Regulation of

Acid-Base
Balance

Duaa Amer Abed

Ahil Al-bayt University

Collage of pharmacy 2st

2019-2020
 Introduction
The human body is exquisitely sensitive to the changes in serum pH. The normal serum pH is typically 7.4, and
changes beyond a narrow range (6.8 to 7.8) are not compatible with life; proteins unravel, enzymatic activity
ceases, and the most basic cellular functions are thrown into disarray. Consequently, the body has developed
a tightly regulated system to defend against the changes in serum pH. For normal individuals, the serum pH
barely changes, despite a wide range of acid and base challenges.

Although we use pH more frequently than hydrogen concentration to describe human physiology, a brief
reminder of this relationship is important. The pH is defined as the negative logarithm (to base 10) of the free
hydrogen ion concentration. Thus, a serum pH of 7.4, which is in the middle of the normal range for humans,
correlates to a serum-free hydrogen concentration of 0.000000039 meq of hydrogen per liter of body fluid.
Since this is a logarithmic scale, increasing the concentration to 0.00000039 (moving the decimal point by one),
correlates to a serum pH of 6.4, which would mean inevitable death to any individual! Every day, the human
body is challenged with large acid loads. Acid arises from cellular metabolism, which produces about 15,000
hydrogen equivalents per day of organic or carbon-based acids, which are metabolized to carbonic acid.

Metabolism of food (primarily protein) releases inorganic acids (e.g., sulfate/sulfuric acid from the degradation
of cysteine and methionine) at a rate of 70 meq of acid per day. To sustain life, the body must be able to
handle all of this acid produced each day without sustaining any change in serum pH.

Net acid production must equal net acid excretion in order to maintain acid balance
 A pH below 7.35 is an acidemia, and a pH above 7.45 is an alkalemia. Due to the
importance of sustaining a pH level in the needed narrow range, the human body contains
compensatory mechanisms. This discussion intends to impart a basic understanding of
acid-base balance in the body while providing a systematic way to approach patients who
present with conditions causing alterations in pH.
The human body experiences four main types of acid-based disorders: metabolic
acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. If one of
these conditions occurs, the human body should induce a counterbalance in the form of
an opposite condition.
For example, if a person is experiencing a metabolic acidemia, their body will attempt to
induce a respiratory alkalosis to compensate. It is rare for the compensation to make the
pH completely normal at 7.4. When using the term acidemia or alkalemia, one is denoting
that overall the pH is acidic or alkalotic, respectively. While not necessary, it can be useful
to employ this terminology to distinguish between individual processes and the overall pH
status of the patient since multiple imbalances can happen at the same time.

OVERVIEW OF ACID-BASE BALANCE

The diet of humans contains many constituents that are either acid or alkali. In addition, cellular metabolism
produces acid and alkali. Finally, alkali is normally lost each day in the feces. As described later in this chapter,
the net effect of these processes is the addition of acid to the body fluids. For acid-base balance to be
maintained, acid must be excreted from the body at a rate equivalent to its addition. If acid addition exceeds
excretion, acidosis results. Conversely, if acid excretion exceeds addition, alkalosis results.

The major constituents of the diet are carbohydrates and fats. When tissue perfusion is adequate, O2 is
available to tissues, and insulin is present at normal levels, carbohydrates and fats are metabolized to CO2 and
H2O. On a daily basis, 15 to 20 moles of CO2 are generated through this process. Normally, this large quantity
of CO2 is effectively eliminated from the body by the lungs. Therefore this metabolically derived CO2 has no
impact on acid-base balance. CO2 usually is termed volatile acid, reflecting the fact that it has the potential to
generate H+ after hydration with. Acid not derived directly from the hydration of CO2 is termed nonvolatile
acid (e.g., lactic acid).

