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Acid-Base

Acid-Base. Basic definitions An acid a substance that can donate hydrogen ions (H + ) A base a substance that can accept H + ions H 2 CO 3 (acid)«H + + HCO 3 - (base) Strong acids completely ionized in body fluids W eak acids incompletely ionized in body fluids. Acid-Base.

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Acid-Base

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  1. Acid-Base Basic definitions An acid a substance that can donate hydrogen ions (H+) A base a substance that can accept H+ ions H2 CO3 (acid)«H+ + HCO3- (base) Strong acids completely ionized in body fluids Weak acids incompletely ionized in body fluids

  2. Acid-Base Basic definitions HCl«H+ + Cl- Hydrochloric acid (HCl) a strong acid - it is present only in a completely ionized form in the body H2 CO3 (acid)«H+ + HCO3- (base) a weak acid - it is ionized incompletely at equilibrium, all 3 reactants are present in body fluids

  3. Acid-Base Basic definitions H2 CO3 (acid)«H+ + HCO3- (base) the law of mass action - the velocity of a reaction is proportional to the product of the reactant concentrations ……………………………………………. the addition of H+ or bicarbonate (HCO3-) drives this reaction to the left

  4. Acid-Base Basic definitions in body fluids the concentration of hydrogen ions - H+ normal physiologic concentration = 40 nEq/L is maintained within very narrow limits the concentration of HCO3-= (24 mEq/L) is 600,000 times that of [H+]

  5. Acid-Base Basic definitions the tight regulation of [H+] at this low concentration is crucial for normal cellular activities H+ at higher concentrations can bind strongly to negatively charged proteins, including enzymes, and impair their function (!!) under normal conditions, acids and bases are being added constantly to the extracellular fluid compartment for the body to maintain a physiologic [H+] of 40 mEq/L,3 processes must take place: Buffering by extracellular and intracellular buffers Alveolar ventilation, which controls PaCO2 Renal H+ excretion, which controls plasma [HCO3-]

  6. Acid-Base

  7. Acid-Base Buffers weak acids or bases that are able to minimize changes in pH by taking up H+ by releasing H+ Phosphate - effective buffer HPO42- + (H+)«H2 PO4- upon addition of an H+ to extracellular fluids, the monohydrogen phosphate binds H+ to form dihydrogen phosphate, minimizing the change in pH when [H+] is decreased, the reaction is shifted to the left Thus, buffers work as a first-line of defense (!!) to blunt the changes in pH that would result from the constant daily addition of acids and bases to body fluids

  8. Acid-Base Buffers HCO3-/H2 CO3 buffering system H2 O + CO2 «H2 CO3 «H+ + HCO3 the major extracellular buffering system a very effective system has the ability to control PaCO2 by changes in ventilation increased carbon dioxide (CO2) concentration drives the reaction to the right, a decrease in CO2 concentration drives it to the left H+ added to the body fluids  formation of carbonic acid = consumption of HCO3 carbonic acid (H2 CO3)  water + CO2 ventilation CO2 concentration is maintained within a narrow range via the respiratory drive, which eliminates accumulating CO2 the kidneys regenerate the HCO3- consumed during this reaction

  9. Acid-Base Buffers H2 O + CO2 «H2 CO3 «H+ + HCO3 this reaction continues to move to the left as long as CO2 is constantly eliminated or until HCO3 - is significantly depleted, making less HCO3 - available to bind H+ HCO3 - and PaCO2 can be managed independently HCO3 in the kidneys PaCO2 in the lungs that makes this a very effective buffering system

  10. Acid-Base Buffers HCO3-/H2 CO3 buffering system H2 O + CO2 «H2 CO3 «H+ + HCO3 Henderson-Hasselbalch equation pH = 6.10 + log ([HCO3 -]/0.03 X PaCO2) expresses the relationship between the 3 reactants in the reaction at equilibrium an alternative - [H+] = 24 X PaCO2/[HCO3 -] Henderson-Hasselbalch equation relates: dissolved CO2 (ie, H2 CO3) to the partial pressure of CO2 (0.03 X PaCO2)

