BIOL
103: BIOLOGY OF ADDICTION -- Lecture
Notes
Stan Eisen
Biology Department
Christian Brothers University
Mail To: seisen@cbu.edu
(901) 321-3447
(Updated
January 6, 2006)
Some Useful Web Addresses:
The National Institute on Alcohol Abuse and
Alcoholism -
Lecture Topics
Addiction Defined
Diffusion
Modes of Entry I. Oral
administration
Minicourse 1: The digestive
system
Inhalation
Minicourse 2: Respiratory
system
Modes of Entry III.
Injection
Minicourse 3: The
circulatory system
Modes of Entry IV.
Miscellaneous
Minicourse 4: The excretory
system
Termination of Drug
Action
Minicourse 5: Structure
of the nervous system
Structure of
neurons
How
Neurotransmitters work
Types of
Neurotransmitters
Principles of
Pharmacokinetics and Pharmacodynamics
On the Use of Depressants
Mode of action, metabolism
& toxicity of alcohol
Alcoholic cirrhosis and
liver transplant surgery
Fetal Alcohol Syndrome
Treatment of alcoholics
& drug addicts
Acupuncture as a detox
treatment modality
Minicourse 6:
Principles of Genetics
The genetics of alcoholism
From Test Tube to Pharmacy
Shelf: Regulation of Drug Development
Inhalants
NS depressants
Barbiturates
Benzodiazepines and
"Second Generation" Anxiolytics
Psychostimulants I: Cocaine
Psychostimulants II:
Amphetamines
Caffeine
Nicotine
Antidepressants
Opioids
Marijuana
Psychedelics
Anabolic-Androgenic Steroids
Schedule of controlled
substances
Perhaps
the easiest way to define addiction is that it constitutes whatever it takes to
follow the following downwards spiral:
A DEFINITION OF ADDICTION, WITH
ALCOHOL AS THE MODEL
|
|
Complete Defeat admitted
This
downwards spiral is due to three phenomena:
1. Tolerance,
in which there is an increased need for greater amounts and more frequent doses
in order to acquire the same effect. This is caused by an increase of catabolic
enzymes which metabolize the drug faster, thereby decreasing blood
concentrations faster. An example of such an enzyme is alcohol dehydrogenase;
2. Physical dependence, in which there are physical symptoms associated with withdrawal, or
the cessation of taking the drug. These symptoms can be life-threatening, as in
alcohol, or they can be inconvenient but not life-threatening, as in heroin or
morphine;
3. Psychological dependence, in which brain chemistry and circuitry are altered
by the continued presence of the drug. The number of receptors for a particular
neurotransmitter may decrease or increase, and this leads to the increasing
amounts of the drug in order "just to feel normal."
Diffusion:
Diffusion
is defined as the "movement of molecules from a region of higher to lower
concentration; it requires no energy and tends to lead to an equal
distribution" (Mader, 1998).
In
the context of living cells, the definition of diffusion is modified to the
"movement of molecules through a plasma membrane from a region of
higher to lower concentration."
Our
present model for the structure of plasma membranes was introduced by S. Singer and G. Nicolson in 1972.
According to the fluid-mosaic model of membrane structure, plasma membranes
have two components, phospholipids and proteins. The phospholipids arrange
themselves spontaneously into a bilayer, in which the (hydrophobic) fatty acid
chains are oriented in the interior of the bilayer, while the (hydrophilic)
phosphate groups are oriented towards the exterior. The proteins are scattered
throughout the membrane in an irregular pattern, and may have several functions:
1. Channel proteins allow a particular molecule or ion to cross the plasma membrane
freely. For example, water can diffuse into or out of cells very quickly;
2. Carrier proteins interact with specific molecules or ions, such as sodium (Na+) or
potassium (K+), so that they can cross the plasma membrane. These proteins are
particularly important in understanding the function of neurons;
3. Cell Recognition proteins
serve as the basis of our immune system. Certain white blood cells, such as
lymphocytes, are capable of recognizing foreign cells or tissues by the types
of cell recognition proteins on the plasma membrane;
4. Receptor proteins are sites on plasma membranes to which compounds will bind, and
thereby cause a change in the function of that cell. Neurotransmitter molecules
and drug molecules exert their effects on neurons by binding to receptor
proteins
For more information regarding receptors, visit http://receptome.stanford.edu/HPMR
;
5. Enzymatic proteins have a catalytic function, in which they will catalyze a specific
reaction. The binding of a neurotransmitter molecule to a receptor protein may,
in turn, activate an enzymatic protein which will catalyze a reaction inside
the cell.
