Physiology II Acid-Base Balance PDF

Physiology II Acid-Base Balance Part 1 Sarah Hooper, DVM, MS, PhD Associate Professor of Veterinary Physiology E-mail: [email protected]  Explain why maintenance of acid-balance is critical to cell function. Explain...

Physiology II Acid-Base Balance Part 1 Sarah Hooper, DVM, MS, PhD Associate Professor of Veterinary Physiology E-mail: [email protected]  Explain why maintenance of acid-balance is critical to cell function. Explain the relationship between H+ concentration and pH. Explain the Henderson-Hasselbalch equation and what can be measured using it. Learning Define acid and provide examples of strong and weak Objectives: acids. Define base and provide examples of strong and weak bases. Define buffer and pK of a buffer system.  Metabolic acid-base alterations can lead to Why should we Altered cardiovascular function care? Altered neurologic function Altered respiratory function Altered response to various drug therapies  A constant pH in the body is essential for cell function Altered Hydrogen ions (H+) concentrations affect the structure of proteins, and consequently, the functions of enzymes, receptors, transport proteins, channels, etc. Acid-Base Balance Abnormal H+ concentrations have adverse effects on the function of all organ systems. Therefore, Background the concentration of H+ ions in the ECF has to be maintained within narrow limits by, for instance, eliminating H+ ions from the body at the same rate at which they are added to the body (= acid-base regulation)  Buffer substances in the body are extremely important to maintain the physiological pH of about 7.4 (blood) which is required for normal cell function Acid-Base intracellular buffer systems Balance extracellular buffer systems Two organs help maintain the physiological Background pH: the lungs the kidneys  Suggested resource to answer questions: Important https://todaysveterinarypractice.com/the- practitioners-acid-base-primer-obtaining- definitions interpreting-blood-gases/ PDF available on Canvas  classify volatile nonvolatile Defining acids and bases What is an acid? Acid = molecule that can release (donate) H+ ions (protons) HCl ------------> H+ + Cl- (ionization) (hydrochloric acid) (proton) H2CO3 --------> H+ + HCO3- (carbonic acid) (proton) (base) Where do acids come from? Carbonic acid (H2CO3) comes from the combination of CO2 with H2O and is called “volatile” acid canbeeliminatedvialungs basicaffymthfyqe.to'ea Acids that are generated as byproducts of metabolism (e.g. lactic acid, sulfuric acid) are called “non-volatile” acids Defining acids and bases Base = molecule that can accept a H+ HCO3- + H+ ----------> H2CO3 (base) (proton) HPO4- + H+ ----------> H2PO4- (base) (proton) Proteins + H+ ------------> PH+ (base) (proton) Hemoglobin + H+ ------------------> HbH+ (base) (proton) Acids and Bases in Veterinary Medicine: Acids: Can be produced by normal daily metabolic processes. Metabolism of proteins (sulfur-containing amino acids) produces sulfuric acid Metabolism of phospholipids produces phosphoric acid Metabolism of carbohydrates and fats produces CO2 (an acidic gas) Bases: Mostly derived from nutrients. For our patients who like to eat things there will be exogenous sources: Excess acids may be introduced into the body in cases such as ethylene glycol toxicity.  pH is a measure of acidity/alkalinity pH is the proton concentration pH: (represented as [H+]) in a solution and both are inversely associated H+  Acid-Base Solutions with a lower pH have a high H+ concentration. Solutions with a higher pH have a low H+ concentration. A solution with the same pH as pure water (pH = 7) is defined as neutral. Figure from WHO  pH is equal to the negative logarithm of H+ concentration We use a logarithmic scale because the concentration of H+ is so extremely low, it is easier to express the H+ concentration using a logarithmic scale Hence, the relationship between H+ concentration and pH Logarithmic is: scale = log = log[ ] [ ] H+ concentration of the blood = 0.00000004 mol/L Therefore, blood pH = - log [0.00000004] = 7.4  DONTNEEDTOMEMORIZE H+ Body fluid H+ concentration pH concentration (mol/L) and pH values Gastric juice 0.01 2.0 of some body Plasma 0.00000004 7.4 Pancreatic juice 0.00000001 8.0 fluids are: How do we calculate the pH in living organisms?  