L07 - Regulation Of Acid-Base Status

Front 1

What is normal plasma pH?

Back 1

7.35 - 7.45 (i.e. 35-45nM [H+])

Front 2

What is acidosis?

Back 2

pH<7.35

Front 3

What is alkalosis?

Back 3

pH>7.45

Front 4

What are buffers?

Back 4

=substances which reduce change in pH
=weak acids (HA) and their conjugate bases (A-) that can donate or accept protons

Front 5

What is the ratio between buffer pairs dependent on?

Back 5

[H+]
& dissociation constant

Front 6

What is the Henderson-Hasselbach equation?

Back 6

pH= pK+log([A-]/[HA])

(NB. derived from K = [H+][A-]/[HA])

note K=dissociation constant

Front 7

When do buffers work best?

Back 7

When pH is close to pK

Front 8

What is the most important buffer pair in the body?

Back 8

HCO3- and H2CO3

Formed by:
CO2 + H20 &lt;-*->H2CO3 &lt;--> HCO3- + H+

*carbonic anhydrase

Front 9

How can we work out the pH of blood using [HCO3-] and [H2CO3]?

Back 9

pH = pK + log [HCO3-]/[H2CO3]
But
[H2CO3] is proportional to [CO2]
[CO2] = PC02 x solubility
(solubility = 0.03 mmole/litre/mmHg)
Nb. K = 6.1
Thus:
pH=6.1+log([HCO3-]/(PCO2Xs))

Front 10

Why does it not matter that the pK is far away from blood pH?

Back 10

As dynamic control of CO2 by lung
and [HCO3-] by the kidney

Front 11

How much CO2 and acid is produced in metabolism?

Back 11

CO2 = 12-20 moles
acid = 40-80mmoles

Front 12

How is plasma [H+] kept constant?

Back 12

CO2 excreted by lungs
HCO3- conserved by kidney
H+ secreted by kidney

Front 13

What is the usual pH of urine and why?

Back 13

acid (5-7)
as H+ is secreted by kidney

Front 14

Why are urinary buffers needed?

Back 14

max. acid secretion but prevent excessive urine acidity - as H+ pumps don't work if pH<4.5

Front 15

What are the major urinary buffers?

Back 15

phosphate and ammonium
(Nb. ammonium responsible for most acid secretion - NH3 + H+ --> NH4+
This works as CO2 and NH3 can cross membranes easily as uncharged
H+, HCO3- & NH4+ cannot because they are charged
Thus they can be trapped in tubule

Front 16

Where is H+ secreted in the kidney

Back 16

active transport
in PCT, distal tubule and collecting duct

Front 17

How is H+ secretion regulated?

Back 17

by need
via an increase in intracellular [H+]
stimulated by increased PCO2
as CO2 acts as a source of H+ ions
(acidosis also increases renin prod. thus angiotensin II and aldosterone)

Front 18

What happens to HCO3- in the kidney?

Back 18

All reabsorbed
by reaction with H+ ions which are secreted into the tubule:

HCO3- + H+ <--> H2CO3 --> CO2 + H20 (reabsorbed)

Front 19

What happens to excess H+?

Back 19

excreted in urine
buffered as H2PO4- (pK 6.8)
or NH4+ (pK 9.2)

Front 20

Describe acid base regulation in the early nephron?

Back 20

In afferent capillary [HCO3-] = 25mM

In PCT
Secreted H+ combines with HCO3- in tubular fluid to form CO2
CO2 diffuses out of tubule and dissociates to H+ and HCO3-
H+ returned to tubule and recycled
Net effect = HCO3- absorption

Front 21

Describe acid base regulation in the late nephron?

Back 21

Thick ascending limb = 15% of HCO3- reabsorbed
By Na+:HCO3- tansporter (both same direction- out into blood)

Distal Tubule and Collecting Duct (5% of HCO3- reabsorbed)
Secretion of H+ ions & therefore
HCO3- reabsorption
& form. from plasma CO2
H+ buffered in tubule by NH4- and PO4-

At end of nephron [HCO3-] in tubule = 0mMole

Front 22

Describe bicarbonate reabsorption in the PCT

Back 22

1. H+ secreted into lumen by Na+/H+ exchanger NHE3
Combines with HCO3- to form H2CO3 (carbonic acid)
2. Carbonic anhydrase facilitates dissociation of H2CO3 -> CO2 + H2O
3. CO2 diffuses -> cell
redissociates to HCO3- and H+
4. H+ recycled
HCO3- reabsorbed by NBCe1 coupled cotransporter (1Na:3HCO3-) (NBCe1)
5. Therefore net absorption of Na+ and HCO3- but not H+

Front 23

Describe Ammonium Production in the PCT?

Back 23

1. Glutamine produced in liver
2. Deanimated in PCT -> 2-oxogluterate and 2NH4+ (can lose H+ -> NH3)
3. NH4+ is membrane impermeable therefore it must substitute for H+ at NHE3 receptor and be extruded in exchanged for Na+
NH3 diffuses across the membrane
4. NH3 combines with H+ -> NH4+ (trapped in lumen)
5. oxogluterate metabolised and HCO3- reabsorbed via NBC1 receptor with Na+
6. Each NH4+ carries 1H+

Front 24

Describe Acid-Base Regulation in the Thick Ascending Loop of Henle?

Back 24

1. HCO3 reabsorbed in the same method as in PCT (ie. redissociates from CO2 and then transported -> interstitium by NBCe1) (15% load)
2. Some NH4+ is reabsorbed as it can substitute for K+ at Na+:K+:Cl- cotransporter
3. NH4+ diffuses out via K+ channel, or dissociates to membrane permeable NH3 - H+ secreted into lumen via NHE3 channel
4. Nb. tubular fluid at the tip of loop of Henle is slightly alkaline, so some NH4+ -> NH3 which diffuses to interstitium but re-enters collecting duct where acidic conditions reform NH4+ which is excreted

Front 25

Describe Acid-Base Regulation in the Late Distal Tubule and Collecting Duct?

