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Physiology and Disorders of Acid-Base Metabolism

Physiology and Disorders of Acid-Base Metabolism. Dr. Sarita Mangukiya ASSISTANT PROFESSOR BIOCHEMISTRY, GMCS. Definitions. Acid – Proton donor Base – Proton acceptor pH – Negative log of H + activity Acidemia – Arterial blood pH < 7.35 Alkalemia – Arterial blood pH > 7.45

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Physiology and Disorders of Acid-Base Metabolism

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  1. Physiology and Disorders of Acid-Base Metabolism Dr. Sarita Mangukiya ASSISTANT PROFESSOR BIOCHEMISTRY, GMCS

  2. Definitions • Acid – Proton donor • Base – Proton acceptor • pH – Negative log of H+ activity • Acidemia – Arterial blood pH < 7.35 • Alkalemia – Arterial blood pH > 7.45 • Acidosis and Alkalosis – Pathological states leading to acidemia and alkalemia

  3. pH SCALE • pH refers to Potential Hydrogen • Expresses hydrogen ion concentration in water solutions • Water ionizes to a limited extent to form equal amounts of H+ ions and OH- ions • H2O H+ + OH- • H+ion is an acid • OH- ion is a base 3

  4. H+ion is an acid 4

  5. OH- ion is a base 5

  6. H+ion is an acid • OH- ion is a base 6

  7. H+ H+ OH- H+ OH- OH- H+ H+ OH- H+ H+ H+ H+ OH- OH- H+ OH- H+ OH- H+ H+ OH- OH- OH- H+ OH- H+ OH- OH- • Pure water is Neutral • ( H+ = OH- ) • pH = 7 • Acid • ( H+ > OH- ) • pH < 7 • Base • ( H+ < OH- ) • pH > 7 • Normal blood pH is 7.35 - 7.45 • pH range compatible with life is 6.8 - 8.0 ACIDS, BASES OR NEUTRAL??? 3 1 2 7

  8. NORMAL ACIDOSIS ALKALOSIS DEATH DEATH 6.8 7.3 7.4 7.5 8.0 Venous Blood Arterial Blood 8

  9. Acid – Base Balance Normal pH of Plasma  7.4 Range  7.35 – 7.45 Production of Acids :- • Volatile Acids – 20,000 m.Eq / day • Carbonic Acid (H2CO3) (b) Non Volatile Acids – 60 – 80 m.Eq / day (fixed Acids) • Lactic Acid, Keto Acids, Phosphoric Acids… Production of bases • Very small Amount (Negligible)

  10. Proton Balance Input (Sources of acid) : • Diet – minimal contribution • Metabolism – Volatile acids – CO2 Nonvolatile acids – -- Sulphuric acid -- Phosphoric acid -- Uric acid -- Pyruvic acid -- Lactic acid -- -OH Butyric acid

  11. Proton Balance Output ( Means of disposal) : • Lungs – CO2 • GIT – HCl, HCO3 • Kidney – Free Acid -- Ammonium -- NaH2PO4

  12. Proton Balance 1st Line of defense Chemical regulatory mechanism • Buffer systems • Respiratory regulatory mechanisms • Renal regulatory mechanisms Input Output 7.35 7.45

  13. Buffer systems • Buffer – mixture of weak acid and a salt of its conjugate base • Function – to resist changes in pH when a strong acid or base is added to the solution • pK – pH at which a buffer exists in equal proportions of its acid and conjugate base • Buffers work best in the interval +/- one pH unit of its pK • Buffers are more effective with concentration • Buffer value() – amount of base required to change pH by one unit

  14. Buffer systems

  15. Bicarbonate/Carbonic acid buffer system H+ + NaHCO3-  H2CO3 + Na H2O + CO2 HCO3- = regulated by kidney CO2 = regulated by lungs High concentration of conjugate base pK = 6.1. Base : Acid concentration  20 : 1 Disposal/retention of CO2 by lungs  /  rate of reclamation of HCO3 by renal tubules Respiratory Component Renal Component

  16. NaHCo3 Na+ HCo-3 HL H+ L- H2Co3 + Na L (Na Lactate) In lung Carbonic Anhydrase H2Co3 H2O + Co2 H2Co3 HCo-3 H+ NaOH OH- Na+ Bicarbonate/Carbonic acid buffer system When strong & non volatile acid enters:- e.g. lactic acid When alkali enters:- H2O + Na H Co3

  17. H+ • Equilibrium shifts toward the formation of acid • Hydrogen ions that are lost (vomiting) causes carbonic acid to dissociate yielding replacement H+ and bicarbonate H2CO3 HCO3- 17

