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Acid-Base Balance Dr Taha Sadig Ahmed At the end of the acid-base balance course, the students should be able to: 1. understand the need for precise regulation of hydrogen ion concentration 2. relate temporal changes in hydrogen ion concentration with three defense systems, body fluids, lungs and kidney 3. define a buffer system 4. relate the bicarbonate buffer system and [CO2] to pH 5. identify the lungs in control of [CO2] 6. relate the long term changes in hydrogen ion concentration with the kidney 7.differentiate between normal and abnormal pH 8.identify clinical causes of acid-base disturbances 9. identify the characteristics of primary acid-base disturbances About 80 mEq of H+ ions are ingested daily or produced by mtabolic processes ; and without buffering, these would produce large changes in body fluid [H+] shifting blood to the acidic side . Therefore , to prevent pathological changes , body systems should strive to maintain hydrogen ion homeostasis ( keeping [H+] nearly within controlled limits ) =7.35-7.45 And resist this natural tendency to produce acidosis Why is H+ homeostasis important ? Because all enzymes are affected by the [H+], which affects almost all body functions. That is why , the blood [H+] is kept in a tight range around the normal concentration of 0.00004 mEq/liter = 0.00004 mmol/liter. pH (power of hydrogen) As the [H+] is very small, the term pH is used for practical purposes . pH is the negative logarithm of hydrogen ion concentration (– log [H+] ) expressed in eq/liter. pH = log 1 [H+] = – log [H+] Normal pH = – log [0.00000004] = 7.4 pH 7 is neutral, above 7 is alkaline and below is acidic. 7.4 is the pH for arterial blood. Venous blood pH is 7.35, because in venous blood there is more CO2 to make carbonic acid. If the pH falls below 7.4, the person is in acidosis, while if more than 7.4, alkalosis. However, the limits of pH that a person can live more than a few hours are 6.8 – 8.0 (10 – 160 nEq/liter). When disturbances result from a primary change in ECF [HCO3-], they are called metabolic disorders. Decreases in [HCO3-] are called metabolic acidosis, while conversely , increase in [HCO3-] metabolic alkalosis. An increase in PCO2 is called respiratory acidosis and a decrease PCO2 a respiratory alkalosis. (Paco2 is arterial Pco2) Acidosis occurs when the HCO3-:PCO2 ratio falls, if HCO3- falls; then metabolic. • About 80 mEq of H+ ions are made or ingested daily, and without buffering, these would produce large changes in body fluid [H+]. •These 3 systems work on differing time scales •(1) Blood & body fluid buffers can immediately bind to excess acid or base . react in a fraction of a second and tie up acids or bases until a balance can be made. •(2) Lungs control removal of CO2 .act within a few minutes. •These two lines of defense ( blood buffer & lung ) are relatively short-term and keep the [H+] close to normal until the kidneys can remove excess acid or base. (3) Kidneys can secrete acid or alkaline urine although relatively slow ( if compared to blood buffers & lung ) taking hours to days they are the most powerful of the 3 systems. Body fluid ( & Blood ) buffers The definition of a buffer is any substance that can reversibly bind H+ ions. Buffer + H+ H Buffer ( 2 way road) H buffer is now a weak acid ( why called acid? Because it has Hbound to it ) , which can remain as it is,Eor dissociate back. x If is high the reaction moves to the right, so that the c buffers takes up & consumes the excess H+ e + Buffer + H H Buffer s Conversely, if [H+] is low, H+ is releaseds from buffer [H+] H Buffer Buffer + H+ Therefore, buffers decrease changes in [H+]. Bicarbonate Buffer System Quantitatively, this is by far the most important buffering system. It consists of a weak acid (H2CO3) and a salt (NaHCO3). H2CO3 is made by: H2O + CO2 H2CO3 H2CO3 weakly ionizes to HCO3- + H+. The bicarbonate salt in the ECF