Acid-Base Balance PDF

ACID BASE BALANCE  Acid–Base Balance ❖Normal H+ concentration = 0.00004 meq/l (40 nmol/l) ❖Because H+ concentration normally is low, it is customary to express H+ concentration on a logarithm scale, using pH units. 1 ❖PH: = log = - log H+ = negative log of 0.0000...

ACID BASE BALANCE  Acid–Base Balance ❖Normal H+ concentration = 0.00004 meq/l (40 nmol/l) ❖Because H+ concentration normally is low, it is customary to express H+ concentration on a logarithm scale, using pH units. 1 ❖PH: = log = - log H+ = negative log of 0.00004 = 7.4 (slightly alkaline) {𝐻+} Acidosis: < 7.35 Normal pH 7.35 - 7.45 >7.45: Alkalosis ❖ pH below 7.0 or above 7.7 is incompatible with life pH is inversely related to H+ concentration: e.g. ↓pH corresponds to ↑ H+ Intracellular pH usually is slightly lower than plasma pH because the metabolism of the cells produces acid; range between 6.0 – 7.4. pH of venous blood and interstitial fluids is slightly acidic (7.35) than that of arterial blood (7.45) because of the extra amounts of carbon dioxide (CO2). Normal PH is essential for normal functions of enzymes, muscles & neurons. Henderson-Hasselbalch Equation The Henderson-Hasselbalch equation is used to quantitate how changes in CO2 and HCO3- affect pH. − − 𝐻𝐶𝑂3 𝐻𝐶𝑂3 pH = pK + log = 6.1 + log 𝑝𝐾×𝑃𝐶𝑂2 0.03×𝑃𝐶𝑂2 Dissociation constant (pK). All acids, e.g. H2CO3, are ionized to+some extent.− 𝐇𝟐𝐂𝐎𝟑 ⇔ 𝐇 + 𝐇𝐂𝐎𝟑 It is the tendency of a substance to dissociate in a solution into smaller components. − pK for 𝐇𝐂𝐎𝟑 = 6.1 pK for CO2 = 0.03 ACIDS Volatile acid: CO₂: produced by oxidative (aerobic) metabolism of CHO, Fat, Protein Co2 produces about 12,500 mmol of H+/day. Excreted through the LUNGS as CO₂ gas CO2 combines with H2O to form the weak acid H2CO3 which dissociated to H+ and HCO3- CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3- Non-volatile (Fixed) acids Acids that do not leave solution; from other sources rather than CO2 → Eliminated by KIDNEYS ✓ Sulfuric acid, phosphoric acid o Metabolism of phospholipids & amino acids containing Sulphur (methionine, cystine) or phosphorus o Produce 50-100 mmol of H+/day. ✓ Organic acids o Lactic acids: produced by anaerobic metabolism of hypoxic muscle cell o Keto acids: produced by liver (e.g. in diabetes as a result of fat catabolism with lack of insulin) o Normally small amount of H+ is given, large amount may result in diseases like hypoxia and diabetes. Three main Responses to ACID BASE challenges 1. Blood buffers 2. Respiratory mechanisms 3. Renal mechanisms Blood Buffers  Blood Buffers ❖Buffer is as a chemical substance that has the ability to bind or release H+ (i.e. weak acid & alkali), in solution to keep its pH relatively constant. ❖Buffer H+ ⇔ Hbuffer. Regulate pH by binding or releasing H⁺ ❖Two most common chemical buffer groups A. Bicarbonate – carbonic acid HCO3- is the principal ECF buffer found in blood, interstitium and urine. B. Non bicarbonate (Hb, protein, phosphate, amonia) Hb & protein are found in the blood. Phosphate & ammonia are important buffer in the urine (PHO4- is also important in ICF) rather than in ECF. ❖First line of defense, act instantaneously within minutes Carbonic Acid–Bicarbonate Buffer System CO2 is converted to carbonic acid, which dissociates into H+ and a bicarbonate ion + − CO2 + H2O → H2CO3 -⇔ 𝐇 + 𝐇𝐂𝐎𝟑 The most important buffer in ECF (for H+ arising from sources other than H2CO3-.) ❑ Limitations of HCO3- buffer: ✓ Functions only when respiratory system working normally.  Protein Buffer o Have the following dissociated groups that act as buffers a) Carboxyl group (RCOOH = RCOO- + H+) b) Amino group (RNH3 = RNH2 + H +) o Contribute little to the buffering capacity in the blood.  