Download Acid/Base Regulation

Dr. Chris Doumen
Collin County Community College
BIOL 2402
Acid Base Homeostasis
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Acid -Base Balance and Regulation
Acid-Base Balance refers to the precise regulation of free
hydrogen ion concentration in the body fluids
Free hydrogen ions determine the acidity of the body fluids and
pH is used as a specific H+ indicator
pH = -log [H+]
H2O
H+ + OH-
where [H+] is the molar concentration
[H+] = 10-7 M
[H2O] = 55 M
pH = - log [10-7 ] = 7
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Acid -Base Balance and Regulation
In physiology, 7.4 is considered neutral because it reflects
the average blood pH ( concentration of H+ = 40 nM; compare
that with [Na+] = 135 mM
• Acidosis or acidemia: A blood pH below 7.35
• Alkalosis or alkalemia : A blood pH above 7.45
Death occurs within seconds when blood pH falls below
6.8 or above 8.0.
Regulation of blood pH, more specifically H+, is thus a
very important homeostatic factor in life.
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Acid -Base Balance and Regulation
Sources of H+ in the body
VOLATILE ACIDS : Carbon dioxide and carbonic acid
• CO2 and H2 CO3
FIXED ACIDS : Inorganic acids (non carbonic acids ) from diet
• phosphoric acid, sulfuric acid, ammonia
• ~ 1 - 1.5 mmoles of H+ /kg/day
ORGANIC ACIDS : resulting from metabolism
• citric acid, lactic acid, pyruvic acid, ketone body acids
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Acid -Base Balance and Regulation
Quantities of H+ produced per day
Diet : 70 000 000 nmoles/day
Metabolism : 5 000 000 000 nmoles/day
Amount of protons free in solution in Blood plasma is around
40 nmol /L ( = pH 7.4) !
Our body is thus constantly challenged by an enormous
overload of protons. It requires different mechanism to keep
the proton levels under control
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Lines of defense against changes in pH
• Chemical Buffers
• Respiratory mechanism
• Renal mechanism
Chemical buffers act immediately ; they bind excess protons
but do not eliminate H+ from the body.
They can only soak up extra H+ depending on the concentration
of the chemical buffers present. When capacity is full, the
additional H+ needs to be removed from the body
The lungs and kidneys aid in the removal of acids from the
body. They act however more slowly, with the lungs being
faster compared to the kidneys.
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Lines of defense against changes in pH
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Lines of defense against changes in pH
1. Chemical Buffers
Chemical Buffers are composed out of compounds that
minimize pH changes when acids or bases are added.
The compounds come in pairs :
• a weak acid : releases H+
• a weak base : binds H+
HY
Weak acid
H+ + YWeak base
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Lines of defense against changes in pH
A. The most important buffer in ICF are the proteins
Proteins contain both acid and basic groups and can thus
bind H+ and release protons quite easily
Hemoglobin in RBC also is important in binding H+ in the
tissues and buffering blood pH.
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Lines of defense against changes in pH
• If pH climbs, the carboxyl group of amino acid acts
as a weak acid
• If the pH drops, the amino group acts as a weak
base
Hemoglobin in RBC also is important in binding H+ in the
tissues and buffering blood pH.
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Lines of defense against changes in pH
B. The most important buffer in ECF is the bicarbonate buffer
CO2 + H2O
H2CO3
H+ + HCO3-
• Has the following limitations:
• It cannot protect the ECF from pH changes due
to increased or depressed CO2 levels
• Only functions when respiratory system and
control centers are working normally
• It is limited by availability of bicarbonate ions
(bicarbonate reserve)
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Lines of defense against changes in pH
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Lines of defense against changes in pH
c. Phosphate buffer is an important urinary buffer
Na2HPO4 + H+
NaH2PO4 + Na+
Humans consume more phosphate than needed. The excess
is filtered into the nephrons and is not re-absorbed by the
kidney.
The phosphate helps to buffer urine pH in the nephron. It
binds the secreted protons and keeps the pH above 5. If it
were not for this buffer, urine pH would be extremely
acidic very fast ( below 4.5) and prevent the nephron from
secreting H+ .
