ACID-BASE BALANCE & DISORDERS

Water is the solvent of life.

Functions of Water:

Provides aqueous medium to organisms.

Water directly participates as a reactant in

several metabolic reactions.

Vehicle for transport of solutes.

Associated with regulation of body

temperature.

Distribution of Water:

Adult human body contains about 60% (42

litres) water.

Distributed in intracellular (28L) & extra

cellular (14L) compartments.

Water turnover and Balance:

Water intake:

Water is supplied to the body by

Exogenous Water.

Endogenous Water.

Ingested water & water content of solid

foods constitute the exogenous source of

water.

Ingestion of water is mainly controlled by

thirst centre located in the hypothalamus.

The metabolic water produced within the

body is the endogenous water.

This water (300-350 ml/day) is derived from the

oxidation of foodstuffs.

The elimination of water from the body

occurs through

Urine

Skin,

Lungs

Feces.

Electrolytes are the compounds which readily

dissociate in solution & exist as ions i.e.

positively & negatively charged particles.

Electrolytes are well distributed in the body

fluids in order to maintain the osmotic

equilibrium and water balance.

Cations:

Na+ =142

K+ =5

Ca2+ =5

Mg2+ =3

Total =155

Anions:

Cl- =103

HCO3- =27

HPO42- =2

SO42- =1

Proteins =16

Organic acids =6

Total =155

Cations

K+ =150

Na+ =10

Mg2+ =40

Ca2+ =2

Total =202

Anions

HPO42- =140

HCO3- =10

Cl- =2

SO42- =5

Proteins =40

Organic acids =5

Total =202

Na+ is the principal extracellular cation.

K+ is the intracellular cation.

Osmolarity:

The number of moles per liter of solution.

Osmolality:

The number of moles per kg of solvent.

Electrolyte & water balance are regulated

together.

Kidneys plays an important role.

Role of Hormones:

Aldosterone:

It is a mineralocorticoid produced by

adrenal cortex.

Aldosterone increases Na+ reabsorption by

renal tubules at the expense of K+ and H+

ions.

The net effect is the retention of Na+ to the

body.

An increase in the plasma osmolality

stimulates hypothalamus to release ADH.

ADH increases water reabsorption by renal

tubules.

The secretion of aldosterone is controlled by

renin-angiotensin system

Decrease in blood pressure is sensed by

juxtaglomerular apparatus of the nephron

which secrete renin.

Renin acts on angiotensinogen to produce

angiotensin I.

Angiotensin I is converted to Angiotensin II

which stimulates the release of aldosterone.

Aldosterone & ADH coordinate with each

other to maintain the normal fluid and

electrolyte balance.

Characterized by water depletion in the body.

It may be due to insufficient intake or

excessive water loss or both.

Causes of dehydration:

Occur as a result of diarrhea, vomiting,

excessive sweating, fluid loss in burns,

adrenocortical dysfunction, kidney diseases &

deficiency of ADH.

Acids:

Acid is a substance whose dissociation in

water releases hydrogen ions (H+)

Addition of an acid to a solution, increases

concentration of free H+ in the solution.

Produces more acidic solution & decrease in

pH

HCL H+ + Cl-

Bases:

A base releases hydroxyl ions (OH-) in aqueous

solution & decreases its H+ concentration by accepting

or by binding with free H+.

This results in increase in pH of the solution.

NaOH Na+ + OH-

The OH-, accepts H+ & results in the formation of water.

Some substances, such as amino acids &

proteins, act acids as well as bases.

These substances are referred to as

Amphoteric substances.

The normal pH of the blood is maintained in

the narrow range of 7.35 - 7.45 (slightly

alkaline).

The body has developed three lines of

defense to regulate the body’s acid-base

balance.

Blood buffers

Respiratory mechanism

Renal mechanism

Blood buffers:

A buffer may be defined as a solution of a

weak acid & its salt with a strong base.

