NEPHRO PHARMACOLOGY

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 potentially reversible & preventable

Subtopics

Drugs induced renal disease (=DIRD)

Drugs presecibing in renal disorders

Mechanisms of DIRD

1) Direct biochemical effect : Heavy metals(Hg,Au,Fe,Pb) Antimicrobial(Aminoglycosidea,

Cephalosporins,sulphonamides) Contrast media(biliary) analgesices(aspirin) Solvents(CCL4,Ethylene Glycol)

2) Indirect biochemical effect : Urisocurics urate

precipitation Calciferol renal calcification Diuretic/laxative tubular

damage Sulphonamides crystallise

in UT Anticoagulant haemorrage

into kidney

3) Immunological effect : Penicilin,sulphonamides,isoniazid,

Rifampicin Phenytoin,procainamide,

hydralazine Au,penicillamineA drugs renal disease,by >1

mechanisms(sulponamides)

Sites & Pathological types of DIRD1. Glomerular2. Tubular Damage proximal,medulla,distal Obstruction 3. Other DIRD

1.Glomerular : large surface area of glomerular

capillaries susceptible to damage from circulation immune complexes

Penicillamine : glomerulonephritis proteinuria nephrotic syndrome

Creatinie clearance (=CcR)a measure of glomerular filtration rate (=GFR)

Formula of Cockcroft & Gault : CcR = (140 – age ) x BW

72 x CsNotes : - Cs = serum creatinine

- Women = Man – 15 %

2. Tubular Tubular damage 200 L/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 condition 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 law Ph) can precipitate in distal tubular when urine is acid

Nucleic acids(in leukemic cells) breakdown by chemotherapy insoluble urate will be precipitate

3. Other DIRD Vasculitis by

sulphonamide,allopurinol, isoniazid

Allergic Interstitial Nephritis by panicillins,sulphonamides, thiazides,allopurinol,phenytoin

SLE by hydralazine,procainamide

ARF by aminoglycosides,cisplatin

NS by penicillamine,Au,ceptopril CRF by NSAID,amphotefricin-B Functional impairment due to

impairment to dilute/concentrate urine,potassium loss,acid-base ambalance

Vulnerability factor to DIRD1) High work-load of renal

function 2) Glomerural endothelial surface

area > 3) Capacity to concentrate of

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

metabolites(in renal insufficiency)

Drugs may :1. Exacerbate renal disease 2. Accumulate,due to failure of

renal excreation / changes in protein binding

3. Be ineffective,e.g thiazide in moderate/severe renal failure, uricosurics

Problem:RF patient must be treated with

neprotoxic dugs & largely eliminated by the kidney

Drugs classification base renal elimination (A) Almost exclusively eliminated by

the kidneydrugs half life(T½)

N S-RF- Benzylpenicilline 0,5 8- Ampicillin 1 14- Acyclovir 2,5 20- Gentamicin 2,5 50- Sotalol 5 41- Atenolol 6 100- Tetracycline 8 75

T½ = half life= The time for its

concentrate to halve,after absorption and distribution of the drug are complete

(B1) Almost entirely metabolizeddrugs half life (T½)N S-RF

- Paracetamol 2 2- Clindamycin 2 3- Propranolol3 3- Rifampicin 3 3- Lorazepam 15 15- Doxycycline 18 18- Notriptyline 30 30- Warfarin 40 40

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

renal eliminationIn RF accumulatee.g. - Acebutolol,hydralazine,

isosorbide - Allopurinol, carbamazepine

- Chordiazepoxide, diazepam,clobazam, flurazepam

- Metronidazole,5-FU

(C) Partly metabolized & partly eliminated by the kidneydrugs Half life (T½) N S-RF

- Lincomycin 5 12- Trimethoprim 10 25- Amphetamine 12 24- Chlorpropamide 36 280- Digoxin 36 120- Digitoxin 150 240

Dosing regimens in renal impairment (general rule)Group A/B2 : Initial dose-normal/slightly Maintenance dose or interval

doseGroup 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 Group A or B regimens in CRF

- DIN = DIo x 1/Q- MDN = MDo x Q

Notes :Q = Adjustment factor=PCcr/NCerDIN = New Interval DoseNCer = Normal CcrMDN = New Maintenance DoseDIo = Old Interval DosePCcr = Patient CcrMDo = Old Maintenance Dose

- Alteration in renal function on drug elimination depend on 2 factor :1. Unchangee drug fraction normally eliminated by the kidney2. Degree of renal insufficiency

- Estimation of Ccr remains the guiding factor for dose regimen design

If the metabolites are inactive & non-toxic and the drug(group C) obey first-order(linear) kinetic,the principle of adjustment factor are :Qc = I – [Fc (1- KF)]- DIN= DIo x 1/Q- MDN = MDo x Q

KF = PCcr/NCcrFc = Unchanged drug fraction

normally eliminated by the kidney

Calculation Dose Regimen by Using Half Life(T½)

DF = T½ normal / T½ RF

DDRF = DDn x DFDIRF = DIN / DF

DF = Drug FractionDD = Drug DoseDI = Drud Interval

Drug prescribing guidelines in RF1. Use a drug in definite indications2. Choose a drug with minimal

nephrotoxics effect3. Use plasma level to adjust the

dose4. Use recommended dosage

regimens for RF 5. Avoid prolonged courses of

potientially toxic drugs6. Avoid potientially nephrotoxic

combination of drugs7. Monitor the patient carefully for

clinical efficacy & evidence of toxicity