BMS12 - Respiratory System :wind_blowing_face:
BMS12 - Respiratory System :wind_blowing_face:
Respiration II - Transport and Exchange of Gases
Air has a particular composition. FN2 (Fractional concentration of Nitrogen gas) in dry air is ~ 79%, FO2 is ~ 21% with trace amounts of other gases such as carbon dioxide. The composition of humidified air is different due to the presence of water vapour.
The pressure exerted by a gas is dependent on temperature and concentration.
Usually pressures are given as '
explains that the pressure exerted by a particular gas in a chemically unreactive mixture is called a partial pressure. So, the total pressure of the mixture is the sum of all the partial pressures.
Gaseous exchange requires oxygen to be absorbed from the air and transported to cells but also carbon dioxide to be transported to cells and then expelled.
The respiratory quotient is 0.8 (Carbon dioxide produced divided by Oxygen consumed). This means they are produced and used in different volumes.
~250ml of oxygen is used by tissues and extracted from the blood each minute whilst only ~200ml of carbon dioxide is produced from tissues and expired per minute. The difference in volume is due to the fact that oxidation of fuels also produces water.
882ml of oxygen reaches the alveoli. 250ml of this is absorbed into the blood and added to an '
' which is at 750ml. The reservoir is 1000ml once that oxygen is added and 250ml of that is used by the tissues. This in the end, leaves the 750ml reservoir again for the next cycle.
Carbon dioxide transport is similar. The tissues produce 200ml of CO2 which is then absorbed into the blood. This volume is added to a large reservoir of 2400ml so is 2600ml all together. 200ml in the end expired from the lungs per minute, this leaves a reservoir of 2400ml again.
During the breathing cycle, the partial pressures vary quite considerably.
Partial pressures during the breathing cycle
During gaseous exchange, oxygen is absorbed in and carbon dioxide is absorbed out into the blood. This causes a fall in oxygen pressure whilst increasing the pressure of carbon dioxide.
In atmospheric air, the partial pressures are as expected. During inspiration, air is humidified which dilutes the oxygen concentration. This causes oxygen pressure to fall whilst water vapour pressure to increase.
As air is expired, it mixes with air trapped in the anatomical space to form mixed expired gas. This air consists mostly of oxygen so when it mixes with the expired air - partial pressure of oxygen increases whilst the pressure of carbon dioxide diminishes.
Direction of diffusion of a gas is
dependent on a concentration difference like other solutes but rather is dependent of the
difference in partial pressures
This explains why oxygen and carbon dioxide diffuse in different directions at the level of the air liquid interface of the alveoli.
the amount of a gas dissolved in a liquid is directly proportional to the partial pressure of that gas in equilibrium with the liquid
Partial pressures are used rather than concentration of gases (in liquid):
Partial pressures are a better indicator of how the gas will move from one compartment to another.
Concentration of gas dissolved in a liquid is dependent on solubility as well as partial pressure but talking about pressures is more simple. Concentration is solubility multiplied by partial pressure.
The rate of gaseous exchange is dependent on
partial pressure difference
The diffusion barrier in the lungs consists of the alveolar epithelium and the capillary endothelium and the fused basement membranes. The rate of transfer depends on the area and thickness of said barrier.
The diffusion barrier and solubility
will not vary
so the main driving force of exchange via diffusion is the
partial pressure difference
Solubility will to some extent limit diffusion. The diffusion barrier causes minimal impedance as it has a large area with a thin thickness.
Gaseous exchange is very rapid and only requires
one-third of the capillary
before the blood is fully saturated with oxygen.
Systemic PO2 is determined by alveolar PO2 whilst alveolar PCO2 is determined by capillary PCO2
- these values should be exactly the same.
systemic PO2 is slightly lower than alveolar
This is due to the mixing of deoxygenated and oxygenated blood which lowers the partial pressure of oxygen.
There is an 'anatomical right to left' shunt in the bronchial artery which mixes deoxygenated blood with oxygenated blood from the pulmonary vein going to the left atrium.
Also, part of the coronary venous blood drains directly into the oxygenated blood of the left ventricle. This mixing of blood lowers the partial pressure of oxygen.
The diffusion barrier at the level of the cells is the capillary endothelium and the cell membrane. Once again, it is the partial pressure difference driving diffusion.
