Acid Base Balance Flashcards
Why should the pH be kept constant in the body?
- Enzymes function at a particular pH within a narrow range
- Enzymes have a huge number of functions around the body
- Abnormal pH can result in disturbances in a wide range of body systems.
What is the result of an abnormal pH?
- Abnormal respiratory and cardiac functions
- Derangements in blood clotting and drug metabolism
How does the metabolism of carbohydrates and fats produce acid?
CO2 + H2O = H2CO3 (volatile acid), which is reversible with H+ and HCO3-
- CO2 doesn’t usually result in an increase in H+ in the plasma - excreted from the body via the lungs
- H2CO3 produced is known as a volatile acid.
How does protein metabolism produce acid?
- Generates non-volatile (fixed) acids.
Examples: - S-containing amino acids (such as cysteine and methionine) make H2SO4
- lysine, arginine and histidine make HCl
Why do non-volatile acids from metabolism need to be removed quickly?
Otherwise there will be a net gain of H+
What are the 3 mechanisms that compensate for the disturbances in body pH?
- the ICF and ECF buffering systems
- the respiratory system adjustment of ECF PCO2
- the renal adjustment of ECG [HCO3-]
What is the first line of defense against changes in body pH?
- Intracellular and extracellular buffer systems.
- Participate in accordance with their pKa and their quantity.
What is a particularly important buffer system? Why is it important?
CO2-HCO3- buffer system
- CO2 and HCO3-, can be regulated independantly
What is the second mechanism against changes in body pH?
Respiratory system that regulates the plasma PCO2
How does the respiratory system respond to changes in pH?
Controls the excretion or retention of metabolically produced CO2
What is the third mechanism against changes in body pH?
Kidneys
How do kidneys respond to changes in pH?
- Regulates excretion or retention of HCO3-
- Regulates the regeneration of HCO3-
What is a buffer?
Solution that minimises the change in [H+]
What are the advantages of the CO2-HCO3- buffering system? PART 1
- CO2 and HCO3- can be regulated independently.
- Excretion or retention of CO2 is controlled by the lung
- Reabsorption and regeneration of HCO3- is controlled by the kidney.
What are the advantages of the CO2-HCO3- buffering system? PART 2
- Readily available supply of CO2 from cellular metabolism.
Why are other mechanisms apart from buffering needed for pH maintenance? PART 1
- Buffers are present in limited quantities.
- As the buffer capacity is used, less is available to control pH.
Why are other mechanisms apart from buffering needed for pH maintenance? PART 2
- Other mechanisms needed to eliminate the excess H+ or base which caused the change in pH and to restore the buffer capacity to normal.
What does the Henderson-Hasselbalch equation describe?
- Derivation of pH as a measure of acidity in biological and chemical systems, using pKa
- Estimating the pH of a buffer solution and finding the equilibrium pH in acid-base reactions.
What is concentration of dissolved CO2 in plasma proportional to?
Partial pressure of CO2
What is the proportionality constant for plasma at 37 °C?
0.03
What are the primary renal mechanisms involved in the renal control of acid-base levels?
- reabsorption and secretion of HCO3-
- formation of HCO3-
- secretion of [H+] into tubular fluid
- buffer systems within the tubule that react with the secreted [H+]
Describe the movement of bicarbonate in the kidneys.
- Bicarbonate ions are freely filtered by the glomeruli.
- Daily filtered load of bicarbonate is 4500 mmol
What would happen if some of this bicarbonate is excreted through urine?
Stores of this buffer would quickly reduce
What prevents the loss of bicarbonate by excretion?
Avid tubular reabsorption of bicarbonate ions
Describe the renal control of [H+] and [HCO3-]. PART 1
- Filtered HCO3- combines with H+ to form carbonic acid
- Carbonic acid dissociates to form CO2 and H2O this is catalyzed by carbonic anhydrase
- CO2 crosses into the tubular cell down a gradient
- Kidney tubule cells form carbonic acid (H2CO3) from CO2 and water using carbonic anhydrase
Describe the renal control of [H+] and [HCO3-]. PART 2
- The carbonic acid then dissociates into HCO3- and H+
- Na+ moving down its concentration gradient from the tubular fluid into the cell provides energy for the secondary active secretion of H+ into the tubule lumen.
- ATP provides energy for the primary active secretion of H+ from the cell into the lumen.
- With each H+ that is secreted, one HCO3- enters the blood accompanied by Na+.
When are new HCO3- ions generated?
When H+ derived from the intracellular H2CO3 is secreted into the tubule and buffered in the tubular fluid by a non-bicarbonate buffer.
What are the effects of carbonic anhydrase inhibitors?
- Inhibit the formation of H+ for the acidification of the tubular fluid.
