Month: November 2015

Mechanics of Breathing – Alveolar Ventilation

November 17, 2015 Physiology and Pathophysiology, Pulmonary Medicine No comments , , , , , , , , , , , , , , , ,

Important Measurements of Lung Functions

The tidal volume (VT) is the volume of air entering or leaving the nose or mouth per breath. It is determined by the activity of the respiratory control centers in the brain as they affect the respiratory muscles and by the mechanics of the lung and the chest wall. During normal, quiet breathing the VT of a 70-kg adult is about 500 mL per breath, but this volume can increase dramatically, for example, during exercise.

The residual volume (RV) is the volume of gas left in the lungs after a maximal forced expiration. It is determined by the force generated by the muscles of expiration and the inward elastic recoil of the lungs as they oppose the outward elastic recoil of the chest wall. Dynamic compression of the airways during the forced expiratory effort may also be an important determinant of the RV as airway collapse occurs, thus trapping gas in the alveoli. The RV of a healthy 70-kg adult is about 1.5 L, but it can be much greater in a disease state such as emphysema, in which inward alveolar elastic recoil is diminished and much airway collapse and  gas trapping occur. The RV is important to a healthy person because it prevents the lungs from collapsing at very low lung volumes. The collapsed alveoli would require very great inspiratory efforts to reinflate.

The expiratory reserve volume (ERV) is the volume of gas that is expelled from the lungs during a maximal forced expriation that starts at the end of a normal tidal expiration. It is therefore determined by the difference between the functional residual capacity (FRC) and the RV. The ERV is about 1.5 L in a heathy 70-kg adult.

The inspiratory reserve volume (IRV) is the volume of gas that is inhaled into the lungs during a maximal forced inspiration starting the end of a normal tidal inspiration. It is determined by the strength of contraction of the inspiratory myscles, the inward elastic recoil of the lung and the chest wall, and the starting point, which is the FRC plus the VT. The IRV of a normal 70-kg adult is about 2.5 L.

The functional residual capacity (FRC) is the volume of gas remaining in the lungs at the end of a normal tidal expiration. The FRC consists of the RV plus the ERV. It is therefore about 3 L in a healthy 70-kg adult. FRC=RV+ERV

The inspiratory capacity (IC) is the volume of air that is inhaled into the lungs during a maximal inspiratory effort that begins at the end of a normal tidal expiration. It is therefore equal to the VT plus the IRV. The IC of a normal 70-kg adult is about 3 L. IC=VT+IRV

The total lung capacity (TLC) is the volume of air in the lungs after a maximal inspiratory effort. It is determined by the strength of contraction of the inspiratory muscles and the inward elastic recoil of the lungs and the chest wall. The TLC consists of all 4 lung volumes: the RV, the VT, the IRV, the ERV. The TLC is about 6 L in a healthy 70-kg adult. TLC=RV+ERV+VT+IRV

The vital capacity (VC) is the volume of air expelled from the lungs during maximal forced expiration starting after a maximal forced inspiration. The VC is therefore equal to the TLC minus the RV, or about 4.5 L in a healthy 70-kg adult. The VC is also equal to the sum of the VT and IRV and ERV. It is determined by the factors that determine the TLC and RV. VC=TLC-RV=VT+IRV+ERV

Physiologic Dead Space

The volume of air entering and leaving the nose or mouth per minute, the minute volume, is not equal to the volume of air entering and leaving the alveoli per minute. Alveolar ventilation is less than the minute volume because the last part of each inspiration remians in the conducting airways and is not expelled from the body. No gas exchange occurs in the conducting airways for anatomic reasons: The walls of the conducting airways are too thick for mucn diffusion to take place; mixed venous blood does not come into contact with the air. The conducting airways are therefore referred to as the anatomic dead space. A reasonable estimate of anatomic dead space is 1 mL of dead space per pound of ideal body weight.

Besides the anatomic dead space, there is another form of wasted ventilation, where the alveoli are ventilated but not perfused with venous blood. No gas exchange occurs in these alveoli for physiologic, rather than anatomic, reasons. A healthy young person has little or no alveolar dead space, but a person with a low cardiac output might have a great deal of alveolar dead space. The anatomic dead space plus the alveolar dead space is known as the physiologic dead space.

Physiologic dead space = anatomic dead space + alveolar dead space [Bohr equation]

The Bohr equation makes use of a simple concept: Any meaurable volume of carbon dioxide found in the mixed expired gas must come from alveoli that are both ventilated and perfused because there are negligible amounts of carbon dioxide in inspired air. Inspired air remaining in the anatomic dead space or entering unperfused alveoli will leave the body as it entered (except for having been heated to body temperature and humidified), contributing little or no carbon dioxide to the mixed expired air:

FEco2 X VT = FIco2 X VDco2 + FAco2 X VA,

FEco2 X VT is volume of CO2 in mixed expired air

FIco2 X VDco2 is volume of CO2 coming from dead space

FAco2 X VA is volume of CO2 coming from alveoli

F means fractional concentration

E means mixed expired

I means inspired

A means alveolar

VDco2 is dead space for CO2 (physiologic dead space)

FAco2 is fractional concentration of CO2 in alveoli that are both ventilate and perfused

Since FIco2 is approximately equal to zero, the FIco2 X VDco2 term drops out. Substituting (VT – VDco2) for VA:

FEco2 X VT =  FAco2 X (VT – VDco2)

VDco2 X FAco2 = VT X (FAco2 – FEco2)

After these mathematic processes, we can calcuate the dead space for CO2/physiologic dead space by the following equation:

VDco2 = VT x (PAco2 – PEco2)/PAco2

The Pco2 of the collected mixed expired gas can be determined with a CO2 meter. The CO2 meter is often also used to estimate the alveolar Pco2 by analyzing the gas expelled at the end of a normal tidal expiration, the "end-tidal CO2". But in a person with significant alveolar dead space, the estimated alveolar Pco2 obtained in this fashion may not reflect the Pco2 of alevoli that are ventilated and perfused because some of this mixed end-tidal gas comes from unperfused alveoli. This gas dilutes the CO2 coming from alveoli that are both ventilated and perfused.

Because there is an equilibrium between the Pco2 of perfused alveoli and their end-capillary Pco2, so that in patients without significant venous-to-arterial shunts, the arterial Pco2 represents the mean Pco2 of the perfused alveoli. Therefore, the equation above could be rewritten as:

VDco2 = VT x (Paco2 – PEco2)/Paco2

If the Paco2 is greater than the mixed alveolar Pco2 determined by sampling the end-tidal CO2, then the physiologic dead space is probably greater than the anatomic dead space; that is, a significant arterial-alveolar CO2 difference means that there is siginifcant alveolar dead space. Situations in which alveoli are ventilated but not perfused include those in which portions of the pulmonary vasculature have been occluded by blood clots from the venous blood (pulmonary emboli), situations in which there is low venous return leading to low right ventricular output, and situations in which alveolar pressure is high (positive-pressure ventilation with positive end-expiratory pressure).