Please open Practical Acid-Base in Veterinary Patients Acid-Base https://todaysveterinarypractice.com/the Interpretation -practitioners-acid-base-primer- methods: obtaining-interpreting-blood-gases/ howmuchCO2will be  pH = pK + log [base] pH = 6.1 + log HCO3 [acid] (0.03 x PCO2) It describes the relationship between pH and the Henderson- mixture of an acid and its conjugate base Hasselbalch Using this equation we can calculate the pH of a equation solution if the HCO3 concentration and PCO2 are known Looking at the equation, it is evident that: HCO3 ------- --------> alkalosis PCO2 ------- --------> acidosis STRONG acid = an acid that rapidly dissociates and releases high amounts of H+ HCl is a strong acid weak acid = release H+ with less vigor H2CO3 is a weak acid STRONG base = a base that reacts rapidly and strongly with H+ and removes H+ very quickly from a solution OH- + H+ ------------> H2O weak base = a base that reacts slowly with H+ Most acids and bases present in HCO3- + H+ ----------> H2CO3 the ECF behave as weak acids and weak bases. The most important ones are H2CO3 and HCO3-  Alkali = a molecule formed by the combination of one or more of the alkaline metals (sodium, potassium, etc.) with a basic ion (OH-) NaOH -------------------> Na+ + OH- Defining acids (sodium hydroxide “caustic soda”) (base) and bases Alkali = Soluble Base If base is soluble in water Contains an alkaline metal What is a buffer? Reversibly binds free hydrogen ions in solutions A mixture of a weak acid and its conjugate base or a weak base and its conjugate acid, thus buffered solutions maintain the pH of the solution relatively stable. Buffers are important for processes and/or reactions which require specific and stable pH ranges. Buffer solutions have a dissociation constant (pK) that tells the pH at which half of the buffer substance is dissociated and half is un-dissociated. Buffers work at a defined pH range 57.10.76 Examples: plasma HCO3-, proteins, and phosphates and intracellular proteins (eg, hemoglobin), etc.  Physiology II Acid-Base Balance Part 2 Sarah Hooper, DVM, MS, PhD Associate Professor of Veterinary Physiology E-mail: [email protected]  List the major buffers found in CSF, renal filtrate, plasma, RBC Compare physiological pH, pH in arterial blood, pH in venous blood, and pH under ischemic conditions Define acidosis, acidemia, alkalosis, alkalemia Learning List the three mechanisms involved in regulating the pH in the body Objectives: List the major buffer systems in the body and explain how they work List relevant extracellular and intracellular buffers List major buffers in CSF, renal filtrate, plasma, RBC Explain how the lungs help regulate the pH (respiratory compensation) What else do we need to learn about as background physiology? Normal pH of the blood  PCO2 in plasma = 40 mmHg CO2 concentration in plasma = 1.2 mmol/L (= 40 x 0.03) HCO3 concentration plasma = 24 mmol/L pK for this buffer system (recall this means how much H2CO3 dissociates in H+ and HCO3-) = 6.1 pH of the blood = 6.1 + 0.03 What is your result?  Calves pH of the Blood https://www.sciencedirect.com/science/article/pii/S00220302 18300316 Intracellular pH is slightly lower than plasma pH (7.0 – 7.4) Varies by cell type and location Cells under ischemia show a more acidic pH than cells under normal conditions  61 9supplyis The normal range of blood pH is assumed to be 7.35-7.45 Acidemia: a depression of pH below the normal range (seriously abnormal < 7.20) Alkalemia: an elevation of pH above the normal range (seriously abnormal when > 7.60) Definitions: Acidosis: a disturbance caused by the addition of excess acid or removal of base from the ECF Alkalosis: a disturbance caused by the addition of excess base or the removal (loss) of acid from the ECF 135 for Block 3 Remember the Henderson-Hasselbalch‘s equation? pH = 6.1 + log [HCO3] (0.03 x PCO2) If: ffhis basically.it CO2 ______________ Acidosis/Acidemia CO2 losingco ______________ Alkalosis/Alkalemia If HCO3 Alkalosis/Alkalemia _____________ HCO3 _____________ Acidosis/Acidemia blood 7.4 Alkaline What happens if Acid the pH changes?  