The Hemoglobin Buffer System o Hb have the following dissociated groups that act as buffers a) Carboxyl and amino groups in its protein part “globin,” b) Imidazole group in the amino acid histidine High buffering capacity i.e. present in large amount. Deoxy-Hb is a better buffer than oxy-Hb → weaker acid. CO2 diffuses to RBCs (no transport mechanism is required) As H2CO3 dissociates, HCO3- diffuse into plasma in exchange for chloride ions (chloride shift): HCO3- leaves the red cells in exchange for Cl-; mediated by anion exchanger 1 (AE1) NB: Cl– displays a reciprocal relationship with HCO3– , increasing when HCO3– is lost to maintain electrical neutrality.  Phosphate Buffer System ❖Consists of: a) Acid phosphate H2PO4- (can donate H+) b) Basic phosphate HPO42- (can accept H+) ❖Importance: in buffering pH of: 1) ICF (i.e. higher ICF concentration) 2) The urine to allow excretion of large amounts of H+ without extremely low urine pH. Limitations of Buffer Systems Provide only temporary solution to acid–base imbalance Do not eliminate H+ ions. Supply of buffer molecules is limited. Respiratory System  Respiratory Acid-Base Control Mechanisms The second line of defense against changes in PH. Eliminate or Retain CO₂ Change in pH are RAPID; within minutes PCO₂ and H+ have a potent stimulatory effect on ventilation via stimulation of peripheral and central chemoreceptors. Renal System Renal Acid-Base Control Mechanisms The third line of defense against wide changes in PH. The only buffer for non-volatile acids. Long term regulator; take hours to days for correction. Four main renal mechanisms: a) Reabsorption of HCO3. b) Formation of new HCO3. c) Secretion of H+ (in PCT in association with HCO3- reabsorption and distal nephron from the intercalated cells) d) Ammonia synthesis (DCT): to allow excretion of large amounts of H+ without extremely low urine pH  Renal reabsorption of bicarbonate ▪ 85% of filtered HCO3- is reabsorbed: a) Proximal tubule: 70-90% b) Loop of Henle: 10-20% c) DT & CD: 4-7% ▪ HCO3– reabsorption does not involve actual transport of this ion into the tubular cells. ▪ Filtered HCO3– reacted with secreted H+ in the presence of the enzyme carbonic anhydrase CA + − ▪ 𝐇 + 𝐇𝐂𝐎𝟑 ⇔ CO2 + H2O ▪ CO2 diffuses into PCT, react with H2O in the presence of CA + − ▪ CO2 + H2O → H2CO3-⇔ 𝐇 + 𝐇𝐂𝐎 ▪ H+ is secreted (anti-ported with Na+) via the Na+ H+ exchange to the lumen ▪ HCO3-enters the interstitium (co-transported with Na+ Carbonic Anhydrase Inhibitors (CAi) Carbonic anhydrase (CA) is critical for the reabsorption of bicarbonate (HCO3-) in the proximal tubule. Mechanism of action: (H+) secretion & HCO3- reabsorption in the PCT are coupled to Na reabsorption. ↓ HCO3- and Na+ reabsorption → remain in the tubules & act as an osmotic diuretic. Side effect: They cause acidosis because of the excessive loss of HCO3- in the urine. NB: the action of this diuretic is weak because of the capacity of more distal sites, particularly the loop of Henle, to increase Na reabsorption.  Renal secretion of H+ ▪ In PCT: ▪ Anti-ported with Na+ to the lumen, by secondary active transport; ▪ On the basolateral membrane, Na, K ATPase moves Na+ to the interstitium → ↓intracellular Na+ ▪ Na+ enter cell, via the Na–H+ exchanger, from the tubular lumen. ▪ In the collecting duct; intercalated cells, under the effect of aldosterone: a) H+ ATPase pump b) Antiported with K+ Ammonium- phosphate excretion Tubular cells cannot secrete H+ if urinary pH is < 4.5 (limiting pH). There are buffers in urine to prevent ↓ of urine pH, permitting more acid to be secreted: a) Phosphate: HPO4-2 + H+ ↔ H2PO4 b) Ammonia (NH3) NH3 + H+ ↔ (NH4) (secreted as ammonium; NH4CL) Acid – Base Imbalance Four Basic Types of Imbalance Metabolic Acidosis Respiratory Acidosis Metabolic Alkalosis Respiratory Alkalosis  Four Basic Types of Imbalance A. Acidosis (↑H+ – ↓ pH: < 7.35 ) 1) Metabolic a) Gain of strong acid e.g. diabetic ketoacidosis. Ingestion of acids e.g. aspirin, methyl alcohol b) Loss of base (HCO₃⁻) ↓HCO₃⁻ (e.g. diarrhoea). c) ↓ renal secretion of H+; renal failure. 