The buffer resists the change in the pH by the

addition of acid or alkali & the buffering

capacity is dependent on the absolute

concentration of salt & acid.

The buffer cannot remove H+ ions from the

body but it temporarily acts as a shock

absorbant to reduce free H+ ions.

Bicarbonate buffer

Phosphate buffer

Protein buffer

Bicarbonate buffer system:

Sodium bicarbonate & carbonic acid (NaHCO3-

H2CO3) is the most predominant buffer system

of ECF (plasma).

Carbonic acid dissociates into hydrogen and

bicarbonate ions.

H2CO3 H+ + HCO3-

By the law of mass action

Ka= -------(1)

Ka=Dissociation constant of H2CO3.

(H+) (HCO3-)

H2CO3

The equation may be rewritten as follows

= Ka -------(2)

pH=log1/H+

By taking the reciprocals & logarithms.

log1/H+ = log1/Ka + log -------(3)

(H+)(H2CO3)

(HCO3-)

HCO3-

(H2CO3)

Log1/Ka = pKa

The equation 3 may now written as

pH = pKa + log --------(4)

The above equation is referred as Henderson

– Hasselbalch equation for any buffer.

pH = pKa + log

(H2CO3)

(HCO3-)

(Acid)

(Base)

The plasma bicarbonate (HCO3-) concentration

is around 24 mmol/l (range 22-26 mmol/l).

Carbonic acid is a solution of CO2 in water.

Its concentration is given by the product of

pco2 (arterial partial pressure of CO2 = 40 mm

Hg) & the solubility constant of CO2 (0.03).

Thus H2CO3 = 40 x 0.03 = 1.2 mmol/l.

The Henderson-Hasselbalch equation for

bicarbonate buffer is

(H2CO3)

(HCO3-)pH = pKa + log

Substituting the values (blood pH = 7.4, pKa

for H2CO3 = 6.1; HCO3- = 24 mmol/l; H2CO3- = 1.2

mmol/l.

7.4 = 6.1 + log 24/1.2

= 6.1 + log 20

= 6.1 + 1.3

= 7.4

The blood pH 7.4, the ratio of bicarbonate to

carbonic acid is 20 : 1

The bicarbonate concentration is much higher

(20 times) than carbonic acid in the blood.

This is referred to as alkali reserve.

Sodium dihydrogen phosphate and

disodium hydrogen phosphate (NaH2PO4-

Na2HPO4) constitute the phosphate buffer

It is mostly an Intracellular buffer.

The plasma proteins & hemoglobin, constitute

the protein buffer.

The buffering capacity of proteins is

dependent on the pK of ionizable groups of

amino acids.

The imidazole group of histidine (pK=6.7) is

the most effective contributor of protein

buffer.

Respiratory system provides a rapid

mechanism for the maintenance of acid-base

balance.

This is achieved by regulating the

concentration of carbonic acid (H2CO3) in the

blood.

The large volumes of CO2 produced by the

cellular metabolic activity endanger the acid-

base equilibrium of the body.

All of this CO2 is eliminated from the body in

the expired air via the lungs

H2CO3 CO2 + H2O Carbonic anhydrase

The rate of respiration is controlled by a

respiratory centre, located in the medulla of

the brain

This centre is highly sensitive to changes in the

pH of blood.

Decrease in blood pH causes hyperventilation

to blow off co2 & reducing the H2CO3

concentration.

H+ ions are eliminated as H2O

Respiratory control of blood pH is rapid but

only a short term regulatory process, since

hyperventilation cannot proceed for long.

Hemoglobin binds to H+ ions & helps to

transport CO2 as HCO3- with a minimum change

in pH.

In the lungs, hemoglobin combines with O2, H+

ions are removed which combine with HCO3- to

form H2CO3 & is dissociates to release CO2 to be

exhaled.

Due to lack of aerobic metabolic pathways,

RBC produce very little CO2.

The plasma CO2 diffuses into RBC along the

concentration gradient, it combines with water

to form H2CO3 by Carbonic anhydrase.

