Dr. Suzana Voiculescu Discipline of Physiology and Fundamental Neurosciences

Carol Davila Univ. of Medicine and Pharmacy

Definition All the processes inside the body which keep

the H+ concentration within normal values.

Depends on

water and ion balance

blood gas homeostasis

Blood acidity may be expressed by:

H+ concentration - 35- 45 mmol/l

Hydrogen activity, as pH- 7,35- 7,45

pH pH= - log [H+]

The more Hydrogen ions, the more acidic the solution and the LOWER the pH

The lower Hydrogen concentration, the more alkaline the solution and the HIGHER the pH

Acid/ base Acids are H+ donors.

Bases are H+ acceptors.

Acids and bases can be:

Strong – dissociate completely in solution

HCl, NaOH

Weak – dissociate only partially in solution

Lactic acid, carbonic acid

Acid and alkali load ACID- Diet (acid containing foods)+ production from

metabolism

ALKALI- Alkali containing foods and production from metabolism in the end they must be buffered leads to extra acid load that must be buffered and then excreted

Acid load- fixed versus volatile FIXED= NON VOLATILE

Daily production of acids= 50-100 mEq of H+- under physiological conditions- from cell metabolism

Dietary acids

VOLATILE- CO2- it can be excreted through ventilation

Fixed acids- catabolism Protein

Amioacids Uric acid Sufphuric acid Phosphoric acid

Carbohydrates Pyruvic acid Succinic acid Lactic acid (anaerobiosis)

Fats Fatty acids Ketoacids (diabetes/starvation)- acetoacetic acid,

betahydroxybutyric acid

Volatile acid THE ONLY VOLATILE ACID= CARBONIC

ACID(H2CO3)

THE ACID IS IN EQUILLIBRUM WITH ITS DISSOLVED GASEOUS COMPONENT (PaCO2)

Carbonic acid Metabolism of fats and carbohydrates result in the

production of 15-20 mol of CO2 per day

Before elimination by the lungs, most of the CO2 is taken up by red blood cells, reacting with H2O to form carbonic acid as shown below:

CO2 + H2O ↔ H2CO3(CA) ↔ H+ + HCO3-

CA= CARBONIC ANHIDRASE- INTRACELLULAR

Acid excretion Lungs – excrete volatile acid (CO2)

Major source of rapid acid excretion

13000 mEq/ day of carbonic acid

Kidneys- excrete fixed acids

40-80 mEq/day

Fixed acids may increase to 300/ 24 h if necessary

Base excretion Only kidney regulated

Primary base in the organism HCO3-

The kidney can retain or excrete bicarbonate as needed

1. Enzyme activity

2. Action potential of myelinated nerve

3. Membrane permeability

4. Control of respiration

5. Heart activity

6. Oxygen Hb dissociation curve

7. Nerve excitability

Biological importance of pH

Enzymes Enzymes are affected by

changes in pH. The most favorable pH value - the point where the enzyme is most active - is known as the optimum pH

pH and synaptic transmission Alkalosis increases transmission- alkalosis> 7.8

seizures

Acidosis decreases transmission- acidosis< 7 coma

(uremic/ diabetic- ketone bodies )

pH and heart activity High H+ in blood H+ diffuses in the cells

electroneutrality law K+ diffuses out of the cells

Hyperpolarisation of heart muscle

Low excitability

Hyperkalemia

Bohr effect

pH and ventilation

chemoR

Peripheral (carotid/ aortic body)

Central(medulla oblongata)

Maintainance of AB balance 2 mechanisms:

1. Buffer systems- composed of a weak acid and it’s salt with a powerful base, which have two origins: plasmatic and cellular (mosly erythrocyte)- they fight against sudden shifts in AB balance (act in seconds)

2. Biological mechanisms- in which lungs (regulates AB in minutes) and kidneys play a major role (regulate AB balance in days)

Buffer systems Take up H+ or release H+ as conditions change

Buffer pairs – weak acid and a base

Exchange a strong acid or base for a weak one

Results in a much smaller pH change

Whenever a buffering reaction occurs, the concentration of one member of the pair increases while the other decreases.

Cannot remove H+ ions from the body

Temporarily acts as a shock absorbant to reduce the free H+ ion.

