Acid Base Balance physiology

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Objectives :

Acids and bases - definition

Relation between pH and pKa Physiological buffers and buffering capacity

Control of acid-base balance

Acidosis and alkalosis

Describe the role of the kidneys in maintaining a normalacid base balance.

Describe the renal compensation for A-B imbalance

Describe the tubular transport of hydrogen and

bicarbonate ions

Describe the regulation of water, sodium and potassium

by the kidney and the disorders of their balance


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Acids: An acid is a substance which dissociates in water

releasing hydrogen ions (H+) or a proton donor. It has a

pH range below 7.0.( HCL, acetic acid, lactic acid)

HCL---------------- H+ + Cl-

Base: A base is a substance which dissociates releasing

hydroxyl ions (OH-) orproton acceptor. pH range above

7.0 (Sodium hydroxide, ammonium hydroxide)

NaOH----------------- Na+ + OH-

NH3 + H+--------------NH4+


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Strong acids: Dissociate completely, Complete ionization,

Concentration ofH+ is high

Weak acids: Partial dissociation, Incomplete ionization,

Concentration ofH+ is less (50%)

For weak acids,

The dissociation is freely reversible, at equilibrium the ratio between

the dissociated and undissociated particle is constant. The

dissociation constant is Ka


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pH

The term pH was introduced by Sorenson (1909)and was defined as the negative log of hydrogen ionconcentration i.e pH is inversely proportional to

acidity

[H+] can range from 1 M to 1 X 10-14 M

Low pH value correspond to high concentrations of H+High pH values corresponds to low concentrations of H+.


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Henderson-Hasselbalch Equation (HHB)

The relationship between pH, pKa, concentration of

acid and conjugate base (salt) is expressed by the

HHB equation


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Functional groups of weak acids have great physiological

significance.

Many biochemicals possess functional groups that areweak acids or bases.

Carboxyl, amino, phosphate esters are present in all

proteins and nucleic acids, coenzymes, intermediary

metabolites. Dissociation behavior of weakly acidic and weakly basic

functional groups is therefore fundamental for

understanding the influence of intracellular pH on the

structure and biochemical activity of these compounds.The separation and identification of the biochemical

compounds in research and clinical medicine is facilitated

by the knowledge of the dissociation behavior of their

functional groups.


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Buffers Solutions that can resist changes in pH when acid or alkali is added.

Two types: Mixture of a weak acid and its salt with a strong base

Mixture of a weak base and its salt with a strong acid

Example:

CH3COOH/CH3COONa (acetic acid and sodium acetate)- acetate buffer

H2CO3/NaHCO3 (bicarbonate buffer)

Na2HPo4/NaH2PO4 (Phosphate buffer)

Factors determining pH of a buffer:

pKa- Lower the value of pKa, the lower is the pH of the solution

Ratio of salt to acid concentrations- No change ofpH as long as the ratio of saltand acid remains the same.

On addition of acid, protons bind to conjugate base A- converting someof it to HA

On addition of OH-, it is buffered by conversion of HA to A-


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How do the buffers act?

When hydrochloric acid is added to the acetate buffer, the salt reacts with

the acid forming the weak acid acetic acid and its salt. Similarly when abase is added the acid reacts with its forming salt and water. Thus the

changes in the pH can be minimized

CH3COOH + NaOH --- CH3-COONa + H2O

CH3-COONa + HCl --- CH3-COOH + NaCl

The buffer capacity is determined by the absolute concentration of the salt

and salt and acid. But the pH of the buffer is dependent on the salt and

acid (HHB equation). When the ratio between salt and acid is 10:1, the

pH will be unit higherthan the PKa. When the ratio between salt and

acids is 1:10, the pH will be lower than the pKa.Effective range of buffer

A buffer is most effective when the concentration of salt and acid are

equal or when pH = pKa. The effective range is 1 pH unit lower or

higher than pKa.


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Various buffer systems are:

1)-Bicarbonate buffer system- main extracellular buffer

: NaHCO3 / H2CO3

[H+] + [HCO3-] [H2CO3]

Normal H2CO3 is 1.2mmols/L and HCO3- is 24mmols/L and the ratio is 20:1

Bicarbonate represents the alkali reserve and should be high to neutralizethe acid load.

2)Phosphate buffers : HPO4/H2PO4 = 5:1

3)Protein buffers albumin, Haemoglobin


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Control of pH of body fluids

Normal pH- The pH of the plasma is7.4, tightly regulated at pH7.4 (range of7.35 to 7.45), pH If pH< 7.38, it is called acidosis. Acidosis

leads to CNS depression and coma. Deathoccurs below 7.0

If pH> 7.42, condition is known as alkalosis. Itis very dangerous if it is above 7.55.Alkalosis induces neuromuscular hyper-excitability and tetany.

