RENAL PHARMACOLOGY

Setyo Purwono Farmakologi & Toksikologi FK - UGM

LOCUS OF ACTION RECEPTORS

TISSUE RESERVOIRS

Bound

Free

Free

Bound

ABSORPTION

Free Drug Bound Drug

SYSTEMIC CIRCULATION

EXCRETION

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
SEVERE MOD MILD

NORMAL

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 = CLCr

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

RENAL CLEARANCE EQUATION

Ux V 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 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 Wright Formula Schwartz Formula (children) Counahan-Barratt Equation (children)

Prescribing in Kidney Disease

Patients

with renal impairment Patients on Dialysis

Changes in dosage or Changes in rate of removal of the drug

from the body determines whether it will disappear from, or accumulate in the patients blood

Considerations by CKD Stage

CVD/CKD risk factor assessment & early intervention Assessment & intervention of CKD complications

Renal Insufficiency
Stage 1
> 90

Renal Failure
Stage 4
30-15

Stage 2
90-60

Stage 3
60-30

Stage 5
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

SS

DOSE CL
E

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
AMPICILLIN

Usual Dosage
Mild to moderate infection: 500mg to 2g ivpb q6h. Severe infection: 2g ivpb q4h (150-200mg/kg/day)

Renal Dosing
>50/ q6h || 10-50/ q6-12h || <10/ q12-24 hours || Hemodialysis: Dose after dialysis || PD: 250mg q12h. >50/ no changes || 10-50/ q6-12h || <10/ q12h

AMPICILLIN (Oral)

Usual dose: 250mg to 1g po q6h (50-100mg/kg/ day).

AMPICILLIN SULBACTAM Usual dose: 1.5 to 3g ivpb (UNASYN) q6h

AUGMENTIN (Oral)

>30/ q6-8h || 15-29/ q12h || 5-14/ q24h

Usual dose: 875mg po q12h or 250-500mg po q8h

>30/ no change || 10-30/ 250-500mg q12h || <10/ 250-500mg po q24h

CEFEPIME (MAXIPIME)

Mild to moderate infection: 500mg to 2g ivpb q12h. Severe: 2g ivpb q8h.

>60/ 0.5-2g q12h || 3060/ 0.5g-2g q24h || 1129/ 0.5g-1g q24h || <10/ 250-500mg q24h or 0.5-2g q48h. || HD: 1g AD || PD: 1-2 grams q48h

CEFOTETAN (IV)

Usual dose: 1g ivpb q12h. Severe: 2-3g ivpb q12h. (Max 6g/day) Mild infection: 1g ivpb q6-8h Moderatesevere: 1g ivpb q4h or 2g ivpb q6-8h. Lifethreatening: 2g ivpb q4h or 3g ivpb q6h.

>30/ Usual dose || 1030/ 50% of dose q12h || <10/ 25% of dose q12h.|| Hemodialysis or PD: 50% of usual dose q24h
10-50/ q8-12h || <10/ q24-48h || HD: give 1g after Dialysis: e.g. Give Cefoxitin 1g ivpb M-W-F after dialysis + a supplemental dose on Sunday.

CEFOXITIN (IV) Back

CEFOTAXIME (IV)

Mild infection: 1-2g ivpb q12h. Moderate: 1-2g ivpb q8h; Severe: 2g ivpb q68h; Life threatening: 2g ivpb q4h (Max dose/day= 12g)

>50/ Usual dose || 10-50/ q8-12h || <10/ q24h || HD: 0.5 to 2g ivpb q24h AD. || PD: 1g ivpb q24h.

CEFUROXIME (IV)

>20/q8h || 10-20/ q12h || <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 No changes req'd (usual oral doses are not significant).

