Acid-Base Balance Lectures 29 & 30 PDF

PHYSG 1501 - Lectures 29 & 30 Acid-Base Balance I & II Johana Vallejo-Elias, Ph.D. Professor Physiology Department College of Graduate Studies Office...

PHYSG 1501 - Lectures 29 & 30 Acid-Base Balance I & II Johana Vallejo-Elias, Ph.D. Professor Physiology Department College of Graduate Studies Office: Science Hall, 380-N Phone: 623-572-3313 Sherwood pp. 316-343 E-mail: [email protected] pp. 547-564 © MWU 2024, J. Vallejo-Elias Learning Objectives Describe the relationship between H+ concentration and pH and discuss the range of pH values in the body. Describe the two types of acids that are produced in the body. What are their sources? Explain how buffers regulate fluid pH and list the major buffers that exist in the body fluids. Explain why the bicarbonate buffer system provide the largest proportion of buffer capacity in the body. Define the four major acid-base disorders and explain the renal and/or respiratory compensations for each. Describe the respiratory control of CO2 in the extracellular fluid (ECF). Describe the renal control of bicarbonate (HCO3-) in the extracellular fluid (ECF):  Explain the mechanisms of renal bicarbonate “recovery” for repairing plasma bicarbonate deficits.  Describe the titratable acidity and role of ammonia (NH3) and ammonium (NH4+) ions in the renal generation of bicarbonate. 2 © MWU 2024, J. Vallejo-Elias Acid-Base Physiology Acid-base physiology describes the regulation of H+ concentrations, [H+], in the extracellular fluid (ECF). Powerful homeostatic mechanisms regulate [H+] in the body. There are three main components (fast to slow):  Buffers: Bicarbonate, proteins, phosphates, etc.  Respiratory compensation: Alters CO2 levels  Renal compensation: Alters HCO3- levels 3 © MWU 2024, J. Vallejo-Elias Hydrogen Ions in the Body Normal plasma [H+] = 0.00000004 Eq/L= 0.00004 mEq/L = 40 nEq/L  Plasma [Na+] = 140 mEq/L by comparison pH = - log [H+]; pH a short-hand method of expressing [H+]  pH = - log [0.00000004 Eq/L] = 7.4 Because [H+] is normally low, it is customary to express  10-fold increase in [H+] = 1 unit change in pH [H+] on a logarithmic scale, using pH units Think of pH as “power of hydrogen” Normal pH of arterial blood = 7.4 (normal range= 7.35 to 7.45) 4 © MWU 2024, J. Vallejo-Elias Review of Chemistry: Henderson-Hasselbalch Equation In 1908 Lawrence Joseph Henderson wrote an equation describing the use of carbonic acid as a buffer solution. Karl Albert Hasselbalch re-expressed the formula in logarithmic terms, resulting in the Henderson- Hasselbalch Equation. He was using this formula to study metabolic acidosis. This equation describes the derivation of pH as a measure of acidity in biological and chemical systems. This equation is also used to estimate the pH of a buffer solution, which is a mixture of a weak acid (HA) and its conjugate base (A-). A modified equation is used to estimate the pH of the blood. 5 © MWU 2024, J. Vallejo-Elias Relationship Between [H+] and pH The relationship between [H+] and pH is pH is inversely as as [H+]  & [H+]  logarithmic, NOT linear. related to [H+] pH  pH   Every 1 unit change in pH represents a 10-fold change in [H+], because of the logarithmic relationship. An increase in pH from 7.4 to 7.6 (0.2 pH units) will decrease [H+] by 15 nEq/L 23 nEq/L A decrease in pH from 7.4 to 7.2 (also 0.2 pH units) will increase [H+] by 23 15 nEq/L nEq/L A given change in pH in the acidic range (pH < 7.4) reflects a larger change in [H+] than the same change in pH in the alkaline range (pH > 7.4). Acidosis Alkalosis 6 © MWU 2024, J. Vallejo-Elias Ranges of [H+] in the body? pH and H+ Concentrations of Body Fluids H+ Concentration Type of Body Fluid pH (mEq/ L) (Mol/L) Pancreatic Juice 0.00001 1 x10-8 8.0 Extreme acidosis 0.0001 1 x 10-7 7.0 Plasma Normal 0.00004 4 x 10-8 7.4 Extreme alkalosis 0.00002 2 x 10-8 7.7 Maximum Urine Acidity 0.03 3 x 10-5 4.5 Gastric HCl 150 0.15 0.8 7 © MWU 2024, J. Vallejo-Elias What are the types of H+ in the body? Volatile acid (eliminated by lungs)  CO2 is produced from aerobic metabolism of cells  The enzyme carbonic anhydrase, presents in most cells, catalyzes the reversible reaction between CO2 and H2O. Non-volatile or fixed acids (eliminated by kidneys)  Sulfuric acid is produced from protein catabolism  Phosphoric acid is produced from phospholipid catabolism  Additional acid loads from exercise (lactate), diabetic ketosis β-hydroxy butyric and acetoacetic acids), and from poison ingestion (salicylic acid from methanol poisoning; glycolic acid from ethylene glycol poisoning). 