Drugs and Kidney: Clinical Pharmacology for

The Nephrologist

Khaled eldahshan , MDLecturer of Nephrology, Mansoura

Urology and Nephrology Center

, Mansoura University

Introduction

Pharmacokinetics

Iatrogenic renal diseases

Drugs acting on the kidney

Special issues

Conclusion

Focus of The Talk

Renal Vulnerability to Drug Toxicity

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010Clin J Am Soc Nephrol 4: 1275–1283, 2009

Introduction

Pharmacokinetics

Iatrogenic renal diseases

Drugs acting on the kidney

Special issues

Conclusion

Focus of The Talk

Bioavailability:

Furosemide dosing oral/IV

Drug absorption

Gastric absorption

Phosphate binders

Antacids

Subcutaneous and intramuscular routes of absorption

Peritoneal absorption

Pharmacokinetics

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Pharmacokinetics: Drugs and Body Compartments

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Hydrophilic drugs: Decreased Vd in dehydration and increased

Vd in edema

CKD affects Vd Digoxin

Protein binding

Pharmacokinetics:Volume of Distribution/Plasma Concentration

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Pharmacokinetics

Distribution:

Higher free fraction of drugs in

plasma in uremia

Lower concentrations of total drug

Lower therapeutic levels of Phenytoin

Biochemical conversion from one chemical form to another mediated by hepatic enzymatic pathways

Pharmacologically active metabolites of inactive prodrugs that depend on renal excretion:

Lisinopril to lisinoprilat

Meperidine to normeperidine

Downregulation of cytochrome P450 in CKD

Pharmacokinetics:Biotransformation or metabolism

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Drugs Use in ICU

Drug Metabolism:

• uremia affects drug metabolism and reduces non-renal clearance of drugs

• First pass metabolism by the liver of some drugs such as inderal or

cimetidine may be reduced in renal impairment

Renal drug excretion:

It depends on

Filteration

Active tubular secretion/reabsorption

Passive diffusion.

Drugs of MW < 60,000 Dalton are filtered through the glomerulus.

Lipid soluble drugs that diffuse readily across tubular cells whereas water

soluble compounds do not.

Factors That Affect DrugsDialysis

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Introduction

Pharmacokinetics

Iatrogenic renal diseases

Drugs acting on the kidney

Special issues

Conclusion

Focus of The Talk

Acute Kidney Problems Caused by Nephrotoxins

Clinical Queries: Nephrology 0101 (2012) 29–33

Acute Kidney Problems Caused by Nephrotoxins

Tubulopathy Syndromes Induced by Antimicrobials

Acute Renal FailureNephrotoxic ATN

Endogenous Toxins

Heme pigments (myoglobin, hemoglobin)

Myeloma light chains

Exogenous Toxins

Antibiotics (e.g., aminoglycosides, amphotericin B)

Radiocontrast agents

Heavy metals (e.g., cis-platinum, mercury)

Poisons (e.g., ethylene glycol)

Aminoglycoside Nephrotoxicity

Nonoliguric acute renal failure

Slow (4-6 wk) recovery of renal function

Proximal tubule dysfunction (enzymuria, proteinuria, aminoaciduria, glucosuria)

Hypomagnesemia

Hypocalcemia

Hypokalemia

AminoglycosideNephrotoxicity

Clinical Queries: Nephrology 0101 (2012) 29–33

Kidney International Supplements (2012) 2, 37–68

Aminoglycoside Nephrotoxicity

ACE Induced Renal Toxicity

Hyperkalemia

Hemodynamic-related renal failure

Etiologic factors

Bilateral renal artery stenosis

↓ blood volume

Chronic renal disease

Concomitant NSAID therapy

Old age

TIN

Comprehensive textbook of

Nephrology, 2010

WBCS casts

TIN

Urinary Sediment Findings in AIN

(AIN 23/839 biopsies)

Am J Kidney Dis. 2012;60(2):327-333

Acute Interstitial Nephritis:Drug induced

Comprehensive textbook of Nephrology, 2010

NSAID

Enhanced vasoconstriction: due to prostaglandin synthesis inhibition

Interstitial nephritis

Sodium and water retention

Hyperkalemia

Papillary necrosis

Hypertension

Nephrotic syndrome

NSAID-associated TIN

1. Heavy proteinuria (> 3.0g/d)2. Tubulointerstitial infiltration on

biopsy specimen: glomeruli well preserved

3. Nonoliguric course4. Eosinophilia/eosinophiluria not

common5. Variable time (weeks to months) to

development6. Role of steroids in resolution is

unclear

Chronic TIN: Pathology

Am J Kidney Dis. 58(6):903-914. © 2011

Pharmacology & Therapeutics (2012) in press

Introduction

Pharmacokinetics

Iatrogenic renal diseases

Drugs acting on the kidney

Special issues

Conclusion

Focus of The Talk

Ceiling Dose/Effect

0.01 0.1 1 10 100 1000 100000

50

100

150

Dose

Re

sp

on

se

Ceiling [Diuretic]TL

Ceiling Effect

Log [Diuretic]TL

Fra

ctional Excre

tion o

f Sodiu

m (

%)

Ceiling Dose/Effect

Determinants of Ceiling Dose

Increased Potency Decrease

Decreased Tubular Transport(e.g., ARF/CRF)

Increase

Increased Binding to UrinaryProteins (e.g., Nephrotic Syndrome)

Increase

Introduction

Pharmacokinetics

Iatrogenic renal diseases

Drugs acting on the kidney

Special issues

Conclusion

Focus of The Talk

Seminars in Dialysis 2011; 24 (4): 370-371

Gadolinium in USA

Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Risk Factors for CIN

Can Gadolinium Be Given Safely to A Patient On Dialysis?

Seminars in Dialysis 2011; 24 (4): 370-371

Roger A. Rodby, said

Comprehensive textbook of Nephrology, 2010

Comprehensive textbook of Nephrology, 2010

Statin and Kidney

Statin and KidneyCochrane and EMBASE databases

80 trials (n 51 099) (statin versus placebo or no treatment).

CKD HD Kid Tx

Mortality 0.81 (0.74-0.88) 0.96 (0.88-1.04)

CV Mortality 0.78 (0.68-0.89) 0.94 (0.82-1.07)

CV events 0.76 (0.73-0.80) 0.95 (0.87-1.03)

RR (CI)

Beneficial No effect

?

Acute interstitial nephritis

Rarely:

Crystal nephropathy

Thrombotic microangiopathy

Tubular necrosis and apoptosis

Ciprofloxacillin Induced AKI