Pharmacokinetics variation of drugs in Kidney diseases

1. PHARMAKOKINETIC
VARIATIONS IN KIDNEY
DISEASES
Biopharmaceutics

2.  The kidney is an important bean shaped
organ in regulating body fluids, removal of
metabolic waste, electrolyte balance and
drug excretion from body located at the
rear of the abdominal cavity in
the retroperitoneal space, the kidneys
receive blood from the paired renal
arteries, and drain into the paired renal
veins. Each kidney excretes urine into
a ureter which empties into the bladder.

3.  Common clinical conditions involving
the kidney include the nephritic and
nephrotic syndromes,
renal cysts, acute kidney injury,
chronic kidney disease,
urinary tract infection,
nephrolithiasis, and
urinary tract obstruction.

4.  Impairment of kidney function effects
pharmacokinetics of drugs.Some of the
common causes for kidney failure include
disease, injury, and drug intoxication.
 Impaired renal function will result in
increased bioavailablity of drugs exhibiting
first-pass metabolism when the function of
drug metabolizing enzyme is compromised.
 The kidneys can excrete only water-soluble
substances.One function of metabolism is
to convert fat soluble drugs into water-
soluble metabolites.

5. Weak acids and weak bases gain or lose
protons depending on the pH. Their
movement between aqueous & lipid mediums
varies with the pH.
Weak acids are excreted faster in alkaline
urine and vice versa.
The sodium bicarbonate alkalinizes the urine,
raising the number of barbiturate ions in the
renal filtrate. The ionized particles cannot
pass easily through renal tubular membranes.
Therefore, less drug is reabsorbed into the
blood and more is excreted by the kidneys.

6. EFFECT OF RENAL DISEASES ON DRUG
DISTRIBUTION:
 Impaired renal function is associated with
important changes in the binding of drugs
to plasma proteins. The reduced binding
occurs, when renal function is impaired, for
the following reason
 Reduction in serum albumin concentration.
 Structural changes in binding sites.
 Displacement of drug from albumin binding
sites by organic molecules that
accumulates in uremia.

7. The volume of distribution of a drug can
decrease if compounds normally excreted by
the kidney accumulates to the extent that
displacement of drug from tissue binding
sites occur.
Distribution of drugs is altered by changes in
ECF, plasma protein binding, and tissue
binding.
Water-soluble drugs are distributed in ECF,
including edema fluid, which is increased in
renal impairment.

8. Plasma protein binding of acidic drugs:
Reidenberg and Drayer have stated that
protein binding in serum from uremic patients
is decreased for every acidic drug that has
been studied. Most acidic drugs bind to the
bilirubin binding site on albumin but there are
also different binding sites that play a role.
One consequence of reduced protein binding
is that the distribution volume elemination
clearance of these drugs is increased.
For example, digoxin can be displaced from
tissue by metabolic products that cannot be
excreted by impaired kidneys.

9. Albumin is the main drug-binding plasma protein for
acidic drugs. Drug binding with albumin is decreased with
renal impairment. This is due to decreased albumin or
reduced binding capacity.
Reasons for decreased albumin include:
 Nephrotic states in which albumin is lost in the urine.
 Hypermetabolic states (stress, trauma, sepsis) in which
protein breakdown exceeds protein synthesis.
 Liver disease that decreases hepatic synthesis of
albumin.
Reasons for reduced binding capacity include:
 Uremic toxins that compete with drugs for binding sites.
 Structural changes in the albumin molecule.

10.  Odar-Cederlof and Borga studied phenytoin
to illustrate some of the changes in drug
distribution and elimination that occur in
patients with impaired renal function. In
patients with normal renal function, 92% of
the phenytoin in plasma is protein bound.
However, the percentage that is unbound
or “free” rises from 8% in these individuals
to 16%, or more, in hemodialysis-
dependent patients.
 The three-fold increase in hepatic
clearance that was observed in uremic
patients was primarily the result of
decreased phenytoin binding to plasma
proteins.

11. Plasma protein binding of basic and
neutral drugs:
 The protein binding of basic drugs tends to
be normal or only slightly reduced.In some
cases, this may reflect the facts that these
drugs bind to alpha1–acid glycoprotein and
that concentrations of this glycoprotein are
higher in hemodialysis-dependent patients
than in patients with normal renal function.
 For basic drugs (clindamycin, propafenone),
larger amounts of a basic drug is bound and
a smaller amount is free to exert an effect.

12. Tissue binding of drugs:
 The distribution volume of some drugs also
can be altered when renal function is
impaired. Sheiner et al have shown that
impaired renal function is associated with
a decrease in digoxin Vd (L/kg). This
presumably reflects a reduction in tissue
levels of Na/K -ATPase, an enzyme
represents a major tissue-binding site for
digoxin.