Acid-base balance


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Mechanisms of regulation of pH

Three interrelated mechanisms to control pH caused by normal

production of carbonic acid and non-volatile acids as well as

pathological disturbances of acid-base balance.

1. Physiological buffer systems of the body

2. Respiratory system; Pulmonary excretion of CO2

3. Renal excretion of [H+] and [HCO3-]


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Regulation of pH in the body1. Physiological buffers

Bicarbonate (HCO3-, ECF)

Solubility of CO2obeys Henrys law in that its concentrationin solution is proportional to its partial pressure.

The ionization of carbonic acid is:H2CO3 H+ + HCO3-In blood, the overall equilibrium for H2CO3 and CO2 is:

CO2 + H2O H2CO3 H+ + HCO3- [HCO

3

-] in plasma is 0.03M

At pH7.4, [HCO3-]:[H2CO3] = 20:1

Bicarbonate resists pH change when blood is being acidified


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Phosphate buffer (mainly ICF) Ionization of phosphoric acid is as follows:

H3PO4 H2PO4- + H+ (pKa = 2.0)H2PO4

- HPO42- + H+ (pKa = 6.5) HPO4

2- PO43- + H+ (pKa = 12.7) [HPO4

2-]:[H2PO4-] = 4:1 in plasma

This is a more efficient buffer than bicarbonate atphysiological values.

Inorganic phosphate is the chief buffer in the urine.


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Amino acids and proteins (ICF)

Buffering capacity of protein depends on thepka value of ionizable side chains.

The most effective is histidine imidazolegroup

There are 16 residues in albumin and 38histidines in hemoglobin

The role of the hemoglobin buffer is

considered along with the respiratoryregulation of pH.


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Respiratory regulation

The second line of defense against change in pH, is the respiration.

The respiratory regulation of pH is achieved by changing the pCO2 (carbonic

acid).The CO2 diffuses from the cells into the extra cellular and reaches the lungs

through the blood.

The rate of respiration (rate of elimination of CO2) is controlled by the

chemo receptors in the respiratory centre which are sensitive to changes in

the pH

When there is a fall of pH of plasma (acidosis), the respiratory rate is

stimulated resulting in hyperventilation.


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This would eliminate more CO2, thus lowering the H2CO3.

However this cannot continue very long. The respiratory system

responds to any change in pH immediately, but it cannot proceed tocompletion.

By means of pulmonary compensation, the normal pH can be

maintained near to normal, in spite of addition of 23 mEq of acids and 18

mEq of alkali.

Acid metabolites enter blood, pH HA H+ + A- H+ + HCO3

-H2CO3 CO2 + H2O Equilibrium far to the right. Dissociation of H2CO3 almost complete.

pCO2 Rate of breathing and CO2 is eliminated until pH returns to normal.


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Action of hemoglobin

The hemoglobin serves to transport the CO2 formed in the tissues, with

the minimum change in pH.

it serves to generate bicarbonate or alkali by the activity of the carbonic

anhydrase system

CO2 + H2O __________H2CO3


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Renal regulation

Acid-base status cannot return to normal solely byphysiological response of lung function.

Minimum pH of urine = 4.5 0.03mM H+ ions Acids found in urine have wide range of pKa eg acetoacectic

acid (pKa = 3.5), 3-hydroxybutyric acid (pKa = 4.7).

Only way for excretion of H+ to be increased is by simultaneous

excretion of a base. In normal urine, the only such base is

HPO42-

Amount of H+ removed from solution by transfer of phosphate

ions (pKa = 6.8) from pH 7.4 to 4.5 is 80% of phosphateexcreted.


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Acidosis

Causes of Acidosis:

1. Metabolic acidosis

Formation of acids in the body eg lactic acid from intense

exercise, oxidation of cys to sulphate, hydrolysis of nucleic

acids to inorganic phosphate (non volatile acids).Reduction in plasma [HCO3

-] due to passage of acids from

tissues into plasma or insufficient bicarbonate production.

1. Respiratory acidosis

2. Increase in pCO2 due to retention of CO2 throughrespiratory obstruction or respiratory failure.


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Alkalosis

Bodys defense against alkalosis less

effective than against acidosis.

Buffer system:

H2CO3-HCO3- buffer system has less

capacity above pH7.4

Urine has little capacity to buffer OH- ions

and no known mechanism for secretingOH- ions directly.


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RENAL regulation of pH

An important function of the kidney is to regulate the

pH of the extracellular fluid. Kidney excretes urine (pH

around 6) with a lower pH than that of ECF (7.4). This is

called acidification of urine. The pH may vary between

4.5-9.8.