Since the plasma membrane consists of protein
and phospholipids, lipid-soluble drug molecules can diffuse easily through
them, but water-soluble molecules cannot. As you will see, an understanding of
diffusion is critical to understanding the passage of drugs from the stomach
and the intestine into the bloodstream, from the fluid bathing cells
(interstitial fluid) into the interior of cells (cytoplasm), and from the
interior of cells into the interstitial fluid, and from the kidneys back into
the bloodstream.
Within 1 minute of entering the bloodstream,
drug molecules will become distributed fairly evenly throughout the blood
volume. By that time, drug molecules which travel back & forth between
blood capillaries and tissues.
Capillaries
have pores which allow the passage of larger molecules between blood and
tissues. As long as molecules can pass through these pores, transport of drug
molecules out of blood capillaries and into tissues, and back into blood is
independent of lipid solubility, since pores are large enough for even
fat-insoluble molecules to penetrate.
The blood-brain barrier is a
system of capillaries in the brain which lack pores. Instead they have
extensions of astrocytes to form a fatty barrier called the glial sheath. Only
fat-soluble molecules can cross the blood-brain barrier.
The placental barrier separates 2 separate living entities. In addition to allowing the free
exchange of normal nutrient and waste molecules, the placental barrier allows
the movement of drug molecules, including alcohol, cigarettes, and cocaine
(Julien, 1998).
Julien,
R. M. 1998. A Primer of Drug Action. W. H. Freeman, edition 8.
Mader,
S. 1998. Biology. WCB MCGraw-Hill, edition 6.
Modes of
For oral administration to occur, the drug
must be soluble, stable in stomach fluid, and capable of penetrating the lining of the intestine. As mentioned earlier, all psychoactive drugs are
lipid-soluble and readily cross cell membranes.
The disadvantages
of oral administration include the following:
1. The drug can cause vomiting and stomach distress;
2. Actual dosage is variable;
3. Some drugs cannot be administered by mouth, e.g.
insulin;
4. It is relatively slow -- requiring sufficient time to
reach the small intestine, which can be 20-40 minutes.
Minicourse 1: Structure
of the digestive system
The
following is a description of the pathway of food through the digestive system:
Food
is typically chewed in the mouth, where it is mixed with saliva secreted by the
salivary glands.
Saliva is a slightly alkaline solution which contains salivary amylase, an
enzyme which initiates the chemical breakdown of starch. Saliva lubricates food
to facilitate its movement from the mouth through the esophagus
into the stomach.
When
food enters the stomach, it is exposed to gastric juices, which contain pepsin
in a solution of hydrochloric acid. The pH of gastric juice is 2. There is also
a small amount of gastric alcohol dehydrogenase, which initiates the breakdown
of alcohol. Females tend to have a lower concentration of gastric alcohol
dehydrogenase in their gastric juice, so a greater amount of alcohol enters
their bloodstream. This may account for the tendency for females to be affected
by a lesser amount of alcohol than males.
Food
will then enter the small intestine, which is lined with small, fingerlike
extensions called villi, whose
function is to increase the surface area of the small intestine. Inside each
villus, there is a capillary system and a lymphatic vessel called a lacteal.
Sugars
and amino acids enter villi cells and are absorbed into the capillaries of the
villus. Fats are first broken down into glycerol and fatty acid molecules,
which diffuse into the lacteals, where they are reassembled into fat molecules.
Drug
molecules will diffuse into the capillaries of the villi, and will then be
distributed throughout the body via the circulatory system.
Inhalation
avoids the unpredictability of the gastrointestinal tract. It is also very rapid. It is so rapid, in fact, that
the amount of time required for a bolus of nicotine from a puff of smoke to
reach the brain is approximately 7 seconds. Drugs which are inhaled, such as halothane
tend to be very small and highly lipid-soluble.
Minicourse 2: The
respiratory system
The
human respiratory system includes a series of structures which conduct air to
and from the lungs. Air enters the respiratory system typically via the nose.
Air is filtered, warmed and moistened as it passes through the nasal cavities towards the pharynx, or throat. Some drugs,
such as cocaine, can be absorbed through the mucous membranes of the upper
respiratory tract.
Air
will then pass through the glottis, an opening into the larynx.
