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What is the main function of the cardiovascular system?
The cardiovascular system circulates blood in order to link together organ systems with highly specialized and specific functions in highly differentiated organisms, such as humans.
- Prevention of blood loss
- Platelets are concerned with hemostasis
Which portion of the blood circulates and distributes drugs to tissues?
The fluid portion of the blood, called plasma, is the primary mechanism whereby drugs are circulated and distributed to the tissues.
How is dosing of a drug typically monitored?
Dosing is typically monitored by measuring plasma drug concentrations and clearance rates.
What is the significance of plasma proteins in terms of pharmacology?
- Plasma proteins can bind drugs and thereby affect the action, metabolism and excretion of a drug.
- Drugs are often said to be "free" or "bound" depending on their affinity towards plasma proteins.
What are the components of Plasma?
What components can blood be broken down into?
- Total Blood Volume: 42 L
- Of the total 42 L, the rest can be categorized as:
- Intracellular Fluid: 28 L
- Interstitial or Extracellular Fluid (ECF): 11 L
- Plasma: 3 L
- Both ECF and Plasma constitute fluid outside the cells, whereas the Intracellular Fluid constitutes the fluid within cells.
What is the interaction between all the components of blood?
- Plasma exchanges freely with the Extracellular Fluid (ECF).
- The ECF exchanges with the Intracellular Fluid.
- The only exception to this interconnected exchange is proteins, which are somewhat limited to the "compartment" of blood they are formed in, such as Intracellular fluid or ECF.
Proteins are components of blood that are somewhat limited to the "compartment"
of blood they are formed in, such as Intracellular fluid or ECF.
Proteins can exert significant osmotic pressure (specifically for proteins this is termed oncotic pressure). Oncotic pressure can affect water distribution
are the most common plasma proteins (~5g/dL
) and are responsible for ~80%
of plasma's oncotic pressure
and therefore Albumins
help prevent excess fluid loss
from the circulation.
- Plasma proteins are primarily synthesized in the liver
- (except for circulating antibodies which are gamma globulins secreted by plasma cells).
Plasma proteins are crucial for the transport of certain molecules
such as the steroid hormones: binding to plasma proteins helps prevent inappropriate metabolism and/or excretion.
Drug molecules binding to various plasma proteins will also affect the availability
Terminology for protein binding is "free
" vs. "bound
" where only "free" can interact with receptors.
Various proteins are involved in hemostasis
(prevention of blood loss, for example, by stopping excessive bleeding).
- Hormones are specialized plasma proteins that function as important chemical messengers.
- The only hormone that is not a protein is adrenalin/epiniphrine.
- Hormones are also circulated via the blood.
What are the functions of plasma proteins?
- The functions of plasma proteins include:
- transport of nutrients for energy
- growth and repair
- removal of wastes
- transport of hormones
- regulation of body temperature
What are the three cellular components of blood?
- The cellular component of blood are:
- Red blood cells (RBC's: erythrocytes) that are involved with the carriage of O2 and CO2,
- White blood cells (WBC's: leukocytes) that are part of the immune system.
- Platelets that are cell fragments (from megakaryocytes) which are involved in hemostasis (prevention of bleeding by blood clotting).
The Cellular Components of Blood
- The hematocrit is found when a centrifuge is used to separate the weight of the packed cell volume of RBC's, WBC's and platelets combined relative to total blood volume.
- The hematorcrit is typically ~40% (♂) to ~36% (♀).
Red Blood Cells (RBC's)
- ● RBC's are biconcave discs ~7.8 x 2.5m (~1 m in center where thinnest) and are present in the blood at ~5.2 x 106 (± 3 x 105 for ♂s) to ~4.7 x 106 (± 3 x 105 for ♀s).
) is a heterotetramic protein (4 subunits composed of 2 different pairs) contained within RBC's vital for the efficient carriage of O2 from the lungs to all tissues of the body
. It can leak
out of blood vessels so it must be contained within the RBC's.