Alveolar Ventilation and Alveolar Oxygen and Carbon Dioxide Levels

The levels of oxygen and carbon dioxide in the alveolar gas are determined by the alveolar ventilation, the pulmonary capillary perfusion, the oxygen consumption of the body, and the carbon dioxide production of the body. Alveolar gas is composed of the 2.5 to 3 L of gas already in the lungs at FRC and the approximately 350 mL per breath entering and leaving the alveoli. About 300 mL of oxygen is continuosusly diffusing from the alveoli into the pulmonary capillary blood per minute at rest and is being replaced by alveolar ventilation. Simiarly, about 250 mL of carbon dioxide is diffusing from the mixed venous blood in the pulmonary capillaries into the alveoli per minute and is then removed by alveolar ventilation.

PS: normal PAO2 is 104 mm Hg and normal PACO2 is 40 mm Hg.

The alveolar PO2 increases by 2 to 4 mm Hg with each normal tidal inspiration and falls slowly until the next inspiration. Similarly, the alveolar PCO2 falls 2 to 4 mm Hg with each inspiration and increases slowly until the next inspiration.

The concentraton of carbon dioxide in the alveolar gas is dependent on the alveolar ventilation and on the rate of carbon dioxide production by the body (and its delivery to the lung in the mixed venous blood). The volume of carbon dioxide expired per unit of time (VECO2) is equal to the alveolar ventilation VA times the alveolar fractional concentration of CO2 (FACO2). No carbon dioxide comes from the dead space: VECO2 = VA X FACO2. Simarily, the fractional concnetration of carbon dioxide in the alveoli is directly proportional to the carbon dioxide production by the body (VCO2) and inversely proportional to the alveolar ventilation: FACO2 is directly proportional to VCO2/VA.

Since FACO2 X (PB – PH2O) = PACO2, then PACO2 is directly proportional to VCO2/VA.

After these mathematic proving, we got the following formula to estimate the PACO2:

PACO2 is in directly proportional to VCO2/VA

where PACO2 is the alveolar CO2 pressure, VCO2 is the carbon dioxide production by the body, and the VA is the alveolar ventilation. In healthy people, alveolar PCO2 is in equilibrium with PaCO2. Thus, if alveolar ventilation is doubled, then the alveolar and arterial PCO2 are reduced by one-half. If alveolar ventilation is cut in half, near 40 mm Hg, then alveolar and arterial PCO2 will double.

For O2, it is evident that as alveolar ventilation increases, the alveolar PO2 will also increase. Doubling alveolar ventilation, however, cannot double PAO2 in a person whose alveolar PO2 is already approximately 104 mm Hg because the highest PAO2 one could possibly achieve (breathing air at sea level) is the inspired PO2 of about 149 mm Hg.

After some mathematic calculation, we got the following formula to estimate the PAO2:

PAO2 = PiO2 – PACO2/R + F

where, R= respiratory exchange ratio, VCO2/VO2, which represents the whole body carbon dioxide produced per time divided by the whole body oxygen consumption per time. It is primarily dependent on the foodstuffs metabolized by the cells of the body. In a person with a typical mixed diet, it is approximately 0.8; a person consuming a diet consisting of mainly carbohydrates or proteins would have an R of approximately 1.0; a person consuming a diet consisting of mainly fat would have an R of approximately 0.7.

As alveolar ventilation increases, the alveolar PCO2 decreases, bringing the alveolar PO2 closer to the inspired PO2.

Regional Distribution of Alveolar Ventilation

As previously discussed, a 70-kg person has about 2.5 to 3 L of gas in the lungs at the FRC. Each eupneic breath brings about 350 mL of fresh gas into the alveoli and removes about 350 mL of alveolar air from the lung. Although it is reasonable to assume that the alveolar ventilation is distributed fairly evenly to alveoli throughout the lungs, this is not the case. Studies performed on normal subjects seated upright have shown that alveoli in the lower regions of the lungs receive more ventilation per unit volume than do those in the upper regions of the lung.


screen-shot-2016-09-16-at-9-03-21-pmPrecise measurements made of the intrapleural surface pressures of intact chests in the upright position have shown that intrapleural surface pressure is not uniform throughout the thorax: The intrapleural surface pressure is less negative in the lower, gravity-dependent regions of the thorax than it is in the upper, nondependent regions. There is a gradient of the intrapleural surface pressure such that for every centimeter of vertical displacement down the lung (from nondependent to dependent regions) the intrapleural surface pressure increses by about +0.2 to +0.5 cm H2O. This gradient is apparently caused by gravity and by mechanical intereactions between the lung and the cehst wall.

Because the difference in intrapleural surace pressure throughout the lung, the transmural pressure of the alveoli between nondependent and dependent lung areas at FRC are not the same. The left side of Figure 3-12 shows that alveolar pressure is zero (equals to atmophere) in both regions of the lung at the FRC. Since the intrapleural pressure is more negative in upper regions of the lung than it is in lower regions of the lung, the transpulmonary pressure (alveolar minus intrapleural) is greater in upper regions of the lung than it is in lower regions of the lung. Because the alveoli in upper regions of the lung are subjected to greater distending pressures than those in more dependent regions of the lung, they have greater volumes than the alveoli in more dependent regions.

It is this difference in volume that leads to the difference in ventilation between alveoli located in dependent and nondependent regions of the lung. This can be seen on the hypothetical pressure-volume curve shown on the right side of Figure 3-12. This curve is similar to the pressure-volume curve for a whole lung, except that this curve is drawn with the pressure-volume characteristics of single alveoli in mind. The abscissa is the transpulmonary pressure. The ordinate is the volume of the alveolus expressed as a percent of its maximum.

The alveolus in the upper, nondependent region of the lung has a larger transpulmonary pressure than does the alveolus in a more dependent region because the intrapleural pressure in the upper, nondependent regions of the lung is more negative than it is in more dependent regions. Because of this greater transpulmonary pressure, the alveolus in the upper region of the lung has a greater volume than the alveolus in a more gravity-dependent region of the lung. At the FRC, the alveolus in the upper part of the lung is on a less steep portion of the alveolar pressure-volume curve in Figure 3-12 than is the more compliant alveolus in the lower region of the lung. Therefore, any change in the transpulmonary pressure during a normal respiratory cycle will cause a greater change in volume in the alveolus in the lower, gravity-dependent region of the lung than it will in the alveolus in the nondependent region of the lung, as shown by the arrows in the figure. Because the alveoli in the lower parts of the lung have a greater change in volume per inspiration and per expiration, they are better ventilated than those alveoli in nondependent regions (during eupneic breathing from the FRC).

