12 Acid Base 1: Physiology Flashcards Preview

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Flashcards in 12 Acid Base 1: Physiology Deck (15):
1

Acids & bases

  • Normal arterial blood H conc
  • Comparison of H conc to other solutes
    • Na
    • K
    • Bicarb
  • What changes in pH affects
  • Regulation of body pH within a limited range
  • Acid
  • Alkali/base

  • Normal arterial blood H conc
    • [H] = 40 nm (4 * 10-8 M)
    • pH = -log[H] = 7.40
  • Comparison of H conc to other solutes
    • [Na] = 140 mmol/L
    • [K] = 4 mmol/L
    • [Bicarb] = 25 mmol/L
  • What changes in pH affects
    • Conformational strucutre (tertiary & quaternary)
    • Functions of many proteins & enzymes
  • Regulation of body pH within a limited range
    • Crucial for the maintenance o normal health
    • Life can't exist outside the pH range of 6.8 to 7.8
  • Acid
    • Substance that adds H to body fluids
  • Alkali/base
    • Substance that removes H from body fluids

2

Bicarbonate-carbonic acid buffer system

  • Buffers
  • Most effective buffering
  • Isohydric principle
  • Physiologic buffers
  • Buffering of the EC compartment is provided by...

  • Buffers
    • Solutes that take up or release H in an aqueous sol'n to minimize changes in pH
    • Prevent precipitous changes in body fluid pH in repsonse to acute acid or alkali loads
    • Consist of acid-base pairs
  • Most effective buffering
    • Occurs near the equilibrium pH (pKa) for the particular buffer pair
  • Isohydric principle
    • Determines the relationsihp b/n buffer pairs
    • Ratio b/n undissociated & dissociated forms of any buffer pair is dpeendent only on the pH & the pKa for the buffer pair
    • All body buffers are in equilibrium
    • Any change in the ratio of any one buffer pair will be reflected in all body buffer pairs
  • Physiologic buffers
    • Proteins (albumin, hemoglobin)
    • Phosphate compounds
    • Bone
    • Bicarb-carbonic acid
  • Buffering of the EC compartment is provided by...
    • Movement of H b/n the EC & IC compartments

3

Bicarbonate-carbonic acid buffer pair

  • Bicarb-carbonic acid buffer pair
  • Carbonic acid & CO2
  • Carbonic anhydrase (CA) enzyme
  • In erythrocytes
  • Henderson-hasselbalch equation

  • Bicarb-carbonic acid buffer pair
    • Most important of all body buffer systems
    • H2CO3 H+ + HCO3-
    • pKa = 6.1
  • Carbonic acid & CO2
    • Carbonic acid is in equlibirum w/ CO2
    • CO2 + H2O H2CO3
  • Carbonic anhydrase (CA) enzyme
    • Reversibly catalyzes the hydration of CO2
    • Absent CA: rxn is slow
    • Present CA: rxn is fast
  • In erythrocytes
    • Dissolved CO2 in the blood is in equlibrium w/ carbonic acid & gaseous CO2
    • CO2 + H2O H2CO3 H+ + HCO3-
  • Henderson-hasselbalch equation
    • pH = pKa + log( [A-] / [HA] )
    • pH = pKa + log( [HCO3-] / [H2CO3] )
    • pH = 6.1 + log { [HCO3-] / (0.3 * PCO2) }

4

Bicarbonate-carbonic acid buffer pair

  • If the carbonic acid-bicarb system were a closed system containing a fixed quantity of the buffer pair
  • If the carbonic acid-bicarb system were an open system
  • What allows the physiologic open carbonic acid-bicarb buffer system to maintain body fluid pH within an extremely narrow range

  • If the carbonic acid-bicarb system were a closed system containing a fixed quantity of the buffer pair
    • It would be a relativley ineffective buffer system at physiolgoic pH b/c the pKa = 6.1
    • pKa = pH at which there's 50% dissociatoin & max buffering capacity
  • If the carbonic acid-bicarb system were an open system
    • There's physiologic regulation of both PCO2 & [HCO3-]
      • PCO2 is regulated by alveolar ventilation
      • [HCO3-] is regulated by the kidney
    • Efficiency as buffer is greater than would be expected given the pKa of 6.1
  • What allows the physiologic open carbonic acid-bicarb buffer system to maintain body fluid pH within an extremely narrow range
    • Ability to "blow off" CO2 generated by titration of bicarb
    • Ability to retain CO2 in response to an alkali load