● The Hb concentration is estimated per 100*mL of blood: it is typically ~15gm%* for ♂
s and ~14gm%* for ♀
● RBC's are very flexible due to a large excess of plasma membrane
(meaning a large surface area). This characteristic is vital so that RBC's can deform and squeeze through the smallest capillaries
that are only ~ 5m in diameter ( contact area gives rate of O2
- ● Mature RBC's do NOT have:
- 1) nucleus (cannot divide)
- 2) mitochondria
- 3) endoplasmic reticulum
- ● However, mature RBC's DO posses enzymes. These enzymes:
- 1) produce ATP (via glycolysis only)
- 2) maintain cell membrane integrity
- 3) keep the iron ions in Hb in the reduced/ferrous state (Fe2+: binds the O2 reversibly)
- 4) prevent the oxidation of cellular proteins
The production of Red Blood Cells
- ● In the embryo, primitive nucleated RBC's are
- produced in the yolk sac. By the middle trimester the liver, spleen and lymph nodes are the main source of RBC's. By the middle of the last trimester production has moved exclusively to the bone marrow: initially this involves all bones but around 5 years of age most long bones' (humerus and tibia for example) marrows start to become "fatty" and have stopped all production. By ~20 years after which RBC production is restricted to the membranous bones such as the vertebrae, sternum, ribs, etc.
● All blood cells originate from pluripotential (meaning the development of the cell is not fixed...it still has the potential to differentiate into one of many cell types) hematopoietic stem cells. A
s these divide a few are retained for future production.
● Once committed
by differentiation to becoming RBC's they cannot become any other cell. For RBC's, the cells become committed
once they reach the colony-forming unit-erythrocyte (CFU-E) stage
are controlled by so-called "growth inducers
." Interleukin-3, for example, promotes growth and reproduction
of virtually all types of committed cells whereas others are type specific.
is induced by "differentiation inducers
." Both types of "inducers" (growth
) are controlled by factors outside the bone marrow
. For RBC's this is primarily due to ↓O2
are formed in large numbers from the CFU-E cells by repeated division.
differentiate into basophil erythroblasts
(whose names come from the name of the basic dyes they are stained for the microscope slides) which still have a nucleus at this stage but contain very little Hb.
● As successive stages occur, the amount of Hb↑ while the nucleus "condenses" to a smaller and smaller size: eventually the nucleus is absorbed or extruded from the cell (along with the ER which has no further function) at which stage it is called a reticulocyte
leave the bone marrow and enter the capillaries by squeezing between endothelial cells by a process called diapedesis.
Remaining basophilic material
and any organelles finally disappear within ~1 - 2 days and the cell is now a mature RBC called an erythrocyte
Regulation of RBC Production
● The number of RBC's is tightly regulated
: the human body needs sufficient RBC's for O2
transport, but too many RBC's would cause the blood to become like "sludge," which places an enormous load on the heart.
● In cardiac failure (↓cardiac output) and many respiratory diseases, RBC production is stimulated to compensate for ↓O2 delivery
● Erythropoietin (a hormone) or hypoxia
stimulates the production of proerythroblasts
and ↑rate of the maturation process. It typically takes ~5 days for new mature RBC's
to appear in the blood and production can increase up to x10!
● RBC's typically have a ½-life
of ~100 - 120 days and therefore the predecessors of RBC's are among the most rapidly dividing cells in the body
. Nutrition is therefore very important (iron
and B vitamins
● However, because of the rapidly dividing process of RBC predecessors, these cells are often significantly affected by cancer chemotherapy
which attempts to target the rapidly-growing tumor cells, but ends up also targeting rapidly dividing blood cells, thus inducing chemotherapy-related anemia
● Vitamin B12
and Folic acid
are necessary for DNA synthesis and a deficiency results in "maturation failure
" and the production of abnormal RBC's called macrocytes. Macrocytes
do not have the correct/strong/deformable shape of normal RBC's and are often fragile with a significantly reduced ½-life.
RBC production is determined by _______ or _______, and mediated by the hormone _______.
RBC production is determined by demand or hypoxia, and mediated by the hormone erythropoietin.
