Excretion Handout (1).pptx

Excretion      Kidney Physiology Renal Excretion Process Passive Reabsorption and Urine pH Renal Clearance: Determination Renal Clearance: Contributions Drug Excretion Organs participating in drug excretion:  Kidney  water-soluble drugs and metabolites  physiologically important metabolit...

Excretion      Kidney Physiology Renal Excretion Process Passive Reabsorption and Urine pH Renal Clearance: Determination Renal Clearance: Contributions Drug Excretion Organs participating in drug excretion:  Kidney  water-soluble drugs and metabolites  physiologically important metabolites, ions and water are reabsorbed  drugs and metabolites with fast trans-bilayer transport may also be reabsorbed  Gastrointestinal tract  orally administered drugs that are not completely absorbed  drugs with other administration routes and their metabolites that undergo biliary excretion  Lungs  volatile drugs and metabolites  Skin  some water-soluble drugs and metabolites Kidney: Morphology 1. Renal Vein 2. Renal Artery 3. Renal Calyx 4. Medullary Pyramid 5. Renal Cortex 6. Segmental Artery 7. Interlobar Artery 8. Arcuate Artery 9. Arcuate Vein 10. Interlobar Vein 11. Segmental Vein 12. Renal Column 13. Renal Papillae 14. Renal Pelvis 15. Ureter Kidney: Function and Structure  The main excretory organ  endocrine functions • erythropoietin • renin/aldosterone: homeostasis of plasma - osmosis, pH, Na/K salts  metabolic waste removal  Main regions are  cortex (outer layer) • tubules of all nephrons, loops of Henle of cortical nephrons  medulla (central region) • renal pyramids (6-8) containing collecting ducts and the loops of Henle of juxtamedullar nephrons • filtrate flow: ducts  calyces  renal pelvis  ureter Renal Blood Flow (RBF) Urine Formation  Renal blood flow (RBF)  1/4 of cardiac output ~1.2 L/min  Renal plasma flow (RPF) RPF = RBF (1 - Hct) Hct - volume fraction of blood cells ~0.45  Glomerular filtration rate ~20% of RPF, i.e., 120 mL/min in a standard patient  Urine represents only ~1% of filtered volume  Renal excretion of drugs includes  glomerular filtration: structure-nonspecific process  active tubular secretion (carrier-mediated  structure-specific, energy driven)  tubular reabsorption (active and/or passive)  Nephron – basic unit  about a million in a kidney  cortical nephrons are Glomerulus located completely in cortex  juxtamedullary nephron have the tubules in the cortex and the Henle loops protruding to medulla  Peritubular capillaries are in close contact or proximal and distal convoluted tubules Bowman’s - separated just by interstitium capsule  Loop of Henle serves just for reabsorption of water and sodium Peritubular capillaries Nephron: Anatomy Nephron: Location of Contributing Processes glomerular filtration glomerulus in Bowman’s capsule Proximal convoluted tubule secretion passive reabsorption active reabsorption Distal convoluted tubule Peritubular capillaries loop of Henle Glomerular Filtration Unidirectional flow through the pores (~80 nm) of glomerular capillaries, 120 mL/min, drug concentration as free drug concentration in plasma Nonspecific for small molecules (up to 2000 g/mol), protein-bound drugs are not filtered Driving force - the difference in hydrostatic pressure between capillaries and nephrons Measured using drugs that are only filtered and do not undergo other processes in the nephron:  inulin – a plant polysaccharide administered by IV infusion  creatinine – physiologic compound Active Renal Secretion Active transport adds to drugs/metabolites removed from the blood by filtration  carrier-mediated (saturable, competition)  energy-dependent Happens mainly in Proximal convoluted tubule Two systems prevailing  organic anion transporting peptides (OATPs)  organic cation transporters (OCTs) Extremely rapid for p-amino-hippuric acid (PAHA) - eliminated in single pass Tubular Reabsorption I  The only way to decrease the drug excretion rate below fu GFR  Includes the following processes and substrates:  active reabsorption • vitamins • nutrients • electrolytes • some drugs  passive reabsorption • water • the majority of drugs  endocytosis • peptides Tubular