Kidney regulates pH by : Excretion of H+ ions

Reabsorption of filtered HCO3

Excretion of titratable acid Excretion of ammonium (NH4

+) ions


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Excretion of H+ in the PCT-process occurs in proximal convoluted tubules

Here, the H+ are

secreted into the

tubular lumen in

exchange for

Na+ which will

be reabsorbedalong with HCO3

into the blood.

There is netexcretion of H+and generation

of HCO3-


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Reabsorption of HCO3-

Here, there is nonet excretion ofH+ or generationof newHCO3.This mech

prevents loss ofHCO3 through

urine

Both the

mechanisms

work

simultaneously

E ti f tit t bl id b Ph h t h i


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Excretion of titratable acid by Phosphate mechanism

The term titratable acidity of urine refers to the number of

milliliters of N/10 NaOH required to titrate 1 litre of urine to

pH 7.4. This is a net measure of net acid excretion by the

kidney As the tubular fluid passesdown the renal tubules more

and more H+ ions are

secreted into the luminal

fluid so that pH steadily falls.

Due to Na+-K+ exchange

occurring at the renal tubularcell border, the basic

phosphate

( Na2HPO4) is converted to

acid phosphate(NaH2PO4)

and helps excrete H+ with

minimum change in pH. The

main advantage of thissystem is that very large

quantities of hydrogen ions

are excreted with minimum

change in PH. If this system is

not available, the urinary pH will

be acidic.


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Excretion of H+- Ammonia mechanism

NH3 generated in

renal tubular cellsfrom glutamine by

glutaminase passes

into the lumen and

traps H+ and

excreted as NH4+

with minor changesin pH. In acidosis,

glutaminase

activity increases

and more H+

excreted as NH4+


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Disturbances in acid-base balance

Increased concentration of hydrogen ions is called acidemia and a

decrease is referred to as alkalemia. The clinical state, where acids

are accumulated is the acidosis and a loss of acid or accumulation ofbase is the alkalosis

Acidosis (fall in pH)

a. Respiratory acidosis: Primary excess of carbonic acid

b. Metabolic acidosis: Primary deficiency of bicarbonate

Alkalosis (rise in pH)

a. Respiratory alkalosis: Primary deficiency of carbonic acid

b. Metabolic alkalosis: Primary excess of bicarbonate

Compensation mechanisms


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Compensation mechanisms1. Adaptive response is always in the same direction as the

primary disturbance . Primary decrease in arterialbicarbonate involves a reduction in arterial blood pCO2

2. Adaptive response involves a change in thecounteracting variable; e.g a primary change inbicarbonate involve an alteration in Pco2.

by hyper ventilation, and primary increase in arterialpCO2 involves an increase in arterial bicarbonate by anincrease in bicarbonate re absorption by the kidney

Clinically, acid-base disturbance states may be dividedinto:

(a) Uncompensated

(b) Partially compensated(c) Fully compensated

Primary changes may be either in the bicarbonate level(metabolic) or carbonic acid (respiratory) .

The secondary compensatory change will affect the other

parameter, try to restore the pH


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In Metabolic acidosis :

[H+] pCO2 [H] pCO2

[HCO3] [HCO3]Acidosis develops Respiratory compensation ventilation

occurs quickly

In Metabolic alkalosis :

[H+] pCO2 [H] pCO2

[HCO3] [HCO3]

Alkalosis develops Respiratory compensation ventilation

occurs quickly


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Metabolic acidosis

Primary deficit in the bicarbonate

May be due to accumulation of acid or depletion of bicarbonate

When there is excess of acid production, bicarbonate is used for

buffering

Anion gap is altered

ANION GAP

The sum of cations and anions in ECF is always equal, so as to

maintain the electrical neutrality

sodium and potassium together account for 95% of the cations

whereas chloride and bicarbonate accounts for 86% of the anions


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Only these electrolytes are commonly measured. Hencethere is a difference between measured cations and anions.The UNMEASURED ANIONS constitute the ANION GAPwhich is due to protein anions, sulphate, phosphate andorganic acids.

Anion gap is calculated as the difference between (Na++K+) and (HCO3- + cl-). Normal value is 12+ 5 mmol/litre.

Normal values for the Anion Gap are 8-16 mEq/L plasma Alteration in anion gap is extremely useful in the clinical

assessment of patients with acid-base disorders.

