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,penicillamine
A drugs renal disease,by >1
mechanisms(sulponamides)
Sites & Pathological types
of DIRD
1. Glomerular
2. 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 Cs
Notes : - 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 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) 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 kidney
drugs half life(T)
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

T = half life
= The time for its concentrate
to halve,after absorption
and distribution of the drug
are complete
(B1) Almost entirely metabolized
drugs half life (T)
N S-RF
- Paracetamol 2 2
- Clindamycin 2 3
- Propranolol 3 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 elimination
In RF accumulate
e.g. - Acebutolol,hydralazine,
isosorbide
- Allopurinol,
carbamazepine
- Chordiazepoxide,
diazepam,clobazam,
flurazepam
- Metronidazole,5-FU
(C) Partly metabolized & partly
eliminated by the kidney
drugs Half life (T)
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
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 Group A or B
regimens in CRF
- DIN = DIo x 1/Q
- MDN = MDo x Q
Notes :
Q = Adjustment factor=PCcr/NCer
DIN = New Interval Dose
NCer = Normal Ccr
MDN = New Maintenance Dose
DIo = Old Interval Dose
PCcr = Patient Ccr
MDo = Old Maintenance Dose
- Alteration in renal function on
drug elimination depend on 2
factor :
1. Unchangee drug fraction
normally eliminated by the
kidney
2. 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/NCcr
Fc = Unchanged drug fraction
normally eliminated by the
kidney
Calculation Dose Regimen
by Using Half Life(T)
DF = T normal / T RF

DDRF = DDn x DF
DIRF = DIN / DF

DF = Drug Fraction
DD = Drug Dose
DI = Drud Interval

Drug prescribing guidelines
in RF
1. Use a drug in definite 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
potientially toxic drugs
6. Avoid potientially nephrotoxic
combination of drugs
7. Monitor the patient carefully for
clinical efficacy & evidence of
toxicity