The vocal cords are located here. The vocal cords consist of flexible
bands of connective tissue imbedded in mucous membranes. Air will continue past
the larynx through the trachea, a hollow tube consisting of cartilage.
The
trachea is lined with tissue endowed with cilia, whose function is to
trap particulate matter such as dust, pollen and soot. These particles are
mixed with mucus and then pushed up the trachea via the beating of the cilia.
When this small plug of mucus with particulate matter reaches the back of the
throat, it induces a gag reflex so that the plug is swallowed. This is the
manner in which the respiratory system cleanses itself. (One of the components
of cigarette smoke anesthetizes the ciliated cells which push these pollutants
out of the respiratory system. The short-term effect is that the particles of
cigarette tar then persist in the lungs, causing local irritation. The
long-term effect is that harmful chemicals, particularly carcinogens, have a
longer period of time to leach out of the particles to affect the tissues of
the lungs.)
The
trachea divides into two primary bronchi which enter the right
and left lungs. The bronchi branch further into progressively finer bronchioles, which finally
terminate in an elongated structure containing air pockets or sacs, called alveoli. It
is here, in the alveoli, where gas exchange actually takes place.
Alveoli
are endowed with numerous capillary beds, which facilitate the diffusion of
oxygen into the bloodstream and carbon dioxide out of the bloodstream.
Ventilation
is accomplished by inspiration, the inhalation of air into the respiratory
system, and expiration, the exhalation out of the respiratory system out of the
respiratory system.
Inspiration
is primarily caused by the contraction of the diaphragm, a dome-shaped
muscle that forms the floor of the thoracic cavity. When the diaphragm
contracts, thus causing negative pressure which forces air into the lungs. The
entry of air into the lungs causes the alveoli to inflate. During forced
inhalation, the external intercostal muscles contract as well. The external
intercostal muscles pull the chest cavity outwards and upwards, thereby
increasing the amount of space available for the lungs to expand.
Expiration
occurs when the diaphragm relaxes. The recoil of the diaphragm pushes air out
of the lungs, thereby partially deflating the alveoli in the lungs. During
exercise or forced expiration, the internal intercostal muscles contract to
pull the chest cavity downwards and inwards.
The
quantity of respired air can be measured with a spirometer. The amount of air
moved into and out of the lungs with each normal breath is called the tidal
volume. Tidal volume averages 500 ml. The extra volume of air which can be
inhaled is called the inspiratory reserve, and it averages 3000 ml in
males and 2100 ml in females. The extra volume of air which can be exhaled is
called the expiratory reserve, and it averages 1200 ml in males and 800
ml in females. The sum of these volumes, tidal volume + inspiratory reserve +
expiratory reserve is called the vital capacity.
Even
when a person has exhaled as much air as possible, there is still air in the
respiratory system. This volume of air is called the residual, and it
averages 1200 ml for males and 1000 ml for females. The sum of vital capacity +
residual is total capacity.
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Average
lung capacities for normal 20-year old males and females Measured in milliliters |
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Parameter |
Males |
Females |
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Tidal volume (TV) |
500 |
500 |
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Inspiratory Reserve (IR) |
3000 |
2100 |
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Expiratory Reserve (ER) |
1200 |
800 |
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Vital Capacity (VC=TV+IR+ ER) |
4700 |
3400 |
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Residual (RE) |
1200 |
1000 |
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Total Capacity (TC=VC + RE) |
5900 |
4400 |
||
As mentioned earlier, gas exchange occurs in
the alveoli. Oxygen
molecules pass from the air space of an alveoli into its capillary bed via
simple diffusion -- oxygen concentration in the air is greater than it is in
the bloodstream. At the same time, carbon dioxide molecules passes out of the
capillary bed of an alveolus into its air space by simple diffusion. The amount
of surface area required for these processes of diffusion is quite large -- the
surface area of the alveoli in an average human lung is roughly equal to the
surface area of a tennis court.
Once
oxygen molecules have entered the bloodstream, they will then diffuse into red
blood cells, where they will bind with hemoglobin. Each hemoglobin molecule can
carry up to four oxygen molecules. With hemoglobin, the oxygen-carrying
capacity of whole blood is 20 ml of oxygen per 100 ml. Without hemoglobin, the
oxygen-carrying capacity drops to a mere 0.25 ml per 100 ml.
