NEPHROPHARMACOLOGY

DARMAWAN,dr.,M.Kes

Introduction• Kidney comprise only 0,5 %

BW, but receive 25% CO• So, drugs can damage the

kidney, renal disease affects responses to drugs

• The recognition of DIRD is very important because the resulting ARF & CRF pottentially reversible & preventable

Subtopics

• Drugs induced renal disease

(=DIRD)

• Drugs prescribing in renal

disorders

Mechanisms of DIRD :1) Direct biochemical effect :

Heavy metals (Hg, Au, Fe, Pb) Antimicrobials (Aminoglycosides, Cephalosporins, sulphonamides) Contrast media (biliary) Analgesics (aspirin) Solvents (CCL4, Ethylene Glycol)

2) Indirect biochemical effect : Uricosurics urate

precipitation Calciferol renal

calcification Diuretic/laxative tubular

damage Sulphonamides crystallise

in UT Anticoagulant

haemorrage into kidney:

3) Immunological effect : Penicillins, sulphonamides, isoniazid, Rifampicin Phenytoin, procainamide, hydralazine Au, Penicillamine

A drug renal disease, by > 1 mechanisms (sulphonamides)

Sites & Pathological types of RD

1.Glomerular2.Tubular

Damage proximal, medulla, distal Obstruction

3.Other DIRD

1. Glomerular : large surface area glomerular capillaries susceptible to damage from circulating immune complexes

Penicillamine: GlomerulonephritisProteinuria Nephrotic syndrome

Creatinine clearance (= CCR) a measure of glomerular filtration rate (= GFR)

Formula of Cockcroft & Gault : (140 – age ) x BW CCR = 72 x Cs

Notes : - Cs = Serum creatinine - Women = Man – 15 %

2. Tubular Tubular damage

200L/day GF 1,5 L/day urine renal tubular cells expose more than other cells to toxins Proximal, medulla, distal tubular

Tubular obstructionCertain physico chemical conditions crystal can deposit within tubular lumen

Tubular proximal toxicity By acids (salicylates,

cephalosporins), bases (aminoglycosides), heavy metals

and contrast media Urinary excretion of glucose, phosphate, HCO3, amino

acids

Medullary toxicity NSAID >< local Pg

ischaemia analgesic nephropathy

Distal tubular toxicity Under physico-chemical conditions, crystal can deposit within tubular lumen Methotrexate (relative insoluble at low Ph) can prepitate in distal tubular when urine is acid Nucleic acids (in leukemic cells) breakdown by chemotherapy insoluble urate will be prescipitate

3. Other DIRD Vasculitis by sulphonamide, allopurinol, isoniazid Allergic Interstitial Nephritis by penicillins, sulphonamides, thiazides, allopurinol, phenytoin SLE by hydralazine, procainamide ARF by aminoglycosides, cisplatin NS by penicillamine, Au, captopril CRF by NSAID, amphotericin-B Functional impairment due to impairment to dilute/concentrate urine, potassium loss, acid-base imbalance

Vulnerability factor to DIRD1) High work-load of renal

function2) Glomerural endothelial surface

area >3) Capacity to concentrate of

drugs & nephrotoxins in lumen4) Liability to immune injury5) Accumucation of drugs &

metabolites (in renal insufficiency)

Drugs may :1. Exacerbate renal diseases2. Accumulate, due to failure of renal excretion/changes in protein binding3. Be ineffective, e.g thiazide in moderate/severe renal failure, uricosurics

Problem: RF patients must be treated with nephrotoxic drugs & largelly eliminated by the kidney

Drugs Classification Base Renal Elimination(A) Almost exclusively eliminated by the kidney

(B1) Almost entirely metabolised

(B2) Drugs produce pharmacologically active metabolites (water-soluble) renal elimination

In RF accumulate e.g. - Acebutolol, hydralazine, Isosorbide dinitrate - Allopurinol, carbamazepine - Chordiazepoxide, diazepam, clobazam, flurazepam - Metronidazole, 5-FU

(C)Partly metabolized & partly eliminated by the kidney

- Doses must be modified in renal function impairment especially digoxin

Dosing regimens in renal impairment (general rule)

Group A/B2 : Initial dose-normal/slightly Maintenance dose or interval dose

Group B1 :Initial dose-normal or in advanced-RD,Hypoproteinemia, drugs with highly protein binding

Group C : Initial dose-normal Maintenance dose/interval dose will be modified

Drugs regimens in CRFGroup A = There are 2 alternative 1. NI = OI x NCCR PCCR 2. NMD = OMD x PCCR NCCRNotes :NI = New IntervalNCCR = Normal CCRNMD = New Maintenance doseOI = Old intervalPCCR = Patient CCROMD = Old maintenance dose

Group C : Calculate correction factor (CF) CF = 1 F(KF – 1 ) +1 F = Unchanged drug fraction in urine KF = Ratio of PCR /NCR

There are 2 alternative 1. NI = OI x CF 2. NMD = OMD x 1 CF

Drugs prescribing guidelines in RF1. Use a drug in define indications2. Choose a drug with minimal

nephrotoxics effect3. Use plasma level to adjust the dose4. Use recommended dosage regimens

for RF5. Avoid prolonged courses of

potentially toxic drugs6. Avoid potentially nephrotoxic

combination of drugs7. Monitor the patient carefully for

clinical efficacy & evidence of toxicity