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:
|
|
Functional areas of the cerebrum (adapted from Mader, 1998) |
|
|
|
Structure |
Function |
||
|
Frontal lobe |
Motor functions |
||
|
Parietal lobe |
Receives information from receptors in the skin |
||
|
Occipital lobe |
Interprets visual input |
||
|
Temporal lobe |
Interprets auditory and olfactory information |
||
|
Broca's area |
Speech |
||
|
Wernicke's area |
Recognition and interpretation of words |
||
References
Cited:
Mader, S. 1998. Biology. WCB
MCGraw-Hill, edition 6.
The functional unit of the nervous system is
the neuron. All neurons have three common structural & functional characteristics:
a. Soma = the cell body where
the nucleus is located;
b. Dendrites = hundreds of
widely branched extensions that come close to but do not touch other neurons;
c. Synaptic terminals = release neurotransmitters that transmit information from one neuron
to another; and
d. Receptors = proteins located
on the plasma membrane which respond to neurotransmitter molecules
Neurons can be classified according to
function. Sensory, or afferent neurons transmit information to the central
nervous system. Neural messages are transmitted from the central nervous system
to muscles and glands via motor, or efferent, neurons. Interneurons, or
association neurons integrate the activity of sensory and motor neurons by
interpreting incoming sensory information and determining the appropriate
response (Solomon et al., 1999).
The
ability of neurons to transmit electrochemical impulses is based on the
differences in ion concentration and electrical charge across the plasma
membrane. The concentrations of ions and proteins in the cytoplasm of a neuron
are quite different than those of the interstitial fluid surrounding the
neuron:
|
|
Comparison of ion concentrations, in mM (Adapted from Campbell, 1996) |
|
||||
|
|
|
Na+ (sodium) |
K+ (potassium) |
Cl- (chloride) |
A- (anions, including proteins and amino acids) |
|
|
|
Inside neuron |
15 |
150 |
10 |
100 |
|
|
|
Outside neuron |
150 |
5 |
120 |
~0 |
|
The
resulting difference in electrical charge produces a membrane potential. In a
resting cell, the membrane potential is called the resting potential, and it is
approximately -70 mV. The gradient in the electrical across the cell membrane
is maintained by the sodium-potassium pump, a collective term to describe the
enzymes embedded in the plasma membrane of neurons, which consume energy in the
form of ATP and pull sodium ions out of the cell and potassium ions into the
cell. The membrane potential can vary, depending on the factors affecting the
neuron:
1. If a stimulus opens a potassium channel, potassium
ions will migrate out of the cell, thus making the interior of the cell more
negative than the exterior, thus hyperpolarizing the cell. As long as a
neuron is hyperpolarized, it is less likely to produce an impulse, or an action potential;
2. If a stimulus opens a sodium channel, sodium ions will
migrate into the cell, thus depolarizing the cell. Depolarizing the cell
increases the likelihood of an action potential.
If a neuron has been sufficiently depolarized
(to -55 mV), a cascade of events occur in which an action potential is formed
and then propagated along the cell body through the axon.
An
action potential is created when the sodium activation gates at a stimulated
site of a neuron open. This causes the rapid migration of sodium ions into the
cell and potassium ions out of the cell at that site, so that the local
membrane potential becomes +35 mV. That site recovers its original membrane
potential by the restoration of the original ion concentrations on both sides
of the plasma membrane. However, the action potential is propagated at each
site along the plasma membrane, so there is a net movement of the action
potential from the dendrite or soma where it originated through the axon.
Action
potential speed is proportional to axon diameter and is related to the presence
of insulating Schwann cells.
Schwann cells are a type of glial cell which are rich in a protein called myelin. These Schwann cells
surround the axon and the myelin insulates it. The gaps between Schwann cells are
called nodes of Ranvier. In a myelinated cell, the action potential will jump from one node to
the next.
In
producing an action potential, individual neurons respond to both spatial and temporal summation. Spatial summation refers to the simultaneous
stimulation of a neuron by several other neurons. Each individual stimulus may
be insufficient to elicit an action potential, but the combined effects may
cause the stimulated cell to reach its threshold potential. Similarly, temporal
summation refers to the cumulative effect of a burst of stimuli from one neuron
on another. The gradual depolarization from each individual stimulus may elicit
an action potential.
Synapses
differ in terms of their net effect on the postsynaptic cell. Some synapses are excitatory,
meaning the neurotransmitter released by the presynaptic cell will cause the sodium activation
channels to open and thereby depolarize the postsynaptic cell. Other synapses
are inhibitory, meaning the neurotransmitter released by the presynaptic cell
will cause potassium channels to open, and thereby hyperpolarize the cell.
References Cited:
Action
potentials do not cross the synapse, but neurotransmitters do, and these
chemicals are the means by which neurons communicate with each other and with
other effector cells.
Presynaptic cells will produce specific
neurotransmitter molecules, and these neurotransmitter molecules will be stored
in sac-like structures called vesicles. When an action
potential reaches the axon terminal, the plasma membrane of some vesicles will
fuse with the plasma membrane of the terminal, and thereby release its contents
into the synaptic cleft. The neurotransmitters then migrate across the synapse,
and will reversibly bind with specific receptor molecules on the postsynaptic
cell.
There are hundreds of different types of
receptors, including multiple subtypes for norepinephrine (NE), dopamine (DA),
gamma-amino butyric acid (GABA), and glutamate (GL).
Receptors can be
divided into 3 groups:
a. "Fast", which are linked directly to an ion
channel and which mediate millisecond responses. These have 4 transmembrane
elements.
b. "G-protein-coupled receptors", somewhat
slower than "Fast" - modulatory receptors may be directly coupled to
ion channels that are linked to intracellular "second messengers".
These then alter internal functioning of the cell.
c. Transporter proteins - located on presynaptic cells,
function to remove neurotransmitter from synapse.
Neurotransmitters are either stimulatory,
i.e., they depolarize the post-synaptic cell, or are inhibitory and
hyperpolarize the post-synaptic cell.
Termination of neurotransmitter action is
accomplished by either reuptake by the presynaptic cell or by inactivation by
the post-synaptic cell. In either case, the synapse is cleared.
The entire process of neurotransmitter
release, binding with post-synaptic cell, and termination is measured in
milliseconds.
Synapses
are a major site of drug action. Most psychoactive drugs act through various
processes that either potentiate or oppose action of neurotransmitters at their
receptors. For example, cocaine blocks the presynaptic transporter protein for
dopamine, so that dopamine is not removed from synapse. As a result, the
activity of dopamine in the synapse is longer, thus leading to the
characteristic behavioral stimulation and reinforcement. Drugs often have much
more specific receptor effects than the endogenous transmitter for that
receptor.
Acetylcholine (Ach) is one of the most common neurotransmitters in both
vertebrates and invertebrates. Motor neurons stimulate muscle cells to contract
by releasing acetylcholine into myoneural junctions. Deficiencies in
Ach-secreting neurons are found in people with memory dysfunctions, e.g. Alzheimer’s Disease. It is synthesized from 2 precursors and then stored in vesicles.
Acetylcholine is deactivated by acetylcholine esterase (AchE, or
cholinesterase), an enzyme found on the plasma membrane of post-synaptic cells,
into 2 fragments which are then reabsorbed into the presynaptic cell.
Irreversible AchE inhibitors such as sarin
and malathion can be lethal. However, reversible AchE inhibitors have
therapeutic applications. By increasing Ach levels in the brain, these
compounds may delay the cognitive decline found in Alzheimer’s Disease
patients.
The catecholamines include dopamine
(DA) and norepinephrine (NE). The term "catecholarmine refers to
the "catechol" nucleus, a benzene ring bonded to 2 hydroxyl groups,
bonded in turn to an amine. The release of catecholamine is controlled by
presynaptic receptors that are activated by Ach, prostaglandins, other amines,
possibly glutamate and endorphins.
Inactivation in the synaptic cleft occurs
primarily by active reuptake by the presynaptic nerve terminal. Within a
presynaptic nerve terminal, catecholamines may be deactivated by enzymes,
especially monoamine oxidase (MAO). Antidepressants known as MAO inhibitors act
by inhibiting MAO, thereby increasing amounts of DA and NE available for
synaptic release. Other antidepressants, by blocking presynaptic reuptake pump
and making more transmitter available at the postsynaptic receptor, may
ultimately "desensitize" postsynaptic function.
Norepinephrine is mostly in
brainstem, while dopamine pathways originate in the brain stem and involve
three circuits. Thompson (1993) describes these dopamine circuits:
1)Cell bodies in
hypothalamus send short axons to pituitary gland;
2)Cell bodies in
the brain stem structure called substantia nigra project to basal ganglia;
3) Cell bodies
in the midbrain (ventral tegmentum) near the substantia nigra, project to
higher brain regions including the cerebral cortex, especially the frontal
cortex, the limbic system, nucleus accumbens, amygdaloid complex, and the
entorhinal cortex, the latter being the major source of neurons projecting to
the hippocampus. This last circuit is particularly important, because it
constitutes the reward pathway of the brain.
Serotonin,
or 5-HT, is found in upper brain stem, especially pons and medulla and opposes
effects of NE. Rostral projections from brain stem terminate throughout the
cerebral cortex, hippocampus, hypothalamus, and limbic system. Selective
Serotonin Reuptake Inhibitors (SSRI's) are prescribed to alleviate depression.
Glutamate
appears to be the primary excitatory neurotransmitter in the brain, receptors
being on the surface of virtually all neurons. Glutamate is also the precursor
for the major inhibitory neurotransmitter, GABA. Glutamate plays a critical
role in cortical and hippocampal cognitive function, pyramidal and
extrapyramidal motor function & cerebellar function, and acts on a family
of receptors:
1. AMPA/kainaic acid receptors are fast channel gates;
2. Metabotropic receptors regulate ion channels and
enzymes, producing secondary messengers coupled to G-proteins;
3. N-methyl-D-Aspartate (NMDA) is a glutamate-activated
ion channel, primarily for calcium ions, widely distributed in brain and spinal
cord, especially in the hippocampus and cerebral cortex, and is involved in
developmental plasticity.
GABA is the
major inhibitory neurotransmitter, found in the brain and spinal cord. Receptors
are found in high density in cerebral cortex, hippocampus, cerebellum. There
are numerous types of GABA receptors. For example, there are 10 different
subtypes of GABAA receptors.
Opioid peptides
are produced in brain and bind to same receptors as opioid narcotics. Opioid
peptides exert similar effects. High concentrations of opioid receptors neurons
line the wall of the 4th ventricle of brain. They are also found in
the medial thalamus and other pain pathways, the limbic system, and the
amygdala.
Principles of
Pharmacokinetics and Pharmacodynamics
The time course of drug distribution and
elimination is measured in terms of its half-life, which is defined as the
amount of time required for the blood concentrations to drop to half of its
original level. It is important to know the half-life in order to do the
following: 1)Predict optimal dosages and dose intervals; 2)Maintain therapeutic
levels; and 3)Determine the time needed to eliminate drugs. See Figure 1.12 -
Time-Concentration relationship).
For example, with intravenous injection of
fentanyl, plasma concentration peaks immediately, then falls rapidly at first, and
then declines more slowly. Process of distribution rapid, with the distribution
half-life lasting 7.9 minutes. The elimination half-life is longer - 44.6
minutes.
The
biological half-life of a drug determines the length of time required to reach
a steady state, i.e. the amount taken in = amount metabolized in the same
internal of time. Since 4 half-lives are needed for 90% elimination of a drug
of a drug to be eliminated and 6 for 98%, a steady state concentration of ~6 x
the drug's elimination half-life will be reached. The steady state
concentration is independent of drug dosage.
The
use of both therapeutic and illicit drugs may induce drug tolerance or dependence.
Drug tolerance may be defined as a state of
progressively decreasing responsiveness to a drug. Three mechanisms are at work
in the onset of drug tolerance:
1. Metabolic,
presence of drug perfusing through induces synthesis of hepatic
drug-metabolizing enzymes;
2. Cellular-adaptive, pharmacodynamic response, receptors in brain adapt to continued presence
of drug by increasing the number of receptors (thus requiring more drug to
occupy them) or by reducing their sensitivity to drug, called down-regulation,
shown in narcotics, barbiturates, alcohol;
3. Behavioral conditioning, if drugs are administered in the context of predrug
cues.