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Lines of defense against changes in pH
2. Respiratory Mechanism of H+ regulation
Regulation occurs by CO2 removal and involves the
bicarbonate reaction
• If not enough CO2 is expelled by the lungs, more CO2
stays behind in the blood
• CO2 drives the bicarbonate reaction to the left and forms
more Bicarbonate and protons and pH drops
CO2 + H2O
H2CO3
H+ + HCO3-
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Lines of defense against changes in pH
• The opposite occurs when too much CO2 is expelled
CO2 + H2O
H2CO3
H+ + HCO3-
The Henderson-Hasselbalch equation for weak acids/bases
dtermines pH levels.
pH = pKa + log {[Base]/[Acid]}
pH = pKa + log {[HCO3-]/[CO2 ]}
pH = pKa + log {[HCO3-]/0.03 PCO2}
Blood pH is 7.4 and pKa for Bicarbonate reaction is 6.1
[HCO3-]/0.03 PCO2 = 10 (pH - pKa) = 10(1.3) = 20
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Lines of defense against changes in pH
So the ratio of [HCO3-] to {0.03 PCO2 } determines blood pH !
The respiratory system uses this to adjust pH by regulating CO2.
Changes can occur within minutes ; changing AVR by 2 ( or 1/2)
will change pH of the blood by 0.2 units
Anything that impairs respiratory system may thus affect acid
base balance of the body.
When a change in acid base balance is due to a problem
with the respiratory system, it is referred to as Respiratory
Acidosis or Respiratory Alkalosis.
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Lines of defense against changes in pH
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Lines of defense against changes in pH
2. Renal Mechanism of H+ regulation
pH = pKa + log {[HCO3-]/0.03 PCO2}
While the lungs take care of the CO2 aspect of the equation,
the kidneys adjust and regulate pH by regulating the
bicarbonate levels in the body.
Kidneys role in acid base is
• Excrete H+ ions
• Reabsorb HCO3 - ions
• Make new HCO3- ions
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Kidneys role in Acid Base
Excretion/secretion of H+
Amount of H+ filtered = Plasma [H+} x GFR
Since under normal circumstances, the amount of
plasma H+ is extremely low, only minute amounts of
H+ are filtered.
The majority of H+ is secreted by the nephron. PCT, DCT
and collecting ducts all participate in secretion of H+.
Note : Urine pH = 6 or lower.
If H+ was only filtered, then urine pH = blood plasma
pH. The fact that it is lower, indicates more acidity
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present; hence, secretion !
Kidneys role in Acid Base
Secretion of H+ is related to HCO-3 and CO2 concentrations
CO2 + H2O
H2CO3
H+ + HCO3-
H+ generated from non-carbonic acids are buffered by HCO3 Loss of a bicarbonate ion to the urine, is equivalent to adding
a H+ to the plasma, since that buffering capacity has been lost.
Thus the primary function of the kidneys is not only H+
secretion but HCO3- reabsorption. The two are closely linked
to each other.
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Kidneys role in Acid Base
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Kidneys role in Acid Base
Filtered load of HCO3- = Plasma [HCO3 -]x GFR
= 24 mmoles/L x 0.125 L/min
= 3 mmoles/min = 4320 mmoles/day
• PCT reabsorbs 85 %
• DCT reabsorbs 10 %
• Collecting ducts Reabsorb 5 %
Excreted 0 mmol/day.
Body makes 1 mmol of noncarbonic acids per day.
• Part of this reacts with HCO3 and lost via CO2
• Part of that acid load is filtered and are excreted
So, even though we absorb most of the HCO3- , some of it is
lost as CO2. This requires us to make new HCO3- or we
cannot buffer the acids formed
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Kidneys role in Acid Base
Nephron Actions in H+ /HCO3- regulation
Proximal convoluted tubule
Principal way of reclaiming HCO3 - is via the
• Na/K pump (basolateral side)
• Na/H antiport (lumen side)
• Bicarbonate transporter ( basolateral side)
• Bicarbonate reaction
• both in lumen and inside PCT cell
• aided by Carbonic Anhydrase enzyme
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PCT
HCO3 -
Na+
H+
H2O
CO2
H+
H2O
Na+
K+
HCO3 -
CO2
HCO3 -
CO2
Net effect : For every Bicarbonate reabsorbed, a proton is
excreted
HCO3- are titrated against H+ in proximal tubule
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Kidneys role in Acid Base
Note that in this process, the H+ ends up in a H2O molecule
and does not add to acidity of urine.
