Drugs in kidney diseases
DrNoushin Hashemi.M.D.
Nephrologist
Drugs and the Kidney
1- Renal Physiology and Pharmacokinetics
2- Drugs and the normal kidney
3- Effect of renal disease on drug metabolism
4- Drugs toxic to the kidney
5- Prescribing in kidney disease
Normal Kidney Function
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1 Extra Cellular Fluid Volume control
2 Electrolyte balance
3 Waste product excretion
4 Drug and hormone elimination/metabolism
5 Blood pressure regulation
6 Regulation of haematocrit
7 regulation of calcium/phosphate balance
(vitamin D3 metabolism)
Clinical Estimation of renal function
• Clinical examination
pallor, volume status, blood pressure measurement,
urinalysis
• Blood tests
• Routine Tests
•
haemoglobin level
•
electrolyte measurement (Na ,K , Ca, PO4)
•
urea
Serum Creatinine and GFR
• Muscle metabolite - concentration
proportional to muscle mass
– High: muscular young men
– Low: conditions with muscle wasting
• Elderly
• Muscular dystrophy
• Anorexia
• Malignancy
• women
• “Normal” range
70 to 140 μmol/litre
GFR Estimation
• Cockroft-Gault Formula
CrCl=Fx(140-age)xweight/CreaP
F♀=1.04
F♂=1.23
• MDRD Formula
• EPI(race,age,gender,cr)
ESTIMATION OF GFR

Creatinine Clearance
Urine crt × Urine volume
Plasma crt
Crt clearance =
Crt clearance =
(140-AGE) × WEIGHT
(Cockcroft-Gault equation)
72 × Crt.
Tests of renal function cont.
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24h Urine sample-Creatinine clearance
gold standard Inulin clearance
urea understimate and cr overestimate
GFR
Pharmacokinetics
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Absorption
Distribution
Metabolism
Elimination
– filtration
– secretion
Farmacodynamic

Complex interactions of other
farmacologic factors including
drugconcentration,receptor-drug
interaction and effect on body chemistry
and clinical factors such as concurrent
disease and degree of organ dysfunction
Drugs and normal kidney
Effects of renal disease on drugs
Effect of uremia on drug disposition
1-Bioavalability :
uremia decreases GI absorption of drugs
(dissolution ,alkalinization,first pass hepatic
metabolism , impaire protein binding)
2-Distribution:
-edema and ascites :increase volume of distribution
-dehydration and muscle wasting :decrease volume of
distribution
-combination of decrease serum Alb concentration
and reduction in Alb affinity reduce protein binding in
uremia

3-Metabolism:
-uremia slows the rate of reduction and
hydrolysis reactions .
-uremia alter the deposition of drugs
metabolize by liver through changes in
plasma protein binding.
TABLE 57-2 -- Drugs That Have Active or Toxic Metabolites in Dialysis Patients
Acetaminophen
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Adriamycin
Allopurinol
Amiodarone
Amoxapine
Azathioprine
Benzodiazepines
β-Blockers
Bupropion
Buspirone
Cardiac glycosides
Clorazepate
Cephalosporins
Chloral hydrate
Clofibrate
Desipramine
Diltiazem
Encainide
Esmolol
H2-blockers
Hydroxyzine
Imipramine
TABLE 57-2-- Drugs That Have Active or Toxic Metabolites in Dialysis Patients
cont…..
Isosorbide
Levodopa
Lorcainide
Meperidine
Metronidazole
Methyldopa
Miglitol
Minoxidil
Morphine
Nitrofurantoin
Nitroprusside
Procainamide
Primidone
Propoxyphene
Pyrimethamine
Quinidine
Serotonin reuptake inhibitors
Spironolactone
Sulfonylureas
Sulindac
Thiazolidinediones
Triamterene
Trimethadione
Verapamil
Vidarabine
Effect of dialysis on drugs:
Drug clearance during dialysis :
-Adsorption
-Convection
-Diffusion
drugs that have small volume of
distribution more effectively removed by
dialysis
Effect of dialysis on drugs
Molecular weight
 Water solubility
 Degree of protein binding
 Membrane clearance
Drugs with MW >500 daltons poorly cleared by
conventional HD membranes.
Protein or tissue binding or lipid soluble are not
dialyzed properly.(<90% proteinbound)
For drugs not removed by HD, it is unusual to be
removed by peritoneal dialysis.
High-flux membranes (porous) are more permeable
to drugs.(treatment time,BFR,DFR)