8 © MWU 2024, J. Vallejo-Elias What Are Buffers and How Do They Work? Buffers consist of weak acid and its conjugate base; Example: HA/A- HA H+ + A-  At low pH’s, [HA] > [A-]  At high pH’s, [A-] > [HA] Buffers prevent a change in pH when H+ ions added to or removed from solution. Under base load, HA can contribute H+; under acid load, A- can absorb H+. Thus, pH changes little. Most effective buffering is in the linear portion of a titration curve,+/- 1.0 pH unit from pK, where the addition or removal of H+ causes little change in pH. 9 © MWU 2024, J. Vallejo-Elias What are Body Buffers? First line of defense against pH changes. Located in extracellular fluid (ECF), intracellular fluid (ICF), and bone. Effectiveness of buffer system depends on the concentration and its pK. The Bicarbonate buffer system is the MOST IMPORTANT buffer in the ECF:  Due to its high concentration (22- 26 mEq/L)  Both CO2 and HCO3- are tightly regulated, respectively, by the lungs and kidneys. CA CA CA= carbonic anhydrase 10 © MWU 2024, J. Vallejo-Elias Buffers in the Blood (Extracellular Fluid) Bicarbonate (53% of total ECF buffering):  pK is low (6.1), but effective due to its conc. and because both the acid (H2CO3/CO2) and base (HCO3- ) are regulated Hemoglobin (35% of total ECF buffering):  Imidazole groups on histidine and  amino groups are the primary buffer sites on all proteins. Proteins (7% of total ECF buffering):  Have good pK’s (6.4 - 7.9), but concentrations are too low Phosphate (5% of total ECF buffering):  Unimportant in blood due to low concentration  Important in urine where concentrations are higher 11 © MWU 2024, J. Vallejo-Elias Buffers in the Cells (Intracellular Fluid) Primary buffers in ICF:  Proteins: High ICF concentrations, pK’s close to 7.4  Phosphates: Same advantages as proteins Secondary buffer in ICF:  Bicarbonate: Low effect due to low concentration Bone: A special case of hydrogen ion buffering  Takes up H+ in exchange for Na+ and K+  Bone minerals may account for a significant amount of body buffering capacity during acute acid load 12 © MWU 2024, J. Vallejo-Elias Image by LabXchange © The President and Fellows of Harvard College How is pH maintained in blood plasma? The carbonic acid–bicarbonate buffer system is an essential physiological mechanism to maintain the pH balance in the human body. The respiratory system and kidneys play crucial roles in regulating the carbonic acid– bicarbonate buffer system. The respiratory system controls the release of carbon dioxide from the body through the breathing rate (label 1). The kidneys regulate the levels of bicarbonate ions in the blood by absorbing or excreting them based on the body’s needs (label 2). 13 © MWU 2024, J. Vallejo-Elias Normal Acid-Base Balance 14 © MWU 2024, J. Vallejo-Elias Normal Acid - Base Balance The Henderson-Hasselbalch equation shows that pH is a function of the RATIO between HCO3- and PCO2. At a normal pH, the Henderson-Hasselbalch equation dictates that the ratio of bicarbonate ions (HCO3-) to dissolved carbon dioxide (CO2) must be 20:1. [HCO3-] This ratio pH = 6.1 + log For a normal (0.03) (PCO2) determines blood pH of 7.40 pH ! ! ! 24 mM 24 20 = = (0.03 mM/mmHg)(40 mmHg) 1.2 1 Decreased bicarbonate or increased PCO2 → Acidosis Increased bicarbonate or decreased PCO2 → Alkalosis 15 © MWU 2024, J. Vallejo-Elias Acid-Base Map and Acid-Base Balance Isohydric lines: constant pH. Note that one can maintain the same pH if both PCO2 and [HCO3-] are changed. Ellipse = range of normal pH values © MWU 2024, J. Vallejo-Elias Renal/ Respiratory Compensation Buffers respond quickly to acid/base disturbances, but they can’t return pH to normal (buffers only minimize pH change). Regulation of pH is called compensation. How does this occur?  