Compare Excretion and Elimination
  • Excretion is both drug and drug metabolites
  • Elimination is drug
Three Renal functions affecting Renal Elimination
  • Glomerular Filtration
  • Tubular Secretion
  • Tubular Reabsorption
Types of molecules passing through the Glomerulus into the Tubules
  • Small polar and non-polar molecules
  • Small Ions
  • Small Proteins
Types of molecules which will not pass through an intact Glomerulus
  • Large proteins
  • Protein-Bound molecules
  • Cells
Physiological factors affecting Renal Function
  • Blood Volume
  • Cardiac Output
  • Urine pH
Disease States affecting Renal Elimination
Mechanism of Tubular Secretion Relatively non-selective, active transport of both acidic and basic drugs in the Proximal Tubule
Mechanism of Tubular Reasborption
  • Reabsorption of fluids occurs by passive diffusion in Proximal Tubule
  • Distal Tubule has a more tightly regulated reabosorption of ion based on endocrine signaling
  • Water, of course, follow ions in both these locations
Factors affecting Tubular Reabsorption
  • Drug ionization state

  • Concentration in blood and urine
  • Molecular size and shape
  • Urine flow
  • Renal health
Approximate Urine pH Ranges
  • Normal ~6.3
  • Acidic ~5
  • Basic ~7.5
How dose Urine pH affect renal elimination
  • Only the Unionized form of the drug can be reabsorbed
  • Therefore drugs with high ionization at urine pH are rapidly excreted
Effects of urine pH on elimination of HA Acids (Most Drugs)
  • Low pKa

    • primarily in the ionized form (A-) at normal pH
    • Cannot be altered significantly even at acid pH
  • Med pKa (~5-9)

    • Significant portions of the drug are in the unionized form (HA) at normal pH
    • If the pH of the urine can be increased (Alkylized) much of the drug can be moved to the ionized form (A-) and eliminated
    • Alkylization of the urine increase the ionized form, Increasing Elimination, decreasing Cmax and AUC
    • Acidification of the urine decreases the ionized form concentration, decreasing Elimination, increasing Cmax and AUC
  • High pKa

    • Most of the drug is always in the ionized from(A-)
Effects of urine pH on Elimination of BH Bases (rare)
  • low pKa

    • The conjugate acid of the base (BH+) exists when the pH is below the pKa
    • The acid form is heavily unfavored even at acidic urine pH
    • Therefore, extremely weak bases have low renal elimination which cannot be altered
  • Mid pKa (~5-9)

    • The Conjugate acid (BH+) and the base (B) are at near equilibrium at urine pH
    • Acidifying the urine can favor the conjugate Acid (BH+) increasing elimination
    • Alkylizing the urine can favor the base, decreasing Elimination, increasing AUC, increasing Cmax, and decreasing Tmax
  • High pKa

    • Unionized state (B) highly favored at normal urine pH, promoting reabsorption
    • Even Alkylizing the urine will not shift this balance significantly
Medicinal Agents used to alter urine pH
  • Ascorbic Acid

    • Decreases pH by increasing the concentration of protons in the urine
    • HA acids are less likely to be charged, increasing reabsorption
    • BH+ acids are more likely to be protonated, decreasing reabsorption
  • Bicarbonate

    • Increases pH by decreasing the concentration of protons in the urine
    • HA acids are more likely to be charged (deprotonated), decreasing reabsorption
    • BH+ acids are less likely to be protonated, increasing reabsorption
Intact Nephron Hypothesis
  • All kidney functions are directly related to nephron population ie loss of nephrons produces a proportional loss in all renal function
  • Therefore , if all functions are proportional, measuring any one renal function will provide an accurate estimate of all other functions
Ideal Characteristics of a renal function marker
  1. Unrestricted movement (Diffusion) across the Glomerulus
  2. No Tubular Secretion
  3. Not metabolized within the body (esp Kidneys)
  4. Marker does not alter kidney function, directly or indirectly
Examples of GFR measurements
  • Inulin Clearance

    • Meets all criteria for Ideal Marker
    • Very expensive
    • Very Accurate
    • Too expensive for clinical use
  • Creatinine Clearance

    • Endogenous, so no administration required
    • primarily filtered, with a small secretion and no reabsorption
    • Tends to overestimate GFR
  • Serum Creatnine
Drug Classes significantly affecting Renal Clearance
Renal Eliminiation kinetic relationships
  • Rate Constant, k, is proportional to the clearance

    • Cl = k x Vd
  • Half life has an opposite, log relationship to Creatinine Clearance

    • Cl = Vd x kd = Vd x ln(2)/t1/2
Age-specific change to Renal Clearance
  • Children have rapidly changing clearance with high interpatient variability

    • Newborns have very low Renal Clearance, therefore longer half life, higher Cmax, etc
    • Renal Clearance to Surface Area peaks in the first year of life
  • Children's Volume Distribution is higher for some drugs (eg Diphenhydramine)

    • Plasma concentrations based on adult dosing may not reflect therapeutic and/or toxic effects in children, dose with caution
    • Any dosing of children based on clearance is somewhat suspect
  • Children often have higher Free Fraction of the drug
  • Renal Clearance to Surface Area declines gradually throughout life

    • Of course, surface area increases throughout life ;)
  • Renal clearance has high interpatient variability
The best we got for child dose adjustments Pediatric Dose = 1.4 x (Surface Area/1.8) x Adult Dose
Gender variations to Renal clearance Women have a higher rate of clearance than men
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