4. H+H+ OH - Acid-base abnormalities should be seen as resulting from other biochemical changes in the extracellular environment Na +, Cl -, K +, SO4 2-, Mg 2+, Ca 2 strong ions ( Na +, Cl -, K +, SO4 2-, Mg 2+, Ca 2+ ) albumin, phosphate weak acids( albumin, phosphate ) carbon dioxide To maintain electrical neutrality

5. PHYSICAL CHEMISTRY OF WATER H2OH2O H+H+ OH - + O H H 105 o O H H O H H fundamental to the existence of life

6. PHYSICAL CHEMISTRY OF WATER H2OH2O H+H+ OH - + 25 o C 1.0 × 10 −7 mmol/L K eq H 2 O = [H + ][OH − ] K eq H 2 O = K eq (55.5) = K w = [H + ][OH − ] A solution is considered acidic if : ([H + ] > 1.0 × 10 −7 mmol/L, [OH − ] < 1.0 × 10 −7 mmol/L). A solution is considered alkaline if ([H + ] 1.0 × 10 −7 mmol/L).

7. ACIDS AND BASES Svante Arrhenius in 1903 established the foundations of acid-base chemistry. In an aqueous solution, an Arrhenius acid is any substance that delivers a hydrogen ion into the solution. (HCl) A base is any substance that delivers a hydroxyl ion into the solution. (KOH) In 1909, L.J. Henderson coined the term acid-base balance. H 2 O + CO 2 → H 2 CO 3 →[H + ] + [HCO 3 - ]Hasselbalch (1916) H 2 O + CO 2 → H 2 CO 3 → [H + ] + [HCO 3 - ] pH = pK a + log [HCO 3 − ] / [H 2 CO 3 ]pH = pK a + log [HCO 3 − ] / [H 2 CO 3 ] pH = 6.1 + log [HCO 3 − ] / PCO 2 × 0.03

8. The degree of dissociation of substances in water determines whether they are strong acids or strong bases. Lactic acid, pKa of 3.4, is a strong acid. Carbonic acid, pKa of 6.4, is a weak acid. sodium potassiumchloride strong ionsSimilarly, ions such as sodium, potassium, and chloride, which do not easily bind other molecules, are considered strong ions; they exist free in solution. Strong cations (Na +, K +, Ca 2+, Mg 2+ ) act as Arrhenius bases Strong anions (Cl -, LA - [lactate], ketones, sulfate, formate) act as Arrhenius acids. One problem with the Arrhenius theory: ammonia (NH 3 ), sodium carbonate (Na 2 CO 3 ), and sodium bicarbonate (NaHCO 3 ) In 1923, Brønsted and Lowry They defined acids as proton donors and bases as proton acceptors.

9. NH 3 + H 2 O ⇌ NH4 + + OH − In this situation, water is the proton donor, the Brønsted-Lowry acid, and ammonia the proteon acceptor, the Brønsted-Lowry base. HCl + H 2 O → H 3 O + + Cl − In the previous reaction, hydrogen chloride acts as a Brønsted-Lowry acid and water as a Brønsted-Lowry base. CO 2 + H 2 O ⇌ H 2 CO 3 ⇌ H + + HCO 3 − In this reaction, carbon dioxide is hydrated to carbonic acid, a Brønsted-Lowry acid, which subsequently dissociates to hydrogen (H + ) and bicarbonate (HCO 3 - ) ions.

11. STEWART APPROACH TO ACID-BASE BALANCE What Determines the Acidity or Alkalinity of a solution? The molar concentration of hydrogen and hydroxide must be used to reflect the relative acidity and alkalinity of a solution. The pH scale, developed by Sorenson in the 1920s. Neutral pH for pure water is 7.0 (1.0 × 10 −7 mmol/L). Physiological pH for the ECF is 7.4, which is alkaline. The pH of the intracellular space is 6.8 to 7.0

12. STEWART APPROACH TO ACID-BASE BALANCE 1. Electrical neutrality. In aqueous solutions in any compartment, the sum of all of the positive charged ions must equal the sum of all of the negative charged ions. 2. Dissociation equilibria. The dissociation equilibria of all incompletely dissociated substances, as derived from the law of mass action, must be satisified at all times. 3. Mass conservation. The amount of a substance remains constant unless it is added, removed, generated, or destroyed. The total concentration of an incompletely dissociated substance is the sum of concentrations of its dissociated and undissociated forms.

