Kinetics in renal disease
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What is rate of excretion?
rate of filtration + rate of secretion - rate of reabsorption
What is secretion?
- facilitates extraction of drug in addition to filtration
- capacity limited
- active process (requires energy)
- kicks in when clearance exceeds filtration
What is reabsorption?
- generally a passive process
- no competition for absorption
- nonpolar, lipophilic, low MW can be reabsorbed (why drugs are usually polar and hydrophilic)
What characteristics must substances used to estimate GFR have?
- freely filtered by the glomerulus
- no renal secretion or reabsorption
- constant concentration during the period of measurement (in blood)
What substances are commonly used to estimate GFR?
- Na iothalamate I
- creatinine (the only one ideal for clinical use - it's endogenous)
Where is creatine produced?
in the liver
Where is creatine converted to creatinine?
in skeletal muscle
What are the characteristics of creatinine?
- freely filtered
- limited secretion (causes over-estimation of filtration)
- no reabsorption
What is normal creatinine clearance?
- male - 125mL/min/1.73m2female - 115mL/min/1.73m2by 60yo = 70% of young adults
What equations are used to estimate CrCl?
What equations are used to estimate GFR?
What disease states influence estimates of CrCl?
- spinal cord injuries (low muscle mass)
- amputations (low muscle mass)
- Cushing's syndrome (low muscle mass)
- muscular dystrophy (low muscle mass)
- Guillain-Barre syndrome (low muscle mass)
- rheumatoid arthritis (low muscle mass)
- liver disease
- glomerulopathic disease (damage to filter)
What diet factors influence estimation of CrCl?
- high meat protein diets (high creatinine values)
- vegetarians (low creatinine values)
- protein-calorie malnutrition (low creatinine values)
What drugs/endogenous substances influence estimation of CrCl?
- non-creatinine chromogens (false elevations)
- cephalosporins (false elevations)
- acetoacetate (false elevations)
- IDMS-traceable assays (decreases values by 0.1-0.2mg/dL)
- trimethoprim (increase values)
- cimetidine (increase values)
- fibric acid derivatives - other than gemfibrozil (increase values)
- tronederone (increase values)
What are the breakpoints to consider dosage adjustment in renal disease?
- 60 mL/min/72kg = modest decrease (first decrease)
- 30 mL/min/72kg = moderate decrease (second decrease)
- 15 mL/min/72kg = significant decrease (third decrease)
What drug pharmacokinetic characteristics call for adjustment in renal disease?
- <50% renal drug elimination - adjust at 60 mL/min/72kg or less
- 50-74% renal drug elimination - adjust at 30-45 mL/min/72kg
- >75% renal drug elimination - adjust at 15 mL/min/72kg
What plasma protein do acidic drugs compete for?
What plasma protein do basic drugs compete for?
alpha-1 acid glycoprotein and lipoproteins
What are the causes of hypoalbuminemia?
- urinary loss
- leakage into interstitial fluid
- decrease in hepatic synthesis
- altered intestinal absorption of dietary amino acids
What endogenous substances can compete and displace drugs from binding sites?
- uric acid
- hippuric acid
- free fatty acids
- various furan carboxylic acids
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