5

Normal acid-base homeostasis

  • Normal acid-base homeostasis
  • Acid production
    • Volatile acid
    • Fixed (non-volatile) acid
  • Base production
    • Bicarb (HCO3-)

  • Normal acid-base homeostasis
    • Normal diet has many substances that contribute acid & alkali to body fluids
    • Cellular metabolism produces acid & alkali
    • Alkali is usually lost in th efeces
    • Net effect: acid is added to body fluids in pts ingesting a meat-containing diet
  • Acid production
    • Volatile acid
      • CO2 (carbonic acid) produced by the oxidative metab of carbs, proteins, & fats
      • Production is dependent on caloric utilization & substrate mix (~15,000 - 20,000 mmol of CO2 / day)
      • Excreted through lungs as CO2 gas
    • Fixed (non-volatile) acid
      • H generated through metabolic processes
        • Oxidation of sulfhydryl groups of cystine & methionine to form H2SO4
        • Hydrolysis of phosphoproteins, phospholipids & nucleic acids to form H3PO4
        • Incomplete metabolism of carbs, fats & proteins to organic acids (e.g., β-hydroxybuteric acid & lactic acid)
        • Metabolism of lysine, arginine & histidine produce HCl
      • Production is ~1 mmol/kg/day
      • Excreted by the kidney to maintain body H balance
  • Base production
    • Bicarb (HCO3-)
      • Metabolism of Aspartate & Glutamate --> formation of HCO3-
      • Metabolism of some organic anions (citrate) --> formation of HCO3-

6

Respiratory & renal acid-base homeostasis

  • Respiratory
    • CO2 production in peripheral tissues
    • CO2 production in pulm capillaries
    • Presence of CA in erythrocytes & the buffering provided by HgB
    • Changes in CO2 production
      • Rapidly matched by...
      • Mediated by...
        • Afferent stimuli
        • Efferent stimuli
      • Increases in CO2 production -->
      • Decreases in CO2 production -->
    • In pathologic conditions of metabolic acidosis or alkalosis
      • Primary change
      • Response
  • Renal: 2 major functiosn in maintaining acid-base balance

  • Respiratory
    • CO2 produced by metabolism in peripheral tissues
      • --> erythrocytes (which contain carbonic anhydrase (CA)) --> forms carbonic acid
      • --> H generated combines w/ Hgb in the presence of low PO2
      • --> some CO2 combines directly with Hgb
    • In the pulm capillaries this sequence is reversed
      • --> release CO2 --> excreted through the lungs
    • Presence of CA in erythrocytes & the buffering provided by Hgb
      • --> transport of large quantities of CO2 from peripheral tissues to the lungs while still maintaining a normal blood pH.
    • Changes in CO2 production
      • Rapidly matched by corresponding changes in excretion through stimulation or inhibition of ventilation
      • Mediated by the ventilatory center in the brain stem
        • Afferent stimuli
          • Direct responses to a change in pH and/or PCO2
          • Afferent neural stimuli from chemoreceptors in the aortic arch and carotid bodies
        • Efferent stimuli
          • Modulation of respiratory rate and tidal volume --> altering minute ventilation
      • Increase CO2 production --> increase minute ventilation
      • Decrease CO2  production --> decrease minute ventilation
    • In pathologic conditions of metabolic acidosis or alkalosis
      • Primary change in the bicarb conc
        • --> minute ventilation increases or decreases respectively
        • --> returns the [HCO3]:PCO2 ratio back towards its normal ratio of ~0.6
      • Response: respiratory compensation
        • Mediated by the same mechanisms as above
        • Minimizes the impact of a primary change in [HCO3-] on pH
  • Renal: 2 major functiosn in maintaining acid-base balance
    • Excretion of metabolically generated fixed (non-volatile) acid
    • Reclamation of filtered bicarb