Effect of dialysis on drugs
Hemofiltration modalities are using in ICU
for management of acute renal failure
significantly increase drug removal due to
increase plasma protein loss.(treatment of
theophylline and aspirin poisoning)
 A drug significantly removed by this modality
if is not protein bound and distributed in
plasma.
 Measurement of serum drug level may be
helpful in guiding the need for supplemental
dosing.

Drug dosing in PD :
PD is less efficient in removing drugs than
HD
 LMW drugs and small volume of
distribution are more effectively removed
 Depends on number and volume
exchange done daily and dwell time.
 Depends on residual kidney function.
 Factors favoring absorption include
inflamation of membrane and
concentration gradient.

Drug dosing in CRRT:
Provide less of a challenge for drug dosing
 Continuous nature of clearance is
analogous with drug removal by kidney
 Depends on MW,membrane
characteristic, BFR,DFR .

Drug dosing recommendations:
loading dose is equal to usual dose in
normal kidney function.
 In HD many drugs are given only at the
end of dialysis.
 Maintenance dose of most drugs should
be given after dialysis.

Drugs toxic to the kidney
Patient –related risk factors for
drug-induced nephrotoxicity
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Absolute or effective intravascular depletion
Age older than 60 years
Diabetes
Exposure to multiple nephrotoxins
Heart failure
Sepsis
Underlying renal insufficiency (glumerular
filtration rate <60 ml per minute per 1.73m2)


Drug toxicity is responsible for 18-27% of
Acute Renal injury
6 major mechanisms are involved:
1.
2.
3.
4.
5.
6.
Hemodymanic mediated
Glomerulonephritis
Acute tubular necrosis
Interstitial nephritis
Papillary necrosis
Obstructive uropathy
GLOMERULUS
1- Hemodynamic mediated Effect


Gradient pressure between afferent and
efferent arterioles are responsible for
glomerular filtration.
Drug involved:
a.
b.
c.
d.
NSAID
ACE inhibitors
ARB
Calcineurin inhibitor
A- NSAID

They are nephrotoxic in patients with
borderline renal function, spesis or haert
failure
◦ COX inhibition will block PG synthesis
(vasodialtor) and consequently,V.C will
dominate and blood flow and GFR will
decrease .
◦ PG also important for maintaining fluid and
electrolyte hemostasis.
NSAIDs (Non-steroidal anti
inflammatory drugs)

Commonly used
◦ Interfere with prostaglandin production, disrupt
regulation of renal medullary blood flow and salt
water balance
◦ Naproxen have the least cardiovascular risk
◦ Antithrombotic effect of ASA antagonized by
NSAID

Chronic renal impairment
◦ Habitual use
◦ Exacerbated by other drugs ( anti-hypertensives,
ACE inhibitors)
Nephrotoxic potential of Nsaid
determine by potency, length of
action,period of administration
 A hypersensivity reaction of Nsaid may
provoke AKI associated with preuteinuria
and nephrotic syndrome and allergic
interstitial nephritis

B & C- ACEIs and ARB
◦ Angiotensin converting enzyme inhibitors (ACEI) and
angiotensin receptor blocker (ARB) are inhibiting
Renin system and decrease the blood hemodynamic:
 It produces VD and decrease perfusion pressure
and decreases GFR
 At the start of the treatment a decrease of urine
volume and increase of creatinine by 30% indicates
 Damage is reversible
 Rehydration of patient is advisable
 Initiate treatment with short acting (captopril) and
titrate later with long acting

It is contraindicated to prescribe it for
patients with renal artery stenosis….
Why???
D- Immunosuppressing agents
Calcineurin inhibitors
◦ Cyclosporine and Tacrolimus forms immunophillin
complex which inhibits protein calcineurin and
mediates T- cell response
◦ It produces VC of afferent arteriols by increasing
endothelin and thromboxan A2, affecting renal
perfusion
 Nephrotoxicity is the dose limiting toxicity
 It can cause also interstitial nephritis and produce
nephritis in renal transplant
 Therapeutic drug monitor is essential to reduce dose
when needed