A second effect of the intrapleural pressure gradient in a person seated upright is on regional static lung volume, as is evident from the above discussion. At the FRC, most of the alveolar air is in upper regions of the lung because those alveoli have larger volumes. Most of the ERV is also in upper protions of the lung On the other hand, most of the IRV and IC are in lower regions of the lung.

Alterations of Distribution at Different Lung Volumes (low volumes/RV, high volumes/)

Most of the air inspired during a tidal breath begun at the FRC enters the dependent alveoli. If a slow inspiration is begun at the RV, however, the initial part of the breath (inspiratory volume less than the ERV) enters the nondependent upper alveoli, and dependent alveoli begin to fill later in the breath. The intrapleural pressure gradient from the upper parts of the lung to the lower parts of the lung is also the cause of this preferential ventilation of nondependent alveoli at low lung volumes.

Positive intrapleural pressures are generated by the expiratory muscles during a forced expiration to the RV. This results in dynamic compression of small airways. At the highest intrapleural pressures these airways close, and gas is trapped in their alveoli. Because of the graident of intrapleural pressure found in the upright lung, at low low lung volumes the pleural surface pressure is more positive in lower regions of the lung than it is in upper regions. Also, alveoli in lower lung regions have less alveolar elastic recoil to help hold small airways open because they have smaller volumes than do the alveoli in upper regions. This means that airway closure will occur first in airways in lower regions of the lung. The expiratory effort has ended and the inspiratory effort has just begun. Airways in the lowest regions of the lung are still closed, and the local pleural surface pressure is still slightly positive. No air enters these alveoli during the first part of the inspiratory efforts until sufficient negative pressure is generated to open these closed airways.

In contrast to the situation at the FRC, at the RV the alveoli in the upper regions of the lungs are now on a much steeper portion of the pressure-volume curve. They now have a much greater change in volume per change in transpulmonary pressure – they are more compliant at this lower lung volume. Therefore, they receive more of the air initially inspired from the RV.

It has already been noted that even at low lung volumes the upper alveoli are larger in volume than are the lower gravity-dependent alveoli. They therefore constitute most of the RV.

Patients with emphysema have greatly decreased alveolar elastic recoil, leading to high FRCs, extremely high RVs, and airway closure in dependent parts of the lung even at high lung volumes. They therefore have relatively more ventilation of nondependent alveoli.

Reference Range of Critical Parameters

Dry Atmospheric Gas at Standard Barometric Pressure

PO2 = FiO2 X Ptot = 0.2093 X 760 mm Hg = 159 mm Hg

PCO2 = FiCO2 X Ptot = 0.0004 X 760 mm Hg = 0.3 mm Hg

Inspired Gas at Standard Barometric Pressure

PO2 = FiO2 X (PB – PH2O) = 0.2093 X (760 – 47) mm Hg = 149 mm Hg

PCO2 = FiCO2 X (PB – PH2O) = 0.0004 X (760 -47) mm Hg = 0.29 mm Hg

Alveolar Gas at Standard Barometric Pressure

PAO2 = 104 mm Hg, PACO2 = 40 mm Hg, PAN2 = 569 mm Hg, PAH2O = 47 mm Hg

Mixed Expired Air at Standard Barometric Pressure

PEO2 = 120 mm Hg, PECO2 = 27 mm Hg, PEN2 = 566 mm Hg, PEH2O = 47 mm Hg

Residents Series – Inflammatory Shock Syndromes

November 14, 2015 Cardiology, Critical Care, Infectious Diseases No comments , , , , , , , , , , ,

Grim-ReaperDefinitions and Impactions

SIRS/Systemic inflammatory response syndrome is a condition that is characterized by signs of systemic inflammation (e.g., fever, leukocytosis). The diagnosis of SIRS requires at least 2 of the following:

1.Temperature >38 C or <36 C

2.Heart rate >90 beats/min

3.Respiratory rate >20 breaths/min, or arterial PCO2 <32 mm Hg

4.WBC count >12,000/mm3 or <4000/mm3, or >10% immature neutrophils (band forms)

Sepsis is a kind of SIRS caused by an infection.

Severe sepsis is a sepsis condition accompanied by dysfunction in one or more vital organs, or an elevated blood lactate level (>4 mM/L).

Septic shock is a severe sepsis accompanied by hypotension that is refractory to volume infusion.

Screen Shot 2016-03-04 at 1.50.29 PM

Inflammatory injury involving more than one vital organ is called multiorgan dysfunction syndrome (MODS), and the subsequent failure of more than one organ system is called multiorgan failure (MOF).

The organs most often damaged by systemic inflammation are the lungs, kidneys, cardiovascular system, and central nervous system. The most common manifestation of inflammatory organ injury is the acute respiratory distress syndrome (ARDS), which has been reported in 40% of patients with severe sepsis, and is one of the leading causes of acute respiratory failure in critical ill patients.

The number of organs that are damaged by inflammatory injury has important prognostic implications. There is a direct relationship between the mortality rate and the number of organ failures related to inflammation. This demonstrates the lethal potential of uncontrolled systemic inflammation.

The Physiologic Characteristics of Septic Shock

Severe sepsis and septic shock have been implicated in one of every four deaths worldwide, and the incidence of these conditions is steadily rising. The mortality rate averages about 30-50%, and varies with age and the number of associated organ failures. The mortality rate is not related to the site of infection or the causative organism, including multidrug-resistant organisms. This observation is evidence that inflammation, not infection, is the principal determinant of outcome in severe sepsis and septic shock.

Hemodynamic Alterations

  • The principal hemodynamic problem is systemic vasodilatation (involving both arteries and veins), which reduces ventricular preload and ventricular afterload. The vascular changes are attributed to the enhanced production of nitric oxide (a free radical) in vascular endothelial cells.
  • Oxidant injury in the vascular endothelium (from neutrophil attachment and degranulation) leads to fluid extravasation and hypovolemia, which adds to the decreased ventricular filling from venodilation.
  • Proinflammatory cytokines promote cardiac dysfunction (both systolic and diastolic dysfunction); however, the cardiac output is usually increased as a result of tachycardia and volume resuscitation.
  • Despite the increased cardiac output, splanchnic blood flow is typically reduced in septic shock. This can lead to disruption of the intestinal mucosa, thereby creating a risk for translocation of enteric pathogens and endotoxin across the bowel mucosa and into the systemic circulation. This, of course, will only aggravate the inciting condition.