The cellular metabolism of other dietary constituents also has an impact on acid-base balance. For example,
cysteine and methionine, which are sulfur-containing amino acids, yield sulfuric acid when metabolized,
whereas hydrochloric acid results from the metabolism of lysine, arginine, and histidine. A portion of this
nonvolatile acid load is offset by the production of HCO− 3 through the metabolism of the amino acids
aspartate and glutamate. On average, the metabolism of dietary amino acids yields net nonvolatile acid
production. The metabolism of certain organic anions (e.g., citrate) results in the production of HCO− 3 , which
offsets nonvolatile acid production to some degree. Overall, in persons who ingest a diet containing meat, acid
production exceeds HCO− 3 production. In addition to the metabolically derived acids and alkalis, the foods
ingested contain acid and alkali. For example, the presence of phosphate (H2PO− 4 ) in ingested food increases
the dietary acid load.

Finally, during digestion, some HCO− 3 is normally lost in the feces. This loss is equivalent to the addition of
nonvolatile acid to the body. Together, dietary intake, cellular metabolism, and fecal HCO− 3 loss result in the
addition of approximately 1 mEq/kg body weight of nonvolatile acid to the body each day (50 to 100 mEq/day
for most adults). This acid, referred to as net endogenous acid production (NEAP), results in an equivalent loss
of HCO− 3 from the body that must be replaced. Importantly, the kidneys excrete acid and in that process
generate HCO− 3 .

Overview of the role of the

kidneys in acid-base balance. HA
represents nonvolatile acids and
is referred to as net endogenous
acid production. HCO− 3 ,
bicarbonate; NaA, sodium salt of
nonvolatile acid; NaHCO3,
sodium bicarbonate; RNAE, renal
net acid excretion.

Regulation of hydrogen ion concentration is of fundamental importance to the living organism because of the
effects on body proteins of changes in acidity. The function of organs such as the heart and brain is critically
dependent on an internal milieu in which the hydrogen ion content is kept within carefully regulated limits.
Both volatile acids (i.e. carbonic acid) and non-volatile acids (e.g. lactic acid) may contribute to the hydrogen
ion concentration in the cells. The acid load produced each day is substantial. Physiological processes alter the
acid-base composition with the kidney excreting non-volatile acids, and the lung volatile acid as carbon dioxide.
Blood pH in health varies between 7.35 and 7.45 (intracellular fluid pH is usually in the range 7.0–7.3). Thus,
hydrogen ion concentration in the blood is in the range 45–35 nmol l–1.
This means that hydrogen ion concentration is about 106 times smaller than the serum sodium ion
concentration, yet it is kept within tight limits. This is a remarkable achievement, made all the more
remarkable by the fact that hydrogen is a very small ion with a very high charge density. It is, therefore,
capable of being extremely mobile with hydrogen bonds being made and broken easily. Indeed, the concept of
an isolated hydrogen ion is a theoretical one; the high charge density of a proton means that hydrogen ions
exist as part of bigger molecules, e.g. H9O4+ .

Regulation of hydrogen ion concentration depends upon homeostatic

mechanisms in the lung, kidney, liver and gut The lungs excrete the acid
produced as a result of metabolism as carbon dioxide The kidneys excrete 40–
70 mmol per day of acid produced from the breakdown of inorganic acids The
liver and the kidney are both involved in ammonium metabolism which is central
to the reabsorption of bicarbonate Application of fundamental principles of
physical chemistry has recently emphasised the importance of the chloride ion
in acid-base balance.

Proper physiological functioning depends on a very tight balance between the concentrations
of acids and bases in the blood. Acid-balance balance is measured using the pH scale. A variety
of buffering systems permits blood and other bodily fluids to maintain a narrow pH range,
even in the face of perturbations. A buffer is a chemical system that prevents a radical change
in fluid pH by dampening the change in hydrogen ion concentrations in the case of excess acid
or base. Most commonly, the substance that absorbs the ions is either a weak acid, which
takes up hydroxyl ions, or a weak base, which takes up hydrogen ions.
 BUFFER SYSTEMS IN THE BODY

The buffer systems in the human body are extremely efficient, and different systems work at different rates. It
takes only seconds for the chemical buffers in the blood to make adjustments to pH. The respiratory tract can
adjust the blood pH upward in minutes by exhaling CO2 from the body. The renal system can also adjust blood
pH through the excretion of hydrogen ions (H+) and the conservation of bicarbonate, but this process takes
hours to days to have an effect.