Back 25

1. CO2 provides source from H+ secretion.
Diffuses from blood, forms H2CO3 which dissociates -> HCO3- and H+
2. HCO3- removed to blood bu HCO3-:Cl- antiport (AE1) (driven by chloride gradient so chloride returned to interstitium via Cl channel)
3. H+ secreted to lumen by H+ATPase and some by H+/K+ ATPase antiport
4. H+ buffered in lumen by HPO42- (HP042- + H+ -> H2PO4-)
and by NH3 Which diffuses in from blood
H2PO4- and NH4+ are trapped in lumen and excreted

Front 26

Describe the interaction of Acid-Base Regulation with K+ homeostasis?

Back 26

1. Increased cystolic H+ binds to -vely charged proteins so K+ exits cells to maintain electroneutrality
2. Acidosis inhibits K+ secretion and Alkalosis enhances it (partly via reducing -ve potential of tubular lumen)
Thus acidosis can cause hyperkalaemia (exarcerbated by low insulin in metabolic ketaacidosis), and alkalosis hypokalaemia
3. Hyperkalaemia inhibits NH4 prod. in PCT and K+ competes with NH4+ at K+:Na+:2Cl transporter in TAL
4. Hypokalaemia enhances NH4+ production and Na+:H+ exchanger in PCT
and stimulates H+:K+ ATPase in TA intercalated cells --> increased H+ secretion

Front 27

Describe Hepatic Regulation of pH?

Back 27

Liver metabolises excess amino acids, yielding NH3 and HCO3-
If alkalosis (i.e. want as little H+ secreted) disposes of them by:
-Excretion of urea
prod. via ornithine citrulline cycle
2HCO3- + 2NH4+ -> CO(NH2)2 + CO2 + 3H20

If acidosis (want to get rid of H+) uses:
Excretion of glutamine
Glutamine sythetase is present in the perivenous hepatocytes
NH4+ + Glutamate -> Glutamine

Nb. excretion of urea consumes HCO3- and urea excreted
Excretion of glutamine does not but glutamine is used in PCT to create and excrete NH4+ thus excreting 1NH4+

Front 28

Describe Respiratory Acidosis?

Back 28

Low pH + high PaCO2 (>5.3kPa)
Insufficient ventilation caused by lung disease or respiratory supression

Front 29

What may cause respiratory acidosis?

Back 29

Neuromotor diseases, opiates

Front 30

Describe Respiratory alkalosis?

Back 30

High pH and low PaCO2 (<5.3kPa)
Hyperventilation due to hypoxia

Front 31

What may cause respiratory alkalosis?

Back 31

altitude, poor alveolar diffusion, ventilation perfusion mismatch, severe anaemia, anxiety, pregnancy (progesterone), drugs

Front 32

Describe metabolic acidosis?

Back 32

low pH and low [HCO3-]
Ingestion of acids or ammonium salts; metabolism producing acids

Front 33

Decribe metabolic alkalosis?

Back 33

High pH and high [HCO3-]
Ingestion of bicarbonate; loss of acid due to vomitting; high levels of aldosterone - indirectly stimulates H+ secretion through opening ENaC; hypokalaemia

Front 34

Describe how to compensate for respiratory failure/hypercapnia?

Back 34

PCO2 high, pH low
=respiratory acidosis
Renal compensation
Increase renal HCO3- absorption
Increase plasma [HCO3-]
Thus pH -> normal

Front 35

Describe how to compensate for hyperventilation/hypocapnia?

Back 35

PCO2 low, pH high
=respiratory alkalosis
Renal compensation
Decrease renal HCO3- absorption
Decrease plasma [HCO3-]
Decrease [HCO3-]/pCo2 and therefore pH

Front 36

Describe how to compensate for metabolic acidosis?

Back 36

HCO3- low, pH low
Respiratory Compesation
Ventilation increase
PCO2 decrease
Therefore [HCO3-]/PCO2 increase
Therefore pH increases to normal

Front 37

Describe how to compensate for diuretics/excess steroids/vomiting?

Back 37

Metabolic alkalosis
pH high, HCO3- high
In theory:
Respiratory compesation
Decrease ventilation
PCO2 increase
Therefore pH decreases to normal
IN PRACTICE difficult to decrease ventilation sufficiently

Front 38

What is anion gap?

Back 38

difference between sum of measured cations (Na+ and K+) and sum of measured anions (HCO3- and Cl-)
Since there can be no actual difference in +ve and -ve charge
actually represents unmeasured anions
eg. as proteins, organic acids, sulphate and phosphate

Front 39

What is the normal anion gap?

Back 39

([Na+] + [K+]) - ([HCO3-] + [Cl-]) = 6-16mmole

Front 40

Why is knowing the anion gap useful?

Back 40

Diagnosing different causes of metabolic acidosis - for some types it is normal for others raised

If acidosis due to loss of bicarb. (eg. diarrhoea) the anion gap is normal as chloride replaces bicarb.
also seen in renal tubule acidosis characterised by bicarb loss

If acid whose anion is not Cl- is inreased (e.g. lacic/ketoacidosis), acid converts bicarb -> CO2
but no corresponding increase in Cl- so anion gap is raised - ie. conc. of unmeasured anions has increased

Front 41

What causes raised anion gap in metabolic acidosis?

Back 41

MILK PUSE

M=methanol
I=Isoniazid
L=lactic acidosis
K=Ketoacidosis (starvation, alcholism, diabetic)
P=paraldehyde
U=uremia
S=salicyclate
E=ethanyl glycol