The typical hemodynamic pattern in septic shock includes low cardiac filling pressure (CVP or wedge pressure), a high cardiac output, and a low systemic vascular resistance (SVR). Because of the high cardiac output and peripheral vasodilatation, septic shock is also known as hyperdynamic shock or warm shock. In the advanced stages of septic shock, cardiac dysfunction is more prominent and the cardiac output is reduced, resulting in a hemodynamic pattern that resembles cardiogenic shock (i.e., high CVP, low CO, high SVR). A declining cardiac output in septic shock usually indicates a poor prognosis.

Tissue Oxygenation

The impaired energy metabolism in septic shock is not the result of inadequate tissue oxygenation, but is caused by a defect in oxygen utilization in mitochondria. This condiditon is known as cytopathic hypoxia, and the culprit is oxidant-induced inhibition of cytochrome oxidase and other proteins in the electron transport chain. A decrease in oxygen utilization would explain the observation that the PO2 in skeletal muscle is increased in patients with severe sepsis.

The proposed decrease in oxygen utilization in sepsis is not consistent with the increase in whole-body O2 consumption that is often observed in sepsis. This discrepancy can be resolved by proposing that the increased O2 consumption in sepsis is not a reflection of aerobic metabolism, but is a manifestation of the increased O2 consumption that occurs during neutrophil activation (i.e., the respiratory burst).

The discovery that tissue oxygenation is (more than) adequate in severe sepsis and septic shock has important implications because it means that efforts to improve tissue oxygenation in these conditions (e.g., with blood transfusions) are not justified.

Serum Lactate Levels

The increase in serum lactate levels in severe sepsis and septic shock is not the result of inadequate tissue oxygenation, but instead appears to be the result of enhanced production of pyruvate and inhibition of pyruvate dehydrogenase, the enzyme that converts pyruvate to acetyl coenzyme A in mitochondria. Endotoxin and other bacterial cell wall components have been implicated in the inhibition of this enzyme. This mechanism of lactate accumulation is consistent with the notion that tissue oxygenation is not impaired in severe sepsis and septic shock.


The management of septic shock is outlined in Table 14-3, and is organized in "bundles", which are sets of instructions that must be followed without deviation to provide a survival benefit. The acute sepsis bundle is considered the most important, and must be completed within 6 hours after the diagnosis of septic shock. Screen Shot 2015-11-14 at 8.15.07 PM

Volume Resuscitation

Volume resuscitation is often necessary in septic shock because cardiac filling pressures are reduced from venodilatation and fluid extravasation. The volume resuscitation requires the insertion of a central venous catheter to monitor the central venous pressure (CVP).

1.Infuse 500-1,000 mL of crystalloid fluid or 300-500 mL of colloid fluid over 30 minutes.

2.Repeat as needed until the CVP reaches 8 mm Hg, or 12 mm Hg in ventilator-dependent patients.

If CVP measurements are not available, a volume of at least 20 mL/kg (crystalloid fluid) can be used for the volume resuscitation.

After the initial period of volume resuscitation, the infusion rate of intravenous fluids should be reduced to avoid unnecessary fluid accumulation. A positive fluid balance is associated with increased mortality in septic shock, so attention to avoid fluid accumulation will improve the chances of a favorable outcome.


If hypotension persists after the initial volume resuscitation, infusion of a vasoconstrictor drug (vasopressor) like norepinephrine or dopamine should begin. Vasoconstrictor drugs must be infused through a central venous catheter, and the goal is to achieve a mean arterial pressure (MAP) >=65 mm Hg.

Norepinephrine is favored by many because it is more likely to raise the blood pressure than dopamine, and is less likely to promote arrhythmias. However, neither agent has proven superior to the other for improving the outcome in septic shock.

When hypotension is refractory to norepinephrine and dopamine, vasopressin may be effective in raising the blood pressure (Vasopressin is used as an additional pressor rather than a replacement for norepinephrine or dopamine). Vasopressin is a pure vasoconstrictor that can promote splanchnic and digital ischemia, especially at high dose rates. Although vasopressin may help in raising the blood pressure, the accumulated experience with vasopressin shows no influence on outcomes in septic shock.


Corticosteroids have two actions that are potentially beneficial in septic shock: they have antiinflammatory activity, and they magnify the vasoconstrictor response to catecholamines. Unfortunately, after more than 50 years of investigations, there is no convincing evidence that steroids provide any benefit in the treatment of septic shock. Yet steroids therapy continues to be popular in septic shock. The following comments reflect the current recommendations regarding steroid therapy in spetic shcok.

1.Steroid therapy should be considered in cases of septic shock where the blood pressure is poorly responsive to intravenous fluids and vasopressor therapy. Evidence of adrenal insufficiency (by the rapid ACTH stimulation test) is not required.

2.Intravenous hydrocortisone is preferred to dexamethasone (because of the mineralocorticoid effects of hydrocortisone), and the dose should not exceed 300 mg daily (to limit the risk of infection).

3.Steroid therapy should be continued as long as vasopressor therapy is required.

Antimicrobial Therapy

For the pharmacotherapy of antimicrobial therapy please view the thread of Systematic Approach for Selection of Antimicrobials at

Mechanics of Breathing – Airway Resistance

November 11, 2015 Physiology and Pathophysiology, Pulmonary Medicine No comments , , , , , , , ,

4685Fig01Events involved in a normal tidal breath


1) Brain initiates inspiratory effort

2) Nerves carry the inspiratory command to the inspiratory muscles

3) Diaphragm and/or external intercostal muscles contract

4) Thoracic volume increases as the chest wall expands

5) Intrapleural pressure becomes more negative

6) Alveolar transmural pressure difference increases

7) Alveoli expand in response to the increased transmural pressure difference. This increases alveolar elastic recoil

8) Alveolar pressure falls below atmospheric pressure as the alveolar volume increases, thus establishing a pressure difference for airflow

9) Air flows into the alveoli until alveolar pressure difference equilibrates with atmospheric pressure

Expiration (passive) –

1) Brain ceases inspiratory command

2) Inspiratory muscles relax

3) Thoracic volume decreases, causing intrapleural pressure to become less negative and decreasing the alveolar transmural pressure difference

4) Decreased alveolar transmural pressure difference allows the increased alveolar elastic recoil to return the alveoli to their preinspiratory volumes

5) Decreased alveolar volume increases alveolar pressure above atmospheric pressure, thus establishing a pressure difference for airflow

6) Air flow out of the alveoli until alveolar pressure equilibrates with atmospheric pressure

Basic Concepts and Ideas

Several factors besides the elastic recoil of the lungs and the chest wall must be overcome to move air into or out of the lungs. These factors include the inertia of the respiratory system, the frictional resistance of the lung and chest wall tissue, and the frictional resistance of the airways to the flow of air. The inertia of the system is negligible. Pulmonary tissue resistance is caused by the friction encountered as the lung tissues move against each other or the chest wall as the lung expands. The airway resistance plus the pulmonary tissue resistance is often referred to as the pulmonary resistance.