Breathing
is regulated by respiratory centers of the brain, located in the medulla. Neurons in the
dorsal region of the medulla regulate the basic rhythm of breathing by sending
a burst of impulses to the diaphragm and external intercostal muscles, causing
them to contract. When the neurons become inactive, the muscles relax, so
expiration occurs. Respiratory centers in the pons help regulate the
transition from inspiration to expiration. These respiratory centers are
sensitive to certain central nervous system depressants, e.g. alcohol.
Injection can be intravenous (directly into
vein), intramuscular (directly into muscle), subcutaneous (just under skin.)
In general, the advantages of injection are
that absorption is faster and more accurate, since the unpredictable digestive
system is bypassed. The disadvantages are the following:
1. Rapid rate of absorption allows little time for
response to overdose;
2. Sterile techniques must be used. The risk of
infection, particularly by AIDS and hepatitis C are much higher by injection
than by ingestion;
3. Administration cannot be recalled, so that lethal
overdoses are possible.
Intravenous injections, in which the drug is injected
directly into a vein, can be administered slowly or stopped, and they can be
very precise. Irritating drugs can be diluted into physiological saline. At the
same time, however, administration may be too fast and allergic reactions may
be too vigorous to be controlled. Drugs that are not soluble in blood or those
that are dissolved in oily liquids cannot be administered intravenously because
of danger of blood clots. Intravenous injections also run the risk of
transmitting pathogens.
The onset of effects with an intramuscular
injection are faster than oral administration but slower than intravenous
injection. Subcutaneous injection in which the drug as administered just
underneath the surface of the skin allows for rapid absorption. Irritating drugs
should not be given subcutaneously.
Minicourse 3: The
circulatory system
According to Solomon et al. (1999),
the human circulatory system performs the following functions:
1. Transports nutrients from the digestive system and from storage depots to
each cell of the body;
1. Transports oxygen from the lungs to the cells of the
body;
2. Transports metabolic wastes from each cell to organs
that excrete them;
3. Transports hormones from endocrine glands to target
tissues;
4. Helps maintain fluid balance;
5. Defends the body against invading microorganisms
6. Helps distribute metabolic heat within the body, which
helps maintain a constant body temperature;
7. Helps maintain appropriate pH
Blood consists of plasma, blood cells and
platelets. Plasma is the fluid component of blood. Approximately 92% of
the volume of plasma is water, and 7% is protein. The remaining 1% includes the
materials being transported in the plasma, including dissolved gases,
nutrients, waste molecules, and hormones.
There are 3 classes of plasma proteins:
Fibrinogen
Globulins
(including alpha, beta and gamma)
Albumin
When
clotting proteins are removed from plasma, the remaining fluid is called serum.
Plasma
proteins help regulate the distribution of fluid between plasma and
interstitial fluid. They are too large to pass through the walls of blood
vessels, so they help regulate osmotic pressure as well. Plasma proteins also
function in regulating blood pH to within a very narrow range, 7.35 to 7.45.
Blood
cells:
Red blood cells, or
erythrocytes function to transport oxygen and carbon dioxide. By the time a red
blood cell is released into the bloodstream from the marrow where it was
produced, the cell is enucleated (without a nucleus). Each red blood cell is 7
to 8 microns in diameter. The biconcave shape of the cell allows for a high
surface-area-to-volume ratio. Red blood cells are flexible enough to allow the
cell to bend and twist as it passes through capillaries.
White
blood cells or leukocytes are an internal defense to pathogens. A typical
stained blood smear will show a variety of leukocytes, each with a specific
function:
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Characteristics and Functions of Leukocytes |
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Type |
Percentage |
Function |
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70% |
Principal phagocytic cells in the blood -- they detect and ingest bacteria. |
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1-3% |
Detoxify foreign proteins and other substances --numbers increase during allergic reactions and in response to certain parasitic infections |
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25-35% |
Produce antibodies and destroy foreign or cancerous cells -- specific immunity |
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6% |
Leave the bloodstream to differentiate into macrophages which attack pathogens |
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Platelets
assist in the clotting process. When a blood vessel is damaged, platelets will
be sticky and will adhere to the edges of the wound. Activated platelets will
then release substances which will initiate the clotting process, eventually
producing a fibrous plug consisting of fibrin. The process of clot formation
involves a cascade of at least 12 different reactions.
