PHYSIOLOGY: S01L25

Acid-Base Regulation
Dr. Sheila Marie O. Baria | 12-09-2020 | MWF | 7:30-10:00 AM | Lec
 OUTLINE  Strong Base – reacts rapidly and strongly with H+ thus quickly
removes H+ from the solution (e.g., OH-)
I. Introduction
 Weak Base – binds with H+ weakly (e.g., HCO3)
II. Acids and Bases  H+ Concentration and pH of body fluids:
III. Defense Against Changes in Hydrogen Ion Concentration ♦ H+ is regulated precisely at low normal value.
IV. Buffering of Hydrogen Ions in the Body Fluids ◦ 0.00004 meq/L (40nEq/L)
V. Buffer Systems ♦ Normal variations are 3-5 nEq/L.
VI. Respiratory Regulation of Acid-Base Balance ◦ Can be as low as 10 nEq/L to as high as 160 nEq/L without
VII. Renal Control of Acid-Base Balance causing death.
♦ H+ is expressed on a logarithmic scale using pH because of
VIII. Secretion of Hydrogen Ions and Reabsorption of HCO3 by the
its normally low concentration.
Renal Tubules
♦ Formula:
IX. Mechanisms of Generating New Bicarbonate
X. Quantifying Renal Acid-Base Excretion
XI. Regulation of Renal Tubular Hydrogen Ions Secretion
XII. Renal Correction of Acidosis and Alkalosis
XIII. Clinical Causes of Acid-Base Disorders
XIV. Clinical Measurements of Acid-Base Disorders ♦ pH is inversely related to H+ concentration.
♦ Low pH = High H+
XV. Acid-Base Disorders
♦ High pH = Low H+
XVI. Use of Anion Gap to Diagnose Acid-Base Disorders
♦ Lower Limit = pH 6.8
XVII. Important Points ♦ Upper Limit = pH 8.0
XVIII. References ♦ Acidosis - when pH falls below this value
♦ Alkalosis - when pH rises above this value
I. INTRODUCTION

 Regulation of H+ balance is similar to the regulation of other ions.

 Balance between production and removal of H+
 Kidneys play a key role in H+ removal.
 Multiple acid-base buffering mechanisms that maintain normal
H+: blood, cells, lungs.
 Regulation of H+ concentration is precise because it can influence
the activities of all enzymes in the body.
 Changes in H+ affects almost all cells and body functions.

II. ACIDS AND BASES

Table 1. pH and H+ Concentration of Body Fluids.
DEFINITION

 Hydrogen ion (H+) – a single proton released from a hydrogen
atom.
 Acids – molecules containing hydrogen atom that can release
hydrogen ions in solutions.
♦ HCl, H2CO3
 Bases – molecules that can accept hydrogen ions in solutions.
♦ HCO3, proteins
♦ Used synonymously with alkali
 Alkali - molecule formed by combination of one or more alkali
metals (Na, K, Li) with a highly basic ion such as hydroxyl ion
(OH-).
 Alkalosis – excess removal of H+ from the body fluids.
 Acidosis – excess addition of H+ in the body fluids.
STRONG AND WEAK ACIDS AND BASES
 Strong Acid – rapidly dissociates and release large amount of
H+ (HCl).
 Weak Acid – less tendency to dissociate their ions and release
H+ slowly (H2CO3).
♦ Why is there a difference between arterial and venous
blood pH?
◦ Production of CO2 in venous blood (results in more acid
concentration).
♦ Why is there a range of pH in intracellular fluid?
◦ It depends on the situation of the patient.
III. DEFENSE AGAINST CHANGES IN HYDROGEN ION
CONCENTRATION
 3 primary systems work to regulate H+ thus preventing acidosis
or alkalosis.
 Chemical Acid Base Buffer Systems
◦ Combines with acid or base to prevent rapid change in
H+ concentration.
◦ React within seconds to minimize changes in H +
concentration.
◦ Does not eliminate H+ or add H+, only keeps it tied up
until balance is re-established.
 Respiratory Center