In acidosis, the HCO3 is reduced causing an increase in AG

In hyperchloremic acidosis, there is no change in the aniongap because as a compensation, chloride ions areincreased


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Causes:

1. Renal disease- Inability to excrete the dietary H+ load

Diminished H+ secretion

Renal HCO3- loss

2. Lactic acidosis due to circulatory failure, drugs and toxins,and hereditary causes

3. Ketoacidosis - Diabetes, alcoholism, and starvation4. Ingestions - Salicylates, methanol, ethylene glycol,isoniazide, ammonium chloride, phenformin/metformin, andhyperalimentation fluids

5. GIT HCO3- loss due to Diarrhea, Pancreatic, biliary, or

intestinal fistulas

6. Renal tubular acidosis- Renal tubular cells are unable to

excrete H+ efficiently, and HCO3- is lost in urineMeasuring ANION GAP - to differentiate the cause of MAc

High anion gap acidosis


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-increase in anion gap resulting from renal failure- excretion of H+ as well

as generation of bicarbonate are deficient . Anion gap increases due to

accumulation of other anions, np change in chloride level.

-Accumulation of keto acids in diabetic ketosis

-Lactic acid produces high anion gap acidosis, Normal lactic acid content in

plasma is less than 2mmol/L. It is increased in tissue hypoxia, circulatory

failure.

-Compensation occurs through elimination of CO2, respiratory centreresponds to low pH by increasing the rate and depth of respiration

(hyperventilation)

Normal anion gap

-When there is loss of both anions and cations, the anion gap is normal, but

acidosis may prevail. Loss of intestinal secretions as in diarrhea can lead to

this type of acidosis

-Hyperchloremic acidosis

--may occur in renal tubular acidosis, acetazolamide (carbonic anhydrase

inhibitor) therapy and uterine transplantation into large gut(bladder


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Renal tubular acidosis may be due to failure to excrete acid

or reabsorb bicarbonate

-chloride is elevated since electrical neutrality has to be

maintained

In uteric transplantation, the chloride ions are reabsorbed in

exchange for bicarbonate ions lost leading to

hyperchloremic acidosis

Acetazolamide therapy results in metabolic acidosisbecause HCO3- generation and H+ secretion are affected.

Renal compensation occurs within 3-4 days with increased

excretion of NH+ ions

Associated abnormalities of potassium level are seen incases of metabolic acidosis.

Hyperkalemia is commonly seen due to redistribution of K+

and H+.

Hypokalemia may result while correcting acidosis.


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Clinical effects Compensatory response is HYPERVENTILATION

since increased H+ acts as stimulus- Kussmaulbreathing

Increased H+ leads to neuromuscular irritability-

arrhythmias leading to cardiac arrest made worse by

hyperkalemia.(HYPERKALEMIA is seen due to a redistribution of

K+ and H+. The intracellular K+ comes out in

exchange for H+ moving into the cells)

Depression of consciousness can lead to coma anddeath


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METABOLIC ALKALOSISPrimary excess of bicarbonate is the characteristic feature

Causes :

1. Loss of acid or from the gain in base Loss of acid may result in severe vomitting or gastric aspiration

leading to loss of chloride and acid, hence hypochloremic alkalosis

2.-Ingestion of large amounts of alkali

Severe hypokalemiaas in hyperaldosteronism( Na is retained andK is lost) and diuretic therapy

(Here, H+ are retained inside cells to replace the missing K+. More H+rather than K+ are exchanged for reabsorbed Na+. So despitealkalosis, patient passes acid urine paradoxical acid urine (Ph ofthe urine remains acidic- paradoxic acidosis

There are two types

1. Chloride responsive: Urinary chloride is less than 10mmol/L

(conditions like prolonged vomiting, nasogastric aspiration,administration of diuretics

2. Chloride resistant: urinary chloride is greater than 10mmol/l

(hypertension, hyperaldosteronism, cushings syndrome)


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Respiratory alkalosis

A primary defect of carbonic acid, hyperventilation may result in

washing out of CO2

-hyperventilation can result from hysteria, raised intracranial pressure

and brain stem injury

Pco2 is low, Ph is high, bicarbonate level remains normal, will fall during

compensation

Early stage of salicylate poisonoing causes respiratory alkalosis due tostimulation of respiratory centre

But later ends up in metabolic acidosis


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Causes of acidosis

1. Diabetic ketoacidosis: (metabolic acidosis) and lactic

acidosis

2. Respiratory acidosis in pnemonia

3. Reduced glomerular filterate

4. Addisons disease (decreased sodium and bicarbonate

reabsorption)

5. Inherited renal tubular acidosis, where acid is nor

excreted

6. Fanconis syndrome-

7. Diarrhea


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Causes for alkalosis

1. Severe vomiting, CL is eliminated and compensatory increase in

bicarbonate

2. Respiratory alkalosis-hyperventilation CO2 is removed and blood

carbonic acid is reduced

3. Cushings syndrome sodium bicarbonate is reabsorbed from the

tubules

4. Treatment of peptic ulcer is to give milk-alkali syndrome

Acid Base Balance physiology

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