H+ OH-Acid-base abnormalities should be seen as

resulting from other biochemical changes in the extracellular environment

strong ions (NaNa++ , , ClCl-- , , KK++ , SO4 , SO4 2-2- , Mg , Mg2+2+ , Ca , Ca22+)

weak acids(albuminalbumin , , phosphatephosphate ) carbon dioxide

To maintain electrical neutrality

PHYSICAL CHEMISTRY OF WATER

H2O H+ OH-+

OH

H105o O

H

HOH

H

fundamental to the

existence of life

PHYSICAL CHEMISTRY OF WATER

H2O H+ OH-+25o C

1.0 × 10−7 mmol/L

Keq H2 O = [H+ ][OH− ]

Keq H2 O = Keq (55.5) = Kw = [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, [OH− ] > 1.0 × 10−7 mmol/L) .

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.

• Hasselbalch (1916)HH22O + COO + CO22 → → H H22COCO33 → → [H[H++] + [HCO] + [HCO33

--]]• pH = ppH = pKKaa + log [HCO + log [HCO33 −− ] / [H ] / [H22 CO CO33 ] ]

• pH = 6.1 + log [HCO3− ] / PCO2 × 0.03

• 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. • Similarly, ions such as sodiumsodium, potassium potassium, and chloridechloride, which

do not easily bind other molecules, are considered strong ionsstrong ions; they exist free in solution.

• Strong cations (Na+ , K+ , Ca2+ , Mg2+ ) act as Arrhenius bases • Strong anions (Cl- , LA- [lactate], ketones, sulfate, formate) act

as Arrhenius acids.• One problem with the Arrhenius theory:

ammonia (NH3 ), sodium carbonate (Na2 CO3 ), and sodium bicarbonate (NaHCO3 )

• In 1923, Brønsted and Lowry They defined acids as proton donors and bases as proton acceptors.

• NH3 + H2 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 + H2 O → H3 O+ + Cl−

In the previous reaction, hydrogen chloride acts as a Brønsted-Lowry acid and water as a Brønsted-Lowry base.

• CO2 + H2 O H⇌ 2 CO3 H⇌ + + HCO3 −

In this reaction, carbon dioxide is hydrated to carbonic acid, a Brønsted-Lowry acid, which subsequently dissociates to hydrogen (H+ ) and bicarbonate (HCO3

- ) ions.

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

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.

Strong IonsStrong Ions• The most abundant strong ions in the

extracellular space are Na+ and Cl- .

• Other important strong ions include K+, SO4 2- , Mg2+, and Ca2+.

• If NaOH and HCl, added to solution([Na+ ] − [Cl− ]) + ([H+ ] − [OH− ]) = 0

• In this system, ([Na+ − [Cl−]) must determine [H+] and [OH−].

•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

Weak Acid Buffer SolutionsWeak Acid Buffer Solutions

• These are These are partially dissociated compoundspartially dissociated compounds

whose degree of dissociation is determined by whose degree of dissociation is determined by

the prevailing temperature and pH.the prevailing temperature and pH.

• The predominant molecules in this group are The predominant molecules in this group are

albuminalbumin and and phosphatephosphate. .

• Stewart used the term Stewart used the term AATOTTOT to represent the to represent the

total concentration of weak ions that total concentration of weak ions that

influenced acid-base balance influenced acid-base balance

Weak Acid Buffer SolutionsWeak Acid Buffer Solutions

• KA [HA] = KAKA [H+] [A−]

• [HA] ++ [A− ] = [ATOT ]

• [H+]× [OH−] = Kw (water dissociation)

• [SID] + [H+] − [A−] − [OH−] = 0 (electrical neutrality)

• SID and ATOT are independent variables

• Kw and KA are constants

• [HA], [H+], [OH-], and [A-] are dependent variables.