The
heart is a
muscular pump which provides the force for moving blood through the circulatory
system. The human heart consists of 4 chambers. The right atrium
receives blood from the superior vena cava (draining the head and neck) and
from the inferior vena cava (from the torso, arms and legs). When it contracts,
blood passes through the tricuspid valve to the right ventricle. When the right ventricle contracts, blood
passes through the pulmonary valve to the pulmonary artery. The
pulmonary artery brings blood to the lungs, where it is oxygenated. Blood will return
to the heart via the pulmonary veins into the left atrium. When
the left atrium contracts, blood passes through the mitral valve into
the left ventricle. When the left ventricle contracts, blood passes
through the aortic semilunar valve into the systemic circulation via the
aorta.
Cardiac muscle cells which comprise the heart are unusual because they can contract
spontaneously. The means by which the contractions of all cardiac muscles are
coordinated to allow for the efficient pumping of the heart is by means of a
pacemaker, the sinoatrial node. The sinoatrial node is the location
where the nerve stimuli to contract originate. The sinoatrial node, in turn, is
connected to the cardiac centers of the medulla. The electrochemical impulses
which regulate the beating of the heart can be recorded in the form of an electrocardiogram.
Cardiac
output is the volume of blood pumped by the left ventricle into the aorta
in one minute, and is equal to the produce of stroke volume x heart rate.
Stroke volume is equal to the amount of blood which can be pumped during each
contraction of the left ventricle. The average stroke volume is 70 ml. At rest,
when the heart is pumping approximately 72 times/minute, the cardiac output is
therefore approximately 5 Liters/minute. During exercise, the cardiac output
can increase 4- or 5-fold.
The
allocation of blood during rest and exercise periods will also change:
|
|
Comparison of Cardiac Output at Rest and During Exercise (All numbers are in ml/minute) |
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|
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At rest |
During exercise |
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Cardiac output |
5,400 |
17,500 |
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Blood flow to: Brain Abdomen Kidney Muscle Skin Heart |
750 1400 1100 850 450 250 |
750 600 600 12,500 (!) 1,900 750 |
||
The
heart pumps the body's total volume of blood in 1 minute. Therefore, once a
drug is absorbed, distribution is within 1 minute.
Blood
pressure is the force exerted by the blood against the inner walls of the
blood vessels. It is proportional to cardiac output, blood volume, and
resistance to blood flow. In a clinical setting, blood pressure is measured
with a stethoscope and a sphygmomanometer at the brachial artery, and is
indicated by two numbers. The first number indicates the systolic pressure,
i.e. the pressure of blood when the heart is contracting. The second number
indicates the diastolic pressure, i.e. the pressure of blood when the heart is
at rest.
The
"plumbing" that is associated with the heart in circulating blood
includes arteries,
which carry blood away from a heart chamber, veins, which
transport blood back to the heart, and capillaries,
where exchange occurs between the bloodstream and internal tissues.
The
capillary system is extensive. No single functioning cell of the body is more
than 20 to 30 microns away from a capillary. In comparison, the average RBC is
7 microns in diameter.)
Drugs quite quickly become evenly distributed
throughout bloodstream, diluted not only by blood but also by total amount of
water contained in the body. Most drugs are not confined to the bloodstream.
Capillaries have pores between cells that allow passage of molecules between
blood and body tissues. Most drugs travel freely from blood through pores in
capillary membrane, passing along concentration gradient until equilibrium is
established.
Transport
of drug molecules out of blood capillaries and into tissues, and back
into blood is independent of lipid solubility, since pores are large enough for
even fat-insoluble molecules to penetrate.
Some drugs can be bound to proteins.
Protein-bound drugs are essentially trapped in bloodstream. However,
protein-bound drugs exist in equilibrium with unbound drugs.
Capillaries comprising the blood-brain barrier and the placental barrier have unusual properties, and thereby affect the diffusion of materials
across those membranes.
The
term blood-brain barrier refers to those capillaries found in the brain. These
capillaries lack pores. Instead, they have extensions of astrocytes to
form a fatty barrier called a glial sheath. This glial sheath allows
only fat-soluble molecules to diffuse out of the bloodstream and into brain
tissue.
The
capillaries of the placental barrier separate 2 living entities. The growing
fetus is completely dependent on the maternal circulation for the delivery of
nutrients and oxygen and for the removal of waste molecules and carbon dioxide.
Psychoactive drugs can also pass through the placental barrier. The effects of
maternal ingestion of alcohol, nicotine and cocaine are well documented.