For oxygen uptake, the partial pressure in the mitochondria will be the lowest as it requires it for respiration. For carbon dioxide expulsion, it will be the highest for PCO2 as it needs to get rid of it.
Oxygen transport in the blood is a crucial element of gaseous exchange. Carrying oxygen to the metabolising cells is essential for the maintenance of life.
Oxygen transport is measured using percent saturation, oxygen concentration (content), carrying capacity and partial pressures.
Measures of oxygen
If we relied solely on dissolved oxygen in blood, we would need a cardiac output of 83L/min to satisfy our oxygen demand due to oxygen's low solubility in blood.
drastically enhances the blood ability to carry oxygen. As a result 98.5% oxygen is carried by haemoglobin.
Haemoglobin consists of four
(four protein sub-units). Each haemoglobin can bind to four molecules of oxygen. At the centre of each
haem-group is an Fe2+ ion
which is able to conjugate with a histidine residue and a molecule of oxygen.
When an oxygen binds this is called
' because the ferrous ion does not change.
Oxygenation in itself is regulated by haemoglobin's structural
and environmental factors e.g.
and the concentration of
The oxygen-haemoglobin dissociation curve is a
. Co-operativity describes the increase in 'affinity' for oxygen after a molecule of oxygen has already bonded. It has an exponential phase (where small changes in PO2 cause large increases in saturation) and a plateau phase.
effect describes that the dissociation curve will shift to the left or right depending on certain conditions.
In the alveoli, PCO2 is low and this will cause a rise in PH. There will also be reduction in temperature due to evaporation and 2,3DPG will be in low concentration as it is a product on anaerobic respiration. This causes a
- this means haemoglobin will have a higher affinity for oxygen meaning
O2 uptake is a lot faster
In the tissues, PCO2 will be high and PH as a result will be low. Metabolism is exothermic so raises temperature. 2,3DPG will also begin to accumulate in hypoxic conditions during anaerobic respiration. This causes a
; decreasing oxygen affinity meaning haemoglobin is
more likely to release oxygen
Deoxygenated blood is just 75% saturated with a lower oxygen content of 15ml/dl. This means that the tissues are able to extract 5ml/dl of oxygen. Oxygen transport to tissues is ~ 1000ml/min with cardiac output at 5L/min and oxygen content at 20ml/dl (1dl is 100ml).
Carbon dioxide transport is a bit different to oxygen transport.
Carbon dioxide is transported either by being dissolved in plasma, as bicarbonate or as carbamino compounds. The composition of venous and arterial blood is different in this respect.
Carbon dioxide is converted into bicarbonate but the reaction tends to be slow. This reaction is faster in erythrocytes due to the presence of carbonic anhydrase. CO2 is taken from the tissues due to a pressure gradient.
The equilibrium of the reversible reaction forming bicarbonate shifts to the right favouring the reaction thanks to - the buffering of protons due to deoxyhaemoglobin (
) and the exchange of bicarbonate with chloride via an exchanger.
Carbon dioxide transport as bicarb
The Haldane effect works in reverse in the lungs as bicarbonate will be converted back into CO2 and CO2 will be released from carbamino compounds which allows CO2 to be easily diffused out of the lung.
Carbon dioxide is also transported as carbamino compounds. Carbon dioxide is able to react with deoxyhaemoglobin to form carboxyhaemoglobin - this promotes the uptake of CO2 from tissues.
The CO2-dissociation curve is semi-linear, the blood has a greater carrying capacity for CO2 at 55ml/dl. With only 4ml/dl being absorbed from tissues to be expelled via the lungs.
CO2 dissociation curve
OVERALL SUMMARIES OF GASEOUS TRANSPORT:
Respiration I - Lung Mechanics
The main function of the respiratory system is to provide oxygen the body and to remove carbon dioxide from circulation.
The exchange of gases happen via diffusion at specialised interfaces such as the alveolar sacs and thinly-walled capillaries.
Whilst the transport of these gases through pulmonary and systemic circulation occurs by bulk flow. Bulk flow is similar to diffusion however, it is dependent on pressure differences rather than concentration.
The lungs contain over 300 million alveoli which provide a large surface area of approx. 85 metres squared and a thin diffusion distance of 0.2nm and this maximizes exchange.
The trachealis muscle spans in-between the C-shaped rings of cartilage and is able to constrict the trachea to increase pressure. This is particularly important for the coughing reflex.