Physical
dependence refers to the onset of
withdrawal symptoms during period of drug deprivation.
Drugs work by binding to receptors on cells, leading
to changes in functional properties of cells. The receptors to which drug
molecules bind are protein receptors on neurons which serve as receptors for
natural neurotransmitters. Binding is reversible. The intensity of drug effect
is determined by percentage of available receptors that are occupied by
molecules of neurotransmitter. Drugs can be agonists, by mimicking of
neurotransmitter, or they occupy space of receptor and they don’t work – these
are called antagonists.
Receptors
have varying degrees of specificity or affinity for drugs and
neurotransmitters. Drugs with "best" fit elicit greater responses.
Selectivity or specificity of drug action is NOT due to selective distribution
of drug molecules, but rather due to: 1) Selective location of drug receptors;
2) Specificity of drugs that bind to particular receptors; 3) Strength of
drug’s attachment; and 4) Consequences of interaction between drugs and their
receptors.
A drug, therefore, is potentially capable of altering any body or brain
function. They do not create effects, but modulate ongoing functions.
Quantifying the percentage of individuals
responding to a given dose of a drug and the intensity of response as a
function of drug dosage are vital for determining the potency, i.e. the
absolute amount of drug needed to produce a defined effect, and the efficacy,
i.e. the maximum effect.
The variability that individuals will show in
response to a dose will depend on genetic predisposition, previous experience
with the drug, and emotional state. Such variability is measured by the ED50,
the effective dose for 50% of subjects, the LD50, the lethal dose
for 50% of subjects, and the therapeutic index with equals the ratio of LD50/ED50.
Drug interactions may occur when there is
concurrent administration of two or more drugs. Usually, the concern is the
potentiation of drug action, as in alcohol with benzodiazepines or alcohol with
marijuana.
Drug toxicity may be measured in terms of
side effects, allergic responses, blood disorders, liver or kidney toxicity, or
fetal development. Organ damage to liver and kidneys results from their role in
concentrating, metabolizing, and excreting drugs. Fetal effects by nicotine,
alcohol, cocaine are well-documented and largely irreversible. Drug allergies
can be fatal.
Alcohol
is classified among central nervous system depressants and sedatives. The
effects of sedative drugs are supra-additive, i.e. depression observed in a
person who has taken more than 1 drug is greater than would be predicted if
person had taken only 1. All CNS sedative-hypnotics carry the risk of inducing
physiological dependence, psychological dependence and tolerance. Considerable
degree of cross-tolerance exists between depressants.
The
use of depressants, particularly alcohol and opium, is quite ancient. In the
mid-1800’s, chloral hydrate & bromide were introduced. In 1912,
phenobarbital was introduced and yielded many different barbiturates over the
next 50 years. In 1961, chlordiazepoxide, the first benzodiazepine was
introduced.
CNS
depressants, which include barbiturates, non-barbiturate sedative-hypnotics,
ethanol, and general anesthetics, share similar sites and mechanisms of action.
At low and normal doses the polysnaptic diffuse brain stem pathways are
depressed. Excitatory synaptic neurotransmitters are depressed while
"inhibitory" neurotransmitters are facilitated. Brain stem depression
continues as dosage increases & accounts for coma and death.
Mode of action, metabolism
& toxicity of alcohol
Alcohol is
the #1 favorite mood-altering drug in the
Alcohol equivalents include the following:
|
|
Ounces/standard serving |
Average alcohol content/volume |
Pure alcohol/standard serving |
|
|
1.25 x |
40.0% |
.50 |
|
|
12 x |
4.5% |
.54 |
|
|
5 x |
11 |
.55 |
After
absorption, alcohol is evenly distributed to all body fluids and will pass through
both the blood-brain and placental barriers immediately.
Approximately 95% is metabolized by alcohol
dehydrogenase, and 5% is excreted, mostly by exhalation from the lungs.
Most
of the breakdown of alcohol (85%) occurs in liver, but some metabolism is
carried out by gastric alcohol dehydrogenase, tends to reduce amount of active
alcohol in blood. Women have 50% less gastric alcohol dehydrogenase, therefore
have more active alcohol entering blood. The major pathway of alcohol
metabolism is shown in the following figure:
Major Pathway of Metabolism
of alcohol in the Liver through ADH
(Modified
from Cotran, Kumar, & Robbins, 1989)
|
|
Ethanol |
|
|||||
|
í
í |
ę
ę |
î
î |
|||||
|
|
(Meos) Microsomal ethanol oxidizing dehydrogenase
|
(ADH) Hepatic ethanol dehydrogenase |
Catalase (H2O2) |
|
|||
|
|
|
Acetaldehyde |
|
|
|||
|
|
|
Via Hepatic Acetaldehyde Dehydrogenase |
Neurotransmitters ę TIQ's (To reward circuitry of the brain?) |
|
|||
Alcohol is first metabolized into
acetaldehyde. Acetaldehyde is converted to acetic acid by aldehyde
dehydrogenase. Acetic acid is eventually converted into carbon dioxide and water.
Alcohol, therefore, has no nutritional value, except for calories.
The rate of metabolic breakdown is
independent of alcohol concentration in blood. This represents a zero-order reaction.
The concentration of blood alcohol can be determined indirectly by measuring
ethanol in exhaled air. This is the basis of "Breathalyzer" tests,
since there is a 1:2300 ratio between ethanol in exhaled air and concentration
in blood. A Blood Alcohol Concentration (BAC) of .08% is considered as
intoxication, but this is arbitrary. The likelihood of being involved in an
accident is proportional to blood alcohol levels, as shown in the following
table:
|
BLOOD ALCOHOL CONC. |
LIKELIHOOD OF ACCIDENT, COMPARED TO SOMEONE WHO IS SOBER |
|
.05% TO .08% |
4X |
|
.10%-.14% |
6-7X |
|
>.15% |
25X |
Acute
alcoholism contributes significantly to over 50% of motor vehicle fatalities.
Prolonged use results in production of liver enzymes
which accelerate breakdown. Antabuse inhibits alcohol dehydrogenase, so alcohol
persists and causes severely unpleasant physical symptoms.
Identifying the mode of action is difficult.
At high doses, where alcohol anesthetizes, it may disrupt functioning of cell
membranes. More recent theories point to action on glutamate and GABA
receptors. Ethanol is a potent and selective inhibitor of the function of
N-methyl-D-Asparate (NMDA) subtype of glutamate receptors. Inhibition of NMDA
receptors occurs by decreasing the frequency of ion channel openings for sodium
ions. Ethanol, like other depressants, augment GABA-mediated synaptic
transmission. Ethanol binds with GABAa receptors at a site other
than barbiturates. Because of GABAergic agonist action, other transmitter
systems are affected, especially cholinergic and dopaminergic. Alcohol inhibits
release of acetylcholine. Since intact cholinergic mechanisms are necessary for
learning and memory, this anticholinergic action may contribute to alcohol’s
impairment of cognition. Such anticholinergic action is probably indirect,
occurring secondary to increased GABA inhibition of acetylcholine.
GABA agonist actions have been linked to
positive reinforcement effects of ethanol. Furthermore, alcohol augments dopamine
neurotransmitter system, particularly projections from the ventral tegmental
area (VTA) where it increases the firing rate, to the nucleus accumbens and to
the frontal cortex.
There are numerous pharmacological effects.
The primary effect is graded, reversible depression of CNS. Alcohol will
initially affect subcortical areas, so motor and intellectual ability becomes
disoriented. At higher levels, the medullary center becomes depressed,
affecting respiration. Respiration becomes progressively depressed. Research is
underway on the relationship between alcohol and snoring and obstructive sleep
apnea (i.e. cessation of breathing during sleep).
Alcohol is a diuretic because it inhibits
secretion of antidiuretic hormone (ADH). Alcohol induces skeletal muscle
weakness, interferes with sexual performance, and disrupts normal protein
synthesis. By changing intracellular concentrations of m-RNA, chronic alcohol
use can affect gene expression.
Prolonged alcohol use induces three forms of
tolerance. First, metabolic tolerance occurs because the liver cells
increase its amount of drug-metabolizing enzyme. This type accounts for 25% of
tolerance. Second, tissue, or functional tolerance, occurs because
neurons in brain adapt to the presence of alcohol by adjusting the number and
types of receptors on postsynaptic cells. Third, associative, (also called
contingent or homeostatic,) tolerance involve environmental cues. No
evidence has been demonstrated to show any degree of tolerance developing to
the positive reinforcing effects of alcohol.
With acute use, a reversible drug-induced
brain syndrome is induced. The syndrome is manifested by disorientation,
amnesia (blackouts), diminished intellectual abilities, and can lead to
hallucinations.
The consequences of chronic prolonged use can
be disastrous. Virtually every organ system in the body is affected by alcohol,
and the net result is a complete deterioration of the body.
The circulatory system
The immediate effect of alcohol use is that
it dilates blood vessels in the skin, producing a warm flush and drop in body
temperature. However, long-term use is related to hypertension, defined as
consistent elevation of systemic arterial blood pressure. More than 62 million
Americans are affected by hypertension, including 2.8 million children aged 6 -
17 years. In addition to genetic predisposition and environment, heavy alcohol
consumption (defined as >3 drinks/day) is considered a significant risk
factor. Hypertension, hyperlipidemia, and glucose intolerance often go
together.
Although moderate use of alcohol may reduce risk
of coronary heart disease by increasing HDL lowering LDL levels, alcohol
generally increases the risk of coronary heart disease by: 1) Increasing body
weight; 2) Increasing triglyceride levels; 3) Increasing systolic blood
pressure; 4) Impairing left ventricular function; 5) Exerting direct
cardiotoxic effects on myocardial tissue, resulting in collagen accumulation;
6) Diminishing nucleic acid pools; and 7) Inducing a loss of membrane transport
systems.
A disproportionate number of individuals with
idiopathic dilated cardiomyopathy are
alcoholics. The damage is caused by 3 mechanisms: 1) Direct toxic effects of
alcohol or of its metabolites; 2) Induction of nutrition deficiencies, especially
of thiamine; and 3) Toxic effects of beverage additives such as cobalt. This
condition may be stopped or reversed with abstention from alcohol.
The digestive system
Hypoglycemia is defined as a deficiency of
glucose in the blood. It is particularly likely in chronically malnourished or
acutely food-deprived individuals and it occurs within 6-36 hours of ingesting
moderate to large amounts of alcohol. Drinking on an empty stomach can induce
alcohol-promoted reactive hypoglycemia. The condition is more associated with
drinks containing alcohol with either glucose or saccharin (e.g. beer, gin and
tonic, rum and cola, whiskey and ginger ale.)
Pancreatitis
is an inflammation of the pancreas, indicating structural or functional
impairment. Chronic alcohol abuse is the most common cause, and its symptoms
include continuous or intermittent abdominal pain and pain intensifying after a
meal. Manifestations of pancreatic enzyme deficiency include steatorrhea and/or
malabsorption. Chronic pancreatic cysts causes pancreatic cysts, lesions
containing pancreatic juice, necrotic debris, and blood.
Chronic exposure to alcoholic will cause
induce the onset of gastritis and peptic ulcers, and will cause
proliferation of rectal cells in rats.
The mechanism by which alcohol induces
cancers of the tongue, mouth, esophagus, throat, larynx and liver are unknown,
but are presumed to involve the liver's inability to rid the body of
carcinogens, possible immune suppression, and interference with cell-membrane
permeability in breast tissue. There is a clear synergistic effect with tobacco
in inducing cancer.
Alcohol consumption causes a depletion of
certain minerals and vitamins. For example, potassium stores are depleted (=
hypokalemia). This alone may lead to renal damage, cardiac dysrhythmias, and
skeletal muscle weakness. In fact, chronic alcohol use is suggested as the most
common cause of vitamin and trace element deficiencies in adults.
The Muscular System
The most common cause of toxic myopathies is
alcohol abuse. Acute symptoms include muscle weakness, pain, and swelling after
a binge. The incidence of acute alcoholic myopathy has been estimated as up to
20% of individuals with acute alcoholic withdrawal. It involves necrosis of
individual muscle fibers in which isolated, damaged fibers may be found next to
undamaged ones. There is a patchy loss of oxidative enzymes in type I fibers,
and electron microscopy shows marked accumulation of intracellular fluid and
destruction of mitochondria. Myoglobinuria and renal failure are also possible.