  11. Acid-Base Buffers pH = 6.10 + log ([HCO3 -]/0.03 X PaCO2) changes in pH or [H+] are a result of relative changes in the ratio of PaCO2 to [HCO3 -] rather than to absolute change in either one if both PaCO2 and [HCO3 -] change in the same direction, the ratio stays the same and the pH or [H+] remains relatively stable the alteration in pH occurs when either HCO3 - or PaCO2 changes the other variable in the same direction

  12. Acid-Base Buffers intracellular buffers - hemoglobin, bone in chronic metabolic acidosis extracellular HCO3 level is low intracellular buffers are more important than HCO3

  13. Acid-Base Renal acid handling Acids are added daily to the body fluids volatile acids - carbonic acid the metabolism of dietary carbohydrates and fat produces approximately 15,000 mmol of CO2 per day, which is excreted by the lungs failure to do so results in respiratory acidosis nonvolatile - eg, sulfuric, phosphoric acids the metabolism of proteins (ie, sulfur-containing amino acids) results in the formation of H2 SO4 dietary phosphate results in the formation of H3 PO4

  14. Acid-Base Renal acid handling these acids first are buffered by the HCO3 -/H2 CO3 system: H2 SO4 + 2NaHCO3 «Na2 SO4 + 2H2 CO3 «2H2 O + CO2 a strong acid (H2 SO4) is buffering by 2 molecules of HCO3a weak acid (H2 CO3) is produced this minimizes the change in pH the lungs excrete the CO2 produced the kidneys replace the consumed HCO3 to prevent progressive HCO3 - loss and metabolic acidosis kidneys perform these principally by H+ secretion in the collecting duct

  15. Acid-Base Renal acid handling prevention of metabolic acidosis  prevention of progressive HCO3 loss amino acids ( glutamate, aspartate)  formation of citrate and lactate   convertion to HCO3 to maintain normal pH, the kidneys must “reabsorb” all the filtered HCO3 - (any loss of HCO3 - is equal to the addition of an equimolar amount of H+) (in the proximal tubule) excrete the daily H+ load (loss of H+ is equal to addition of an equimolar amount of HCO3 -) (in the collecting duct)

  16. Acid-Base Renal acid handling / HCO3 - reabsorption the daily glomerular ultrafiltrate in a healthy subject, contains 4300 mEq of HCO3– for a serum HCO3 - concentration of 24 mEq/L a daily glomerular ultrafiltrate of 180 L all of filtered HCO3 – has to be reabsorbed 90% in the proximal tubule, the remainder in the thick ascending limb and the medullary collecting duct the energy for this process  the 3Na+ -2K+ «ATPase maintains a low intracellular Na+ concentration and a relative negative intracellular potential  indirectly provides energy for the apical Na+/H+ exchanger - NHE3 (gene symbol SLC9A3)  transports H+ into the tubular lumen  H+ in the tubular lumen combines with filtered HCO3 – HCO3 - + H+ «H2 CO3 «H2 O + CO2

  17. Acid-Base Renal acid handling / HCO3 - reabsorption HCO3 - + H+ «H2 CO3 «H2 O + CO2 the dissociation of H2 CO3 into H2 O + CO2 is accelerated by Carbonic anhydrase (CA IV isoform) present in the brush border of the first 2 segments of the proximal tubule this shifts the reaction shown above to the right and keeps the luminal concentration of H+ low CO2 diffuses into the proximal tubular cell, via the aquaporin-1 water channel carbonic anhydrase (CA II isoform) combines CO2 and water to form HCO3 - and H+ the HCO3 - formed intracellularly returns to the pericellular space and then to the circulation via the basolateral Na+/3HCO3 - cotransporter, NBCe1-A (gene symbol SLC4A4)

  18. Acid-Base Renal acid handling / HCO3 - reabsorption In essence the filtered HCO3 - is converted to CO2 in the lumen CO2 diffuses into the proximal tubular cell in the tubular cell CO2 is converted back to HCO3 – HCO3 – is returned to the systemic circulation in this way the filtered HCO3 – is recuperated

  19. Acid-Base Renal acid handling Acid excretion the daily acid load = 50-100 mEq of H+is excreted through H+ secretion by the apical H+ «ATPase in A-type intercalated cells of the collecting duct