The bronchioles have no cartilage but have smooth muscle and usually only contract to prevent particulates and irritants from getting into the alveoli.
No gaseous exchange occurs in the conducting zone of the tract. Exchange only occurs in the respiratory zone after the terminal bronchioles.
The alveolar sacs consist of many alveoli and are supplied by a respiratory bronchiole. The entire sac is highly vascularised, with a dense network of capillaries. The capillaries are fed deoxygenated blood via a branch of the pulmonary artery. Gaseous exchange occurs at this level.
The alveolar cells are called pneumocytes and come in two types:
Type 1 pneumocytes are squamous cells with a flattened epithelium and are involved in the gaseous exchange.
Type 2 pneumocytes are the thicker cells and they produce
The main functions of the lung are:
Provide oxygen to the body tissues and to remove carbon dioxide from circulation.
The lungs are also responsible for phonation (speech).
Protection from microbes and other foreign matter.
Regulates blood PH as carbon dioxide is a big determinant due to the formation of carbonic acid in solution.
The lung is also responsible for the activation of Angiotensin II as there is ACE on the pulmonary epithelium. AngII is a vasoconstrictor and leads to aldosterone secretion.
When studying the lungs, their effectiveness is measured using volumes and capacities. The difference between the two is that a capacity is the sum of
'two or more'
Different lung volumes
Lung volumes are measured using a spirometer/vitalograph. Residual volume relies on the 'baseline' figure but the lungs cannot be completely emptied so a spirometer cannot be used to measure it.
Alveolar ventilation is the exchange of air between the atmosphere and the alveoli. Alveolar ventilation is measured as the volume of fresh air reaching the alveoli per minute. Minute ventilation is the total ventilation in a minute and is,
tidal volume multiplied by respiratory rate
The amount of air trapped in the conducting zone during breathing is known as
anatomical dead space
. This volume is approx. 150ml.
This means after every breath, 150ml of air will remain in the lung. Therefore, 350ml of every 500ml new breath will ventilate the alveoli alongside with a new 150ml becoming dead space after every inspiration.
Alveolar ventilation is minute ventilation minus dead space ventilation.
Ventilation occurs due to a pressure gradient between atmospheric and alveolar pressures. Air flows from a region of high to low pressure. Flow is measured by the difference of pressure divided by resistance.
explains the pressure differences in the lung and in a nutshell explains that
volume and pressure are inversely proportional.
At residual capacity (full expiration), the muscles are relaxed - this leads to a recoil of the lungs but this is balanced by an outward pressure of the chest wall. This generates a
pressure due to the serous fluid between membranes, this helps the alveoli inflate.
Trans-pulmonary pressure is alveolar pressure minus intrapleural pressure.
rely on changes in pressure and volumes.
Nervous stimulation causes the chest cavity to expand. This causes a fall in intrapleural pressure. This increases transpulmonary pressure causing the volume of the alveoli to increase. Due to Boyle's law, alveolar pressure falls. As alveolar pressure falls below atmospheric, air flows into the lungs. Expiration is the opposite.
As air flows through the airways, it can encounter
. A majority of this, is from congestion in the upper respiratory tract. Bronchioles also contribute to resistance due to their small diameter, however they are numerous so their total resistance is low.
In normal breathing, air flow is laminar to reduce friction however, during heavy breathing - air flow is a lot more turbulent and noisy.
Obstructive lung diseases usually cause an increase in resistance by the narrowing of the airways either by excessive mucous production or by the hypersensitivity to constrictors. As a result this reduces gaseous exchange e.g. asthma and bronchitis.
explains the relationship between flow, pressure and resistance.
explains the relationship between resistance and the radius of the tube.
Neural and chemical effectors can cause changes in the lumen size of the bronchi.
Sensory nerves, carbon dioxide and adrenaline on Beta-2 receptors act as dilators.
Inflammatory cells acts as constrictors. The vagus nerve acts using acetylcholine to constrict the airways; the receptors being the pulmonary stretch receptors (-) and the airway irritant receptors (+).
The lungs also have
. Compliance is defined as the change in lung volume divided by change in transpulmonary pressure. This describes the '
' of lung tissue as it is a measure of how easily the lungs expand once exposed to a given pressure. Approx. 1.5-3 L/Kpa.