7

Reclamation of filtered bicarb

  • Bicarb filtration
  • Bicarb reabsorption

  • Bicarb is freely filtered at the glomerulus
    • Normal GFR (180 L/day) + normal serum bicarb conc (25 mmol/L)
    • --> approximately 4500 mmol of bicarb is filtered each day
  • This bicarb load must be completely reabsorbed to prevent metabolic acidosis 
    • Bicarb reabsorption occurs primarily (>90%) in the PT
    • Bicarb that escapes the PT is normally reabsorbed in the distal nephron 
    • Proximal bicarbonate reabsorption is a high-capacity, low gradient system

8

Excretion of fixed-acid

  • Kidney excretion of non-volatile acid load
  • 2 major processes involved in renal excretion of fixed-acid
  • Renal acid excretion

  • Kidney excretes non-volatile acid load (~1 mmol/kg/day) generated by metabolism
    • Each H that's generated is buffered by a bicarb
    • Excrete acid load in urine --> regenerate lost bicarb --> maintain acid-base balance
  • 2 major processes involved in renal excretion of fixed-acid
    • Distal tubular acid secretion
    • Ammonium generation & subsequent excretion
  • Renal acid excretion
    • H secretion is coupled to HCO3 reabsorption
    • For each H tha'ts secreted into the tubular lumen, a HCO3 is generated & secreted across the basolateral membrane

9

Renal acid excretion:
Proximal tubule H secretion & HCO3 reabsorption

  • HCO3 in the PT
  • Bicarb reabsorption process
    • H secretion
    • Once H is secreted
    • CO2 gas
    • H ion
    • Bicarb
    • Entire tranpsort process is driven by...
  • Bicarb reabsorption threshold
    • Low serum bicarb
    • High serum bicarb
    • Threshold maintains...

  • HCO3 in the PT
    • Not directly reabsorbed
    • Reclaimed via H secretion & itnerconversion of CO2 gas & carbonic acid
  • Bicarb reabsorption process
    • H secretion
      • H is secreted into the tubular lumen in exchange for Na via the Na/K antibporter (passive)
    • Once H is secreted
      • H + filtered bicarb (HCO3) --> carbonic acid (H2CO3)
      • H2CO3 + carbonic anhydrase (CA) along the PT brush border --> CO2 gas & water
    • CO2 gas
      • Freely diffuses into the PT
      • Catalyzed by IC CA --> H2CO3 --> H + bicarb
    • H ion
      • Available for secretion into the lumen
    • Bicarb
      • Secreted into the blood via Na/3HCO3 cotransporter
    • Entire tranpsort process is driven by...
      • Na/K ATPase in the basolateral membrane
  • Bicarb reabsorption threshold
    • Low serum bicarb (<24) --> filtered bicarb load = reabsorption --> low bicarb excretion in urine
    • High serum bicarb (~26-28) --> threshold for bicarb reabsorption increases --> tubule can't reabsorb additional filtered load --> bicarb reabsorption remains constant --> all additional filtered bicarb is excreted int ehurine
      • Slay (curve at threshold rather than a sharp cutoff) is observed due to nephron heterogeneity
    • Threshold maintains a normal bicarb conc
      • If bicarb conc increases due to metabolic perturbatoin (alkalosis) & threshold is exceeded, the excess bicarb will be excreted & the bicarb conc will be restored

10

Renal acid excretion:
Proximal tubule H secretion & HCO3 reabsorption:
Stimulatory & inhibitory factors

  • Intravascular volume
    • Stimulatory
    • Inhibitory
  • Chloride
    • Stimulatory
  • Acid-base status
    • Stimulatory
    • Inhibitory
  • Serum K
    • Stimulatory
    • Inhibitory
  • PCO2
    • Stimulatory
    • Inhibitory