The buffer systems functioning in blood plasma include plasma proteins, phosphate, and bicarbonate and
carbonic acid buffers. The kidneys help control acid-base balance by excreting hydrogen ions and generating
bicarbonate that helps maintain blood plasma pH within a normal range. Protein buffer systems work
predominantly inside cells.
 PROTEIN BUFFERS IN BLOOD PLASMA AND CELLS

Nearly all proteins can function as buffers. Proteins are made up of amino acids, which contain positively
charged amino groups and negatively charged carboxyl groups. The charged regions of these molecules can
bind hydrogen and hydroxyl ions, and thus function as buffers. Buffering by proteins accounts for two-thirds of
the buffering power of the blood and most of the buffering within cells.

HEMOGLOBIN AS A BUFFER

Hemoglobin is the principal protein inside of red blood cells and accounts for one-third of the mass of the cell.
During the conversion of CO2 into bicarbonate, hydrogen ions liberated in the reaction are buffered by
hemoglobin, which is reduced by the dissociation of oxygen. This buffering helps maintain normal pH. The
process is reversed in the pulmonary capillaries to re-form CO2, which then can diffuse into the air sacs to be
exhaled into the atmosphere. This process is discussed in detail in the chapter on the respiratory system.

PHOSPHATE BUFFER

Phosphates are found in the blood in two forms: sodium dihydrogen phosphate (Na 2H2PO4−), which is a weak
acid, and sodium monohydrogen phosphate (Na2HPO42-), which is a weak base. When Na2HPO42- comes into
contact with a strong acid, such as HCl, the base picks up a second hydrogen ion to form the weak acid
Na2H2PO4− and sodium chloride, NaCl. When Na2HPO42− (the weak acid) comes into contact with a strong
base, such as sodium hydroxide (NaOH), the weak acid reverts back to the weak base and produces water.
Acids and bases are still present, but they hold onto the ions.

HCl + Na2HPO4→NaH2PO4 + NaCl

(strong acid) + (weak base) → (weak acid) + (salt)

NaOH + NaH2PO4→Na2HPO4 + H2O

(strong base) + (weak acid) → (weak base) + (water)

BICARBONATE-CARBONIC ACID BUFFER

The bicarbonate-carbonic acid buffer works in a fashion similar to phosphate buffers. The bicarbonate is
regulated in the blood by sodium, as are the phosphate ions. When sodium bicarbonate (NaHCO 3), comes into
contact with a strong acid, such as HCl, carbonic acid (H2CO3), which is a weak acid, and NaCl are formed.
When carbonic acid comes into contact with a strong base, such as NaOH, bicarbonate and water are formed.

NaHCO3 + HCl → H2CO3+NaCl

(sodium bicarbonate) + (strong acid) → (weak acid) + (salt)

H2CO3 + NaOH→HCO3- + H2O

 (weak acid) + (strong base)→(bicarbonate) + (water)

As with the phosphate buffer, a weak acid or weak base captures the free ions, and a significant change in pH
is prevented. Bicarbonate ions and carbonic acid are present in the blood in a 20:1 ratio if the blood pH is
within the normal range. With 20 times more bicarbonate than carbonic acid, this capture system is most
efficient at buffering changes that would make the blood more acidic. This is useful because most of the
body’s metabolic wastes, such as lactic acid and ketones, are acids. Carbonic acid levels in the blood are
controlled by the expiration of CO2 through the lungs. In red blood cells, carbonic anhydrase forces the
dissociation of the acid, rendering the blood less acidic. Because of this acid dissociation, CO 2 is exhaled (see
equations above). The level of bicarbonate in the blood is controlled through the renal system, where
bicarbonate ions in the renal filtrate are conserved and passed back into the blood. However, the bicarbonate
buffer is the primary buffering system of the IF surrounding the cells in tissues throughout the body.