Must be measured when airflow is zero so when alveolar pressure is equal to atmospheric pressure. This means that transpulmonary pressure will be the negative of intrapleural pressure.
The main determinants for compliance are elasticity and surface tension of the alveoli.
Elasticity/ability to recoil should not be too high - too much resistance to recoil due to excess collagen, leads to fibrosis and low compliance. Not enough recoil leads to emphysema and a high compliance.
Compliance is useful clinically in checking disease states. Abnormally low compliance would suggest fibrotic lung whilst high compliance would show emphysema.
Increasing compliance is not good as it causes the lung to collapse and be unable to force air out of the alveoli. This would increase residual volume.
Alveoli have an air-fluid interface as they have a thin layer of serous fluid on their inner surface. Water molecules form intermolecular bonds and create a tension which is exerted over the entire fluid.
Tension is fixed so only pressure and radius will vary. The relationship was describe by Laplace, pressure is equal to two multiplied by tension divided by radius. So, clearly - anatomically smaller alveoli will have large pressures.
As alveoli vary in size, pressure differences will be established between adjacent alveoli. Air will flow from these smaller alveoli to larger alveoli with lower pressures.
The smaller alveoli would then collapse and impair exchange. However,
Surfactant reduces surface tension. This will reduce the pressure in the smaller alveoli to a point where it is equal with the large alveoli. Therefore, air will not flow. Surfactant increases compliance.
Histology of the Respiratory system
The respiratory system deals with the exchange of gases mainly oxygen from the air to the blood and carbon dioxide from the blood to the air.
Not all inspired air reaches the alveoli so all the 'dead space' of the purely conducting airways is known as anatomical dead space. It's about one third of a breath.
Any alveoli with poor supply of blood perhaps due to an embolus contributes little to exchange. Such alveoli together with anatomical dead space,make up the physiological dead space.
The lungs are supplied by the pulmonary arteries which are
in character. Pulmonary pressure is low compared to systemic. The system also receives blood from the bronchial arteries which branch off the aorta; mainly supplying blood to the pleura and bronchial walls. These arteries eventually anastomose with the pulmonary arteries.
The system consists of the lungs and the upper and lower respiratory tracts which are connected by the pharynx.
respiratory tract consists of the nasal cavity, paranasal sinuses and nasopharynx.
This part of the tract is responsible for filtration of large impurities in air via the nose-hairs, moistening and warming of air due to the special type of epithelium.
respiratory tract consists of the larynx, trachea and the further subdivisions of the bronchi.
The larynx is responsible for phonation (vocal sounds) and also houses the epiglottis, a sphincter responsible for allowing air down the trachea or food down the oesophagus.
The trachea is a long tube which at a point bifurcates into two
bronchi which each supply a single lung.
The trachea has a
C-shaped rings of cartilage
which prevents the collapse of the tube during inspiration and expiration. Contraction of the
, decreases the diameter but increases intrathoracic pressure assisting with forcing air in or out.
The epithelium sits on a
which is rich in
. Beneath the lamina is a
thick submucosal layer
which contains many
which are usually found between cartilage rings.
Primary bronchi further subdivide into
bronchi which supply a lobe of the lung.
The bronchi still have a respiratory epithelium with fewer goblet cells. They have
plates of cartilage rather than rings
. There is a layer of discontinuous muscle separating the lamina from the submucosa.
Secondary bronchi then also divide into
bronchi which supply individual bronchopulmonary segments.
Tertiary bronchi also have a respiratory epithelium but it has fewer goblet cells with less pseudostratification. There is a
complete layer of smooth muscle
beneath the lamina innervated by the PNS to contract and antagonised by the SNS. There is some cartilage but it is very irregular.
The smallest processes of the tertiary bronchi are called
. These then get smaller and divide and which supply
. These ducts then finally, supply air to the
which are the actual site of exchange.
The bronchioles completely lack cartilage and submucosal glands. They have bits of discrete muscle which are responsible for asthma attacks. They also have a respiratory epithelium but the cells are more cuboidal than columnar.
The bronchioles subdivide once more into
terminal and respiratory bronchioles
The terminal bronchioles are the smallest part of the airways. They have a cuboidal ciliated epithelium with
rather than Goblet cells. Clara cells secrete surfactant, pump chloride ions and maybe stem cells.