"Balance is not something you find. It's something you create." - Jana Kingsford 1
 ◦ Regulates the removal of CO2 from ECF (and therefore
H2CO3 from the body).
◦ Acts within a few minutes.
◦ Second line of defense.
 Kidneys
◦ Excrete either acid or alkaline urine thereby re-adjusting
ECF H+ concentration.
◦ Most powerful of the acid base regulatory system.
◦ Slow to respond, over a period of hours to several days.
◦ Third line of defense.
IV. BUFFERING OF HYDROGEN IONS IN THE BODY FLUIDS
 Buffer – any substance that can reversibly bind hydrogen ions.
 Buffering Reaction:
 ↑ H+ concentration → Right → and more H+ bind to the buffer.
 ↓ H+ concentration → Left → more H+ are released from the
buffer.
♦ As a result, changes in H+ concentration are minimized.
♦ Limits lethal changes in the body as evidenced by low
concentration of H+ (0.00004 mEq/L) in the body fluid
despite the large amounts of acids (80mEq/L) produced by
the body (due to cell metabolism) every day.
V. BUFFER SYSTEMS
BICARBONATE BUFFER SYSTEM
 Quantitatively most important extracellular buffer.
 Most powerful extracellular buffer in the body.
 Two elements:
♦ H2CO3, a weak acid
♦ NaHCO3, a bicarbonate salt
 H2CO3
♦ Formed in the body by the reaction of CO2 with H2O.
♦ The reaction is slow and exceedingly small amounts of
H2CO3 are formed unless the enzyme carbonic anhydrase
is present.
♦ Carbonic anhydrase an enzyme that is specifically
abundant in:
◦ Walls of lung alveoli, where CO2 is released
◦ Renal tubules, where CO2 reacts with H20 → H2CO3
 NaHCO3
♦ Second component of the system.
♦ Occurs predominantly in the ECF.
♦ NaHCO3 ionizes almost completely to form HCO3- and Na+.
 Entire system together (H2CO3 and NaHCO3)
♦ Weak dissociation of H2CO3
"Balance is not something you find. It's something you create." - Jana Kingsford
♦ H+ is decreased
♦ As a result, the pH of the ECF can be precisely controlled
by the rate of removal and addition of HCO 3 by the kidneys
and the rate of removal of CO2 by the lungs.
HENDERSON - HASSELBALCH EQUATION
 Can calculate the pH of the solution if the molar concentration
of HCO3 and pCO2 is known.
 Increase in HCO3 causes the pH to rise, shifting the acid base
balance toward alkalosis.
 Increase in pCO2 causes the pH to decrease, shifting the acid
base toward acidosis.
 Importance:
♦ Define the determinants of normal pH regulation and acid-
base balance in ECF.
♦ Provides insight into the physiologic control of acid and
base composition of ECF.
 HCO3 concentration is regulated by the kidney.
 pCO2 in the ECF is controlled by the rate of respiration.
♦ Increasing the rate of respiration, the lungs remove CO2
from the plasma.
♦ Decreasing the rate of respiration, the lungs elevate pCO2.
 Normal acid-base balance results from the coordinated
function of both kidneys and lungs.
♦ Acid-base disorders occur when one or both of the control
mechanism is impaired – altered HCO3 or pCO2 level in
ECF.
♦ Metabolic acid-base disorder – results from primary
change in HCO3
♦ Respiratory acid-base disorder – results from primary
change in pCO2
PHOSPHATE BUFFER SYSTEM
 Intracellular and tubular fluid buffer increases in pCO2 causes
the pH to decrease, shifting the acid base toward acidosis.
 Plays a major role in buffering renal tubular fluid and
intracellular fluid.
 Main elements: H2PO4, HPO4
 Reasons why it is an important tubular fluid buffer:
♦ Phosphate is concentrated in the tubules, thus increasing
the buffering power of the phosphate system.
♦ The lower pH of the tubular fluid brings the operating
range of the buffer close to pK 6.8.
 Reasons why it is an important buffer of ICF:
♦ Concentration is many times more than in the ECF.
♦ pH of the ICF is lower than that of the ECF, therefore closer
to the pK of phosphate buffer system.
PROTEINS
 Important intracellular buffers.
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  Most plentiful buffers in the body, due to high concentration
within the cells.
 pH of the cell, though slightly lower than ECF, changes in
proportion to ECF changes.
 60-70% of the buffering of body fluids is inside the cells and
most results from intracellular proteins.
 The slowness of H+ and bicarbonate ions through cell
membrane delays the maximum ability to buffer extracellular
acid-base abnormalities (except in RBCs).
 The pK of many of these protein systems are fairly close to 7.4
which is another factor that contributes to the buffering effect.

ISOHYDRIC PRINCIPLE

 A change in the hydrogen ion concentration in the ECF make

changes to all the buffer systems at the same time.
Figure 1. Change in extracellular fluid pH caused by increased or decreased
 Implication:
rate of alveolar ventilation, expressed as times normal.
♦ Any condition that changes the balance of one buffer
system also changes the balance of all other buffers.
♦ Buffer systems actually buffer one another by shifting INCREASED H+ CONCENTRATION STIMULATES ALVEOLAR
hydrogen ions back and forth to one another. VENTILATION

VI. RESPIRATORY REGULATION OF ACID-BASE BALANCE
 The second line of defense against acid base disturbances is
control of ECF CO2 concentration.
♦ Increased ventilation eliminates CO2 from ECF, reducing
H+ concentration.
♦ Decreased ventilation increases CO2, increasing H+
concentration in ECF.
 H+ concentration affects the rate of alveolar ventilation.
 Alveolar ventilation increases four to five times normal as pH
decreases (↑ H+) from the normal value of 7.4 to strongly
acidic value of 7.0.
 A rise in plasma pH above 7.4 causes a decrease in the
ventilation rate.

PULMONARY EXPIRATION OF CO2 BALANCES METABOLIC

FORMATION OF CO2

 CO2 is formed intracellularly by metabolism.