Alcoholic cirrhosis and
liver transplant surgery
Alcohol-induced
Liver Disease (ALD) is a major cause of
illness and death in the U.S. Fatty liver, its most common form, is manifested
by: 1) Deposition of fat; 2) Enlargement of the liver; 3) Decreased
triglyceride use; 4) Problems with apoprotein and lipoprotein use; 5)Damage to
endoplasmic reticulum by free radicals; 6) Interruption of microtubules -
transport of protein and then secretion; 7) Increase in intracellular water; 8)
Depression of fatty acid oxidation in mitochondria; 9) Increased membrane
rigidity; and 10) Acute liver cell necrosis.
Deaths from ALD have increased in past
decade. Its incidence highest among middle-aged men, and is most prevalent
among non-whites. The amount and duration of alcohol consumption is related to
the extent of liver damage.
More serious forms of ALD includes two
potentially fatal conditions: 1) Alcoholic hepatitis, characterized by
persistent inflammation of the liver; and 2) Cirrhosis, characterized by progressive scarring of tissue,
accounts for 75% of deaths attributed to alcoholism.
The prevalence of ALD is quite high among
heavy drinkers. Approximately 10-35% of heavy drinkers develop alcoholic
hepatitis, and an additional 10-20% develop cirrhosis. Cirrhosis is the 7th
leading cause of deaths among young and middle aged adults. Between 10,000 to
24,000 deaths from cirrhosis per year are attributable to alcohol consumption.
ALD is caused by long-term exposure to the
breakdown products of alcohol metabolism. Most alcohol is broken down by the
liver to acetaldehyde, which is more toxic than ethanol. Furthermore, free
radicals are formed during the breakdown of ethanol, which promotes
inflammation, impairing vital functions such as energy production. Typically,
the inflammatory response is supposed to generate some free radicals to destroy
disease-causing microorganisms. Long-term alcohol consumption prolongs the
inflammatory process, leading to excessive production of free radicals, which
can destroy healthy tissue. Furthermore, the body’s natural defenses against
free radicals (e.g. anti-oxidants) can be inhibited by alcohol consumption,
leading to increased liver damage.
Bacteria which live in human intestine play a
key role in initiating ALD. These bacteria secrete endotoxin in response to
alcohol consumption. This endotoxin enters the bloodstream, and it activates
Kupffer cells in the liver to secrete cytokines that regulate inflammatory
response. Typically, cytokines are produced by cells of the liver and immune
system in response to infection or cell damage. However, alcohol consumption
increases cytokine levels. Recent studies implicate cytokines in scar formation
and in depletion of oxygen in liver cells. Death of liver cells leads to
vicious cycle.
Scar formation is part of the wound-healing process. Alcohol-induced
cell death and inflammation can result in scarring that distorts the liver’s
internal structure and impairs its function. Stellate cells of liver
proliferate and lose vitamin A stores and begin to form scar tissue. Stellate
cells also constrict blood vessels , impeding the deliver of oxygen to liver
cells. Acetaldehyde may activate stellate cells directly, promoting scarring in
absence of inflammation.
Several factors have been found to influence
vulnerability to ALD. First, there is clearly a genetic component. Genetic
differences in alcohol dehydrogenases have been identified. Chronic alcoholics
develop levels of tolerance because of enzyme induction, especially of P450.
The risk of developing alcoholism among individuals with one affected parent is
3 to 5 times higher than those with unaffected parent. Concordance rates for
dizygotic twins are < 30%, whereas rates for monozygotic twins are greater
than 60%.
There is also a dietary component. High-fat,
low-carbohydrate diets promote liver damage in alcohol-fed rats.
Finally, there is a gender component. Females
develop ALD faster and with less alcohol. Females also have a higher rate of
alcoholic hepatitis and a higher mortality rate from cirrhosis than men.
Abstinence is the cornerstone of treatment.
Fatty liver and alcoholic hepatitis are reversible with abstinence. Other
strategies include suppressing the release of endotoxin, inactivating key
cytokines, and providing a diet with polyunsaturated lecithin and an adequate
supply of carbohydates.
Alcoholic hepatitis is the precursor of
cirrhosis, and is characterized by inflammation, degeneration, necrosis of
hepatocytes, and infiltration of polymorphonuclear leukocytes and lymphocytes
into liver tissue. Injured hepatocytes have "Mallory bodies",
indicate onset of fibrosis.
The mechanism of hepatocyte injury probably
is immunological. Serum IgA is often elevated in alcoholic hepatitis. Liver
antigen and antibody have been identified in progressive ALD, and inflammation
and necrosis caused by alcoholic hepatitis stimulate the fibrosis
characteristic of the cirrhotic stage of the disease.
Cellular damage initiates an inflammatory
response. Inflammation and necrosis result in excessive collagen formation.
Fibrosis and scarring alter the structure of the liver and obstruct biliary and
vascular channels.
Initially, fatty infiltration causes no
specific symptoms or abnormal liver function test results. However, the liver
will become enlarged, and anorexia, nausea, jaundice and edema develop with
advanced fatty infiltration. Clinical manifestations of alcoholic hepatitis can
be mild or severe. Nonspecific symptoms, such as fatigue, weight loss, and
anorexia can occur. Toxic effects can cause testicular atrophy, reduced libido,
azoospermia, and decreased testosterone in men. Acute illness includes nausea,
anorexia, fever, abdominal pain & jaundice.
Unfortunately, alcoholic cirrhosis is
irreversible. Alcoholic cirrhosis begins with fatty infiltration, which can
occur without subsequent hepatitis or cirrhosis. Cirrhosis is a multiple-system
disease, showing hepatomegaly, splenomegaly, ascites, gastrointestinal
hemorrhage, portal hypertension, hepatic encephalopathy, esophageal varices,
and anemia from anemia from blood loss, poor nutrition & hypersplenism. The
onset of cirrhosis can be accelerated by infection with the hepatitis C virus.
It is incurable, and may necessitate liver-transplant surgery. A visual tour of the procedure can be accessed via http://www.surgery.usc.edu/divisions/hep/patientguide/livertransplanttour.html .
References
Cited:
Alcohol
and the Liver: Research and Update" - Alcohol Alert #42, October 1998,
National Institute on Alcohol Abuse and Alcoholism
(From the
July 23, 2001 issue of In the News, a daily science digest from Sigma Xi):
SCIENTISTS LINK SMOKING, EARLY MENOPAUSE from The Boston Globe
Cigarette
smoking can cause female infertility by hastening menopause, researchers are to
announce today, a discovery that further lengthens the
list of ills
associated with smoking. Doctors had long believed that cigarettes can impede
childbearing, but Massachusetts General Hospital researchers say they have
established a direct connection between the chemicals in cigarette smoke and
the genetic signals that cause ovarian cells to die.The finding, which is to be
published online today by the journal Nature Genetics, also raises the
possibility that menopause could be delayed until later in life by blocking
those genetic signals. In addition to cigarette smoke, infertility-causing
chemicals are found in several environmental pollutants, including fossil fuel
emissions and certain types of industrial waste.
Fetal
Alcohol Syndrome
Fetal alcohol syndrome (FAS) is the collective term
to describe a set of features associated with infants exposed to alcohol while in
utero. Features of the syndrome include the following (Julien, 1998):
1. CNS dysfunction, including low intelligence,
microcephaly, mental retardation, and behavioral abnormalities;
2. Retarded body growth rate;
3. Facial abnormalities;
4. Other anatomical abnormalities such as congenital
heart defects and malformed eyes and ears.
Fetal alcohol syndrome occurs in 30-50% of
children born to alcoholic mothers. Recent research suggests that congenital
abnormalities will arise regardless of whether the mother drinks either
continuously or sporadically, as in binging (Elberger, 1999). Furthermore, the
syndrome of fetal alcohol syndrome may actually be a composite of synergistic
effects by alcohol and nicotine, since virtually all women who give birth to
babies with fetal alcohol syndrome have concurrent addictions to both alcohol
and nicotine (Matta, 1999).
The effects of paternal drinking on the fetus
are unknown.
References
Cited:
Elberger,
Dr. Andrea. 1999. Personal communication.
Julien,
R.M. 1998. A Primer of Drug Action, edition 8, W. H. Freeman.
Matta,
Dr. Shannon, 1999. Personal communication.
Treatment of alcoholics
& drug addicts
Alcoholism affects an estimated 7 million
Americans. Alcoholics show signs of malnutrition and chronic physiological
degeneration, including a bloated appearance, flabby muscles, fine tremors, and
increased susceptibility to disease. An estimated 30-50% of alcoholics meet
criteria for major depression, and 33% have coexisting anxiety disorder.
There are a number of drugs used to treat
acute and chronic alcoholism. Benzodiazepines are mainstays in treatment of
acute alcohol withdrawal syndromes. Disulfiram (Antabuse) inhibits breakdown of
alcohol, and thereby causes severe gastric distress when a person ingests
alcohol. Haldoperol and other antipsychotic agents are used to treat for
hallucinations.
Since alcoholics often have a coexisting
problem with depression, antidepressants such as selective serotonin reuptake
inhibitors (SSRI's), tricylics or imipramine sometimes help to reduce alcohol
use.
Naltrexone, a long-acting, orally
administered narcotic antagonist works over a 12-week period to reduce alcohol
craving and relapse.
The long-term treatment of alcoholism has
three goals:
1. Continued sobriety;
2. Amelioration of concurrent psychiatric conditions; and
3. Long-term prevention of relapse.
The prognosis is not good. Approximately 90%
of alcoholics undergoing treatment will experience a relapse within 4 years. Nonetheless,
long-term sobriety can be achieved by joining a 12-step recovery group. Modern
12-step recovery groups are based modeled after Alcoholics Anonymous, which
began in the mid-1930's. Alcoholics Anonymous presents the following as a
suggested program of recovery:
1. "We admitted we were powerless over alcohol-that
our lives had become unmanageable."
2. "Came to believe that a Power greater than
ourselves could restore us to sanity."
3. "Made a decision to turn our will and our lives
over to the care of God as we understood Him."
4. "Made a searching and fearless moral inventory of
ourselves."
5. "Admitted to God, to ourselves, and to another
human being the exact nature of our wrongs."
6. "Were entirely ready to have God remove all these
defects of character."
7. "Humbly asked Him to remove our
shortcomings."
8. "Made a list of all persons we had harmed, and
became willing to make amends to them all."
9. "Made direct amends to such people wherever
possible, except when to do so would injure them or others."
10. "Continued to take personal inventory and when we
were wrong promptly admitted it."
11. "Sought through prayer and meditation to improve
our conscious contact with God as we understood Him, praying only for
knowledge of His will for us and the power to carry that out."
12. "Having had a spiritual awakening as the result
of these steps, we tried to carry this message to alcoholics, and to practice
these principles in all our affairs.
The success of these groups is based on a
number of assumptions:
1. The affected individual recognizes that there is a problem;
2. The alcoholic/addict must remain abstinent to remain mentally healthy, i.e.
they cannot engage in "social" or "moderate" drinking.
(This contrasts to the British model of alcohol consumption, which recognizes
the possibility of non-addictive controlled drinking, even among
"heavy" drinkers);
3. The affected individual must make substantial changes in lifestyle and
attitude to maintain sobriety.
