1. Principles of Acid-Base Physiology Mazen Kherallah, MD, FCCP Internal Medicine, Infectious Disease and Critical Care Medicine

2. Note Acids are compound that are capable of donating a H + Bases are compound that are capable of accepting a H + When an acid HA dissociates, it yields a H + and its conjugate base (anion, A - ) HA  H + + A -

3. Valence The number of charges a compound or ion bears in solution, expressed in mEq/L. The term mEq reflects the number of charges or valences. Therefore multiply mmol by the valence to obtain mEq. Valence is especially important for albumin, which has a large valence on each molecule.

4. Characteristics of H + The free H + is tiny and must be kept so for survival A very large accumulation of H + may kill by binding to proteins in cells and changing their charge, shape, and possibly their function

5. Normal Concentration of Cations and Anions in Plasma

6. Number of H + in the body ECF: 15 L X 40 nmol/L = 600 nmol ICF 30 L X 80 nmol/L = 2400 nmol Total free H + in the body is close to 3000 nmol/L Close to 70.000.000 nmol of H + is formed and consumed daily Affinity of H + for chemical groups on organic and inorganic compounds determine whether H + will be bound or remain free (gastric)

7. Compartmental [H + ]

8. Gastric [H + ] Very high concentration is needed to initiate digestion The anion secreted by the stomach along with [H + ] is Cl - Cl - will not bind H + because HCl dissociates completely in aqueous solution and there are no major buffers in the gastric fluid H + bind avidly when they come in contact with ingested proteins. Binding of H + makes the protein much more positively charged and alters its shape so that pepsin can gain access to the sites it will hydrolyze in that protein.

9. Intracellular Buffers Binding to Proteins Buffered by inorganic phosphate

10. Intracellular Buffers Inorganic Phosphate HPO 4 2- pH= pK + log ---------- H 2 PO 4 - HPO 4 2- : divalent inorganic phosphate ion H 2 PO 4 - : monovalent dihydrogen inorganic phosphate ion pK for inorganic phosphate is close to 6.8

11. pH of Different Compartments

12. Physiology of Phosphate Buffers

13. Definition of Metabolic Process A metabolic process starts with either dietary or stored fuels and ends with ATP or an energy store (glycogen, triglyceride) If part of the pathway generates H+ and is intimately linked to another part that removes H+, both parts can be ignored from an acid-base perspective

14. No Change in Net Charge Neutrals to Neutrals Glucose  Glycogen + CO2 + H2O TG  CO2 + H2O Alanine  Urea + Glucose

15. No Net Production or Removal of H + At the Cellular Level H + is formed when ATP is hydrolyzed to perform biologic work: reabsorb Na + –ATP 4-  ADP 3- + P i 2- + H + As soon as ATP is regenerated in the mitochondria of that cell, H + are removed –ADP 3- + P i 2- + H +  ATP 4-

16. No Net Production or Removal of H + Multiple Organ Process Adipocyte: –TG  3 Palmitate - + 3 H + + Glycerol Liver: –3 Palmitate - + 3 H + + 18 O2  12 ketoacid anions + 12 H + Brain: –12 ketoacid anions + 12 H +  CO 2 + H 2 O + ATP

17. Reactions that Yield H + Glucose  Lactate - + H + Fatty acid  4 Ketoacid anions + 4 H + Cysteine  Urea + CO 2 + H 2 O + SO 4 2- + 2H + Lysine +  Urea + CO 2 + H 2 O + H +

18. Reactions that Remove H + Lactate- + H+  Glucose Citrate 3- + 3H+  CO2 + H2O Glutamine  Glucose + NH4 + + CO 2 + H 2 O + HCO3 -

19. Dietary Acid-Base Impact

20. Sulfur-containing Amino Acids Cysteine/Cystine and Methionine Sulfur-containing amino acids can be oxidized to yield the terminal anion SO 4 2- plus neutral end- product (glucose, urea, CO 2 and and H 2 O) Because the affinity SO 4 2- of for H + is so low (SO 4 2- has a very low pK), SO 4 2- cannot help in removing H + by urinary excretion Hence other ways are needed to remove these H+ ( renal excretion of NH 4 + ) For each SO 4 2- mEq of that accumulate or excreted without NH 4 +, H + accumulate

21. Cationic Amino Acids Lysine, Arginine, and Histidine Are metabolized to neutral end-products plus H+ These H+ requires the excretion of NH4+ to prevent accumulation of protons

22. Rate of Production of H +

23. Anions are metabolized to neutral products almost as fast as they are produced: Starvation Ketoacidosis L-lactic acid: usual rate Anions that are produced slowly and excreted with H + and NH4 + H 2 SO 4 from proteins DKA L-lactic acid: liver problem Organic acids from gut: butyric acid, acetic, and propionic Anions from toxins NH4 excretion problem L-lactic acid due to low supply of O2: Exercise Shock

24. Range of [H + ] in Plasma in Clinical Conditions

25. HCO 3 - Fuels  H+ CO 2 Kidneys Glutamine NH4 + Lungs (70 mmol per day) (Kidney must generate 70 mmol of HCO3 per day)

26. Generation of New HCO3 - Each day 70 mmol is derived from the normal oxidative metabolism of dietary constituent and is buffered mainly by bicarbonate buffer system (BBS) To achieve acid-base balance, the kidney must generate 70 mmol of new HCO3- to replace the HCO3- consumed by the buffering process Should this process fails, the patient will become acidemic

27. CO 2 + H 2 O HCO3 - (to blood) H + (Secreted) Filtered HPO4 2 - H 2 PO 4 - (to urine) Glutamine NH4 + (to urine) HCO3 - (to blood) Generation of New HCO 3 in the Kidney

28. Concept Buffers work physiologically to keep added H+ from binding to proteins; instead H+ are forced to react with HCO3-

29. Chemistry of Buffers Each buffer has its unique dissociation constant (pK), which determine the range of [H+] at which the buffer is effective HA  A - + H + pH= pK+ log HA/A- A buffer is most effective at a [H+] or pH the is equal to its pK Strong acids have a lower pK, and weak acids have higher pK.

30. Buffers for an Acid Load

31. Protein Buffer System The major non-BBS buffer is protein in the ICF (imidazole group in histidine) When H+ binds to proteins, the charge, shape, and possibly function of proteins may change Total content of histidines is close to 2400 mmol in 70-kg individual PH of ICF is close to pK of histidine Only 1200 mmol of histidine are potential H+ acceptors

32. Bicarbonate Buffer System (BBS) HCO 3 - pH= pK + log ---------- H 2 CO 3 H + + HCO3 -  H 2 CO 3  H 2 O + CO 2 Each mmol of HCO3 - remove 1 mmol of H+ [H+] = 24 X PCO 2 /HCO 3 -

33. Bicarbonate Buffer System Quantities Total content of HCO3- in the ECF is: –25 mmol/L X 15 = 375 mmol Total content of HCO3- in the ICF is: –13 mmol/L X 30 = 360 mmol

34. Bicarbonate Buffer System Physiology A function of the BBS is to prevent H + from binding to proteins in the ICF The BBS is used first to remove a H + load, providing that hyperventilation occurs The key to the operation of the BBS is the control of the PCO 2

35. Teamwork in BBS buffer ECF: H + + HCO3 -  H2O + CO2  lungs ICF: H + + HCO3 -  H2O + CO2 HB + BB (falls)

36. Bicarbonate Buffer System Importance of CO2 Removal