  • Intravascular volume
    • Stimulatory: volume depletion
      • Increase PT Na reabsorption --> increase H secretion --> increase bicarb reabsorptoin
    • Inhibitory: volume expansion
      • Decrease PT Na reabsorption --> decrease H secretion --> inhibit bicarb reabsorption
  • Chloride
    • Stimulatory: chloride depletion
      • Cl is unavailable for reabsorption w/ na --> increase in Na : bicarb coupled transport
      • Usually accompanies volume depletion
  • Acid-base status
    • Stimulatory: acidemia
      • Increase IC H --> decrease IC pH --> increase gradient for H secretion --> increase bicarb reabsorption
    • Inhibitory: alkalemia
      • Decrease IC H --> increase IC pH --> decrease gradient for H secretion --> decrease bicarb reabsorption
  • Serum K
    • Stimulatory: hypokalemia
      • Decrease IC K --> replace w/ IC H --> decrease IC pH --> increase bicarb reabsorption
    • Inhibitory: hyperkalemia
      • Increase IC K --> don't replace w/ IC H --> increase IC pH --> decrease bicarb reabsorption
  • PCO2
    • Stimulatory: hypercapnia
      • Increase IC PCO2 --> increase IC carbonic acid --> decrease IC pH --> increase apical H transport via Na/H exchanger --> increase bicarb reabsorption from the PT
    • Inhibitory: hypocapnia
      • Decrease IC PCO2 --> decrease IC carbonic acid --> increase IC pH --> decrease apical H transport via Na/H exchanger --> decrease bicarb reabsorption from the PT

11

Renal acid excretion:
Distal tubule H secretion

  • DT H secretion process
    • Major acid secreting cell
    • H & bicarb generation
    • H secretion
    • Bicarb secretion
    • In the CCD, the process is promoted by the...
  • Intercalated apical H pump
  • Ability to excrete an acid load is dependnet on urinary buffers
    • Titratable acids
    • Ammonium (NH4+)
    • Bicarb

  • DT H secretion process
    • Major acid secreting cell
      • Intercalated cell
    • H & bicarb generation
      • CO2 + H2O --[CA]--> H + bicarb
    • H secretion
      • Occurs via ATP-driven H-ATPase & H/K ATPase in the apical membrane
    • Bicarb secretion
      • Occurs via the basolateral Cl/HCO3 exchanger
    • In the CCD, the process is promoted by the...
      • Negative lumen charge established by Na reabsorption by the principal cells
  • Intercalated apical H pump
    • Generates a significant H gradient across the DT
    • Max pH gradient that can be generated = 2-2.5 pH units w/ min urine pH = 4.9
    • To excrete an avg fixed-acid load of 100 mmol in a urine volume of 2 L, urine pH needs to = 1.3 w/o buffers
  • Ability to excrete an acid load is dependnet on urinary buffers
    • Titratable acids
      • Non-ammonia buffers in urine
      • Quantitiy measured by titrating urine & excreting the titratable acid in the urine
      • Principal titratable acid: filtered HPO4- --> H2PO4
      • Other titratable buffers: sulfates, organic acids
    • Ammonium (NH4+)
      • Major form of buffered H
    • Bicarb
      • Secreted H combines w/ bicarb that wasn't reclaimed int he PT to form H2CO3 (carbonic acid)
      • Decomposition of H2CO3 --> CO2 proceeds slowly since CA isn't present along the luminal membrane of the distal nephron
      • Urinary bladder: diffusional barrier to CO2 --> titration of bicarb --> urine to blood PCO2 gradient

12

Renal acid excretion:
Distal tubule H secretion:
Stimulatory & inhibitory factors

  • Distal tubular Na delivery & reabsorption
    • Stimulatory
    • Inhibitory
  • Urinary buffer
    • Inhibitory
  • Mineralocorticoids
    • Stimulatory
    • Inhibitory
  • K
    • Stimulatory
    • Inhibitory