  18. Bicarbonate/Carbonic Acid Buffer System • Plasma HCO3 is taken as measure of base excess or deficit. High concentration (24 mEq/L : 1.2 mEq/L) • Alkali Reserve

  19. Na2HPo4 Na+ NaHPo-4 HCl H+ Cl- Acid Phosphate (NaH2Po4)+ NaCl NaH2Po4 NaHPo4- H+ NaOH OH- Na+ Phosphate buffer system Phosphate Buffer system Na2 H PO4 / NaH2 PO4 When strong acid enter:- e.g. Hcl When an alkali enters:- :-NaOH Alkaline Phosphate (Na2HPo4)+ H2O

  20. Phosphate Buffer System NaHPO4 2+ + H+ NaH2PO4+ NaH2PO4+ + OH- NaHPO4 2+ + H2O • pK = 6.8 pK. Base : Acid concentration  4 : 1 • Plasma – 5% of non-HCO3 buffer • RBC -- 6% of non- HCO3 buffer in the form of 2,3 DPG • Important in excretion of acids in urine

  21. 1) Phosphate buffer system Na2HPO4 + H+ NaH2PO4+ Na+ • Most important in the intracellular system + Na2HPO4 H+ + Na+ NaH2PO4 Click to animate 21

  22. Na2HPO4 + H+ NaH2PO4+ Na+ • Alternately switches Na+ with H+ Disodium hydrogen phosphate + Na2HPO4 H+ + Na+ NaH2PO4 Click to animate 22

  23. Na2HPO4 + H+ NaH2PO4+ Na+ • Phosphates are more abundant within the cell and are rivaled as a buffer in the ICF by even more abundant protein Na2HPO4 Na2HPO4 Na2HPO4 23

  24. Regulates pH within the cells and the urine • Phosphate concentrations are higher intracellularly and within the kidney tubules • Too low of aconcentration inextracellular fluidto have muchimportance as anECF buffer system HPO4-2 24

  25. PROTEIN BUFFER SYSTEM • 2) Protein Buffer System • Behaves as a buffer in both plasma and cells • Hemoglobin is by far the most important protein buffer 25

  26. PROTEIN BUFFER SYSTEM • Proteins are excellent buffers because they contain both acid and base groups that can give up or take up H+ • Proteins are extremely abundant in the cell • The more limited number of proteins in the plasma reinforce the bicarbonate system in the ECF 26

  27. PROTEIN BUFFER SYSTEM • As H+Hb picks up O2 from the lungs the Hb which has a higher affinity for O2 releases H+ and picks up O2 • Liberated H+ from H2O combines with HCO3- HCO3-H2CO3CO2 (exhaled) O2 O2 H+ Hb O2 O2 27

  28. PROTEIN BUFFER SYSTEM • Venous blood is only slightly more acidic than arterial blood because of the tremendous buffering capacity of Hb • Even in spite of the large volume of H+ generating CO2 carried in venous blood 28

  29. Plasma Protein Buffer System HPr  H+ + Pr- • Mainly intracellular action • 95% of non-HCO3 buffer of plasma • Imidazole group of Histidine most important • 1 Albumin molecule contains 16 Histidines

  30. PROTEIN BUFFER SYSTEM • Proteins can act as a buffer for both acids and bases • Protein buffer system works instantaneously making it the most powerful in the body • 75% of the body’s buffer capacity is controlled by protein • Bicarbonate and phosphate buffer systems require several hours to be effective Pr - added H+ + Pr - 30

  31. PROTEIN BUFFER SYSTEM • Proteins are very large, complex molecules in comparison to the size and complexities of acids or bases • Proteins are surrounded by a multitude of negative charges on the outside and numerous positive charges in the crevices of the molecule - - - - - - - - - + + + + - + + + - - + - + - + - + + + + - - + - - + - - + + + - + - + + - - + + - + - - - - 31 - - -

  32. PROTEIN BUFFER SYSTEM - - - - - - - - - + + + + - + + + - - + - + - + - + + + + - - + - - + - - + + + - + - + + - - + + - + - - - - - - - • H+ ions are attracted to and held from chemical interaction by the negative charges H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ 32 H+ H+ H+

  33. PROTEIN BUFFER SYSTEM - - - - - - - - - + + + + - + + + - - + - + - + - + + + + - - + - - + - - + + + - + - + + - - + + - + - - - - - - - • OH- ions which are the basis of alkalosis are attracted by the positive charges in the crevices of the protein OH- OH- OH- OH- OH- OH- OH- OH- OH- OH- OH- 33 OH-

  34. Respiratory Regulation of Acid-Base Balance • Peripheral chemoreceptors – In carotids and aorta -- Stimulated by  pH d/t CO2 accumulation or PO2 • Central chemo-receptors -- In medulla oblongata -- Stimulated only by  pH of CSF • Onset of response – immediate • Maximal response – 3-6 hrs

