Acid-Base Balance Flashcards

1
Q

Why is is important for H+/pH be kept constant?
What can this disturb?

What is the normal pH value?
why do we use pH? What does a low pH mean in terms of H+?

A

It is very important for normal body functions that [H+]/pH of body fluids is kept constant.
This is because enzymes function at a particular pH within a narrow range and as enzymes have such a huge number of functions in the body an abnormal pH can disturb may body systems e.g. blood clotting, cardiac function, drug metabolism.

• The normal [H+]/pH of body fluids is 7.35-7.45.
• Normal plasma [H+] is 0.00000004mol/L (40nM). This would be difficult to communicate so we use pH which is the inverse log of [H+]. –log10[H+].
Because it is inverse correlation, a low pH means there is a high concentration of hydrogen ions, it is acidic.

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2
Q

Source of this acid in the body?

How can we control H2CO3?
How does the meabolism of proteins differ?
Why acids are produced and why do they need to be removed?

A

We get acid from the metabolism of carbs and fats, which produces CO2, this reacts in the well-known equation
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-

H2CO3 is carbonic acid, it is a volatile acid and so it is usually not really a problem, because we can reduce the amount of carbonic acid by blowing off CO2, which shifts some of those protons to the left.

Another source of acid is the metabolism of proteins and this generates non-volatile (fixed) acids.
So, proteins that contain Sulphur containing amino acids (cysteine, methionine) will produce H2SO4.
- Lysine, arginine, histidine will produce HCl

These non-volatile acids need to be removed otherwise we will build up H+

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3
Q

Control of pH

We learnt about control of pH through experiments about dog and water

A

• 156ml of HCl were infused IV into a dog and the same amount of acid was added to 11.4L of water (equivalent to total body water of the dog), the pH changes in both were compared.

  • It was found the pH of the dog’s arterial plasma decreased gradually from 7.44 to 7.14 (a state of severe acidosis, but one still comparable to survival). However, the pH of the distilled water dropped rapidly to a final level of 1.84, that would be fatal if it occurred in vivo (in living thing).
  • So, it is the presence of buffers which are controlling the pH in vivo.
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4
Q

Overview of pH control

What 3 systems compensate for a disturbance in pH?

What is the base buffer?

What contols the acids?

What system has a dual role? How can it have dual roles?

A

A disturbance in [H+]/pH is compensated for by:

  1. ICF and ECF buffering systems
  2. The respiratory system
  3. The kidney.

The first line of defence against pH changes consists of the intracellular and extracellular buffer systems. All buffer systems participate according to their pK and their quantity. Of particular importance is the bicarbonate buffer system which is the major EC buffer.

The second mechanism is the respiratory system which regulates plasma PCO2, by controlling excretion or retention of metabolically produced CO2, the acid component of the bicarb buffer system.

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-.
 This is how the kidney helps regulate pH by dealing with H+ through bicarbonate.

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5
Q

Blood Buffering Systems
what are the three blood buffering systems?
How do they work? (equations)

A

Bicarbonate buffer system
H+ + HCO3- H2CO3 CO2 + H2O

[H+] = K1 [CO2] / [HCO3-]

The phosphate system
H+ + HPO42- H2PO4-

[H+] = K2 [H2PO4-] / [HPO42-]

The protein buffers (inc. Hb)
H+ + Pr- HPr

H+ = K3 [HPr] / [Pr-]

The equilibrium reactions shown (with acid on top and anion on bottom) tell us that by altering the concentrations of what is in the numerator/denominator will alter the [H+] and hence pH.

K is the equilibrium constant of the reaction.

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6
Q

pH Buffering

How do we measure the effectiveness of a buffer? What value do we look at?

When is the phosphate system effective? Bi-carbonate system?

BIochemistry wise which is the better buffer?

Why is this different in reality?

A

To measure the effectiveness of a buffer we look at the pK, when the pH is equal to the pK is means the concentration of acid equals the concentration of the base. A buffer is means to be effective 1pH under and above its pK.

The phosphate system is very effective over the pH range of 5.8-7.8 and the bicarbonate buffer system is most effective over 5.1-7.1. We know that physiologically the range of survival of for us is around 6.8-7.8.

If we take a line up from the x-axis for this range so that it intersects each curve at two points, we can see the effectiveness of each buffer.