13. Strong Ions The most abundant strong ions in the extracellular space are Na + and Cl -. Other important strong ions include K +, SO 4 2-, Mg 2+, and Ca 2+. If NaOH and HCl, added to solution ([Na + ] − [Cl − ]) + ([H + ] − [OH − ]) = 0 In this system, ([Na + − [Cl − ]) must determine [H + ] and [OH − ].

14. In any solution, the sum total of the charges imparted by strong cations minus the charges from strong anions represents the SID. The SID independently influences hydrogen ion concentration. In human ECF, the SID is positive. SID is an independent variable and [H + ] and [OH - ] are dependent, meaning that the addition of hydrogen ions alone (without strong corresponding anions) cannot influence the pH of the solution

16. Weak Acid Buffer Solutions These are partially dissociated compounds whose degree of dissociation is determined by the prevailing temperature and pH.These are partially dissociated compounds whose degree of dissociation is determined by the prevailing temperature and pH. The predominant molecules in this group are albumin and phosphate.The predominant molecules in this group are albumin and phosphate. Stewart used the term A TOT to represent the total concentration of weak ions that influenced acid-base balanceStewart used the term A TOT to represent the total concentration of weak ions that influenced acid-base balance

17. Weak Acid Buffer Solutions KAKA [HA] = KA [H + ] [A − ] +[HA] + [A − ] = [A TOT ] [H + ]× [OH − ] = Kw (water dissociation) [SID] + [H + ] − [A − ] − [OH − ] = 0 (electrical neutrality) SID and A TOT are independent variables K w and K A are constants [HA], [H + ], [OH - ], and [A - ] are dependent variables.

18. Carbon Dioxide 1- carbon dioxide, denoted CO 2 (d); 2- carbonic acid (H 2 CO 3 ) 3- bicarbonate ions (HCO 3 - ) 4- carbonate ions (CO 3 2- ) [CO 2 (d)] = [SCO 2 ] × PCO 2 [CO 2 (d)] × [OH − ] = K 1 × [HCO 3 − ] [H + ] × [HCO 3 − ] = K c × PCO 2 [H + ] × [CO 3 2− ] = K 3 × [HCO 3 − ]

19. Factors Independently Influencing Water Dissociation Water dissociation equilibrium: [H + ] × [OH - ] = K W Weak acid dissociation equilibrium: [H + ] × [A - ] = K A × [HA] Conservation of mass for weak acids: [HA] + [A - ] = [A TOT ] Bicarbonate ion formation equilibrium: [H + ] × [HCO3 - ] = K C × PCO 2 Carbonate ion formation equilibrium: [H + ] × [CO 3 2- ] = K 3 × [HCO 3 - ] Electrical neutrality: [SID] + [H + ] - [HCO 3 - ] - [A - ] - [CO 3 2- ] - [OH - ] = 0

20. [H + ] 4 + ([SID] + K A ) × [H + ] 3 + (K A × ([SID] − [A TOT ]) − K w − K c × PCO 2 ) × [H + ] 2 − (K A × (K w + K c × PCO 2 ) − K 3 × K c × PCO 2 ) × [H + ] − K A × K 3 × K c × PCO 2 = 0 [H + ] is a function of SID, A TOT, PCO 2, and several constants. All other variables, most notably [H + ], [OH - ], and [HCO 3 - ], are dependent and cannot independently influence the acid-base balance

22. ACID-BASE ABNORMALITIES Stewart approach : SID, A TOT, PCO 2Stewart approach : SID, A TOT, PCO 2 Traditional approach Alterations in (PaCO2) tension : respiratory acidosis or alkalosis Alterations in blood chemistry : ( HCO 3 -, BE ) metabolic acidosis, or alkalosis