13. Effect on Absorption:
Absorption of oral drugs may be decreased
indirectly in renal failure by delayed gastric
emptying, changes in gastric pH, GI symptoms
such as vomiting and diarrhea, edema of the
GI tract (in the presence of generalized
edema).
In CRF, gastric pH is altered by Oral
alkalinizing agents (sodium bicarbonate,
citrate). This causes decrease in absorption
of oral drugs that require an acidic
environment for absorption. Increases
absorption of drugs that are absorbed from a
more alkaline environment.

14. The absorption of D –xylose is less complete
(48.6% vs. 69.4%) in patients with chronic
renal failure than in normal subjects.This
primary absorptive defect may explain the
fact that patients with impaired renal
function have reduced bioavailability of
furosemide and pindolol.
However, it also is possible that impaired
renal function will result in increased
bioavailability of drugs exhibiting first pass
metabolism when the function of drug
metabolizing enzymes is compromised.

15. Drug absorption and bioavailability, these
shortcomings can be overcome by
conducting a single study in which an
intravenous formulation of the stable isotope
labeled drug is administered simultaneously
with the oral drug dose.
This technique was used to study a 64-year-
old man with a creatinine clearance of 79
ml/min who was started on N-
acetylprocainamide (NAPA) therapy for
ventricular arrhythmias .
The oral NAPA dose was 66% absorbed in this
patient, compared to 91.6% ± 9.2% when this
method was used to assess NAPA absorption
in normal subjects.

16. Effect on Metabolism:
 Metabolism can increase, decrease, or does
not change by renal impairment.
 One factor is alteration of drug metabolism in
the liver. In uremia, reduction and hydrolysis is
slower, but oxidation by CYP enzymes and
conjugation reactions proceed at normal rates.
 Another factor is the inability of impaired
kidneys to eliminate drugs and active
metabolites.Metabolites may have
pharmacologic activity similar to or different
from that of the parent drug.

17. A third factor is impaired renal metabolism
of drugs. The kidney contains many of the
same metabolizing enzymes found in the
liver.
For example it has renal CYP enzymes,
which metabolize some chemicals and
drugs. Most drugs are not excreted by the
kidneys unchanged but are first
biotransformed to metabolites that are then
excreted.
Renal failure not only may retard the
excretion of these metabolites, which in
some cases have important pharmacologic
activity, but, in some cases, alters the
metabolic clearance of drugs.

18. Effect of Renal diseases on Drug
Metabolism:
 I. OXIDATIONS : NORMAL OR INCREASED
EXAMPLE: PHENYTOIN
 II. REDUCTIONS: SLOWED
EXAMPLE: HYDROCORTISONE
 III. HYDROLYSES
• PLASMA ESTERASE: SLOWED
EXAMPLE: PROCAINE
• PLASMA PEPTIDASE: NORMAL
EXAMPLE: ANGIOTENSIN
• TISSUE PEPTIDASE: SLOWED
EXAMPLE: INSULIN

19. IV. SYNTHESES
• GLUCURONIDE FORMATION : NORMAL
EXAMPLE: HYDROCORTISONE
• ACETYLATION: SLOWED
EXAMPLE: PROCAINAMIDE
• GLYCINE CONJUGATION: SLOWED
EXAMPLE: PAS
• O-METHYLATION : NORMAL
EXAMPLE: METHYLDOPA
• SULFATE CONJUGATION: NORMAL
EXAMPLE: METHYLDOPA
Clinical experience suggests that creatinine clearance
must fall below 25 ml/min before the acetylation rate of
procainamide is impaired.

20. Effect on Elimination:
 Excretion of many drugs is reduced in renal failure. The
kidneys normally excrete both the parent drug and
metabolites produced by the liver. Renal excretion
includes: glomerular filtration, tubular secretion, and
tubular reabsorption all of which is affected by renal
impairment. An adequate fluid intake is required to excrete
drugs by the kidneys.Any factor that depletes ECF
increases the risk of worsening renal impairment which
include:
 Inadequate fluid intake
 Diuretic drugs
 Loss of body fluids (bleeding, vomiting, diarrhea)

21.  In the kidneys of elderly, blood flow, GFR, and tubular
secretion of drugs is decreased. All of these changes slow
excretion and promote accumulation of drugs in the
body.Impaired kidney function greatly increases the risks of
adverse drug effects. For many drugs, CLE actually consists of
additive renal (CLR) and non renal (CL NR) components, as
indicated by the following equation:
CLE = CLR + CLNR
 Non-renal clearance is usually equated with drug metabolism,
but also could include hemodialysis and other methods of drug
removal.

22.  Generally one should consider a possible,
modest decrease in drug doses when
creatinine clearance is <50-60ml/min.
 A moderate decrease in drug doses when
creatinine clearance is <25-30ml/min.
 A substantial decrease in drug doses when
creatinine clearance is <15ml/min.
 LMW Heparin excreted by kidney if
eGFR<30ml/min lengthens elimination half
life causing drug accumulation thus
increased risk of bleeding not easily
reversed so need dose adjustments.