So, if we take the line up and see on the phosphate graph, we can see that for 100mmol of phosphate buffer will buffer this amount [H+] (the height on y-axis) over that range of pH we’re looking at.
- I.e. The phosphate buffer can maintain this range of pH compatible with life despite adding this large amount of [H+]

If we do the same for bicarbonate, we see that 100mmol of bicarbonate will only buffer a small amount of [H+] over this range compatible with life.
- I.e. It can only cope with a smaller amount of [H+] to keep pH within range, if we add just a bit more, pH will start drop below 6.8

This obviously tells us at the range of pH we’re looking at, compatible with life, the phosphate buffer is much better than the bicarbonate buffer. This is from the biochemical perspective

However, despite this we know that physiologically the bicarbonate buffer system is the most important buffer in the body. The reason is because both the CO2 and HCO3- can be regulated independently and relatively quickly in the body.

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7
Q

Bicarbonate Buffer System

HOw do we switch H+ equation to pH?
whta is plasma co2 proportional to?
how do we convert pco2 to co2?

what is the concentration ratio of bicarbonate to carbon dioxide?

How can you calculate pH clinically?

A

We have the equation to calculate [H+] but as this is tedious we want to work out the pH, so we do the inverse log of it instead, this means we have to log K, so it becomes pK and also switch around the fraction.

The equation allows us to focus on the [HCO3-]: [CO2] ratio, this is the most important thing in determining pH.
Plasma [CO2] is proportional to partial pressure of CO2 (pCO2) in plasma.
So, to convert PCO2 to [CO2] we multiply PCO2 by 0.03.

This gives us a ratio of 24:1.2. Commonly measured and spoken about clinically is 20:1.

measure pH with arterial blood gases (ABG)

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8
Q

Importance of Buffers Summary

What is pK?
When is buffer most effective?
What is unique about the co2-hco3 buffer?
(2 systems)

role of renal and resp systems? (why must excess base/acid be eliminated quickly?)

A

pK is the equilibrium constant of the reaction. Buffer solutions resist changes in pH when [base] = [acid], the buffer is most effective 1pH either side of the pK.

At 6.1 the pK of CO2-HCO3- buffer is not close to the desired plasma pH of 7.4.
However the unique thing about this buffer is that alveolar ventilation controls PCO2 (acid form) and the kidneys control [HCO3-]ECF (salt form).
Each do this INDEPENDENTLY, we can control it very quickly, we can add/replenish each.

Very importantly, buffers are in limited supply, as buffer capacity is used there is less available to control pH! So the excess acid/base must eventually be eliminated otherwise it will start to cause a change in pH, this is the role of the renal and respiratory systems.

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9
Q

Renal Control of Acid-Base Levels

How does kidney control both acid and base levels?
what is the primary renal mechanism behind this? (hco3- and H+)
How can we release H+ in the urine?

A

So these H+ we are generating need to be eliminated, kidneys control acid-base levels by excretion of acidic or basic urine.

The primary renal mechanisms involved in this are:
- We can reabsorb and secrete HCO3- to alter the ECF levels of bicarb (if HCO3- is excreted into urine it removes the base from the blood, similarly to replenish bicarb that was used in buffering fixed acids, an equivalent amount of H+ are excreted into urine)

  • Kidney can also form new HCO3-
  • Kidney can secrete [H+] into the tubular fluid
  • Remember that [H+] does have to be buffered in the urine, so there are buffer systems within the tubule that react with secreted [H+]:
  • > NH3 – NH4+, HPO42- - H2PO4-, HCO3- - H2CO3
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10
Q

Kidneys & Buffering System

What are the 3 main buffers?
Role of each buffer

A

The main buffers as we spoke of previously are bicarbonate, phosphate and proteins.

o Proteins are not filtered so remain in the plasma while the bicarbonate and phosphate are freely filtered through.

o The phosphate can be reabsorbed from the tubule, if needed back in blood. But they are also present in the tubular fluid to bind any [H+] present in the tubular fluid.

o The bicarbonate can also be reabsorbed in order to replenish its levels in the blood, if it is being used up. However, the kidney also has the ability to make new bicarbonate.

Even if small amounts of bicarb were excreted, our normal body stores of this buffer would quickly be exhausted, which is why reabsorption is so important.

Ammonia also contributes to buffering. Overall, we produce an acidic urine.

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11
Q

Renal Control of [H+] and [HCO3-]

How do we get carbonic acid? what enzyme is needed?

How is H+ excreted into urine? 2 ways

What happens to bi-carbonate?

What inhibits carbonic anhydrase? What is a consequence of this?

A

In the tubular cells, water combines with CO2 to form carbonic acid and this is via the enzyme, carbonic anhydrase.

Carbonic acid dissociates into its two ions, bicarbonate and H+.