EC- BICARBONATE- SECONDS

IC- HEMOGLOBIN, PHOSPHATE, PROTEINS

BONE

Buffers

The Major Body Buffer Systems

Site Buffer System Comment

ISF Bicarbonate For metabolic acids

Phosphate Not important because concentration too low

Protein Not important because concentration too low

Blood Bicarbonate Important for metabolic acids

Haemoglobin Important for carbon dioxide

Plasma protein Minor buffer

Phosphate Concentration too low

ICF Proteins Important buffer

Phosphates Important buffer

Urine Phosphate Responsible for most of 'Titratable Acidity'

Ammonia Important - formation of NH4+

Bone Ca carbonate In prolonged metabolic acidosis

Bicarbonate buffer

The most important extracellular buffer Sodium Bicarbonate (NaHCO3) and carbonic acid

(H2CO3)

Maintain a 20:1 ratio : HCO3- : H2CO3

HCl + NaHCO3 ↔ H2CO3 + NaCl NaOH + H2CO3 ↔ NaHCO3 + H2O

Buffering power of the bicarbonate system Efficiency of a buffer system depends on the change in pH

when a base or an acid are added- inversely prop (the smaller the change, the better the buffering effect)

Buffering power depends on:

The relatinve conc of buffer components: the highest when components ratio is 1:1 <-> pH= pK

The amount of buffer comp

Open/ closed system (if the system can equillibrate with the environment)

Bicarbonate buffer system Pk=6,1

H2CO3+ NaHCO3

H2CO3- forms from CO2 + H2O (carbonic anhidrase)

H2CO3 H+ + HCO3-

NaHCO3 Na+ + HCO3-

CO2 + H2O H2CO3 H+ + HCO3-

Na+

When a strong acid is added to the solution Carbonic acid is mostly unchanged, but bicarbonate

ions of the salt bind excess H+, forming more carbonic acid.

H+ + HCO3- H2CO3 H2O+ CO2 (excess CO2-- > eliminated through respiration)

When a strong base is added to solution Sodium bicarbonate remains relatively unaffected, but

carbonic acid dissociates further, donating more H+ to bind the excess hydroxide.

NaOH + H2CO3 NaHCO3 + H2O H2CO3 consumes more CO2 is used to bring H2CO3 back to normal low CO2 inhibits respiration

Also: NaHCO3 Na+ + HCO3- high HCO3- urine excreted

Protein buffer systems Proteins are highly concentrated inside the cells

They buffer extracellular H+ because IC pH is lower than EC pH ions are slowly diffusing inside the cell

This process is slow- it takes several hours

RBC – equilibrium happens fast; Hb is an important buffer:

H+ + Hb= HHb

Hemoglobin buffer system Hb is an “amphoteric substance”

• It can act as a proton donor (an acid)

• It can act as a proton acceptor (a base)

• Plays a considerable role in acid-base balance (second most important buffer after bicarbonate)

Blood buffer systems comparison Protein buffers in blood include haemoglobin (150g/l)

and plasma proteins (70g/l). Buffering is by the imidazole group of the histidine residues which has a pKa of about 6.8. This is suitable for effective buffering at physiological pH.

Haemoglobin is quantitatively about 6 times more important then the plasma proteins as it is present in about twice the concentration and contains about three times the number of histidine residues per molecule. For example if blood pH changed from 7.5 to 6.5, haemoglobin would buffer 27.5 mmol/l of H+ and total plasma protein buffering would account for only 4.2 mmol/l of H+.

Cellular buffers Muscle and bone 60-70% of the total chemical

buffering of the body fluids

Phosphate buffer system

Protein buffer system

Slight diffusion of elements of bicarbonate buffer through the cell mb (except for RBC- fast)

Takes hours (2-4) to become maximally effective

Phosphate buffer system The phosphate buffer system operates in the urine and

intracellular fluid similar to the bicarbonate buffer system (in the EC fluid, it’s concentration is 8% of the bicarbonate one)

Pk=6.8- but low conc in the plasma

sodium dihydrogen phosphate (NaH2PO4) is its weak acid, and monohydrogen phosphate (Na2HPO4) is its weak base.

HCl + Na2HPO4 NaH2PO4 + NaCl

NaOH + NaH2PO4 Na2HPO4 + H2O

Bone Bone represents an important site of buffering acid

load.

An acid load, is associated with the uptake of excess H+ ions by bone which occurs in exchange for surface Na+ and K+ and by the dissolution of bone mineral, resulting in the release of buffer compounds, such as NaHCO3, CaHCO3, and CaHPO4.