2) Respiratory Hypoventilation → retention of CO2 ( pCO2), due to: a) Airway obstruction; asthma. b) Suppression of respiratory center; stroke, drugs c) Neuromuscular disorders; Myasthenia Gravis  Four Basic Types of Imbalance B. Alkalosis (↓ H+ – ↑pH: > 7.45) 1) Metabolic (↑ HCO₃⁻) a) Loss of gastric acids; (e.g., vomiting, nasogastric suctioning) → compensated by stimulation of parietal cells → secretion of HCL in exchange with HCO3 b) Diuretics (except carbonic anhydrase inhibitors) → ↑ flow of fluid along the tubules → ↑ reabsorption of Na in the distal and collecting tubules coupled with H+ secretion. c) ↑ aldosterone → ↑ reabsorption of Na & excretion of H+ d) Ingestion of alkaline drugs, such as sodium bicarbonate, for the treatment of gastritis or peptic ulcer. 2) Respiratory (↓ PCO2) - Caused by excessive ventilation (hyperventilation) - Rarely occur; e.g. hysteria - Mild physiological respiratory alkalosis occurs when a person ascends to high altitude; ↓O2 stimulate respiration. Compensation for Acid – Base imbalance  Compensation for Acid – Base imbalance Respiratory imbalance is compensated Metabolic imbalance is compensated mainly the Renal system. mainly the respiratory system. Respiratory Acidosis: Metabolic Acidosis ↑ Renal secretion of H+. Hyperventilation → ↓PCO₂ ↑ Renal reabsorption and synthesis of HCO₃⁻ Renal system: only if the causes of acidosis (↓ HCO₃⁻ secretion) is not renal. Ammonium and phosphate secretion. Respiratory Alkalosis Metabolic Alkalosis: ↓ Renal secretion of H+. Hypoventilation →  PCO2 ↓ Renal reabsorption of HCO₃⁻ (↑ HCO₃⁻ Renal system; if not caused by renal disease secretion)  Acid Base Disorders Primary Secondary Disorder pH [H+] disturbance response M. acidosis M. alkalosis R. acidosis R. alkalosis Metabolic acidosis/alkalosis → primary change in HCO3- HCO3- is regulated mainly by the rate of respiration Respiratory acidosis/alkalosis → primary change in PCO2 PCO2 in ECF is controlled by the kidneys  Acid Base Disorders Primary Secondary Disorder pH [H+] disturbance response M. acidosis    [HCO3-]  pCO2 M. alkalosis    [HCO3-]  pCO2 R. acidosis    pCO2  [HCO3-] R. alkalosis    pCO2  [HCO3-] Metabolic acidosis/alkalosis → primary change in HCO3- HCO3- is regulated mainly by the kidneys Respiratory acidosis/alkalosis → primary change in PCO2 PCO2 in ECF is controlled by the rate of respiration.  Effect of acid-base imbalance on electrolytes 1. Potassium K+ Acidosis ↑ plasma K+ [hypekalemia], whereas alkalosis decreases it (hypokalemia). This could be due to: 1. Movement of H+ into cells promotes movement of K+ out of cells to maintain electroneutrality. 2. Acidosis inhibits the transporters that accumulate K+ inside cells, e.g. Na+–K+ ATPase. 2. Calcium: Ionized calcium binds to negatively charged sites on protein molecules, competing with hydrogen ions. Acidosis→ ↓ protein binding → ↑ free calcium levels. Alkalosis → ↑ protein binding → ↓ free calcium Evaluation of acid-base disturbances Step – By Step  The following measures will help to assess patient with acid base- imbalance 1. pH 2. PCO2 3. HCO3-- 4. Anion gap (plasma and urine) Step-1 pH: Acidosis, alkalosis or Normal Normal pH = 7.35 – 7.45 < 7.35 ➔ acidosis > 7.45 ➔ alkalosis E.g. identify the abnormality? pH = 7.25? pH = 7.55?  