Renal Disease Drugs 02 03 2015

Question 1

3 partitioning events

Answer 1

1. glomerular filtration
2. tubular secretion
3. tubular reabsorption

Question 2

Glomerular filtration

Answer 2

• only free (non-protein- bound) drug can be filtered.
• Drug pH and lipophilicity have no effect
• Unfiltered drug continues through kidney arterioles and contributes to the concentration gradient in cortex.

Question 3

Tubular Secretion

Answer 3

Both protein free and protein-bound ( albumin-bound) drugs can be secreted.

Drugs move from blood to lumen of nephron by an energy dependent active transport mechanism

Question 4

Tubular reabsorption

Answer 4

by the time the drug reaches the distal tubule, the concentration of the drug is very high.
- drug diffuses passively back out of the nephron lumen into the blood.

Only free and unionized drugs diffuses back.

Bicarbonate alkalinizes urine and increases anionic (acidic) clearance.

Ammonium chloride (NH4Cl) acidifies urine and increases cationic (basic) clearance.

Question 5

6 ways that drug can induce nephrotoxicity

Answer 5

1. altered intraglomerular hemodynamics
   - disrupts autoregulation of intraglomerular pressure and GFR
2. Tubular Cell Toxicity : impaired mitochondrial function= disrupted tubular transport
3. Inflammation: cahgnes glomerulus, tubular cells, scarring
4. Crystal nephropathy : drug produces crystals that are insoluble = obstruct urine flow
5. Rhabdomyolysis: lysis of skeletal muscle myocytes causes myoglobin release into plasma = renal toxicity, obstruction, and altered GFR
6. Thrombotic microangiopathy (TMA) - direct endothelial toxicity ( anti-VEGF agents)

Question 6

Clinical features of Aminoglycoside nephrotoxicity

Answer 6

• Manifests 5-7 days after initiation of therapy
• Usually non-oliguric
• loss of urine concentration ability
• Magnesuria
• Phosphaturia
• recovery usually ensues within 2-3 weeks after stopping therapy.
• Ototoxicity– damage nerve of ear – irreversible

Question 7

Risk factors for Aminoglycoside nephrotoxicity

Answer 7

• prolongued duration of therapy
• advanced age
• reduced effective arterial volume
• sepsis
• ELEVATED PLASMA DRUG CONCENTRATIONS
• frequency of dosing
• type of aminoglycoside

Question 8

Aminoglycoside induced nephrotoxicity

Answer 8

Highly polar bactericidal agents that are eliminated (unchnaged) by the kidney, with drug clearance being directly proportional to creatinine clearance.

Drugs reach very high concentrations in renal cortex and are directly toxic to proximal tubular cells.

• Hijack transporters ( Megalin)
• once inside, they are so polar that they mess up mitochondria – oxidative stress

= Caspase and Cyto-C = APOPTOSIS

Acute Kidney Injury: increase in tubular necrosis; decrease in GFR

Question 9

who are the most nephotoxic Aminoglycosides?

Answer 9

Neomycin (used now only topically), Tobramycin, and gentamicin

Question 10

What is the Cockroft-Gault variables?
- when is it used for?

When is the schwartz formula?

What are the variable for modification of Diet in Renal Disease (MDRD)

Answer 10

Baseline renal function; prevention of AG induced nephrotoxicity
- age, weight, serum creatine, gender

Children

Serum creatine, age, gender, african american

Question 11

One way to consolidate aminoglycoside dosing

Answer 11

exploit Post- Antibiotic Effect

- an inhibitor or cidal effect that persists after the AG is cleared by metabolism and elimination

Question 12

Role of vascular endothelial growth factor ( VEGF) in renal function

Answer 12

VEGF expressed in glomerular podocytes and tubular epithelial cells.

• induces fenestration formation in the endothelium and modulates vascular permeability
• supports endothelial cell survival and interstitial matrix remodeling
• mediates endothelium- dependent vasodilation

VEGF = normal presentation of glomerulus

Question 13

Anti-VEGF Therapy

1. Who is the anti-VEGF antibody?
2. Who are the VEGFR inhibitors ?
3. Who are the soluable captures of VEFG molecule?

Answer 13

1. bevacizumab
2. Sorafenib, Sunitinib
3. VEGF- trap

Question 14

Effects of anti-VEGF therapy

Answer 14

1. Hypertension
   - reduced expression of nitric oxide synthase!
   = decreased NO
   = vasoconstriction
2. Proteinuria
   - dose-dependent adverse reaction
   - alter fenestration formation of endothelial glomerular cells
   - temporary – resolves with drug discontinuation and not generally associated with renal dysfunction.
3. Acute Kidney Injury ( AKI)
   - mesangiolysis – swelling endothelial cells, loss of endothlial fenestrae, and effacement of foot processes
   - acute thrombotic microangiopathy (TMA) is most common histopahtologic lesion reported

renal function returned to normal or stabilized and proteinuria resolved after drug discontinuation

Question 15

Aritolochi Acid

Answer 15

herbal remedies Found in many tradition medicine in China, Japan, and India

cause AA nephropathy

Question 16

Aritolochi Acid Nephropathy ( AAN)

1. what is AAN?
2. Mechanism?

Answer 16

progressive form of nephritis that can lead to end-stage renal disease and urothelial malignancy
- interstitial fibrosis and tubular necrosis

• AA is heavily metabolized (vs. Aminoglycosides). Phase I and phase II. PHASE I = highly reactive radical ( an electrophile)
• electrophile interacts with EVERYTHING
  = tubular necrosis ( interacts with tubular DNA)
  Eventually also leads to interstitial nephritis.