23. Respiratory Acid-Base Abnormalities principally because of respiratory failureRespiratory acidosis → acute rise in PaCO 2 principally because of respiratory failure (signs of CO 2 retention)Clinically, : (signs of CO 2 retention) Cyanosis, vasodilatation, and narcosis. (caused by hyperventilation.)Respiratory alkalosis → acute decrease in PaCO2 (caused by hyperventilation.) Clinically : Vasoconstriction: light-headedness, visual disturbances, dizziness, and perhaps hypocalcemia ACID-BASE ABNORMALITIES

24. Respiratory acidosis Causes a rapid increase in [H + ]. Compensation for hypercarbia is slow chlorideIncreased urinary excretion of chloride bicarbonateCO 2 loadThere is a concomitant increase in the serum bicarbonate, reflecting a higher total CO 2 load, rather than compensation. The acuity of respiratory failure can be deduced by looking at the relative ratio of CO 2 to HCO 3 – notharmfulMany investigators have suggested that respiratory acidosis may not necessarily be harmful. "permissive hypercapnia"There has been extensive clinical experience with "permissive hypercapnia" for acute respiratory failure, which appears to be well tolerated. Causes a rapid increase in [H + ]. Compensation for hypercarbia is slow chlorideIncreased urinary excretion of chloride bicarbonateCO 2 loadThere is a concomitant increase in the serum bicarbonate, reflecting a higher total CO 2 load, rather than compensation. The acuity of respiratory failure can be deduced by looking at the relative ratio of CO 2 to HCO 3 – notharmfulMany investigators have suggested that respiratory acidosis may not necessarily be harmful. "permissive hypercapnia"There has been extensive clinical experience with "permissive hypercapnia" for acute respiratory failure, which appears to be well tolerated.

25. TABLE 41-1 -- Changes in PaCO 2 and [HCO 3 _ ] in response to acute and chronic acid-base disturbances [HCO 3 - ] vs. Pa CO 2 Disturbances ΔHCO 3 - = 0.2 ΔPa CO 2 Acute respiratory acidosis ΔHCO 3 - = 0.2 ΔPa CO 2 Acute respiratory alkalosis ΔHCO 3 - = 0.5 ΔPa CO 2 Chronic respiratory acidosis ΔPa CO 2 = 1.3 ΔHCO 3 - Metabolic acidosis ΔPa CO 2 = 0.75 ΔHCO 3 - Metabolic alkalosis Δ, change in value; [HCO 3 - ], concentration of bicarbonate ion; Pa CO 2, partial pressure of arterial carbon dioxide.

26. ACID-BASE ABNORMALITIES Metabolic Acid-Base Disturbances Metabolic acid-base abnormalities → SID or A TOT, or both An increase in the SID causes alkalemia A decrease in the SID causes acidemia (e.g., hyperchloremia, lacticemia, dilutional acidosis ) Metabolic acidosis is of clinical significance for two reasons: 1.pathologies arising from the acidosis itself (Increased ionized calcium → vasodilation, diminished muscular performance (particularly myocardial), and arrhythmias ) 2.pathologies arising from the cause of the acidosis (Increased ionized calcium → vasodilation, diminished muscular performance (particularly myocardial), and arrhythmias )

27. SID weak acids. A man of 70 kg total-body water content : 45 L, extracellular: 15 L [Na+ ] : 140 mEq/L, [Cl- ]: 100 mEq/L, and [K+ ] : 4 mEq/L. In this system, the SID is 44 mEq/L, with this positive charge being balanced principally by weak acids. SID ↓ 38.5 mEq/LWhen the volume ECF is expanded by 2 L, as occurs with rapid infusion of 5% dextrose, [Na + ] ↓ 123 mEq/L, [K+ ] ↓ 3.5 mEq/L, [Cl- ] ↓ 88 mEq/L. SID ↓ 38.5 mEq/L. The system becomes more acidic. This is the basis of dilutional acidosis. SID ↑ 50.6 mEq/LIf 2 L of free water are removed from the system and the total concentration of ions remains unchanged ( profuse sweating or dehydration ), [Na+ ] ↑ 161 mEq/L, [K+ ] ↑ 4.6 mEq/L, and [Cl- ] ↑ 115 mEq/L., and SID ↑ 50.6 mEq/L. The system becomes more alkaline. This is the basis of contraction alkalosis. SID ↓ 29 mEq/LA patient who loses 5 L of ECF and is given 5 L of NaCl as replacement would be expected to have a net gain in sodium and chloride. In this scenario, [Na+ ] ↑ 144 mEq/L, [K+ ] ↓ 2.6 mEq/L, and [Cl- ] ↑ 118 mEq/L. SID ↓ 29 mEq/L. This is the basis of hyperchloremic acidosis