Step-2: Respiratory or Metabolic PCo2 is regulated by the lungs. HCo3 is regulated by Kidneys. Abnormal PCo2 & Normal HCo3 → Respiratory Abnormal HCo3 & Normal PCo2→ Metabolic Normal pH = 7.35 – 7.45 Normal PCo2 = 35 – 45 Normal HCo3 = 22 – 26 Exercise; identify the abnormalities: a) pH = 7.25 - PCo2 = 50 HCo3 = 24 → ? b) pH = 7.56 - PCo2 = 28 HCo3 = 22 → ? c) pH = 7.25 - PCo2 = 37 HCo3 = 18 → ? d) pH = 7.56 - PCo2 = 40 HCo3 = 35 → ?  Step-3: compensated or not If the pH is Normal (or nearly normal) and HCo3 and PCo2 are abnormal that means there is a compensation going on. Full compensation; Normal pH. Partial compensation; pH close to normal. Respiratory problems are compensated by HCo3 Acidosis → ↑HCo3 Alkalosis →↓HCo3 Metabolic problems are compensated by PCo2 Acidosis → ↓ PCo2 Alkalosis → ↑PCo2 Exercise- 1 Normal pH = 7.35 – 7.45 Normal PCO2 = 35 – 45 Normal HCO3 = 22 – 26 Exercise; identify the abnormalities: pH = 7.30 PCO2 = 50 HCO3 = 49 What is the abnormality→ Exercise- 2 Normal pH = 7.35 – 7.45 Normal PCO2 = 35 – 45 Normal HCO3 = 22 – 26 Exercise; identify the abnormalities: pH = 7.50 PCO2 = 51 HCO3 = 41 What is the abnormality→ Exercise- 3 Normal pH = 7.35 – 7.45 Normal PCO2 = 35 – 45 Normal HCO3 = 22 – 26 Exercise; identify the abnormalities: ▪ pH = 7.35 ▪ PCO2 = 49 7.35 7.4 7.45 ▪ HCO3 = 30 ▪ What is the abnormality→ ?  Exercise- 4 Normal pH = 7.35 – 7.45 Normal PCO2 = 35 – 45 Normal HCO3 = 22 – 26 Exercise; identify the abnormalities: pH = 7.44 PCO2 = 48 7.35 7.4 7.45 HCO3 = 35 What is the abnormality → ?  Exercise - 5 Normal pH = 7.35 – 7.45 Normal PCO2 = 35 – 45 Normal HCO3 = 22 – 26 Exercise; identify the abnormalities: ▪ pH = 7.20 ▪ PCO2 = 55 ▪ HCO3 = 17 ▪ The abnormality→ ?  Plasma Anion Gap Plasma is electrically neutral; cation = anion The primary measured cation is Na+ The primary measured anion is HCO3- & Cl. Normally unmeasured anion (proteins, organic & non-organic acids) exceeds unmeasured cations (K+, Ca2+, Mg+). Anion gap is difference between unmeasured anion & cation. The serum anion gap is typically calculated as following: Serum anion gap = Measured cations - Measured anions = Na - (Cl + HCO3-). Or = (Na + K) - (Cl + HCO3) Normal anion gap: ❑ 8 – 12 → without K ❑ 12 – 16 → with K It is always best for each laboratory to determine its own normal range for the serum anion gap.  Urine Anion Gap (UAG) Urine anion gap: = ={uNa + K}- uCl. Normal urine anion gap: Urine Cl usually exceeds uNa ➔ Normal urine anion gap return negative value UAG is usually an estimate of renal ammonia production & is useful in evaluating a normal anion gap acidosis: A. Renal HCO3 loss → UAG>0: E.g. impaired reabsorption B. Non renal HCO3 loss → negative UAG: E.g. diarrhea.  Classification of Metabolic Acidosis According to Anion Gap (AG) is primarily used in the differential diagnosis of metabolic acidosis. Normal Anion Gap (hyperchloremic) Frequently associated with ↓ (HCO3-); directly or indirectly. Both Cl– and H+ are increased, so a normal AG acidosis is also referred to as ‘hyperchloraemic’. Cl– displays a reciprocal relationship with HCO3– , increasing when HCO3– is lost to maintain electrical neutrality. Causes: a) Carbonic anhydrase inhibitors; e.g. acetazolamide. b) Diarrhea. c) Renal loss; acute renal failure & renal tubular acidosis. d) Ingestion of ammonium chloride.  Classification of Metabolic Acidosis According to Anion Gap High anion Gap ❑Due to retained H+ → ( ‘ Hypo- ’ or ‘ normochloraemic ’ acidosis). 1. Ketoacidosis a) Diabetic ketoacidosis "DKA” b) Starvation c) Alcohol ketoacidosis: Chronic alcohol use. d) Drugs; Aspirin toxicity, SGLT2 inhibitors 2. Lactic acidosis 3. Accumulation of uremia; chronic renal failure. References Ganong’s Review of Medical Physiology - 25th (2016) Hall Guyton and Hall Textbook of Medical Physiology (2016) Berne-Levy-Physiology 7th edition. Ameman Human Anatomy and Physiology. The core of medical physiology, volume 2.