Acid/Base Balance Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction.

Acid/Base Balance Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction

Key Concepts Mechanisms that maintain a constant body pH (buffering, respiratory compensation and renal compensation) How do they operate for each acidotic or alkalotic conditions (acute and chronic) Henderson-Hasselbalch Equation Calculations What are the renal and pulmonary roles in pH regulation and compensation? Acid/base map Weak acid/base pairs that are good physiological buffers pKa and titration curves What is the role of hemoglobin and carbonic anhydrase in the RBC? Review phosphate buffer system Titratable acid Mechanisms and “players” Excretion as NH4+ Mechanisms and players ECF and ICF buffers Tubular transporters for acid/base balance Anion gap (calculation) Rules of thumb for compensatory responses

Key Concepts Buffers-resist change in pH and are the body’s first line “defense” against pH changes pH regulation Renal and pulmonary systems contribute by controlling acidic CO2 levels and alkaline HCO3- levels Yet, these two systems are also of major contributors to compensation when normal regulatory buffer mechanism are overwhelmed Generally a failure of either the renal or pulmonary system results in the other facilitating more compensation Ex: Patient has low ventilation capacity and thus cannot expel CO2 Renal mechanisms used to excrete HCO3- and H+

Reading Textbook of Physiology Chapter 30, pp.379-396 Guyton
Medical Physiology Chapter 7 pp (optional) Costanzo

Control of Body pH Normal Arterial Blood pH Range 7.35 – 7.45
Kidney Secretes urine to adjust blood pH Acidic or alkaline Response in hours to days Respiratory Removal of volatile gases (CO2) Expired from plasma via lungs Primary regulator of bicarbonate Response in minutes Chemical Acid/base buffering of body fluids Response is immediate Normal Arterial Blood pH Range 7.35 – 7.45 pH Range Compatible with Life 6.8 – 8.0 Acidosis pH < 7.35 Alkalosis pH > 7.45 Note: McKinney pH

Metabolic Disturbances Metabolic Acidosis pH < 7.35
Caused by: Abnormal removal of HCO3- or another alkali Abnormal addition of acids Note: Other than CO2 or H2CO3 Ex. Renal failure

Metabolic Disturbances Metabolic Alkalosis pH > 7.45
Caused by: Abnormal loss of acid Ex. Vomiting – resulting in the loss of gastric HCl Addition of a weak base

Respiratory Disturbances Respiratory Acidosis pH < 7.35
Caused by: Abnormal loss of acid Ex. Vomiting – resulting in the loss of gastric HCl Addition of a weak base

Respiratory Disturbances Respiratory Alkalosis pH > 7.45
Caused by: Excessive loss of CO2 through ventilation Driving the equilibrium to the left

Normal Acid/Base Conditions

Balance Approximation
pH of a CO2/HCO3- solution depends upon the ratio of these two buffers Lung control CO2 1.2 M/L of CO2 is dissolved in plasma, which is a partial pressure or pCO2 of 40 mmHg. Kidney controls HCO3-

Predicting Acid/Base Disturbances
Buffering of pH and the effects of acid-base disturbances is due to a complex interaction of many buffering systems, open and closed, with differing buffering capacities. all HB (n+1)   H+ + all B (n) weak acid/base Predictions of the effects of these disturbances is done using a “Davenport Diagram.” Combining chemical buffers with CO2/HCO3 such that CO2 + H2O  HCO H B(n)  HB(n+1) Now, the final pH depends on two buffering pathways that affect the [H+] with two different equilibria equations.

Overview Davenport diagram: the blue curve is the pCO2 isobar (isopleth) represents the relationship between pH and HCO3 at a pCO2 of 40 mmHg. Orange line is in respiratory alkalosis (pCO2 = 20). The green line is respiratory acidosis. These occur due to changing pCO2 via altered respiratory function

Overview The red lines represent the influence of non-CO2/HCO3 buffering systems. Point A1 would occur if these did not exist. Point A if these exist at 25 mM/pH (normal for whole blood), and A2 if these buffering systems were infinite. Note that this red line to point A is shown in panel A and describes the changing buffer capacity of the non CO2/HCO3 systems during each respiratory disturbance

Acid-Base Physiology pH= log 1 = -log10 [H+]  log scale (not linear) [H+] Normal [H+]= 40 nEq/L = pH= -log [ ] pH=7.4 Note: pH is inversely related to the [H+] so as [H+] increases, pH decreases and conversely Log scale (not linear) –so, equal changes in equal changes in pH do not mean equal changes in [H+] an increase of 0.2 units in pH translates to a decrease in [H+] of 15 nEq/L (pH 7.4 to 7.6) While a 0.2 unit decrease in pH (7.4 to 7.2) translates to a 23 nEq/L increase in [H+]

