Professional Documents
Culture Documents
Setyo Purwono
Farmakologi & Toksikologi
FK - UGM
LOCUS OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound
SYSTEMIC
Bound Drug CIRCULATION
BIOTRANSFORMATION
The Kidney as Excretory Organ
GFR
RENAL EXCRETION OF DRUGS
INTACT NEPHRON HYPOTHESIS: Provides a
basis for dose adjustment when renal excretion of
drug is impaired.
• Regardless of mechanism, renal drug elimination
declines in parallel with decreases in GFR.
• Therefore, CLCr can be used to assess impact of
renal impairment on renal excretion of drugs.
CL E CL R CL NR
CLR = RENAL CLEARANCE
CLNR = NON-RENAL CLEARANCE
BASIC “FULL” STUDY DESIGN
ESRD NORMAL
CLR = α CLCr
U = URINE
CONCENTRATION
V = URINE VOLUME
P = PLASMA
CLEARANCE TECHNIQUES FOR
ASSESSING RENAL FUNCTION
GLOMERULAR FILTRATION:
Normal: 120 – 130 mL/min/1.73 m2
CLEARANCE MARKERS:
Inulin
Creatinine
125
I-Iothalamate
RENAL BLOOD FLOW:
Normal: ♂ 1,209 ± 256 mL/min/1.73 m2
♀ 982 ± 184 mL/min/1.73 m2
CLEARANCE MARKER:
Para-Aminohippuric Acid
Tests of renal function
Estimate GFR:
Calculating Creatinine Clearance
Cockcroft-Gault Equation
CrCl men = (140 - Age) x LBW
Scr x 72
CrCl women = CrCl men x 0.85
Modification of Diet in Renal Disease Equation (MDRD)
CrCl men = (Scr) -1.154 x (age) -0.203
CrCl women = CrCl men x 0.742
CrCl African American = CrCl men x 1.210
Other Formulas Include (but are not limited to):
• Jelliffe Method • Schwartz Formula (children)
• Wright Formula • Counahan-Barratt Equation (children)
Prescribing in Kidney Disease
Renal Renal
Insufficiency Failure
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
> 90 90-60 60-30 30-15 15; ESRD
AUGMENTIN
(Oral) Usual dose: 875mg po >30/ no change || 10-30/
q12h or 250-500mg po 250-500mg q12h || <10/
q8h 250-500mg po q24h
CEFEPIME >60/ 0.5-2g q12h || 30-
(MAXIPIME) Mild to moderate 60/ 0.5g-2g q24h || 11-
infection: 500mg to 2g 29/ 0.5g-1g q24h || <10/
ivpb q12h. 250-500mg q24h or 0.5-
Severe: 2g ivpb q8h. 2g q48h. || HD: 1g AD ||
PD: 1-2 grams q48h
• DOSAGE ADJUSTMENT
1/2 normal dose if CLCr < 30 mL/min
• PHARMACOKINETICS
Following I.V. of I.M. administration in normal
subjects,
~ 75% of drug is recovered from the urine as
parent compound.
* Physician’s Desk Reference. 58th edition, 2004.
NOMOGRAM FOR CIMETIDINE DOSING*
CLE ≈ 25% OF
NORMAL IF
FUNCTIONALLY
ANEPRHIC
• EXAMPLES:
PROCAINAMIDE - Acetylation
PHENYTOIN - Hydroxylation
PROCAINAMIDE ACETYLATION
RENAL
ELIMINATON
NAT2: FAST VS. SLOW NORMALLY 50%
Procainamide Kinetics in
DIALYSIS PATIENTS*
FUNCTIONALLY
NORMALS ANEPHRIC PATIENTS
Fast Slow Fast Slow
T1/2 (hr) 2.6 3.5 12.2 17.0
CLE (L/kg) 809 600 118 94
CLR (L/kg) 426 357 0 0
CLNR (L/kg) 383 243 118 94
Vd(ss) (L/kg) 1.95 1.93 1.41 1.93
* From: Gibson TP. Kidney Int 1977;12:422-9.
PHENYTOIN HYDROXYLATION BY P450
UNCHANGED BIOAVAILABILITY:
CIMETIDINE
DIGOXIN
DECREASED BIOAVAILABILITY:
D-XYLOSE
FUROSEMIDE
INCREASED BIOAVAILABILITY:
PROPRANOLOL
DEXTROPROPOXYPHENE
Risk Factors for nephrotoxicity or Renal Failure
1.Susceptible kidney
Advanced age
Prior renal insufficiency , Renal transplantation
2.Comorbid condition associated with renal insufficiency
Diabetes Mellitus , Multiple Myeloma
Systemic Lupus Erythematosus , Proteinuria
Acute trauma (associated with Rhabdomyolysis)
3.Sodium-retaining states
Cirrhosis , Congestive Heart Failure
Nephrotic Syndrome
4.Diminished Effective Circulation
Dehydration , Vascular disease
Coronary Artery Disease , Sepsis or shock
5.Electrolyte or acid-base disturbance
Metabolic Acidosis , Hypokalemia
Hypomagnesemia , Hyperuricemia or Hyperuricosuria
6.Nephrotoxic Drugs alone or in combination
Nephrotoxic Drugs:Drug-induced Nephrotoxicity
Antibiotics
A.Aminoglycosides
B.Amphotericin B
C.Tetracycline
D.Acyclovir
E.Pentamidine
Chemotherapy and Immunosuppressants
A.Cisplatin
B.Methotrexate
C.Mitomycin
D.Cyclosporine
Heavy Metals
A.Mercury
B.Lead
C.Arsenic
D.Bismuth
Miscellaneous Drugs
A.Radiographic contrast
B.ACE Inhibitors
C.NSAIDs
D.Aspirin