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Flashcards in Acid-Base Balance Deck (22)
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Why should the pH be kept constant in the body?

Enzymes function at a particular pH within a narrow range, and as enzymes have a huge number of functions around the body, an abnormal pH can result in disturbances in a wide range of body systems.
Thus, disturbances in pH may result in abnormal respiratory and cardiac functions, derrangements in blood clotting and drug metabolism, etc.


What are some sources of acid in the body?

The metabolism of carbs and fats produces CO2.
CO2 + H2O = H2CO3 (volatile acid), which is reversible with H+ and HCO3-

CO2 produced as a result of carbohydrate metabolism doesn't usually result in an increase in H+ in the plasma because it is excreted from the body via the lungs - hence, the H2CO3 produced is known as a volatile acid.

The metabolism of proteins generates non-volatile (fixed) acids.
- S-containing amino acids (such as cysteine and methionine) make H2SO4
- lysine, arginine and histidine make HCl

Sulphur-containing amino acids produce sulphuric acid, which is non-volatile - these non-volatile acids need to be removed, 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?

The first line of defence consists of the intracellular and extracellular buffer systems. All the buffer systems participate in accordance with their pKa and their quantity.
Of particular importance is the CO2-HCO3- buffer system, which is the major extracellular buffer system. The importance of this system is physiological in that the components of the system, CO2 and HCO3-, can be regulated independantly.


What is the second mechanism against changes in body pH?

The second mechanism is the respiratory system that regulates the plasma PCO2 by controlling the excretion or retention of metabolically produced CO2 in response to changes in pH.


What is the third mechanism against changes in body pH?

The third mechanism is the kidney, which plays a dual role; it regulates excretion or retention of HCO3-, and also regulates the regeneration of HCO3-.


What is a buffer?

It is a solution that minimises the change in [H+].
A buffer is usually a base that accepts H+.


What are the advantages of the CO2-HCO3- buffering system?

The unique physiological advantage of this buffer system is that the acid form (CO2) and the salt form (HCO3-) can be regulated independently. Excretion or retention of CO2 is controlled by the lung and reabsorption and regeneration of HCO3- is controlled by the kidney.

A second advantage is that there is a readily available supply of CO2 from cellular metabolism. It is important to note that, while buffering is the first, and immediate defense against changes in H+ concentration, the buffers are present in limited quantities. As the buffer capacity is used, less is available to control pH. It is, therefore, necessary to have mechanisms to eliminate the excess H+ or base which caused the change in pH and to restore the buffer capacity to normal. This is the role of the renal and respiratory systems.


What does the Henderson-Hasselbalch equation describe?

The Henderson-Hasselbalch equation describes the derivation of pH as a measure of acidity (using pKa, the negative log of the acid dissociation constant) in biological and chemical systems. The equation is also useful for estimating the pH of a buffer solution and finding the equilibrium pH in acid-base reactions.
The concentration of dissolved CO2 in the plasma is proportional to the partial pressure of CO2 (pCO2). The proportionality constant for plasma at 37°C, which converts PCO2 in mmHg to the concentration of dissolved CO2 expressed as mmol/L is 0.03. Hence, you can equate the denominator in the HH equation as 0.03 x PCO2. Thus, when you rewrite the concentration ratio of bicarbonate to carbon dioxide is ~20:1.


What are the primary renal mechanisms involved in the renal control of acid-base levels?

- 'reabsorption' and secretion of HCO3-
- formation of 'new' HCO3-
- secretion of [H+] into tubular fluid
- buffer systems within the tubule that react with the secreted [H+] (such as: NH3:NH4+ / HPO4 2-:H2PO4- / HCO3-:H2CO3


Describe the movement of bicarbonate in the kidneys.

Like Na+ and other small solutes, bicarbonate ions are freely filtered by the glomeruli. In adult humans, the daily filtered load of bicarbonate is 4500 mmols.

If even a small portion of this was excreted in the urine, normal stores of this important buffer would be quickly exhausted. This is prevented by avid tubular reabsorption of bicarbonate ions (>99.9%), such that only 2 mmol of bicarbonate ions are excreted in the urine each day.


Describe (molecularly) the renal control of [H+] and [HCO3-].

Kidney tubule cells form carbonic acid (H2CO3) from CO2 and water under the influence of the enzyme carbonic anhydrase.
The carbonic acid then dissociates (into HCO3- and H+), and the 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 provided 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+, which has been swapped for the H+ buffering in the ECF.

New HCO3- is generated only when H+ derived from the intracellular H2CO3 is secreted into the tubule and buffered in the tubular fluid by a non-bicarbonate buffer. Inhibitors of this enzyme, such as acetazolamide, will inhibit the formation of H+ for the acidification of the tubular fluid. When this occurs, reabsorption of HCO3- is inhibited, leading to acidosis, loss of Na+, which is oblogated to the unreabsorbed HCO3- and diuresis.


Describe (molecularly) the regeneration of bicarbonate.

The 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. The process of reabsorption of bicarbonate occurs mostly in the proximal convoluted tubule.

Filtered bicarbonate combines with secreted hydrogen ions forming carbonic acid. Carbonic acid then dissociates to form CO2 and water. This reaction is catalysed by carbonic anhydrase, which is present in the luminal brush border of the proximal tubular cells only. The 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, In this way, virtually all the filtered bicarbonate is reabsorbed in the healthy individual.

Technically, HCO3- cannot be reabsorbed at the luminal membrane. It's really the formation of new HCO3- from within the tubule that accounts for the 'reabsorption'. One HCO3- ion disappears from the tubular fluid and another HCO3- ion is added to the blood.


Describe the acidification of urine.

