Dr Matthew Ho

BSc(Med) MBBS(Hons) FANZCA

Acid-Base Physiology

1990 Write short notes on buffers.

1. A buffer is a solution which has the ability to minimised changes in pH when an acid or base is
added to it. It usually consists of a weak acid and its conjugate base. In the body, the buffer
binds H+ ions reversibly to minimise change in pH:
𝐁𝐮𝐟𝐟𝐞𝐫 + 𝐇 + ⇔ 𝐇. 𝐁𝐮𝐟𝐟𝐞𝐫
2. Effectiveness of a buffer:
a. Amount of buffer present
b. pKa of buffer (pH when 50% of acid is dissociated): buffers are most effective in pH
solutions ± 1 of their pKa.
c. Open (physiological) or closed (chemical) system.

3. Buffers in the body:

Buffer Equation pKa

Extracellular
Bicarbonate H+ + HCO3-  H2CO3  6.1
H2O + CO2
Haemoglobin H+ + Hb  H.Hb 6.8
Protein H+ + protein-  H.protein 2/9
Intracellular
Protein H+ + protein-  H.protein 2/9
Phosphate H+ + HPO42-  H2PO4- 6.8
Renal Tubules
Ammonia H+ + NH3  NH4+
Bicarbonate H+ + CO3-  H2O + CO2 6.1
Phosphate H+ + HPO42-  H2PO4- 6.8

4. Bicarbonate System:
a. Weak acid (carbonic acid) + bicarbonate salt (ECF – sodium, ICF – potassium,
magnesium)
b. Adding:
i. Strong acid  buffering by HCO3-  HsCO3  H2O + CO2  CO2 excreted from
ECF by the lungs.
ii. Strong base  buffering by H2CO3  HCO3-  excreted by kidney.
c. Despite pKa 6.1, it is an effective buffering system because it is an open system  CO2 is
regulated by the pulmonary system, while HCO3- is regulated by renal system. It can only
buffer metabolic acids (not carbonic acid).

5. Haemoglobin: see notes below

6. Proteins:
a. Amino (pKa 9) and carboxyl (pKa 2) and imidazole (pKa 6.8) side chains can buffer H +
ions. Not very significant in ECF
b. More important in ICF as proteins are higher in concentration and the more acidic
environment improves buffering ability.

7. Phosphate:
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

a. Low ECF concentration  not significant as ECF buffer

b. Significant contribution to ICF and renal DCT buffering due to higher concentrations and
more acidic conditions

EXTRA NOTES:

8. Acid load in the body:

Acid Amount/day Mechanism

Carbon dioxide 15000mmol CO2 produced by decarboxylation reactions of
Krebs cycle  carbonic acid. Most excreted
by lungs.
Sulphuric acid 45 Metabolism of sulphur containing amino
acids
Hydrochloric acid 12 Metabolism of lysine, arginine and histidine.
Phosphoric acid 13 Metabolism of phosphoroproteins
Lactic acid 1500 Anaerobic metabolism of glucose in RBCs,
skin, skeletal muscle. Most metabolised by
liver  HCO3-
Ketones Metabolism of TGs during fasting
Total 50-100mmol
Net
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

Physiol-10B15/03A9/92 Discuss the role of haemoglobin as a buffer.

1. A buffer is a solution which has the ability to minimised changes in pH when an acid or base is
added to it. It usually consists of a weak acid, its salt and its conjugate base. In the body, the
buffer binds H+ ions reversibly to minimise change in pH:
𝐁𝐮𝐟𝐟𝐞𝐫 + 𝐇 + ⇔ 𝐇. 𝐁𝐮𝐟𝐟𝐞𝐫

2. Haemoglobin is a metalloprotein present within erythrocytes (intracellularly). It is the most

important extracellular buffer for CO2 produced by aerobic metabolism, due to its unique
properties and accounts for 90% buffering of carbonic acid. This is important because the
bicarbonate system cannot buffer carbonic acid from CO2 as they form part of the same weak
acid-conjugate base pair. Hb is present in RBCs with a potassium salt:
H+ + KHb HHb + K+
H2CO3 + KHb HHb + HCO3-