Terminal bronchioles terminate in at the respiratory bronchioles. These bronchioles have a
in their walls. These then continue into alveolar ducts.
The alveolar ducts are made entirely of alveoli supported by collagen and elastin. These terminate in alveolar sacs.
The alveoli are the site of gaseous exchange. They are either lined by Type 1 or Type 2 pneumocytes.
pneumocytes are squamous lining cells. These take up a majority of the surface area but less than half of the cellular abundance.
pneumocytes secrete surfactant, these are the most abundant cell type but barely cover much surface area.
These cells contain lamellar bodies which secrete phospholipid and cholestrol. These bind to surfactant proteins to form a lipoprotein lattice - this overcomes a
so that the alveolar walls can separate.
The alveolar wall contains the capillary plexus. These share a lamina with the Type 1 pneumocytes - the diffusion distance is 0.2 micrometers.
A majority of the respiratory system is lined by a
epithelium. This epithelium is pseudostratified, columnar and ciliated with large numbers of goblet cells. This type of epithelium lines much of the upper respiratory tract, the trachea, bronchi and large bronchioles.
Goblet cells account for about 30% also.
Basal cells usually are cuboidal and account for about 30% also and are the stem cell population of the system.
Tall, columnar and ciliated cells account for about 30% of cells in the system.
Neuroendocrine cells (Kulchitsky cells) account for the remaining 10%. These cells secrete neurotransmitters such as serotonin and calcitonin.
The respiratory epithelium has a number of useful functions.
The goblet cells produce mucus whilst sub-mucosal glands trap dust.
The cilia are able to propel mucus and dirt upward toward the pharynx. This is known as the muco-cillary escalator.
Cilia are motile structures approx ~8nm long, constructed using 20 microtubules (a pair surrounded by nine pairs). It grows out of a basal body which is very similar to a centriole.
Sub-mucosal glands also produce a serous secretion which humidifies inspired air.
The alveoli have a number of special features:
Inhaled particulate material that escapes the mucocillary escalator is taken up by alveolar macrophages. These macrophages then crawl to the lymphatic system or the pharynx.
The alveolar pores are perforations in the alveolar walls and allow the equilibration of pressure between adjacent alveoli and provide an alternative route for air to travel in case of a blocked bronchiole.
Alveolar walls are supported by elastin bundles. Elastin along with collagen support the lung paranchyma. Elastin is important in the recoil of the alveoli; destruction of the elastin prevents recoil leading to emphysema.
Respiration III - Control of Breathing
Breathing is rhythmic and in healthy individuals is controlled by the autonomic nervous system.
respiratory muscles contract
whilst during expiration - the muscles relax and air is
expelled mostly through elastic recoil
All respiratory muscles are skeletal in origin so require neural input for stimulation.
The main respiratory muscle is the diaphragm which is innervated by the Phrenic Nerve - this nerve stems from between cervical vertebrae C3-C5.
The intercostals are innervated by spinal nerves.
This rhythmicity is generated in the brain stem by three brain centres: Hypothalamus, Pons and the medulla oblongata.
These centres particularly the Pons and the medulla - help to form the medullary respiration centre.
The respiration centre receives inputs from higher brain centres and lung receptors:
The Limbic system mediates responses in response to emotion. Emotion can lead to hyperventilation/hypoventilation in extreme cases.
Voluntary control of breathing can override the respiratory centre thanks to the cerebral cortex. The cortex has motor neurons which directly innervate respiratory muscles via the pyramidal tract.
The hypothalamus has thermoreceptors which can alter breathing rate.
The lung has
in bronchial smooth muscle which is innervated by the vagus nerve. The vagus nerve sends impulses to the DRG to inhibit inspiratory neurons and thus inspiratory muscles. This inhibits inspiration by giving expiration time to occur. This has negative feedback on this reflex.
is used during heavy breathing to ensure that the lungs are not over stretched,
The lung has irritant receptors. There are nerve endings in-between epithelial cells - once exposed to irritants (smoke, dust etc.). The vagus nerve sends impulses to the medulla to trigger the coughing reflex (to remove irritants), bronchoconstriction (prevents irritants reaching the alveoli), surfactant release and deep breaths (prevents lung collapse).
The respiration centre consists of the dorsal respiratory group (DRG) and the ventral respiratory group (VRG).