Drug toxicity is responsible for 18-27% of
Acute Renal injury in USA
6 major mechanisms are involved:
1.
2.
3.
4.
5.
6.
Hemodymanic mediated
Glomerulonephritis
Acute tubular necrosis
Interstitial nephritis
Papillary necrosis
Obstructive uropathy
2- Glomerulonephritis

4 Different immunological drug induced
GN:
1. Minimal change syndrome: by: NSAID,
ampicillin, rifampicin
2. Focal segmental glomeruloscerosis (FSGS):
lithium, heroin
3. Membranous nephropathy (MN): NSAID,
gold therapy, mercury, penicillamine
4. Membranoproliferative: hydralazine


Drug toxicity is responsible for 18-27% of
Acute Renal injury in USA
6 major mechanisms are involved:
1.
2.
3.
4.
5.
6.
Hemodymanic mediated
Glomerulonephritis
Acute tubular necrosis
Interstitial nephritis
Papillary necrosis
Obstructive uropathy
3- Acute Tubular Necrosis


Due to ischemia from exposure to
toxin. Death of the tube, sloughing of
Renal tubules.
Caused by:
1.
2.
3.
4.
Aminoglycosides
Amphotericin B
Radiocontrast dye
Cisplatin
Aminoglycosides
Highly effective antimicrobials
◦ Particularly useful in gram -ve sepsis
◦ bactericidal
 BUT
◦ Nephrotoxic
◦ Ototoxic
◦ Narrow therapeutic range

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Aminoglycisdes
 Gentamycin and Kanamycin
◦ Affecting PCT by binding of +ve charges of
AG to phospholipids in plasma, mitochondria
and lysosomal membranes. It will interfere in
the functions of organelles.
◦ Renal toxicity appears 5-10 days of treatment
by monitoring serum creatinine.
◦ AKI is reversible
Prescribing Aminoglycosides
Once daily regimen now recommended
in patients with normal kidneys
 High peak concentration enhances efficacy
 long post dose effect
 Single daily dose less nephrotoxic
 Dose depends on size and renal function
 Measure levels!


Amphotericin B
◦ In 80% of patients after 3-4 grams
◦ Affecting PCT and DCT to increase
permeability and increase O2 requirements,
VC of blood vessels.
◦ Avoid co administration of other nephrotoxic
agents especially: carbicillin and Ticarcillin
Intravenous contrast
Used commonly
 CT scanning, IV urography, Angiography
 Unsafe in patients with pre-existing renal
impairment
 Risk increased in diabetic nephropathy, heart
failure & dehydration
 Can precipitate end-stage renal failure
 Cumulative effect on repeated administration
 Radiocontrast Dye
• low osmolarity,nonionise,low dose
Max dose BW multiply 5 devided by cr
• Affecting tubular cells, renal ischemia, renal VC
 Use NaHCO3 and N-acetyl cysteine
 Deterioration happens 2-3 days after radiocontrast
injection,recover after 1 week
 Hydration is the most important and use mannitol
pre and post injection and diuretics not advised
 Cisplatin
• Chemotherapeutic agent
• binding to tubular cells


Drug toxicity is responsible for 18-27% of
Acute Renal injury in USA
6 major mechanisms are involved:
1.
2.
3.
4.
5.
6.
Hemodymanic mediated
Glomerulonephritis
Acute tubular necrosis
Interstitial nephritis
Papillary necrosis
Obstructive uropathy
4- Acute Allergic Interstitial Nephritis
Due to hypersensitivity to medications
 T- Cell mediated

◦ Antibiotics: penicillin, cephalosprorins and
sulfonamides.
◦ Vancomycin (therapeutic drug monitoring is essential,
5% alone produce AKI and percentage increases to
35% when adding other nephrotoxic drug).
◦ NSAID (fenoprofen)
◦ PPI: proton pump inhibitors (omeprazole)
◦ Calcineurin inhibitors: cyclosporin