Cellular

A basic comprehension of respiration at the cellular level is important in understanding acid-base equilibrium
in the human body. Aerobic cellular respiration is necessary for human life; humans are obligate aerobes.
While individual cells can perform anaerobic respiration, in order to sustain life, oxygen must be present. One
of the byproducts of aerobic cellular respiration is carbon dioxide. The simplified chemical equation denoting
aerobic cellular respiration is:
 C6H12O6 (glucose) + 6O2 --> 6CO2 + 6H20 + energy (38 ATP molecules and heat)
The first stage of cellular respiration is glycolysis, which takes a six-carbon glucose and breaks it down into two
pyruvate molecules which contain three carbons each. Glycolysis uses two ATP and creates four ATP, meaning
it generates two net ATP. This process does not need oxygen to occur. Since patients are often deficient, it is
worth noting that magnesium is a cofactor for two reactions in glycolysis.
Eventually, the pyruvate molecules are oxidized and enter into the TCA Cycle. The TCA cycle generates NADH
from NAD+, FADH2 from FAD, and two ATP molecules. It is an aerobic process and does demand oxygen.
Pyruvate is brought into the mitochondria and forms acetyl-CoA with the loss of carbon dioxide. This excess
carbon dioxide is then exhaled during the process of expiration.
The last step in aerobic cellular respiration is the electron transport chain (ETC). The ETC produces the majority
of the ATP created in cellular respiration with 34 ATP molecules being created. For the ETC reaction to occur,
oxygen is needed. If there is not enough oxygen present, the products of glycolysis proceed to a reaction
called fermentation to produce ATP. The byproduct of fermentation is lactic acid. During glycolysis and the
TCA cycle, NAD+ is reduced to NADH and FAD is reduced to FADH2. Reduction is characterized by a gain of
electrons. This is what drives the ETC. For every single molecule of glucose, ten NAD+ molecules are converted
to NADH molecules, which produce three ATP molecules a piece in the ETC.
This process of aerobic cellular respiration characterizes why humans need oxygen. Anaerobic respiration
allows the body to produce some ATP when there is not enough oxygen present; however, the process only
generates two ATP as opposed to the 38 ATP produced with aerobic respiration. The two ATP molecules per
reaction are not enough to sustain life.
As noted above, carbon dioxide is produced as a byproduct of the TCA cycle. This carbon dioxide is
instrumental to acid-base balance in the body which is demonstrated with the following reaction:
 CO2 + H20 <-> H2C03 <-> HCO3- + H+
The carbon dioxide formed during cellular respiration combines with water to create carbonic acid. Carbonic
acid then dissociates into bicarbonate and a hydrogen ion. This reaction is one of the many buffer systems in
the human body; it resists dramatic changes in pH to allow a person to remain within the narrow physiological
pH range. This buffer system is in equilibrium, that is, all components of the reaction exist throughout the
body and are shifted to the side of the equation appropriate for the environment. This reaction can and does
occur without an enzyme; however, carbonic anhydrase is an enzyme that assists with this process. It catalyzes
the first reaction above to form carbonic acid which can then freely dissociate into bicarbonate and a
hydrogen ion. Carbonic anhydrase is located in red blood cells, renal tubules, gastric mucosa, and pancreatic
cells.
Other buffer systems in the human body include the phosphate buffer system, proteins, and hemoglobin. All
of these contain bases which accept hydrogen ions which keep the pH from plummeting. The phosphate
buffer system, while present globally, is important for the regulation of urine pH. Proteins assist with
intracellular pH regulation. Red blood cells use the reaction above to help hemoglobin buffer; carbon dioxide
can diffuse across red blood cells and combine with water. This alone would cause an increase in hydrogen
ions; however, hemoglobin can bind hydrogen ions. Hemoglobin also can bind carbon dioxide without this
reaction. This depends on the amount of oxygen that is bound to hemoglobin. This is called the Haldane effect
and the Bohr effect. When hemoglobin is saturated with oxygen, it has a lower affinity for CO2 and hydrogen
ions and is able to release it.

Organ Systems Involved

Every organ system of the human body relies on pH balance; however, the renal system and the pulmonary
system are the two main modulators. The pulmonary system adjusts pH using carbon dioxide; upon expiration,
carbon dioxide is projected into the environment. Due to carbon dioxide forming carbonic acid in the body
when combining with water, the amount of carbon dioxide expired can cause pH to increase or decrease.
When the respiratory system is utilized to compensate for metabolic pH disturbances, the effect occurs in
minutes to hours.
The renal system affects pH by reabsorbing bicarbonate and excreting fixed acids. Whether due to pathology
or necessary compensation, the kidney excretes or reabsorbs these substances which affect pH. The nephron
is the functional unit of the kidney. Blood vessels called glomeruli transport substances found in the blood to
the renal tubules so that some can be filtered out while others are reabsorbed into the blood and recycled.
This is true for hydrogen ions and bicarbonate. If bicarbonate is reabsorbed and/or acid is secreted into the
urine, the pH becomes more alkaline (increases). When bicarbonate is not reabsorbed or acid is not excreted
into the urine, pH becomes more acidic (decreases). The metabolic compensation from the renal system takes
longer to occur: days rather than minutes or hours.
 RESPIRATORY REGULATION OF ACID-BASE BALANCE