 Pulmonary ventilation transfers CO2 to the atmosphere.
 1.2 mol/L of dissolved CO2 is in the ECF corresponding to pCO2
of 40 mmHg.
♦ Increased metabolism increases CO2 and leads to
increased ECF pCO2
♦ Low metabolism decreases CO2 leading to low ECF pCO2
♦ Increased pulmonary ventilation leads to CO2 blowing off
which lowers ECF pCO2 Figure 2. Effect of blood pH on the rate of alveolar ventilation.
 Changes in either pulmonary ventilation or rate of CO2
formation can change the ECF pCO2  Change in ventilation rate per unit pH change is greater at
reduced levels of pH (↑ H+) compared with increased levels
INCREASING ALVEOLAR VENTILATION DECREASES of pH.
♦ As the alveolar ventilation decreases (because of ↑ pH) →
EXTRACELLULAR FLUID H+ CONCENTRATION AND RAISES PH
oxygen added to blood decreases→ partial pressure of
oxygen decreases → increased ventilation rate occurs.
 The higher the alveolar ventilation, the lower the pCO2
 CO2 concentration increases → H2CO3 and H+ ions also
increases → lowering ECF pH. FEEDBACK CONTROL OF H+ CONCENTRATION BY THE
 Increasing alveolar ventilation to about 2x normal raises ECF RESPIRATORY SYSTEM
pH by about 0.23
♦ pH = 7.40  Increase in H+ concentration stimulates respiration.
♦ Increased alveolar ventilation → 7.40 + 0.23 = 7.63  And increased alveolar ventilation in turn decreases the H+
 A decrease in alveolar ventilation to ¼ normal reduces the pH concentration.
by 0.45.  Respiratory system acts as a negative feedback controller of
♦ pH = 7.40 H+
♦ Reduced alveolar ventilation →7.40 – 0.45 = 6.95