Pulmonary tissue resistance normally conributes about 20% of the pulmonary resistance, with airways resistance responsible for the other 80%. Pulmonary tissue resistnace can be increased in such conditions as pulmonary sarcoidosis, silicosis, asbestosis, and fibrosis. Because the airway resistance is the major component of the total resistance and because it can increase tremendously both in healthy people and in those suffering from various diseases, the remainder of this chapter will concentrate on airways resistance.

Generally, the relationship among pressure, flow, and resistance is stated as

Resistance = Pressure Difference (cm H2O) / Flow (L/s)

This means that the resistance is a meaningful term only during flow. When airflow is considered, the units of resistance are usually cm H2O/L/s. Similarly to blood flow, the resistances in series and parallel are as follows, respectively.

Rtot = R1 + R2 + … (in series)

1/Rtot = 1/R1 + 1/R2 + … (in parallel)

And again similarly to blood flow, the resistance (Poiseuille's law) is directly proportional to the viscosity of the fluid (air) and the length of the tube and is inversely proportional to the fourth power of the radius of the tube:

R = 8 x n x L / (Pi x r4)

In a normal adult about 35% to 50% of the total resistance to airflow is located in the upper airways: the nose, nasal turbinates, oropharynx, nasopharynx, and larynx. Resistance is higher when one breathes through the nose than when one breaths through the mouth. As for the tracheobronchial tree, the component with the highest individual resistance is the smallest airway, which has the smallest radius. Nevertheless, because the smallest airways are arranged in parallel, their resistances add as reciprocals, so that the total resistance to airflow offered by the numerous small airways is extremely low during normal, quiet breathing. Therefore, under normal circumstances the greatest resistance to airflow resides in the large to medium-sized bronchi.

Forced Vital Capacity

screen-shot-2016-09-20-at-2-18-44-pmThe main concept underlying these pulmonary function tests is that elevated airways reistance takes time to overcome.

One way of assessing expiratory airways resistance is to look at the results of a forced expiration into a spirometer, as shown in Figure 2-21. This measurement is called a forced vital capacity (FVC). The VC is the volume of air a subject is able to expire after a maximal inspiration to the total lung capacity (TLC). An FVC means that a maximal expiratory effort was made during this maneuver.

In an FVC test, a person makes a maximal inspiration to the TLC. After a moment, he or she makes a maximal forced expiratory effort, blowing as much air as possible out of the lungs. At this point, only a residual volume (RV) of air is left in the lungs. This procedure takes only a few seconds, as can be seen on the time scale.

The part of the curve most sensitive to changes in expiratory airways resistance is the first second of expiration. The volume of air expired in the first second of expiration (the FEV1, or forced expiratory volume in 1 second), especially when expressed as a ratio with the total amount of air expired during the FVC, is a good index of expiratory airways resistance. In normal young subjects, the FEV1/FVC is greater than 0.80; that is, at least 80% of the FVC is expired in the first second. An FEV1/FVC of 75% would be more likely in an older person. A patient with airway obstruction caused by an episode of asthma, for example, would be expected to have an FEV1/FVC far below 0.80, as shown in the middle and bottom panels in Figure 2-21.

The bottom panel of Figure 2-21 shows similar FVC curves that would be obtained from a commonly used rolling seal spirometer. The curves are reversed right to left and upside down if they are compared with those in top and middle panels. The TLC is at the bottom left, and the RVs are at the top right. The time scale is left to right. Note the calculations of FEV1 to FVC ratios.

Another way of expressing the same information is the FEF25%-75%, or forced (mid) expiratory flow rate (formerly called the MMFR, or maximal midexpiratory flow rate). This variable is simply the slope of a line drawn between the points on the expiratory curve at 25% and 75% of the FVC. In cases of airway obstruction, this line is not nearly as steep as it is on a curve obtained from someone with normal airway resistance. The FEV1/FVC is usually considered to represent larger airways, the FEF25%-75%, smaller to medium-sized airways.

Physiologic Quantitive Relationships and Phenomenon

Lung Volume and Airways Resistance

Screen Shot 2015-11-09 at 8.53.54 PMAirways resistance decreases with increasing lung volume, as shown in the figure on the left. This relationship is still present in an emphysematous lung, although in emphysema the resistance is higher than that in a healthy lung, especially at low lung volumes.

Transmural Pressure and Traction on Airway by elastic recoil of alveolar septa

There are 2 reasons for this relationship; both mainly involve the small airways, which have little or no cartilaginous support. The small airways are therefore rather distensible and also compressible. Thus, the transmural pressure difference across the wall of the small airways is an important determinant of the radius of the small airways: Since resistance is inversely proportional to the radius to the fourth power, changes in the radii of small airways can cause dramatic changes in airways resistance, even with so many parallel pathways. To increase lung volume, a person breathing normally takes a "deep breath", that is, makes a strong inspiratory effort. This effort causes intrapleural pressure to become much more negative than the -7 or -10 cm H2O seen in a normal, quiet breath. The transmural pressure difference across the wall becomes much more positive, and small airways are distended.

Transmural pressure = inside pressure – outside pressure

PS: Transumral presssure = Pin – Pout = Ptrans; Pin = Palve, Pout = Ppleu; at static, Ptrans = Preco; so, Preco = Ptrans = Pin – Pout = Palve – Ppleu; finally we ge this conclusion, Palve = Ppleu + Preco.


Screen Shot 2015-11-09 at 8.59.54 PMA second reason for the decreased airways resistance seen at higher lung volume is that the so-called traction on the small airways increases. As shown in the schematic drawing in the Figure 2-18, the small airways traveling through the lung from attachments to the walls of alveoli. As the alveoli expand during the course of a deep inspiration, the elastic recoil in their walls increases; this elastic recoil is transmitted to the attachments at the airway, pulling it open.

Dynamic Compression of Airways

Airways resistance is extremely high at low lung volumes, as can be see in the airways resistance versus lung volume curve above. To achieve low lung volumes, a person must make a forced expiratory effort by contracting the muscles of expiration, mainly the abdominal and internal intercostal muscles. This effort generates positive intrapleural pressure, which can be as high as 120 cm H2O during a maximal forced expiratory effort. (Maximal inspiratory intrapleural pressures can be as low as -80 cm H2O.)