The respiratory system contributes to the balance of acids and bases in the body by regulating the blood levels
of carbonic acid . CO2 in the blood readily reacts with water to form carbonic acid, and the levels of CO 2 and
carbonic acid in the blood are in equilibrium. When the CO2 level in the blood rises (as it does when you hold
your breath), the excess CO2 reacts with water to form additional carbonic acid, lowering blood pH. Increasing
the rate and/or depth of respiration (which you might feel the “urge” to do after holding your breath) allows
you to exhale more CO2. The loss of CO2 from the body reduces blood levels of carbonic acid and thereby
adjusts the pH upward, toward normal levels. As you might have surmised, this process also works in the
opposite direction. Excessive deep and rapid breathing (as in hyperventilation) rids the blood of CO 2 and
reduces the level of carbonic acid, making the blood too alkaline. This brief alkalosis can be remedied by down
toward normal.

The chemical reactions that regulate the levels of CO2 and carbonic acid occur in the lungs when blood travels
through the lung’s pulmonary capillaries. Minor adjustments in breathing are usually sufficient to adjust the
pH of the blood by changing how much CO2 is exhaled. In fact, doubling the respiratory rate for less than 1
minute, removing “extra” CO2, would increase the blood pH by 0.2. This situation is common if you are
exercising strenuously over a period of time. To keep up the necessary energy production, you would produce
excess CO2 (and lactic acid if exercising beyond your aerobic threshold). In order to balance the increased acid
production, the respiration rate goes up to remove the CO2. This helps to keep you from developing acidosis.

Respiratory Regulation of Blood pH. The respiratory system can

reduce blood pH by removing CO2 from the blood.
The body regulates the respiratory rate by the use of chemoreceptors, which primarily use CO 2 as a signal.
Peripheral blood sensors are found in the walls of the aorta and carotid arteries. These sensors signal the brain
to provide immediate adjustments to the respiratory rate if CO2 levels rise or fall. Yet other sensors are found
in the brain itself. Changes in the pH of CSF affect the respiratory center in the medulla oblongata, which can
directly modulate breathing rate to bring the pH back into the normal range.

Hypercapnia, or abnormally elevated blood levels of CO2, occurs in any situation that impairs respiratory
functions, including pneumonia and congestive heart failure. Reduced breathing (hypoventilation) due to
drugs such as morphine, barbiturates, or ethanol (or even just holding one’s breath) can also result in
hypercapnia. Hypocapnia, or abnormally low blood levels of CO2, occurs with any cause of hyperventilation
that drives off the CO2, such as salicylate toxicity, elevated room temperatures, fever, or hysteria.

RENAL REGULATION OF ACID-BASE BALANCE

The renal regulation of the body’s acid-base balance addresses the metabolic component of the buffering
system. Whereas the respiratory system (together with breathing centers in the brain) controls the blood
levels of carbonic acid by controlling the exhalation of CO2, the renal system controls the blood levels of
bicarbonate. A decrease of blood bicarbonate can result from the inhibition of carbonic anhydrase by certain
diuretics or from excessive bicarbonate loss due to diarrhea. Blood bicarbonate levels are also typically lower
in people who have Addison’s disease (chronic adrenal insufficiency), in which aldosterone levels are reduced,
and in people who have renal damage, such as chronic nephritis. Finally, low bicarbonate blood levels can
result from elevated levels of ketones (common in unmanaged diabetes mellitus), which bind bicarbonate in
the filtrate and prevent its conservation.