pH = 6.1 + log [HCO3] (0.03 x PCO2) CO2 Acidosis ______________ CO2 Alkalosis ______________ = 6.1 + = 6.1 + (. ) (. ) / / = 6.1 + log( ) = 6.1 + log( ) (. ) (. ) / / = 6.1 + = 6.1 +. /. / = 6.1 + log(3.33) = 6.1 + log(33.33) = 6.1 + 0.52 = 6.1 + 1.52 = 6.62 = 7.62  Buffer systems Bicarbonate (act within Phosphate seconds) Proteins Three systems regulate H+ and HCO3- Lungs/Respiration concentration, and the (regulates CO2; act within minutes) pH, in the body: Kidneys (excrete/reabsorb H+ and HCO3-; act within hours or days but is a long- lasting effect) 1) Buffer systems of the body Buffer: substance that can bind H+ reversibly 1.A) Bicarbonate buffer system: bicarbonate buffer is the most important extracellular buffer in the body The hydration reaction: CA CO2 + H2O H2CO3 H+ + HCO3- Two elements of this system can be regulated, i.e. HCO3, with the kidneys, and CO2, with the lungs It is, therefore, considered an “open” buffer system pK of bicarbonate buffer system is 6.1 1.A) Bicarbonate buffer system: If the concentration of H+ increases... Excess of H+ will combine with HCO3- CO2 + H2O H2CO3 H+ + HCO3- and more H2CO3 and CO2 will be generated CO2 CO2 (the reaction shifts to the left) CO2 CO2 CO2 Excess of CO2 CO2 is eliminated with the lungs not it iii saying 1.A) Bicarbonate buffer system: If the concentration of H+/H2CO3 decreases... more CO2 combines with H2O to produce H2CO3 CO2 + H2O H2CO3 H+ + HCO3- and more H+ + HCO3- will be generated and CO2 levels are reduced (the reaction shifts to the right) Respiration is CO2 CO2 inhibited to CO2 CO2 conserve CO2  1) Buffer systems (act within seconds) Check-in Bicarbonate Phosphate How are we Proteins doing?  Picture Big 1.B) The phosphate buffer system: very important in the intracellular fluid and renal tubule fluid (high concentration of phosphate in the tubular lumen) NaHPO4, HPO4- HCl + HPO4- ------------> H2PO4 + Cl HCl + NaHPO4- --------> H2PO4 + NaCl pK of phosphate buffer system is 6.8 (closer to the physiological pH) not relevant in ECF 1.C) The protein buffer system: Proteins are highly concentrated in the body and in the cells, and represent important buffers in both the intracellular and extracellular compartments Proteins are buffers because they contain a large number of basic amino acid groups that can accept protons H+ Proteins Slow diffusion HCO3- Hb CO2 Rapid diffusion 1.C) The protein buffer system: In erythrocytes, Hemoglobin (Hb) is a very important buffer system Hb can accommodate protons at two positions: Histidine’s side chain (imidazole) Carboxyl groups R-COO- + H+ RCOOH Intracellular buffers: In cells, acids can accumulate as byproducts of metabolism as well as CO2 Intracellular buffers: amino acids, proteins, phosphate x Membrane carriers: do also play an important role in acid-base regulation Ion exchangers: Na+/H+ exchanger Cl-/HCO3- exchanger For instance, if pH in the cytosol decreases: Na+/H+ exchanger will be activated Cl-/HCO3 exchanger activity will be inhibited Buffer systems in different body fluids: Intracellular buffers: HPO4-, Protein, Hb in erythrocytes Interstitial fluid: HCO3-, HPO4-, Protein CSF: HCO3- Tubular fluid: HCO3-, HPO4-, NH3 Plasma: HCO3-, HPO4-, Protein  1) Buffer systems (act within seconds) Bicarbonate Phosphate Proteins Check-in 2) Respiration (regulates CO2; acts within How are we minutes) doing? 3) Kidneys (excrete/reabsorb H+ and HCO3-; acts within hours or days, but is a long-lasting effect) 2) Respiration and acid-base regulation ---> 2 + concentration ---> 2 elimination (it accumulates in + concentration Changes in blood pH help mitigate by increasing or decreasing the rate of alveolar ventilation Alveolar ventilation influences H+ concentration by changing the PCO2 of body fluids 2) Respiration and acid-base regulation H+ affects the alveolar ventilation rate as well A decrease in plasma pH from the normal value of 7.4 to the very acidic value of 7.0 would increase the ventilation rate four times A rise in plasma pH above 7.4 causes a decrease in the ventilation rate Note that the respiratory compensation for an increased pH is not so effective as the response to a marked reduction in pH 2) Respiration and acid-base regulation Implications: An impaired lung function (e.g. severe emphysema) can cause acidosis because of the accumulation of CO2 in the body Non-volatile acids cannot be excreted by the lungs What happens in such situations? When the lungs cannot respond to this imbalance, the kidneys represent the sole physiological mechanism for returning pH toward normal  Physiology II Acid-Base Balance Part 3 Sarah Hooper, DVM, MS, PhD Associate Professor of Veterinary Physiology E-mail: [email protected]  