  20. Acid-Base Renal acid handling / Acid excretion HCO3 - formed intracellularly is returned to the systemic circulation via the basolateral Cl-/HCO3 -exchanger, AE1 (gene symbol SLC4A1) H+ enters the tubular lumen via 1 of 2 apical proton pumps, H+ «ATPase or H+ -K+ «ATPase The secretion of H+ in these segments is influenced by Na+ reabsorption in the adjacent principal cells of the collecting duct The reabsorbed Na+ creates a relative lumen negativity, which decreases the amount of secreted H+ that back-diffuses from the lumen

  21. Acid-Base Renal acid handling / Acid excretion Hydrogen ions secreted by the kidneys can be excreted as free ions > 99.9% of the H+ load - buffered by the weak bases NH3 or phosphate The reason for limited excretion of free H+ ions the lowest achievable urine pH = 5.0 = 10 µEq/L H+ would require excretion of 5,000-10,000 L of urine a day urine pH cannot be lowered much below 5.0 because the gradient against which H+ «ATPase has to pump protons (intracellular pH 7.5 to luminal pH 5) becomes too steep

  22. Acid-Base Renal acid handling / urine-buffering system titratable acidity the amount of secreted H+ that is buffered by filtered weak acids is called titratable acidity buffers in this system phosphate as HPO4 2 ammonia (NH3) uric acid creatinine H2 PO4 «H+ + HPO42- the amount of phosphate filtered is limited and relatively fixed only a fraction of the secreted H+ can be buffered by HPO42-

  23. Acid-Base Renal acid handling / urine-buffering system / ammonia Ammonia NH3 + H+ «NH4 + ammonia is produced in the proximal tubule from the amino acid glutamine this reaction is enhanced by an acid load hypokalemia

  24. Acid-Base Renal acid handling / urine-buffering system / ammonia Intracellular - proximal tubules NH3 + H+ «NH4 + NH4 + is secreted into the proximal tubular lumen by the apical Na+/H+ (NH4 +) antiporter Intraluminal - thick ascending limb of the loop of Henle the apical Na+/K+ (NH4 +)/2Cl- cotransporter in the thick ascending limb of the loop of Henle then transports NH4 + into the medullary interstitium it dissociates back into NH3 and H+ NH3 diffuses into the lumen of the collecting duct - available to buffer H+ ions and becomes NH4 +. NH4 + is trapped in the lumen and excreted as the Cl salt .

  25. Acid-Base Renal acid handling / urine-buffering system NH3 + H+ «NH4 + the increased secretion of H+ in the collecting duct  shifts the equation to the right  decreases the NH3 concentration  facilitates continued diffusion of NH3 from the interstitium down its concentration gradient  allows more H+ to be buffered the kidneys and the liver can adjust the amount of NH3 synthesized to meet demand, making this a powerful system to buffer secreted H+ in the urine

  26. Acid-Base Renal acid handling / urine-buffering system every H+ ion buffered  an HCO3- gained to the systemic circulation

  27. Lichid extracelular Celulă tub proximal Lumen tubular Transportactiv Na+ Na+ Na+ HCO3- Na HCO3 HCO3- HCO3- + H+ H+ + CO3- contraschimb H2 CO3 H2CO3 Anhidraza carbonică CO2 CO2 + H2O CO2 + H2O eliminată (rezultat din metabolism) Cantitate redusă, aciditatea urinii Filtrare glomerulară NaHCO3- Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+ Intervenţia rinichiuluiîn condiţii de normalitate Relaţia [H+] [NaHCO3-] la ph normal al mediului intern

  28. Celulă tub proximal Na+ HPO42- NaHCO3- H2PO4- HCO3- H+ HCO3- Na+ eliminare H2CO3 AC CO2 + H2O CO2 Filtrare glomerulară a Na2HPO4 Lichid extracelular Lumen tubular Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+ Na2HPO4 Na+ Intervenţia rinichiului în acidoză sistemul tampon fosfaţi