Lungs and kidneys regulate CO2 and HCO3-, respectively, such that the ratio of [HCO3-] to dissolved CO2 remains near 20. 17 © MWU 2024, J. Vallejo-Elias Acid/Base Functions of the Lungs Lungs exchange CO2 and O2 and maintain PaCO2 and PaO2 within relatively narrow limits via respiratory control mechanisms. PaCO2 primary regulator of ventilation; control important for acid/base balance (affected by both hyper- and hypo-ventilation). 18 © MWU 2024, J. Vallejo-Elias Renal Control of Bicarbonate Role of kidney in A/B is to stabilize plasma [HCO3-] at 22-26 mEq/L. Kidneys stabilize HCO3- by: 1) Complete “recovery” of filtered bicarbonate when [HCO3-]plasma is < 26 mEq/L 2) Synthesis of “new” HCO3- above and beyond that entering in the glomerular filtrate 3) Excretion of HCO3- when present in excess > 26 mEq/L in plasma, HCO3- appears in urine reabsorption saturated at 40 mEq/L 19 © MWU 2024, J. Vallejo-Elias Mechanism of HCO3- Recovery Driven by H+ secretion  H+ formed in ICF by reaction of CO2 + water via carbonic anhydrase. HCO3- HCO3- H+ exchanged for Na+ (PT; directly stimulated by AT II) AT II + or actively secreted (DT). HCO3- enters peritubular capillary blood. Secreted H+ reacts with filtered HCO3- HCO3- does not cross apical membrane. HCO3- HCO3- 20 © MWU 2024, J. Vallejo-Elias Renal Control of HCO3- One HCO3- is released into the peritubular capillaries for every HCO3- neutralized in the tubule. 99.9 % of the filtered HCO3- is neutralized in the nephron, mostly in the proximal tubule. Once HCO3- is gone from the filtrate, luminal pH falls. Can go as low as 4.5 (normal average is 6). Net H+ extrusion stops at this pH w/o additional buffering (pH gradient from 7.4 to 4.5 is ≈ 1000 fold). Plasma acidosis promotes H+ secretion, and plasma alkalosis decreases H+ secretion. 21 https://www.youtube.com/watch?v=9DQb-Vi0XWo 22 © MWU 2024, J. Vallejo-Elias Repairing Plasma HCO3- Deficits Metabolism liberates non-volatile acids (fixed acid= 50 mEq per day):  e.g., sulfuric and phosphoric acid  HCO3- deficit is repaired by kidneys which release more HCO3- into peritubular capillary blood than is present in filtrate. But how?  New HCO3- from tubule cell requires secretion of H+ in excess of filtered HCO3- Tubular fluid pH cannot go below 4.5 Uses phosphate and NH4+ to unload additional H+ 23 © MWU 2024, J. Vallejo-Elias Titratable Acidity for Urine Buffering Titratable acidity is primarily filtered phosphate (also lactate, aceto-acetate, etc.) pK for phosphate (6.8) is excellent for buffering urine H+ picked up by phosphate allows synthesis of additional + HCO3-. Aldosterone stimulates the secretion of H+ into the lumen through the H+/ATPase in the intercalated cells of the cortical collecting tubules. Aldosterone 24  Mechanism of Excretion of H+ as NH4+ Proximal tubule metabolizes glutamine from blood to yield NH3 and - ketoglutarate.  Highly diffusible NH3 is enters tubular fluid  NH3 is protonated in lumen, becomes NH4+  H+ secretion as NH4+ is referred to as diffusion trapping.  -ketoglutarate metabolized to HCO3- Each glutamine yields two HCO3- (to blood) and two NH4+ (lost in urine). NH4+ is highly impermeable in most cell membranes of the nephron (esp. collecting duct). 25 © MWU 2024, J. Vallejo-Elias Excretion of H+ as NH4+ is regulated by intracellular pH Acidosis stimulates glutamine catabolism; this allows additional HCO3- to be returned to the blood to neutralize the H+. This is the primary mechanism for dealing with chronic acid loads (e.g., diabetic ketoacidosis). 26  Renal/ Respiratory Compensation: Acid-Base Disturbances Changes in [HCO3-] are metabolic disturbances; loss or gain of HCO3- is compensated for by both the lungs and the kidneys:  After initial buffering, changes take minutes to days  Respiratory system is quick, kidneys are slow  Kidneys sometimes cause the metabolic defect; in those cases, only the lungs can compensate Changes in CO2 levels are respiratory disturbances, and must be compensated for by the kidneys:  After initial buffering, compensation takes hours to days  Renal compensation is very powerful. 