- Reabsorption of HCO3- is inhibited
- Causes acidosis and loss of Na+
Describe the regeneration of bicarbonate. PART 1
- Concentration of bicarbonate in the tubular fluid is equivalent to that of plasma.
- If the bicarbonate were not reabsorbed, the buffering capacity of the blood would rapidly be depleted.
- Reabsorption occurs in PCT
Describe the regeneration of bicarbonate. PART 2
- Filtered bicarbonate combines with secreted hydrogen ions forming carbonic acid.
- Carbonic acid then dissociates to form CO2 and water - catalysed by carbonic anhydrase, which is present in the luminal brush border of the proximal tubular cells
Describe the regeneration of bicarbonate. PART 3
- CO2 readily crosses into the tubular cell down a concentration gradient.
- Inside the cell, the CO2 recombines with the water, again under the influence of of carbonic anhydrase, to form carbonic acid.
- The carbonic acid further dissociates to bicarbonate and hydrogen ions.
- The bicarbonate passes back into the blood stream, whilst the H+ passes back into the tubular fluid in exchange for sodium.
Describe the acidification of urine. PART 1
- H+-ATPase pump becomes more important in the later part of the nephron in allowing H+ to be secreted against a substantial [H+] gradient.
- Secretion of H+ is rate limiting and the pH can fall to as low as 4.5 in the collecting duct when the maximal rates of H+ secretion are achieved.
- At this pH, the rate of H+ back diffusion equals the rate of H+ secretion. Urine becomes acidified
Outline the role of the collecting tubule in urine acidification.
- Bicarbonate concentration of the tubular fluid reaching the collecting tubule is low
- Proton secretion can reduce the tubular fluid pH substantially.
- Phosphate and ammonia are titrated and acid is formed for excretion.
How can the amount of H+ secreted during HCO3- regeneration be estimated?
Measuring the amount of NaOH required to titrate the urine back to pH 7.4
Describe phosphate as a buffer. PART 1
- Poor buffers in the ECF because they are low in concentration.
- Filtered at the glomerulus and the filtered load of phosphate exceeds its reabsorptive Tm, so the excess phosphate becomes concentrated in its progress along the tubule. - Good buffer in tubular fluid
- Large amount reabsorbed in the proximal tubules, so it is not present in very high quantities.
Describe phosphate as a buffer. PART 2
- pK is 6.8, close to the pH of the filtrate
- Acceptance of a proton still leaves it with one negative charge.
- Remains lipid-insoluble and cannot diffuse back into the blood carrying protons with it.
Where are the largest amounts of carbonic anhydrase found?
Intercalated cells of the distal tubule and the collecting duct
Where is there no carbonic anhydrase?
Luminal brush border
What transporter protein is used for bicarbonate transport?
Secondary active Cl-HCO3- exchanger.
What does the regeneration of HCO3- occur by?
Secretion of H+ that reacts with nonbicarbonate buffers present in the glomerular filtrate.
Describe ammonia as another buffer. PART 1
- Ammonium ions are produced in several tubular segments from glutamine, which enters the tubular epithelial cells by an active mechanism.
- 2 NH4 and 2 HCO3- molecules are produced from each glutamine molecule.
- Glutamine is metabolised to NH3 and an α-ketoglutarate ion, which is further metabolised to CO2 and H2O.
Describe ammonia as another buffer. PART 2
- Hydrated to form H+ and HCO3- by carbonic anhydrase.
- H+ combines with the NH3, forming NH4+, which is secreted into the lumen by a sodium-driven secondary active antiporter.
List the three stages of urine buffering and the reinforcement of plasma bicarbonate concentration.
- reabsorption of bicarbonate
- formation of titratable acid phosphate
- ammonia secretion which creates new bicarbonate
Describe the role of the respiratory system.
- Regulated by the H+ concentration of the CSF (cerebrospinal fluid) in the chemosensitive area of the medulla.
- Chemosensitive area doesn’t respond to plasma H+ directly because of the inability of charged ions to cross the blood-brain barrier.
- CO2, however, can cross the barrier and then be hydrated to form H2CO3, which dissociates to produce H+ and HCO3-.
What is the result of an elevated plasma PCO2?
- Decreased CSF pH
- Stimulates pulmonary ventilation
- Increases respiratory excretion of CO2 - decreases the PCO2
- Returns ECF pH towards the normal range of 7.35 to 7.45.
- Opposite for decreased PCO2
Where are peripheral chemoreceptors found?
- Aortic arch
- Carotid bodies
How do chemoreceptors respond to decreased plasma pH?
Stimulating respiratory excretion of CO2
How is pH regulated in red blood cells? PART 1
- CO2 equilibrates rapidly across the RBC membrane.
- In the RBC the high concentration of carbonic anhydrase facilitates the reaction of CO2 with H2O.
