustment in RF patients (contd’.)

Dose must be altered (tailored / customized) to each
individual patient.
Drugs excreted by the kidneys require a huge reduction
in doses in order to achieve therapeutic drug conc. in
patients w/ renal dysfunction.

22. Basis for Dose Adjustment in Uremic Patients
Loading dose:
•Is based on the apparent V
d of the patient;
•Is generally assumed that the apparent V
d is not
altered significantly, (implying that the loading dose of
the drug is the same in uremic patients as in subjects
with normal renal function).

Maintenance dose :
•Is based on drug CL in the patient.
•In uremic patients, the ↓ed rate of renal drug excretion
leads to a ↓ed total body CL.
•Most methods for dose adjustment assume non-renal
drug CL to be unchanged.
•The fraction of normal renal function remaining in the
uremic patient is estimated from CrCl.

23. Basis for Dose Adjustment in Uremic Patients (contd’.)

•After the remaining total body CL in the uremic patient
is estimated, the appropriate dosage regimen may
be developed by:
(a) decreasing the maintenance dose,
(b) increasing the dosage interval, or
(c) changing both maintenance dose and dosage
interval.

24. Basis for Dose Adjustment in Uremic Patients (contd’.)

Although total body clearance is a more accurate
index of drug dosing, the elimination half-life of
the drug is more commonly used for dose
adjustment due to it’s convenience .

CL allows to predict steady-state drug
concentrations (Css), while elimination half-life
yields information on the time it takes to reach
steady-state concentration.

25. Assumptions of Giusti-Hayton Method and Tozer
approach:
Kidney dysfunction does not affect the non-renal
excretion.
↓ in kidney function….
•proportional ↓ in rate of renal drug elimination;
•does not affect non-renal drug elimination;
•does not affect the drug’s absorption and/or
distribution.

26. U
Cr x V

CrCl = ________
S
Cr x t

where,
U
Cr = urine creatinine conc.;
V = volm. of urine collected;
S
Cr = serum creatinine (from blood) measured at
midpoint of urine collection;
t = time interval of urine collection

27. Issue with CrCl formula:
Some creatinine found in the urine is due to ‘Tubular
Secretion’.
CrCl formula therefore overestimates GFR at all levels
of renal function.
Dgs. (like amiloride, cimetidine, trimethoprim,
salicylate, triamterene, spironolactone) which inhibit
secretory function may increase SCr, and decrease the
overestimate, without actually affecting the GFR.

28. Note FYI:
Declining kidney function is accompanied by an
increasing contribution of tubular creatinine
secretion to the total creatinine
clearance; secretion may account for as much as 50%
of creatinine clearance in the later stages of chronic
kidney disease (CKD).

29. Dosing adjustment is not usually done unless
GFR < 1 ml/s/70 kg (GFR 60 ml/min/1.73m
2
)

Dosage regimen need NOT be altered if fraction of drug
excreted unchanged in urine (f
u) is ≤0.3% and renal
function is ≥ 0.7% of normal;
•Based on some assumptions: inactive metabolites;
unaltered binding characteristics and drug availability;
kidney function is not greatly reduced;
BUT….
•If f
u is almost unity and renal function is almost
zero, dosing should be reduced drastically
(elimination is extremely slowed down);
•The significance of non-renal Cl increases in such
conditions.

30. Dosing adjustment usually includes dose reduction,
increasing dosing interval(s), or both.

Dose reduction more consistent dg. conc. (but
↑es toxicity risk if dosing interval is too short)

↑ ing Dosing interval ↓es toxicity risk (but ↑es risk
of sub-therapeutic effect is concs. fall below MEC)

Loading doses are usually not adjusted.
When rapid effect is needed (in severe infection, etc.),
patient’s response is the most imp. factor to consider.

31. Creatinine Clearance (CrCl) in Adults
•The formula below estimates CrCl from SCr concentration.
•This method considers both the age and the weight of the patient.
•For males,



•For females, use 90% of the Cl
Cr value obtained in males.



•FYI: SCr and C
Cr refer to the same parameter serum creatinine conc.

32. The nomogram method of Siersback-Nielsen et al (1971):
•estimates CrCl based on age, weight, and SCr conc.

33. Homework:
What is the creatinine clearance for a 25-year-old male patient
with C
Cr of 1 mg/dL and a body weight of 80 kg?