"Balance is not something you find. It's something you create." - Jana Kingsford 3
  Increase in H+ concentration above normal:
♦ Stimulates respiratory system.
♦ Increase alveolar ventilation.
♦ Decrease pCO2 in ECF.
♦ Reduces H+ concentration towards normal.
 Fall of H+ below normal:
♦ Respiratory center depressed.
♦ Alveolar ventilation decreases.
♦ H+ increases towards normal.
EFFICIENCY OF RESPIRATORY CONTROL OF H+
CONCENTRATION
 The respiratory control cannot return the H+ concentration
back to normal when a disturbance outside the respiratory
system has altered the pH.
 Respiratory control of H+ concentration is between 50-75%,
only corresponding to feedback gain of 1 to 3 for metabolic
acidosis.
♦ Example: Decreased pH by addition of acid to the ECF.
◦ If pH falls from 7.4 to 7.0, respiratory system can return
to pH to about 7.2 to 7.3 only.
BUFFERING POWER OF THE RESPIRATORY SYSTEM
 Physiologic type of buffer that acts rapidly and keeps the H+
from changing too much until the slowly responding kidneys
eliminate the imbalance.
 Overall buffering power is one to two times as great as the
buffering power of all other chemical buffers in the ECF.
IMPAIRMENT OF LUNG FUNCTION CAN CAUSE RESPIRATORY
ACIDOSIS
 Respiratory disorders and lung impairment can change
hydrogen ion concentration in the ECF.
♦ Emphysema decrease lung ability to eliminate CO 2 →
build-up of CO2 in the ECF → Respiratory acidosis.
♦ Impaired respiratory response mechanism to metabolic
acidosis because the compensatory reduction in CO 2
caused by increase ventilation is blunted.
 Kidneys represent the remaining physiologic mechanism for
returning pH back to normal.
VII. RENAL CONTROL OF ACID-BASE BALANCE
 Kidneys – excrete an acidic or basic urine
 Overall mechanism by which kidneys excrete acidic or basic
urine is as follows:
♦ Large numbers of HCO3- are filtered continuously into the
tubules, and if excreted into the urine, this removes base
from the blood.
♦ Large numbers of H+ are also secreted into the tubular
lumen by the tubular epithelial cells, thus removing acid
from the blood.
♦ If more H+ is secreted than HCO3- is filtered, there will be
a net loss of acid from the ECF. Conversely, if more HCO 3-
is filtered than H+ is secreted, there will be a net loss of
base.
 Metabolic acidosis
♦ Filtered bicarbonate ions, if not reabsorbed, leads to loss
of base in the ECF.
"Balance is not something you find. It's something you create." - Jana Kingsford
 Metabolic alkalosis
♦ Hydrogen ions secreted by the tubules to the tubular
lumen will remove acid from blood.
 Body produces 80 mEq/day of nonvolatile acids from
metabolism of proteins.
♦ Nonvolatile since they are not H 2CO3 and cannot be
excreted by the lungs.
♦ Renal excretion – primary mechanism for removal of these
acids.
VIII. SECRETION OF HYDRGEN IONS AND REABSORPTON
OF HCO3- BY THE RENAL TUBULES
 3 mechanisms for kidney regulation of ECF H+ Concentration:
♦ Secretion of hydrogen ions.
♦ Reabsorption of filtered bicarbonate ions.
♦ Production of new bicarbonate ions.
 Summary of bicarbonate reabsorption:
♦ 80-90% – reabsorbed in the proximal tubule
♦ 10% – reabsorbed in thick ascending loop of Henle
♦ 5% – reabsorbed in distal tubule and collecting duct
Figure 3. Reabsorption of bicarbonate in different segments of the renal
tubule. The percentages of the filtered load of HCO3− absorbed by the various
tubular segments are shown, as well as the number of milliequivalents
reabsorbed per day under normal conditions.
H+ IS SECRETED BY SECONDARY ACTIVE TRANSPORT IN THE
EARLY TUBULAR SEGMENTS
 Hydrogen ions are secreted by secondary sodium-hydrogen
counter-transport (sodium-hydrogen counter-transport) in
the early segments of the tubules.
 More than 90% of the bicarbonate is reabsorbed through
hydrogen secretion in the proximal tubule.
 For every hydrogen ion secreted in the tubular lumen, a
bicarbonate ion is reabsorbed into the blood.
 Primary active hydrogen ion secretion occurs in the
intercalated cells of the late distal and collecting tubules.
♦ H+ moves across the luminal membrane by an active H+
pump.
♦ Contributes to only about 5% of the total hydrogen ion
secreted.
♦ Important in forming a very acidic urine
♦ H+ concentration can increase to as high 900-fold
4
 ♦ Decreases urine pH to 4.5, which is the lower limit that can
be achieved in normal kidney.
Figure 4. Cellular mechanisms for (1) active secretion of H+ into the renal
tubule; (2) tubular reabsorption of HCO3 − by combination with H+ to form
carbonic acid, which dissociates to form carbon dioxide and water; and (3)
sodium ion reabsorption in exchange for H+ secreted. This pattern of H+
secretion occurs in the proximal tubule, the thick ascending segment of the
loop of Henle, and the early distal tubule.
 Secretory process begins when:
♦ CO2 either diffuses into the tubular cells or is formed by
metabolism in the tubular epithelial cells.
♦ CO2 under the influence of carbonic anhydrase combines
with H2O to form H2CO3
♦ H2CO3 then dissociates to into HCO3- and H+
♦ H+ is secreted from the cell into the lumen by sodium-
hydrogen counter-transport as Na+ moves from the lumen
into the cell.
♦ Na+ moves into the cell down a concentration gradient by
the sodium-potassium ATPase pump in the basolateral
membrane.
FILTERED HCO3- IS REABSORBED BY INTERACTION WITH H + IN
THE TUBULES
 (Refer to Figure 4.)
 As H2CO3 is formed in the tubular cells, it dissociates to form
HCO3- and H+
 HCO3- diffuses through basolateral membrane into interstitial
fluid which is facilitated by two mechanisms:
♦ Na+ - HCO3- co-transport in the proximal tubules.
♦ Cl- - HCO3- exchange in the late segments of proximal
tubule, thick ascending loop of Henle, and the collecting
tubules and ducts.
♦ Then it is taken up into the peritubular capillary blood.
♦ Thus, each time a H+ is formed in the tubular epithelial
cells, a HCO3- is also formed and released back into the
blood.
♦ HCO3- and H+ normally “titrate” each other in the tubules.
PRIMARY ACTIVE SECRETION OF H+ IN THE INTERCALATED
CELLS OF LATE DISTAL AND COLLECTING TUBULES
 The secretion of H+ in the late tubules is transported by specific
proteins, a hydrogen-transporting ATPase and a hydrogen-
potassium-ATPase transporter.
 Type A intercalated cells are a special type of cell where the
primary active secretion of H+ occur.
"Balance is not something you find. It's something you create." - Jana Kingsford
 Hydrogen ion secretion in these cells is accomplished in two
steps:
♦ Dissolved CO2 in this cell combines with H 2O to form H2CO3
♦ H2CO3 then dissociates into HCO3- and reabsorbed into the
blood and H+ is secreted into the tubules by means of
specific proteins.
Figure 5. Active secretion of H+ through the luminal membrane of the type A
intercalated epithelial cells of the late distal and collecting tubules. Type A cells
contain hydrogen–adenosine triphosphatase (ATPase) and hydrogen-potassium-
ATPase in the luminal membrane and secrete hydrogen ions while reabsorbing
bicarbonate and potassium ions in acidosis. Note that one HCO3 − is absorbed for
each H+ secreted, and one chloride ion is passively secreted along with H +.
IX. MECHANISMS OF GENERATING NEW BICARBONATE
PHOSPHATE BUFFER
 Composed of HPO4 and H2PO4 concentrated in tubular fluid
due to its poor reabsorption.
 Effective as a buffer in tubular fluid.
 Hydrogen secreted combining with HPO4 generates one new
HCO3
 HCO3 generated in tubular cell and that enters peritubular
blood represents a net gain of HCO3 rather than a replacement
of filtered HCO3
 Normal condition, much of filtered phosphate is reabsorbed.
 30-40 mEq/day phosphate is available for buffering H+ ion.
AMMONIA BUFFER
 Composed of ammonia (NH3) and ammonium (NH4+).
 2nd buffer system in tubular fluid.
 For each glutamine molecule metabolized, two NH4 ions are
excreted into the urine and two HCO3 ions are reabsorbed in
the blood.
 Important features:
♦ Increase in ECF H+ ion stimulates renal glutamine
metabolism, increases formation of NH4 and new HCO3 to
be used in H+ ion buffering.
♦ Decrease H+ ion concentration has the opposite effect.
 In normal conditions, hydrogen secretion eliminated by
ammonia buffer accounts for about 50% of the acid excreted
and 50% of the new HCO3 generated by kidneys.
 Chronic acidosis can increase rate of NH4 excretion to 500
mEq/day.
♦ Dominant mechanism by which acid is eliminated (through
NH4)
5
 ♦ Important mechanism for generating new bicarbonate.
ALKALOSIS
X. QUANTIFYING RENAL ACID-BASE EXCRETION
 Decreased H+ secretion to a level that is too low to achieve
QUANTIFYING THE KIDNEYS’ NET EXCRETION OF ACID OR complete HCO3 reabsorption enabling the kidneys to increase
NET ADDITION OR ELIMINATION OF HCO3- FROM THE HCO3- excretion.
 Titratable acid and ammonia are not excreted (no excess H+ to
BLOOD IS AS FOLLOWS
combine with non-bicarbonate buffers).
 No new HCO3- added to the blood.
 Bicarbonate Excretion = urine flow rate x urine HCO3
concentration
♦ Indicates how rapid the kidneys remove HCO3- in the ACIDOSIS
blood (same as adding H+ ion in the blood).
♦ In alkalosis, loss of HCO3- return the plasma pH toward  Increased H+ secretion sufficiently to reabsorb filtered HCO 3
normal. with enough H+ left over to excrete large amounts of NH4+ and
titratable acids, thereby contributing large amounts of new
 Ammonia and Phosphate – primary source of non- HCO3- in the blood.
bicarbonate urinary buffers  Stimuli for increasing H+ secretion:
♦ Amount of HCO3- added to the blood (and H+ excreted by ♦ Increase in pCO2 of the ECF in respiratory acidosis.
NH4) is calculated by measuring NH4 excretion ♦ Increase in hydrogen ion concentration of the ECF
♦ NH4 excretion = urine flow rate x urinary NH4 (decrease pH) respiratory or metabolic acidosis.
concentration
Increase H+ Secretion and HCO3- Decrease H+ Secretion and HCO3-
Reabsorption Reabsorption
 Titratable Acid – measures the non-bicarbonate, non-NH4+
↑ pCO2 ↓ pCO2
buffer excreted in the urine.
↑ H+, ↓ HCO3- ↓ H+, ↑HCO3-
♦ Measured by titrating the urine with a strong base NaOH, ↓ Extracellular fluid volume ↑ Extracellular fluid volume
to a pH of 7.4 which is the pH of normal plasma, and the ↑ Angiotensin II ↓ Angiotensin II
pH of the glomerular filtrate. ↑ Aldosterone ↓ Aldosterone
♦ Titration reverses the events occurring in the tubular Hypokalemia Hyperkalemia
lumen when the fluid is titrated by hydrogen ions. Table 2. Factors that increase or decrease H+ secretion and HCO3-
reabsorption by the renal tubules.
 Net acid excretion = NH4 excretion + urinary titratable acid -
HCO3 excretion XII. RENAL CORRECTION OF ACIDOSIS AND ALKALOSIS
♦ The reason we subtract HCO3- excretion is that loss of
HCO3- is the same as adding H+ in the blood. RENAL CORRECTION OF ACIDOSIS RENAL CORRECTION OF ALKALOSIS
♦ Must equal the nonvolatile acid production in the body to - Increased hydrogen ion secretion - Decreased tubular secretion of
maintain acid-base balance. - Increased bicarbonate ion addition hydrogen
to the blood - Increased excretion of bicarbonate
ACIDOSIS - Acidosis decreases the ratio of ions
HCO3/H+ in renal tubular fluid - Alkalosis increases the ratio of
 Net acid excretion increases markedly. HCO3/H in renal tubular fluid
 Increased NH4+ excretion, removing acid in the blood. Table 3. Renal correction of acidosis and alkalosis.
 Net acid excretion = rate of net HCO3 - addition to the blood.
 Net addition of HCO3- back to the blood as more NH4+ and RENAL CORRECTION OF ACIDOSIS
more urinary titratable acid are excreted.
 Metabolic acidosis – fall in HCO3−
ALKALOSIS  Respiratory acidosis – increase in pCO2