Pathological pH States
Result from a wide range of disorders Presence or absence of acidosis/alkalosis provides important clues that serious metabolic situation exists pH changes have great effects on normal cell function

Examples of pH Changes on Cellular Function
Changes nerve and muscle cell excitability pH < 7.4 depresses CNS pH > 7.4 can produce over-excitability Tingling sensations, muscle twitches Alter enzyme function in cell Increase or decreases in local enzymatic environment can alter protein 3D structure rendering it non-functional Influences K+ Renal secretion of K+ changes Acidosis More H+ secreted than normal Increases ICF K+ retention Potential for cardiac arrhythmias

Acid Production in Body
Two forms: fixed acid and volatile acid (CO2) Volatile Acid (CO2) end product or aerobic metabolism---13,000-20,000 mmoles/day when CO2 combines with H2O it is converted to weak carbonic acid—H2CO3 CO2 + H2O H2CO H+ + HCO3- carbonic anhydrase expired in lung (volatile acid) Fixed Acid Catabolism of proteins and phospholipids yields 50 mmoles/day proteins with methionine, cysteine, cystine produce sulfuric acid H2SO3 Phospholipids produce phosphoric acid with water (H3PO4) Need to be buffered in body before excreted by renal mechansims

Other Fixed Acids Pathophysiological states can produce other fixed acids in large amounts resulting in metabolic acidosis. Examples Ingestion of Fixed Acids Salicylic acid from aspirin overdose Formic acid from methanol Glycolic and oxalic acids from ethylene glycol Strenuous Exercise Lactic acid in hypoxic conditions Untreated diabetes mellitus β-hydoxybutyric acid and acetoacetic acid

Buffers Defined Mixture of a weak acid and its conjugate base
Mixture of a weak base and its conjugate acid A buffered solution resists changes in pH Therefore, H+ can be added or subtracted but pH changes are minimal

Brønstead-Lowry Acid/Base
Weak Acid (HA)  Conjugate base ( A-) H+ donor H+ acceptor Weak base (BH+)  conjugate acid (B)

Henderson-Hasselbalch Equation
Used to calculate the pH of a buffered solution Derived from the behavior of weak acids (and bases) in solution k1 HA H+ + A- k2 If k1 = k2 then the reaction is in a state of chemical equilibrium i.e. No further net change in [HA] or [A-] Law of mass action gives this for chemical equilibrium: k1 [HA] = k2 [H+] [A-]

Rearrange: k1 [HA] = k2 [H+][A-] to k1 = [H+][A-] k1/k2 = equilibrium rate constant Ka k2 [HA] Ka = [H+][A-] [HA]

Ka = [H+][A-] Now, take the negative log10 of both sides: and exclude [H+] alone [HA] -log10 Ka= -log10 [H+] + -log10 [A-] [HA] -pKa = -pH +log10 [A-] pH = pKa + log10 [A-] Note the following: pH = -log10 [H+] pKa = -log10 Ka (k1/k2) [A-] = concentration base form (mEq/L) [HA] = concentration of acid form (mEq/L)

Physiological Sources of H+
Cellular metabolism of carbohydrates Release CO2 Food products Sauerkraut, Yogurt, citric acid Medications Stimulate parietal cells stomach Intermediate metabolic products of catabolism Lactatte, pyruvate, acetoacetic acid, fatty acids Disease States DM resulting in the release of ketoacids

Titration Curves At acidic pH buffer exits primarily in HA form.
Only small changes in pH occur in linear portion of sigmoidal curve ± 1 pH unit around the pKa (dotted lines) At alkaline pH the buffer exists primarily as A- form

Buffers in ECF HCO3- and HPO42- are the major ECF buffers
HCO3-/CO2 system is the most important Phosphate is more of an ICF molecule

Regulation of ECF pH HCO3- is high in the ECF
20-28 mm Hg pKa of HCO3-/CO2 buffer pair is reasonably close to the pH of the ECF CO2 is lost from lungs Volatile gas CO2 freely diffuses across cell membranes