Any condition that ↓O2 delivery to tissues ↑RBC production.
- The general term anemia is defined as a decrease in the ability of the blood to carry O2.
- Accordingly the loss/destruction/damage of/to the kidneys can result in severe anemia.
- Vitamin B 12, Folic acid and iron are all required for Red Blood cell production; a lack thereof induces anemia.
Pathology of Anemia
● Anemia is a deficiency of Hb
/↓O2 carrying capability of blood
. It is caused by either ↓numbers of RBC's or ↓amount of Hb in each RBC.
● Anemia due to blood loss (hemorrhage) may require 3 - 6 weeks for full recovery of RBC
numbers. However, the plasma loss is replaced in ~1 - 3 days.
- ● With chronic blood loss, Fe levels become
- critical often with the production of small RBC's containing ↓amounts of Hb as described in microcytic hypochromic anemia.
● Aplastic anemia
(bone marrow aplasia
) is caused by lack of functioning bone marrow as caused by X-rays, other forms of harmful radiation, etc.
- ● Pernicious anemia and Sprue are caused by lack of absorption of B12 and Folic acid. These conditions often result in ↓numbers of RBC's with bizarre shapes and oversized cells (Megaloblastic
- anemia: large RBC's) with fragile membranes. This is due to the slow development of these RBC's.
- ● Hemolytic anemia is an inherited condition that results in fragile RBC's (excluding previous examples) that easily lyse (burst) resulting in a
- short ½-life. Basically, RBC's are lost faster than they are replaced.
● Sickle cell anemia
is due to a single amino acid change in a specific position in the globin polypeptide chain of Hb (b
for glutamic acid
). Under ↓O2
conditions, this Hb crystallizes (up to 15m long crystals!) which can rupture the RBC membrane and make access to the smallest capillaries difficult (~5 m diameter).
● Erythroblastosis fetalis
is when a Rh-
mother (Rhesus group [Rh
] refers to a RBC surface antigen) produces a Rh+
baby and the mother's immune system produces antibodies to attack the baby's RBC's (almost autoimmune!). The RBC's will be made fragile by these antibodies and lyse so the baby is born with severe anemia
● Polycythemia vera
is when too many RBC's are produced. It is caused by a mutation which allows uncontrolled division of cells like a cancer and make the blood difficult to pump.
Pernicious Anemia & Sprue
- In the condition known as pernicious anemia, vitamin B12 is not absorbed properly from the GI tract due to the lack of "Intrinsic factor" which is necessary for the receptor-mediated endocytosis of this vitamin.
- This is similar to the condition known as Sprue which is due to poor absorption of both vitamin B12 and Folic acid.
- RBC's contain lower amounts of Hemoglobin than normal.
- Caused by lack of transferrin.
If someone is very anemic for any reason (hemorrhage for example), then the bone marrow immediately ↑RBC production. Destruction of bone marrow (by X-rays or radiation for example), causes hyperplasia of the remaining tissue to compensate.
● The major substance causing ↑RBC production is the glycoprotein erythropoietin. If there is no erythropoietin, then there is no response to hypoxia.
● ~90% of erythropoietins form in the kidneys (remainder principally from the liver). This hormone (blood-born chemical messenger) is probably secreted by the tubular epithelial cells which have ↑O2 requirement for their transporting/reuptake functions (↑no. mitochondria as expected).
● Some current evidence suggests other possible "sensors," plus the involvement of adrenaline, noradrenaline and some prostaglandins in erythropoietin production.
Synthesis of Hemoglobin (Hb)
● The function of Hb (and RBC's as a whole) is gas transport
● Synthesis of Hb begins in the proerythroblast
but is not complete until the RBC is mature in the circulation.
from the Krebs cycle combines with the amino acid glycine
to form pyrrole
. Then four pyrrole
combine to make protoporphyrin IX
to which an Fe2+ ion
is added to make heme
. Finally heme
is joined to the polypeptide globin
to form a hemoglobin monomer
● Each monomer has a mw ~16,000 and four monomers are assembled to make the functional tetramic hemoglobin
molecule. Subunit variation is observed with four possible globin variants
● The "normal
"or most common adult version of Hb contains two a's and two b's
while fetal Hb
is different possessing an ↑affinity for O2
(greater than "normal") to facilitate transfer of O2
from the mother to the fetus.
