Lisa M Harrison-Bernard, PhD 11/16/2011

Integrative Sciences: Biological Systems A Fall 2011 Recommended Textbook Body Fluids Compartments, Renal and Renal Excretion of Drugs Monday, November 21, 2011 Lisa M. Harrison-Bernard, Ph.D. Department of Physiology; Associate Professor 568-6175; Rm 7213; [email protected]

Body Fluid Compartments Terminology Chapters 1 & 3 in Koeppen Molarity – number of moles & Stanton of solute / Liter of • Molar (M) = moles/L a) Terminology • millimolar (mM) = mmol/L b) Compartments

Terminology Terminology Osmole – amount of substance Tonicity – of solution related to effect that dissociates in solution to form on volume – ability of solute to 1 mole of osmotically active cross particles • Isotonic solution: no change in cell • 1 mole = 1 osmole of volume solute • Hypotonic solution: causes cell to swell • 1 mole NaCl = 2 osmoles of • Hypertonic solution: causes cell to shrink solute

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Terminology Terminology

Osmolality - osmoles/kg H2O Osmolarity - concentration of • dependent on number molecules osmotically active particles in in solution, not size, nature, solution – charge • osmoles/Liter (Osm/L) • body fluid shifts between compartments • mosmoles/Liter (mOsm/L) • Normal value - 290 mOsmoles/kg Dilute : solution osmolality ~ osmolarity

Terminology Role of Kidneys

Isosmotic - same Maintain the volume and osmolarity as plasma composition of body fluids constant despite wide • hypoosmotic - below variation in daily intake of • hyperosmotic - above & solute.

Osmotic EQ Across Membrane Osmotic Driven Water Flow INITIAL CONDITIONS solutes solutes A B Total Volume (L) 3 3 6 Conc (mOsm) 400 200 --- H 0 H 0 2 2 Total Solute 1,200 600 1,800 (mosmoles)

Water diffuses across semipermeable Total Solute (mosmoles) = Conc (mosmoles/L) X Volume (L) cell membranes through water channels, Conc (mOsm) = 1,800 mosmoles / 6 L AQUAPORINS. Net movement of water = 300 mOsm to achieve osmotic EQ.

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Solute Composition of Body Fluid Compartments Osmotic Driven Water Flow Appendix B INITIAL CONDITIONS A B Total Solute Units Normal PLASMA Cell Plasma Conc Volume (L) 3 3 6 Range Conc (mOsm) 400 200 --- Total Solute 1,200 600 1,800 (mosmoles) Na+ mmol/L 135 - 147 * 145 10-15

EQ CONDITIONS K+ mmol/L 3.5 - 5.0 4.4 *150 A B Total +2 Final Volume (L) 4 2 6 Ca mmol/L 1.14 - 1.3 1.2 100nM (ionized) Conc (mOsm) 300 300 --- H+ pH 7.35 - 7.45 7.4 ~7.2 Amount Solute 1,200 600 1,800 (mosmoles)

Solute Composition of Body Fluid Compartments Appendix B Major Cations and Anions Solute Units Normal PLASMA Cell Plasma Conc Cation Anion Range

- + - - Cl mmol/L 95 – 105 * 102 20 Extracellular Na Cl , HCO3 - HCO3 mmol/L 22 – 28 * 24 15 g/dl 6 - 7.8 7 *30 Intracellular K+ Organic Glucose mg/dl 70 – 110 100 --- Phosphates, Osmolality mOsm/kg 285 - 295 290 290

H2O

Water in Body Size of Body Fluid Compartments

Water - most abundant substance in body

3L Solvent for all dissolved constituents 3L Intracellular volume – volume of fluid in 3L all cells Extracellular volume – fluid throughout compartment 3L •interstitial space, vascular compartment

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Size of Body Fluid Compartments Approximate Water Distribution = 17L = 25L 70Kg Adult Human • Total (TBW) ~ 60% Body Weight (BW) = ~ 42L 13L 3L • Intracellular Fluid (ICF) 25L ~ 40% BW = ~ 25L • (ECF) 1L ~ 20% BW = ~ 17L “ 20, 40, 60 ” rule of thumb TBW = 42L

Approximate Water Distribution ECF = 17L 70Kg Adult Human • TBW •Interstitial Fluid (ISF) – 75% ECF = 13L 60% BW = ~ 42L – • Plasma Volume (PV) • Intracellular Fluid (ICF) – 20% ECF = 3L – 60% TBW = ~ 25L • Volume (BV) – PV/(1-Hct) = 5.5L • Extracellular Fluid • Transcellular Fluid (synovial & (ECF) ) – 40% TBW = ~ 17L – 5% ECF = 1L