The DRG contains
. These are rhythmic in nature and innervate inspiratory muscles. The DRG also receives inputs from receptors via the vagus nerve.
The VRG contains both
inspiratory and expiratory neurones
. The neurones do have a degree of spontaneous pacemaker rhythmicity. It receieves additional inputs from chemoreceptors and the DRG.
During normal breathing, the inspiratory muscles tend to be more stimulated than the expiratory. Expiration is mostly by elastic recoil so requires little neural input.
During exercise, your breathing is heavier. This leads to the expiratory muscles being innervated as well via other inputs.
Inspiratory neurones and expiratory neurones
leads to 'alternate stimulation' of the different muscle groups.
Two regions from the Pons receives inputs from the cerebrum and hypothalamus and then feed these forward to the respiration centre in the medulla oblongata.
centre inhibits the DRG to promote expiration thus affecting breathing rate by changing the space between breaths.
Centre stimulates the DRG to promote inspiration this increases the duration of a single breath.
The pneumotaxic and apneustic centres of the Pons inhibit eachother and allow a fine-tuning of the basic rhythmicity established in the medulla.
When ventilation mismatches metabolic demand, this can lead to hyperventilation or hypoventilation. Exercise is not a mismatch as ventilation rises to meet metabolic demand.
Hyperventilation is usually caused by stress. PCO2 will fall leading hypocapnia. This causes respiratory alkalosis as the carbonic acid reaction shifts to the left.
Low PCO2 in the brain causes cerebral vasoconstriction leading to cerebral hypoxia and dizziness.
Hypoventilation on the other hand is caused by lung disease. This raises PCO2 leading to hypercapnia and respiratory acidosis; carbonic acid reactions shifts to the right.
Hypercapnia can adversely affect the CNS which is potentially fatal. Hypoventilation lowers PO2, causing hypoxia.
Ventilation needs to regulated to control PO2 (~12.5kPa) and PCO2 (~5.3kPa)/PH.
Increasing alveolar PCO2 leads to a direct increase in ventilation. Small changes in PCO2 lead to large changes in ventilation.
Alveolar PCO2 graph
Top of the curve decreases as there is excessive hypercapnia - there is no point of increasing ventilation. Near bottom of the curve is the basal rate of ventilation.
PCO2 directly affects pH balance but protons can be generated or lost from other chemical reactions/processes (metabolic acidosis/alkalosis). For example:
Diabetes Mellitus causes the build up of ketone bodies, one of these is acidic causing an aggregation of H+.
Kidney disease and diarrhoea can both lead to a loss of bicarbonate causing the gain of protons and drop in pH.
Physical exercise also contributes by lactic acid production but this is usually normal and transient. All the above contribute to
on the other hand could be caused by a loss of H+ e.g. by vomiting or by excessive use of diuretics which causes a loss of water but high retention of bicarbonate raising pH.
Chemoreceptors detect changes in PCO2, PO2 and pH. The most important are the
central chemoreceptors in the medulla
(80% - PCO2 and H+) and the others are peripheral; they are present in the
aortic and carotid bodies
(20% - responsible for PO2, PCO2 and H+).
The central chemoreceptors are bathed in cerebrospinal fluid and sense the pH of the fluid.
These indirectly measure PCO2. As protons cannot pass through the blood-brain barrier - H+ and bicarbonate must from CO2 and water. CO2 can diffuse through the barrier and then reforms protons which are then detected by the medulla.This means that H+ is directly proportional to PCO2.
The peripheral chemoreceptors send impulses to the medulla via the vagus and glossopharyngeal nerves.
Most important of the peripheral receptors is the carotid bodies. These are at the bifurcation of the common carotid artery. The body contains two types of cell:
Glomus cells respond to decrease in PO2 and increases in PCO2 and H+. These are the main O2 sensing cells and they release dopamine at the nerve junction. The body also contains sheath cells.
The aortic bodies are found on the aortic arch.
pH directly affects the PCO2-ventilation relationship. A low pH/increase in H+ causes a left-ward shift; enhancing the effect of PCO2 on ventilation. Whilst a high pH/decrease in H+ causes a right-ward shift; suppressing the effect on PCO2 on ventilation.
pH on curve
is more a curved relationship, PO2 does not really effect ventilation until PO2 drops below 8kPa as a hypoxic response. As PO2 decreases, there will be an exponential rise in ventilation.