completely ionizes to form HCO3- & Na+. Putting both together we have: H2O + CO2 H2CO3 H+ + HCO3- H2CO3 weakly ionizes to HCO3- + H+. CA=carbonic anhydrase enzyme is the catalyst for this reaction & without CA this reaction is very slow . H2O + CO2 H2CO3 H+ + HCO3+ Na+ Bicarbonate Buffer System Quantitatively, this is by far the most important buffering system. It consists of a weak acid (H2CO3) and a salt (NaHCO3). H2CO3 is made by: H2O + CO2 H2CO3 H2CO3 weakly ionizes to HCO3- + H+. The bicarbonate salt in the ECF completely ionizes to form HCO3- & Na+. Putting both together we have: H2O + CO2 H2CO3 H+ + HCO3- H2CO3 weakly ionizes to HCO3- + H+. CA=carbonic anhydrase enzyme is the catalyst for this reaction & without CA this reaction is very slow . CA enzyme is found in (1) RBCs, (2) alveoli & (3) renal tubular cells . Due to the weak dissociation of H2CO3, [H+] is low. •However, when HCl ( strong acid) is added, to the bicarbonate solution, then the increased [H+] from HCl are buffered by HCO3-. H+ + HCO3- H2CO3 H2O + CO2 More H2CO3 is formed, and then H2O & CO2 are made. From a strong acid, a weak acid is made which dissociates and is lost as water and CO2 which is blown off. •The opposite takes place if a strong alkali is added, like NaOH. NaOH + H2CO3 NaHCO3 + H2O In this situation, the strong base (NaOH) is replaced by a weak base (NaHCO3). Also the [H2CO3] falls as it is combining with NaOH. This results in more H2O & CO2 being used to replace the H2CO3: H2O + CO2 H2CO3 H+ + HCO3+ + NaOH Na+ •Therefore, CO2 would decrease, but this inhibits respiration, so less is expired. The increase in HCO3kidneys. is removed by the Phosphate Buffer system This is important as an intracellular and renal tubular fluid buffer. The components of this system are H2PO4- and HPO42-. HCl + Na2HPO4 NaH2PO4 + NaCl Therefore, a strong acid, HCl, is replaced by a weak acid, NaH2PO4, so the decrease in pH is minimized. Protein buffer system •These are found in high concentrations inside cells. Intracellular pH does change when extracellular pH changes. • H+ & HCO3- are not very permeable through the membrane, though CO2 is highly permeable. In the RBCs, hemoglobin is also a buffer. H+ + Hb HHb Of the total buffering capacity of body fluids, 60 – 70 % is in the cells, but as the permeability of H+ & HCO3- are poor, it delays the effectiveness of these intra-cellular proteins to buffer acid-base disturbances in the ECF Respiratory effects in acid-base balance If there is an increase in the ECF PCO2, by decreased ventilation or increased metabolism, pH falls, and vice versa. Therefore, by changing the PCO2, the lungs can regulate the [H+] in the ECF. PCO2 in the ECF is about 40 mm Hg (1.2 mol/liter). The [H+] also affects alveolar ventilation, where a low pH can increase the rate 4-5 times, and a high pH can decrease the rate. Therefore, the respiratory system acts as a negative feedback controller of [H+], either being stimulated or depressed: [H+] Alveolar ventilation -ve PCO2 The efficiency of the respiratory control system is not 100 %, so if [H+] increased from pH 7.4 to 7.0, the lungs can return this value to 7.2 – 7.3 in 3-12 minutes. Renal control system The kidneys can secrete either acidic or basic urine, to alter ECF pH. The overall mechanism is that the kidneys continuously filter a large number of HCO3- ions into the tubules. If they are excreted into the urine, this removes base from the blood. Many H+ ions are secreted into the lumen, thus removing acid from the blood. If more H+ ions are secreted than HCO3ions filtered, then ECF will have a net loss of acid, and vice versa. Each day, the body makes about 80 mEq of non-volatile acids from protein metabolism. Non-volatileacids , unlike H2CO3, cannot be excreted by the lungs, only by the kidneys. Also the kidneys must prevent loss of HCO3- in the urine. 