 Titratable acid and NH4+ drops to zero.
 HCO3- excretion increases.
 Negative net acid secretion.
 Net loss of bicarbonate from the blood (adding H + to the
blood).
 No new bicarbonate is generated by the kidneys.
XI. REGULATION OF RENAL TUBULAR HYDROGEN ION
SECRETION
 Necessary for both HCO3 reabsorption and generation of new
HCO3 associated with titratable acid formation.
 In normal conditions, kidneys must excrete enough H+ to
reabsorb HCO3 that is filtered.
 Enough H+ to be excreted as titratable acid or NH4+ to get rid
of the nonvolatile acids produced each day.
ACIDOSIS DECREASES HCO−/H+ RATIO IN RENAL TUBULAR
FLUID.
 Respiratory and metabolic acidosis both cause a decrease in
the ratio of HCO3−/H+ in the renal tubular fluid.
 There is excess H+ in the renal tubules, causing complete
reabsorption of HCO3− and still leaving additional H+ available
to combine with the urinary buffers NH4+ and HPO4.
 The kidneys reabsorb all the filtered HCO3− and contribute new
HCO3− through formation of NH4+ and titratable acid.
 In metabolic acidosis, an excess of H+ over HCO3 occurs in the
tubular fluid, because of decreased extracellular fluid
concentration of HCO3− and therefore decreased glomerular
filtration of HCO3−.
 In respiratory acidosis, the excess H+ is due mainly to the rise
in extracellular fluid pCO2, which stimulates H+ secretion.
 With chronic acidosis:

"Balance is not something you find. It's something you create." - Jana Kingsford 6
 ♦ There is increased production of NH4+, which contributes ♦ Decreased pulmonary lung volume (emphysema)
to excretion of H+ and addition of new HCO3− to the  Means of Compensation (Respiratory Acidosis)
extracellular fluid. ♦ Buffers of the body fluids
♦ 500 mEq/day of H+ can be excreted in the urine, mainly in ♦ Kidneys (require several days to compensate)
the form of NH4+; this excretion, in turn, contributes up to
500 mEq/day of new HCO3− that is added to the blood. RESPIRATORY ALKALOSIS
♦ Increased secretion of H+ by the tubules helps eliminate
excess H+ from the body and increases the quantity of  Increased ventilation
HCO3− in the extracellular fluid.  Decreased pCO2
♦ Helps raise the extracellular pH and corrects the acidosis  Psychoneurosis – over breathing
♦ If the acidosis is metabolically mediated, additional  Ascend in a high altitude
compensation by the lungs causes a reduction in pCO2, ♦ Low O2 content stimulates respiration, causes loss of CO2
also helping correct the acidosis.  Means of Compensation (Respiratory Alkalosis)
♦ Chemical buffers
CHARACTERISTICS OF PRIMARY ACID-BASE DISTURBANCES ♦ Kidneys

pH H+ pCO2 HCO3- METABOLIC ACIDOSIS

Normal 7.4 40 mEq/L 40 mmHg 24 mEq/L
Respiratory ↓ ↑ ↑↑ ↑  Refers to all types of acidosis, besides those caused by
Acidosis increased CO2 in the body fluids.
Respiratory ↑ ↓ ↓↓ ↓  General causes include:
Alkalosis ♦ Failure of kidneys to excrete metabolic acids.
Metabolic ↓ ↑ ↓ ↓↓ ♦ Formation of excess quantities of metabolic acids in the
Acidosis body.
Metabolic ↑ ↓ ↑ ↑↑ ♦ Addition of metabolic acids through ingestion or infusion
Alkalosis
of acids.
Table 4. The primary event is indicated by the double arrows (↓↓ or ♦ Loss of base from the body fluids.
↑↑). Note that respiratory acid-base disorders are initiated by an
increase or decrease in pCO2, whereas metabolic disorders are initiated by Conditions that cause Metabolic Acidosis
an increase or decrease in HCO3-.
 Renal Tubular Acidosis
RENAL CORRECTION OF ALKALOSIS ♦ Results from a defect in renal secretion of H+, reabsorption
of HCO3−, or both.
 The ratio of HCO3 to CO2 in the extracellular fluid increases ♦ Impairment of renal tubular HCO3− reabsorption, causing
causing a rise in pH (a decrease in H+ concentration). loss of HCO3− in the urine
♦ Inability of the renal tubular H+ secretory mechanism to
ALKALOSIS INCREASES HCO3−/H+ RATIO IN RENAL TUBULAR establish normal acidic urine, causing the excretion of
FLUID alkaline urine.
♦ Some causes of renal tubular acidosis include:
 The net effect of this is an excess of HCO 3 that cannot be ◦ Chronic renal failure
reabsorbed from the tubules and is excreted in the urine. ◦ Addison disease - insufficient aldosterone secretion
 HCO3− is removed from the extracellular fluid by renal ◦ Fanconi syndrome - impair tubular function
excretion, which helps return the H+ concentration and pH  Diarrhea
toward normal. ♦ Most frequent cause of metabolic acidosis.
 In metabolic alkalosis: ♦ Loss of large amounts of sodium bicarbonate into the
♦ Decreased plasma H+ concentration, increased pH, which feces.
rise in the extracellular fluid HCO3− concentration. ♦ Has the same effect as losing large amounts of bicarbonate
♦ Partly compensated for by a reduction in the respiration in the urine.
rate, which increases pCO2 and helps return the ♦ Can be serious and can cause death, especially in young
extracellular fluid pH toward normal children
♦ Increased HCO3− concentration in the extracellular fluid  Vomiting of Intestinal Contents
increases the filtered load of HCO3−, causes excess HCO3− ♦ Causes loss of bicarbonate (vomiting from deeper in GI
over H+ secreted in the renal tubular fluid. tract) and results in metabolic acidosis in the same way
that diarrhea causes acidosis.
XIII. CLINICAL CAUSES OF ACID-BASE DISORDERS  Diabetes Mellitus
♦ Caused by lack of insulin secretion by the pancreas (type 1
RESPIRATORY ACIDOSIS diabetes) or insufficient insulin secretion to compensate
for decreased sensitivity to the effects of insulin (type 2
 Decreased ventilation diabetes).
 Increased pCO2 ♦ Fats are split into acetoacetic acid, and this acid is
 Occur from pathological conditions: metabolized by the tissues for energy in place of glucose.
♦ Damaged respiratory center (medulla oblongata) ♦ With severe diabetes mellitus, blood acetoacetic acid
♦ Decreased ability to eliminate CO2 levels can rise very high.
♦ Obstruction to air passages (pneumonia)