28. TABLE 41-2 -- Classification of primary acid-base abnormalities AlkalosisAcidosisAbnormalities Decreased PCO2Increased PCO2 Respiratory Metabolic Abnormal SID Water deficit = contraction ↑ SID ↑ [Na + ] Water excess = dilutional ↓ SID + ↓ [Na + ] Caused by water excess or deficit Chloride deficit Chloride excess Caused by electrolytes ↑ SID + ↓ [Cl - ] ↓ SID ↑ [Cl - ] Chloride (measured) ↓ SID ↑ [UMA - ] Other (unmeasured) anions, such as lactate and keto acids Abnormal A TOT ↓ [Alb] ↑ [Alb] (rare) Albumin [Alb] ↑ [Pi] Phosphate [Pi] [Alb], concentration of serum albumin; A TOT, to represent the total concentration of weak ions; [Cl - ], concentration of chloride ions; [Na + ], concentration of sodium ions; P CO 2, partial pressure of carbon dioxide; [Pi], concentration of inorganic phosphate; SID, strong ion difference; [UMA - ], unmeasured anions; ↑, increased; ↓, decreased.

29. REGULATION OF ACID-BASE BALANCE A buffer is a solution of two or more chemicals that minimizes changes in pH in response to the addition of an acid or base.A buffer is a solution of two or more chemicals that minimizes changes in pH in response to the addition of an acid or base. Most buffers are weak acids. Ideally, a buffer has a pK a that is equal to the pH, and an ideal body buffer has a pK a between 6.8 and 7.2.Most buffers are weak acids. Ideally, a buffer has a pK a that is equal to the pH, and an ideal body buffer has a pK a between 6.8 and 7.2. The major source of acid in the body is CO 2, from which is produced 12,500 mEq of H + each day.The major source of acid in the body is CO 2, from which is produced 12,500 mEq of H + each day. The metabolic compensation for respiratory acidosis is increased SID by removal of chloride.The metabolic compensation for respiratory acidosis is increased SID by removal of chloride. Volatile acid is principally buffered by hemoglobin.Volatile acid is principally buffered by hemoglobin. Chloride shift:Chloride shift:

30. Erythrocyte Buffering System And Chloride Shift Erythrocyte Buffering System And Chloride Shift

31. Metabolic acid is buffered principally by increased alveolar ventilation, producing respiratory alkalosis and extracellular weak acids.Metabolic acid is buffered principally by increased alveolar ventilation, producing respiratory alkalosis and extracellular weak acids. These weak acids include : plasma proteins, phosphate, and bicarbonate.These weak acids include : plasma proteins, phosphate, and bicarbonate. The bicarbonate buffering system ( 92% of plasma buffering and 13% overall ) is probably the most important extracellular buffer.The bicarbonate buffering system ( 92% of plasma buffering and 13% overall ) is probably the most important extracellular buffer. REGULATION OF ACID-BASE BALANCE

32. The major effect of the kidney on acid-base balance is related to renal handling of sodium and chloride ions. In metabolic acidosis, chloride is preferentially excreted by the kidney. In metabolic alkalosis, chloride is retained, and sodium and potassium are excreted. In renal tubular acidosis, there is an inability to excrete Cl - in proportion to Na +. The diagnosis can be made by observing a hyperchloremic metabolic acidosis with inappropriately low levels of Cl - in the urine; the urinary SID is positive. If the urinary SID is negative, the process is not renal. Gastrointestinal losses (diarrhea, small bowel or pancreatic drainage), parenteral nutrition, excessive administration of saline; and the use of carbonic anhydrase inhibitors. REGULATION OF ACID-BASE BALANCE