3. Properties of the Hb buffer:

a. Present in large concentrations – 150g/L
b. Structure: metalloprotein (65000 Da) containing 4 polypeptide Haeme-globin chains.
i. Each Hb molecule contains 38 histidine residues (with imidazole side-chain)
which buffer H+ (pKa 6.8).
Imidazole- + H+  Imidazole.H
c. pKa 6.8 is similar to intracellular pKa which ↑ buffering capacity.
d. Deoxy-Hb is a better buffer than oxy-Hb (Haldane-effect):
i. Deoxy-Hb (pKa 8.2) is a weaker acid, and dissociated more than oxy-Hb (pKa
6.6).
ii. 1 mmol oxyHb  DeoxyHb allows ↑0.7mmol H+ buffering  0.7mmol CO2
enters system without change in pH.
iii. Venous blood has ↑buffering capacity compared to O2 blood, thus pH venous is
only slightly reduced compared to ↑pCO2  carried as bicarbonate and
carbamino compounds which contribute to H+ load.

4. Chemical Hb buffering: the properties of CO2 as a volatile acid contribute to Hb buffering

a. CO2 rapidly diffuses across the red cell membrane
b. RBCs contain carbonic anhydrase which catalyses:
H2O + CO2  H+ + HCO3-
c. Hb buffers the H and favours formation of HCO3-  diffuses down concentration
+

gradient out of cell.

d. Thus, the presence of acid in the ECF leads to maintenance of concentration gradient
and ongoing diffusion of HCO3- out of the cell  30% Haldane effect.
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

EXTRA-NOTES
5. Carbamino compounds: produced by the reaction of CO2 with terminal amine groups of each Hb
chain  carbamic acid. This has a low pKa such that at plasma and intracellular pH, the acid is
mostly dissociated:
R-NH-COOH  R-NH-COO- + H+
Thus, the carriage of CO2 by Hb as carbamino compounds actually adds H+ to the intracellular
system. This requires buffering. Carbamino compounds do NOT contribute to Hb as a buffer.
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

Physiol-06B15/98B5 Explain how a metabolic acidosis develops in hypovolaemic shock. Describe the
consequences of this metabolic acidosis for the body.

1. Metabolic Acidosis is the pathological process resulting in a decrease in pH primarily through

depletion of HCO3-. Hypovolaemic shock is the pathological reduction in intravascular volume
leading to inadequate perfusion to meet the metabolic demands of tissues.

2. Shock:
a. Inadequate delivery of O2 to tissues:
i. The lack of O2 does not allow removal of the end-products of glycolysis and
the citric acid cycle  build-up of pyruvate and NADH/FADH2.
ii. Shift to anaerobic glycolysis: pyruvic acid converted to lactic acid which
diffuses out of cells to ↓pyruvic acid concentration  allows glycolysis to
continue.
𝐩𝐲𝐫𝐮𝐯𝐚𝐭𝐞 + 𝐍𝐀𝐃𝐇 + 𝐇 + ⇋ 𝐥𝐚𝐜𝐭𝐢𝐜 𝐚𝐜𝐢𝐝 + 𝐍𝐀𝐃+
iii. Energy inefficient – produces 2ATP for every pyruvate converted.
b. Inadequate removal of lactate via the Cori cycle:
i. Under normal circumstances, lactate produced by anaerobic metabolism
(RBCs, kidney etc) is cycled in the liver and reconverted to pyruvate 
glucose (gluconeogenesis).
ii. Shock: exhausted pathways for this conversion, and low hepatic blood flow
 accumulation of lactate  metabolic acidosis