References:
Solomon, E. P.; Berg, L. R.; Martin, D. W.
1999. Biology. Saunders College Publishing, edition 5.
Modes of Entry IV.
Miscellaneous
Drugs can be administered through a variety of
mucous membranes. For example, heart patients take nitroglycerine as a tablet
under the tongue, absorption directly through the mouth. Cocaine, when sniffed,
adheres to the membranes on inside of nose and is absorbed directly into
bloodstream.
Other examples include nicotine in snuff or
chewing gum, nasal decongestants which are administered via a nasal spray, and
Fentanyl, a narcotic pain-killer given to children post-surgery as a lollipop.
Some drugs can be administration through the
skin. With this method, the active ingredient is slowly absorbed through the
skin into bloodstream. For example, people trying to discontinue smoking will
self-administer nicotine with a patch. Estrogen is given in the same manner to
postmenopausal women. The drug is slowly released from the patch and is
absorbed into the systemic circulation over a period of days so that blood
levels remain relatively constant.
Minicourse 4: The
excretory system
The
functions of the excretory system include osmotic regulation, excretion of nitrogenous and other waste
products, and the regulation of a constant blood pH.
In
the course of a single day, the kidneys will
process 180 liters of blood, and will produce 1.5 liters of urine. The
functional unit of kidneys is the nephron. As
blood passes through a glomerulus,
some fluid, which has dissolved nutrient, waste and salt molecules in it, will
diffuse into the glomerular capsule. This fluid, called the filtrate,
will become progressively more urine-like as it progresses through the nephron.
All of the nutrient molecules, and most of the water will be reabsorbed and
returned to the bloodstream. By the time this filtrate has reached the collecting
duct, it will have become urine. The following chart shows the
concentrations of selected materials in blood, the filtrate as it first enters
the glomerular capsule and the collecting duct:
|
|
CONCENTRATIONS, IN MG/ML OF SELECTED MATERIALS |
|
|||
|
Molecule |
Efferent arteriole (blood) |
Glomerular capsule (filtrate) |
Collecting duct (urine) |
||
|
Urea |
30 |
30 |
2000 |
||
|
Uric acid |
4 |
4 |
50 |
||
|
Inorganic salts |
720 |
720 |
1500 |
||
|
Proteins |
8000 |
0 |
0 |
||
|
Amino acids |
50 |
50 |
0 |
||
|
Glucose |
100 |
100 |
0 |
||
While
amino acids, glucose molecules and water are reabsorbed into the blood, some
materials are secreted across the tubule epithelium in a direction opposite to that
of reabsorption. Potassium, hydrogen, and ammonium ions are secreted into the
filtrate. The secretion of hydrogen ions is important in the regulation of
blood pH.
The
amount of water that is released is regulated by antidiuretic hormone,
(ADH or vasopression), a hormone secreted by the posterior pituitary gland. ADH
makes the collecting ducts more permeable to water so that more water is
reabsorbed and a smaller volume of concentrated urine is produced. Alcohol
inhibits the activity of ADH, thus causing people to produce more urine per
unit time.
As
urine is produced, it flows from the collecting ducts into the renal pelvis,
a funnel-shaped structure inside the kidney. Urine then flows into one of two ureters,
which are tubular muscles. By peristaltic movement, the ureters bring urine to
the urinary bladder, where it is stored. The urinary bladder can retain
up to 100 ml of urine. Urine exits the body via the urethra. The process
of voiding the bladder involves the voluntary relaxation of the outer sphincter
muscle, which is composed of (voluntary) striated muscle fibers. The change in
pressure bearing on the inner sphincter muscle, which is composed of
(involuntary) smooth muscle fibers, causes a reflex in which the inner
sphincter muscle relaxes, thus allowing the flow of urine. Muscles in the wall
of the urinary bladder then push urine out of the bladder.
Drug
action can be terminated by two processes. First, the active molecule can be
metabolized into an inactive form. Because psychoactive drugs are small and
lipid-soluble, they will follow concentration gradient back into bloodstream.
From there, drug molecules are converted into metabolites which are more
water-soluble, bulkier, and less biologically active. The enzymes which
catalyze these metabolic processes in liver cells are collectively called P450
enzymes. Drug-metabolizing enzymes in liver cells have low specificity,
therefore cross-tolerance will occur. The factors affecting drug metabolism can
be genetic, environmental, or physiological. Most metabolites exit via the
urine, so they form the basis for urine testing.