  35. RESPIRATORY CENTER Pons Respiratory centers Medulla oblongata 35

  36. CHEMOSENSITIVE AREAS • Chemosensitive areas of the respiratory center are able to detect blood concentration levels of CO2 and H+ • Increases in CO2 and H+ stimulate the respiratory center • The effect is to raiserespiration rates • But the effectdiminishes in1 - 2 minutes CO2 CO2 Click to increase CO2 CO2 CO2 36 CO2 CO2 CO2 CO2 CO2

  37. CHEMORECEPTORS • Overall compensatory response is: • Hyperventilation in response to increased CO2 or H+(low pH) • Hypoventilation in response to decreased CO2 or H+(high pH) 37

  38. RENAL CONTROL OF pH • pH of Plasma : 7.4 • pH of Urine : 6.0 • ... Kidney excretes acids

  39. Renal regulation of Acid-base Balance Excretion of H+ (Na+ -H+ exchange) Reclamation / Re-absorption of filtered HCO3- Renal production of NH3 and excretion of NH4+ ions Excretion of H+ as H2PO4- (titrable Acids) Excretion of other acids

  40. I Renal Regulation of pH of Blood Urine pH is normally lower than blood pH Acidification of urine – pH  6.0 (1) Excretion of H+ and generation of HCO3 Plasma P. C. Tubular Cells Tubular Lumen Na Na+ Na HCO3- HCO3- + H+ H++ Base- HB H2CO3 CA Excreted CO2+ H2O

  41. Na+ -H+ exchange • Renal tubular Na+ -H+ exchanger extrudes H+ into tubular fluid in exchange for Na+ • Exchange  in acidosis and  in alkalosis • Max urine acidity reached at pH 4.4

  42. Na+ -H+ exchange CO2 +H2O Na+H2PO4- HHCO3 HCO3- Na+ HCO3- H+ Na+ H+ Na+ Na+HPO42- Plasma and interstitial fluid Glomerular filtrate Tubular cell

  43. Na+ -H+ exchange • K+ compete with H+ in renal tubular NHE •  Renal intracellular K+  H+ excretion •  Acidity of body fluids • Hyperkalemia  acidosis • Hypokalemia  alkalosis • Potassium : weather vein : Serum K+ can be used as a poor man’s pH meter in the absence of pH measure.

  44. Reabsorption of Bicarbonate – (from Glomerular Filtrate) Tubular Lumen (Glomerular filtrate) Plasma Tubular Cells Na+ Na+ Na + HCO3- HCO3 HCO3- + H+ H+ H2CO3 H2CO3 C.A. C.A. CO2 + H2O H2O + CO2

  45. (3) Excretion of Ammonium (NH4) Plasma TubularCells TubularLumen Glutamic Acid Glutamin Glataminase NH3 NH3 AA Oxidative Deamination Na+ Na+ Na+ HCO3 HCO3-+ H+ H+ H2CO3 NH4 C. A. CO2 + H2O

  46. Renal production of NH3 and excretion of NH4+ ions • NH3 gas diffuses from renal tubular cells into tubular lumen • In lumen, NH3 + H+  NH4+ • At the acid pH of urine NH4+ : NH3 10000:1 • NH4+ cannot cross cell membrane easily • Excreted with anions like PO4, Cl- or SO4

  47. Renal production of NH3 and excretion of NH4+ ions • In normal persons, NH4+ production in tubular lumen  excretion of 60% of H+ associated with non-volatile acids (30-60 mmols/day) • In acidosis, greatest net renal excretion of H+ as NH4+ • Max. rate of NH3 production (400 mmols/d) by 3 days • In CRF, insufficient NH3 production leads to acidosis

  48. (4) Excretion of Titrable Acid Tubular Lumen Plasma Tubular Cells Na2HPO4 7.4 Na+ Na+ Na+ Na HPO4- HCO3 HCO3- + H+ H+ NaH2PO4 6.0 H2CO3 C.A. CO2 + H2O Excreted

  49. Excretion of H+ as H2PO4- H+ + Na+Na+HPO42-  Na+ + Na+H2PO4- • H+ secreted by NHE into tubular lumen • Depends on PO4 filtered by glomeruli and pH of urine •  30 mmols/d of H+ excreted as H2PO4 •  90% of titratable acidity of urine • pH gradient maintained, Na+ conserved

  50. Excretion of H+ as H2PO4- Urine pH is normally lower than blood pH • High protein intake  PO4 production and filtration  • Acidemia PO4 excretion buffer for reaction with H+ • GFR as in renal disease H2PO4 excretion

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