NEPHROPHARMACOLO GY 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

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. Glomerular 2. Tubular Obstruction

Damage proximal, medulla, dista

3. Other DIRD

1. Glomerular : large surface area glomerular capillaries susceptible to damage from circulating immune complexes Penicillamine: Glomerulonephritis Proteinuria 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 creatinine - Women

Serum

= 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 obstruction Certain physico chemical conditions crystal can deposit

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

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,

Vulnerability factor to DIRD

1) High work-load of renal function 2) Glomerural endothelial surface area > 3) Capacity to concentrate of drugs & nephrotoxins in lumen 4) Liability to immune injury 5) Accumucation of drugs & metabolites (in renal insufficiency)

Drugs may : 1. Exacerbate renal diseases 2. Accumulate, due to failure of renal excretion/changes in protein binding 3. 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
Drugs Benzylpenicilline Ampicillin Acyclovir Gentamicin Sotalol Atenolol Tetracycline Plasma half life (T 1/2) N S-RF 0,5 1 2,5 2,5 5 6 8 8 14 20 50 41 100 75

(B1) Almost entirely metabolised

Drugs Plasma half life (T1/2) N S-RF
2 2 3 3 15 18 30 40 2 3 3 3 15 18 30 40

Paracetamol Clindamcycin Propranolol Rifampicin Lorazepam Doxycycline Nortriptyline warfarin

(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

Drugs Lincomycin Trimethoprim Amphetamine Chlorpropamide Digoxin Digitoxin Plasma half life N S-RF 5 10 12 36 36 150 12 25 24 280 120 240

- 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 advancedRD, Hypoproteinemia, drugs with highly protein binding Group C : Initial dose-normal

Drugs regimens in CRF

Group A = There are 2 alternative 1. NI = OI x NCCR PCCR 2. NMD = OMD x PCCR NCCR Notes : NI = New Interval NCCR = Normal CCR NMD = New Maintenance dose OI = Old interval PCCR = Patient CCR OMD = 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 RF

1. Use a drug in define indications 2. Choose a drug with minimal nephrotoxics effect 3. Use plasma level to adjust the dose 4. Use recommended dosage regimens for RF 5. Avoid prolonged courses of potentially toxic drugs 6. Avoid potentially nephrotoxic combination of drugs 7. Monitor the patient carefully for clinical efficacy & evidence of toxicity