"Balance is not something you find. It's something you create." - Jana Kingsford 7
 ♦ Large amounts of acid are excreted in the urine
(sometimes as much as 500 mmol/day).
 Ingestion of Acids
♦ Rarely are large amounts of acids ingested in normal food
♦ Some of these substances include:
◦ Acetylsalicylic compounds (e.g., aspirin)
◦ Methyl alcohol - forms formic acid when metabolized
 Chronic Renal Failure
♦ Kidney function declines markedly.
♦ Buildup in the body fluids of the anions of weak acids that
are not being excreted by the kidneys.
♦ Decreased glomerular filtration rate reduces excretion of
phosphates and NH4+, which reduces the amount of
HCO3− added back to the body fluids.

METABOLIC ALKALOSIS

 Excess retention of bicarbonate or loss of H ion in the body.

Conditions that Cause Metabolic Alkalosis

Figure 6. Analysis of simple acid-base disorders. If the compensatory responses are
 Diuretics except carbonic anhydrase inhibitors markedly different from those shown at the bottom of the figure, one should
suspect a mixed acid-base disorder.
♦ Leads to increased reabsorption of Na+ from these parts of
the nephrons.
♦ Sodium reabsorption is coupled with H + secretion, the EXPECTED COMPENSATORY RESPONSE TO ACID-BASE
enhanced sodium reabsorption also leads to an increase in DISORDERS
H+ secretion and increase in bicarbonate reabsorption.
 Excess Aldosterone  Acute Respiratory Acidosis
♦ Aldosterone promotes extensive reabsorption of Na+ from ♦ For every 10 mm Hg rise in pCO2, the HCO3 increase by 1
the distal and collecting tubules and stimulates secretion mmol/L .
of H+ and HCO3− reabsorption by the intercalated cells of  Chronic Respiratory Acidosis
the collecting tubules. ♦ For every 10 mm Hg rise in pCO2, the HCO3 increase by 3.5
 Vomiting of Gastric Contents mmol/L
♦ Causes loss of the HCl secreted by the stomach mucosa.  Acute Respiratory Alkalosis
♦ Occurs especially in neonates who have pyloric stenosis ♦ For every 10 mm Hg fall in pCO2, the HCO3 decrease by 2
caused by hypertrophied pyloric sphincter muscles. mmol/L .
 Ingestion of Alkaline Drugs (NaHCO3)  Chronic Respiratory Alkalosis
♦ A common cause. ♦ For every 10 mm Hg fall in pCO2, the HCO3 decrease by 5
♦ Sodium bicarbonate – treatment of gastritis or peptic mmol/L.
ulcer.  Metabolic Acidosis
♦ 1.2 mm Hg decrease in pCO2 for each 1 mmol/L fall in HCO3
TREATMENT OF ACIDOSIS AND ALKALOSIS
Disorder Prediction of Compensation Range of values
 Best treatment is to correct the condition that cause
abnormality.
pH HCO3 pCO2
 Acidosis
pCO2 = (1.5xHCO3] + 8 +/-2
♦ Sodium bicarbonate - IV, oral
♦ Sodium lactate pCO2 will ↓ 1.25 mmHg per
Metabolic Low Low Low
♦ Sodium gluconate Acidosis mmol ↓ in HCO3
 Alkalosis
♦ Ammonium chloride - IV, oral pCO2 = (HCO3) + 15
♦ Lysine monohydrochloride – occasionally pCO2 will ↑ 0.75 mmHg per
XIV. CLINICAL MEASUREMENTS OF ACID-BASE mmol ↑ in HCO3
Metabolic
DISORDERS pCO2 will ↑ 6 mmHg per 10
Alkalosis High High High
mmol/L ↑ in HCO3
 The simple acid–base disorders can be diagnosed by analyzing
three measurements from an arterial blood sample: pCO2 = (HCO3) + 15
♦ pH Respiratory
♦ plasma HCO3− concentration Alkalosis
♦ pCO2 HCO3 will ↓ 0.2 mmol/L per
Acute mmHg ↓ in pCO2 High Low Low

HCO3 will ↓ 0.4 mmol/L per

Chronic mmHg ↓ in pCO2

"Balance is not something you find. It's something you create." - Jana Kingsford 8
 Respiratory
Acidosis
HCO3 will ↑ 0.1 mmol/L per
Acute mmHg ↑ in pCO2 Low High High

HCO3 will ↑ 0.1 mmol/L per

Chronic mmHg ↑ in pCO2

Table 5. Prediction of Compensatory Responses on Simple Acid-

Base Disturbances and Pattern of Changes.