Second, the active drug molecule may be
secreted via several routes. Highly volatile or gaseous agents, such as
anesthetics or alcohol can exit via the lungs. Other routes of drug elimination
include the lungs, bile, sweat, saliva, breast milk. For example, measurable
amounts of nicotine can be detected in mother's milk, and antibiotics given to
cows may end up in milk served to babies.
|
Mode of Admini-stration |
Time of onset of effects |
Persis-tence of effects |
Precision of blood concentra- tions & dosage |
Likelihood of reversing effects of an overdose |
Suscepti-lity to blood-borne diseases, e.g. AIDS |
|
Oral |
Slow (20-40 minutes) |
Long |
Least predictable |
Possible - in hospital setting, it is possible to pump the stomach contents |
Virtually nil |
|
Inhalation |
Fairly rapid (< 1 minute) |
Relatively long |
More reliable |
Less likely |
Very unlikely |
|
Intravenous injection |
Very rapid (<< 1 minute) |
Relatively short |
Most precise |
Least likely |
High susceptibi-lity |
Minicourse 5:
Structure of the nervous system
The nervous system
can be divided into 2 parts, the central nervous system (CNS), and the peripheral nervous system (PNS). The central nervous system consists of nerves
that are in the brain and spinal cord, while the peripheral nervous system
consists of nerves that lie outside the brain and spinal cord. These nerves are
both sensory (afferent) and "motor" to (efferent) all muscles and
organs.
The Central Nervous System:
There are an estimated 100 billion neurons in
the brain and spinal cord.
The spinal cord extends from the lower end of the medulla to the sacrum and
consists of neurons involved in the following:
a. Carrying sensory information from skin, muscles,
joints, and internal body organs to the brain;
b. Organizing and modulating the motor outflow to the
muscles (to produce coordinated muscle responses.);
c. Modulating sensory input (including pain - impulse
input);
d. Providing autonomic (involuntary) control of vital
body functions.
The lower part of the brain, the brain stem,
includes the medulla, pons, and midbrain.
All impulses that are conducted between the spinal cord and brain pass through
brain stem. The three parts of the brain stem collectively regulate vital body
functions, such as respiration, blood pressure, heart rate, GI functioning, and
stages of sleep and wakefulness. They are also involved in behavioral alerting,
attention, and arousal responses.
Behind the brain stem is the cerebellum. It is a highly convoluted structure connected to
brain stem by large fiber tracts and is necessary for proper integration of
movement and posture. Alcohol & barbiturates depress cerebellar function.
Above the brain stem is the diencephalon,
which includes the hypothalamus,
pituitary gland,
various fiber tracts, subthalamus,
and thalamus.
The subthalamus lies underneath the thalamus
in the midbrain. Together with basal ganglia, it constitutes one of our motor
systems, the extrapyramidal system. In Parkinson’s disease, there is a
deficiency of dopamine which originate from cell bodies in the substantia
nigra, one of the subthalamic structures.
The hypothalamus is the principal center of
integration for the entire autonomic (involuntary or vegetative) nervous
system. It controls eating, drinking, sleeping, regulation of body temperature,
sexual behavior, blood pressure, emotion & water balance. It also controls
hormonal output of the pituitary gland, by secreting releasing factors and is
the site of action for primary and side effects of drugs.
The limbic system is closely
associated with the hypothalamus. Its major components are the amygdala and hippocampus.
These structures exert primitive types of behavioral control. They integrate emotion,
reward, and behavior with motor and autonomic function. Because the limbic
system and hypothalamus interact to regulate emotion and emotional expression,
these structures are targets of psychoactive drugs.
The hypothalamus and limbic areas contain
structures important in psychopharmacology, including dopamine-rich reward
centers such as the ventral tegmental area, median forebrain bundle,
and nucleus accumbens. Activity of dopaminergic neurons in these areas
is affected by opioid, GABA-ergic, and other neuronal influences. As a result,
drugs subject to compulsive abuse act here.
The
cerebrum is
the largest portion of brain and is separated into 2 distinct hemispheres
divided by function. Interpretation of sensory input and of motor activity are
controlled by different areas of the brain:
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Functional areas of the cerebrum (adapted from Mader, 1998) |
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Structure |
Function |
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Frontal lobe |
Motor functions |
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Parietal lobe |
Receives information from receptors in the skin |
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Occipital lobe |
Interprets visual input | ||