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RENAL PHARMACOLOGY

Setyo Purwono
Farmakologi & Toksikologi
FK - UGM
LOCUS OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
The Kidney as Excretory Organ

 Most drugs are eliminated in urine either chemically


unchanged or as metabolites.
It can be life threatening
Steady state
How to measure renal function?

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.

WHAT ABOUT OTHER EXCRETION ROUTES?



rate of removal known as ‘Clearance’
the removal of drug by all processes
from the biological system

 Definition: A volume of fluid (could be plasma, blood or


total body fluid) from which a drug is irreversibly removed
in unit time

 Atenolol Cltotal = Clrenal


 Paracetamol Cltotal = Clhepatic + Clrenal
 Ethanol Cltotal = Clhepatic + Clrenal + Cllung
ADDITIVITY OF CLEARANCES

CL E  CL R  CL NR
CLR = RENAL CLEARANCE
CLNR = NON-RENAL CLEARANCE
BASIC “FULL” STUDY DESIGN
ESRD NORMAL

SEVERE MOD MILD


Key ASSUMPTIONS of Dettli Method

• CLNR remains CONSTANT when renal


function is impaired.
• CLR declines in LINEAR FASHION with CLCR

- Intact Nephron Hypothesis


- Some drugs ↓ SECRETION > GFR
with aging*
* Reidenberg MM, et al. Clin Pharmacol Ther 1980;28:732-5.
CL R VS. CL Cr IS LINEAR*

CLR = α CLCr

* From: Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.


RENAL CLEARANCE EQUATION

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

 Patients with renal impairment


 Patients on Dialysis

Changes in dosage or Changes in rateof removal of the drug


from the body determines whether it will disappear from,
or accumulate in the patient’s blood
Considerations by CKD Stage
CVD/CKD risk factor assessment
& early intervention
Assessment & intervention of CKD complications

Renal Renal
Insufficiency Failure
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
> 90 90-60 60-30 30-15 15; ESRD

GFR (mL/min/1.73 m2)


Modified from Macdougall LC. Nephrol Dial Transplant. 2000;15(Suppl 3):3-7. &
Coresh et al. Am J Kidney Dis 2003 Jan;41(1):1-12
Principles
 Establish type of kidney disease
• Most patients with kidney failure will already be
taking a number of drugs
• Interactions are common
• Care needed to avoid drug toxicity
 Patients with renal impairment and renal
failure
• Antihypertensives
• Phosphate binders
DOSE ADJUSTMENT OPTIONS FOR
PATIENTS WITH RENAL IMPAIRMENT

• MAINTAIN USUAL DOSING INTERVAL BUT


REDUCE DOSE IN PROPORTION TO ↓CLE
• MAINTAIN USUAL DOSE BUT INCREASE
DOSING INTERVAL IN PROPORTION TO ↓CLE
• ADJUST BOTH DOSE AND DOSING INTERVAL
Agent Usual Dosage Renal Dosing
AMPICILLIN
Mild to moderate >50/ q6h ||
infection: 500mg to 2g 10-50/ q6-12h ||
ivpb q6h. Severe <10/ q12-24 hours ||
infection: 2g ivpb q4h Hemodialysis: Dose after
(150-200mg/kg/day) dialysis || PD: 250mg q12h.

AMPICILLIN Usual dose: 250mg to 1g


>50/ no changes || 10-50/
(Oral) po q6h (50-100mg/kg/
q6-12h || <10/ q12h
day).
AMPICILLIN -
SULBACTAM Usual dose: 1.5 to 3g ivpb >30/ q6-8h || 15-29/ q12h
(UNASYN) q6h || 5-14/ q24h

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

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 10-50/ q8-12h || <10/
Mild infection: 1g ivpb
(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; Severe:
q8-12h || <10/ q24h || HD:
2g ivpb q6-8h; Life
0.5 to 2g ivpb q24h AD. ||
threatening: 2g ivpb
PD: 1g ivpb q24h.
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 Usual dose: 1g ivpb
(IV) q8-12h. Severe: 2g Crcl 30-50/ q12h || 10-
ivpb q8-12h. (Max 30/ q24h || <10/ q48h
Back 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 >50/ no change || 20-
Usual dose: 500mg po
(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
q6h (range: q6-12h > 10/ no change || <10/
Back
--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

Captopril 1.9 21 - 32 12 Unch Unch 50


Lisinopril 12 - 36 36 - 48 24 Unch 75 50
Atenolol 6-9 15 - 35 24 Unch 50 25
Propranolol 2 -6 1-6 6 - 12 Unch Unch Unch

Diclofenac 1-2 1-2 6 – 12 Unch Unch Unch


Ibuprofen 2 -5 Unch 12 Unch Unch Unch
Elimination Normal Dose Adjustment
dose
Half Life (t ½) interval Creatinine Clearance
(hour) (ml/min)
Normal ESRD > 50 10 - 50 < 10

Phenobarbital 60 -150 117 -160 8 - 24 Unch Unch Unch


Lorazepam 6 - 25 32 - 70 8 - 24 Unch Unch 50
Glibenclamide 10 - 16 ? 24 Unch Unch Unch
Insulin reguler 2-3 prolonged 8 Unch 75 50
Carbamazepine 20 - 36 ? 8 - 12 Unch Unch 75
Chloroquine 2-4 5 h – 50 days 12 Unch Unch 50
Cisplatine 2 -72 1 - 240 24 Unch 75 50
Cimetidine 2 5 8 Unch 75 50
Calculating Creatinine Clearance
CIMETIDINE Case History

A 67-year-old veteran had been functionally


anephric, requiring outpatient hemodialysis
for several years. He was hospitalized for
revision of his arteriovenous shunt and
postoperatively complained of symptoms of
gastroesophageal reflux. This complaint
prompted institution of cimetidine therapy
in a dose of 300 mg every 6 hours.
CIMETIDINE Case History
(cont.)
Rationale for Prescribed Cimetidine Dose:

At that time, 600 mg every 6 hours was the


usual cimetidine dose for patients with
normal renal function and the Physician’s
Desk Reference recommended halving the
cimetidine dose for patients “with
creatinine clearance less than 30 cc/min”.
CIMETIDINE Case History (cont.)
Three days later the patient was noted to be
confused. The nephrology service
entertained the diagnosis of dialysis
dementia and informed the family that
hemodialysis might be discontinued. The
teaching attending suggested that cimetidine
be discontinued first. Two days later the
patient was alert and was discharged from
the hospital to resume outpatient
hemodialysis therapy.
LABELING FOR CIMETIDINE*

• 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

*From: Atkinson AJ Jr, Craig RM. Therapy of peptic ulcer disease.


EFFECT OF RENAL DISEASE ON DRUG
METABOLISM

• 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

CYP2C9: Major, CYP2C19: Minor


PHENYTOIN
KINETICS IN DIALYSIS PATIENTS*

NORMALS UREMIC PATIENTS


(N = 4) (N = 4)
% UNBOUND (fu) 12% 26%
CLH 2.46 L/hr 7.63 L/hr
CLint 20.3 L/hr 29.9 L/hr NS
CLH = fu  Clint , So: Clint = CLH/fu
* From: Odar-Cederlöf I, Borgå O: Eur J Clin Pharmacol 1974;7:31-7.
EFFECT OF RENAL DISEASE
ON BIOAVAILABILITY

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

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