E. Triametrene

Vinnytsa 2012

Nephrotoxic Drugs

The major mechanisms of nephrotoxicity are:

1. Hemodymanic mediated

2. Glomerulonephritis

3. Acute tubular necrosis

4. Interstitial nephritis

5. Papillary necrosis

6. Obstructive uropathy

Hemodynamic mediated eff ec t:

n Drug involved in change of renal hemodynamics:

A. Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

B. Angiotensin Converting enzyme Inhibitors (ACEI)

C. Angiotensin receptors blockers (ARB)

D. Immunosuppressant agents Calcineurin inhibitors.

E. Triametrene

Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

Mechanism of action:

¨ Cyclooxygenase (COX) inhibition will block PG synthesis (vasodilator) and consequently, V.C will dominate and elevate the pressure in afferent and efferent arterioles.

¨ Renin-angiotensin system and norepinephrine will elevate renal and systemic B.P.

n They are nephrotoxic in patients with borderline renal function, sepsis or heart failure.

n NSAIDs can also induce: nephrotic syndrome, interstitial nephritis, electrolyte abnormalities.

n In borderline patients, it is advised to use drug with short half life as Aspirin or Celecoxib a selective COX 2 inhibitor. However recently, reports indicated its involvement in kidney injury.

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB):

They are inhibiting Renin system and decrease the

blood hemodynamic:

Ø It produces VD and decrease perfusion pressure and decreases glomerular filtration rate

Ø At the start of the treatment a decrease of urine volume and increase of creatinine by 30% indicates nephrotoxicity

Ø Damage is reversible

Ø Rehydration of patient is advisable

Ø Initiate treatment with short acting (captopril) and titrate later with long acting.

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB):

They are inhibiting Renin system and decrease the

blood hemodynamic:

¨ It produces VD and decrease perfusion pressure and decreases glomerular filtration rate

¨ At the start of the treatment a decrease of urine volume and increase of creatinine by 30% indicates nephrotoxicity

¨ Damage is reversible

¨ Rehydration of patient is advisable

¨ Initiate treatment with short acting (captopril) and titrate later with long acting

Immunosuppressant agents Calcineurin inhibitors:

Cyclosporine and Tacrolimus forms immunophillin complex which inhibits protein calcineurin and mediates T- cell response

It produces VC of afferent arterioles by increasing endothelin and thromboxane A2, affecting renal perfusion

n Nephrotoxicity is the dose limiting toxicity

n It can induce also interstitial nephritis and produce rejection or nephritis in renal transplant

n Therapeutic drug monitor is essential to reduce dose if needed

Triametrene:

§ It is K sparing diuretics. It decreases blood volume.

§ Co-administration with NSAIDs will affect the kidneys especially in susceptible patients

N.B. Cyclophosphamide is one of the anticancer drugs that causes hemorrhagic cystitis.

2.Glomerulonephritis GN:

4 Different immunological group of drugs induced GN:

n Nephrotic syndrome: It is leakage of small protein particles from glomeruli, proteinuria >3.5 gm/day& hyperlipidemia. Cause: unknown (autoimmune)

n Treatment supportive measurement & steroids in certain cases

n It is caused by: NSAIDs, ampicillin, rifampicin and lithium.

2. Focal segmental glomerulosclerosis (FSGS): It is interstitial sclerosis:

n treatment by Steroids

n It is caused by lithium, heroin.

3.Membrane nephropathy (MN): immune complex deposition along glomeruli → thickening of the membranes

§ Remission is usually happening and the condition is reversible

§ NSAIDs, gold therapy, mercury and penicillamine could be the cause

1. Acute Tubular Necrosis:

§ Due to ischemia from exposure to toxin→ direct sloughing of Renal tubules.

§ Caused by:

o Aminoglycosides

o Amphotericin B

o Radiocontrast dye

o Cisplatin

A-Aminoglycosides:

n Example:Gentamycin and Kanamycin

n Affecting PCT by binding of +ve charges of aminoglycosides to phospholipids in plasma, mitochondria and lysosomal membranes. It will interfere in the functions of organelles.

n Renal toxicity appears 5-10 days of treatment by monitoring serum creatinine and the level of the drug.

n It is reversible

B-Amphotericin B:

In 80% of patients after 3-4 grams

Mechanism of action:

§ It is incompletely understood.

§ It causes renal vasoconstriction and tubular injury by inserting into the cell membrane → creation of pores that increase membrane permeability

§ Avoid co-administration of other nephrotoxic agents especially: carbincillin and Ticarcillin.

C-Radiocontrast Dye:

n PD: unclear

§ Affecting tubular cells, renal ischemia, renal VC

§ Use NaHCO3 and N-acetyl cysteine

§ Deterioration happens 2-3 days after radiocontrast injection

§ Hydration is important and use mannitol pre and post injection.

D-Cisplatin

Ø Chemotherapeutic agent

Ø PD: binding to tubular cells

Ø Use fluids & osmotic diuretics decrease it toxicity.

4- Acute Allergic Interstitial Nephritis:

§ Due to hypersensitivity to medications

§ T- Cell mediated

o Antibiotics: penicillin, cephalosprorins and sulfonamides.

¨ Vancomycin (therapeutic drug monitoring is essential, 5% alone produce acute decline in renal function and percentage increases to 35% when adding other nephrotoxic drug).

¨ NSAIDs (fenoprofen)

¨ proton pump inhibitors (omeprazole)

¨ Calcineurin inhibitors: cyclosporine.

5- Papillary Nephritis:

Death of renal papillae due to:

Ø Analgesics (aspirin, acetaminophen, phenacetin and NSAIDs)

Ø Diabetic nephropathy

Ø Kidney infection

Ø Renal transplantation

Ø Sickle cell anemia

6- Obstructive nephropathy:

n Due to mechanical obstruction

n Mainly stone formation

n Acyclovir (hydration of patients is critical)

n Sulfadiazine

n Methotrexate

¨ Excessive administration of vit D may cause renal calcification.

List of some nephrotoxic drugs:

n Antibiotics:

n Aminoglycosides (10-15% Incidence of Acute Tubular Necrosis)

n Occurs in 10-20% patients on 7 day course

n Results in non-oligurics; increased serum Creatinine

n A single dose early in septic course is usually safe

n Sulfonamides

n Amphotericin B (Incidence 80-90%)

n Levofloxacin

n Ciprofloxacin

n Rifampin

n Tetracycline

n Acyclovir (only nephrotoxic in intravenous form)

n Pentamidine

n Hypolipodemic agents

n Statins

n Gemfibrozil

n Associated with Acute Renal Failure due to Rhabdomyolysis

n Fenofibrate (Tricor)

n Increases Serum Creatinine without significant decrease in GFR

n Serum Creatinine rise is reversible on stopping Fenofibrate.

N.B:

n Acute Renal Failure

¨ Dialysis indications: Creatinine >2.5 or Seizures, Rhabdomyolysis

n Chronic kidney disease with fibrosis.

References:

n Up To Date website

n Clinical Pharmacology: Melmon and Morrelli, McGraw-Hill, 2000

n Taber SS and Pasko, Epidemiology of drug-induced disorders: the kidney; Exper.Opin.Drug Saf. 7(6):679-690, 2008

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