Drug Induced Nephrotoxicity

Question 1

Kidney and drug filtration

Answer 1

Kidney can filter small drug molecules and those NOT bound to plasma proteins

Question 2

Kidney and drug excretion

Answer 2

Active tubular secretion in proximal tubule that involves 2 carrier systems (acids, bases)

Question 3

Reabsorption of weak acids, bases by

Answer 3

Passive diffusion

Question 4

Rate of reabsorption depends on

Answer 4

Urinary pH and lipid solubility of UNionized drug whether acidic or basic

Question 5

Drug metabolism in the kidney

Answer 5

Just like in the liver ie involves oxidation, acetylation, conjugation NOTE: less specific than in the liver CP450 with oxidation

Question 6

Reasons for kidneys susceptibility to adverse effects of drugs

Answer 6

1. High blood flow 2. Ability to concentrate drugs in tubules—> expose tubules to high concentrations of drug 3. Metabolize drugs—> active metabolites 4. Large surface area of tubular epithelium provides site for interaction

Question 7

Mechanism of Acute Renal Failure

Answer 7

1. Altered intraglomerular hemodynamics 2. Vasoconstriction 3. Acute tubular necrosis 4. Aminoglycosides 5. Acetaminophen 6. Acute interstitial nephritis 7. Tubular obstruction ( crystal nephropathy) 8. Thrombotic microangiopathy 9. Rhabdomylosis 10. Osmotic nephrosis

Question 8

Altered intraglomerular hemodynamics and ARF

Answer 8

NSAIDS and ACE-I→ deccline in blood prssure/ renal blood flow → prerenal failure

Question 9

Altered intraglomerular hemodynamics and NSAIDS

Answer 9

NSAIDS

inhibit vasodilator effects of prostaglandins

Question 10

Altered intraglomerular hemodynamics and ACE-I

Answer 10

ACE-I

inhibit Ang 2 acivity→ affect kidnyes ability to regulate glomerular pressure → decreased GFR

Question 11

Captopril and ARF

Answer 11

Captopril: ACE-I

induces ARF in patients with decreased renal blood flow ie pt with bilateral Renal Artery Stenosis, shock, hypovolemia.

Question 12

Reversibility of ARF induced by ACE-I and NSAIDs

Answer 12

Reversible after discontinuation

Question 13

Vasoconstriction and ARF mainly associated with which drugs

Answer 13

Main mechanism of ARF in Cylosporine and vasopressors

ALSO: Amphoterecin B, radiocontrast media

Question 14

Cyclosporin and vasocostriction→ ARF

Answer 14

Causes dose and concentration dependent predominating preglomerular vasoconstrition → reduced renal plasma flow and GFR→ ARF

Question 15

How is the nephrotoxicity associated with cyclosporin managed

Answer 15

Reduced dose

Question 16

Acute tubular necrosis and ARF

Answer 16

• Mostly caused by drugs that are excreted by the kidney
• Direct tubuar toxicity→ tubuoepithelial injury in PCT

Question 17

Drugs associated with acute tubular necrosis → ARF

Answer 17

1. Gentamycin
2. Amphoterecin B
3. Antiviral
4. Cisplatin
5. Acetaminophen (in cases of overdose + usualy acompained by hepatic failure)
6. Radiocontrast media

Question 18

Aminoglcosides and ARF pathophysiology

Answer 18

Aminoglycosides:

• highly cationic
• actively reabsorbed in PCT→ high concntrations in cotex
• accumulate within lysosomes→ interfere with protein synthesis and miochondrial function→ NECROSIS

Question 19

Reversibility of Aminoglycosides→ARF

Answer 19

Reversible after discontinuation of drug

Question 20

Acute interstitial nephritis→ ARF mediated by

Answer 20

Inflammation of interstitium and tubules

Question 21

Acute interstitial nephritis→ ARF pathophysiology

Answer 21

Idiosyncratic non dose dependent hypersensitivity reaction

Question 22

Acute interstitial nephritis→ ARF associated with which drugs

Answer 22

1. Antibiotics (penicillins, cephalosporins, sulfonamides, quinolones)
2. NSAIDS
3. ANtivirals (acyclovir)

Question 23

Crystal nephropathy an ARF pathophysiology

Answer 23

Drugs that produce crystals (pH DEPENDENT) insoluble in urine → precipitate in lumen of DT→ obstruct renal flow + interstitial reaction

Question 24

Crystal nephropathy → ARF associated with which drugs

Answer 24

1. Antivirals (acyclovir)
2. ANtibiotics (sulfonamides, ciprofloxacin)
3. METHOTREXATE

Question 25

Thrombotic miroagiopathy→ ARF pathophysiology

Answer 25

1. formation of platelet thrombi in microcirculation 2. secondary mechanism of immune mediated 3. direct endothelial toxicity Result in **severe renal failure**

Question 26

Drugs implicated in Thrombotic microangiopathy→ARF

Answer 26

* **CYCLOSPORIN** * Chemotherepeutics eg mitomycin-c * antiplatelet drugs eg ticlopidine

Question 27

Rhabdomylosis associated with

Answer 27

**STATINS** esp if adminostered with other drugs may occur with other drugs

Question 28

Osmotic Nephosis assoicated with

Answer 28

**Hyperosmolar agents** radiocontrast media, plasma expanders, Ig

Question 29

Oveview of drug induced CRF

Answer 29

* presents as tubulointerstitial disease * assocaited with **analgesics** (NSAIDs) **cyclosporin, lithium, cisplatin** * renal injury may be irreversible *(lithium, cyclosorin)*

Question 30

Analgesic nephropathy→CRF

Answer 30

* associated with long term use of analgesics * characterized by **interstitial nephritis and renal papllary necrosis** * cobinations eg. **acetaminophen and aspirin**→more toxic than single drug because aspirin deplete the *glutathione* that detoxofies the active metabolote of aceta

Question 31

Nephrotic syndrome associated with which drug

Answer 31

**NSAIDs** immunological MINIMAL CHANGE NEPHROTIC SYNDROME

Question 32

Patient related RF for drug-induced nephrotoxicity

Answer 32

* age \>60 * volume depletion * diabetes * heart failure * spesis * shock * GFR,60ml/min/1.73m² * exposure to multiple nephrotoxins * Race * sex * allergies * genetic variations

Question 33

Drugs with inherent nephrotoxic effect

Answer 33

* Aminoglycosides * Amphoterecin B * Cisplatin * Cyclsporine * Contrast dye **NOTE:** Risk factor for drug induced nephrotoxicity

Question 34

drugs whos nephrotoxicity is dose dependent

Answer 34

* Acyclovir * NSAIDs NOTE: Risk factor for drug induced nephrotoxicity

Question 35

other dug related RF

Answer 35

* repeated exposure * immune effexts * drug interations

Question 36

Prevention

Answer 36

* awareness of nephrooxicity of drugs and combinations * correct rf * elderly more succeptible * avoid dehydration esp in high risk pt * adjust daily dosage to onhoig alteration in GFR **cockcroft gault formula** * Limit daily dosage and duration of treatment with NSAIDs * alternatives