XV. ACID-BASE DISORDERS

 In some instances, acid–base disorders are not accompanied

by appropriate compensatory responses.
♦ This abnormality is known as a mixed acid-base disorder,
which means there are two or more underlying causes for
the acid–base disturbance.

COMPLEX ACID–BASE DISORDERS AND USE OF ACID–BASE

NOMOGRAM FOR DIAGNOSIS Figure 7. Acid-base nomogram showing arterial blood pH, arterial plasma
HCO3 −, and PCO2 values. The central open circle shows the approximate
 A convenient way to diagnose acid–base disorders that can be limits for acid base status in normal people. The shaded areas in the
used to determine the type of acidosis or alkalosis, as well as nomogram show the approximate limits for the normal compensations
its severity. caused by simple metabolic and respiratory disorders. For values lying
 pH, HCO3− concentration, and pCO2 values intersect according outside the shaded areas, one should suspect a mixed acid-base disorder.
to the Henderson-Hasselbalch equation.
 The central open circle shows normal values and the XVI. USE OF ANION GAP TO DIAGNOSE ACID-BASE
deviations that can still be considered within the normal
range. DISORDERS
 The shaded areas of the diagram show the 95% confidence
limits for the normal compensations to simple metabolic and  The concentration of anions and cations in plasma must be
respiratory disorders. equal to maintain electrical neutrality.
 When using this diagram, one must assume that sufficient  No real anion gap in the plasma.
time has elapsed for a full compensatory response:  Na+ - normally measured cation
♦ 6 to 12 hours for the ventilatory compensations in  Cl+ & HCO3- - normally measured anions
primary metabolic disorders.  Anion gap - difference between unmeasured anions and
♦ 3 to 5 days for the metabolic compensations in primary unmeasured cations.
respiratory disorders.  Plasma Anion Gap
♦ Simple acid–base disturbance – if a value is within the
shaded area
♦ Mixed acid–base disorder – if the values for pH,  Anion gap increases if unmeasured anions rise or unmeasured
bicarbonate, or pCO2 lie outside the shaded area cations fall.
♦ Serves as a quick way to assess the type and severity of  Ca, Mg, K – important unmeasured cations
disorders that may be contributing to abnormal pH, pCO2,  Albumin, phosphate, sulfate – unmeasured anions
and plasma bicarbonate concentrations.  Range of anion gap – 8-16 mEq/L
♦ Note: It is important to recognize that an acid-base value  Used in diagnosing different causes of metabolic acidosis.
within the shaded area does not always indicate a simple ♦ In metabolic acidosis, plasma HCO3 is reduced.
acid-base disorder is present. ♦ If plasma Na is unchanged, the concentration of anions
must increase to maintain electroneutrality.
♦ If plasma Cl increases in proportion to the fall in plasma
HCO3, the anion gap remains normal (hyperchloremic
metabolic acidosis).
Increased Anion Gap Normal Anion Gap
(Normochloremia) (Hyperchloremia)
Diabetes mellitus (Ketoacidosis) Diarrhea
Lactic Acidosis Renal Tubular Acidosis
Chronic renal failure Carbonic anhydrase inhibitors
Aspirin (acetylsalicylic acid) Addison’s disease
poisoning
Methanol poisoning
Ethylene glycol poisoning
Starvation
Table 6. Metabolic Acidosis Associated with Normal or Increased
Plasma Anion Gap.

"Balance is not something you find. It's something you create." - Jana Kingsford 9
XVII. IMPORTANT POINTS

A. SIMPLE ACID-BASE DISORDERS

Type of Disorder pH pCO2 HCO3

Metabolic Acidosis Decreased Decreased Decreased
Metabolic Alkalosis Increased Increased Increased
Respiratory Acidosis Decreased Increased Increased
Respiratory Alkalosis Increased Decreased Decreased

B. COMPENSATORY RESPONSE FOR PRIMARY ACID-BASE

DISTURBANCES

Disorder Primary Change Compensatory

Response
Metabolic Acidosis Decreased HCO3 Decreased pCO2
Metabolic Alkalosis Increased HCO3 Increased pCO2
Respiratory Acidosis Increased pCO2 Increased HCO3
Respiratory Alkalosis Decreased pCO2 Decreased HCO3

XVIII. REFERENCES

 Dr. Baria’s PowerPoint Presentation

 Guyton and Hall Textbook of Medical Physiology 13th Ed.
Chapter 31

"Balance is not something you find. It's something you create." - Jana Kingsford 10