Regulation of Arterial Blood pH
CA H+ + Cl- + Na+ + HCO Na+ + Cl- + H2CO CO2 + H2O HCl (strong acid) and NaCl (salt) will readily dissociate in solution Provides opportunity for H2CO3 to form and Carbonic Anhydrase (CA) to enzymatically convert H2CO3 to CO2 and H2O Both CO2 and H2O are lost during expiration from the lungs Loss of CO2 and H2O will drive the direction of the reaction to the right (i.e. formation of additional CO2 and H2O (Le Châtelier's principle)

Calculation of Arterial Blood pH Bicarbonate Buffer System
H+ + Cl- + Na+ + HCO Na+ + Cl- + H2CO CO2 + H2O pCO2 (in mm Hg) needs to be converted to [CO2]. Accomplished by multiplying the solubility coefficient of CO2 in blood 0.03 mmol/L/mmHg pH= pKa + log HCO3- 0.03 x pCO2 pH= log mEq/L = log10 20 = 7.4 0.03 x 40 mm Hg HCO3- range is mEq/L (Avg. = 24 mEq/L) pCO2 range is mm Hg (Avg. = 40 mmHg) Normal Avg. pH = 7.4 Note: mEq/L and mmol/L are interchangeable here.

Phosphate Buffer System
HPO4-2/H2PO4- buffer pair [H2PO4-] is low= 1-2 mmol/L Remember: HCO3- is 12X higher HPO4-2/H2PO4- buffer pair DOES NOT contain a volatile component pKa= 6.8, therefore already near its maximum buffering capacity in body fluids Therefore this system is only a minor player

Phosphate Buffer System
H+ + Cl- + 2Na+ + HPO Na+ + H2PO4- + Na+ + Cl- Note: NO enzymatic control of this system Phosphate plays a major role in buffering renal tubular fluid Increased phosphate concentration in renal tubular fluid compared to arterial blood Renal tubular fluid has lower pH than blood so pKa close to maximum buffering capacity Phosphate is an important buffer in ICF [PO42-]ICF much greater than [PO42-]ECF pH of ICF fluid is closer to phosphate pKa than ECF pH

Proteins Operate as ICF Buffers
Proteins are most the plentiful ICF buffers (high concentrations in ICF) Contain a large number of acidic or basic groups (COOH/COO- or NH3+/NH2) Approximately 60-70% of buffering in ICF is by intracellular proteins

Proteins Operate as ICF Buffers Ex. Hemoglobin
The most significant ICF protein buffer is hemoglobin (Hb) found in RBCs Oxygenated Hb (pKa 6.7) is an effective physiological buffer Note: Remember that high [H+] will drive the release of O2 Deoxygenated Hb (pKa 7.9) increases buffering capacity As RBC/ blood flows through capillaries, Hb releases O2 to tissues converted to deoxygenated Hb. Simultaneously CO2 added to systemic capillaries, diffuses in RBC and forms H2CO3 that dissociates to HCO3- and H+. H+ generated is buffered by Hb (now in it’s deoxy form) pH of venous blood = 7.37 while arterial blood pH = 7.4 Note there is only a 0.03 unit change considering how much CO2 is dumped into venous blood.

Organic Phosphates in ICF can act as Buffers
Intracellular Buffering Mechanisms Excess CO2 diffuses into cells forming H2CO3 with water and dissociates to H+ and HCO3- H+ is buffered by intracellular buffers If there is an excess or deficit of fixed acid, H+ can enter or leave cell with an organic anion (i.e. lactate) This preserves electroneutrality When no accompanying anion available for a fixed acid, H+ is moved by exchange with K+ This also preserves electroneutrality Organic Phosphate Buffers in ICF ATP, ADP, AMP, Glucose-1-P and 2,3-BPG pKa range from

Henderson-Hasselbalch Equation Acid/Base Map
Shows relationships between pCO2, HCO3-, and pH Lines from origin Same [H+] or pH = Isohydric lines Each line gives all the combinations of pCO2 and HCO3- that yield the same pH value. Ex. Where pCO2 = 40 mm Hg HCO3- = 24 mEq/L

Ex: Add 12mmol/L of strong acid HCl to ECF 12mmol/L H+ combines with 12mmol/L of HCO3- Result = 12 mmol/L H2CO3 12mmol/L CO2 (action of CA) New [HCO3-] = 12mmol/L New [CO2] = 1.2 mmol/L (from pCO2 = 40 mm Hg) Plus the 12 mmol/L = 13.2 mmol/L (assume no CO2 lost from lung) pH= log 12 mmol/L = 6.06 13.2 mmol/L

pH = 6.06 not compatible with life. However, the CO2 is volatile and is lost in lungs i.e. Respiratory compensation Acidemia stimulates chemoreceptors in carotid bodies that increase ventilation rate immediately All the excess CO2 + more expired drives pCO2 to lower value (24 mm Hg) pH = log 12mmol/L = 7.32 (0.03 x 24 mm Hg) Full restoration depends on slower responses in kidneys