The twelve steps outlined above have been
modified, as needed, in the creation of the following support groups:
Adult Children of Alcoholics (ACA)
World Service Organization
http://www.adultchildren.org/
e-mail: info@AdultChildren.org
P.O. Box 3216
Torrance, CA 90510
1-310-534-1815
Al-Anon/Alateen
Family Group Headquarters
http://www.al-anon.org/
1600 Corporate Landing Parkway
Virginia Beach, VA 23454-5617
1-888-4AL-ANON
Alcoholics Anonymous
General Service Office
http://www.alcoholics-anonymous.org/
475 Riverside Drive
New York, NY 10015
1-212-870-3400
FAX: 1-212-870-3003
Cocaine Anonymous
World Service Organization
http://www.ca.org/
Public Info requests: pubinfo@ca.org
P.O. Box 2000
Los Angeles, CA 90049-8000
1-310-559-5833
FAX: 1-310-559-2554
Gamblers Anonymous
International Service Office
http://www.gamblersanonymous.org/
e-mail: isomain@gamblersanonymous.org
P.O. Box 17173
Los Angeles, CA 90017
1-213-386-8789
FAX: 1-213-386-0030
Marijuana Anonymous
World Services Office
http://www.marijuana-anonymous.org/
e-mail: MAWS98@aol.com
P.O. Box 2912
Van Nuys, CA 91404
1-800-766-6779
Narcotics Anonymous
World Service Office
http://www.na.org/
e-mail: info@na.org
P.O. Box 9999
Van Nuys, CA 91409
1-818-773-9999
FAX: 1-818-700-0700
Nicotine Anonymous
http://www.nicotine-anonymous.org/
e-mail: Info@nicotine-anonymous.org
P.O. Box 591777
San Francisco, CA 94159-1777
1-415-750-0328
Overeaters Anonymous
World Service Office
http://www.overeatersanonymous.org/
e-mail: overeatr@technet.nm.org
6075 Zenith Ct, NE
Rio Rancho, NM 87124
1-505-891-2664
FAX: 1-505-891-4320
Sex Addicts Anonymous
http://www.sexaa.org/
e-mail: info@saa-recovery.org
ISO of SAA
P.O. Box 70949
Houston, Texas 77270
1-800-477-8191
How
the Twelve Steps have been adapted to a variety of self-help groups
|
Step # |
Alcoholics Anonymous |
Narcotics Anonymous |
Al-anon |
|
1 |
We admitted we were powerless over alcohol - that our lives had become unmanageable. |
We admitted that we were powerless over our addiction, that our lives had become unmanageable. |
We admitted we were powerless over alcohol - that our lives had become unmanageable. |
|
2 |
Came to believe that a Power greater than ourselves could restore us to sanity. |
We came to believe that a Power greater than ourselves could restore us to sanity. |
Came to believe that a Power greater than ourselves could restore us to sanity. |
|
3 |
Made a decision to turn our will and our lives over to the care of God as we understood Him. |
We made a decision to turn our will and our lives over to the care of God as we understood Him. |
Made a decision to turn our will and our lives over to the care of God as we understood Him. |
|
4 |
Made a searching and fearless moral inventory of ourselves. |
We made a searching and fearless moral inventory of ourselves. |
Made a searching and fearless moral inventory of ourselves. |
|
5 |
Admitted to God, to ourselves and to another human being the exact nature of our wrongs. |
We admitted to God, to ourselves, and to another human being the exact nature of our wrongs. |
Admitted to God, to ourselves and to another human being the exact nature of our wrongs. |
|
6 |
Were entirely ready to have God remove all these defects of character. |
We were entirely ready to have God remove all these defects of character. |
Were entirely ready to have God remove all these defects of character. |
|
7 |
Humbly asked Him to remove our shortcomings. |
We humbly asked Him to remove our shortcomings. |
Humbly asked Him to remove our shortcomings. |
|
8 |
Made a list of all persons we had harmed, and became willing to make amends to them all. |
We made a list of all persons we had harmed, and became willing to make amends to them all. |
Made a list of all persons we had harmed, and became willing to make amends to them all. |
|
9 |
Made direct amends to such people wherever possible, except when to do so would injure them or others. |
We made direct amends to such people wherever possible, except when to do so would injure them or others. |
Made direct amends to such people wherever possible, except when to do so would injure them or others. |
|
10 |
Continued to take personal inventory and when we were wrong promptly admitted it. |
We continued to take personal inventory and when we were wrong promptly admitted it. |
Continued to take personal inventory and when we were wrong promptly admitted it. |
|
11 |
Sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out. |
We sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out. |
Sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out. |
|
12 |
Having had a spiritual awakening as the result of these steps, we tried to carry this message to alcoholics and to practice these principles in all our affairs. |
Having had a spiritual awakening as a result of these steps, we tried to carry this message to addicts, and to practice these principles in all our affairs. |
Having had a spiritual awakening as the result of these Steps, we tried to carry this message to others, and to practice these principles in all our affairs. |
Acupuncture as a detox
treatment modality
In recent years, acupuncture has been used as
an integrated part of detoxification programs. Considering the fact that 80% of
all crimes in the Memphis, Tennessee area are drug related, there is a
considerable interest in the applications of acupuncture (Dr. Judi Herrick,
4/9/99, personal communication.)
Acupuncture can eliminate withdrawal
symptoms, and is always used as an adjunct component of drug treatment. It
helps to treat physical manifestations, and requires only a daily
administration for 45 minutes/day, 5 needles in ear.
The success of acupuncture as a treatment
modality is based on the concept of "Chi". In Oriental medicine, Chi
= life force. It is allotted at birth, and is gone when you die. There are two
forms of Chi, including Ancestral Chi, which is genetically-based and given at
birth, and Jing, which is the energy of growth. The essential life energy of
Chi circulates throughout body on a 24-hour cycle through 12 basic & 2
central channels. Drugs burn up the liver, which is a source of shen, and leads
to anger.
It is assumed that the ear reflects entire
body. The ear is in the shape of an upside-down human being, and has 150
points, corresponding to each of the points in the body. Applying pressure onto
selected points with acupuncture needles elicits an effect which restores the
proper balance of energy. The specific points which are stimulated by ear
needles include the following:
1. Sympathetic (heals physical manifestations of
withdrawal)
2. Shen men (calms emotional anxiety)
3. Kidney (and next two are filtering organs of body.)
4. Liver
5. Lung
As a group, addicts have a terrible imbalance
of energy, and are yin-deficient. (Yin is dark, female, internal earth,
sustenance, and nurturing. Its complement, Yong, is the energy of movement,
male, active, hot, protective, heaven.)
Some recovery programs add Tai Chi and yoga.
Minicourse 6:
Principles of Genetics
Clearly, alcoholism runs in families. We know
from twin studies that if one sibling is an alcoholic, the likelihood of the
other sibling being an alcoholic is increased by 70%. Furthermore, adopted
children whose biological parents were alcoholic tend to have a higher
likelihood of becoming alcoholics, even if they are raised by non-alcoholic
adoptive parents. Therefore, alcoholism (and drug abuse) may have a genetic
component. In this section, we will study the general principles of genetics, and in the following section, we will look at how
those general principles are applied to the possible transmission of genes
associated with alcoholism.
In 1866, Gregor Mendel
presented a series of basic laws to explain the transmission of morphological
traits among pea plants:
1. Hereditary traits are controlled by discreet factors. The biologists of his time assumed that traits were
controlled by "vital fluids", which circulated throughout the body of
the organisms. When those vital fluids were mixed, the resulting offspring
would have traits which were intermediate from the parents. The proof presented
by these biologists would be point out that if the pollen from a red flower
were to be transferred to the pistil of a white flower, all the offspring would
appear pink. With the color traits which Mendel examined, one trait would be
masked in the first generation of offspring, but the trait would reappear among
the second generation of offspring in a definite predictable ratio. Mendel did
not know the composition of these discreet factors, nor did he know where they
were located;
2. Each trait is controlled by two factors;
3. When two contrasting factors are present only one will
be expressed. The expressed factor is
dominant and the other recessive;
4. Each parent contributes only one of the two hereditary
traits to each gamete;
5. When gametes unite, the two hereditary factors are
brought together;
6. The factors of different traits are segregated
independently.
Over the next century, research provided
refinements to each of these laws:
1. Hereditary traits are controlled by discreet factors. We now recognize the hereditary factors as genes,
sequences of DNA which code for a specific protein. Alternative forms of a gene
are called alleles, and they are located on chromosomes.
Genes occupy a specific position, or locus, on homologous, or matching,
chromosomes. The particular set of genes an organism has which controls a
specific trait is called the genotype, while the visible expression of a
genotype is defined as the phenotype. Individuals whose alleles for a gene are
identical are homozygous for that gene, while individuals whose alleles for a
gene are different are heterozygous for that gene.
2. Each trait is controlled by two factors. Most human traits are polygenic, i.e. they are
controlled by more than one pair of genes. Another exception to this law is the
phenomenon of sex-linked traits, i.e. traits whose genes are located on the X-
or Y- chromosome. The karyotype of a normal female is XX, while that of
a normal male is XY. If a gene is located on the Y-chromosome, females will not
show that trait at all. If a gene is located on the X-chromosome, its phenotype
will be expressed in males, because males have only one X-chromosome. Among
females, a recessive trait will be expressed only if she is homozygous for it.
3. When two contrasting factors are present only one will
be expressed. Unlike the traits
examined by Mendel, the alleles of some traits really are codominant. In other
words, the heterozygote will show a phenotype which is intermediate to its
parents. (This will explain the generation of pink flowers from red and white
ones.)
4. Each parent contributes only one of the two hereditary
traits to each gamete. The
development of the electron microscope provided insight into the phenomenon of
cytoplasmic inheritance. Usually we associate DNA or chromosomes with the
nucleus, but mitochondria and chloroplasts have their own DNA which codes for
proteins which are required by that organelle. Mitochondrial DNA from maternal
and paternal lines may code for slightly different proteins. Since the volume
of the human egg is far greater than the volume of the sperm, the vast majority
of mitochondria in the zygote will be derived from the egg. Therefore,
cytoplasmic inheritance follows the maternal line.
5. When gametes unite, the two hereditary factors are
brought together. Years after Gregor
Mendel published his work, Rudolf Virchow observed the fusion of a sperm
nucleus with an egg nucleus. Virchow then proposed that the chromosomes he was
watching behaved exactly like the hereditary factors discussed by Mendel. If
that were so, then Virchow reasoned that these hereditary factors could be
located on the chromosomes. (GASP! WHAT AN IDEA!!);
6. The factors of different traits are segregated
independently. We now know that the
human genome contains between 70,000 to 100,000 genes. We also know that humans
have only 46 chromosomes, so it is reasonable to assume that genes will be
linked onto specific chromosomes. Genetic variability is still possible by genetic
recombination, in which pieces of homologous chromatids are exchanged
during meiosis, the
cellular process by which gametes are produced.
By the 1950's, most biologists were convinced
that DNA was the
genetic material, but the structure of DNA was still unknown. However, Rosalind Franklin studied the
X-ray crystallography of DNA, and produced a photo which suggested that
the DNA molecule had a helical structure. That photo provided James Watson and Francis Crick with vital information as to how to construct a model
of the DNA molecule.
We know now that DNA is a
double-stranded polymer of nucleotides. Each nucleotide consists of a nitrogenous
base, the sugar deoxyribose, and a phosphate group. There are four nitrogenous
bases, including adenine (A), thymine (T), guanine (G), and cytosine (C). The
strands are anti-parallel, so that facing each adenine on one strand is a
thymine, and facing each guanine is a cytosine. The two strands are held
together by hydrogen bonds, weak attractive forces between a
positively-charged hydrogen atom on one molecule and a negatively-charged atom
(usually either oxygen or nitrogen) on the other. There are two hydrogen bonds
between each adenine-thymine pair, and three hydrogen bonds between
guanine-cytosine pair.
Watson and Crick recognized that the sequence
of nitrogenous bases on the DNA molecule coded for the type of protein which could
be produced, and that this was the molecular basis for Mendel's discreet
factor.
The connection between DNA and the proteins
which a cell can produce began to be elucidated in 1961 with an experiment
conducted by Marshall Nurenberg. By 1964, the entire genetic code was deciphered.
Each triplet (or codon) of bases codes for a specific amino acid to be added at
the corresponding position along a growing protein chain. The process by which
a protein is constructed according the instructions inherent in the sequence of
bases is called translation.
All proteins are produced in this manner.
The existence of a genetic component in
alcoholism is supported by a number of studies, including the following:
1. Pickens et al. (1991) studied 169 same-sex
pairs of twins, both males and females, at least one of which had sought
treatment for alcoholism. They found a higher concordance of alcohol dependence
in identical twins, whose genome is identical, than in fraternal twins, who
share 50% of their genome. They also found higher concordance in identical male
twins, but not female twins;
2. Partanen et al. (1966), in studying 902 male
Finnish twins, found that less severe drinking patterns were less heritable,
while more severe drinking patterns were more heritable;
3. Children of alcoholics who are adopted by
non-alcoholics and grow up in a non-drinking environment have a higher
likelihood of developing alcoholism as an adult that children of non-alcoholics
who are adopted by non-alcoholics (Cloninger, 1981; Bohman, 1981);
4. Individuals who show a relatively low sensitivity to
alcohol are more likely to develop alcoholism as adults (Schuckit, 1995).