40% of an acute acid load BONES

Chronic acidosis bone demineralisation

Muscle Half the cellular mass

Most intracellular buffering

Acid base balance and lungs CO2 formed by tissue metabolism is eliminated through

respiration

CO2 regulates ventilation rate and depth indirectly by H+ increase

CO2 passes the blood brain barrier

It hidrates (CA) and forms H2CO3 H+ + HCO3-

H+ influences central chemoR

Acid base balance and lungs

High pCO2= hyperventilation

Low pCO2= hypoventilation

Ex: ventilation increases 4-5 x when pH is 7!

Kidneys and AB balance Kidneys excrete nonvolatile acid load H+ are buffered in the blood, they are not filtered Kidneys SECRETE H+ IN the tubes: 1. H+ combines with filtered HCO3 bicarbonate

reabsorption 2. H+ combines with urinary buffers TITRABLE ACIDS

and AMMONIUM 3. Low amount free in the urine

Bicarbonate reabsorption Bicarbonate freely filtrates

But ... almost none excreted in urine:

Proximal tubule reabsorption 85%- Na+/H+ exchanger

Distal and collecting tubules- 15%- H+ pump and Na+/H+ exchanger (aldosterone)

Secretion of H+ in proximal tubule For each H+ secreted, there is a HCO3-

reabsorption

Mostly in the proximal tube (85%)

Secondary active secretion

Na+ gradient established by Na+-K+ pump in basolateral membrane of tubular cells

Secretion of H+ in the late distal and collecting tubules In intercalated cells

Primary active transport- H+ pump (aldosterone)

For each H+ secreted, a HCO3- is reabsorbed by Cl-/ HCO3- antiporter

H+ secretion and bicarbonate reabsorpion

Reabsorption of filtered HCO3-= new bicarbonate formation! HCO3- cannot pass the apical membrane of tubular cell

They combine with H+ in the lumen H2CO3 H2O + CO2

CO2 diffuses in the cell

CO2+ H2O--- H+ + HCO3-

HCO3- reabsorbed in the blood

H+ free excretion in limited Excretion of 70 mEq /day of non-volatile acids as free

H+ would require more than 2000 l of urine output/24 h

Limited by transporter activity

Minimum urinary pH= 4.5 (0,03 mEq/l)

Any H+ that exceeds this limit urinary buffers- phosphate (titrable acidity) and NH4+

Combination of excess H+ with phosphate and ammonia buffers If high amounts of H+ are secreted (> HCO3- filtered),

H+ is buffered by phosphate and ammonia systems in the tubule

H+ is eliminated by:

H+ + NaHPO4- NaH2PO4

NH3 + H+ NH4+

Formation and excretion of titrable acid (TA) pK HPO42- /H2PO4-= 6,8 and 90% of the buffering

activity of HPO42- occurs above a pH of 6.8

Daily filtered dibasic phosphate accounts for the excretion of approx 50% of the daily fixed H+ excretion

Titrable acid because it is measured by back titration of the urine with NaOH to a pH of 7.4

Limited by the quantity of dibasic phosphate filtered

Titrable acidity Proximal tubule

Collecting tubule

For each H+ buffered by a weak acid and excretion in the urine as titrable acid, a HCO3- is released in the plasma

Formation and excretion of ammonium (NH4+) 30-40 mEq of fixed acid per day

Less limited up to 300 mEq/day

Ammonium- synthesized in proximal tube by glutamine deamination

GLUTAMINE GLUTAMATE + NH4+

NH4+ is transported in the interstitium in the thick ascending limb substituting a K+ in the Na+/K+/2Cl carrier

Then, ammonium dissociates to ammonia in the medullary interstitium (higher pH)

Cortical collecting duct ammonium trapping Ammonia subsequently diffuses into the medullary

collecting duct

It is trapped in the increasingly acidic urine as NH4+

A HCO3- is released in the systemic circ for each ammonium that is excreted in the urine

Bicarbonate as an open system Lungs eliminate CO2 (volatile acid) and determine the

conc of H2CO3 by regulating pCO2 at 40 mmHg

pCO2 dissolved CO2 by hydration is in equillibrum with H2CO3

The kidneys maintain [HCO3-] at 24mEq/l

Thus pH= 7.4 !!