Renal Mechanisms for Acid/Base Balance
Kidneys do two things to help maintain acid-base balance Reabsorption of HCO3- preservation of buffer for blood/not lost in urine Excretion of fixed H+ Produced from protein and phospholipid metabolism Can be excreted buffered by urinary phosphate (titratable acid) i.e. Excretion with NH3 as NH4+ Both methods of H+ excretion make more HCO3- to replace anything that was lost 99.9% of filtered HCO3- reabsorbed in PCT Conserves ECF buffer Reabsorption rate Given GFR = 180 L/day and [HCO3-]Plasma = 24 mEq/L Filtered load = 180 x 24 = 4320 mEq/day Measured excretion rate of HCO3- = 2mEq/day Reabsorption rate = 4320 – 2 = 4318 mEq/day 4318/4320 = 99.9% filtered load

Segmental Reabsorption of Bicarbonate
Most HCO3- is reabsorbed in the PCT (80%) Under normal circumstances NO HCO3- is excreted.

Na+/H+ Exchanger Secondary active transport. Both Na+ and H+ move against gradients

H+ secreted into tubular lumen combines with filtered HCO3- forms H2CO3 and is then then catalyzed by carbonic anhydrase in brush border to H2O and CO2. Acetazolamide, a carbonic anhydrase inhibitor diuretic inhibits this step. CO2 and H2O diffuse across the cell membrane and enter the ICF

Inside the cell, CO2 and H2O are catalyzed to H2CO3 by carbonic anhydrase. H2CO3 then disassociates to form H+ and HCO3- HCO3- is transported across basolateral membrane to blood via a Na+/HCO3- cotransporter Cl-/HCO3- exchanger helps to drive this process Na+/K+ gradient is maintained by the Na+/K+ ATPase

Results Net absorption of Na+ and HCO3- Note: Some Na+ reabsorption linked to glucose, amino acids, Cl- and phosphate No net secretion of H+ Formation of CO2 and H2O in lumen that re-enter cell is recycled Tubular pH does not change much

Renal Mechanisms for Acid-Base Balance
Filtered load = GFR x [X] plasma when X = HCO3-= 40 mEq/L = 180L/day x 40 mEq/L =7200 mEq/day compared to 4320 (normal from 24 mEq/L) The filtered load becomes high enough that the reabsorption mechanism are is saturated. Metabolic Alkalosis: [HCO3- ]plasma is elevated , restoration of normal acid-base balance requires excretion of HCO3- as [HCO3- ]plasma increases , filtered load in lumen increases excretion of HCO3- occurs lowering the [HCO3- ]plasma

Effect of ECF volume increase
Recall isosmotic reabsorption in the proximal tubule via changes in the peritubular capillary Starling forces Changes in ECF volume will alter reabsorption of HCO3- in predictable ways volume expansion inhibits isosmotic reabsorption that decreases HCO3- reabsorption volume contraction stimulates isosmotic reabsorption , that increases HCO3- HCO3- reabsorption also, decreases in volume activate RAAS Angiotensin II stimulates Na+-H+ exchanger in the proximal tubule increasing number of H+ transported to lumen that can combine with HCO3- H2CO3 recycled to ICF HCO3- to blood Explains Contraction Alkalosis---treated by infusing isotonic saline to restore ECF metabolic alkalosis secondary to volume contraction results from loop diuretics or thiazide diuretics complicates metabolic alkalosis caused by vomiting

Effect of pCO2 Renal compensation for chronic respiratory acid base disorders Chronic changes pCO2 change the reabsorption of filtered HCO3- Increases in pCO2  increase HCO3- reabsorption decreases in pCO2  decrease HCO3- reabsorption Mechanism not clear but involves supply of CO2 to renal cells if [CO2] increases respiratory acidosis more CO2 available to renal cells to generate H+ for secretion by Na+-H+ exchanger, more HCO3- can be reabsorbed Result: [HCO3-]plasma increases arterial pH increases (the compensation) If [CO2] decreases respiratory alkalosis less CO2 available for renal cells to generate H+ for exchange less HCO3-reabsorbed Result: [HCO3-]plasma decreases arterial pH decreases (the compensation)