Low-level response to alcohol is 4 times more common in sons of alcoholics than
in control subjects, and this may have diagnostic value (Li, in
Begleiter, H. et. al., 1995);
5. Certain individuals who are alcoholic or who are at
risk demonstrate a reduced P300 response, an event-related potential that
occurs about 300 milliseconds after a stimulus. Typically, the height of the
wave (amplitude) of this response is related to the significance of the
stimulus. This reduction was first assumed to be associated with the toxic
effects of alcohol. However, a reduction in amplitude of the P300 response has
been found among the following populations: 1) Abstinent alcoholics; 2) Sons of
alcoholic fathers, even before alcoholic exposure, 3) Persons who have multiple
alcoholic first-degree relatives (Porjesz and Begleiter, in Begleiter,
H. et. al., 1995). It has been theorized that persons with low P300
amplitude have difficulty distinguishing significant from insignificant
stimuli.
Two types of alcoholism are now recognized.
Type I usually develops after the age of 25, and occurs in males and females.
It is marked by frequent psychological dependence, as well as guilt and fear of
alcohol dependence. Type II is before age 25, and is generally limited to
males. It is frequently marked by spontaneous alcohol-seeking and aggressive
behavior (e.g. fighting and arrests). Type II has a greater genetic component.
What is being inherited? It may be a mix of
personality traits, such as those related to antisocial behavior, rather than
alcoholism itself (Schuckit, 1987). Genes might play a direct role in the
development of alcoholism, as in affecting the body's metabolism of ethanol, or
they may play an indirect role, influencing a person's temperament or
personality in such a way that the person becomes vulnerable to alcoholism.
In the late 1980's, the Human Genome Project was initiated. The goal of the Human Genome Project is to sequence the
entire human genome, an estimated 3 billion base pairs. The project is
international in scope, and should be completed by the year 2003. By being able
to identify and map the genes responsible for genetic diseases, clinicians will
also be able to diagnose, treat, and perhaps even prevent these diseases.
On the basis of research conducted on a
population of southwest American Indians, genes implicated in neurotransmission
and alcoholism have been found on the short arm of chromosome 11 (Long and
Goldman, in NIH News Release, 1998a). The specific genes found in that
area include the DRD4 dopamine receptor gene, which has been associated with
novelty-seeking in Israelis and Euroamericans, the tyrosine hydroxylase gene,
involved in dopamine biosynthesis, and the tryptophan hydroxylase gene, which
is involved in serotonin biosynthesis.
Genes associated with the P300 anomaly found
among alcoholics and individuals who are at risk have been found on chromosomes
2, 5, 6, and 13 (Begleiter and Porjesz, in NIH News Release 1998b).
References cited:
Blum,
K.; Noble, E.P.; Sheridan, P.J.; Montgomery, A.; Ritchie, J.; Jagadeeswaran,
P., Nogami, H.; Briggs, A.H.; and Cohn J.B. (1995). Allelic association of
human dopamine D2 receptor gene in alcoholism. Journal of the American Medical
Association 263(15): 2055-2060.
Li,
T-K. in Begleiter, H.; Reich, T.; Hesselbrock, V.; Porjesz, B.; Li, T-K;
Schuckit, M.; Edenberg, H.; and Rice, J. (1995). The Collaborative Study on the
Genetics of Alcoholism. Alcohol Health and Research World 19(3): 228-226.
Partanen,
J.; Bruun, L.; and Markkanen, T. (1966). Inheritance of Drinking Behavior.
Pickens,
R.W.; Svikis, D.S.; McGue, M.; Lykken, D.T.; Heston, L.L.; & Clayton, P.J.
(1991). Heterogeneity in the inheritance of alcoholism. Archives of General
Psychiatry 48: 19-28.
Porjesz,
B. and Begleiter, H. in Begleiter, H.; Reich, T.; Hesselbrock, V.;
Porjesz, B.; Li, T-K; Schuckit, M.; Edenberg, H.; and Rice, J. (1995). The
Collaborative Study on the Genetics of Alcoholism. Alcohol Health and Research
World 19(3): 228-226.
Schuckit,
M.A. (1987). Biological vulnerability to alcoholism. Journal of Consulting and
Clinical Psychology 55(3): 301-309.
Schuckit,
M.A. (1995). A Long-term study of sons of alcoholics. Alcohol Health and
Research World 19(3): 172-175.
From Test Tube to
Pharmacy Shelf: Regulation of Drug Development
The federal government is engaged in drug regulation
in order to protect the public and to apply standards of efficacy and safety.
Before a drug is approved for use by the public, it must undergo several stages
of development:
Before a drug is approved for public use, it
must undergo a series of tests. In vitro and in vivo
pharmacological effects form the rationale for considering a drug. Animal
studies set the stage for clinical trials. The reason they are used is that
they may serve as models of human disease. The success of the model depends on how
closely the pathophysiology in the animal model mimics that in humans. Animals
can be used to investigate the relationship between drug dose and plasma
concentration to beneficial and toxic effects. Furthermore, they can be used to
screen for carcinogenic and teratogenic effects.
Human testing of drugs then progresses
through a series of clinical trials. Phase I trials are usually single-blind,
i.e. the health professionals know what is being administered to the patients,
but the patients receiving the treatment do not know. The purpose of Phase I
testing is to determine the maximum tolerated dose. All further dosing is done
at concentrations less than the maximum determined with Phase I. Traditionally,
healthy subjects were used. (For example, male prisoners were the first people
to take female birth control pills.) More recently, patients for whom the
treatment is intended are being used more frequently.
Phase II trials begin after the
tolerated drug range has been defined. IT is done to gather evidence that the
drug has the effects which were suggested in preclinical animal trials. Tests
are done to define the pharmacokinetics of a drug and to relate plasma
concentrations to observed effects. Phase II trials may be simple, or
double-blind, parallel or cross-over.
Phase III trials consist of definite clinical
trials that establish the efficacy and safety of the new drug. Whenever
possible, trials are double-blind, randomized and controlled. They are almost
always parallel in design.
Drug regulation and approval proceed by
several steps. In the
1. Data that support approval;
2. Pharmacological actions of drug
3. Indication (approved use) of the drug;
4. A description of adverse effects;
5. Instructions on dosing.
Drug development is a lengthy process. The
time taken from submitting an application for approval to receiving a decision
can take from 6 months to many years, although 1-2 years is typical. Therefore,
the process of drug development, drug discovery to approval, takes from 6 to
more than 10 years.
The Drug Enforcement Administration (DEA)
administers the regulations and governs the export of narcotic and non-narcotic
substances. Controlled substances are listed in a series of schedules, as
described below:
.
Schedules of controlled substances
The Controlled Substances Act of 1996 empowers the Drug Enforcement Administration (DEA) to
administer the regulations and to govern the export of narcotic and non-narcotic
substances. Controlled substances are divided into 5 schedules, depending on
their therapeutic application and on their abuse potential. These schedules
include the following:
Substance I
Substances
Drugs in this schedule are those that have no
accepted medical use in the
Substance II Substances
Drugs in this schedule have a high abuse
potential with severe psychic or physical dependence liability. Schedule II
controlled substances consist of certain narcotic drugs, and drugs containing
amphetamines or methamphetamines as the single active ingredient, or in
combination with each other. Examples of Schedule II controlled substances are:
opium, morphine, codeine hydromorphone (Dilaudid), methadone (Dolophine),
Meperdine (Demerol), Cocaine, Oxycodone (Percodan), and straight Amphetamines
and Methamphetamines. Also in Schedule II are Methylphenidate (Ritalin),
Amobarbital, Pentobarbital, Secobarbital, Phencyclidine, and Methaqualone.
Schedule III
Substances
These drugs have an abuse potential less than
those in Schedules I and II, and include compounds containing limited
quantities of certain narcotic drugs, and non-narcotic drugs such as:
derivatives of barbituric acid except those that are listed in another
Schedule, such as Glutethimide (Doriden), Methyprylon (Noludar),
Sulfondiethylmethane, Sulfonmenthane, Nalorphine, Benzphetamine, Mazindol, and
Paregoric.
Schedule IV
Substances
The drugs in this schedule have an abuse
potential less than those listed in Schedule III and include such drugs as:
Barbital, Phenobarbital, Methylphenobarbital, Chloral Betaine (Beta Chlor),
Chloral Hydrate, Ethchlorvynol (Placidyl), Ethinamate (Valmid), Meprobamate
(Equanil, Miltown), Paraldehyde, Pentaerythritol Chloral (Petrichloral),
Fenfluramine, Diethylpropion, and Phentermine.
Schedule V
Substances
The drugs in this schedule have an abuse
potential less than those listed in Schedule IV and consist of preparations
containing moderate, limited quantities of certain narcotic drugs generally for
antitussive and antidiarrheal purposes, which may be distributed without a
prescription order.
Inhalants
are found a variety of common household products, including the following:
A. ADHESIVES, such as toluene, ethyl acetate, hexane,
toluene, methyl chloride, acetone, methyl ethyl ketone, methyl butyl ketone;
B. AEROSOLS (as found in spray paint, hair spray,
deodorant, analgesic spray, asthma spray) such as butane, flurocarbons,
propane;
C. CLEANING AGENTS (as used in dry cleaning, spot remover,
degreaser) such as tetrachloroethylene, trichloroethane, xylene,
chlorohydrocarbons;
D. SOLVENTS AND GASES (e.g. nail polish remover, paint
thinner, correction fluid, fuel gas, lighter fluid) such as acetone, ethyl
acetate, toluene, methyl chloride, methanol, ethyl acetate, butane, isopropane
E. WHIPPED CREAM propellant nitrous oxide)
F. "ROOM ODORIZERS" (e.g. Locker Room, Rush,
popper) include isoamyl, isobutyl, isopropyl, or butyl nitrate, cyclohexyl.
ANESTHETICS, such as nitrous oxide,
halothane, enflurane, and ethyl chloride are sometimes abused by health
professionals.
Three age groups predominate in the users of
inhalants: 1) Young males between 14 and 20; 2) Inhalant-dependent adults; and
3) Multidrug users. Current use is highest among eighth graders, and nearly 20%
of all adolescents report using inhalants at least once in their lives. Ninety
percent (90%) of inhalant deaths occur in males.
All inhalants have a rapid onset of
intoxication which resembles alcohol. The progression of sedation includes anxiolysis,
disinhibition, drowsiness, light headedness, and euphoria. This progresses to
ataxia, dizziness, delirium and disorientation. Severe intoxication leads to
muscle weakness, lethargy and anesthesia. Hypoxia leads to hallucinations and
behavior changes.
Induction of tolerance and physical
dependence are possible, resulting in withdrawal symptoms. Withdrawal symptoms
can include hallucinations, headaches, chills, delirium tremors, and stomach
cramps. Death follows from brain anoxia, cardiac arrhythmia, aspiration of
vomitus, and trauma. Fatal consequences, as described above, can occur with
first use.
Chronic abuse of solvents leads to serious
symptoms:
1. Partially reversible dysfunction of the peripheral and
central NS
2. Liver and/or kidney failure
3. Severe toxicity to fetus among pregnant female users.
General anesthetics can be administered by
inhalation or injection. They induce a generalized, gradual, dose-related
depression of all CNS functions. Their mode of action still not known, but
injectable forms act as GABAA receptor facilitators and glutamate
receptor inhibitors.
The central nervous system (CNS) is exquisitely
sensitive to nonselective depressant effects of barbiturates, nonbarbiturate
sedative-hypnotics, ethyl alcohol & general anesthetics. At low doses,
polysynaptic, diffuse brain stem pathways are first to be suppressed. Brain
stem depression continues with increasing dosage and accounts for deep coma
& death, and involves both suppression of excitatory synapses and facilitation
of inhibitory synapses. NMDA component of glutamate protein - receptor complex
is inhibited. Then, GABAA receptors respond to barbiturates by
becoming easier to open and remaining open longer. Chloride ions move in,
causing hyperactivity. Barbiturates do not bind to the same GABAA
receptor as benzodiazepines.