27 © MWU 2024, J. Vallejo-Elias Examples of Alkalosis 28 © MWU 2024, J. Vallejo-Elias Vomiting and Metabolic Alkalosis 29 © MWU 2024, J. Vallejo-Elias Examples of Metabolic Alkalosis Plasma [HCO3-] increases and leads to elevated pH (pH > 7.45; alkalosis). Caused by vomiting (loss of gastric acid) or the gain of HCO3-: ingestion of excessive antacids (e.g., alkaline drugs). Kidneys conserve H+ (↓ H+ secretion) and excrete the excess HCO3- in the urine. Respiratory system responds by reducing ventilation (hypoventilation) to retain CO2 (increasing PCO2). Causes of Metabolic Alkalosis Alkaline antacid ingestion, Metabolic Alkalosis ↓ Stomach HCl secretion, Vomiting Renal correction HCO3- ↓ H+ secretion,↑ HCO3- excretion pH = 6.1 + log 0.03 x PCO2 Respiratory compensation ↓ventilation (hypoventilation); (↑ PCO2, ↓ pH) 30 © MWU 2024, J. Vallejo-Elias Examples of Respiratory Alkalosis Plasma PCO2 decreases which causes an increase in pH (pH > 7.45; alkalosis). Caused by hyperventilation, which results in excessive CO2 loss (e.g., fever, anxiety, aspirin poisoning, stress, high altitude, etc.) and a decrease in PCO2 NO respiratory compensation; the respiratory system is the cause. Kidneys will conserve H+ and excrete more HCO3- in urine, causing the urine to become alkaline; blood HCO3- and pH will decrease. Cause of Respiratory Alkalosis Respiratory Alkalosis ↑ Ventilation (hyperventilation) Renal compensation HCO3- ↓ H+ secretion pH = 6.1 + log 0.03 x PCO2 ↑ HCO3- excretion (↓ HCO3-, ↓ pH) No respiratory compensation 31 © MWU 2024, J. Vallejo-Elias Examples of Acidosis 32 © MWU 2024, J. Vallejo-Elias Examples of Respiratory Acidosis Plasma PCO2 increases from CO2 retention, and it leads to a low pH (pH < 7.35; acidosis). Caused by decreased ventilation (e.g., drug overdose, airway obstruction, etc.). Renal compensation: If condition persists, the kidneys synthesize and reabsorb “new” HCO3- and excrete H+ in the urine as titratable acid and NH4+ to raise blood pH. There is NO respiratory correction since the respiratory system is the cause. Cause of Respiratory Acidosis ↓ Ventilation (suppressed breathing leads to Respiratory Acidosis retention of CO2 in body) Renal compensation: HCO3- ↑ synthesis and reabsorption of “new” HCO3-; pH = 6.1 + log 0.03 x PCO2 (↑HCO3- leads to ↑ pH) ↑ H+ excretion as titratable acid and NH4+ (↑ pH) No respiratory compensation 33 © MWU 2024, J. Vallejo-Elias Examples of Metabolic Acidosis Plasma [HCO3-] decreases and leads to a low pH (pH < 7.35; acidosis). Caused by ingestion of acid or formation of metabolic acids (e.g., lactic acid, acetoacetic acid, etc.), or loss of HCO3- -rich fluids from the body (e.g., diarrhea). Kidneys synthesize and reabsorb “new” HCO3- to correct the fall in HCO3- Respiratory system responds by increasing ventilation (hyperventilation) to expel CO2. Causes of Metabolic Acidosis Acid ingestion, severe diarrhea, Metabolic Acidosis extreme exercise, diabetes mellitus Renal correction HCO3- ↑ synthesis and reabsorption of “new” HCO3- pH = 6.1 + log (↑HCO3- leads to ↑ pH) 0.03 x PCO2 Respiratory compensation ↑ ventilation (hyperventilation); ↓ PCO2, ↑ pH 34 © MWU 2024, J. Vallejo-Elias Renal/ Respiratory Compensation: Acid-Base Disturbances 35 36 © MWU 2024, J. Vallejo-Elias https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/disorders-of-acid-base-balance 37 © MWU 2024, J. Vallejo-Elias Summary of Acid- Base Disorders Primary Respiratory Renal Disorder pH [H+] Disturbance Compensation Compensation or Correction Metabolic ↓ ↑ ↓ [HCO3-] Hyperventilation ↑ H+ excretion as titratable acid and NH4+ acidosis (↓ PCO2) ↑synthesis and reabsorption of “new” HCO3- Metabolic ↑ ↓ ↑ [HCO3-] Hypoventilation ↓ H+ secretion alkalosis (↑ PCO2) ↑ HCO3- excretion Respiratory ↓ ↑ ↑ PCO2 None ↑ H+ excretion as titratable acid and NH4+ acidosis ↑ synthesis and reabsorption of “new” HCO3- Respiratory ↑ ↓ ↓ PCO2 None ↓ H+ secretion alkalosis ↑ HCO3- excretion Normal values: pH = 7.35-7.45; PaCO2 = 35-45 mmHg; HCO3= 22-26 mEq/L 38