3. Consequences of metabolic acidosis:

a. Respiratory:
i. Ventilation:
1. Sensors: peripheral chemoreceptors detect ↓pH
2. Controller: activated by chemoreceptors in ↑ ventilation
3. Effectors: muscles of respiration ↑RR, TV  ↑MV  ↓pCO2
(respiratory compensation). ↓pH 1  ↑MV 3L/min
ii. HbO2 dissociation curve: R shift  ↑offloading O2 to peripheral tissues
b. Cardiovascular:
i. Direct negative inotrope: inhibits slow Ca2+ influx, and release from SR.
ii. Tachycardia due to catecholamine release
iii. Vessels: ↓SVR (metabolic autoregulation), ↑PVR. This is offset by
hypovolaemic ↑SVR (local, neural and hormonal autoregulation).
iv. Impaired response to catecholamines when pH < 7.2
v. Arrhythmogenicity:
1. Hyperkalaemia: K exchanged with H into ECF. pH ↓0.1  ↑K
0.6mmol/L
2. ↑ free Ca2+ via dissociation from albumin (H+ competes for binding
sites on albumin).
c. CNS: neuronal dysfunction  impaired consciousness.
d. GIT: ↓ GI motility.
e. Renal: correction (delayed)
i. ↑reabsorption of HCO3-
ii. ↑excretion H+ as titratable acid and ammonium
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

Physiol-07A11/05A15 Discuss how the body handles a metabolic acidosis.

1. Metabolic Acidosis is the pathological process resulting in a decrease in pH primarily through

depletion of HCO3-. The body’s responses can be classified into rapidity of activation. Its overall
aim is to shift pH back to normal (ECH 7.4, ICF 6.8) as this is required for normal cell
homeostasis.

2. Buffering: the body contains several buffer systems consisting of a weak acid and its conjugate
base. Buffers minimise the change in pH when a strong acid or base is added. This occurs in
minutes – hours.

Buffer Equation pKa Description

Extracellular: pH range 7.36-7.44
Bicarbonate H+ + CO3-  H2O + CO2 6.1 Most important ECF buffer. Open system
(mechanisms to change pCO2 and HCO3-)
↑effectiveness
In metabolic acidosis, relative ↓HCO3-  bicarbonate
not as effective.
Haemoglobin H+ + Hb  H.Hb 6.8 Imidazole residues of histidine groups (38 / Hb
molecule).
Favours formation of HCO3- (via carbonic anhydrase
inside RBC).
Protein H+ + protein-  H.protein Less important in ECF due to low concentration
Intracellular: pH lower range 6.8-7.1
Protein H+ + protein-  H.protein
Phosphate H+ + HPO42-  H2PO4- 6.8
Bone
Ca- Exchange of ECF H+ for ICF Over time, high acidity demineralises bone and
bicarbonate Na+/Ca2+ releases alkaline compounds CaCO3, CaHPO4.

3. Compensation: the respiratory system responds to metabolic acidosis by ↑ CO2 excretion to

restore the [HCO3-]/PaCO2 ratio. CO2 can be considered as a volatile acid and alterations in body
pH occur quickly because CO2 crosses cell membranes easily.
a. Sensor: peripheral chemoreceptors in carotid/aortic bodies detect ↓pH  stimulation
medulla via the vagus and glossopharyngeal nerves.
Central chemoreceptors have a delayed response due to the diffusion of HCO3- across
the BBB, thus lowering brain ECF pH.
b. Controller: respiratory centre in the medulla
c. Effector:
i. Change ventilation causes change pCO2: ↑RR / TV  ↑MV  ↓pCO2
𝐕̇𝐂𝐎𝟐
𝐏𝐚 𝐂𝐎𝟐 = 𝐤.
𝐕𝐀̇

ii. Change pCO2 causes change pH:

𝐇𝐂𝐎𝟑 −
𝐩𝐇 = 𝐩𝐊𝐚 + 𝐥𝐨𝐠 𝟏𝟎
𝟎. 𝟎𝟑 𝐱 𝐩𝐂𝐎𝟐
There is no direct excretion of metabolic acids and thus this mechanism is limited in
dealing with fixed metabolic acidosis.