Bicarbonate ions, HCO3–, found in the filtrate, are essential to the bicarbonate buffer system, yet the cells of
the tubule are not permeable to bicarbonate ions. The steps involved in supplying bicarbonate ions to the
system are seen in this figure and are summarized below:

Step 1: Sodium ions are reabsorbed from the filtrate in exchange for H + by an antiport mechanism in the
apical membranes of cells lining the renal tubule.

Step 2: The cells produce bicarbonate ions that can be shunted to peritubular capillaries.

Step 3: When CO2 is available, the reaction is driven to the formation of carbonic acid, which dissociates
to form a bicarbonate ion and a hydrogen ion.

Step 4: The bicarbonate ion passes into the peritubular capillaries and returns to the blood. The hydrogen ion
is secreted into the filtrate, where it can become part of new water molecules and be reabsorbed as such, or
removed in the urine.
 Conservation of Bicarbonate in the Kidney. Tubular cells
are not permeable to bicarbonate; thus, bicarbonate is
conserved rather than reabsorbed. Steps 1 and 2 of
bicarbonate conservation are indicated.

It is also possible that salts in the filtrate, such as sulfates, phosphates, or ammonia, will capture hydrogen ions.
If this occurs, the hydrogen ions will not be available to combine with bicarbonate ions and produce CO 2. In
such cases, bicarbonate ions are not conserved from the filtrate to the blood, which will also contribute to a
pH imbalance and acidosis.

The hydrogen ions also compete with potassium to exchange with sodium in the renal tubules. If more
potassium is present than normal, potassium, rather than the hydrogen ions, will be exchanged, and increased
potassium enters the filtrate. When this occurs, fewer hydrogen ions in the filtrate participate in the
conversion of bicarbonate into CO2 and less bicarbonate is conserved. If there is less potassium, more
hydrogen ions enter the filtrate to be exchanged with sodium and more bicarbonate is conserved.

Chloride ions are important in neutralizing positive ion charges in the body. If chloride is lost, the body uses
bicarbonate ions in place of the lost chloride ions. Thus, lost chloride results in an increased reabsorption of
bicarbonate by the renal system.

Disorders of the…

Acid-Base Balance: KetoacidosisDiabetic acidosis, or ketoacidosis, occurs most frequently in people with
poorly controlled diabetes mellitus. When certain tissues in the body cannot get adequate amounts of glucose,
they depend on the breakdown of fatty acids for energy. When acetyl groups break off the fatty acid chains,
the acetyl groups then non-enzymatically combine to form ketone bodies, acetoacetic acid, beta-
hydroxybutyric acid, and acetone, all of which increase the acidity of the blood. In this condition, the brain
isn’t supplied with enough of its fuel—glucose—to produce all of the ATP it requires to function.

Ketoacidosis can be severe and, if not detected and treated properly, can lead to diabetic coma, which can be
fatal. A common early symptom of ketoacidosis is deep, rapid breathing as the body attempts to drive off
CO2 and compensate for the acidosis. Another common symptom is fruity-smelling breath, due to the
exhalation of acetone. Other symptoms include dry skin and mouth, a flushed face, nausea, vomiting, and
stomach pain. Treatment for diabetic coma is ingestion or injection of sugar; its prevention is the proper daily
administration of insulin.

A person who is diabetic and uses insulin can initiate ketoacidosis if a dose of insulin is missed. Among people
with type 2 diabetes, those of Hispanic and African-American descent are more likely to go into ketoacidosis
than those of other ethnic backgrounds, although the reason for this is unknown.
 References

VANDER’S HUMAN PHYSIOLOGY: THE MECHANISMS OF BODY FUNCTION,

FOURTEENTH EDITION.

BRUCE A. STANTON, PhD. Renal Physiology fifth edition.

Brinkman JE, Sharma S. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Mar
4, 2019. Physiology, Metabolic Alkalosis.

Rajkumar P, Pluznick JL. Acid-base regulation in the renal proximal tubules: using novel pH
sensors to maintain homeostasis. Am. J. Physiol. Renal Physiol. 2018 Nov 01;315(5):F1187-
F1190.

Open Stax . Anatomy and Physiology ; Fluid, Electrolyte and Acid-Base Balance; 184 26.4
ASID-BASE BALANCE. Publisher: OpenStax: March 6, 2013.