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 CO 2 per day Before elimination by the lungs, most of the CO 2 is taken up by red blood cells, reacting with H 2 O to form carbonic acid as shown below: CO 2 + H 2 O H 2 CO 3 (CA) H+ + HCO 3 - 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
Biological importance of ph 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
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.
Buffers 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
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 NH 4 + Bone Ca carbonate In prolonged metabolic acidosis
Bicarbonate buffer The most important extracellular buffer Sodium Bicarbonate (NaHCO 3 ) and carbonic acid (H 2 CO 3 ) Maintain a 20:1 ratio : HCO 3 - : H 2 CO 3 HCl + NaHCO 3 H 2 CO 3 + NaCl NaOH + H 2 CO 3 NaHCO 3 + H 2 O
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 (NaH 2 PO 4 ) is its weak acid, and monohydrogen phosphate (Na 2 HPO 4 ) 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 buffersphosphate (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 HPO4 2- /H2PO4-= 6,8 and 90% of the buffering activity of HPO4 2- 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!!