34. How to use the Siersback-Nielsen nomogram:
•Connect the patient's weight on the 2
nd
line from the left with the
patient's age on the 4
th
line with a ruler.
•Note the point of intersection on R and keep the ruler there.
•Turn the right part of the ruler to the appropriate serum creatinine
value and the left side will indicate the clearance in mL/min.

35. Nomogram of Traub and Johnson (1980):
For calculating CrCl in pediatric patients (aged 6–12
years)

36. Drug classes requiring dosage adjustment in CKD

37. Subsequent doses should be titrated based on patient’s
response and/or serum conc.
Conventional GFR estimates are not accurate for
children, elderly pts., pregnant women, weight
extremes (‘over’ or ‘under’ weight)
For obese pts. (> 30% over IBW):
Use CG eqn. and use Lean body weight;
Increase the ‘No weight’ CrCl by a factor of 0.3 – 0.4
Use the Salazar-Corcoran eqn.


Elderly patients:
Usual methods overestimate GFR;
Dosing should be based on risk vs benefit analysis,
patient’s response and clinical judgment.

38. Required dose in patients with renal impairment can be
calculated by:
Normal dose x RF
where, RF = Renal Function
Dosing interval (in hrs.) can be derived by:

Normal interval (in hrs.) / Renal Function

When the drug is excreted by both renal and non-renal
mechanisms, the dose to be administered in RF
patients is:

40. In pts. w/ CKD stages 1 – 5 (pre-dialysis), the
Cockroft-Gault (CG) eqn. is used to estimate the CrCl
in the presence of stable renal function.

(140-age) x (W)
CrCl = ______________
(72) x S
Cr

CrCl (females) = CrCl (males) x 0.85

where, S
Cr is in mg/dl and W is in kgs
The IS conversion for males is
1.23 x (140-age) x (W)
CrCl = ___________________
(72) x S
Cr

41. Weight-corrected (‘No weight’) CG equ ation:
meta-analysis showed this formula provided the best
estimate of GFR (Park E., et al., 2012)

42. CKD-EPI Equations for calculation of eGFR

CKD-EPI creatinine equation (Levey, et. al.)

eGFR = 141 x min(S
Cr/κ, 1)
α
x max(S
Cr /κ, 1)
-1.209
x
(0.993)
Age
x [1.018 if female] x [1.159 if Black]

•eGFR (mL/min/1.73 m
2
); S
Cr = standardized serum creatinine (mg/dL)
•κ = 0.7 (females); 0.9 (males); α = - 0.329 (females), - 0.411 (males)
•min = indicates the minimum of S
Cr/κ or 1
•max = indicates the maximum of S
Cr/κ or 1
The CKD-EPI eqns. are mainly used for identifying CKD
and staging the degree of severity.
More accurate than the MDRD4 equation, especially for
patients with higher levels of GFR.
Not yet being used in Malaysia.

43. CKD-EPI Equations for calculation of eGFR (contd’.)

CKD-EPI cystatin C equation (Inker, et. al.)

eGFR = 133 x min(S
Cys/0.8, 1)
-0.499
x max(S
Cys /0.8, 1)
-1.328
x
(0.996)
Age
x [0.932 if female]

•eGFR (mL/min/1.73 m
2
); S
Cys = standardized serum cystatin C
CKD-EPI creatinine-cystatin C equation (Inker, et. al.)

eGFR = 135 x min(S
Cr/k, 1)
-a
x max(S
Cr /k, 1)
-0.601
x
min(S
Cys/0.8, 1)
-0.375
x max(S
Cys /0.8, 1)
-0.711
(0.995)
Age
x
[0.969 if female] x [1.018 if Black]

K = 0.7 (females), 0.9 (males);
a = -0.248 (females), -0.207 (males)

44. MDRD4 equation :



•Where, eGFR = estimated GFR (ml min
-1
/ 1.73 m
2
BSA)
•(Cs)cr = serum creatinine conc.(mg/dl)

If serum albumin (ALB) and BUN values are known,
then the formula can be expressed as:





•(Cs)cr and BUN units is mg%; ALB is %

45. MDRD4 eqn. limitations:
Underestimates eGFR for patients with GFR > 60
ml/min
MDRD4 eqn. is not adjusted for body weight…
•Smaller eGFR values for heavy patients,
•Larger eGFR values for thinner patients

Jelliffe Equation:

CrCl (ml/min) = {[98 – 0.8 × (age – 20)] × [1 – (0.01 × sex)] ×
(BSA/1.73)}/(SCr × 0.0113)



vs CG eqn.