Drug toxicity is responsible for 18-27% of
Acute Renal injury in USA
6 major mechanisms are involved:
1.
2.
3.
4.
5.
6.
Hemodymanic mediated
Glomerulonephritis
Acute tubular necrosis
Interstitial nephritis
Papillary necrosis
Obstructive uropathy
5- Papillary Necrosis

Death of renal papillae due to
◦ Analgesics (aspirin, acetaminophen, phenacetin
and NSAID),morphin is choice,avoid
meperidine and propoxyphen
◦ Diabetic nephropathy
◦ Kidney infection
◦ Renal transplantation
◦ Sickle cell anemia


Drug toxicity is responsible for 18-27% of
Acute Renal injury in USA
6 major mechanisms are involved:
1.
2.
3.
4.
5.
6.
Hemodymanic mediated
Glomerulonephritis
Acute tubular necrosis
Interstitial nephritis
Papillary necrosis
Obstructive uropathy
6- Obstructive nephropathy
Due to mechanical obstruction
 Mainly stone formation

◦ Acyclovir (hydration of patients is critical)
◦ Sulfadiazine
◦ Methotrexate
Anticonvulsants:
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Generalized seizure occur in severe uremia
Phenytoin frequently used for treatment
Phenytoin absorption is slow and erratic
Hepatic metabolism is concentration
dependent and saturable
Concentration of active ,free drug is higher
in uremia .
Seizure is a manifestation of toxicity
Free serum phenytoin concentration
measurement should done
Hypoglycemic drugs :
46% of new dialysis patient have DM
 Kidney account for 30% elimination of
insulin
 Initial drug dose should be low and titrate
carefully
 Risk of metformin accumulation and lactic
acidosis increase with age and renal
failure

Antiplatelet and anticoagulant :
Low dose Aspirin had no adverse effect
on kidney function.
 In AKI and CKD have inhance bleeding
risk
 UFH is prudent in advanced CKD
 LMWH is problematic due to absence of
activated factor10 monitoring

Sedatives :
Benzodiazepines are usually used in
dialysis patients .
 Benzodiazepines are usually safe and
effective
 BNZD have active metabolites
 Lorazepam and Alprazolam advised
 MAOI are avoided

Prescribing in Kidney Disease
Patients with renal impairment
 Patients on Dialysis
 Patients with renal transplants

Principles

Establish type of kidney disease
 Most patients with kidney failure will already be
taking a number of drugs
 Interactions are common
 Care needed to avoid drug toxicity

Patients with renal impairment and renal
failure
 Antihypertensives
 Phosphate binders
Dosing in renal impairment
Loading dose does not change (usually)
 Maintenance dose or dosing interval does

T ½ often prolonged
◦ Reduce dose OR
◦ Increase dosing interval
◦ Some drugs have active metabolites that are
themselves excreted renally
 Warfarin, diazepam,allopurinol
dialysis
indications
Renal replacement therapy in AKI
1-absolute indications:
a-volume overload unresponsive to diuretic
therapy
b-hyperkalemia despite medical treatment
c-persistant metabolic acidosis
d-overt uremic syndroms:
encephalopathy
pericarditis
uremic bleeding diathesis

Renal replacement therapy in AKI

2-relative indications:
a-progressive azotemia without uremic
manifestations
b-persistant oliguria
Renal replacement therapy in CKD

1-complications that prompt initiation of
renal replacement therapy:
a-intractable extracellular overload and
or hypertension
b-hyperkalemia refractory to dietary
restriction and pharmacologic
treatment
c-metabolic acidosis refractory to
bicarbonate treatment
d-hyperphosphatemia refractory to
dietary counselling and to treatment
to phosphate binder
e-anemia refractory to EPO and iron
f-otherwise unexplained decline in
functioning or well-being
g-recent weight loss or deteroriation of
nutritional status,specialy if
accompanied by nausea ,vomiting or
evidence of gastrodeodenitis

2-urgent indications:
a-neurologic dysfunction(neuropathy,
encephalopathy , psychiatric
disturbance)
b-pleuritis or pericarditis without any
explanation
c-bleeding diathesis manifested by
prolonged bleeding time