Calculating Changes in Body Fluid Body Fluid Compartments Volumes

Osmoles = Osmolarity Body Water (milliosmoles) (milliosmoles/L) X (L)

Total Body 12,180 milliosmoles = 290 mosmoles/L X 42 L ICF 7,250 milliosmoles = 290 mosmoles/L X 25 L ECF 4,930 milliosmoles = 290 mosmoles/L X 17 L

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INFUSE 1.5L Isotonic Saline (145 mM NaCl) Infuse 1.5 L Pure Water (Isotonic Glucose)

(17 + 1.5) (17 + 1.5) EARLY ↑ ECF 1.5L

(4930 + 435) FINAL Expand ECFV ICFV Stays + 1.5L Same ↑ ECF 40% of 1.5L = 0.6L ↑ ICF 60% of 1.5L = 0.9L

Summary I 1. Determine body fluid Renal Clearance volumes based on body weight 1. Concept of Clearance 2. Predict changes in 2. Clearance of Inulin, Creatinine = Estimates of fluid volume and Glomerular Rate osmolality caused by (GFR) salt and fluid loss and 3. PAH, estimate of Renal gains Plasma Flow (RPF)

Tubular Epithelium Renal Processes • Filtration Glomerular lumen ⇒ Bowman’s space (bulk flow) • Tubular Reabsorption Tubular lumen ⇒ peritubular capillary plasma • Tubular Secretion Peritubular plasma (capillary lumen) ⇒ interstitial space ⇒ tubular cell ⇒ tubular lumen (tubular cell interior to tubular lumen)

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Renal Plasma Clearance Clearance X = • Renal CLEARANCE of any substance volume of plasma from which a Mass X excreted / time substance is completely removed (cleared) by kidneys per unit time Plasma [X] • Units = Volume plasma per time ClX • PX = UX • V ml/min • ClX = UX • V • QUANTITATIVE evaluation of how handles a specific PX substance

Substance CLEARANCE (ml/min) Glucose 0 Inulin Na+ 0.9 ClIN = GFR K+ 12 Inulin 125 Creatinine 140 PAH 560

Inulin ~ Fig 3-2 Inulin • MW 5,000 Da Measurement of GFR • Freely filterable Amount Filtered = Amount Excreted • NOT reabsorbed • NOT secreted • NOT metabolized, GFR · P = U · V • P X GFR IN IN synthesized, stored IN • Does not alter GFR • GFR = U · V = Cl • Nontoxic = IN IN • Infusion required P . IN • P ,U - analytic IN IN UIN X V method

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Creatinine Rate of Production = Rate of Excretion Creatinine 1 g/day = 1 g/day Index of GFR ClCr ~ GFR • GFR(ClearanceCr) = UCr •V

PCr

ClCr is inversely related to PCr

Creatinine Fig 3-2 PlasmaCr Inversely Related to GFR Fig 3-3 • Metabolism of creatine phosphate in muscle • Produced continuously PCr = 6mg/dl • Freely filtered GFR 1/6

• NOT reabsorbed PCr X GFR PCr=2mg/dl • Small amount secreted PT GFR ½ • NO infusion required = Normal P =1mg/dl • Stable P[Cr] . Cr • P[Cr] & U[Cr] – UCr X V colorimetric method Normal GFR

Plasma Creatinine Concentrations PAH PCr = 0.8 – 1.2 mg/dl (1.0 mg/dl) normal range for adult Para-amino hippuric Plasma inversely related to GFR Cr acid

GFR PCr ml/min mg/dl ClPAH ~ RPF 120 1 60 2 30 4 15 8

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Para-amino hippuric acid (PAH) Para-amino hippuric acid (PAH) • Organic anion PAH Clearance ~ Renal Plasma Flow • Freely filtered • RPF • P = U •V • Vigorously secreted PAH PAH PT Rearrange • ≥ 90% removed in • single circuit ClPAH = RPF = UPAH •V • ~ 10% remains RV P • NOT produced PAH • Infusion required

Clearance • Filtered Load of Substance A • ClX < GFR net reabsorption X GFR x Plasma [A] • ClX > GFR net secretion X

GFR • PA • CX < CIN reabsorbed, i.e. glucose

• Excretion Rate • CX > CIN secreted, i.e. PAH [A] x Urine flow • Protein bound drug is not filtered • UA •V • filtered load > rate of excretion = reabsorption X

Summary II Problem Set Posted on Schedule 1. Clearance of certain substances – index of 1. Body Fluid renal function Problems 2. Plasma creatinine - 2. Renal Clearance tool for diagnosing and following renal Time for Questions function

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