The effect of this high positive intrapleural pressure on the transmural pressure gradient during a forced expiration can be seen at right in Figure 2-19, a schematic drawing of a single alveolus and airway.

Alveolar Pressure = Intrapleural Pressure + Alveolar Elastic Recoil PressureScreen Shot 2015-11-10 at 7.56.09 PM

At this instant, during the course of a forced expiration, the muscles of expiration are generating a positive intrapleurual pressure of +25 cm H2O. Pressure in the alveolus is greater than intrapleural pressure because of the alveolar elastic recoil pressure of +10 cm H2O, which together with intrapleural pressure, given an alveolar pressure of +35 cm H2O. The alveolar elastic recoil pressure decreases at lower lung volumes because the alveolus is not as distended. In the figure, a gradient has been established from the alveolar pressure of +35 cm H2O to the atmospheric pressure of 0 cm H2O. If the airways were rigid and incompressible, the large expiratory pressure gradient would generate very high rates of airflow. However, the airways are not uniformly rigid and the smallest airways, which have no cartilaginous support and rely on the traction of alveolar septa to help keep them open, may be compressed or may even collapse. Whether or not they actually collapse depends on the transmural pressure gradient across the walls of the smallest airways. Small airway collapse is the main reason that airways resistance appears to be approaching infinity at low lung volumes.

The situation during a normal passive expiration at the same lung volume (note the same alveolar elastic recoil pressure) is shown in the left part of Figure 2-19. The transmural pressure gradient across the smallest airways is

+1 cm H2O – (-8) cm H2O = +9 cm H2O

tending to hold the airway open. During the forced expiration at right, the transmural pressure gradient is 30 cm H2O – 25 cm H2O, or only 5 cm H2O holding the airway open. The airway may then be slightly compressed, and its resistance to airflow will be even greater than during the passive expiration. This increased resistance during a forced expiration is called dynamic compression of airways.

Consider what must occur during a maximal forced expiration. As the expiratory effort is increased to attain a lower and lower lung volume, intrapleural pressure is getting more and more positive, and more and more dynamic compression will occur. Furthermore, as lung volume decreases, there will be less alveolar elastic recoil pressure and the difference between alveolar pressure and inrapleural pressure will decrease.

One attention must be paid when dynamic compression of airways occur. During a passive expiration the presure gradient for airflow is simply alevolar pressure minus atmospheric pressure. But if dynamic compression occurs, the effective pressure gradient is alveolar pressure minus intrapleural pressure (which equals the alveolar elastic recoil pressure) because intrapleural pressure is greater than atmospheric pressure and because intrapleural pressure can exert its effects on the compressible portion of the airways.

Polymorphisms in Pharmacotherapy

November 10, 2015 Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Pharmacotherapy, Therapeutics No comments

dna_istock_rustycloudPolymorphisms related to pharmacotherapy include polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in drug transporter genes, and polymorphisms in drug target genes.

Polymorphisms in Genes for Drug-Metabolizing Enzymes

Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. eTable 6-1 lists examples of polymorphic metabolizing enzymes and corresponding drug substrates whose plasma concentrations and pharmacologic effects may be altered as a consequence of genetic variation.

Screen Shot 2015-11-10 at 2.38.46 PMPolymorphisms in the CYP2D6 gene are the best characterized among all polymorphisms in genes for drug-metabolizing enzymes. For example, the presence of two defective alleles coding for CYP2D6 in PM (poor metabolizer) results in significant impaired ability to metabolize CYP2D6-dependent substrates. Depending on the importance of the affected CYP2D6 pathway to overall drug metabolism and the drug's therapeutic index, clinically significant side effects may occur in PMs as a result of elevated drug concentrations.Screen Shot 2015-11-10 at 2.39.27 PM
Conversely, if the polymorphisms in CYP2D6 genes significantly enhance the activity of the drug-metabolizing enzyme, large amount of drugs will be metabolized and as a result the serum concentraton and pharmacologic effect of the drug would probablely be significantly lower.Screen Shot 2015-11-10 at 2.39.54 PM

The therapeutic implication of CYP2D6 polymorphism is different if the substrate in question is a prodrug. In this case, PMs would not be able to convert the drug into the therapeutically active metabolite (if low CPY2D6 activity).

Polymorphisms in Drug Transporter Genes

Certain membrane-sparnning proteins facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells.


Polymorphisms in drug transporters on gastrointestinal tract would affect the absorption of drugs. The role of drug transproters on gastrointestinal tract is to put the drug molecule back into GI lumen. So the activity of these drug transporters would significantly alter the bioavailability/absorption of the drug.


Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism.


Some drug are transported into bile or urine by drug transporters. So the polymorphisms in these transporters which result in significant change of the activity of the drug transporters would enhance or weaken the ability of these drug transporters's ability to excret the drug.

Drug Uptake by Target Cells

Even the drug could reach the therapeutic sites of action, efflux pumps (drug transporters) available on the surface of target cells could put the drug molecules back into extracellular environment, which prevent the pharmacologic effect of the drug if the drug's target receptors are inside the target cells.

Polymorphisms in Drug Target Genes

Genetic polymorphisms occur commonly for durg target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drugs could bind to enzymes, ion channels, and intracellular signaling proteins directly to produce pharmacologic effects, or they just only bind to the receptor and the after-binding (drug-receptor) process is altered by polymorphisms in enzymes, ion channels, and intracellular signaling proteins.

Receptor Genotypes and Drug Response

The beta1-adrenergic receptor gene (ADRB1) has been the primary focus of research into genetic determinants of responses to beta-adrenergic receptor antagonists in hypertension and cardiovascular disease. The polymorphisms in beta1-adregergic receptors causes pharmacologic (or even clinical) responses in different extent to its agonists and antagonists.

Enzyme Genes and Drug Response

Some drugs exert their clinical efficacy by affect enzymes which play some roles in the life of a cell. Polymorphisms in these enzymes therefore determine what degree of responsiveness they respond to these drugs. One example is the warfarin resistance, where there is a SNP in the VKORC1. Warfarin exerts its anticoagulant effects by inhibiting VKOR and thus preventing carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X. VKORC1 encodes for the warfarin-sensitive component of VKOR. Mutations in VKORC1 coding region cause rare case of warfarin resistance, with carriers of these mutations requiring either exceptionally high doses (>100 mg/wk) to achieve effective anticoagulation or failing to respond to warfarin at any dose (the mutated VKOR lose sensitivity to warfarin).