In RBC, H2CO3 dissociates to produce H+ & HCO3-

The H+ ions are buffered by Hemoglobin.

As the concentration of HCO3- increases in the

RBC, it diffuses into plasma along with

concentration gradient, in exchange for Cl-

ions, to maintain electrical neutrality.

This is referred to as chloride shift, helps to

generate HCO3- .

Erythrocyte

CO2 + H2O

CAH2CO3

HHb

HCO3- + H+ Hb

Cl-

Plasma

CO2

HCO3-

Cl-

The kidneys plays an important role in the

regulation of pH

Normal urine has a pH around 6.

The pH of the urine vary from 4.5 to 9.8.

Excretion of H+ ions

Reabsorption of Bicarbonate

Excretion of titratable acid

Excretion of ammonium ions

Kidney is the only route through which the H+

can be eliminated from the body.

H+ excretion occurs in the proximal

convoluted tubules & is coupled with

generation of HCO3-.

Carbonic anhydrase catalyses the production

of carbonic acid (H2CO3) from CO2 & H2O in

renal tubular cells.

H2CO3 then dissociates to H+ & HCO3-

H+ ions are secreted into tubular lumen in

exchange for Na+

Na+ in association with HCO3- is reabsorbed into

blood

An effective mechanism to eliminate acids (H+)

from the body with a simultaneous generation of

HCO3-

H+ combines with non-carbonate base & excreted.

Renal Tubular Cell

Na+

HCO3- + H+

CA

H2CO3

CA

CO2 + H2O

Blood

Na+

HCO3-

Na+

H+ + B-

HB

Excreted

Tubular lumen

This mechanism is responsible to conserve blood

HCO3-, with simultaneous excretion of H+ ions.

Bicarbonate freely diffuses from plasma into

tubular lumen.

HCO3- combines with H+, secreted by tubular cells,

to form H2CO3.

H2CO3 is then cleaved to form CO2 and H2O.

As the CO2 concentration builds up in the

lumen, it diffuses into the tubular cells along

the concentration gradient.

In the tubular cell, CO2 again combines with

H2O to form H2CO3 which then dissociates into

H+ & HCO3-

The H+ is secreted into the lumen in exchange

for Na+.

The HCO3- is reabsorbed into plasma in

association with Na+.

Reabsorption of HCO3- is a cyclic process with

the net excretion of H+ or generation of new

HCO3-

This mechanism helps to maintain the steady

state & will not be effective for the elimination

of H+ or generation of new HCO3- .

Renal Tubular Cell

Na+

HCO3- + H+

H2CO3

CA

H2O + CO2

Blood

Na+

HCO3-

Na+

Tubular lumen

H+

HCO3-

Plasma

H2CO3

CO2 + H2O

Titratable acidity is a measure of acid

excreted into urine by the kidney.

Titratable acidity refers to the number of

milliliters of N/10 NaOH required to titrate

1liter of urine to pH 7.4.

Titratable acidity reflects the H+ ions excreted

into urine.

H+ ions are secreted into the tubular lumen in

exchange for Na+ ion.

This Na+ is obtained from the base, disodium

hydrogen phosphate (Na2HPO4).

This combines with H+ to produce the acid,

sodium dihydrogen phosphate (NaH2PO4), in

which form the major quantity of titratable

acid in urine is present.

Tubular fluid moves down the renal tubules,

more and more H+ ions are added, resulting

in the acidification of urine.

Causes a fall in the pH of urine as low as 4.5.

Renal Tubular CellNa+

HCO3- + H+

H2CO3

CA

H2O + CO2

Blood

Na+

HCO3-

Na+

Tubular lumen

H+

Na2HPO4

NaHPO4-

NaH2PO4

Excreted

The H+ ion combines with NH3 to form

ammonium ion (NH4+).

The renal tubular cells deaminate glutamine

to glutamate and NH3 by the action of

enzyme glutaminase.

