Last edited: 9/13/2021

1. INTERNAL RESPIRATION
Internal Respiration Medical Editor: Dr. Sofia Suhada M. Uzir

OUTLINE (3) Carbon dioxide distribution

Comes from the tissues into the blood to be transported
I) EXTERNAL RESPIRATION to the alveoli
II) INTERNAL RESPIRATION
o 2-10 % dissolved in the blood plasma
III) REVIEW QUESTIONS
o 20% bound to the amino acids of the globin chains
IV) REFERENCES
o 70% hidden in the form of bicarbonate

(i) Carbon dioxide in the form of bicarbonate

They are abundant in the plasma
o Control acid base balance
The bicarbonates move into RBC
I) EXTERNAL RESPIRATION o Chloride moves out (chloride shift)
RBCs go through the pulmonary capillaries where the  This is to balance the shift of ion moving into the
alveoli are located → gas exchange occur cell
o Oxygen o Interact and combine with the protons on RBC
 Moves from the alveoli into the blood  Happens when hemoglobin affinity for CO2,
o Carbon dioxide (CO2) protons and 2,3 BPG decrease
 Moves from the blood into the alveoli  Bicarbonates that combine with proton will
produce carbonic acid (H2CO3) → dissociate into
(A) DEOXYGENATED HEMOGLOBIN (T STATE) CO2 and water in the presence of carbonic
anhydrase enzyme
Low affinity for oxygen
(1) The structure of deoxygenated hemoglobin
Particularly HbA1, consist of

(i) 4 globin chains

2 Alpha chains
2 Beta chain

(ii) 4 iron containing heme groups

In the ferrous state, Fe 2+
It is bound to only 1 oxygen

(iii) Positive charged pocket Figure 1. The structures of hemoglobin in the T state vs in the
Made up of positively charged amino acids R state
o Histidine (B) POSITIVE COOPERATIVITY
o Arginine
o Lysine Happens when the oxygen moves from alveoli into the
blood to bind with the hemoglobin
(2) Molecules bound to the hemoglobin It is extremely hard for the first oxygen to bind to the
hemoglobin but it gets easier as more oxygen bind to it
(i) CO2
(C) OXYGENATED HEMOGLOBIN (R STATE)
Which is bound to amino acids at globin (protein) chains
o Account for 20% CO2 transported in the blood The structure of oxygenated hemoglobin changes from
circulation from the tissue to the alveoli→ carbamino the deoxygenated state
hemoglobin Affinity to oxygen is high

(ii) Protons (1) Partial pressures

Which are positively charged (i) Oxygen

o Bound to amino acids on the beta/alpha chains
In the alveoli is 104 mmHg
which are negatively charged
In the blood is 40 mmHg
 The amino acids interact with the protons
→ protons bind to the hemoglobin → deoxy state (ii) Carbon dioxide
(T state) Figure 1
In the alveoli is 40 mmHg
(iii) 2,3 BPG In the blood is 45-46 mmHg
Even with the little difference, CO2 move easily from the
A negatively charged glycolytic intermediate
plasma to the alveoli because is it 20 times more
Bind to the positively charged pocket to stabilize the
soluble than the oxygen in the plasma and alveolar fluid
hemoglobin in the T state → affinity for oxygen is low
(2) Movement of gases
The gases move down the concentration gradient
o From high to low until equilibrium is reached
 The alveoli = pulmonary arterial blood