Explain how the kidneys help regulate the pH (renal compensation) Describe nephron segments and transport mechanisms involved in pH regulation Explain how protons are eliminated with the urine Explain the mechanisms in the nephron that are activated during acidosis and alkalosis Learning Explain the interrelation potassium homeostasis / acid-base disorders Evaluate plasma values (HCO3- concentration, PCO2, pH, BE) to objectives: recognize whether an acid-base disturbance is present or not Describe the terms anion gap and base excess Recognize metabolic acidosis, respiratory acidosis, metabolic alkalosis, respiratory alkalosis and if compensation is occurring List common disorders that promote acid-base disturbances in animals  1) Buffer systems (act within seconds) Bicarbonate Phosphate Proteins 2) Respiration (regulates CO2; acts within Last system! minutes) 3) Kidneys (excrete/reabsorb H+ and HCO3-; acts within hours or days, but is a long-lasting effect) Kidneys can produce either acidic or basic urine Kidneys can form / reabsorb / excrete HCO3- Excrete H+ at variable levels If H+ excretion > HCO3- excretion net acid loss from ECF  Scavenger Hunt https://www.anaesthesiamcq.co m/AcidBaseBook/ab2_4.php https://open.oregonstate.education/aandp/chapter/25-2-microscopic- anatomy-of-the-kidney-anatomy-of-the-nephron/  Luminal HCO3- concentration Luminal flow rate 4 factors that control Arterial pCO2 bicarbonate Angiotensin II (via decrease in cyclic reabsorption: AMP)  H+ secretion requires - Na/ H+ antiporter - H+ ATPase at the apical membrane HCO3- reabsorption requires - HCO3/Na cotransporter - HCO3/Cl antiporter / at the basolateral membrane HCO3 Cl- H+ excretion implies HCO3- reabsorption that mail.fighHIetahsorYigiIarimpies  hold 9H19 Lto  Summary of question answers: In acidosis, the high concentration of H+ promote complete reabsorption of HCO3-, while the excess of H+ Renal regulation are excreted into the urine of acids and In alkalosis, the excess HCO3- will not be reabsorbed bases: and is left in the tubules and excreted into the urine  no f iii fif.fi iffiiffi B fiiii iiiiiiiii iii Tubular lumen Renal regulation of acid-base balance I In the distal nephron, type A cos intercalated cells secrete H+ (H+ ATPase and H+/K+ ATPase) and reabsorb HCO3-. For each H+ excreted one HCO3- is reabsorbed Type B intercalated cells reabsorb H+ Interstitium and eliminate HCO3-  Control rat Intercalated cells do respond to acid-base imbalances modifying their morphology and transporter expression Rat with acute respiratory acidosis pattern  Ammonia (NH3) + Protons (H+) can be secreted in the late nephron. Ammonia (NH3) + Protons (H+) can be secreted in the late nephron. What happens to the excess H+ in the tubular Excretion of most H+ is accomplished by lumen? combining H+ with buffer substances in the tubular lumen (phosphate buffer, bicarbonate and ammonia NH3) Only a small part is excreted as H+ in the urine In acidosis (IC type A): - Antiport H+/K+ - H+ leaves the cell (apically); K+ enters into the cell (apically) - H+ goes into the lumen for excretion In alkalosis (IC type B): - Reabsorption of protons and elimination of K+ - H+ leaves the cell (basolat.), K+ enters into the cell (basolat.) Decreased pH hyperkalemia Increased pH hypokalemia Ktt  Hypokalemia is a decreased concentration of K ions in the ECF. Generates and impaired neural transmission and may lead to muscle weakness Relationships If [K+] is high (Hyperkalemia) interferes between with membrane potential leading to cardiac toxicity (weakness of heart contraction and hypokalemia and arrythmias) acid-base disturbances In acid-base disturbances always consider that H+ elimination means K+ reabsorption and H+ reabsorption means K+ elimination  Implications: An impaired lung function (e.g. severe emphysema) can cause acidosis because of the accumulation of CO2 in the body Non-volatile acids cannot be excreted by the lungs Consider these: What happens in such situations? When the lungs cannot respond to this imbalance, the kidneys represent the sole physiological mechanism for returning pH toward normal  Remember our case study? Respiratory vs Metabolic acidosis/alkalosis  Compensation Respiratory Acidosis/alkalosis renal compensation Acidosis/alkalosis respiratory compensation Metabolic We will also need Base excess to understand Anion Gap it IE onsnere