Barbiturates act as sedative-hypnotics,
i.e., they exert a nonselective general suppressant action on the NS. They have
similar effects, including diminishing environmental awareness, reducing
response to sensory stimulation, depressing cognitive function, decreasing
spontaneity, and reducing physical activity. Higher doses produce increasing
drowsiness, lethargy, amnesia, antiepileptic effects, hypnosis, anesthesia.
Depressant effects are supra-additive, can lead to fatal overdose.
All barbiturates carry the risk of inducing
physiological dependence, psychological dependence, tolerance, cross-tolerance,
and cross-dependence.
The use of barbiturates has declined over
recent years because of its side effects -- lack of selective CNS action,
narrow therapeutic-to-toxic range, high potential for inducing dependence and
abuse, and dangerous interactions with many other drugs. Nonetheless,
barbiturates are still used as anticonvulsants and intravenous anesthetics.
They are also used to protect the brain after severe head injury.
Barbiturates have no significant effects on
the GI tract, cardiovascular system, kidneys or other organs. Sedative doses
have minimal effects on respiration, but overdoses or combinations can be
lethal.
Adverse reactions include disruption in REM
sleep, drowsiness, tolerance, physical dependence, and sleep deprivation. Its
effects in pregnancy include possible congenital deformities and physical
dependence of the newborn.
By altering the residue groups attached to
barbiturate molecules, the half-life can be adjusted from minutes to days.
Benzodiazepines
and "Second Generation" Anxiolytics
Anxiety can be described as apprehension,
tension or uneasiness to anticipated danger. It may be a response to external
stimuli, or it may not have precipitating stimuli. It is a complex of
subjective feelings, including tension, fear, worry and helplessness, and may
manifest in a variety of behavioral or physiological signs.
A number of anxiety disorders are described
in the DSM-IV:
1. Panic disorder (with or without agoraphobia)
2. Specific phobia
3. Social phobia
4. Obsessive-compulsive disorder (OCD)
5. Post-traumatic stress disorder (PTSD)
6. Acute stress disorder
7. Generalized anxiety disorder
8. Anxiety due to medical condition, e.g.
hyperthyroidism, Cushing's Disease, coronary heart disease
9. Substance-induced anxiety disorder, e.g. cocaine,
caffeine, asthma medications, nasal decongestants, withdrawal from alcohol or
sedatives
Anxiety disorders are common in our culture,
with 55 million prescriptions for anxiolytics prescribed yearly. Treatment
differs according to the type of anxiety disorder.
Obsessive-compulsive disorder (OCD) responds
to serotonin-selective reuptake inhibitors (SSRI's), tricyclics, or monoamine
oxidase inhibitors (MAOI), while post-traumatic stress syndrome (PTSD) responds
to antidepressants, carbamazine or lithium. Delusions and/or hallucinations may
respond to antipsychotics. For children with attention deficit disorder (ADD),
antidepressants or stimulants are prescribed.
Benzodiazepines are the drugs of choice for
short-term pharmacological treatment of stress-related anxiety and insomnia.
They are easy to use, effective, and they have relatively low toxicity. Their
usage is limited to 1-6 weeks because of adverse effects and potential
dependency. Because of this limited period of time, they are used for
situational grief, acute incapacitating stress reactions, and insomnia for
short-lived external events.
Benzodiazepines are NOT used for chronic
anxiety disorders, endogenous depression, or situations requiring fine motor,
cognitive skills, or mental alertness. They are not prescribed to the elderly
or to children because of sluggish metabolism.
The target of action for benzodiazepines is
the GABAA receptor. Whether they are used as sedatives, hypnotics,
anxiolytics, muscle relaxants, amnestics, or anticonvulsants, binding of the
benzodiazepine molecule to a GABAA receptor facilitates the binding
of the neurotransmitter GABA to its receptor. This, in turn, opens chloride
gates. The influx of chloride ions hyperpolarizes the postsynaptic neuron. Low
doses alleviate anxiety, agitation and fear by their action on the amygdala.
Mental confusion and amnesia result due to effects on the cerebral cortex and
cerebrum. Muscle relaxant effects are caused by the action of benzodiazepines
on the spinal cord, cerebellum and brain stem, while anti-epiletic effects
follow from actions on GABA receptors in the cerebellum and hippocampus. The
behavioral rewarding effects and abuse of these drugs probably result from
actions on GABA receptors that modulate the discharge of neurons located in the
ventral tegmentum and nucleus accumbens.
Even therapeutic doses can be addicting.
Cessation of use produces a rebound effect, marked by insomnia, restlessness,
agitation, irritability and unpleasant dreams. People who abuse benzodiazepines
tend to have preexisting drug problems. Finally, unborn fetuses can develop
dependence.
Flumazenil is a benzodiazepine agonist,
displacing benzodiazepine from receptors.
In recent years, Zopidem (Ambien) and
Buspirone (Buspar) have been developed as anxiolytics which do not have the
unpleasant side effects that benzodiazepines do. Like benzodiazepines, Zopidem
binds to GABAA receptors, but does not show all the actions of
benzodiazepine agonists. It is used for short-term insomnia, and should be part
of a treatment package, including biofeedback therapy, stimulus control, sleep
restriction, and good sleep hygiene. The metabolic half-life is short, so
morning drowsiness is not a problem. Zopidem can induce drowsiness, dizziness,
and nausea.
Buspirone (Buspar) is an anxiolytic with
unusual properties. It produces no significant sedation or drowsiness, and it
induces minimal amnesia or mental confusion. It does not depress the CNS like
alcohol does, nor does it show cross-tolerance or cross-dependence with
benzodiazepines. Its mode of action is different than that of benzodiazepines
-- it does not bind to GABA receptors. Instead, Buspirone binds selectively to
a subgroup of serotonin receptors, called 1-A. After binding, buspirone acts as
a weak agonist for serotonin. Receptor binding is confined to areas of the
brain involved in mechanisms of anxiety, especially the hippocampus.
Cocaine and
amphetamines are powerful psychostimulants which augment synaptic action of
catecholamine, dopamine, and to a lesser extent, NE neurotransmitters. They have
a direct action on the nucleus accumbens, and they have similar behavioral
consequences. Both will elevate mood, induce euphoria, increase alertness,
reduce fatigue, decrease appetite, improve task performance, relieve boredom.
Anxiety, insomnia and irritability are common side effects. Higher doses result
in more intense irritability, anxiety, and psychotic behavior.
Low-dose responses are similar to those
described in the "fight-or-flight" syndrome, which is characterized
by an increase in blood pressure, increase in pulse, dilation of pupils,
reallocation of blood flow, and an increase in both O2 & glucose
levels in blood. All this mimics and overwhelms the natural release of
biological amines, e.g. adrenalin, as part of normal alerting or activity response.
The source of cocaine is Erythroxylon
coca, a tree native to
Addicts are typically young, (12-31 years of
age), dependent on 3 or more drugs, and male. All tend to have coexisting psychopathology.
Cocaine use is associated with violent, premature deaths.
Leaves of E. coca contain .5 to 1%
cocaine. The paste extracted from the leaves contains 60-80% cocaine, and is
treated to make cocaine hydrochloride salts, so that a single line provides a
dose of 25 mg. The typical dose is 50-100 mg. Crack is formed by boiling drug
in baking soda or ammonia until the water evaporates. Free-basing is a less
common method of creating base from hydrochloride salt – alkaline water-cocaine
mixture is extracted into ether, so that evaporating ether yields a smokable
product. Smoking of crack yields an average of dose of 250-1000 mg. (Compare
that to the amounts used by natives and what was in Coca-Cola).
Cocaine can be absorbed from all sites of
administration - mucous membranes, GI tract, and lungs. The three principal
routes are intranasal, inhalation, and intraveous injection. Once absorbed,
initial brain concentrations far exceed that of plasma, then is redistributed.
Cocaine has a half-life of 30-90 minutes. It is rapidly and almost completely
metabolized by plasma & liver enzymes.
Urine tests used for the detection of cocaine
will be positive for only 12 hours. Nonetheless, the principal metabolite,
benzoylecgonine, can be detected for 48 hours.
Cocaine users often use alcohol as well, and
these two compounds can form an active metabolite, cocaethylene.
Cocaine is a potent local anesthetic,
vasoconstrictor, and psychostimulant with strong reinforcing qualities. It has
these actions because it blocks the reuptake of dopamine (DA), norepinephrine
(NE) and serotonin. The ventral tegmentum area of midbrain is rich in
DA-containing neurons involved in reinforcement & hyperactivity. Dopamine
and cocaine exert inhibiting effects by decreasing discharge rate of neurons in
VT and NA areas of brain. How this inhibitory synaptic transmitter action
translates into behavioral reinforcement is still unclear, but likely involves
disinhibition of frontal cortical activity from chronic dopaminergic
inhibition. Chronic use leads to decrease in the number of postsynaptic
dopamine receptors, with the development of a 2-fold increase in the amount of
dopamine necessary to produce a postsynaptic action, so that tolerance
develops.
Side
effects depend on the term and dosage:
|
|
SIDE EFFECTS OF COCAINE |
|
|
|
|
Short-term, low-dose use |
Long-term, high dose use |
|
|
|
Physiological responses include increased alertness, motor hyperactivity, tachycardia, vasoconstriction, pupillary dilation, increased glucose availability. Psychological responses include euphoria, enhanced self-consciousness, boastfulness, all of which last ~30 minutes. Milder euphoria with anxiety follows for 60-90 minutes, leads to potent behavioral reinforcement to take MORE cocaine instead of, say, food. |
Toxic, psychotic side effects result from long-term, high-dose use, including anxiety, vigilance, suspiciousness, paranoia, hallucinations. Serious physiological toxicity follows doses higher than 1-2 mg/kg body weight. Combination of vasoconstriction to heart and peripheral hypertension lead to inadequate oxygenation of heart tissue. This accounts for sudden death episodes among high-profile atheletes. |
|
Babies can be injured in utero. Physiological
damage is caused by vasoconstriction, leading to inadequate oxygen delivery to
the fetus.
Recent research on rats indicates that the
brain can be conditioned to anticipate cocaine ingestion, as evidenced by this
article, which appeared in the Wednesday, April 9, 2003 issue of the San
Francisco Gate
Scientists find clues to cocaine's hold on
addicts
RICK CALLAHAN, Associated Press Writer
Wednesday, April 9, 2003
©2003 Associated Press
URL:
http://www.sfgate.com/cgi-bin/article.cgi?file=/news/archive/2003/04/09/national0322EDT0466.DTL
Cocaine-addicted rats experience bursts of
brain chemical activity just before seeking out their next fix, scientists
report in a finding that could open a new avenue for treating human addicts.
When the rats merely heard or saw cues
associated with cocaine, their brains pumped out extra doses of the same
reward-related chemical that helps produce the euphoria that human users feel.
The rats' brain activity may explain the
intense cravings human addicts experience when something reminds them of the
drug.
"They're having a miniature high before
they even get there," said Anna Rose Childress, a professor of psychiatry
at the
"It acts like a salty potato chip, or the
smell of the brownie across the room, the chocolate croissant in the window--
it's a primer, it's a seductive pull."
The new work may help scientists find drugs
that can dampen drug cravings in people who have quit cocaine, said Childress,
who was not involved in the research.
She said the findings could also apply to
other drugs such as amphetamines, heroin, opium, nicotine and possibly even
alcohol.
The rat study is presented in Thursday's
issue of the journal Nature by psychologist Regina M. Carelli and chemist R.
Mark Wightman of the
They detected the dopamine pulses in rats
using a new technique that makes rapid "real-time" measurements of
changes in rat's brain chemicals.
The scientists made the rats addicted to
cocaine, then implanted an electrode in a portion of a rat's brain associated
with drug use. The rodents could receive cocaine by pressing a special bar
which activated a pump implanted in them that injected cocaine into their
system.
The drug delivery was accompanied by a tone
that sounded and a light that turned on in the area where the experiment was
unfolding.