46. Dialysis and Hemoperfusion
For severe renal failure cases
To remove toxic waste products, drugs and
metabolites, which accumulate in the body;
Dialysis: Process in which easily diffusible substances
are separated from poorly diffusible substances by a
semi-permeable membrane.

2 types: Hemodialysis and Peritoneal dialysis

Peritoneal dialysis:
•The semi-permeable membrane is the natural
membrane of the peritoneal cavity.

47. Hemodialysis(HD)
•Artificial, semi-permeable membrane , outside the body
(extracorporeal dialysis);
•Equipment is Hemodialyzer (Artificial Kidney);
•Removes toxic wastes from the body;
•Very useful in treatment of overdose or poisoning
situations;
•Patients require hemodialysis every 2-3 days; each
session lasts 3-4 hrs. (average).

48. Factors governing HD
•Water solubility: only water-soluble drugs; lipophilic
drugs (e.g., glutethimide) cannot be dialyzed;
•Mol. Size: only those drugs < 500 Da; larger sized
drugs (e.g., vancomycin) cannot be dialyzed;
•Protein binding: PP-bound drugs cannot be dialyzed as
this process is a passive diffusion process;
•V
d or V: Drugs with large Vd easily distributed
throughout the body difficult to remove by
dialysis (e.g., digoxin)

49. Rate of drug removal by dialyzer depends on:
•Blood flow rate to the machine
•Dialyzer’s performance
Dialysance (Dialysis Cl): Ability of the dialyzer to
clear the drug from the blood.




•where, Cl
d = Dialysance
•Q = blood flow rate to dialyzer
•C
in = drug conc. in blood entering the dialyzer
•C
out = drug conc. in blood exiting the dialyzer

50. Dosage regimen adjustment for hemodialysis pts.
1° objective: To design an appropriate dg. regimen for
admn. on dialysis days such that the dose given at the
end of dialysis is sufficient to achieve the desired max.
drug conc.

Prospective individualization of dosage regimen is
recommended for dgs. with narrow therapeutic index
(aminoglycosides, vancomycin, etc..).
Why is this imp. in ambulatory care patients on chr.
hemodialysis?
Avoid admn. of dgs. in the hrs. just before HD to
prevent excessive removal of the dgs. during the HD
process.

51. Admn. of higher doses just prior to HD has been
recommended for certain drugs to compensate the
removal of drugs during HD (Mohamed et al., 2007;
Scott MK et al., 1997).
Use simple consistent admn. schedules that minimize
the need for variable drug doses to be administered on
dialysis and non-dialysis days.
Dose to be administered post-HD:
D
postHD = V x (C
max – C
postHD)
C
postHD = C
preHD x (e
-kt
+ e
-kHDt
)

•where, V = volm. of distribution for the drug of interest
•e
-kt
= fraction of drug that remains post-HD, as a result of
the patient’s residual total body Cl.
•e
-kHDt
= fraction of drug that remains post-HD, as a result
of the elimination by the dialyzer.

52. Cl
HD = {C
art – C
ven/C
art} x [Qb (1 – Hct)]

•where, C
art = drug conc. in plasma entering the dialyzer
•C
ven = drug conc. in plasma exiting the dialyzer
•Qb = blood flow through the dialyzer
•Hct = patient’s hematocrit value

Dosage individualization for patients on CRRT
CRRT is a viable management approach for
hemodynamically unstable patients with or without
AKI.
The dosage regimen for patients receiving CRRT can be
individually ascertained by adding the estimated or
measured drug Cl by CRRT to the patient’s residual
drug Cl.

53. Roles of the pharmacist
Identify patients who are at high risk for CKD (DM,
HTN, Glomerulonephritis).
Verify the renal functional status of the patient based
on the lab values (incl. of the latest test results).
Identify the medications which require dosage
adjustment, and determine the dosage adjustment
(use BANND CAMP, among others).
Check medication profile for DIs which could …
•affect serum levels of renally-excreted drugs (p-gp
inhibitors);
•↓ renal function (nephrotoxic dgs.)
Communicate the recommendations regd. patient’s
medication(s) to the doctor.
Set up monitoring plan for the medications.

54. FYI
The K/DOQI classification of CKD
K/DOQI = Kidney Disease Outcome Quality Initiative;
(by the National Kidney Foundation)

55. To be continued…..