  29. Lichid extracelular Celulă tub proximal Na+ Na+ Na H CO3 glutamină NH3 HCO3- HCO3- H+ H+ H2CO3 eliminare AC CO2 CO2 + H2O Filtrare glomerulară a NaCl Lumen tubular Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+ Na+ Cl- NH4Cl (acid slab) Intervenţia rinichiului în acidoză Formarea amoniacului din glutamină

  30. Din catobolismul normal • al proteinelor în ficat rezultă • amoniac • bicarbonat • Din amoniac se formează uree • Funcţie de necesităţi, o parte din amoniac • este transformată în glutamină • acidoza stimulează • alcaloza inhibă • Glutamina trece în circulaţie • şi ajunge la nivelul celulei tubulare renale • Dezaminarea glutaminei la nivelul celulei tubulare • determină refacerea de HCO3- • acidoza stimulează • alcaloza inhibă • Acidoza favorizează eliminarea urinară • a NH4+ şi se evită transformarea lui în uree • care privează de regenerarea HCO3- Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

  31. Filtrare glomerulară a NaCl Lichid extracelular Celulă tub proximal Lumen tubular Na+ Na+ Na+ Cl- Na H CO3 glutamină NH4Cl (acid slab) NH3 HCO3- HCO3- H+ H+ H2CO3 eliminare AC CO2 CO2 + H2O Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+ Intervenţia rinichiului în acidoză Formarea amoniacului din glutamină • Eliminarea urinară de amoniu • normal - 30 mmol/24 ore • la nevoie - până la 300 mmol/zi

  32. Lichid extracelular CL- Filtrare glomerulară a NaCl Celulă tub distal Lumen tubular Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+ Cl- Na+ Cl- H+HCO3- HCO3- Intervenţia rinichiului /factori perturbatori, de reglare funcţiede necesităţi/ Ph-ul mediului intern H2CO3 Na+ AC CO2 CO2 + H2O NaHCO3 Alcaloză hipercloremică

  33. Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

  34. Acid-Base Metabolic acidosis / Pathophysiology In healthy people blood pH is maintained at 7.39-7.41 pH is the negative logarithm of [H+] (pH = - log10 [H+]) an increase in pH indicates a decrease in [H+] and vice versa an increase in [H+] and a fall in pH is termed acidemia a decrease in [H+] and an increase in pH is termed alkalemia the underlying disorders that lead to acidemia and alkalemia are acidosis and alkalosis, respectively metabolic acidosis is a primary decrease in serum HCO3 - concentration and, in its pure form, manifests as acidemia (pH <7.40)

  35. Acid-Base Metabolic acidosis / Pathophysiology rarely, metabolic acidosis can be part of a mixed or complex acid-base disturbance 2 or more separate metabolic or respiratory derangements occur together pH may not be reduced or the HCO3- concentration may not be low

  36. Acid-Base Metabolic acidosis / Pathophysiology compensatory mechanism = alveolar hyperventilation  a fall in PaCO2 normally, PaCO2 falls by 1-1.3 mm Hg for every 1-mEq/L fall in serum HCO3- compensatory response that can occur fairly quickly change in PaCO2 not within this range = a mixed acid-base disturbance ex, if the a less decrease in PaCO2 than the expected change = a primary respiratory acidosis also present

  37. Acid-Base Metabolic acidosis / Pathophysiology often the first clue to metabolic acidosis is a decreased serum HCO3 - concentration observed when serum electrolytes are measured remember, however, that a decreased serum [HCO3 -] level can be observed as a compensatory response to respiratory alkalosis an [HCO3-] level less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis

  38. Acid-Base Metabolic acidosis / Anion gap plasma, like any other body fluid compartment, is neutral - total anions match total cations the major plasma cation is Na+ the major plasma anions are Cl- and HCO3– in lower concentrations other cations: K+, Mg2+, and Ca2+ other anions: phosphate, sulfate, and some organic anions

  39. Acid-Base Metabolic acidosis / Anion gap the anion gap (AG) = the difference between the concentration of the major measured cation Na+ (140 mEq/L) and the major measured anions Cl- (108 mEq/L) and HCO3–(24 mEq/L) the gap is usually between 6 and 12 mEq/L