Genes For Intracellular Signaling Proteins, Ion Channels, and Drug Response

Cellular responses to many drugs are mediated through receptor-coupled guanosine diphosphate (GDP)-bound proteins also called G-proteins. Following receptor activation, the receptor couples to the G-protein, resulting in dissociation of GDP from the alpha subunit in exchange for guanosine triphosphate (GTP) and activation of the alpha, beta, and gamma subunits. The alpha subunit and beta-gamma subunit complex are released intracellularly and interact with various effectors to produce a cellular responses. Changes in the activity of G-proteins might influence response to agonists/antagonists which bind the receptors coupled with G-proteins.

Proximal Tubule Reabsorption and Secretion – Organic Solutes

November 5, 2015 Uncategorized No comments , , , , , , , , , , ,

1920px-JointcolorsA major function of the kidneys is the excretion of organic waste, forerign chemicals and their metabolites. As the kidneys excrete these substances they also filter large amounts of organic substances that they do not excrete, such as gllucose and amino acids. Therefore, the kidneys msut discriminate between what to keep and what to discard. The handling of small organic solutes by the kidney has several generalizations, including:

  • Many transporters on renal tubule are promiscuous, accepting multiple solutes, sometimes over 100 different ones. This allows the kidneys to operate without expressing a separate transporter for each and every solute.
  • Most organic solutes are transported only in the proximal tubule. Those that are secreted or escape reabsorption in the proximal tubule end up being excreted (an exception is when charged species become neutral as a result of changes in tubular pH and are reabsorbed passively in regions beyond the proximal tubule).
  • Transport involves a cascade of interrelated transport events always beginning with active extrusion of sodium across the basolateral membrane by the Na-K-ATPase. Neutral or negatively charged organic solutes then enter via symporters with sodium, while cations enter via uniporters driven by the netagive membrane potential. The resulting intracellular accumulation of the solute in question establishes a favorable gradient for its efflux. The accumulated solutes then leave through a variety of pathways across the opposite membrane from which they entered or couple via an antiporter to the influx of another organic solute.

Proximal Reabsorption of Organic Nutrients

Most of the useful organic nutrients in the plasma that should not be lost in the urine are freely filtered. These include glucose, amino acids, acetate, Krebs cycle intermediates, some water-soluble vitamins, lactate, acetoacetate, beta-hydroxybutyrate, and many others. The proximal tubule is the major site for reabsorption of the large quantities of these organic nutrients filtered each day by the renal corpuscles.


Under most circumstances, it would be deleterious to lose glucsoe in the urine, particularly in conditions of prolonged fasting. Thus the kidneys nromally reabsorb all the glucose that is filtered. A typical plasma glucose level is about 90 mg/dL. It rises transiently to well over 100 mg/dL during meals and falls somewhat during fasting. Usually all the filtered glucose is reabsorbed in the proximal tubule. This involves taking up glucose from the tubular lumen across the apical membrane via sodium-glucose symporters, followed by its exit across the basolateral membrane into the interstitium via a GLUT uniporter. Most of the glucose is reabsorbed by a high-capacity, low-affinity sodium-glucose symporter (SGLT-2) that has a stoichiometry of 1 sodium per glucose. Then the last remaining glucose is taken up in the late proximal tubule (S3 segment) by a low-capacity, high-affinity transporter (SGLT-1) that transports 2 sodium ions per glucose. This 2-for-1 stoichiometry provides additional energy to move glucose up its concentration gradient in the  region where the luminal concentration is nromally very low. Unlike the case for sodium and many other solutes, the tight junctions are not significantly permeable to glucose. Therefore, as glucose is removed from the lumen and the luminal concentration falls, there is no back-leak, resulting in virtually complete reabsorption.Screen Shot 2015-11-05 at 10.09.58 PM

Because the sodium-glucose symporters are saturable (Tm systems), abnromally high-filtered loads overwhelm the reabsorptive capacity (exceed the Tm). This occurs when plasma glucose approaches 200 mg/dL, a situation often found in untreated diabetes mellitus. In very sever cases, plasma glucose can exceeed 1000 mg/dL, or over 55 mmol/L, leading to a significant loss of glucose.

Assume that the glucose Tm is 375 mg/min (a typical value). With a glomerular filtration rate (GFR) of 125 mL/min (1.25 dL/min) and a normal plasma glucose of 90 mg/dL, the filtered load is 1.25 dL/min X 90 mg/dL = 112.5 mg/min, well below the Tm of 375 mg/min. Thus the kidneys easily reabsorb the entire filtered load. When plasma glucose reaches 200 mg/dL, the filtered load becomes 1.25 dL/min X 200 mg/dL = 250 mg/min. At this point, some individual nephrons have reached the upper limit of what they can reabsorb, and a little glucose begins to spill into the urine. Further increases in plasma glucose saturate the remaining transporters and any amount filtered above 375 mg/min is excreted. This leads to loss of glucose and an unwanted osmotic diuresis.

Proteins and Peptides

Although we sometimes say the glomerular filtrate is protein free, it is not truly free of all protein; it just has a total protein concentration much lower than plasma. First, peptides and smaller proteins (e.g., angiotensin, insulin), although present at low concentrations in the blood, are filtered in considerable quantities. Second, while the movement of large plasma proteins across the glomerular filtration barrier is extremely limited, a small amount does make it through into Bowman's space. For albumin, the plasma protein highest concentration in the blood, the concentration in the filtrate is normally about 1 mg/dL, or roughly 0.02% of the plasma ablumin concentration (5 g/dL). Because of the huge volume of fluid filtered per day, the total filtered amount of protein is not negligible. Normally all of these proteins and peptides are reabsorbed completely, although not in the conventional way. They are enzymatically degraded into their constituent amino acids, which are then returned to the blood.

For the larger proteins, the initial step in revovery is endocytosis at the apical membrane. This energy-requiring process is triggered by the binding of filtered protein molecules to specific receptors on the apical membrane. The rate of endocytosis is increased in proportion to the concentration of protein in the glomerular filtrate until a maximal rate of vesicle formation, and thus, the Tm for protein uptake is reached. The pinched-off intracellular vesicles resulting from endocytosis merge with lysosomes, whose enzymes degrade the protein to low-molecular-weight fragments, mainly individual amino acids. These end products then exit the cells across the basolateral membrane into the interstitial fluid, from which they gain entry to the peritubular capillaries.

To understand the potential problem associated with a failure to take up filtered protein, remember that for a healthy young adult,

Total filtered protein = GFR X concentration of protein in filtrate = 180 L/day X 10 mg/L = 1.8 g/day

If this protein was not removed from the lumen, the entire 1.8 g would be lost in the urine. In fact, most of the filtered protein is endocytosed and degraded so that the excretion of protein in the urine is normally only 100 mg/day. The endocytic mechanism by which protein is taken up is easily saturated, so a large increase in filtered protein resulting from increased glomerular permeability causes the excretion of large quantities of protein.