Excretion of H+ as Titratable Acid
Definition: H+ excreted with urinary buffers inorganic phosphate is high in urine and has an ideal pK 15% of inorganic phosphate is excreted Phosphate is primarily excreted in late distal tubule and collecting ducts Two primary active transport systems on luminal side H+-ATPase stimulated by aldosterone H+-K+ ATPase also transports K+ in intercalated cells Aldosterone (+) Late distal tubule [A-] [HA] It can be shown that [A-] form is 4x greater than [HA] - favors excretion of [HA]

Excretion of H+ as Titratable Acid
H+ excreted by transporters is made in cells from H2O and CO2 For each H+ excreted one new HCO3- is made/reabsorbed (red box) helps restore depleted blood/ECF [ ] from buffering other ---so HCO3- is continuously replaced

Urinary Buffer Available
Remember: buffers resist changes in pH by accepting or donating H+ ion when they are high or low concentration amount of H+ excreted is going to depend on available urinary buffer Blood pH=7.4 and minimum urinary pH=4.4 This represents a 1000-fold H+ difference across the luminal cells large concentration gradient to move against for H+ transport when urine pH reaches 4.4 exchange stops Ability to secrete H+ into urine depends on amount of urinary buffer available as a counter-ion Distinguish between—amount of H+ excreted and the value for urine pH If there are NO urinary buffers—the first H+ secreted will immediately decrease urine pH and excretion will stop at pH=4.4 If a large amount of urinary buffer is available then H+ secretion continues until urinary pH =4.4

Compare Phosphate and Creatinine as Urinary Buffers
Glomerular filtrate = pH 7.4 Both HPO42- and H2PO4- are available BUT [HPO42- ] higher than the acid form As H+ secreted into tubular fluid it combines with HPO42- converting it to H2PO4- Linear portion of curve (pH= ) very small changes with addition of H+ Then, sharp increase in pH as more H+ secreted. Then pH 4.4 secretion stops. Only way to secrete more H+ would be to provide more HPO42- Thus, amount of H+ added (secreted) depends on amount of HPO42- available as buffer

Urinary Buffer pKa Affects Amount of H+ Secreted
Creatinine (pKa 5.0) is not a good urinary buffer Much less effective than HPO42- The amount of H+ secreted is less than with phosphate. Because the effective range of pH (1 unit either side of pKa) is very close to urinary pH. Therefore H+ secretion stops.

Excretion of H+ as NH4+ Production of H+ from protein and phospholipid catabolism = 50 mEq/day 20 mEq/day secreted as titratable (fixed) acid using urinary PO42- as buffer Remaining 30 mEq/day of H+ is excreted by NH4+

Mechanisms for H+ Excretion as NH4+
Three Segments Involved Proximal tubule Na+/H+ exchanger (NHE) Thick Ascending limb NH4+ secreted to tubular fluid recaptured and added to corticopapillary gradient α-intercalated cells of collecting ducts NH3 and H+ combine to form NH4+ and secreted in urine

Mechanisms for H+ excretion as NH4+ PCT
Glutamine metabolized to NH3 and α-ketoglutarate α-ketoglutarate metabolized to HCO3- and H+ HCO3- reabsorbed into blood replenish blood buffer stores H+ combines with NH3 forming NH4+ NHE secretes NH4+ Positive charge allows NH4+ to substitute for H+

Mechanism for H+ excretion as NH4+ TA LOH
NH4+ secreted into lumen in PCT partially reabsorbed Positively charged NH4+ substitutes for K+ Na+/K+/2Cl cotransporter NH4+ participates in countercurrent multiplication Similar to NaCl Becomes concentrated in the inner medulla and papilla of the kidney

Mechanism for H+ excretion as NH4+ CD
Two transporters secrete H+ into tubular lumen H+-K+ ATPase H+-ATPase BOTH stimulated by aldosterone Source of H+ is enzymatically derived from CA H2O + CO2  HCO3- + H+ NH3 diffuses from medullary interstitial space to lumen (concentration gradient) NH3 combines with secreted H+ in lumen to yield NH4+ Note: Diffusion Trapping NH3/NH4+ is available in the medullary interstitium BUT only NH3 is lipid soluble and can diffuse to lumen NH4+ it is not lipid soluble and is “trapped” in the tubular fluid for excretion End Result: (1) HCO3- synthesized + reabsorbed per (1) H+ secreted Replenish HCO3-blood buffer stores