4. Correction: the renal system responds to metabolic acidosis by ↑ the reabsorption of HCO3-, and
↑ the net excretion of H+ as titratable acids. This is the only way of excreting fixed acids.
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

a. Reabsorption of HCO3- and Secretion of H+ from PCT: high capacity, low gradient
(secretes 4320mmol H+, limiting pH 7.0). Energy from Na-K ATPase.
i. Tubular cell: H2O + CO2  H+ + HCO3-
ii. H+ excreted with Na+ counter-transport
iii. Lumen: H+ + HCO3- (filtered from glomerulus)  H2O + CO2
iv. CO2 reabsorbed into PCT  combines OH-  HCO3-  reabsorbed into blood.
v. HCO3- thus reabsorbed indirectly. This occurs 80% PCT, 10% TALH, 10% DCT/CD.
vi. H+ reforms H2O which is excreted in the urine. Thus, overall no H+ is excreted in
the PCT.

b. Secretion of H+ from DCT: low capacity, high gradient (secretes 70mmol H+, limiting pH
4.4).
i. Intercalated cells: H2O + CO2  H+ + HCO3-
ii. H+ secreted by H/K-ATPase pump
iii. Lumen: H+ + HCO3- (filtered from glomerulus)  H2O + CO2
iv. Cl- passively secreted as HCO3- is reabsorbed.
v. Can concentrate urine to pH 4.4 (1000-fold H+ concentration)
vi. Pump activated by aldosterone  ↑H+ secretion and K reabsorption.

c. Secretion of H+ as titratable acid: H+ excreted to filtered buffers in the urine. Measured

by the amount of alkali required to titrate urine to pH 7.4. This allows secreted of extra
H+ after all HCO3- is reabsorbed.
H+ + HPO42-  H2PO4- (DCT)
i. H is trapped by the phosphate buffer and unable to combine with HCO3- to form
+

H2O + CO2.
ii. Exhausted pH 4.4

d. Secretion of NH4+ from PCT/DCT: accounts for 75% of excretion of metabolic acids in
body (50mmol/day).
H+ + NH3  NH4+
i. PCT/TALH/DCT: glutamine  NH4+ + HCO3-
NH4 secreted into lumen in exchange for Na, whilst HCO3- reabsorbed into blood.
NH3 + H+  NH4+ (pKa = 9.2, thus most present as NH4+ in PCT)
ii. Cycling of NH4+: Reabsorption of ammonium on ALH  medulla interstitium
(facilitated by low urine pH). High acid load (low urine pH)  ↑NH4+ transfer
from interstitium  lumen  excretion in urine.
iii. Older theory: NH3 is soluble to cell membranes and diffuses into the lumen to
absorb H+  thus H+ secreted as ammonium.
iv. HCO3- is also reabsorbed in this way.
v. During metabolic acidosis, the liver ↑production of glutamine  ↑ available
pool of ammonium.
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

1995 Explain how a metabolic alkalosis develops in an adult patient with a small bowel obstruction
and nasogastric losses in excess of 1000ml per day for 5 days. Give a brief account of the
physiological principles determining fluid replacement.

1. The body maintains HCO3- at a relatively stable level of 24mmol/L. It does so through:
a. Reabsorption of nearly all filtered bicarbonate
b. Excretion of fixed acid paired with regeneration of bicarbonate.
If the plasma bicarbonate exceeds 24mmol/L, this is normally promptly excreted by rapid renal
excretion of excess bicarbonate.

2. Maintenance of alkalosis: requires impairment of bicarbonate excretion.

a. Chloride depletion: the kidney reabsorbs anions with Na/K reabsorption to maintain
electrical neutrality. The depletion of Cl  ↑HCO3- reabsorbed as this is the only
other main ECF anion.
b. Potassium depletion: ↑ HCO3- reabsorption in PCT/DCT in the presence of ↓K.
i. ↑aldosterone  ↑Na reabsorption, ↑H/K excretion
ii. ↓K  cells exchange H/K  ↓ECF H+.