Also note, that Bicarbonate needs to be in a 1:1 ratio with H+
for reabsorption of HCO3 - to proceed.
Under normal conditions, the Kidneys secrete about 4400
mmol H+/day and 4320 mmol HCO3- /day.
Thus in theory, under normal conditions, all bicarbonate gets
to be reabsorbed and none should appear in the urine
The excess of H+ combines with urinary buffers and is
excreted in urine (4400 - 4320 = 80 mmol/day = noncarbonic
acids made per day by the body).
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Kidneys role in Acid Base
Distal convoluted tubule/Collecting Duct
Under normal conditions, very little HCO3 - is left in the
distal parts of the nephron
In these areas, H+ secretion is regulated by a proton
pump.
In addition, urinary buffers aid in soaking up these
protons, allowing more H+ to be secreted.
The net result is that in this area, new bicarbonate ions
are created and redirected into the bloodstream
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In the distal tubules,
protons are actively
secreted via H+ - ATPase.
The net result is that
“new” bicarbonate ions
are synthesized in the
tubule cells, as long
as a “sink” for
hydrogen ions (here
HPO42-) is available.
The pumps can only pump out protons until tubular fluid is
800 times more acidic than plasma. That’s why pH of urine
will never drop lower than 4.5
Peritubular capillary
Kidneys role in Acid Base
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Kidneys role in Acid Base
Note that in this
scheme, a
H+/K+ pump
exchanger is
involved as well,
which also
explains the
hyperkalemia
when there is
acidosis.
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Kidneys role in Acid Base
Ammonia and H+ buffering
Additional H+ secretion occurs via Ammonia generation
This involves Glutamine uptake from filtrate into tubule
cells
• Uptake of Glutamine via symport with Na+ from
filtrate into tubule cells
• Transamination of Glutamine to form 2 NH4+ and
two HCO3- molecules .
• Transport of HCO3- towards the blood
• Transport of NH4+ into the lumen in exchange for Na+
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Kidneys role in Acid Base
Peritubular capillary
Once again, additional
“new” bicarbonate ions are
synthesized from catalysis of
the amino acid glutamine.
If a person is acidotic, the
increased acidity stimulates
renal glutamine metabolism,
hence increases NH4+
production and the new
bicarbonate is used to buffer
the additional hydrogen ions.
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Kidneys role in Acid Base
Summary of Renal actions
Acidosis
• Means we have more protons than the HCO3- can buffer
• Thus nephron filtrate will have more protons than
bicarbonate ions
• All bicarbonate ions will be reabsorbed, no bicarbonate
spills over in urine
• New bicarbonate is made by means of the Phosphate and
Glutamine buffering systems.
• Excess of H+ filtered will combine with urine buffers
and be excreted in urine.
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Kidneys role in Acid Base
Alkalosis
• Means we have more HCO3- compared to protons
• So, not every HCO3- is matched with a proton in the
nephron filtrate.
• Bicarbonate ions will spill over in the urine.
• The loss of Bicarbonate ion has the same effect as
adding a proton to the blood plasma.
The buffers in the nephrons are very important. Without
them , we would only be able to excrete 1% of the normally
excreted protons.
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Acid/Base Disturbances and Compensations
Acid/Base Disturbances are divided into 4 main categories
• Respiratory acidosis
• Respiratory alkalosis
• Metabolic acidosis
• Metabolic alkalosis
Respiratory disturbance will be compensated for by renal
actions, while metabolic deviations will be regulated by
respiratory actions.
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Acid/Base Disturbances and Compensations
To find the reason for the disturbances , we need to remember
who controls what and thus look at the factors responsible for
a particular acid-base status.
pH = pKa + log {[HCO3-]/0.03 PCO2}
pH ~
[HCO3-] (controlled by kidneys)
PCO2 (controlled by lungs)
We thus need to look at the ratio of bicarbonate to CO2
(which should be 20 to 1 in order to have a pH of 7.4)
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Acid/Base Disturbances and Compensations
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Acid/Base Disturbances and Compensations
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RESPIRATORY ACIDOSIS
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RESPIRATORY ALKALOSIS
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METABOLIC ACIDOSIS
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METABOLIC ALKALOSIS
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Acid/Base Disturbances and Compensations
Steps to consider
1.