Urinary Buffering of NH4+
Using NH4+ to carry H+ into urine is advantageous (Ex. DKA) During Acidosis Urinary pH low Large amounts of H+ to be disposed Diffusion-trapping mechanism is initiated As urinary pH decreases more diffused NH3 trapped as NH4+ Decreased [NH3] in tubular fluid causes more NH3 to diffuse from medullary space at high concentration gradient More NH3 for H+ so large amounts of H+ are excreted Process also drives HCO3- production and reabsorption recovering HCO3- for compensation Chronic acidosis Adaptive increase in NH3 synthesis in PCT occurs ICF pH decreases, enzymes involves in glutamate metabolism induced Results in increased NH3 More H+ can be excreted as NH4+

Effect of [K+]Plasma on NH3 synthesis
Hyperkalemia Inhibits NH3 synthesis Reduces H+ excretion as NH4+ Type 4 renal tubular acidosis (RTA). K+ enters cells and H+ leaves Hypokalemia Stimulates NH3 synthesis from glutamine Increases the excretion of H+ as NH4+ K+ leaves cells and H+ enters Mechanism Effects likely mediated by exchange of H+ and K+ across renal cell membranes In turn alters ICF pH K+ enters cells and H+ leaves Increase in intracellular pH (>7.4) Inhibits NH3 synthesis K+ leaves cells and H+ enters Decrease in intracellular pH (<7.4) stimulates NH3 synthesis from glutamine.

Summary and Comparison
Condition Total Production Fixed H+ (mEq/day) Excretion of H+ as Titratable Acid NH4+ mEq/day Normal 50 20 (40%) 30 (60%) Diabetic Ketoacidosis 500 100 400 Chronic Renal Failure 10 5  15/50=30% Normal Daily, all H+ produced from metabolism is excreted as titratable (HCO3-) acid and NH4+ All HCO3- needed to buffer the titratable acid is replenished Acidosis Enzymes making glutamine induced A- forms (butyrate and acetoacetate) act as urinary buffers Similar to PO42- H+ formed, combines with butyrate and acetoacetate and excretes as organic acids Chronic Renal Failure Also a cause of metabolic acidosis Progressive loss of nephrons Renal mechanisms impaired GFR reduced Reduces filtered load of phosphate reducing urinary buffering capacity NH4+ excretion reduced due to decreased NH3 synthesis Tx. Low protein diet =  H+

Acid/Base Disorders Characterized by abnormal [H+]plasma yield
Resulting in  or  in blood pH Acidemia/Acidosis increase in H+ decrease in pH pathophysiology=acidosis Alkalemia/Alkalosis Decrease in H+ increase in pH pathophysiology=alkalosis Causes Primary disturbance of [HCO3-] or PCO2 Recall HCO3-/PCO2 ratio of Henderson-Hasselbalch Equation Metabolic Change in [HCO3-] is metabolic Respiratory Change in PCO2 is respiratory

Acid/Base Disorders Metabolic Acidosis Metabolic Alkalosis  [HCO3-]
 pH (< 7.35)  fixed H+ Cannot be buffered adequately Causes Overproduction of H+ Ingestion of fixed H+ Decreased excretion H+ Metabolic Alkalosis  [HCO3-]  pH (> 7.45) Causes Gain of HCO3- Loss of fixed H+

Acid/Base Disorders Respiratory Acidosis Respiratory Alkalosis
Hypoventilation CO2 retention  PCO2  pH (< 7.35) Respiratory Alkalosis Hyperventilation CO2 loss  PCO2  pH (> 7.45) Note: Combinations can result in mixed disorders

Acid/Base Disorders If there is an acid/base disturbance, body attempts to restore normal blood pH by compensating via (3) mechanisms: Changing buffering in the ECF or ICF Respiratory compensation Renal compensation Metabolic Acid/Base Disturbances Indicating altered HCO3- Compensatory response is respiratory (altered PCO2) Respiratory Acid/Base Disturbances Indicating altered PCO2 Compensatory response is renal (metabolic) to alter [HCO3-] Compensatory response is always in the same direction as the original disturbance Ex. Metabolic acidosis Caused by decrease in [HCO3-]plasma Compensation will be hyperventilation to decrease PCO2

Plasma Anion Gap A useful measurement for assessing acid-base disorders is the “anion gap” based on the idea of electroneutrality For any body compartment (ECF, ICF, Plasma, etc.) [cation]=[anion] Ions measured: Na+, Cl-, HCO3- When added up there is an electro neutral gap i.e. More Na+, therefore, there must be unmeasured anions Protein, phosphate, citrate, sulfate Plasma Anion Gap = [Na+] – ([HCO3-] + [Cl-]) All units in mEq/L Normal Range: 8-16 mEq/L