3. Vomiting and nasogastric loss is an important clinical cause of metabolic acidosis through the
loss of H+ ions in the acid juice. Gastric juice pH 1.4  [H+] concentration 0.04mol/L. Thus, over 5
days 0.04mmol H+ and Cl- are lost. Thus, this causes a Hypochloraemic metabolic alkalosis.
a. Depletion of H+  ↑HCO3- by bicarbonate buffering
b. Depletion of Cl-  ↑HCO3- by renal reabsorption to maintain electrical neutrality.
c. Depletion of ECF volume  ↑fluid, Na reabsorption in kidney  coupled to ↑HCO3-
reabsorption.

4. Fluid replacement therapy: aimed at restoring H, Cl and volume.

a. Chloride replacement: the most important fluid therapy and allows correction even
if H and fluid depletion are untreated. Usually this is given in the form of normal
saline infusions which contain 150mmol Cl-.
b. HCl infusion: can be given if rapid correction of acid-base status and Cl is required.
This must be done through a central line in ICU.
i. Cl- is rapidly replaced
ii. H+ consumed excess HCO3- from the bicarbonate buffering system.
c. Carbonic anhydrase inhibitors: inhibits the conversion of H2O + CO2  HCO3- and H+
in PCT  inhibits reabsorption of HCO3-. Can be used where fluid overload is a
problem.

EXTRA NOTES:

5. Effects of metabolic alkalosis:

System Effect
CVS ↓ contractility
arrhythmias
Resp Impaired O2 unloading (shift Hb-O2 curve left)
Compensatory hypoventilation  atelectasis,
hypoxaemia, V/Q mismatch
CNS ↓ CBF
Confusion, mental obtundation
NMJ NMJ excitability
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

6. Body response:
a. Compensation: respiratory hypoventilation due to peripheral chemoreceptors 
↑pCO2. This response is somewhat variable due to concomitant hypoxaemia, pain
and pulmonary congestion.

𝐄𝐱𝐩𝐞𝐜𝐭𝐞𝐝 𝐩𝐂𝐎𝟐 = 𝟎. 𝟕 𝐱 𝐇𝐂𝐎−

𝟑 + 𝟐𝟎
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

Physiol-95A6 Describe the effects of intravenously administered sodium bicarbonate (8.4%) 100ml
used in asystolic cardiac arrest in a 70 kg man.

1. A sodium bicarbonate infusion is commonly administered as part of ALS in cardiac arrest. The
physiological handling of bicarbonate by the body has much to do with this.

2. 8.4% of 100mL sodium bicarbonate contains 8.4g of sodium bicarbonate is 100mLs water. As
NaHCO3 has MW 84g and it dissociates into Na+ + HCO3-, the osmolality is 2 Osmoles
(2000mosm) per kilogram and 200mosm in the solution.

3. The normal 70kg male has fluid distribution as follows:

a. TBW 42L (60% weight)
b. ICF 23L (55% TBW)
c. ECF 19L (45% TBW)
d. Interstitial fluid 8.4 L (20% TBW)
e. Plasma fluid 3.2L (7.5% TBW)
f. Other slowly exchangeable ECF (dense CT, TCF, bone water) 7.4L (17.5%)