23. Use dosage adjustments in one of following ways:
Divide the dose you determined for normal renal function by
the dosage adjustment factor and continue with the same
dosage interval. (Dosage adjustment factor is the ratio of the
half life of the drug in the patient to the half life of the drug in
the normal person)
Continue with the same dose but multiply the dosage interval
you determined for normal renal function by the dosage
adjustment factor.
A regimen combined dose reduction and dose interval
prolongation may maintain a more uniform serum
concentration.

24. IMPORTANT MECHANISMS OF RENAL ELIMINATION OF
DRUGS
 GLOMERULAR FILTRATION:
• AFFECTS ALL DRUGS & METABOLITES OF APPROPRIATE
MOLECULAR SIZE
• INFLUENCED BY PROTEIN BINDING (f = FREE FRACTION)
DRUG FILTRATION RATE = GFR x f x [DRUG]
 RENAL TUBULAR SECRETION:
• NOT INFLUENCED BY PROTEIN BINDING
• MAY BE AFFECTED BY COMPETITION WITH OTHER DRUGS,
ETC.
EXAMPLES: ACTIVE DRUGS: ACIDS – PENICILLIN ,
BASES – PROCAINEAMIDE
METABOLITES: GLUCURONIDES, HIPPURATES, ETC.

25.  REABSORPTION BY NON-IONIC DIFFUSION
• AFFECTS WEAK ACIDS & WEAK BASES
• ONLY IMPORTANT IF EXCRETION OF FREE DRUG IS
MAJOR ELIMINATION PATH
EXAMPLES: WEAK ACIDS: PHENOBARBITAL ,
WEAK BASES: QUINIDINE
 ACTIVE REABSORPTION
• AFFECTS IONS, NOT PROVED FOR OTHER DRUGS
EXAMPLES: HALIDES: FLUORIDE, BROMIDE
ALKALINE EARTH METALS: LITHI

26. Reidenberg et al. have shown that renal secretion of
some basic drugs declines with aging more rapidly than
GFR. Also studies with N-1-methylnicotinamide, an
endogenous marker of renal tubular secretion, have
demonstrated some degree of glomerulo-tubular
imbalance in patients with impaired renal function.
Despite the paucity of detailed studies, it is possible to
draw some general conclusions from renal clearance
values:
• If renal clearance exceeds drug filtration rate , there is
net renal tubular secretion of the drug.
• If renal clearance is less than drug filtration rate, there
is net renal tubular reabsorption of the drug.

27. Adjustment and Guidelines:
 Therapy must be individualized according to the extent
of renal impairment. This is determined by measuring
creatinine, which is used to calculate creatinine
clearance as a measure of the GFR. Creatinine is
determined by muscle mass and the GFR, so its
measurement cannot be used as the sole indicator of
renal function.
 Serum creatinine is a relatively unreliable indicator of
renal function in elderly clients. Because they have
diminished muscle mass, they may have a normal
creatinine even if their GFR is markedly reduced.

28.  drugs (cimetidine and trimethoprim) increase creatinine and
create a false impression of renal failure. They interfere with
secretion of creatinine into kidney tubules.
 Some drugs are excreted exclusively by the kidneys
(aminoglycosides, lithium).
 Some drugs are contraindicated in renal impairment
(tetracyclines except doxycycline).
 Drugs can be used if safety guidelines are followed (reducing
dosage, using TDM and renal function tests, avoiding
dehydration).
 Drugs known to be nephrotoxic should be avoided when
possible. In some instances, however, there are no effective
substitutes and nephrotoxic drugs must be given.
 Some commonly used nephrotoxic drugs include
aminoglycoside antibiotics, amphotericin B, and cisplatin.

29. Aspirin is nephrotoxic in high doses, and protein binding of
aspirin is reduced in renal failure so that blood levels of active
drug are higher.
NSAIDs can decrease blood flow in the kidneys by inhibiting
synthesis of prostaglandins that dilate renal blood vessels.
When renal blood flow is normal, these prostaglandins have
limited activity.
When renal blood flow is decreased, their synthesis is
increased to protect the kidneys from ischemia. In those who
depend on PGs to maintain renal blood flow, NSAIDs result in
decreased GFR, and retention of salt and water. NSAIDs can
also cause kidney damage by a hypersensitivity reaction that
leads to ARF.

30.  Lithium is not metabolized by the body. It is entirely
excreted by the kidneys and has a very narrow
therapeutic range.
 Adequate renal function is required for lithium therapy.
If it has to be given in renal impairment, the dose must
be reduced and TDM must be done.
 80% of a lithium dose is reabsorbed in the proximal
renal tubules. The amount of reabsorption depends on
the concentration of sodium in the proximal tubules.
 A deficiency of sodium causes more lithium to be
reabsorbed => risk of lithium toxicity ↑.Excessive
sodium intake lowers lithium levels to non therapeutic
ranges.

31. Conclusions:
Prescribing in CKD is an ART.
No substitute for knowing the drug Pharmacology and
the individual patient.
Individualize “Go Low/Go Slow” is a good general rule.
Review medicine list including otc supplements at each
visit.
Watch for nephrotoxins.