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Principles of Acid-Base Physiology

Mazen Kherallah, MD, FCCPInternal 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 (40nmol/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 BuffersInorganic Phosphate

HPO42-

pH= pK + log ---------- H2PO4

-

HPO42-: divalent inorganic phosphate ion

H2PO4-: monovalent dihydrogen inorganic phosphate ion

pK for inorganic phosphate is close to 6.8

pH of Different Compartments

PH Compartment Ratio ofHPO4

2-/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 TotalInorganicPhosphate

% as ofH2PO4

-Equation

ECF 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 ChargeNeutrals 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- + Pi

2- + 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 ImpactNutrient Product H+

(mEq/day)Reactions generating H+

Sulfur-containing amino acids: Cysteine/cystine, methionine

H+ 70

Cationic amino acids: Lysine, arginine, histidine

H+ 140

Organic phosphates HPO42-+H+ 30

Reactions removing H+

Anionic amino acids: Glutamate, aspartate

HCO3- -110

Organic anions (citrate3-) HCO3- -60

Posphate excretion H2PO4- -30

Net total H+ load to be excreted asNH4+

40

Sulfur-containing Amino AcidsCysteine/Cystine and Methionine

• Sulfur-containing amino acids can be oxidized to yield the terminal anion SO4

2- plus neutral end-product (glucose, urea, CO2 and and H2O)

• Because the affinity SO42- of for H+ is so low (SO4

2- has a very low pK), SO4

2- 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 AcidsLysine, 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 H+

Event Rate( mmol/min)

Comment

Production of H+

Lactic acid 72 Complete anoxia7.2 10% hypoxia

Ketoacids 1 Lack of insulin

Toxic alcohols <1 Poisening metabolites

Removal of H+

Excretion of NH+ 0-2 Lag period

Metabolism

Lactic acid 4-8 Oxidation and glucogenesis

Ketoacids 0.8 Oxidized in brain and kidney

Y E s N o

W as H + p rod u cedat a m u ch fas te rra te th an it w as

rem oved

Y es N o

Is H + accu m ila tin g

R eac tion s th a t p rod u ce H +

Anions are metabolized to neutralproducts almost as fast as they areproduced:

Starvation KetoacidosisL-lactic acid: usual rate

Anions that are produced slowlyand excreted with H+ and NH4+

H2SO4 from proteinsDKAL-lactic acid: liver problemOrganic acids from gut: butyric acid, acetic, and propionicAnions from toxinsNH4 excretionproblem

L-lactic aciddue to low supply of O2: Exercise Shock

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 Clinicallyimportant

Normal 402 7.400.002 Normal

Alkalemia 20-36 7.44-7.69 Clinicallyimportant

Alkalemia <20 >7.70 Can be lethal

HCO3-

Fuels H+

CO2

Kidneys

Glutamine NH4+

Lungs

(70 mmol per day)

(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

CO2 + H2O

HCO3- (to blood)

H+ (Secreted)

FilteredHPO42

-

H2PO4- (to urine)

Glutamine

NH4+ (to urine)

HCO3- (to blood)

Generation of New HCO3 in the Kidney

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)

HCO3-

pH= pK + log ---------- H2CO3

H+ + HCO3- H2CO3 H2O + CO2

Each mmol of HCO3- remove 1 mmol of H+

[H+] = 24 X PCO2/HCO3-

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: H+ + HCO3- H2O + CO2 lungs

ICF: H+ + HCO3- H2O + CO2

HB+

B(falls)

Bicarbonate Buffer SystemImportance of CO2 Removal

Condition [H+](nmol/L)

PH PCO2(mm Hg)

HCO3-

(mmol/L)

Closed system(PCO2 rises)

871 6.06 455 12.5

No change inPCO2

77 7.11 40 12.5

Lower PCO2 52 7.29 27 12.5