Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Dr. Chris Doumen Collin County Community College BIOL 2402 Acid Base Homeostasis 1 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 2 1 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. 3 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 4 2 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 5 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. 6 3 Lines of defense against changes in pH 7 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 8 4 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. 9 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. 10 5 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) 11 Lines of defense against changes in pH 12 6 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+ . 13 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- 14 7 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 15 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. 16 8 Lines of defense against changes in pH 17 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 18 9 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 19 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. 20 10 Kidneys role in Acid Base 21 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 22 11 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 23 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 24 12 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). 25 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 26 13 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 27 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. 28 14 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+ 29 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. 30 15 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. 31 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. 32 16 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. 33 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) 34 17 Acid/Base Disturbances and Compensations 35 Acid/Base Disturbances and Compensations 36 18 RESPIRATORY ACIDOSIS 37 RESPIRATORY ALKALOSIS 38 19 METABOLIC ACIDOSIS 39 METABOLIC ALKALOSIS 40 20 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 41 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 42 21 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 43 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 ! 44 22 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 46 23 47 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. 48 24 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 49 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 25 Causes of Acid Base Disturbances Metabolic alkalosis ( high HCO3- and high pH ) • Vomiting • Ingestion of alkaline drugs ( such as baking soda) 51 26