INTERNAL RESPIRATION RESPIRATORY PHYSIOLOGY: Note #1. 1 of 4

 The oxygen from the alveoli binds to iron containing the
heme groups of hemoglobin in the blood
o A lot of oxygen bind causing → oxygen loading
CO2 unloaded → moves from the blood into the alveoli
o Bicarbonates converted to CO2 → unloaded
o CO2 dissolved in the plasma → unloaded
The arterial blood leaving the lungs into the systemic
circulation reaching the tissues will contain
o 104 mmHg Oxygen
o 40 mmHg CO2
(3) Molecules bound to the hemoglobin
(i) 2,3 BPG
When the iron in the hemoglobin is bound the oxygen, the
positively charged moieties will not be exposed → 2,3
BPG cannot bind to it Figure 1
(ii) Carbon dioxide (CO2)
CO2 moves to the alveoli
(iii) Oxygen
Oxygen binds to the hemoglobin molecule
CO2 unloaded + oxygen loaded = Haldane effect
(D) HALDANE EFFECT
Blood coming to the lungs which had a low affinity
for oxygen becomes high
This is due to the oxygen moving down its concentration
gradient and bind to iron containing heme groups
o The hemoglobin affinity for CO2, protons and 2,3 BPG
decrease → unload
o The hemoglobin affinity for oxygen increase →
positive cooperativity → oxygen loaded on the
hemoglobin
II) INTERNAL RESPIRATION
Oxygenated state of hemoglobin → travel to tissues
Structure of oxygenated hemoglobin include
o Oxygen bound to the iron
o Globin chains without CO2
o Hidden positively charged moiety
 Not exposed to the 2,3 BPG → cannot bind
(1) Partial pressure during rest
(i) Oxygen
o In the tissue cells is 40 mmHg
o In the arterial blood is 104 mmHg
(ii) Carbon dioxide (CO2)
o In the tissue cells 45-46 mmHg
o In the arterial blood 40 mmHg
Gases move from area of high pressure to low pressure
o Oxygen moves from the arterial blood into the tissue
cells
o CO2 moves from the tissue cells into the arterial
blood
2 of 4 RESPIRATORY PHYSIOLOGY: Note #1.
(B) MECHANISM OF GAS EXCHANGE
(1) Carbon dioxide (CO2)
Is made through cellular respiration
In metabolizing oxygen, cellular respiration reaction takes
place → giving off the CO2
o C6H12O6 (glucose) + 6 O2 (oxygen) → 6 CO2 + 6 H2O
+ ATP + heat
CO2 moves from the tissue cells into the blood Figure 2
(i) 2-10% of CO2
Dissolve in the blood plasma
(ii) 20% of CO2
Bind to the amino acids of alpha/beta chains
o In the form of carbamino hemoglobin
(iii) 70% of CO2
Taken into the RBC to bind with water → formation of
carbonic acid (H2CO3) in the presence of carbonic
anhydrase enzyme
Carbonic acid is very unstable → dissociate into proton
and bicarbonate
o The protons bind to the negatively charged amino
acids on the globin chains → electrostatic
interactions
o The bicarbonate goes to the plasma to act as a buffer
system in the blood
 Has pKa that closely match the pH of the blood
 As the bicarbonate goes out of the cell, chloride
will enter in order to balance the shift of negative
ion leaving the cell (chloride shift)
(2) Dissociation of oxygen
When protons and CO2 bind to amino acids of the globin
chain → allosterically regulating the hemoglobin
o Changes the shape of the hemoglobin molecule
o Weakens the bond between the iron and oxygen
→ until eventually the bond breaks
o The heat produced as a biproduct from the metabolic
process of the tissues also contribute to the weaking
and breaking of the iron and oxygen bond Figure 2
The oxygen will dissociate and go to the tissues
When the oxygen dissociates, the positively charged
pocket will be exposed for the binding of 2,3 BPG →
stabilize the hemoglobin in the T state → deoxy
hemoglobin
(3) Oxygen
Oxygen leaves the blood and enters the tissue to be
utilized in metabolic processes
o Produce ATP
o Break down different types of molecules
o Produce heat
(4) Temperature/heat
Heat is the biproduct from the electron transport chain
that occurs in the tissues
It is used as the measurement of temperature /thermal
energy
o Delta H is the form of energy
Protein structures change when they’re exposed to
excessive heat and different types of pH
o Hemoglobin protein will undergo confirmational
change due to the heat → contributing to the breaking
of the iron and oxygen bond
INTERNAL RESPIRATION