Depending on the part of the kidney you’re in, the H+ will be kicked out into the lumen via an antiport that brings in a Na+ at the same time, or in another part of the kidney you’ll have it kicked out via a H+ ATPase pump (common in intercalated cells)

The bicarbonate goes back into blood along with Na+ which moves down its gradient.

Carbonic anhydrase can be inhibited by acetazolamide and other thiazide diuretics, a consequence of this is there will not be formation of H+ or bicarbonate, hence you will not get acidification of the urine, you will instead be at risk of becoming acidotic.

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12
Q

Renal Control of [H+] and [HCO3-]
What happens in pct?

What happens to HCO3 in PCT?
Is there H+ ATPase in PCT?
Comparison of HCO3 levels in plasma vs GF?
Why must HCO3 must be reabsorbed?
What happens in the lumen to filtered hco3?
Where is carbonic anhydrase situated in lumen?
What happens to co2?
What happens to Bicarb and H+ in cell?
Why is it the formation of new bicarb that accounts for reabsorption?
Why isn’t urine pH very low?
what is the net result?

A

In the PCT, the majority of HCO3- is ‘reabsorbed’. The PCT also has a great capacity to secrete H+

(note in PCT we do not have the H+ ATPase)

Bicarbonate ions are freely filtered by the glomerulus, hence the concentration of bicarbonate in the tubular fluid is equivalent to that of plasma.
If bicarbonate were not reabsorbed the buffering capacity of the blood would rapidly be depleted.

The process of reabsorption of bicarbonate mainly occurs in the PCT, filtered bicarb combined with secreted H+ forming carbonic acid in the tubular lumen. Carbonic acid then dissociates into carbon dioxide and water, this reaction is catalysed by carbonic anhydrase present on the luminal brush border of the PCT cells only.

The CO2 readily crosses the tubular cell down its conc. gradient. Once inside, CO2 recombines with water and again under carbonic anhydrase forms carbonic acid.

Carbonic acid dissociates into H+ and bicarbonate. Bicarb passes back into blood with Na+ and H+ passes back into the tubular fluid in exchange for Na+.

In this way, virtually all filtered bicarb is ‘reabsorbed’ in a healthy individual. Technically the bicarb cannot be absorbed at the luminal membrane it is really the formation of a new bicarb from within the tubule that accounts for ‘reabsorption’.
One bicarb ion disappears from the tubular fluid and another one is added to the blood.

The H+ appear in urine as water and hence the urine pH is not changed that dramatically. The net result is the reabsorption of bicarb, a slight fall in tubular pH (from 7.4 – 7, there is not much acidification) and no change in PCO2 of tubular fluid.

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13
Q

What happens in DCT? Cell involved?
what pump is more important here?
What is the pH at this point?
IF bicarb levels are low, what does H+ react with?
Will this lower ph? what is the point of reacting wth other buffer?

A

Remember that Ang II can also stimulate the Na+/HCO3- symporter, which can (in cases of high Ang II) lead to alkalosis.

In the intercalated cells of the late distal tubule and collecting duct the H+ ATPase pump is much more important.

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.

Here we have a lot of H+ being pumped in and the pH drops quite significantly (a lot of acidification, from 7-4.6 by end of collecting duct).

In the distal part of the nephron, the bicarb levels are low as most has been reabsorbed, so H+ needs to react with other buffers (remember, these will not lower the pH, they are weak acids themselves, instead they help reform the HA by accepting protons, keeping H+/pH around about constant) in the tubule.

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14
Q

Other Buffers – Phosphate

why is phopshate a poor buffer in ECF?
Why does this change in kidneys?
Why is phosphate an effective buffer in kidneys?
Why is the ATP-H+ effective here?
what happens to H+?
What happens to bicarb?
A

One of the very important buffers as mentioned earlier is phosphate. Phosphate ions are poor buffers in ECF due to their low concentration. But when filtered at the glomerulus the filtered load of phosphate exceeds the Tm, so excess phosphate gets concentrated.

The further secretion of H+ into the lumen is buffered by HPO42-. This is because it is a very effective buffer due to the pK being 6.8 (close to pH of filtrate). It also is lipid-insoluble due to its negative charge even after accepting a proton so can’t carry it back into blood.

On a cellular level, we get the same reaction of generating carbonic acid. The H+ ATPase pump is effective here (note it is aldosterone sensitive).

The H+ is pumped through and binds to the mono-hydrogen phosphate and it accepts it very readily. Because the phosphate retains a –ve charge it essentially traps the proton in the urine.

In this part of the tubule, the bicarbonate enters back into the blood through an antiporter system with chloride.

