DRUGS AND RENAL

DISEASES

BY

Prof. CFB Nhachi

 Quantification of Renal Function

⦿Renal function -----processes of filtration,

reabsorption, secretion, endocrine and
metabolic functions.
⦿Changes in all five functions are associated
with GFR.
 Quantification of Renal Function
⦿Stage of Chronic Kidney Disease (CKD) - -
determined for all individuals- - - based on
level of kidney function--- irrespective of
cause.
⦿Persistent proteinuria - -----CKD
⦿Measurement of spot urine albumin-to-
creatinine ratio recommended…..determines
severity of CKD and monitors disease
progression
 Quantification of Renal Disease
⦿GFR ---- best indicator of overall kidney
function
⦿N/B GFR measurement most accurate after
administration of inulin (iothalamate,
technetium-99m diethylenetriamine
pentaacetic acid (99m Tc-DPTA…an isotope)
⦿Creatinine clearance not routinely
recommended –BUT pretreatment with
cimetidine improves accuracy.
 Quantification of Renal Disease
⦿Longitudinal assessment of GFR and
proteinuria important for monitoring efficacy
of therapeutic interventions e.g. ACE
inhibitors and angiotensin receptor blockers
(used to slow down KD)
⦿Qualitative assessments of Kidney… X-ray,
computed tomography magnetic resonance
imaging, sonography, biopsy…useful for
determining etiology and structural aspects of
KD.
 SYNOPSIS OF IMPORTANT PRINCIPLES
⦿Kidney disorder alters chemical composition of body
fluids and hence pharmacokinetic parameters of drugs.
Standard regimens of some drugs may be inappropriate
and need to be adjusted if adverse toxic reactions are to
be avoided.
⦿Dosage of some drugs which are mainly excreted in
active form by the kidney need to be modified to avoid
accumulation – either giving the usual dose at
increased intervals or reduced dose at the usual
intervals.
⦿There is increased incidence of drug adverse reactions
in patients with uraemia.
 DRUG USE IN RENAL FAILURE
⦿Renal disease presents:
- modification of pharmacokinetics and
pharmacological response.
- increased incidence of drug adverse
reactions.
⮚ Response to drugs may be enhanced:
accumulation of drugs and active metabolites which
are mainly eliminated by kidneys.
- therefore modification and careful monitoring
necessary, especially important for drugs with
low therapeutic ratio.
 ANTIBACTERIAL AGENTS
⦿Penicillins;
- mainly excreted in urine
- large therapeutic ratio
- therefore rarely necessary to modify dose.
o T1/2 of benzyl penicillin = 10 hours in
anephrenic patients. Thus large doses >20
mega units may cause encephalopathy in
uraemic patients.
❑T1/2 of semi – synthetic penicillins is 1 to 4 hours and
dose regimens do not need to be modified in uraemic
patients except for carbenicillin and methicillin
 AMINOGLYCOSIDES
- low therapeutic ratio
- gentamicin and kanamycin excreted mainly unchanged in urine
- T1/2 of gentamicin = 2 to 3 hours
- T1/2 kanamycin = 3 hours
- trough concentrations of > 16µg/ml kanamycin and 10µg/ml
gentamicin associated with high incidence of ototoxicity
-therefore dose in chronic renal failure may be reduced
- if extended interval regimen is used , drug should be given every 2 nd or
3rd day.
- similar modifications apply for streptomycin and tobramycin.
N/B other side effects include ;
- blockade of neurotransmission
- nephrotoxicity
 CO -TRIMOXAZOLE
- Trimethoprim 80 mg
- Suphamethoxazole 400mg
❑In chronic renal failure overall excretion of
both drugs is reduced (when creatinine
clearance falls below 15ml/min.)

❑Doses should be reduced to 2 tablets daily

instead of twice daily.
 TETRACYCLINES

❑To be avoided in patients with impaired renal

function because they accumulate and lead to
further deterioration in renal function
 DRUGS AFFECTING THE HEART
❑Digitalis glycosides
- High individual variations in response
- T1/2 = 26 to 45 hours
- ⅓ or > of an oral dose excreted unchanged via
kidney
- After an oral dose of 0’25mg [plasma] of digoxin 1
hour after ingestion in normal renal function is
around or 1ng/ml.
- Toxic effects are associated with [plasma] of
around 2ng/ml.
- Therefore reduce doses in renal failure
 DIGITALIS GLYCOSIDES
N/B doses of 0.125 to 0.25 3 times a weak is suitable for
patients with creatinine clearance of < 5ml/min.
N/B some reduce dose only when glomerular filtration rate
falls below 35ml/min.
- Free fatty acids (release of which is stimulated by heparin)
compete with digoxin for albumin binding sites.
- Binding of digoxin also reduced in nephrotic syndrome, with
consequent increase in volume of distribution and clearance.
DIGOXIN RADIOIMUNOASSAY IS PROBABLY THE
ONLY BEST WAY TO IMPROVE STANDARDS OF
THERAPY /PRECISION OF DOSAGE.
 B\ADRENOCEPTOR BLOCKING
- Elimination almost entirely by metabolism.
AGENTS
- Propranolol is metabolised to 4-OH-propranolol
which is pharmacologically active as propranolol.
- First pass metabolism of oral propranolol is
reduced in chronic renal failure.
- Peak [blood] and bioavailability are elevated.
Elimination of propranolol is reduced in C.R.F.
- Therefore dose reduction in renal failure necessary.
 DIURETICS