4320 mEq of HCO3- is filtered daily (24mEq/liter x 180 liters/day), and almost all is reabsorbed. The filtered HCO3- ion has to combine with a secreted H+ ion to make H2CO3 before it can be reabsorbed. Therefore 4320 mEq of secreted H+ ions are needed only for bicarbonate reabsorption. •Then non-volatile acids add 80 mEq, for a total of 4400 mEq of H+ ions secreted into the tubular fluid daily. •If there is an alkalosis in the body, the kidneys will not reabsorb all the bicarbonate, and the loss of one HCO3- ion is similar to adding one H+ ion to the ECF. Therefore, the kidneys regulate ECF [H+] in 3 ways (all are done through the same mechanism): 1. secretion of H+ ions 2. reabsorption of filtered bicarbonate ions 3. production of new bicarbonate ions H+ ion secretion & HCO3- ion reabsorption by renal tubules H+ secretion and HCO3- reabsorption occur along the whole tubule, except the descending and ascending thin limbs of the loop of Henle. 80 – 90 % of HCO3- reabsorption and H+ secretion takes place in the proximal tubule, the rest in the thick ascending limb of the loop of Henle, distal tubule and collecting duct. Hydrogen ion secretion Epithelial cells of the proximal tubule, thick ascending limb of the loop of Henle and distal tubule secrete H+ by Na+/H+ countertransport. This is secondary active transport, where the energy is derived from Na+ going down its electro-chemical gradient, helped by the Na+/K+ ATPase pump on the basolateral membrane. More than 90 % of HCO3- is reabsorbed this way, requiring 3900 mEq of H+ to be secreted daily. H+ inside the cell is made from H2O and CO2, making H2CO3 using carbonic anhydrase The HCO3- ion made in the cell goes down its concentration gradient onto the renal interstitial fluid and into the capillary blood. Therefore, the net effect is that for every H+ ion secreted - The HCO3- ion made in the cell goes down its concentration gradient onto the renal interstitial fluid and into the capillary blood. Therefore, the net effect is that for every H+ ion secreted into the tubular lumen, one HCO3- ion enters the blood. Bicarbonate ion reabsorption HCO3- ions have low membrane permeability on the luminal side of renal tubular cells, and cannot be directly reabsorbed. Therefore, they combine with H+ to form H2CO3, which dissociates to CO2 and H2O . The CO2 easily moves across the tubular membrane and in the cell it combines with H2O, with the help of carbonic anhydrase, to make H2CO3. This again dissociates in the cell to H+ & HCO3-. The HCO3- ion diffuses through the basolateral membrane to the capillary blood. Therefore, the reabsorption of HCO3- ions occurs, though these ions are not the same ones that were filtered into the tubules. As mentioned, the rate of H+ ions secreted into the tubular fluid is 4400 mEq/day, and the rate of HCO3- ion filtration is 4320 mEq/day. The amounts of these two ions entering the tubules are almost equal, therefore, it is said that these ions titrate each other. The titration is not exact, as the non-volatile acids have to be removed. In metabolic alkalosis, there are more HCO3- than H+ ions in the urine, so the HCO3- cannot be reabsorbed and are excreted. In acidosis, the opposite is true, where HCO3- ions are reabsorbed, and excess H+ ions are lost in the urine. Here they are buffered by phosphate and ammonia and are excreted as salts. Active secretion of H+ ions in late distal tubules & collecting ducts From the late distal tubules onwards, the tubular epithelia secrete H+ ions by H+ ATPase, which lies on the luminal membrane. This is different from the mechanism in the proximal tubule and the loop of Henle. This primary active transport occurs in specialized cells called intercalated cells. Although the late distal tubule and collecting duct only make up 5 % of the total H+ ions secreted, the [H+] can be concentrated here up to 900 fold. In comparison, the proximal tubule can only concentrate the [H+] 3 or 4 fold. The minimum pH secreted from the kidneys can be 4.5. Excess H+ ions combine with phosphate & ammonia, making new bicarbonate When H+ ions are secreted in excess of HCO3- ions filtered, only some H+ ions can be in the ionic form, as pH 4.5 (0.03 mEq/liter) is the lower limit of urine. Therefore, for each liter of urine, only 0.03 mEq of H+ ions can be secreted. But, a minimum of 80 mEq of non volatile acids have to be secreted daily. So, 2, 666.6 l of urine would have to be excreted daily if H+ ions were free. This is done by combining the H+ ions with phosphate and ammonia buffers. The phosphate buffer system is made of HPO42- and H2PO4-. They have poor reabsorption, and are concentrated in the tubular fluid. H+ ions enter the tubule by H+/Na+ counter transporter and combine with HCO3- ions. But if all HCO3- ions are reabsorbed, then H+ ions bind to HPO42, to finally make a sodium salt, carrying excess hydrogen (NaH2PO4). One major difference here is that the HCO3- ion made in the tubular cell and which enters the capillary blood causes a net gain in HCO3- ions by the blood. When H+ ions are buffered by HCO3- ions then that HCO3- ion represents only a replacement of the ion reabsorbed. So whenever a H+ ion is buffered by a buffer other than bicarbonate, a new HCO3- is added to the blood. Only a small amount of phosphate is available for buffering … Ammonia (NH3) buffer system Quantitatively, NH3 and ammonium ion (NH4+) is an important buffer. The ion is made from glutamine and for each molecule metabolized, 2 new HCO3- ions are made which are reabsorbed by the blood. A decrease in ECF pH stimulates glutamine metabolism, and more NH4+ and HCO3- ions and vice versa. Regulation of tubular H+ ion secretion In alkalosis, the kidneys must reduce H+ ion secretion, so less HCO3- ions will be reabsorbed, and vice versa for acidosis, except here more H+ ions which get buffered with ammonia will make new HCO3- ions . In acidosis, 2 stimuli are needed for increasing tubular H+ ion secretion: 1. increased PCO2 in the ECF, causing increased PCO2 in the tubular cells, which increase [H+] and therefore H+ ion secretion 2. decreased pH (or increased [H+]) in the ECF, causing the same as above In alkalosis, the opposite occurs. Whether acidosis is due to metabolic or respiratory reasons, the kidneys reabsorb all the HCO3- ions, and make new HCO3- ions by titration of NH4+. In metabolic acidosis, there is primarily a decrease in filtration of HCO3- ions, while in respiratory acidosis, there is excess H+ ion secretion due to increased PCO2 in the ECF. Compensatory mechanisms In respiratory acidosis, there is a compensatory response to increase plasma HCO3- ions by making new HCO3- in the kidney. In metabolic acidosis, the response is an increase in ventilation, and renal compensation to make new HCO3in the kidney. In respiratory alkalosis, the response to the primary reduction in PCO2 is to increase renal excretion of HCO3ions . In metabolic alkalosis, the response is a decrease in ventilation, which increases PCO2 and also an increased renal excretion of HCO3- ions. Respiratory Adjustments Metabolic Acidosis Metabolic Alkalosis Respiratory Rate Tidal Volume Ventilation Rate of CO2 removal Rate of H2CO3 formation Rate of H+ generation from CO2 Renal Adjustments Respiratory Respiratory Acidosis Alkalosis HCO3reabsorption H+ secretion Ammonia synthesis Factors causing respiratory acidosis: (1) respiratory center damage (2) obstructive airways diseases (asthma, COPD), pneumonia, fibrosis Factors causing respiratory alkalosis: (1) Hyperventilation ( of any cause ) (2) acute stay at high altitude Factors causing Metabolic Acidosis Diabetic keto-acidosis ( fats converted to acetoacetic and keto acids) Renal failure (reduced GFR reduces ammonium & phosphate excretion) Severe diarrhea (loss of NaHCO3) ingesting/infusing acids lactic acidosis Factors causing Metabolic Alkalosis Hyperaldosteronism (Na+ is reabsorbed in exchange with H+ ions) vomiting overdose of antacids used in gastric/peptic ulcers Thank you!!