● The Fe2+
in each heme group binds one O2 molecule loosely in ↑O2
concentrations (in lungs) but releases it in ↓O2
concentrations. Each Hb molecule can therefore bind four O2 molecules if 100% saturated
- ● An iron ion (in the Fe2+/ferrous state) is vital for Hb function in transporting O2 plus many other
- crucial proteins/enzymes such as the cytochromes.
● Total body Fe ~4 - 5 g with ~65% of this bound to Hb
, ~4% in muscle myoglobin
, ~1% in other heme-containing protein
s, ~0.1% in plasma bound to Transferrin
, plus the remaining ~30% stored principally in the liver bound to Ferritin
● Typically ♂s excrete ~0.6 mg
of Fe daily in feces whereas ♀s lose roughly twice
this due to menstruation.
- ● Transferrin transfers the Fe from the GI tract to receptors on the developing erythrocyte membranes
- in the bone marrow where it is endocytosed. Once in the RBC's it enters the mitochondria where heme is synthesized.
● Lack of transferrin
can result in hypochromic anemia
where RBC's contain ↓amount of Hb than normal.
Red Blood Cell Recycling
● RBC's do deteriorate (limited ½-life) and usually rupture/self-destruct in the spleen
as they squeeze through the "red pulp" reticular mesh
(~3 m gaps).
- ● The released Hb is phagocytized by macrophages of the spleen and bone marrow and
- especially the Kupffer cells of the
- liver. The Fe is released back into the circulation bound to transferrin.
● The porphyrin portion of Hb
is converted in the macrophages to Bilirubin
which is used by the liver as a component of bile necessary for fat digestion in the GI tract.
Summary Question: What are the principal functions of blood?
- 1) Transport of gases, nutrients, waste products and chemical messengers.
- 2) Thermoregulation
Summary Question: What is the Red Blood Cell's shape optimized for?
The function of gas exchange. The surface area to volume ration is built to maximize diffusion.
Summary Question: Why are Red Blood Cell's deformable?
To allow them to pass through the smallest capillaries, which are only 5 microns in diameter (whereas a RBC is 7 microns in diameter).
What dietary requirements are particularly important for RBC production?
- 1) Fe (Iron)
- 2) B12 (for Hemoglobin)
- 3) Folic Acid (for DNA)
What mediates the response to increased number of Red Blood Cells (a condition known as "hypoxia")?
Erythrpoietin, which is probably mainly from tubule cells of the kidneys.
Summary Question: What is anemia and what causes it?
Anemia is defined as a deficiency in the oxygen carrying capacity of the blood. It is caused by decreased number of Red Blood Cells or a decrease in Hemoglobin content.
Summary Question: Pernicious Anemia and Sprue are caused by what?
- Pernicious anemia is due to lack of absorption of B12.
- Sprue is due to lack of absorption of B12 and folate (lack of folate means it cannot synthesize DNA).
Summary Question: Sicle Cell Anemia is caused by what?
Sickle Cell Anemia is caused by a single amino acid mutation in b-globin portion of Hb causing crystallization in low oxygen conditions.
Summary Question: Erythroblastosis fetalis is caused by what?
An Rh- mother rejecting the blood of an Rh+ baby. The result is the mother produces antibodies in response to the baby's blood...then those antibodies are able to cross the placenta and essentially attack the baby.
•Fe2+-containing heme group is linked to various “globins” to produce functional heterotetramer hemoglobin for O2 carriage.
•Iron is absorbed and transported as transferrin, stored as Ferritin and recycled via macrophages (WBC’s).
•Any deficiency in the amount/function of hemoglobin carried by RBC’s/↓O2 carrying capacity results in anemia. This includes vitamin deficiencies, fragile RBC membranes, abnormal hemoglobin and the Rh blood group.