- Mercurial diuretics to be avoided in chronic

renal failure. They accumulate and induce
acute tubular necrosis.
- Spirinolactone, amiloride to be avoided due to
their K⁺ retaining properties.
- Thiazide diuretics not effective in advanced
renal failure. Cause increased ototoxicity.
 C.N.S. DRUGS

⦿Benzodiazepines , phenothiazines, tricyclic

antidepressants—
- Extensively metabolised
- No dose modification needed
 ANALGESICS
- Aspirin is contraindicated in uraemia due to its
irritative effect on the gastric mucosa and ability to
enhance bleeding tendency in uraemia.
- Morphine and pentazocine activity is not affected by
uraemia except for potentiation of their side effects.
- Excitatory effects of pethidine are enhanced in patients
with renal failure.
- Accumulation of dextropropoxyphene is a potential
toxic indicator.
- N/B PARACETAMOL IS PROBABLY THE ONLY
SAFE MILD ANALGESIC
 DOSAGE GUIDE OF SOME
ANTIMICROBIAL AGENTS
agent Normal renal function Severe renal failure
DOSE DOSE DOSE DOSE
INTERVAL
(hrs) INTERVAL(hrs)
Co-trimoxazole 2tbs 12hrs 2tbs 24hrs
erythromycin 250mgs 6hrs 250mgs 6hrs
gentamicin 80mgs 8hrs 80mgs 24 – 48hrs
ampicillin 500mgs 6hrs 500mgs 6hrs
carbenicillin 1gm 6hrs 1gm 12 – 16hrs
tetracycline 500mgs 6hrs Avoid avoid
 Drug – Induced Kidney Disease
(Epidemiology)
⦿DIN (drug induced nephrotoxicity) accounts
for about 20% of hospital admissions acute
renal failure and up to 7% of drug toxicities
⦿Aminoglycosides, NSAIDs, amphotericin B,
ACEI and radio contrast media the main cause
⦿
 DIKD Epidemiology

⦿Prescribed and OTC NSAIDs therapy

associated with 4X increased risk of
hospitalisation for acute renal failure.
⦿IN USA >50 million people develop NSAID
nephrotoxicity every year
 Drug - Induced KD
⦿Initial diagnosis….determination of elevated
serum creatinine (ESC) and blood urea
nitrogen (BUN).
⦿Acute tubular necrosis…. Most common
presentation in hospitalised patients mostly due
to aminoglycosides, radio contrast media,
amphotericin B, osmotically active agents
(manitol dextran).
 Drug – Induced KD
⦿ACEIs and NSAIDs are associated with
haemodynamically mediated renal failure.
⦿Acute allergic and interstitial nephritis cause
of up to 3% of all acute renal failure.
Drug Induced Renal Structural-Functional
Alterations
⦿Tubular Epithelial Cell Damage
--aminoglycosides
--radiographic contrast media
--cisplatin/carboplatin
--amphotericin B
--manitol
--dextran
--intravenous immunoglobulin
Haemodynamically mediated renal failure

⦿ACEIs
⦿Angiotensin 11 receptor antagonists
⦿NSAIDs
 Obstructive Nephropathy (intratubular
obstruction)

⦿Acyclovir
⦿Indinavir
⦿Methotrexate

EXTRARENAL OBSTRUCTION
⦿Tricyclic antidepressants
⦿indinavir
Tubulointerstitial Disease (acute allergic
interstitial nephritis)

⦿Penicillins
⦿Ciprofloxacin
⦿NSAIDs
⦿Omeprazole
⦿Furosemide
CHRONIC INTERSTITIAL NEPHRITIS
⦿Cyclosporine
⦿Lithium
⦿PAPILLARY NECROSIS
⦿Combined phenacetin, aspirin and caffeine
analgesics
 Re
⦿VASCULITIS and THROMBOSIS
-- hydralazine
-- propylthiouracil
-- allopurinol
-- penicillamine
-- mitomycin C
-- methamphetamines
CHOLESTTEROL EMBOLI
-- warfarin
-- thrombolytic agents
 Potential Risk Factors for
Aminoglycoside Nephrotoxicity

⦿RELATED TO AMINOGLYCOSIDE
DOSE
-- large total cumulative dose
-- pronged therapy
-- trough concentration exceeding 2mg/L
-- recent previous aminoglycoside therapy
 Aminoglycoside in combination with:

⦿Cyclosporine
⦿Amphotericin B
⦿Vancomycin
⦿diuretics
⦿ Related To Preconditions in the Patient
⦿PRE-EXISTING RENAL INSUFFICIENCY
-- increased age
-- poor nutrition
-- shock
-- gram-negative bactercemia
-- liver disease
-- hypoalbuminaemia --
obstructive jaundice
-- dehydration
-- potassium and magnesium deficiencies