DOSAGE

ADJUSTMENT IN
RENAL DISEASE

PRIYA SUNNY PHILIP

2ND YEAR PHARM D POST BACC
INTRODUCTION

KIDNEY

 Drug elimination.
 Excretion of metabolic waste products.
 Maintains normal fluid volume & electrolyte
composition.
 Regulates BP.
 Stimulates RBC production.
 N
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N
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DRUG ABSORPTION

 Changes in gastrointestinal transit time

 Gastric pH
 Edema of the gastrointestinal tract
 Vomiting and diarrhoea
 Antacid administration

Drug absorption is slowed and/or that the

extent of absorption is reduced as the result
of the development of CKD.
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N
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 An increase in bioavailability has been
noted for some β-blockers - bufuralol,
oxprenolol, propranolol, and tolamolol;
dextropropoxyphene; and
dihydrocodeine.

 unexpected adverse effects have only

been demonstrated with
dextropropoxyphene and
dihydrocodeine.
DRUG DISTRIBUTION

N
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The volume of distribution is increased

 Decreased protein binding - acidic drugs (e.g.,

warfarin and phenytoin)
binding of basic drugs (e.g., quinidine and
lidocaine) is normal or only slightly decreased or
increased.

 Increased tissue binding, or

 Pathophysiologic alterations in body

composition.
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Eg: Erythromycin, Phenytoin, Furosemide,
Gentamicin

The volume of distribution is decreased

 Decrease in tissue binding as a result of

competitive inhibition by endogenous or
exogenous substances.

Eg: Chloramphenicol, Digoxin, Ethambutol

METABOLISM

N
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 Preclinical evidence states that CKD may
lead to alterations in Nonrenal clearance
as the result of changes in cytochrome
P450 (CYP)-mediated metabolism in the
liver and other Organs.

 In addition to changes in hepatic metabolism,

chronic renal failure has also been shown in
animals to affect the expression and activity of
CYP enzymes in the intestine.
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 Nonrenal Clearance decreased –
 Cefotaxime, Erythromycin, Isoniazid,

 Methylprednisolone, Zidovudine.

 Unchanged-
 Acetaminophen, Chloramphenicol,
 Theophylline

 Increased-
 Nifedipine, Phenytoin.
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RENAL EXCRETION

 Alterations in filtration, tubular

secretion, or reabsorption.

 Quantitation of the patient’s renal

function - measurement of creatinine
clearance or serum creatinine
concentration.
DOSAGE ADJUSTMENT
GUIDELINES
Fixed dose or interval.

 Mild renal insufficiency – 20 to 50

mL/min.
 Moderate renal insufficiency – CLcr 10
to 20 mL/min.
 Severe renal insufficiency - clearance of
<10 mL/min.
 D(f) = D(n) × Q

 Q = CLfail/Clnorm
The ratio (Q) of the estimated
elimination
rate constant or total body clearance
of the patient relative to subjects with
normal renal function.

 τ (f) = τ(n)/Q
GFR
 The gold standard quantitative index of kidney
function is a measured GFR.

 Protein intake may increase GFR.

 The GFR is expressed as the volume of plasma

filtered across the glomerulus per unit time.

 The normal values for GFR are 127 ±

20mL/min/1.73 m² for men.
 and 118 ± 20 mL/min/1.73 m² for women.
 GFR cannot be measured directly in humans,
clearance methods that use substances that are
freely filtered without additional clearance because
of tubular secretion or reduction as the result of
reabsorption are required.

 The substance should not be susceptible to

metabolism within renal tissues and should not
alter renal function.

 Thus GFR is equivalent to the renal clearance of

the solute marker.
GFR = renal CL = (Ae) / AUCo–t
where, Ae - the amount of marker excreted
in the urine in a specified period of time,
t,
and AUCo-t is the area under the plasma-
concentration-versus-time curve of the
marker.
Markers- exogenous agents, such as inulin,
iothalamate, iohexol, and radioisotopes.
Endogenous compounds – creatinine.
CREATININE CLEARANCE
EQUATIONS

 In adults - Cockcroft and Gault

produces consistent results in patients of
average size and build, with stable renal
function and a SCr less than 3 mg%.

 The Salazar and Corcoran equation derived for

obese patients.
MDRD
 For the estimation of GFR.

 six-variable Modification of Diet in Renal Disease

Study (MDRD6) equation:
GFR = 170 × (Pcr)-0.999 × [Age]-0.176 ×
[0.762 if patient is female] ×
[1.180 if patient is black] ×
[SUN]-0.170 × [Alb]-0.318

where , Pcr = plasma creatinine,

SUN = serum nitrogen concentration,
and Alb = serum albumin concentration.
 provided a more precise estimate of GFR than
measured CLcr or CLcr estimated by the
Cockcroft-Gault equation.

 Four variable version of the original MDRD

equation:
GFR = 186* (Pcr)-1.154 × (Age)-0.203 ×
(0.742 if patient is female) × (1.210 if
patient is black)

 less accurate than the Cockcroft-Gault equation in

healthy subjects, diabetic patients with normal
GFR, and healthy potential kidney donors.
MDRD equations should not be used

 ill, hospitalized patients

 individuals with normal renal function,
 used with caution in children, the elderly, and
those with extremes in muscle mass (cachectic
and obese)
 renal drug dose adjustment
ESTIMATION OF CREATININE CLEARANCE IN
ADULTS WITH STABLE RENAL FUNCTION

Cockroft and Gault

 Men: CLcr = (140 — age) ABW/

(Scr × 72)
 Women: CLcr × 0.85
CHILDREN
Renal function does not mature to reach adult values
until one year of age.
 rapid changes in GFR.
 Estimation of CLcr - Schwartz is dependent on the
child’s age and length:
GFR = [length (cm) × k] / Scr
where, k is defined by age group:
pre-term infants = 0.33
infant (1 to 52 weeks) = 0.45;
child(1 to 13 years) = 0.55;
adolescent male = 0.7;
and adolescent female= 0.55.
ELDERLY
Age-related decline in renal function.
 decreased GFR.
 Decreased muscle mass and resultant lower
production rate of creatinine.
 Body weight.
 Volume status. Patients with dehydration have a
higher predisposition to drug toxicity. The total
body volume decreases by 10 to 15%.
 Reduced tissue perfusion, and increase in fat
content.
 Coexisting hepatic dysfunction.
OBESE
 IBW is used in place of actual body weight
(ABW) in the Cockcroft-Gault equation, where:

 IBW(kg, males) = 50 + 2.3 (Height in inches >60)

 IBW (kg, females) = 45 + 2.3 (Height in inches
>60)

 An alternative approach - Salazar-Corcoran

equation
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