nephrotoxicity Flashcards
(30 cards)
list the soluble drug transporters
-
OATs/OCTs - organic anion and cation transporters
- MOST IMPORTANT. TRANSPORT ALMOST ALL SUBSTANCES
- OATPs - organic anion transporting polypeptides
- PEPT - peptide transporters (amino acids and
- peptides)
WHAT TYPE OF TRANSPORTER IS MATE
- multi-drug and toxin extrusion - family of ABC transporters
- ABC TRANSPORTERS TRANSPORT THINGS OUTSIDE THE CELL
EXPLAIN THE MECHANISM BY WHICH PROBENICID AS WELL AS SIMILIAR SUBSTRATE RESULT IN PENICILIN AND CEPHALOSPORIN EXCRETION
- PENICILIN AND CEPHALOSPORINS ARE NORMALLY NT TOXIC
- THEY HAVE TO COMPETE WITH PROBENICID FOR TRANSPORT INTO KIDNEY CELLS AND INTO URINE
- PROBENICID IS A SUBSTRATE
EXPLAIN ADV. AND DISADVANTAGES OF PROBENICIN AS A SUBSTRATE FOR OTA
- REDUCE ENTRY OF OTA INTO THE KIDNEY CELLS
- BUT OTA IS GONNA ACCUMULATE IN BLOOD
- AND ITS GONNA DAMAGE THE LIVER AND OTHER ORGANS INSTEAD
DISCUSS MECHANISM OF PARA-AMINO HIPPURIC ACID IN KIDNEYS
- SAME AS PROBENICIN
- IT IS A CO-SUBSTRATE
WHICH DRUGS ARE TRANSPORTED BY ABC TRASPORTERS
- IVERMECTIN
- FLOUROQUINOLONES
- NOT GENTAMYCIN
KEY ENZYME FOR Glutathione conjugate
processing
- N-acetyl-transferase (NAT1 and
NAT2) - A renal-specific biotransformation pathway
- A renal-specific biotransformation pathway
- Slow and fast metabolizes of drugs (see sulfonamide sensitivity of dogs)
- Bioactivation of certain halogenated benzenes and other toxins (benzene-ring structures)
NON TOXIC END PRODUCT OF GLUTATHIONE CONJUGATE PROCESSING
- Mercapturic acid (renal end-product) in urine
- N-acetyltransferase INACTIVATES THE toxic COMPOND
THE TOXIC COMPOUND OF GLUTATHIONE CONJUGATE PROCESSING
- Venylthiole episulfonium ions
- SITE SPECIFIC RENAL TOXICITY
- animals with genetic polyphomophism will nt express more
of N. ACETYL TRSANSFERASE leaing to the toxic pathway
AVANTAGE AND DISADVANTAGES OF METALLOTHIONEINS
- BINDS METALS PREDOMINANTLY IN THE LIVER AND STOP LIVER DAMAGE
- THE METAL COMPOUNDS GETS DEPOSITED IN KIDNEY N END P DAMAGED
DISCUSS THE MECHANISM FOR KIDNEY DAMAGE BY METALLOTHIONEINS (MT)
- Heavy metals (particularly Cd:
replaces Zn and binds to and
induces MT - predominantly in the
liver) - The MT complex is transported tothe kidney
- In the kidney the MT complex is cleaved due to a pH shift
- Free metal ions - accumulation- oxidative stress - cell injury/renal toxicity
DISCSS ROUND UP PESTICIDE TOXICIDE
- Glycophosphate toxicity
- Normally very safe
- pesticide/herbicide
- Combined with heavy
- metals results in toxicity
- Chronic kidney disease of
- unknown origin
MECHANISM FOR ETHYLENE GLYCOSIDE
- Acute acidosis
- Decreased renal perfusion
- Calcium oxalate crystals in the renal tubules
- LD50 1.5 ml in cats; 5.5ml in
- dogs
DISCUSS TX OF ETHELYNE GLYCOL
- Ethylene glycol itself is not toxic,
the metabolites are
- Therapy in dogs: 4-MP (fomepizol
or 4-methylpyrazone; Atizol®)
Inhibition of alcohol
dehydrogenase (only in higher
concentrations in cats!)
- Ethanol: competition for alcohol
dehydrogenase
cs of ethelyn glycol intoxication
- 0.5-12hrs: vomiting, ataxia, polyuria
- Cardiopulmonary symptoms: tachypnea, tachycardia
- 4EX. Oxalate nephrosis: anorexia, azotemia, oliguria
- leading to kidney failure
- Rapid intervention is required:
- Interrupt exposure: induce vomiting (binds poorly to
- activated charcoal, bentonite is better)
- Correct metabolic acidosis: Na-bicarbonate
discuss toxicity of melamine
- Feed contamination: technical melamine contains residual amounts of cyanuric acid
- Melamine and cyanuric acid - amorphous brownish crystals in collective duct and urinary bladder: may result in acute renal failure
- Migration agent from plastic?
- Disease not reproducible with melamine
- Melamine toxicity is completely documented - no renal toxicity
WHICH toxin affects the DT
- Distal tubular damage
- in contrast to other toxins
causing proximal tubular damage - Melamine plus cyanuric acid complexes
MELAMINE TOXICITY
China September 2008: large scale fraude with
infant formula to which melamine was added to
pretend a higher protein content (interferes with
protein measurement)
Thousands of infants with renal failure
Therapy: symptomatic, prognosis is poor
TOXICITY FOR GENTAMICINE
- Nephrotoxicity - neurotoxicity -ototoxicity
- Substrates for OAT1 and OAT3;
- down regulation of OAT expression following continuing exposure
- Time-dependent passive reabsorption; active secretion
- Concentration dependent bacterial killing
- TOXICITY OF GENTAMYCIN DEPENDS ON
- Duration of treatment
- Cumulative dose
- Average daily dose
- Peak and trough serum
- concentrations
- Concurrent diuretic use
- Underlying disease status
- Previous exposure to
- aminoglycosides
THIS DRUG CAUSE HYPERTENTION LEADING TO CARDIOPATHY AND CHRONIC RENAL INSUFICIENCY
- Melengestrol acetate
- Long-term glucocorticoid treatment
- THIS CONDITION IS CALLED AMES: Apparent Mineralocorticoid Excess
Syndrome (liquorice) IN PPLE
mechanism by which hypertension causing drugs like Melengestrol acetate cause renal damage
Inhibition of 11-β-hydroxy-steroid
dehydrogenase
drugs causing PT damage
Aminoglycosides
Amphotericin B
Cisplatin
rugs causing distal tubular damage
NSAIDs
ACE-inhibitors
Cyclosporin
Lithium salts