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15
Q

Other Buffers – Phosphate

why is phopshate a poor buffer in ECF?
Why does this change in kidneys?
Why is phosphate an effective buffer in kidneys?
Why is the ATP-H+ effective here?
what happens to H+?
What happens to bicarb?
A

One of the very important buffers as mentioned earlier is phosphate. Phosphate ions are poor buffers in ECF due to their low concentration. But when filtered at the glomerulus the filtered load of phosphate exceeds the Tm, so excess phosphate gets concentrated.

The further secretion of H+ into the lumen is buffered by HPO42-. This is because it is a very effective buffer due to the pK being 6.8 (close to pH of filtrate). It also is lipid-insoluble due to its negative charge even after accepting a proton so can’t carry it back into blood.

On a cellular level, we get the same reaction of generating carbonic acid. The H+ ATPase pump is effective here (note it is aldosterone sensitive).

The H+ is pumped through and binds to the mono-hydrogen phosphate and it accepts it very readily. Because the phosphate retains a –ve charge it essentially traps the proton in the urine.

In this part of the tubule, the bicarbonate enters back into the blood through an antiporter system with chloride.

The ammonium is secreted as ammonium salts, these levels can vary.

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16
Q

Summary of ammonia

A
  1. Reabsorption of bicarbonate
  2. Formation of titratable acid phosphate
  3. Ammonia secretion which creates new bicarbonate
17
Q

Disturbances in Acid- Base Balance

what is acidosis and alkosis?
how can these be further categorised?

Change in pH corrected by 3 mechanisms

A

Disturbances in acid-base balance are described as acidosis (plasma pH < 7.4) or alkalosis (plasma pH > 7.4), the cause can either be respiratory or metabolic

Change in pH corrected by 3 mechanisms

1) Intra- and extra-cellular buffering
2) Respiratory adjustment of ECF PCO2
3) Renal adjustment of ECF [HCO3-]

Importantly, if we do not correct the underlying cause of the acidosis/alkalosis, then we will not be able to bring everything back to normal.

18
Q

Disturbances in Acid- Base Balance

what is acidosis and alkosis?
how can these be further categorised?

Change in pH corrected by 3 mechanisms

what happens if we dont fix underlying cause?

A

Disturbances in acid-base balance are described as acidosis (plasma pH < 7.4) or alkalosis (plasma pH > 7.4), the cause can either be respiratory or metabolic

Change in pH corrected by 3 mechanisms

1) Intra- and extra-cellular buffering
2) Respiratory adjustment of ECF PCO2
3) Renal adjustment of ECF [HCO3-]

Importantly, if we do not correct the underlying cause of the acidosis/alkalosis, then we will not be able to bring everything back to normal.

19
Q

Role of the Respiratory System

what regulates respiration?
Where are the central chemoreceptors?
How do they measure pH? role of co2?

where are peripherial chemo receptors?
what happens if increase in plasma co2?

Role of haemogloblin?

A

In brief, respiration is regulated primarily by the [H+] in the CSF in the Chemosensitive areas of the medulla. These are the central chemoreceptors.

Charged ions (such as H+) cannot cross the BBB, however CO2 can so it diffuses through undergoes the reaction with water to ultimately produce H+. The central chemoreceptors measure the pH of the CSF which is how they monitor pH balance.

If there is an increase in plasma PCO2, due to whatever reason, then the plasma pH will drop (detected by peripheral chemoreceptors in aortic arch and carotid bodies) as will the CSF pH.

As a result, to prevent further acidosis the central chemoreceptors will signal to increase ventilation to blow off this excess CO2 and normalise pH.

Erythrocyte Haemoglobin Links Respiratory and Renal Mechanisms

Because Hb in RBCs acts as a buffer, it is important in signalling changes in pH to the lungs and kidney.

20
Q

Metabolic Acidosis
what is characterised by?
key equations?
3 ways it can be caused

A

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

Remember the equation
[H+] = K1 [CO2] / [HCO3–]

pH = pK + log [HCO3-] / [CO2]

Metabolic acidosis may be caused by:

  • Severe sepsis, where you end up producing a lot of lactic acid
  • Uncontrolled diabetes, where there is overproduction of 3-OH butyric acid and other keto acids
  • In diarrhoea there may be substantial loss of HCO3- from GI tract
21
Q

Integrated renal & pulmonary compensation

If there is an increased H+
what is the first line of defence?
what comes into play next and why? what sets this off/detects H+?

what is the last mechanism?
what is levels are very high, what happens then? (why is ammonia secretion beneficial?)