Plasma Anion Gap Anion gap most useful for differential diagnosis of metabolic acidosis Results from a decrease in [HCO3-] [Na+] does not change so to preserve electroneutrality in plasma Therefore, some anion must increase to replace the “lost” HCO3- Possibilities: Cl- or one of the unmeasured anions (phosphate, citrate) What is fixing the gap? Replaced by Cl- Normal anion gap Replaced by unmeasured anion Abnormal anion gap (Patient is gapped) Unmeasured Anion Gapping As unmeasured anion replaces HCO3- the gap increases Plasma Anion Gap = [Na+] – ([HCO3-] + [Cl-]) = 140 –(10+105) = 25 mEq/L Examples of Gapped Metabolic Acidosis DKA, lactic acidosis, salicylate poisoning, methanol poisoning, ethylene glycol poisoning and chronic renal failure

Anion Gap with Osmolar Gap
Can occur in cases of Gapped Metabolic Acidosis Determined by the difference between measured plasma osmolarity and the estimated plasma osmolarity (from summing the solutes in the blood like Blood Osmolality = 2(Na+) + glucose/18 + BUN/2.8 Normally little difference between measured and estimated EtOH or MeOH Poisoning Significant addition of small solutes to the plasma increasing the measured plasma osmolarity. The estimated won’t estimate unusual solutes so an osmolar gap is produced. Note: High molecular weights of salicylate etc. do not have this effect

Normal Anion Gap Metabolic disorders Respiratory disorders
If Cl- fills the anion gap created by HCO3- loss, that is a measured anion and there no change in the anion gap i.e. Non-gapped Metabolic acidosis The acid-base map can be superimposed with the acid-base disorders (next slide) Metabolic disorders One range of expected values since the compensation occurs immediately Respiratory disorders Two ranges of expected values Acute Before renal compensation Chronic After renal compensation Takes several days to appear

Acid/Base Disorder Map
Patient’s values fall within a shaded area (1) disorder present Patient’s values fall outside shaded area (> 1) disorder present (mixed disorder)

Renal Rules Predicting Compensatory Changes in Simple Acid/Base Disturbances
Primary disturbance Compensation Predicted Compensatory Response Metabolic Acidosis  [HCO3-]  PCO2 1 mEq/L  [HCO3-] 1.3 mm Hg  PCO2 Metabolic Alkalosis  [HCO3-]  PCO2 1 mEq/L  [HCO3-] 0.7 mm Hg  PCO2 Respiratory Acidosis Acute 1 mm Hg  PCO2 0.1 mEq/L  [HCO3-] Chronic 0.4 mEq/L  [HCO3-] Respiratory Alkalosis PCO2 1 mm Hg  PCO2 0.2 mEq/L  [HCO3-] 0.4 mEq/L  [HCO3-]

Metabolic Acidosis Caused by decreased [HCO3-] in blood
Inherent Causes: Increased production of fixed acids DKA, lactic acidosis Ingestion of fixed acid Ex. salicylic acid-aspirin) Kidney disease causing inability to excrete fixed acid from metabolism Ex. Type 2 Renal tubular necrosis Loss of [HCO3-] from kidneys or GI tract Ex. Diarrhea Compensation and Correction Gain of fixed acid Excess H+ increased production, ingestion or decreased excretion. Buffering Excess H+ buffered in both ICF and ECF, produces decrease in [HCO3-] yielding decreased pH. In ICF H+ buffered by organic phosphates and proteins, must enter cell with an anion (lactate/formate) of by exchange with K+ (hyperkalemia occurs) Respiratory Compensation (fast) Decreased arterial pH stimulates chemoreceptors causing hyperventilation decreasing PCO2 that normalizes the HCO3-/PCO2 ratio Renal Compensation (slow): excess fixed H+ excreted as titratable acid and NH4+ HCO3- synthesized to replenish blood buffer

Metabolic Alkalosis Caused by increased [HCO3-] in blood Causes:
Loss of fixed H+ from GI tract (vomiting) Loss of fixed H+ from kidney (hyperaldosterone) ECF volume contraction (diuretics) Administration of solutions containing HCO3- Arterial blood profile: increased pH, [HCO3-] and PCO2 Sequence of events to correct: Loss of fixed acid –vomiting reducing H+Cl- in stomach---increased pH Buffering: occurs in both ICF and ECF; in ICF H+ leaves cells in exchange for K+ causing hypokalemia 3) Respiratory Compensation (fast): increased pH inhibits chemoreceptors, hypoventilation, increased PCO2  normalization of HCO3-/PCO2 ratio Renal Compensation/ Correction (slow): increased HCO3- excreted by kidneys when filtered load HCO3- exceeds the ability to reabsorb HCO3- it will be excreted