The liberated NH3 diffuses into the tubular

lumen where it combines with H+ to form

NH4+.

Ammonium ions cannot diffuse back into

tubular cells and excreted into urine.

Renal Tubular CellGlutamine

NH3 Glutamate

Na+

HCO3- + H+

H2CO3

CA

H2O + CO2

Blood

Na+

HCO3-

Na+

Tubular lumen

H+

Excreted

NH3

NH4+

The acid-base disorders are mainly two

types

Acidosis-a decline in blood pH.

Metabolic acidosis-due to a decrease in

bicarbonate

Respiratory acidosis-Due to an increase in

carbonic acid.

Alkalosis-a rise in blood pH.

Metabolic alkalosis-due to an increase in

bicarbonate.

Respiratory alkalosis-due to a decrease in

carbonic acid.

Metabolic acidosis:

Occur due to DM (ketoacidosis).

Lactic acidosis & renal failure.

Respiratory acidosis:

Severe asthama

Cardiac arrest

Metabolic alkalosis:

Vomiting

Hypokalemia

Respiratory alkalosis- due to

Hyperventilation

Severe anemia

The total concentration of cations & anions is

equal in the body fluids.

It is required to maintain electrical neutrality.

The commonly measured electrolytes are Na+,

K+, Cl- & HCO3-.

Na+ & K+ together constitute about 95% of the

plasma cations.

Cl- & HCO3- are the major anions, contributing

to about 80% of plasma anions.

The remaining 20% of plasma anions include

proteins, phosphate, sulfate, urate and

organic acids.

Anion gap is defined as the difference

between the total concentration of measured

cations (Na+ & K+) and that of measured anion

(Cl- & HCO3-).

The anion gap (A-) in fact represents the

unmeasured anions in the plasma which may

be calculated as follows, by substituting the

normal concentration of electrolytes (mEq/l).

Na+ + K+ = Cl- + HCO3- + A-

136 + 4 = 100 + 25- + A-

A- = 15 mEq/l

• Anion gap in healthy individual is 15 mEq/l.

• Acid-Base disorders associated with alteration in

anion gap.

Reduction in bicarbonate leads to fall in blood

pH.

This is due to excessive production of organic

acids which can combine with NaHCO3- and

deplete the alkali reserve

NaHCO3- + Organic acid Na salts of

organic acids + CO2

Commonly seen in DM.

The primary defect is due to a retention of CO2

(Increased H2CO3)

Causes for respiratory acidosis are

depression of respiratory centre, pulmonary

disorders & breathing air with high content of

CO2

This is due to increase in HCO3- concentration

Occur due to excessive vomiting or an

excessive intake of sodium bicarbonate for

therapeutic purposes.

Respiratory mechanism initiates

compensation by hypoventilation to retain

CO2, this is taken over by renal mechanism

which excrete more HCO3- and retain H+

This is due to decrease in H2CO3

concentration.

This is due to prolonged hyperventilation

resulting in increased exhalation of CO2 by

the lungs

Renal mechanism tries to compensate by

increasing the urinary excretion of HCO3-

Plasma potassium concentration (normal 3.5-

5.0 mEq/l) is very important as it affects the

contractility of the heart.

Hyperkalemia (high plasma K+) or

hypokalemia (low plasma K+) can be life-

threatening.

Insulin increases K+ uptake by cells.

The patient of severe uncontrolled diabetes (i.e. with

metabolic acidosis) is usually with hypokalemia.

When such a patient is given insulin, it stimulates K+

entry into cells.

The result is that plasma K+ level is further depleted.

Hypokalemia affects heart functioning and is life

threatening.

Low plasma concentration of K+

(hypokalemia) leads to an increased

excretion of hydrogen ions, and thus may

cause metabolic alkalosis.

Conversely, metabolic alkalosis is associated

with increased renal excretion of K+.

Textbook of Biochemistry – U Satyanarayana