A

So, when there is an increase in [H+] for metabolic reason, the first line of defence is the ICF/ECF buffering. So, this will come into play and the HCO3- will be used up trying to buffer this system, this will work to a certain extent but there are not infinite amounts of bicarbonate so [H+] remains high.

The high [H+] will stimulate peripheral chemoreceptors to increase ventilation to get rid of carbon dioxide. This will therefore decrease pCO2 and from the Henderson-Hasselbach equation we know this will result in an increase in pH. This will help compensate for some of that decreased extracellular pH.

After a day or two the kidneys come into play, they will increase H+ secretion, this will bind to bicarbonate or phosphate in the urine.

But as levels get high it needs to bind to something else, so will need to increase NH3+ secretion.

A good consequence of producing this ammonia is you get increased bicarb formation and increased bicarb reabsorption.

So, the bicarb that has been used up can now be replenished.

This will all help compensate for decreased pH. But you do have to try remove the causative factor, e.g. diabetes, otherwise the system will get overloaded.

22
Q

Metabolic Alkalosis
what is characterised by?
4 ways it can be caused

A

Metabolic alkalosis is characterised by high pH caused by high ECF [HCO3-] or low [H+]

Metabolic alkalosis may be caused by:
- Excessive use of diuretic (thiazide) use, leading to chronic loss of Cl-, Na+ and K+ and you get increased H+ secretion

  • Excess vomiting can lead to a loss of H+ from the GI tract
  • Ingestion of alkaline antacids
  • Hypokalaemia
23
Q

Thiazide Diuretics & Metabolic Alkalosis
mechanism which cause hypokalemia and metabolic alkalosis? -> how do they work? and what is the chain reaction from here?

A

Inhibition of Na-Cl symporter -> ↑↑ luminal [Na+]

Increase in sodium re-absorption via aldosterone-sensitive pump in exchange for increased secretion of K+ and H+

Also activation of RAAS system secondary to volume reduction

Hence potentially causing hypokalemia & metabolic alkalosis

Thiazide diuretics are the most commonly used diuretic and work by inhibiting sodium-chloride transporter in the distal tubule, this will increase luminal [Na+] which in the distal end of distal tubule signals increased Na+ reabsorption via an aldosterone sensitive pump (ENaC) in exchange for increased secretion of K+ and H+ which are lost in urine.

This can lead to hypokalaemia as well as metabolic alkalosis.

In a situation of volume reduction and reduction in BP you will also get activation of RAAS. Which would also exacerbate sodium reabsorption and loss of potassium and hydrogen ions.

24
Q

Integrated renal & pulmonary compensation

What is the first line of defence for increased HCO3-?
what will this lead to and what detects this change?
How does resp compensation come into play?
what effect does the kidney have?

A

What happens here is essentially the opposite of what occurs in metabolic acidosis.

In the face of increased HCO3-, our ICF and ECF buffering comes in to play first, H+ is used up trying to reduce bicarb (by reacting with bicarb to reform carbonic acid), but HCO3- remains high.

A fall in [H+] will stimulate the peripheral chemoreceptors.

Ventilation will then be reduced and so less CO2 is expelled and [CO2] in blood rises. This respiratory compensation will drive the reaction further to the right so more H+ is generated and also [HCO3-] rises further, however pH start to return to normal as the ratio of HCO3-: CO2 falls.

The kidneys then correct this disturbance over the next few days, a rise in pH in tubule cells will reduce H+ secretion and HCO3- reabsorption/formation, allowing plasma [H+] to rise and correct the plasma [HCO3-], this will remove the ventilation inhibition.

25
Q

LOOK AT THE SUMMARY TABLE FOR COMPENSATION MECHANISMS

what causes resp acidosis?
what causes resp alkalosis?

A

Respiratory acidosis – caused by hypoventilation due to actions of drugs (anaesthetics/barbiturates), chronic emphysema, bronchitis. These conditions impair the removal of CO2 from the lungs, hence it builds up in plasma. Because CO2 enters into cells very rapidly and they contain CA get rapid rise in H+. Rapid ↑[H+] quickly buffered by proteins in plasma (within hours)  ↑[HCO3-]. Limited by buffering capacity of blood. Within days kidney compensates by stimulating H+ secretion & increasing HCO3- reabsorption.

Repiratory alkalosis - Less CO2 enters cells and less HCO3 diffuses out into plasma so [HCO3] is reduced. Within days kidney compensates by reducing H+ secretion & decreasing HCO3- reabsorption
Talking here about pure acidosis & alkalosis – very often not like this. Can be mixed