Discussions of the renal handling of protein logically tend to focus on albumin because it is, by far, the most abundant plasma protein. There are, of course, many other plasma proteins. Although present in lower levels than albumin, they are smaller and thus more easily filtered. For eample, growth hormone (molecular weight, 22,000 Da) is approximately 60% filterable, and the smaller insulin is 100% filterable. The total mass of these filtered hormones is insignificant; however, because even tiny levels in the plasma have importnat signaling functions in the body, renal filtration becomes an important influence on concentrations in the blood. Relatively large fractions of these smaller plasma proteins are filtered and then degraded in tubular cells. The kidneys are major sites of catabolism of many plasma proteins including peptide hormones. Decreased rates of degradaton occuring in renal disease may result in elevated plasma hormone concentrations.

Very small peptides are catabolized into amino acids or di- and tri-peptides within the proximal tubular lumen by peptidases located on the apical surface of the plasma membrane. These products are then reabsorbed by the same transporters that normally reabsorb filtered amino acids.

Finally, in certain types of renal damage, proteins released from damaged tubular cells may appear in the urine and provide important diagnostic information.

Proximal Secretion of Organic Cations

There are many organic cations that does excrete, both endogenously produced waste products and foreign chemicals. Many of these organic cations are filterable at the renal corpuscles, with proximal secretion adding to the amount filtered. Others are extensively bound to plasma proteins and undergo glomerular filtration only to a limited extent; accordingly, proximal tubular secretion constitutes the only significant mechanism for their excretion.

The proximal tubules possess several closely related transport systems for organic cations. Because there are a number of different transporters that are relatively nonselective as to which solute species they accept, a substantial number of foreign and endogenous organic cation species are transported. Although the transporters manifest Tm limitation, in many cases over 90% of a given cation species entering the renal circulation is removed, indicating that the transport capacity is high. The process begins with the Na-K-ATPase, which establishes a potassium concentration gradient and resulting negative membrane potential. Organic cations enter across the basolateral membrane via one of several uniporters, members of the OCT family (Organic Cation Transporter) driven energetically by the negative membrane potential. This raises the cytosolic concentration of the cation well above that in the interstitium. The cations then exit into the lumen via an antiporter that exchanges a proton for the organic cation. Because this antiporter exchanges 2 univalent cations, it is electroneutral and unaffected by the membrane potential.

Proximal Secretion of Organic Anions

The active secretory pathway for many organic anions in the proximal tubule uses the recycling of alpha-ketoglutarate (alphaKG) as a tool. First, alphaKG, which is a divalent anion, is actively taken up from both the lumen and interstitium by a sodium-alphaGK symporter (stoichiometry of 3 sodium per alphaKG), which raises the cellular levels of alphaKG. Then alphaKG effluxes across the basolateral membrane via an antiporter that imports an organic anion that is destined to be secreted. This antiporter is a member of the QAT family (Organic Anion Transporter) of basolaeral membrane proteins. The alphaKG keeps recycling, entering with sodium and effluxing back to the interstitium in exchange for the other organic solute. Finally, the second organic solute is secreted across the apical membrane via one of several pathways, including the multidrug resistance protein MDR-2, which is an ATPase that drives the efflux of many different organic anions.

Screen Shot 2015-11-05 at 10.25.46 PMAnalogous to the transporters for cations, the basolateral membrane of proximal convoluted tubule epithelial cells contains several QAT species, each one accepting multiple solutes to be transported. The proximal tubule thus has the capacity to secrete many organic anions. These organic anions are not sinificantly permeable through tight junctions or lipid membranes, and their transport is characterized by Tm. If the plasma concentration of an organic anion is too high, it will not be efficiently removed from the blood by the kidneys.

Metabolic transformations in the liver are very important, where many foreign (and endogenous) substances are conjugated with either glucuronate or sulfate. The addition of these groups renders the parent molecule far more water-soluble. These conjugates are actively transported by the organic anion secretory pathway.


An increase in the plasma concentration of urate can cause gout and is thought to be involved in some forms of heart disease and renal disease; therefore, its removal from the blood is important. However, instead of excreting all the urate it can, the kidneys actually reabsorb most of the filtered urate. Urate is freely filterable. Almost all the filtered urate is reabsrobed early in the proximal tubule, primarily via antiporters (URAT1) that exchange urate for another organic anion. Further on in the proximal tubule urate undergoes active tubular secretion. Then, in the straight portion, some of the urate is once again reabsorbed. Because the total rate of reabsorption is normally much breater than the rate of secretion, only a small fraction of the filtered load is excreted.

Although urate reabsorption is greater than secretion, the secretory process is controlled to maintain relative constancy of plasma urate. In other words, if plasma urate begins to increase because of increased urate production, the active proximal secretion of urate is stimualted, thereby increasing urate excretion.

Given these mechanisms of renal urate handling, you should be able to deduce the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout: 1.decreased filtraton of urate secondary to decreased GFR, 2.excessive reabsorption of urate, and 3.diminished secretion of urate.

pH Dependence of Passive Reabsorption or Secretion

Many of the organic solutes handled by the kidney are weak acids or bases and exist in both, neutral and ionized forms. The state of ionization affects both the aqueous solubility and membrane permeability of the substance. Neutral solutes are more permeable than ionized solutes. As water is reabsorbed from the tubule, any substance remaining in the tubule becomes progressively more concentrated. Because the luminal pH may change substantially during flow through the tubules, both the progressive concentration of organic solutes and change in pH strongly influence the degree to which they are reabsorbed by passive diffusion through regions of tubule beyond the proximal tubule.

At low pH weak acids are predominantly neutral (acid form), while at high pH they dissociate into an anion and a proton. Imagine the case in which the tubular fluid becomes acidified relative to the plasma, which it does on a typical Western diet. For a weak acid in the tubular fluid, acidification converts much of the acid to the neutral form and therefore, increases kts pe2meability. This favors diffusion out of the lumen (reabsorption). High acidic urine (low pH) tends to increase passive reabsorption of weak acids (and promote less excretion). For many weak bases, the pH dependence is just the opposite. At low pH they are protonated cations (trapped in the lumen). As the urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted.

Some organic solutes, although more membrane permeable in the neutral form, are less soluble in aqueous solution and tend to precipitate. This specifically applies to urate. The combination of excess plasma urate and low urinary pH, which converts urate to the neutral uric acid, often leads to the formation of uric acid kidney stones.