When the rats were presented with the light
and the tone was sounded, the researchers detected rapid pulses of dopamine in
the rodents' brains. Dopamine levels also rose as the rats approached and
pushed the bar to receive their fix.
In contrast, rats that had not been addicted
to cocaine showed no comparable increase in dopamine levels when exposed to the
same cues. That indicates that the dopamine levels increased in response to
cues the rats learned to associate with cocaine, Carelli said.
She said the rodent findings may explain
bursts of brain activity seen in human addicts when they crave cocaine or see
paraphernalia associated with it.
"People had suspected for some time that
just the anticipation of receiving cocaine could cause rapid increases in
dopamine levels, but no one had been able to accurately measure it,"
Carelli said.
Roy Wise, chief of behavioral neurosciences
at the National Institute on Drug Abuse, said although the studies were
conducted in rats, rodents have proven to be a good predictor of how humans
respond to drugs. "The same thing is almost certainly happening in humans,"
he said.
Michael Kuhar, a professor of pharmacology at
Psychostimulants II:
Amphetamines
As mentioned earlier in the section
pertaining to cocaine, cocaine and amphetamines are powerful
psychostimulants which augment synaptic action of catecholamine, dopamine, and
to a lesser extent, norepithephrine neurotransmitters. They have a direct
action on the nucleus accumbens, and they have similar behavioral consequences.
Both will elevate mood, induce euphoria, increase alertness, reduce fatigue,
decrease appetite, improve task performance, relieve boredom. Anxiety, insomnia
& irritability are common side effects. Higher doses result in more intense
irritability, anxiety, and psychotic behavior.
Low-dose responses are similar to those
described in the "fight-or-flight" syndrome, which is characterized
by an increase in blood pressure, increase in pulse, dilation of pupils,
reallocation of blood flow, and an increase in both O2 and glucose
levels in blood. All this mimics and overwhelms the natural release of
biological amines, e.g. adrenalin, as part of normal alerting or activity
response.
Amphetamines are sympathomimetic agents,
because they mimic the actions of adrenaline (also called epinephrine, one of
the transmitters of our sympathetic NS). Immediate effects of amphetamine
include vasoconstriction, hypertension, tachycardia, and other signs and
symptoms of our normal alerting response. The effects of amphetamines on the
central nervous system include include tremor, restlessness, increased motor
activity, agitation, insomnia, and loss of appetite. These effects are from
indirect action involving presynaptic release of dopamine and norepinephrine
and, to a lesser extent, direct stimulation of postsynaptic catecholamine
receptors.
Amphetamines have been used for a multitude
of disorders, including schizophrenia, morphine addiction, tobacco smoking,
heart block, head injury, radiation sickness, hypotension, seasickness, severe
hiccups, and caffeine dependence.
Amphetamines exert their effects by causing
the release of newly synthesized catecholamines, especially dopamine, from
presynaptic storage sites in nerve terminals. Behavioral stimulation and
increased psychomotor activity appear to follow from the resulting stimulation
in the mesolimbic system (including the nucleus accumbens). High-dose
stereotypical behavior (e.g. repetition of meaningless acts), involve dopamine
neurons in the caudate nucleus and putamen of the basal ganglia. Although its
mode of action is different than that of cocaine (which inhibits reuptake), the
net effect of increasing the amount of dopamine in the synapses is the same. In
fact, addicts can't tell the difference between 8-10 mg of cocaine and 10 mg of
intravenous dextroamphetamine.
At low doses (5-20 mg), amphetamine will
increase in blood pressure, slow heart rate, and relax bronchial muscle. In the
central nervous system, amphetamine is a potent psychomotor stimulant which
will produce increased alertness, euphoria, excitement, wakefulness, a reduced
sense of fatigue loss of appetite, mood elevation, increased motor and speech
activity and a feeling of power.
At moderate does (20-50 mg), amphetamines
will cause stimulation of respiration, slight tremors, restlessness, greater
increase in motor activity, insomnia, and agitation.
Persons who chronically use high doses of
amphetamine have a different set of drug effects. Stereotypical behaviors
include the tendency to perform continual, purposeless, repetitive acts, sudden
outbursts of aggression and violence, paranoid delusions, severe anorexia,
psychosis, weight loss, skin sores, and infections resulting from neglected
health care.
Most show a progressive deterioration of
social, personal, and occupational affairs.
Dependence is readily induced in both humans
and lab animals. One drug use is stopped, the person will experience
withdrawal, which includes the following symptoms: increased appetite; weight
gain; decreased energy; and increased need for sleep. Severe depression is
possible.
"Ice" is a 'free-base' form of
methamphetamine, which is more potent than dextroamphetamine. Methamphetamine
can be easily synthesized in labs from readily available chemicals, and is
typically smoked. In essence, "ice" is to amphetamine as
"crack" is to cocaine.
The half-life of methamphetamine is 11 hours.
Approximately 60% is metabolized in liver whose end products are excreted
through kidneys, while 40% is excreted as is. Repeated high doses are
associated with violent behavior and paranoid psychosis. Such doses cause
long-lasting decreases in dopamine and serotonin in the brain. The changes
caused by amphetamines in the brain may be irreversible.
Despite the hazards of amphetamine abuse, it
still has some therapeutic uses in the treatment of narcolepsy, Attention
Deficit Hyperactivity Disorder (ADHD), and obesity.
Narcolepsy is a relatively uncommon condition
characterized by attacks of irresistible sleepiness that disrupts the patient's
daily life. It is accompanied by cataplexy and hypnogogic hallucinations.
Treatment consists of both nonpharmacologic and pharmacologic interventions.
Attention Deficit Hyperactivity Disorder
(ADHD) is the most common psychological disorder of childhood, estimated to
affect 3-9% of school-age children. It is characterized by age-inappropriate
problems with attention, learning, impulse control and hyperactivity. It
persists into adulthood in 40 to 60% of affected individuals, at which time it
is associated with increases in antisocial personality disorder, a 5-fold
increase in drug abuse, a 25-fold increase in risk for institutionalization for
delinquency, and a 9-fold increase for incarceration.
Amphetamines have been used in the treatment
of ADHD since ~1936. Presently, methylphenidate is used most frequently for
treatment of ADHD (~90% of patients). Because of its a rapid onset and short
duration, methylphenidate must be given once in morning and again at lunchtime.
No dose given in evening to allow the child to sleep. Ten to 30% of ADHD
patients do not respond adequately and are therefore called "treatment
resistant." For these patients, antidepressants have been used as an
alternative, but the results with antidepressants are less than stellar.
Obesity affects > 40% of Americans and is
an ongoing chronic disease. Drugs are used to reduce food craving or appetite.
However, they work only for first 2 weeks, then they lose their potency.
Recently, one of the dopaminergic compounds (phentermine) has found recent
popularity used in combination with a serotonin-potentiating agent
(fenfluramine), called fen-phen. Unfortunately, it is associated with pulmonary
hypertension, which can be fatal. For that reason, the use of
"fen-phen" has been largely discontinued.
As stated by Julien (1998), caffeine is the most popular
and widely consumed drug in the world. It is found naturally in coffee, tea,
cola drinks, chocolate candy and cocoa, and it is added to variety of soft
drinks and over-the-counter (OTC) drug preparations, as shown in the following
table:
|
CAFFEINE CONTENT IN SELECTED BEVERAGES, FOODS, AND MEDICINES (Adapted from Table 6.1 of Julien, 1998 and from an article, Caffeinated Kids, which appeared in the July 2003 issue of Consumer Reports.) |
||
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Caffeine content (mg) |
|
|
Item |
Average |
Range |
|
Beverages (8 fluid ounces) Coffee (5-ounce cup) |
160 |
50-100 |
|
Snacks Starbucks Coffee Java Chip Ice Cream (1/2 cup) |
28 |
|
|
Over-the-Counter (OTC) Medicines Stimulants, e.g. No Doz |
65 |
|
When taken orally, significant levels appear in
the blood within 30-45 minutes post-ingestion. Plasma levels will peak in about
2 hours. By then, caffeine is freely and equally distributed throughout the
body. Most caffeine is metabolized by the liver before it is excreted by the
kidneys. Approximately 10% is excreted unchanged. The half-life in healthy
adults is 3.5-5 hours, but it will be longer in infants and pregnant females.
Caffeine easily crosses the placenta and can be found in measurable amounts in
breast milk.
Caffeine is an effective psychostimulant,
ingested to "obtain a rewarding effect usually described as feeling more
alert and competent." Recent research has indicated that caffeine does not
stimulate the nucleus accumbens, so it is not addicting in the sense that other
stimulants such as cocaine or amphetamines do. The alertness which comes from
the use of caffeine is a behavioral reinforcer. The cerebral cortex is affected
first, with increased mental alertness, a faster and clearer flow of thought,
and wakefulness. Fatigue is reduced and the need for sleep is delayed. Although
increased mental awareness may result in sustained intellectual effort, tasks
that require delicate muscular coordination and accurate timing or arithmetic
skills may be impaired. Caffeine does not counteract the intoxicating effects
of alcohol, although it is sometimes used to make a drowsy drunk more alert.
Heavy caffeine consumption can cause more intense effects, such as agitation,
anxiety, tremors, rapid breathing and insomnia.
The physical effects of caffeine include
increasing cardiac contractility and output, dilating coronary arteries, and
constricting cerebral arteries. Cardiac arrhythmias are not uncommon, but they
are rarely serious. Bronchial relaxation, increased secretion of gastric juice
and increased urine output also result from caffeine use.
The effects described above are mediated by
caffeine's mode of action, which is to attach to and block adenosine receptors
in the central and peripheral nervous systems. Adenosine is an autacoid that
acts on specific receptors on the surface of cells to produce behavioral
sedation, regulate the delivery of oxygen, and to dilate cerebral and coronary
blood vessels. Although there are no discrete adenosine pathways in the central
nervous system, adenosine indirectly inhibits the release of other
neurotransmitters, including norepinephrine, dopamine, acetylcholine,
glutamate, and GABA, by binding to caffeine-sensitive receptors. The blockade
of adenosine receptors by caffeine stimulates activity of such neurotransmitters
such as dopamine and acetylcholine.
Side effects include an increased incidence
of anxiety, insomnia, and mood changes. The frequency and severity of panic
attacks can be exacerbated. The risks to the cardiovascular system appear
minimal, but hospitalized patients are frequently not permitted to drink
caffeinated beverages. The existence of mild withdrawal symptoms suggests that
there is some physical dependence.
Nicotine is
an extremely addicting compound. The following table shows how nicotine
compares to heroin, cocaine, alcohol, and caffeine:
|
|
Comparison of nicotine to heroin, cocaine, alcohol, and caffeine |
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|
In terms of: |
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Dependence among users |
nicotine>heroin>cocaine> alcohol>caffeine |
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Difficulty achieving abstinence |
(nicotine=alcohol=cocaine= heroin)>caffeine |
|
|
|
Severity of physical withdrawal |
alcohol>heroine>nicotine> cocaine>caffeine |
|
|
|
Intoxication |
alcohol>(cocaine=heroin)> caffeine>nicotine (because people will get nauseated before they reach intoxication levels -- infants ingesting a pack of cigarettes with show toxicity.) |
|
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|
Deaths |
nicotine>>>alcohol> (cocaine=heroin); caffeine n.s. |
|
Administration is either by smoking or by
chewing.
Smoking will kill you. There are at least
4,000 chemical species in cigarette smoke. In 1990, there were 430,000 deaths
attributed to smoking, as compared to 125,000 to alcohol. Statistics from 1998
indicate that there are presently 45.8 million smokers in the United States,
and at any one year, approximately 34% of smokers are trying to quit, only 8%
succeed for >2 years.
Cigarettes themselves are very effective and
highly-engineered drug-delivery systems. The mixture of tobacco and air is to
increase burning temperature, and that increases the amount of nicotine
released. Tobacco leaves are treated to be slightly alkaline, which also
maximizes release of nicotine. Behavioral studies have shown that the average
smoker smokes 1.5 packs per day, and takes 10 puffs per cigarettes. That comes
to 300 separate hits/day for average smoker. The bolus from each puff hits
the brain within 10 seconds of inhalation, and courses through it in 8.5 seconds.
Unlike nicotine patches, only cigarettes provide nicotine in a continuous
stream of boluses. This continuous stream causes addiction.