Figure 2. The overall mechanism of internal respiration
(C) BOHR EFFECT
Hemoglobin affinity for oxygen that was initially high
becomes low
This is due to the CO2, protons and 2,3 BPG which bind
to the hemoglobin with the contribution of heat from the
tissues → change overall structure of hemoglobin
o This change eventually breaks iron and oxygen bond
→ oxygen dissociate →decrease in hemoglobin
affinity for oxygen → unload the oxygen
Hemoglobin affinity for CO2, proton, 2,3 BPG increase
o Loaded on the hemoglobin
(D) PRESSURES OF GASES
The partial pressures of gases when the blood drains
from the capillary bed going to the vein
(i) Oxygen
40 mmHg in the cells
104 mmHg in the capillary bed
Hence the oxygen will move from the capillary bed into
the cells until it reaches the equilibrium of 40 mmHg
(ii) CO2
45-46 mmHg in the cells
40 mmHg in the capillary bed
Hence, the CO2 will move from the cells into the capillary
beds until it reaches the equilibrium of 45 mmHg
Remember
Gas exchange occurs until the concentration of gases in the
blood is equal to the tissues
(1) Veinous blood
When the blood leaves the capillary bed, and enters the
vein, the partial pressure will be as follows
o CO2 45 mmHg
o Oxygen 40 mmHg
These gases will go to the lungs
In the lungs, once again the gas exchange occurs down
the concentration gradient
o The oxygen from the alveoli will enter the blood
 From 104 mmHg to 40 mmHg until the equilibrium
of 104 mmHg is reached
o The CO2 will move from the blood to the alveoli
 From 45-46 mmHg to 40 mmHg until the
equilibrium of 40 mmHg is reached
INTERNAL RESPIRATION
(2) Arterial blood
The blood, which is now the arterial blood, leaving the
lungs will have the partial pressures of gases as follows
o Oxygen 104 mmHg
o CO2 40 mmHg
The gases will then again travel to the tissues and the
cycle continues
III) REVIEW QUESTIONS
1) Regarding oxygen, which is true
a) It travels from the blood to the alveoli
b) Binding of carbon dioxide to the hemoglobin helps in
the release of oxygen into the tissues
c) The partial pressure of oxygen in cell tissues is 104
mmHg
d) In internal respiration, it moves from the alveoli into
the blood
2) Which of the following is not a part of the circulatory
system?
a) Pulmonary ventilation
b) External respiration
c) Transport
d) Internal respiration
3) The most important factor that determines how much
oxygen combines with hemoglobin is
a) Oxygen
b) Temperature
c) CO2
d) 2,3 DPG
4) Hemoglobin has a tendency to release oxygen where
a) temperature is lower
b) pH is more acidic
c) partial pressures of carbon dioxide are lower
d) pH is more alkaline
5) Most of the carbon dioxide transported by the blood
is
a) converted to bicarbonate ions and transported in
plasma
b) dissolved in plasma
c) bound to the same protein as carbon dioxide
d) bound to hemoglobin
6) Approximately 20% of carbon dioxide is transported
in the blood as
a) bicarbonate ions
b) carbaminohemoglobin
c) hydrogen ions
d) dissolved gas in the plasma
7) In the alveoli, the partial pressure of oxygen is
a) lower than the PO2 of venous blood
b) much higher than the PO2 of arterial blood
c) the same as the PO2 of venous blood.
d) about 104 mm Hg
8) In the internal respiration
a) Oxygen moves from the tissues into the alveoli
b) Oxygen moves from the blood to the alveoli
c) Oxygen moves from the blood into the tissues
d) Oxygen moves from the tissues into the blood
9) Regarding the Bohr effect
a) The hemoglobin affinity to oxygen decreases
b) The hemoglobin affinity to carbon dioxide decreases
c) The carbon dioxide leaves the hemoglobin
d) Oxygen will bind to the hemoglobin
10) Breaking of the iron and oxygen bond is caused by
a) Change in the red blood cell membrane potential
b) Release of carbon dioxide into the plasma
c) Binding of carbon dioxide to the hemoglobin
d) Decrease in the 2,3 BPG levels in the blood
CHECK YOUR ANSWERS
RESPIRATORY PHYSIOLOGY: Note #1. 3 of 4
 IV) REFERENCES
● Sabatine MS. Pocket Medicine: the Massachusetts General
Hospital Handbook of Internal Medicine. Philadelphia: Wolters
Kluwer; 2020.
● Le T. First Aid for the USMLE Step 1 2020. 30th anniversary
edition: McGraw Hill; 2020.
● Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL,
Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth
Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical; 2018
● Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ:
Pearson; 2020.
● Boron WF, Boulpaep EL. Medical Physiology.; 2017.
● Guyton and Hall Textbook of Medical Physiology. Philadelphia,
PA: Elsevier; 2021.

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