The hypoxic response of PO2 (<7kPa) and the hypercapnic response from PCO2 act synergistically. When a person is hypoxic, ventilation becomes more sensitive to small changes in PCO2.
The pharmacology of respiratory drugs tend to be broncho-dilators or anti-inflammatory in nature and this is because of the illnesses they try to appease.
Asthma and Bronchitis are in the upper part of the airways e.g. trachea, bronchi and bronchioles.
The asthmatic response is triggered by an allergen binding to immunoglobulin-E receptors on a mast cell which activates the cell. Once activated, the mast cell will secrete
histamine, prostaglandins, leukotrienes and cytokines
. These have a strong
broncho-constrictive effect causing inflammation, oedema and mucus
with inflammation due to the aggregation of white blood cells.
An asthma attack occurs in
is the initial response to the allergen which only takes a
. The mast cells release a number of mediators and cause a strong broncho-spasm thus reducing respiratory ability.
. This occurs due to a narrowing of the airways by oedema, inflammation and high mucus production as a result of all the recruited cells releasing various mediators.
The last phase is a '
' of the airways to any inhaled irritants which can cause sudden broncho-constriction. This sort of response takes days to occur and does not occur all the time.
The drugs used to help treat asthma are
Beta 2 adrenergic- agonists
are used in the immediate treatment of asthmatic symptoms due their dilative effect of the airways. Examples are:
is also used in prophylaxis but is not a B2-agonist.
B2 agonist action
These drugs work by a GPCR (Gs). The drug binds and causes a conformational change to activate the receptor. Adenylyl cyclase converts ATP into Cyclic AMP - this then activates Protein Kinase A to activate Myosin light chain kinase (MLCK) to become phosphorylated. This form of MLCK causes the relaxation of the muscle.
Theophylline is a Xanthine which acts to inhibit Cyclic AMP Phosphodiesterase (isoform 3)
. This forces the reaction process forward which promotes the relaxation of the muscle. It's structure is very similar to that of Caffeine.
Beta 2 drugs are chemically/structurally similar to endogenous B2 - agonists e.g. adrenaline. They cause a relaxation of the muscle and inhibit degranulation of mast cells.
also cause a relaxing/dilative effect by preventing the contraction of smooth muscle in the airways. There are
(pre-synaptic) receptors and
receptors on the muscle fibres which are inhibited to prevent contraction.
These are used mostly in treating chronic obstructive pulmonary disease. The main two inhibitors are:
ipratropium bromide and tiotropium bromide
which differ by how long-acting they are.
The main type of anti-inflammatory drugs used are Glucocorticosteroids. Other examples of anti-inflammatory drugs are: Theophylline, Leukotriene antagonists, Anti-Immunoglobin E and Cromones.
are lipophilic so are able to diffuse through the membrane with ease. They then bind to a receptor which is bound to a protein called HSP90 (heat shock protein). HSP90 helps to transport the steroid into the nucleus of the cell. The steroid then binds to a specific gene and thus affects protein synthesis.
This can either be
(preventing the synthesis of certain proteins) of chemical mediators e.g. prostaglandins or
(encouraging the production of certain proteins) of proteins with a broncho-dilative effect e.g. annexin (lipocortin), mitogen kinase phosphatase 1 (inhibits MAP kinase) prevents oxidative stress or enhancing B2 receptors.
These drugs are
anti-oedema, inhibit the recruitment of inflammatory cells (mast cells, eosinophils, white blood cells etc.) and increase B2 receptor function
These drugs have a number of side effects. Possible effects are oral candidiasis and osteoporosis etc.
work as a result of taking glucocorticosteroids. They produce
which inhibits Phospholipase A2. This prevents the formation of Leukotrienes which cause a number of effects such as:
broncho-constriction, oedema and mucus production
reduce inflammatory cell recruitment but are not as effective as steroids e.g. Sodium Cromoglicate.
Anti-immunoglobulin E drugs
bind to free igE, this reduces the activation of mast cells and the recruitment of inflammatory cells. This means that, there will be reduced secretion of chemical mediators thus reducing the asthmatic reaction. The example drug is Omalizumab.
Chronic obstructive pulmonary disease occurs in the lower regions of the airways from the terminal bronchioles onward e.g. emphysema etc.