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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