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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
UxV
CL
P
U = URINE CONCENTRATION
V = URINE VOLUME
P = PLASMA CONCENTRATION
CLEARANCE TECHNIQUES FOR
ASSESSING RENAL FUNCTION
GLOMERULAR FILTRATION:
Normal: 120 – 130 mL/min/1.73 m2
CLEARANCE MARKERS:
Inulin
Creatinine
125I-Iothalamate
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
DOSE τ
C
SS CL
E
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) 60/ 0.5g-2g q24h || 11-
Mild to moderate
29/ 0.5g-1g q24h ||
infection: 500mg to 2g
<10/ 250-500mg q24h or
ivpb q12h.
0.5-2g q48h. || HD: 1g
Severe: 2g ivpb q8h.
AD || PD: 1-2 grams
q48h
CEFOTETAN >30/ Usual dose || 10-
(IV) Usual dose: 1g ivpb 30/ 50% of dose q12h ||
q12h. <10/ 25% of dose
Severe: 2-3g ivpb q12h.|| Hemodialysis or
q12h. (Max 6g/day) PD: 50% of usual dose
q24h
CEFOXITIN Mild infection: 1g ivpb
10-50/ q8-12h || <10/
(IV) q24-48h || HD: give 1g
q6-8h Moderate-
Back after Dialysis: e.g. Give
severe: 1g ivpb q4h or
Cefoxitin 1g ivpb M-W-F
2g ivpb q6-8h. Life-
after dialysis + a
threatening: 2g ivpb
supplemental dose on
q4h or 3g ivpb q6h.
Sunday.
CEFOTAXIME Mild infection: 1-2g
(IV) ivpb q12h. Moderate:
>50/ Usual dose || 10-50/
1-2g ivpb q8h;
q8-12h || <10/ q24h || HD:
Severe: 2g ivpb q6-
0.5 to 2g ivpb q24h AD. ||
8h; Life threatening:
PD: 1g ivpb q24h.
2g ivpb q4h (Max
dose/day= 12g)
CEFUROXIME >20/q8h || 10-20/ q12h ||
(IV) <10/ 750mg q24h. ||
Usual: 750mg to 1.5g
Hemodialysis: Give single
ivpb q8h. Severe: 1.5g
dose after dialysis or give
ivpb q6-8h.
750mg q12h. || PD:
750mg-1.5g q24h
CEFTIN (ORAL)
No changes req'd (usual
Back Usual dose: 250-
oral doses are not
500mg po q12h
significant).
CEFTRIAXONE Usual dose: 1-2g No dosage adjustments
(IV) ivpb q24h. Severe: req'd in renal failure. PD:
2g ivpb q12h 750mg ivpb q12h
CEFTAZIDIME (IV) Usual dose: 1g ivpb
q8-12h. Severe: 2g Crcl 30-50/ q12h || 10-
Back ivpb q8-12h. (Max 30/ q24h || <10/ q48h
dose/day= 6 grams).
CEPHALEXIN Keflex: 10-50/ q6-12h ||
KEFLEX/VELOSEF Usual dose: 250- <10/ q12-24h . Velosef:
500mg po q6h; >20/ no change || 5-20/
500mg-1g q12h. 250mg q6h || < 5/ 250mg
q12h
CIPROFLOXACIN >50/ no change || 10-50/
(CIPRO) Oral dosing: 250- 50-75% of usual dose q12h
750mg po q12h; || <10/50% of usual dose
Back cystic fibrosis: q12. Alternatives: [200mg
750mg po q8h. IV ivpb or 250mg po q12h] or
dosing: 200-400mg [400 mg ivpb or 500mg po
ivpb q12h. Febrile q24h]. || HD/PD: 250-
neutrapenic pt: 500mg po or 200-400mg
400mg ivpb q8h ivpb q24h AD or 200mg
ivpb or 250mg po q12h.
IMIPENEM Mild to moderate
31-70/ 500mg q6-8h ||
(PRIMAXIN) infection: 250-500mg
21-30/ 500mg q8-12h
ivpb q6-8h. Severe
max || 0-20/ 250-500mg
infection: 500mg to 1g
q12h max. || HD: 250
ivpb q6-8h. Max
mg AD + q12h. || PD:
dose/day=
max dose= 1gram/day
50mg/kg/day or
i.e. 500mg ivpb q12h.
4g/day
LEVOFLOXACIN Usual dose: 500mg po
>50/ no change || 20-
(LEVAQUIN) 49/ 500mg x 1 then
or ivpb q24h. UTI or
250mg q24h ||
pyelonephritis: 250mg
<19/HD/PD: 500mg x 1
po/ivpb q24h.
then 250mg q48h
METRONIDAZOLE IV: 1 gram or 15
(FLAGYL) mg/kg load IV, then
500mg or 7.5 mg/kg
Back q6h (range: q6-12h -- > 10/ no change || <10/
long T � ). Oral: 250- 500mg ivpb q12h.
750mg po tid.
(occasionally bid). Max
4g/day.
Elimination Normal Dose Adjustment
dose
Half Life (t ½) interval Creatinine Clearance
(hour) (ml/min)
Normal ESRD > 50 10 - 50 < 10
• 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
H OH
H
O N
O N
N
N H O
H O
PHENYTOIN p - HPPH
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