CEFTIN (ORAL)

Back

Usual dose: 250500mg po q12h

CEFTRIAXONE (IV)

Usual dose: 1-2g ivpb q24h. Severe: 2g ivpb q12h

No dosage adjustments req'd in renal failure. PD: 750mg ivpb q12h

CEFTAZIDIME (IV) Usual dose: 1g ivpb Back CEPHALEXIN KEFLEX/VELOSEF

q8-12h. Severe: 2g Crcl 30-50/ q12h || 1030/ q24h || <10/ q48h ivpb q8-12h. (Max dose/day= 6 grams). Usual dose: 250500mg po q6h; 500mg-1g q12h. Keflex: 10-50/ q6-12h || <10/ q12-24h . Velosef: >20/ no change || 5-20/ 250mg q6h || < 5/ 250mg q12h

CIPROFLOXACIN (CIPRO) Back

Oral dosing: 250750mg po q12h; cystic fibrosis: 750mg po q8h. IV dosing: 200-400mg ivpb q12h. Febrile neutrapenic pt: 400mg ivpb q8h

>50/ no change || 10-50/ 50-75% of usual dose q12h || <10/50% of usual dose q12. Alternatives: [200mg ivpb or 250mg po q12h] or [400 mg ivpb or 500mg po q24h]. || HD/PD: 250500mg po or 200-400mg ivpb q24h AD or 200mg ivpb or 250mg po q12h.

IMIPENEM (PRIMAXIN)

Mild to moderate infection: 250-500mg ivpb q6-8h. Severe infection: 500mg to 1g ivpb q6-8h. Max dose/day= 50mg/kg/day or 4g/day Usual dose: 500mg po or ivpb q24h. UTI or pyelonephritis: 250mg po/ivpb q24h. IV: 1 gram or 15 mg/kg load IV, then 500mg or 7.5 mg/kg q6h (range: q6-12h -long T ). Oral: 250750mg po tid. (occasionally bid). Max 4g/day.

31-70/ 500mg q6-8h || 21-30/ 500mg q8-12h max || 0-20/ 250-500mg q12h max. || HD: 250 mg AD + q12h. || PD: max dose= 1gram/day i.e. 500mg ivpb q12h. >50/ no change || 2049/ 500mg x 1 then 250mg q24h || <19/HD/PD: 500mg x 1 then 250mg q48h

LEVOFLOXACIN (LEVAQUIN)

METRONIDAZOLE (FLAGYL) Back

> 10/ no change || <10/ 500mg ivpb q12h.

Elimination Half Life (t ) (hour)

Normal Captopril Lisinopril Atenolol Propranolol Diclofenac Ibuprofen 1.9 12 - 36 6-9 2 -6 1-2 2 -5 ESRD 21 - 32 36 - 48 15 - 35 1-6 1-2 Unch

Normal dose interval

Dose Adjustment Creatinine Clearance (ml/min)

> 50 10 - 50 Unch 75 50 Unch Unch Unch < 10 50 50 25 Unch Unch Unch Unch Unch Unch Unch Unch Unch

12 24 24 6 - 12 6 12 12

Elimination Half Life (t ) (hour)

Normal Phenobarbital Lorazepam Glibenclamide Insulin reguler 60 -150 6 - 25 10 - 16 2-3 ESRD 117 -160 32 - 70 ? prolonged

Normal dose interval

Dose Adjustment Creatinine Clearance (ml/min)

> 50 10 - 50 Unch Unch Unch 75 < 10 Unch 50 Unch 50

8 - 24 8 - 24 24 8

Unch Unch Unch Unch

Carbamazepine
Chloroquine Cisplatine Cimetidine

20 - 36
2-4 2 -72 2

?
5 h 50 days 1 - 240 5

8 - 12
12 24 8

Unch
Unch Unch Unch

Unch
Unch 75 75

75
50 50 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 Physicians 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. * Physicians 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

NAT2: FAST VS. SLOW

RENAL ELIMINATON NORMALLY 50%

Procainamide Kinetics in DIALYSIS PATIENTS*

NORMALS Fast Slow T1/2 (hr) CLE (L/kg)
CLR (L/kg) CLNR (L/kg) FUNCTIONALLY ANEPHRIC PATIENTS

Fast
12.2 118 0 118

Slow
17.0 94 0 94

2.6 809 426 383

3.5 600 357 243

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 O H N N O O H N

H N O

OH

PHENYTOIN

p - HPPH

CYP2C9: Major, CYP2C19: Minor

KINETICS IN DIALYSIS PATIENTS*

PHENYTOIN

NORMALS (N = 4)

UREMIC PATIENTS (N = 4)

% UNBOUND (fu)
CLH CLint

12%
2.46 L/hr 20.3 L/hr

26%
7.63 L/hr 29.9 L/hr NS

CLH = fu Clint , So: Clint = CLH/fu

* From: Odar-Cederlf I, Borg 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