4. Distribution: The high Na+ content restricts distribution to the ECF

Dimension Distribution
Osmolality Total osmolality before = 285mosm/L
(𝟐𝟖𝟓 𝐱 𝟑𝟒. 𝟔 + 𝟐𝟎𝟎) 𝟐𝟗𝟎𝐦𝐨𝐬𝐦
𝐓𝐨𝐭𝐚𝐥 𝐨𝐬𝐦 𝐚𝐟𝐭𝐞𝐫 = = (↑ 𝟏. 𝟖%)
𝟑𝟒. 𝟕 𝐋
Plasma tonicity ↑ > 1-2%  activation of osmoreceptors  release ADH  ↓urine
output.
Water Hyperosmolality draws water out of ICF  ECF by osmosis
𝟐𝟖𝟓 𝐱 𝟏𝟏. 𝟔 + 𝟐𝟎𝟎
𝐓𝐨𝐭𝐚𝐥 𝐯𝐨𝐥𝐮𝐦𝐞 𝐄𝐂𝐅 = = 𝟏𝟐. 𝟏𝐋 (↑ 𝟒%)
𝟐𝟗𝟎
Sodium Hypernatraemia occurs from administration of Na+, partly controlled by osmosis
Bicarbonate HCO3- before = 24mmol/L x 11.6 = 278.4mosm
HCO3- after = 378.4mosm
[HCO3-] after = 378.4/12.1 = 31.2mosm/L
↑HCO3- will cause metabolic alkalosis
When HCO3- > 27mmol/L  rapid excretion in urine
K H moves out of cells in exchange for K  hypokalaemia
This stabilises cardiac membrane by reducing resting membrane potential.
Oncotic Decreases due to ↑ECF volume  ↓ water reabsorption in PCT (glomerulotubular
Pressure imbalance)  ↑ urine flow.
pH Assuming intubated patient with pCO2 = 40mmHg
𝐇𝐂𝐎𝟑 −
𝐩𝐇 = 𝐩𝐊𝐚 + 𝐥𝐨𝐠 𝟏𝟎
𝟎. 𝟎𝟑 𝐱 𝐩𝐂𝐎𝟐
pH = 7.51
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

MAKE-UP Describe the effects of intravenously administered 1N Hydrochloric Acid 100mls.

1. 1N Hydrochloric acid 100mLs contains 100mmol H+. This is sufficient to cause a metabolic
acidosis. The body’s defence involves buffering, compensation, and correction.

2. Effects on the body:

a. Shift of Hb-O2 dissociation curve to the right  assists with O2 unloading
b. Anion gap unchanged  Hyperchloraemic metabolic acidosis
c. No direct effects on CNs as metabolic acids to not cross BBB
d. Hyperkalaemia: exchange of H/K

3. Buffering:
a. Bicarbonate system: H+ + CO3-  H2O + CO2
b. Total bicarbonate load = 24 mmol/L x 19L = 456mmol
c. After acid infusion, [HCO3-] = 356/19 = 18.7mmol/L

𝐇𝐂𝐎𝟑 −
𝐩𝐇 = 𝐩𝐊𝐚 + 𝐥𝐨𝐠 𝟏𝟎
𝟎. 𝟎𝟑 𝐱 𝐩𝐂𝐎𝟐
𝐩𝐇 = 𝟕. 𝟐𝟗

d. Hypocapnoea causes intracellular alkalosis  general depressant effect on cell

activity
e. ↓pCO2  ↓H+ ECF near central chemoreceptors (CO2 diffuses across BBB and
produces H+ + HCO3-)  inhibits ventilatory response initially. Bicarbonate slowly
equilibrates across BBB into ECF  ↑H+  removal of central inhibition after 12-24
hours.

4. Compensation: ↓pH will stimulate peripheral chemoreceptors to ↑ ventilation  ↓pCO2

which returns HCO3:pCO2 ratio to normal. This returns pH towards normal. This response occurs
within minutes but takes 12-24 hours to reach maximum value.

𝐄𝐱𝐩𝐞𝐜𝐭𝐞𝐝 𝐩𝐂𝐎𝟐 = 𝟏. 𝟓 𝐱 𝐇𝐂𝐎−

𝟑 + 𝟖
pCO2 = 36mmHg

5. Correction:
a. Excretion of excess Cl-  equivalent reabsorption of HCO3-
b. Takes days
 Dr Matthew Ho
BSc(Med) MBBS(Hons) FANZCA

MAKE-UP: Rules for interpreting an ABG

1. Respiratory Acidosis:
a. Acute - ↑10mmHg CO2  ↑1mmol HCO3-
b. Chronic - ↑10mmHg CO2  ↑4mmol HCO3-

2. Respiratory Alkalosis:
a. Acute - ↓10mmHg CO2  ↓2mmol HCO3-
b. Chronic - ↑10mmHg CO2  ↓5mmol HCO3-

3. Metabolic Acidosis:
a. Expected CO2 = 1.5[HCO3-] + 8mmHg

4. Metabolic Alkalosis:
a. Expected CO2 = 0.7[HCO3-] + 20mmHg