Metabolic Alkalosis-Vomiting
Vomiting adds the aspect of ECF volume contraction Produces three (possible) secondary effects that act in concert to maintain the metabolic alkalosis (termed contraction alkalosis): 1) ECF volume contraction causes increased HCO3- reabsorption in proximal tubule 2) ECF causes RAAS system to produce more angiotensin II; stimulates Na+-H+ exchange that promoted rabsorption of filtered HCO3- 3) Increased levels of aldosterone stimulate secretion of H+ that complement reabsorption of “new” HCO3- Hence [HCO3-] is increased and the alkalosis is maintained even after vomiting has stopped

Respiratory Acidosis Caused by hypoventilation that results in CO2 retention Causes: Inhibition of medullary respiratory center (central sleep apnea, opiates) Paralysis of respiratory muscles (ALS, polio, MS and Guillain-Barre Syndrome) Airway obstruction (obstructive sleep apnea) Disorders of gas exchange at pulmonary capillary/alveolar interface (pulmonary edema, pneumonia, COPD) Arterial blood profile: decreased pH ; increased [HCO3-] and PCO2 Sequence of events to correct: Retention of CO2: hyperventilation causes CO2 retention and increases PCO2 Buffering: buffering the increased CO2 occurs in the ICF only largely in RBCs within RBCs CO2 H+ + HCO3- where the H+ is buffered by Hb and organic phosphates 3) Respiratory Compensation (fast): no compensation since respiratory problem ‘is’ cause 4) Renal Compensation (slow): increased excretion of H+ and NH4+ and increased synthesis and reabsorption of HCO3- (no renal compensation in acute; only chronic)

Respiratory Alkalosis
Caused by hyperventilation that leads to excessive CO2 loss Caused by: 1) Stimulation of medullary respiratory center (salicylate poisoning, gram-negative septicemia) 2) Hypoxemia-severe anemia, pulmonary embolism, pneumonia, and high altitude 3) Mechanical ventilation Arterial blood profile: increased pH, decreased [HCO3-] and PCO2 Sequence of steps for correction: Loss of CO2- : stimulates peripheral chemoreceptors Buffering: occurs exclusively in the ICF especially RBCs; CO2 leaves cells and pH increases Respiratory compensation: none this is the cause Renal compensation (slow): decreased excretion of of H+ as titratable acid and NH4+ decreased reabsorption of HCO3- that decreases [HCO3-] further chronic: normalizes the hCO3-/CO2 ratio and pH Difference between acute and chronic lies with the renal compensation

Simple Acid/Base Disturbances and Compensation
Important Note Metabolic acidosis and alkalosis move on an axis related to the ability of the kidney to reabsorb HCO3-. Acidosis occurs when plasma HCO3- is low. Alkalosis occurs when plasma HCO3- is high and the ratio to H+ in the nephron is also high. < 7.35 > 7.45

Acidosis Conditions Metabolic Acidosis: Renal Tubular Acidosis (RTA):
Kidney fails to excrete acids formed in the body Excess ingestion of acid Failure to excrete base Renal Tubular Acidosis (RTA): Defect in HCO3- reabsorption Defect in H+ excretion Chronic renal failure Decreased renal function- acid build-up in circulation Decreased HCO3- reabsorption Diarrhea (most common cause): Excess HCO3- lost in feces without time to reabsorb Acid Ingestion Toxins like aspirin and methyl alcohol result in acid build-up Diabetes mellitus Abnormal glucose metabolism Formation of acetoacetic acid, pH decrease May induce renal acid wasting

Alkalosis Conditions Metabolic Alkalosis Diuretic Therapy:
Excess retention of HCO3- Excess loss of H+ Diuretic Therapy: Increased tubular flow Increased Na+ load Increased Na+ reabsorption Increased HCO3- reabsorption Excess Aldosterone Excess Na+ reabsorption Stimulates H+ secretion Vomiting Loss of stomach contents depletes H+ Compensatory removal of H+ from circulation Ingestion of Alkaline Drugs (upset stomach/ulcers) Increased in HCO3-

Acid/Base Balance Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction.

Similar presentations

Presentation on theme: "Acid/Base Balance Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Acid/Base Balance Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction.

Similar presentations

Presentation on theme: "Acid/Base Balance Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction."— Presentation transcript:

Similar presentations

About project

Feedback