The H+-ATPase pump becomes more important in the later part of the nephron in allowing H+ to be secreted against a substantial [H+] gradient.
This secretion of H+ is rate limiting and the pH can fall to as low as 4.5 in the collecting duct (though urine never becomes more acidic than this) when the maximal rates of H+ secretion are achieved. At this pH, the rate of H+ back diffusion equals the rate of H+ secretion. The urine is acidified in this process and the amount of H+ secreted in the regeneration of HCO3- can be estimated by measuring the amount of NaOH required to titrate the urine back to pH 7.4, hence the term titratable acid.

The collecting tubule plays a substantial role in the acidification of urine. Usually, the bicarbonate concentration of the tubular fluid reaching the collecting tubule is low and the proton secretion can reduce the tubular fluid pH substantially. In doing so, phosphate and ammonia are titrated and acid is formed for excretion.


Describe phosphate as another buffer.

Phosphate ions are poor buffers in the ECF because they are low in concentration. However, it is 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. Thus, it is a very good buffer in tubular fluid; however, we also get a large amount being reabsorbed in the proximal tubules, so it is not present in very high quantities.

Phosphate is one of the more important urinary buffers: its pK is 6.8, close to the pH of the filtrate, and the acceptance of a proton still leaves it with one negative charge. Thus, it remains lipid-insoluble and cannot diffuse back into the blood carrying protons with it.

There are large amounts of carbonic anhydrase within intercalated cells of the distal tubule and the collecting duct, but there is none in the luminal brush border. Bicarbonate transport is via the secondary active Cl-HCO3- exchanger.

The regeneration of HCO3- occurs by the secretion of a H+ that reacts, not with HCO30, but with nonbicarbonate buffers present in the glomerular filtrate.


Describe ammonia as another buffer.

The ammonia buffer system plays an important role in the regeneration of HCO3-.
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 H"O. This is then hydrated to form H+ and HCO3- by carbonic anhydrase. The 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.

1) reabsorption of bicarbonate
2) formation of titratable acidphosphate
3) ammonia secretion with creates new bicarbonate


Describe the role of the respiratory system.

Briefly, respiration is regulated primarily by the H+ concentration of the CSF (cerebrospinal fluid) in the chemosensitive area of the medulla. The 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-. Thus, the elevated plasma PCO2 leads to a decreased CSF pH, which stimulates pulmonary ventilation, increasing the respiratory excretion of CO2, decreasing the PCO2 and returning ECF pH towards the normal range of 7.35 to 7.45.

An decrease in PCO2 has the opposite effect on the central regulation of ventilation and respiratory excretion of CO". Peripheral chemoreceptors in the aortic arch (and particularly in the carotid bodies) also respond to decreased plasma pH by stimulating respiratory excretion of CO2.

An increase in pH has the opposite effect. Erythrocyte haemoglobin content plays a central role in linking respiratory and renal mechanisms. CO2 equilibrates rapidly across the RBC membrane. In the RBC the high concentration of carbonic anhydrase facilitates the hydration. dehydration reaction of CO2 with H2O. The dissociation of H2CO3 to HCO3- and H+, followed by the buffering of H+ by haemoglobin and the subsequent exchange of HCO3- for CL- has a direct effect on the ECF HCO3- and PCO2 levels, and therefore on pH.


Describe metabolic acidosis.

It is characterised by low pH as a result of increased ECF [H+] or decreased ECF [HCO3-].

It is caused by:
- severe sepsis or shock, producing lactic acid
- uncontrolled diabetes, leading to the 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.

In the ECF/ICF buffering system, the [HCO3-] falls as it is used to mop up the H+. Assuming there is no respiratory disorder, the rise in [H+]/decreased pH stimulates respiration by acting on the peripheral chemoreceptors to cause hyperventilation and expel more CO2. This respiratory compensation allows the pH to return towards normal because the ratio of HCO3 to CO2 rises.

However, because the buffering and hyperventilation are not fully effective inpreventing a rise in [H+], the [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. To do this, the kidney stimulates H+ secretion to increase HCO3- reabsorption. Over days, the kidney (except in renal failure) may be able to correct the disturbance by excreting the excess H+ and adding to the plasma [H+[ that was lost as a result of the primary disturbance and as a secondary consequence of the respiratory compensation.

Once this has happened, 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.

In alkalosis, we get alkaline urine with bicarbonate in it. Normally, we would always get acidic urine as the HCO3- is destroyed.

Diuretics such as frusemide and thiazides interfere with reabsorption of chloride and sodium in the renal tubules. The urinary losses of chloride exceed those of bicarbonate. The patients on diuretics who develop an alkalosis are those who are also volume depleted (increasing aldosterone levels) and have a low dietary chloride intake ('salt restricted' diet).

Hypokalaemia is common in these patients. If dietary chloride intake is inadequate, then an alkalosis is unlikely to develop. This is the main reason why every patient taking diuretics (such as thiazides or lasix) doesn't develop a metabolic alkalosis.


Describe the integrated renal and pulmonary compensation for metabolic alkalosis.

What happens in this scenario is, essentially, the opposite of what happens in metabolic acidosis. The 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 and, therefore, less CO2 is expelled, so [CO2] rises. This respiratory compensation therefore drives the reaction further to the right so that more H+ is generated and [HCO3-] rises further. The pH returns to normal because the ratio of HCO3-:CO2 falls towards normal.

However, the kidney corrects this disturbance over several days. The rise in pH in the tubule cells reduces H+ secretion and HCO3- reabsorption, so allowing the plasma [H+] to rise and correct the plasma HCO3-, finally removing the inhibitory effect on ventilation.

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