  • Distal tubular Na delivery & reabsorption
    • Stimulatory: increased distal Na delivery
      • Processes that increase CD Na transport --> increase tubular electronegativity --> increase H ion secretion
      • Ex. increase distal tubular Na delivery
      • Ex. increase Na reabsorption via ENAC
      • Ex. increase delivery of poorly reabsorbed (non-Cl) anions
      • Ex. mineralocorticoid (aldo) excess
    • Inhibitory: decreased distal Na delivery
      • Processes that decrease CD Na transport --> decrease tubular lumen electronegativity --> decrease H secretion
      • Ex. decreased distal tubular Na delivery
      • Ex. increase Na reabsorption via ENAC
      • Ex. mineralocorticoid deficiency
  • Urinary buffer
    • Inhibitory: urinary buffer deficiency
      • Urinary buffers titrate secreted H
        • Ex. sulfates, phosphates, organic anions
      • Decrease availability of urinary buffers --> increase H gradient --> inhibit acid secretion
  • Mineralocorticoids
    • Stimulatory: excess mineralocorticoid effect
      • Increase aldo & other MR hormones --> increase distal tubular acidification via Na reabsorption & direct H secretion stimulation --> increase H secretion
    • Inhibitory: hypoaldosteronism
      • MR deficiency --> decrease H secretion
  • K
    • Stimulatory: hypokalemia
      • K depletion --> increase MR effects --> increase H secretion
      • Mediated by increased K reabsorption via H/K ATPase
      • However, hypokalemia decreases aldo secretion
    • Inhibitory: hyperkalemia
      • However, hyperkalemia increases aldo secretion

13

Renal acid excretion:
Ammonium:
Proximal tubular ammoniagenesis

  • Ammonium
  • Ammonium --> bicarb process
  • Stimulated by...
  • Inhibited by...

  • Ammonium
    • Major urinary buffer for 1/2 to 2/3 of net H secretion
  • Ammonium --> bicarb process
    • Deaminated glutamine --> 2 NH4+ + alpha-ketoglutarate (alphaKG) across the apical membrane into the PT
      • As NH4 via Na/H antiporter or dissociated as NH3 & H
    • Metabolized alphaKG --> glucose (gluconeogenesis) or CO2 + water (citric acid cycle)
    • 2 H consumed --> net generation of 2 bicarb
    • 2 bicarb exit via the basolateral membrane
    • Net result: for each ammonium secreted into the PT, 1 bicarb ion is regenerated
  • Stimulated by decreased IC pH
    • Acidemia
    • Hypokalemia
  • Inhibited by increased IC pH
    • Alkalemia
    • Hyperkalemia

14

Renal acid excretion:
Ammonium:
Medullary shunting & CD trapping

  • Ammonium transport
  • CD permeability to ammonium & ammonia
  • pH gradient b/n medullary interstitum & CD lumen

  • Ammonium transport
    • Most ammonium secreted into the PT is transported to the CD via a medullary shunt
    • Ammonium is transported from the TkAL into the medullary interstitium in place of K via the Na/K/2Cl transporter
  • CD is impermeable to ammonium but freely permeable to ammonia
    • In the interstitium, some ammonium --> ammonia + H
    • Ammonia can then diffuse across the CD into the lumen to recombine w/ H & be "trapped" as ammonium
  • pH gradient b/n medullary interstitum & CD lumen --> ammonium gradient despite ammonia being in equilibrium
    • Interstitial pH = 7 --> no gradient when luminal pH = 7
    • Gradient increases as urine acidifies
    • At any given urine pH, total ammonium excretion increases during acidoses compared to normal due to increased ammoniagenesis

15

Summary of daily acid secretion

  • H & ammonium vs. bicarb
  • Total H secretion
  • Net H excretion

  • H & ammonium vs. bicarb
    • For each H secreted (in the PT or DT) or ammonium excreted in the urine, a bicarb is returned to the blood
    • Any bicarb lost int he urine = net gain of H in the body
  • Total H secretion
    • Reclamation of filtered bicarb (4500 mmol)
    • Ammonium ion (30-50 mmol)
    • DT acidification
      • Titratable acid (30-50 mmol)
      • Free H ion (negligible)
  • Net H excretion
    • Excludes H secreted for reclamation of filtered bicarb
    • Net acid excretion = (titratable acid, UTA) + (ammonium excretion, UNH4+) - [ (any bicarb left in the urine, UHCO3-) * (urine volume, V) ]
      • UHCO3- is usually close to 0
    • Normally (steady state): net acid excretion = body's acid production
      • Amt of new bicarb generated by the kidney & returned to the blood = amt of bicarb consumed in buffering fixed-acid produced by metabolism