Carbon DioxideCarbon Dioxide• 1- carbon dioxide, denoted CO2 (d);

2- carbonic acid (H2 CO3)

3- bicarbonate ions (HCO3- )

4- carbonate ions (CO32- )

• [CO2 (d)] = [SCO2] × PCO2

• [CO2 (d)] × [OH− ] = K1 × [HCO3− ]

• [H+ ] × [HCO3− ] = Kc × PCO2

• [H+ ] × [CO32− ] = K3 × [HCO3

− ]

Factors Independently Influencing Water Dissociation

• Water dissociation equilibrium: [H+ ] × [OH- ] = KW

• Weak acid dissociation equilibrium:[H+ ] × [A- ] = KA × [HA]

• Conservation of mass for weak acids:[HA] + [A- ] = [ATOT ]

• Bicarbonate ion formation equilibrium:[H+ ] × [HCO3 - ] = KC × PCO2

• Carbonate ion formation equilibrium:[H+ ] × [CO3

2- ] = K3 × [HCO3 - ]

• Electrical neutrality:[SID] + [H+ ] - [HCO3

- ] - [A- ] - [CO3 2- ] - [OH- ] = 0

• [H+ ]4 + ([SID] + KA ) × [H+ ]3 + (KA × ([SID] − [ATOT ]) − Kw − Kc × PCO2 ) × [H+ ]2 − (KA × (Kw + Kc × PCO2 ) − K3 × Kc × PCO2 ) × [H+ ] − KA × K3 × Kc × PCO2 = 0

• [H+ ] is a function of SID, ATOT , PCO2 , and several constants.

• All other variables, most notably [H+], [OH-], and [HCO3 -], are dependent and cannot independently influence the acid-base balance

ACID-BASE ABNORMALITIESACID-BASE ABNORMALITIES

• Stewart approachStewart approach :: SID, SID, A ATOTTOT, PCO, PCO22

Traditional approach • Alterations in (PaCO2) tension :

respiratory acidosis or alkalosis

• Alterations in blood chemistry : ( HCO3- ,

BE )

metabolic acidosis, or alkalosis

RespiratoryRespiratory Acid-Base Abnormalities Acid-Base Abnormalities• Respiratory acidosis → acute rise in PaCO2

principally because of respiratory failureprincipally because of respiratory failure

• Clinically, : (signs of CO(signs of CO22 retention) retention)Cyanosis, vasodilatation, and narcosis.

• Respiratory alkalosis → acute decrease in PaCO2 (caused by hyperventilation.)(caused by hyperventilation.)

• Clinically : Vasoconstriction: light-headedness, visual disturbances, dizziness, and perhaps hypocalcemia

ACID-BASE ABNORMALITIESACID-BASE ABNORMALITIES

Respiratory acidosis

• Causes a rapid increase in [H+]. • Compensation for hypercarbia is slow • Increased urinary excretion of chloridechloride• There is a concomitant increase in the serum

bicarbonatebicarbonate, reflecting a higher total COCO22 load load, rather than compensation.

• The acuity of respiratory failure can be deduced by looking at the relative ratio of CO2 to HCO3

–

• Many investigators have suggested that respiratory acidosis may notnot necessarily be harmfulharmful.

• There has been extensive clinical experience with "permissive hypercapnia""permissive hypercapnia" for acute respiratory failure, which appears to be well tolerated.

• Causes a rapid increase in [H+]. • Compensation for hypercarbia is slow • Increased urinary excretion of chloridechloride• There is a concomitant increase in the serum

bicarbonatebicarbonate, reflecting a higher total COCO22 load load, rather than compensation.

• The acuity of respiratory failure can be deduced by looking at the relative ratio of CO2 to HCO3

–

• Many investigators have suggested that respiratory acidosis may notnot necessarily be harmfulharmful.

• There has been extensive clinical experience with "permissive hypercapnia""permissive hypercapnia" for acute respiratory failure, which appears to be well tolerated.

TABLE 41-1 -- Changes in PaCO2 and [HCO3_ ] in response to acute

and chronic acid-base disturbances

Disturbances[HCO3 - ] vs. PaCO2

Acute respiratory acidosisΔHCO3 - = 0.2 ΔPaCO2

Acute respiratory alkalosisΔHCO3 - = 0.2 ΔPaCO2

Chronic respiratory acidosisΔHCO3 - = 0.5 ΔPaCO2

Metabolic acidosisΔPaCO2 = 1.3 ΔHCO3 -

Metabolic alkalosisΔPaCO2 = 0.75 ΔHCO3 -

Δ, change in value; [HCO3-], concentration of bicarbonate ion; PaCO2, partial pressure of arterial carbon dioxide.

