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Principles of Acid-Base Physiology Mazen Kherallah, MD, FCCP Internal Medicine, Infectious Disease and Critical Care Medicine 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- 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. 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 Normal Concentration of Cations and Anions in Plasma Cations (mEq/L) Anions (mEq/L) Na+ 140 CL- 103 K+ 4 HCO3- 25 Ca2+ 5 Proteins 16 Mg2+ 2 Organic 4 H+ 0.00004 (40 nmol/L) Other inorganics 3 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) Compartmental + [H ] ECF 40 nmol/L ICF 80-100 nmol/L Urine 10,000 nmol/L Gastric fluid 70 mmol/L 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. Intracellular Buffers • Binding to Proteins • Buffered by inorganic phosphate Intracellular Buffers Inorganic Phosphate HPO42-: divalent inorganic phosphate ion H2PO4-: monovalent dihydrogen inorganic phosphate ion HPO42pH= pK + log ---------H2PO4pK for inorganic phosphate is close to 6.8 pH of Different Compartments PH Compartment Ratio of HPO42-/H2PO4- 7.4 ECF 4/1 (0.62) 7.1 ICF 2/1 (0.3) 5.8 Urine 1/10 (-1) Physiology of Phosphate Buffers Compartment ECF Total % as of Equation Inorganic H2PO4Phosphate 1 mmol/L 20% H+ +HPO42-H2PO4- ICF 4-5 mmol/L 33% H+ +HPO42-H2PO4- Urine 30 mmol/L 90% H+ +HPO42-H2PO4- 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 No Change in Net Charge Neutrals to Neutrals • Glucose Glycogen + CO2 + H2O • TG CO2 + H2O • Alanine Urea + Glucose No Net Production or Removal of H+ At the Cellular Level • H+ is formed when ATP is hydrolyzed to perform biologic work: reabsorb Na+ – ATP4- ADP3- + Pi2- + H+ • As soon as ATP is regenerated in the mitochondria of that cell, H+ are removed – ADP3- + Pi2- + H+ ATP4- 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+ CO2 + H2O + ATP Reactions that Yield H+ • Glucose Lactate- + H+ • Fatty acid 4 Ketoacid anions + 4 H+ • Cysteine Urea + CO2 + H2O + SO42+ 2H+ • Lysine+ Urea + CO2 + H2O + H+ Reactions that Remove H+ • Lactate- + H+ Glucose • Citrate 3- + 3H+ CO2 + H2O • Glutamine Glucose + NH4+ + CO2 + H2O + HCO3- Dietary Acid-Base Impact Nutrient Product H+ (mEq/day) H+ 70 H+ 140 HPO42-+H+ 30 Anionic amino acids: Glutamate, aspartate Organic anions (citrate3-) HCO3- -110 HCO3- -60 Posphate excretion H2PO4- -30 Reactions generating H+ Sulfur-containing amino acids: Cysteine/cystine, methionine Cationic amino acids: Lysine, arginine, histidine Organic phosphates Reactions removing H+ Net total H+ load to be excreted as NH4+ 40 Sulfur-containing Amino Acids Cysteine/Cystine and Methionine • Sulfur-containing amino acids can be oxidized to yield the terminal anion SO42- plus neutral endproduct (glucose, urea, CO2 and and H2O) • Because the affinity SO42- of for H+ is so low (SO42- has a very low pK), SO42- cannot help in removing H+ by urinary excretion • Hence other ways are needed to remove these H+ ( renal excretion of NH4+) • For each SO42- mEq of that accumulate or excreted without NH4+, H+ accumulate 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 Rate of Production of Event Rate ( mmol/min) + H Comment Production of H+ Lactic acid Ketoacids 72 7.2 1 Complete anoxia 10% hypoxia Lack of insulin Toxic alcohols <1 Poisening metabolites 0-2 Lag period Lactic acid 4-8 Oxidation and glucogenesis Ketoacids 0.8 Oxidized in brain and kidney Removal of H+ Excretion of NH+ Metabolism Reactions that produce H+ Is H+ accumilating Yes No Anions are metabolized to neutral products almost as fast as they are produced: Starvation Ketoacidosis YEs No L-lactic acid: usual rate Anions that are produced slowly L-lactic acid and excreted with H+ and NH4+ due to low DKA H2SO4 from proteins supply of O2: L-lactic acid: liver problem Exercise Organic acids from gut: butyric acid, acetic, and propionic Shock Anions from toxins NH4 excretion problem Was H+ produced at a much faster rate than it was removed Range of [H+] in Plasma in Clinical Conditions Condition [H+] nmol/L pH Importance Acidemia >100 <7.00 Can be lethal Acidemia 50-80 7.1-7.30 Normal 402 7.400.002 Clinically important Normal Alkalemia 20-36 7.44-7.69 Alkalemia <20 >7.70 Clinically important Can be lethal Fuels H+ (70 mmol per day) Lungs CO2 HCO3Glutamine NH4+ Kidneys (Kidney must generate 70 mmol of HCO3 per day) 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 Generation of New HCO3 in the Kidney HCO3- (to blood) HCO3- (to blood) CO2 + H2O H+ (Secreted) Glutamine Filtered HPO42NH4+ (to urine) H2PO4- (to urine) Concept • Buffers work physiologically to keep added H+ from binding to proteins; instead H+ are forced to react with HCO3- Chemistry of Buffers • Each buffer has its unique dissociation constant (pK), which determine the range of [H+] at which the buffer is effective • HAA- + 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. Buffers for an Acid Load Buffers (mmol) Location HCO3- Proteins Phosphate Other ECF 375 <10 <15 0 ICF (muscle) 330 400 <50 CrP 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 Bicarbonate Buffer System (BBS) H+ + HCO3- H2CO3 H2O + CO2 HCO3pH= pK + log ---------H2CO3 [H+] = 24 X PCO2/HCO3Each mmol of HCO3- remove 1 mmol of H+ 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 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 PCO2 Teamwork in BBS buffer ECF: ICF: H+ + HCO3- H2O + CO2 lungs H+ + HCO3- H2O + CO2 B HB+ (falls) Bicarbonate Buffer System Importance of CO2 Removal Condition [H+] (nmol/L) PH PCO2 HCO3(mm Hg) (mmol/L) Closed system (PCO2 rises) 871 6.06 455 12.5 No change in PCO2 77 7.11 40 12.5 Lower PCO2 52 7.29 27 12.5