Metabolic acidosis: a primary gain in acid or loss of base Characterized by decreased pH, either from accumulation of fixed acids which consume HCO3- Metabolic or by loss of HCO3-, which exceeds the buffering acidosis systems in the body Compensatory mechanism Decrease PCO2 through hyperventilation RR Consider watching this: https://www.merckvetmanual.com/pages-with-widgets/videos?mode=list  Possible “Differential Diagnosis“ Renal failure Hyperkalemia Diarrhea Fistulas (pancreatic duct fistula) Metabolic During mineralization of bones; during infusion of CaCl2 acidosis Lactate formation (anaerobic glycolysis, (very common): severe physical exercise, tumors) Starvation, diabetes mellitus, increased fat mobilization A protein-rich diet Rumen acidosis  Metabolic alkalosis: a primary gain in base or loss of acid Characterized by increased pH (decreased H+) caused by a loss of fixed acids, Metabolic increased HCO3- and increased base excess. alkalosis Compensatory response is hypoventilation to increase PCO2. Base excess (BE: the amount acid or alkali needed to return the blood to the normal pH; BE are all bases over the normal) Metabolic Possible “Differential Diagnosis“ Vomiting alkalosis: Torsion of the abomasum in ruminants Hypokalemia  Respiratory acidosis: retention of CO2 due to CO2 production outpacing alveolar ventilation Characterized by decreased pH and Respiratory increased PCO2 with acidosis Compensatory increase in HCO3- Remember the kidney filters and creates HCO3-  Alveolar hypoventilation (damage or depression of the respiratory centers in Respiratory SNC) acidosis: Fractured ribs Bloated abdomen Respiratory obstructive diseases  Respiratory alkalosis: removal of CO2 (by alveolar ventilation) outpacing CO2 production Characterized by increased pH, decreased PCO2 Respiratory alkalosis: Compensatory decrease in HCO3- Remember the kidney filters and creates HCO3-  Alveolar hyperventilation during anesthesia Respiratory High altitude alkalosis: Damage to the respiratory centers Emotional excitement Analyzing acid-base status Four (three) parameters are needed: pH of the blood (at 37 degrees C and temp. corrected) pCO2 (both 37 degrees and temp. corrected) Standard bicarbonate (SB; measured bicarbonate concentration in blood standardized to a pCO2 of 40 mmHg and normal body temperature) Base excess (BE: the amount acid or alkali needed to return the blood to the normal pH; BE are all bases over the normal) Currently all parameters mentioned are obtained using a blood gas analyzer  Two purposes: Can be used to evalaute acid-base disorders when a gas analyzer is not available. Note: less precise than a blood gas analyzer Can be used to further characterize metabolic acidosis Anion Gap Increased AG (normochloremic) metabolic acidosis (AG) Normal AG (hyperchloremic) metabolic acidosis Use concept of electroneutrality Law of electroneutrality: the concentrations of anions and cations in plasma must be equal Simplier explanation: pluses = minuses  How anion gap is calculated UA = unmeasured anions Anions = sulfates, phosphates, proteinates, organic acids Proteins such as albumin with net negative charge contribute most UC = unmeasured cations (Na+ + K +) + UC = (Cl- + HCO3-) + UA Ca++ and Mg++ (Na+ + K +)- (Cl- + HCO3-) = UA - UC  P Healthy metabolicacidosis chloride alotmore metfugh metfugh's Anion gap Often times in daily clinical practice [K+] is omitted. Plasma anion gap = [Na+] – ([HCO3-] + [Cl-]) = 142 – (25 + 105) = 12 (accepted “normal” range 8-16 mEq/L**) Anion gap will increase if unmeasured anions rise or if unmeasured cations fall **reported normal range slightly varies based upon source Anion gap = [Na+] - ([HCO3-] + [Cl-]) = 12 (± 4) If > 16 means that unmeasured anions rise From: Kraut and Madias, Clin J Am Soc Nephrol 2007  Metabolic acidosis means: your body is either retaining a lot of protons or you’re losing a lot of bicarbonate. Scenario- our bicarbonate is lowering Arterial blood sample 7.4 How is the pH? Acidosis ieunascans.no respAcidosis Alkalosis causesincramounto co.in BLOODSTREAM BICARB HCO3 PCO2 HCO3 PCO2 IFKIDNEYS LOSING IN causerminners Metabolic Respiratory Metabolic Respiratory iuwasareissu ifkidneysabl.to compensate Respiratory Renal Respiratory Renal compensation compensation compensation compensation PCO2 HCO3 PCO2 HCO3 ftp.inou mayormaynotbeabletocompensate justtellingusthatsom.is's