ACID-BASE ABNORMALITIESACID-BASE ABNORMALITIES

Metabolic Acid-Base DisturbancesMetabolic Acid-Base Disturbances• Metabolic acid-base abnormalities → SID or ATOT, 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 2. pathologies arising from the cause of the acidosis

(Increased ionized calcium (Increased ionized calcium →→ vasodilation, diminished vasodilation, diminished muscular performance (particularly myocardial), and muscular performance (particularly myocardial), and arrhythmias )arrhythmias )

TABLE 41-2 -- Classification of primary acid-base abnormalities

AbnormalitiesAbnormalitiesAcidosisAcidosisAlkalosisAlkalosis

RespiratoryIncreased PCO2Decreased PCO2

Metabolic

Abnormal SIDAbnormal SID

Caused by water excess or deficitWater excess = dilutionalWater excess = dilutional↓ ↓ SID + ↓ [NaSID + ↓ [Na++ ] ]

Water deficit = contractionWater deficit = contraction↑ ↑ SID ↑ [NaSID ↑ [Na++ ] ]

Caused by electrolytesChloride excessChloride excessChloride deficitChloride deficit

Chloride (measured)  ↓ ↓ SID ↑ [ClSID ↑ [Cl-- ] ]↑ ↑ SID + ↓ [ClSID + ↓ [Cl-- ] ]

Other (unmeasured) anions, such as  

lactate and keto acids

↓ ↓ SID ↑ [UMASID ↑ [UMA-- ] ]

Abnormal ATOT

Albumin [Alb]↑ ↑ [Alb] (rare)[Alb] (rare)↓ ↓ [Alb[Alb]]

Phosphate [Pi]↑ ↑ [Pi][Pi]

[Alb], concentration of serum albumin; ATOT , to represent the total concentration of weak ions; [Cl- ], concentration of chloride ions; [Na+ ], concentration of sodium ions; PCO2 , partial pressure of carbon

dioxide; [Pi], concentration of inorganic phosphate; SID, strong ion difference; [UMA - ], unmeasured anions; ↑, increased; ↓, decreased.

REGULATION OF ACID-BASE BALANCEREGULATION OF ACID-BASE BALANCE

• A A bufferbuffer is a solution of two or more chemicals is a solution of two or more chemicals that minimizes changes in pH in response to the that minimizes changes in pH in response to the addition of an acid or base. addition of an acid or base.

• Most buffers are Most buffers are weak acidsweak acids. Ideally, a buffer has . Ideally, a buffer has a pa pKKaa that is equal to the pH, and an ideal body that is equal to the pH, and an ideal body buffer has a pbuffer has a pKKaa between between 6.86.8 and and 7.27.2..

• The The major sourcemajor source of acid in the body is of acid in the body is COCO22 , from , from which is produced which is produced 12,500 mEq12,500 mEq of of HH++ each day. each day.

• The The metabolic compensationmetabolic compensation for respiratory for respiratory acidosis isacidosis is increasedincreased SIDSID by removal of by removal of chloridechloride..

• VolatileVolatile acid is principally buffered by acid is principally buffered by hemoglobinhemoglobin..

• Chloride shift:Chloride shift:

Erythrocyte Buffering Erythrocyte Buffering SystemSystem

And Chloride ShiftAnd Chloride Shift

Erythrocyte Buffering Erythrocyte Buffering SystemSystem

And Chloride ShiftAnd Chloride Shift

• Metabolic acidMetabolic acid is buffered principally by is buffered principally by

increased alveolar ventilation, producing increased alveolar ventilation, producing

respiratory alkalosisrespiratory alkalosis and extracellular and extracellular weak weak

acidsacids. .

• These These weak acidsweak acids include : include :

plasma proteinsplasma proteins, , phosphatephosphate, and , and bicarbonatebicarbonate. .

• The The bicarbonatebicarbonate buffering system buffering system ((92% of plasma 92% of plasma

buffering and 13% overallbuffering and 13% overall)) is probably the most is probably the most

important extracellular buffer.important extracellular buffer.

REGULATION OF ACID-BASE BALANCEREGULATION OF ACID-BASE BALANCE

• 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 BALANCEREGULATION OF ACID-BASE BALANCE