Reabsorption II  Active reabsorption proceeds in proximal tubule  Passive reabsorption happens alone the entire tubule, including the loop of Henle  Endocytosis proceeds in proximal tubule, the vesicles are formed from the brush-border membrane and internalized  The extent of reabsorption also depends on urine flow  Increase in the urine flow   decreases the time for reabsorption lowers the reabsorption extent, regardless of the reabsorption mechanism Passive Tubular Reabsorption  Drugs are passively transported through bilayers from the filtrate back into the bloodstream  The walls of peritubular capillaries are separated from the nephron tubules only by interstitial water  two cell layers need to be crossed by drug molecules  20 or so bilayers to be crossed  All rules about the rate of the transport apply: the optimal lipophilicity (logP), amphiphilicity, and cephalophilicity ensure the fastest reabsorption  Influence of pH in urine: non-dissociated molecules have faster reabsorption from renal tubule back into blood than ionized molecules pH of Urine  Normal range is pH 4.5 – 8.0+  Depends on various factors, e.g.  nutrients – high pH values are caused by bicarbonate or alkali supplements  urinary tract infections – pH > 7.5 is an indicator of UTI  Passive reabsorption of ionized molecules into the blood (pH 7.2) is affected by trapping – drug molecules accumulate where they ionize more  low urine pH values  reabsorption of acids  high urine pH values  reabsorption of bases pH-Dependence of Passive Permeability Permeability coefficient is proportional to the membranes/lumen partition coefficient Pm For ionizable drugs, all species in the nonpolar phase and water are considered – the apparent partition coefficient Papp is used This reflects the pH-Partition Hypothesis: For ionizable drugs, nonionized species are transported much faster than ionized species Papp as Function of [H+] & Counterions  The equation is valid for acids and bases although qH and qC are calculated differently The term qH contains pH and pKa values. The term qC contains Kc and concentration of counterions. Papp: Dependence on pH (no ion pairing) Papp acids bases 0 pH Passive Reabsorption Extent Compounds are reabsorbed from the filtrate  actively in proximal tubule  passively along entire tubule For easily transported drugs  nonionized molecules in significant fraction  optimal lipophilicity (-2 < logP < 4)  optimal amphiphilicity and cephalophilicity the extent of passive reabsorption is given by the equilibrium urine/plasma ratio  pH of urine: 4.5 – 8.0 Low Tubular Reabsorption Extent  The distribution equilibrium is not achieved by:  hydrophilic drugs (logP < -2)  lipophilic drugs (logP > 4)  amphiphilic or cephalophilic drugs  drugs completely ionized in urine • acids even under most acidic conditions (pH ~4.5), i.e., having pKa < 2.5 • bases even under most basic conditions (pH ~8), i.e., having pKa > 10  Consequence: compounds with the above properties have low reabsorption and high excretion Drug Clearance Cl characterizes drug elimination (excretion + metabolism) Cl is the proportionality constant between the drug amount eliminated per time unit (the elimination rate) and the drug concentration in the given compartment For any organ:  Drug Clearance II Eqs. 1 and 2 are model-independent and valid for any time moment and any organ For the whole body, Eq. 2 can be rearranged as …and integrated for the whole period of presence of drug in the body Drug Clearance III Eq. 1 can also be rearranged for any organ as  Cl is equal to the volume of fluid completely cleared of the drug per the unit of time The units of Cl are mL/min or L/hr Cl can be defined for compartmental and physiologic models Determination of Renal Clearance I cP (5) cUr Integrated between the times t1 and t2 (6) t1 t2 time Determination of Renal Clearance II The volume of urine (VUr) collected between t1 and t2 is known slope ClR ¿ for various t1 and t2, are plotted against 0 0 Renal Clearance: Mechanism Clearance of a drug is compared to the measured inulin clearance < 1: reabsorption rate > secretion rate = 1: filtration only > 1: secretion rate > reabsorption rate