How is pH regulated in red blood cells? PART 2
- Dissociation of H2CO3 to HCO3- and H+
- Buffering of H+ by haemoglobin
- Subsequent exchange of HCO3- for CL- has a direct effect on the ECF HCO3- and PCO2 levels, and therefore on pH.
Describe metabolic acidosis.
Low pH as a result of increased ECF [H+] or decreased ECF [HCO3-].
What is metabolic acidosis caused by? For each cause, briefly state how acidosis is induced.
- severe sepsis or shock, producing lactic acid
- uncontrolled diabetes - overproduction of 3-OH-butyric acid and other ketoacids
- diarrhoea, leading to the loss of HCO3- from the GI tract
Describe integrated renal and pulmonary compensation for metabolic acidosis. PART 1
- In the ECF/ICF buffering system, the [HCO3-] falls as it is used to mop up the H+.
- Rise in [H+]/decreased pH stimulates respiration by acting on the peripheral chemoreceptors to cause hyperventilation and expel more CO2.
- Respiratory compensation allows the pH to return towards normal because the ratio of HCO3 to CO2 rises.
Describe integrated renal and pulmonary compensation for metabolic acidosis. PART 2
- Buffering and hyperventilation are not fully effective in preventing a rise in [H+]
- [H+] remains raised throughout the body.
- Renal compensation for metabolic acidosis involves the maximal conservation of filtered HCO3- and the increased regeneration of new bicarbonate.
- Kidney stimulates H+ secretion to increase HCO3- reabsorption.
Describe integrated renal and pulmonary compensation for metabolic acidosis. PART 3
- Over days, the kidney (except in renal failure) may be able to correct the disturbance by excreting the excess H+.
- Plasma [H+] returns to normal and ventilation is also normalised.
- Ammonium secretion also plays a major role in renal generation of new HCO3-.
Describe metabolic alkalosis.
- Alkaline urine with bicarbonate in it.
→ Increase in ECF HCO3-
→ Decrease in ECF H+
How do diuretics such as frusemide and thiazide contribute to alkalosis?
- Inhibit carbonic anhydrase
- Interfere with reabsorption of chloride and sodium in the renal tubules.
- Urinary losses of chloride exceed those of bicarbonate.
- Also volume-depleted (increasing aldosterone levels) and have a low dietary chloride intake (‘salt restricted’ diet).
What condition is common in alkalosis patients?
Hypokalaemia
Describe the integrated renal and pulmonary compensation for metabolic alkalosis. PART 1
- H+ in the blood is used up in trying to reduce an increase in bicarbonate ions, and the fall in H+ reduces the stimulation of peripheral chemoreceptors
- Ventilation is reduced
- Less CO2 is expelled, so [CO2] rises.
Describe the integrated renal and pulmonary compensation for metabolic alkalosis. PART 2
- More H+ is generated and [HCO3-] rises further.
- pH returns to normal because the ratio of HCO3-:CO2 falls towards normal.
How do the kidneys help remove the inhibitory effect on ventilation?
- Rise in pH in the tubule cells reduces H+ secretion and HCO3- reabsorption
- Allows the plasma [H+] to rise and correct the plasma HCO3-
What is it about plasma that controls pH?
→ Presence of buffers that are effective in vivo
What is the equation for the bicarbonate system?
→ H+ + HCO3- ⇌ H2CO3 ⇌ CO2 + H2O
What is the equation for the phosphate system?
→ H+ + HPO4 2- ⇌ H2PO4-
What is pK?
→ The equilibrium point of a buffer
→ Where it most strongly resists changes in pH
Which buffer is theoretically better and why?
→ Phosphate
→because the PK lies within the body pH ranges
What are the 2 ways H+ gets into urine?
→ H+ ATPase
→ while Na+ moves in H+ moves out
What happens to the HCO3- in tubular cells?
→ diffuses out and goes back into blood
→ Via a symporter with Na+ ions
Where is most HCO3- reabsorbed?
→ 85-90% at the proximal tubule
What can bicarbonate reabsorption also be stimulated by?
→ angiotensin II
What is the pH like in the DCT and why?
→H+ ATPase pumps out the H+
→ DCT has a lower pH
→ HCO3- is low because it has been reabsorbed and H+ needs to react with other buffers
What is the fate of H+ with phosphate in intercalated cells?
- Carbonic acid dissociates into H+ and HCO3-
- H+ is secreted via ATPase (aldosterone sensitive)
- Reacts with phosphate andbecomes H2PO4-
- Excreted into urine
- HCO3- reabsorbed with a HCO3- / Cl antiporter
What is metabolic alkalosis caused by?
→ Excessive diuretic use
→ Vomiting - loss of H+
→ Antacids
→ Hypokalemia