  40. Acid-Base Metabolic acidosis / Anion gap the AG represents the difference between unmeasured anions and unmeasured cations: AG = [Na+]-([Cl-] + [HCO3 -]) = unmeasured anions - unmeasured cations an increase in the AG can result from: a decrease in unmeasured cations: hypokalemia, hypocalcemia, hypomagnesemia or an increase in unmeasured anions: hyperphosphatemia, high albumin levels in certain forms of metabolic acidosis, other anions accumulate by recognizing the increasing AG  a differential diagnosis for the cause of acidosis

  41. Horacio J. Andorgué & Nicolaos E. Midias

  42. Acid-Base Metabolic acidosis / Urinary AG helpful in evaluating some cases of non-AG metabolic acidosis the major measured urinary cations: Na+, K+ the major measured urinary anion is Cl- Urine AG = ([Na+] + [K+]) - [Cl-] the major unmeasured urinary anions HCO3- the major unmeasured urinary cations NH4+ HCO3- excretion in healthy subjects - usually negligible NH4+ daily average excretion - approximately 40 mEq/L results in a positive or near-zero gap

  43. Acid-Base Metabolic acidosis / Urinary AG Urine AG = ([Na+] + [K+]) - [Cl-] in metabolic acidosis the kidneys increase the amount of NH3 synthesized to buffer the excess H+  NH4 Cl excretion increases the increased unmeasured NH4+ increases the measured anion Cl- in the urine,  a negative AG == a normal response to systemic acidification the finding of a positive urine AG in a non-AG metabolic acidosis == a renal acidification defect: renal tubular acidosis [RTA]

  44. Acid-Base Metabolic acidosis / Urinary AG Caveats the presence of ketonuria makes this test unreliable the negatively charged ketones are unmeasured  urine AG will be positive or zero despite the fact that renal acidification and NH4 + levels are increased severe volume depletion from extrarenal NaHCO3 loss  avid proximal Na+ reabsorption little Na+ reaching the lumen of the collecting duct is reabsorbed in exchange for H+ limited H+ excretion  reduced NH4+ excretion  positive urinary AG

  45. Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status transcellular shift of K+ intracellular K+ is exchanged for extracellular H+ or vice versa influence on renal acid secretion in hypokalemia  intracellular acidosis in hyperkalemia  intracellular alkalosis

  46. Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status Hypokalemia increased renal production of NH3 increase in renal acid excretion_____ __ relative intracellular acidosis increasedHCO3- reabsorption relative intracellular acidosis high activity of the apical Na+/H+ exchanger The increase in NH3 production by the kidneys may be significant enough to precipitate hepatic encephalopathy in patients who have advanced liver disease. Correcting the hypokalemia can reverse this process.

  47. Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status increased renal ammoniagenesis relativelyalkaline urine excessive NH3 then binds more H+ in the lumen of the distal nephron  increased urine pHsuggestion of RTA as an etiology for non-AG acidosis differential diagnoses  urine AG negative in patients with normal NH4+ excretion positive in patients with RTA

  48. Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status causes for hypokalemia + metabolic acidosis most common - GI loss: diarrhea, laxative use less common - renal loss of potassium secondary to RTA or salt-wasting nephropathy differential diagnoses the urine pH the urine AG the urinary K+ concentration

  49. Acid-Base Metabolic acidosis / Effect of potassium balance on acid-base status Hyperkalemia opposite effect to hypokalemia reduction of NH3 synthesis in the proximal tubule reduction of NH4+ reabsorption in the thick ascending limb reduced medullary interstitial NH3 concentration decrease in net renal acid secretion causes for hyperkalemia + metabolic acidosis primary or secondary hypoaldosteronism treatment for hyperkalemia + metabolic acidosis hyperkalemia has the central role in the generation of the acidosis lowering serum the K+ concentration  correction of the associated metabolic acidosis

  50. Acid-Base Metabolic acidosis / History symptoms - not specific patients may report varying degrees of dyspnea hyperventilation respiratory center stimulation in an effort to compensate for the acidosis nausea, vomiting, and decreased appetite clinical history helpful in establishing the etiology (related to the underlying disorder ) the age of onset and a family history – to point to inherited disorders

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