First look if we have an acidosis or alkalosis problem
2.
A change in pH with a respiratory origin will have
abnormal CO2 values, giving rise to the abnormal pH.
• Normal plasma values for PCO2 = 40 mm Hg
• So, if we have a PCO2 of 50 mmHg, the expectations are
that the person will become acidotic
3.
A change in pH with a metabolic origin will have
abnormal HCO3 - values, giving rise to the abnormal pH.
• Normal plasma values for HCO3- = 24 mEq/L
• So, if we have a HCO3- of 20 mEq/L, the expectations are
that the person will become acidotic
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Acid/Base Disturbances and Compensations
[CO2]
[HCO3-]
pH = pKa + log {[HCO3-]/0.03 PCO2}
pH = pKa + log {20/1} = 6.1 + 1.3 = 7.4
pH = pKa + log {20/2} = 6.1 + 1.0 = 7.1
Acidosis is of a Respiratory origin
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Acid/Base Disturbances and Compensations
[CO2]
[HCO3-]
pH = pKa + log {[HCO3-]/0.03 PCO2}
pH = pKa + log {20/1} = 6.1 + 1.3 = 7.4
pH = pKa + log {10/1} = 6.1 + 1.0 = 7.1
Acidosis is of a Metabolic origin
Normal
Patient
7.4
7.22
pH
Pco2
40 mm Hg
27 mm Hg
[HCO3-]
24 mEq/L
11 mEq/L
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1. Patient is acidotic
2a. Is Acidosis due to too much CO2 retention ?
2b. Is Acidosis due to too much HCO3 elimination ?
Nope
Yep
3. It is thus Metabolic Acidosis ; the body is compensating via
Respiratory system and is eliminating more CO2 !
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pH
Normal
Patient
7.4
7.51
Pco2
40 mm Hg
27 mm Hg
[HCO3-]
24 mEq/L
11 mEq/L
1. Patient is alkalotic
2a. Is it due to retention of too much HCO3 ?
2b. Is this due to too much CO2 elimination ?
Nope
Yep
3. It is thus Respiratory Alkalosis ; the body is compensating
via Renal system and is eliminating more HCO3 ! 45
Acid/Base Disturbances and Compensations
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Causes of Acid Base Disturbances
Respiratory Disturbances
They all involve a change in CO2
Respiratory Acidosis
• Lung diseases that prohibit enough CO2 expiration
• Drugs that depress respiratory centers
• Nerve/muscle disorders that reduce respiratory muscle actions
Result is increase in CO2 levels above normal and drop in pH
Note that the bicarbonate reaction will produce H+ and HCO3- . However,
concentrations of HCO3- is 600,000 times that of H+ . So, H+ will change
rapidly but HCO3- concentration will barely change.
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Causes of Acid Base Disturbances
Respiratory alkalosis
• Relatively rare condition
• Most of the times the result of hyperventilation
• Fever, anxiety, aspirin poisoning
• High altitude
Result is decrease in CO2 levels from normal and increase in pH
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Causes of Acid Base Disturbances
Metabolic Disturbances
Metabolic acidosis ( low HCO3- and pH )
All acidosis conditions that are not caused by CO2 changes
• Severe diarrhea
• Bicarbonate is lost via digestive tract (bile makes lots of HCO3-)
• If loss of Bicarbonate is greater than loss of NH4+ by kidneys,
H+ will accumulate
• Max . Rate of NH4+ excretion by Kidneys ~ 200 mmoles/day
• [HCO3-] in diarrhea fluid ~ 50 mmol / L
• Diabetes mellitus : excess ketoacids in blood
• Strenous exercise : excess lactic acids in blood
• Renal failure : can’t get rid of H+, can’t conserve HCO3-50
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Causes of Acid Base Disturbances
Metabolic alkalosis ( high HCO3- and high pH )
• Vomiting
• Ingestion of alkaline drugs ( such as baking soda)
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