What would happen if you were to quit
smoking?
- Within 20 minutes: Blood
pressure, body temperature and pulse rate will drop to normal;
- Within 8 hours: Smoker's
breath disappears; carbon monoxide level in blood drops and oxygen level
rises to normal;
- Within 24 hours: Chance
of heart attack decreases;
- Within48 hours: Nerve
endings begin to regroup. Ability to taste and smell improves;
- Within 3 days: Breathing
is easier;
- Within 2 to 3 months:
Walking becomes easier. Lung capacity increases up to 30%;
- Within 1 to 9 months:
Sinus congestion and shortness of breath decrease. Cilia that sweep debris
from your lungs grow back. Energy increases;
- Within 1 year: Excess
risk of coronary heart disease is half that of a person who smokes;
- Within 2 years: Heart
attack risk drops to near normal;
- Within 5 years: Lung
cancer death rate for average, former pack-a-day smoker decreases by
almost half. Stroke risk is reduced. Risk of mouth, throat and esophageal
cancer is half that of a smoker;
- Within 10 years: Lung
cancer death rate is similar to that of a person who does not smoke. The
precancerous cells are replaced;
- Within 15 years: Risk of
coronary heart disease is the same as a person who has never smoked.
(From an Ann Landers advice column, May
2001.)
Smokeless tobacco is also addictive, and the
percentages are increasing drastically. Until 1970, the only people using
smokeless tobacco were males >60 years old. Now, typically it is a much
younger male, 18-27 years old. The transition to a younger crowd is the result
of marketing strategy.
Typically, the reward center of the brain is
supposed to reinforce natural rewards, such as food, water, sex, and nurturing.
The amounts of dopamine that are typically released following food, water, sex,
or nurturing are limited.
The components of the reward circuitry of the
brain include the ventral tegmentum area (VTA), located in midbrain, the
nucleus accumbens (NA), and the prefrontal cortex, which controls judgement.
Dopamine neurons to VTA connect to the NA, which in turn, connects to other
areas, including the prefrontal cortex. ALL drugs of abuse activate the VTA-to-nucleus
accumbens pathway. That, in turn, stimulates projections to prefrontal cortex,
the center of judgement. Continued stimulation by the administration of drugs
will result in changes in the hardwiring of the reward center.
Nicotine acts by activating acetylcholine
receptors. When acetylcholine binds with its receptor receptor, cAMP is formed
inside the cell. Continuous exposure to nicotine causes neurons to Cell adapt
and operate at higher level of cAMP
Recent research has indicated that fetal
alcohol syndrome (FAS) may actually be fetal nicotine syndrome (FNS), since
virtually all alcoholic mothers also smoke cigarettes.
Despite the health hazards of the vehicles
for nicotine, nicotine itself may have therapeutic value. It may protect
dopaminergic cells of substantia nigra. It is an appetite suppressor because of
its action on serotonin and norepinephrine. Its effect on acetylcholine may
help in the treatment of conditions marked by loss of memory, such as
Alzheimer's Disease and Parkinson's Disease. Other conditions which may respond
to nicotine include schizophrenia, Tourette's Syndrome, ADHD, obesity,
ulcerative colitis, and endometrial cancer. The following letter sent to Dr.
Peter H. Gott, M.D., printed in the December 6, 2001 issue of the Memphis Commercial
Appeal, gives a glimpse of nicotine's potential as a therapeutic drug:
Dear Dr. Gott:
My husband, 87 has severe Parkinson's
disease and lives in a special nursing home. Three months ago, his conversation
was non-existent, despite the use of L-dopa.
Then I read an article in "The
Economist" telling of the enhancement of life for patients with
Alzheimer's Disease, Parkinson's disease and Tourette's syndrome given the
nicotine patch. My husband's neurologist was skeptical, but his doctor permitted
me to use it.
It's been wonderful. A month ago, my
husband grasped my hand and kissed it. He speaks clearly, can feed himself and
shows more interest in life. It is not a cure, but I know that the patch has
made a difference.
I use the lowest dosage (Nicoderm 7) and
apply the patch for 3 days. Last week, he looked up, smiled, and said: "I
think I'm catching cold." And he was. Why is this information not being
released to the public? IT could make an enormous difference in quality of life
among many old people.
Here is Dr. Gott's response:
Indeed it could. I am publishing your
letter while I research the issue because I believe that your perceptions are
crucial. I welcome feedback from physicians, neurologists and family members
about this revolutionary therapy, which is new to me. Share your insights with
me and I'll follow up in a future column.
On Friday, November 1, 2002, the Food and
Drug Administration approved the Commit nicotine lozenge for over-the-counter
sales. "It marks the first nicotine-containing lozenge to win the agency's
approval."
The following article appeared at http://www.pharmacist.com/articles/h_ts_0141.cfm
Nicotine lozenges approved
Commit Lozenges have been approved for OTC
sale as nicotine replacement therapy (NRT) to aid smoking cessation. This
first-ever lozenge dosage form for NRT is produced by GlaxoSmithKline Consumer
Healthcare (GSK) and contains the same active ingredient, nicotine polacrilex,
as GSK's Nicorette gum.
The lozenges are available in 2 mg and 4 mg
strengths. Dosing instructions advise patients to choose a dosage based on how
long they go between waking and smoking their first cigarette of the day;
patients who go less than 30 minutes before lighting up should use the higher
dosage. (Time to first cigarette is a major component of the widely used
Fagerstrom Test for Nicotine Dependence.)
Sold in packs of 72 and 168, Commit Lozenges
should be used for 12 weeks, with the number of lozenges used daily being slowly
decreased over time. The lozenges should be held in the mouth until completely
dissolved to ensure full delivery of each nicotine dose.
As with all NRT products, Commit Lozenges
should not be used with other NRT agents or by individuals continuing to use
tobacco.
Purchasers of Commit Lozenges will be invited
to enroll, at no charge, in GSK's Committed Quitters program. The program
offers counseling and support both online and via telephone. Go to
www.committedquitters.com for more details.
The Commit Lozenge Web site is www.commitlozenge.com .
Contact the writer: Ed Lamb
(elamb@aphanet.org), Pharmacy Today
Julien (2002) describes depression as an
affective disorder that is characterized by a number of symptoms:
- Loss
of interest or pleasure in almost all of a person's usual activities or
pastimes;
- Intense
sadness and despair;
- Diminished
energy;
- Decreased
sexual drive;
- Mental
slowing and loss of concentration;
- Pessimism;
- Feelings
of worthlessness or self-reproach;
- Inappropriate
guilt;
- Recurrent
thoughts of death, suicide, and hopelessness;
- Blunted
affect;
- Fatigue;
- Insomnia.
The causes of depression may be situational
or endogenous. Situational causes of depression include death of a loved one or
unexpected disappointment, as in a poor performance on a test. Situational
depression is highly treatable with short-term protocols.
Endogenous depression is indicative
of defective neurotransmitter release or uptake patterns in the brain and may
require long-term drug treatment for management. The neurotransmitters which
are implicated in endogenous depression include the catecholamines,
norepinephrine and dopamine, and serotonin. The strategies for treatment,
therefore, include:
|
Strategy |
Drug(s) which act in that manner |
|
Block the presynaptic norepinephrine reuptake transporter protein |
|
|
Inhibit the enzyme which inactivates norepinephrine |
|
|
Block the presynaptic dopamine reuptake transporter protein |
|
|
Inhibit the enzyme which inactivates dopamine |
|
|
Block the presynaptic serotonin reptake transporter protein |
|
|
Block postsynaptic histamine receptors |
|
|
Block postsynaptic acetylcholine receptors |
|
- Blocking the reuptake of norepinephrine by the presynaptic neuron;
- Inhibiting the destruction of norepinephrine by blocking monoamine
oxidase;
- Blocking the reputake of norp
The perception of pain is caused by the activation
of small-diameter (afferent) fibers of peripheral nerves. Nociceptive neurons
originate in peripheral tissues, e.g. skin, muscle, viscera, and can be
activated by mechanical, thermal, chemical, and injury. Action potentials are
conducted to terminals in the dorsal horn of the spinal cord where substance
P is released.
Substance P is a neuropeptide 11 amino acids
in length. It transmits nociceptive information from the site of injury to the
spinal cord. Its release in dorsal horn of the spinal cord is regulated
intrinsically by endogenous endorphins and extrinsically by any drug of a class
called opioids.
Endorphins and opioids exert at least part of
their analgesic action by inhibiting release of substance P by presynaptic
cells. When substance P is released, it activates other spinal cord neurons
which in turn transmit information about noxious stimuli to the brain via the
spinothalamic tract and the spinoreticular tract. Opioid receptors are also
found in the thalamus, brain stem, and limbic system. Two descending pathways,
which originate in the lower brain stem, modulate the transmission of pain
impulses by activating pain-inhibitory systems. Activation of either pathway,
which consist of descending NE and serotonin-releasing neurons, activates endorphin
neurons in the dorsal horn of the spinal cord, which in turn, exerts an
analgesic action by further inhibiting substance P release. The affective
component of pain is the component that determines our emotional response by
reducing the distress associated with pain.
Opioids have been used for thousands of years
to produce euphoria, analgesia, sleep and relief from diarrhea. Greek, Roman
documents show both medicinal and recreational use. In the
The term opioid is generic and
all-inclusive that applies to any agonist drug with morphine-like activity. It
applies to both semisynthetic and synthetic compounds. Opioid antagonists
antagonize the effects of morphine.
An opiate refers specifically to any
drug derived from the juice of the opium poppy, Papaver somniferum, including morphine and codeine. Heroin is a chemical
derivative of morphine.
An endorphin is any "endogenous
substance", i.e. one naturally formed in the living animal, that exhibits
pharmacological properties of morphine. The term includes three families of
endogenous opioid peptides -
a. Enkephalins
b. Dynorphins
c. Beta-endorphins
The term "narcotic" is
derived from Greek word narke, meaning numbness or stupor, and was used
to refer to any drug inducing sleep. The term is now an imprecise and
pejorative term.
Opioids exert their effects at highly
specific receptor sites, including Mu, Kappa and Delta receptors. All of have
these have been cloned & sequenced. Opioids are classified according to the
receptors they affect and their interactions with those receptors:
1. agonist
2. partial agonist
3. mixed agonist-antagonist
4. pure antagonist
"Strong" opioids, such as morphine,
primarily act on mu receptors. Pharmacological effects include analgesia,
respiratory depression, miosis (pin-point pupils), euphoria, and constipation.
All opioid receptors belong to a superfamily
of "G-protein-coupled receptors". They have 7 membrane-spanning
regions, and each is a chain of ~400 amino acids. Identicalities are higher in
transmembrane regions (75%) and intracellular regions (65%) than in
extracellular regions (35-40%). Extracellular diversity is probably responsible
for specific "fit" of an endorphin or opioid to a specific receptor.
The primary effect of opioid receptor
activation (by either an endorphin or an opioid) is a reduction in or
inhibition of neurotransmission, specifically by inhibition of neurotransmitter
release. This is mediated by inhibition of calcium channels and activation of
potassium channels. These actions follow from a coupling of the intracellular
loops and the terminal amino acid chain of the receptor protein to the
inhibitory system of adenylate cyclase enzyme through the release of an
intermediate inhibitory protein (termed G0). There may also be
postsynaptic inhibition of cyclic adenosine monophosphate, suppression of
voltage-sensitive channels and hyperpolarization of the postsynaptic membrane
through increased potassium conductance.
Mu receptors and the m-RNA that expresses the
receptor protein are present in all structures in the brain and spinal cord
involved in morphine-induced analgesia, including the periaquaductal gray,
spinal trigeminal nucleus, caudate and geniculate nuclei, thalamus and dorsal
horn of the spinal cord. Mu receptors are also present in brain stem nuclei
involved in control of respiration, in structures involved in initiation of
nausea and vomiting, and in the nucleus accumbens. Few are found in the
cerebral cortex or cerebellum.
Kappa receptors and the m-RNA that expresses
the receptor protein are found in high concentrations in the basal ganglia,
nucleus accumbens, ventral tegmentum, deep layers of cerebral cortex,
hypothalamus, periaquaductal grey, dorsal horn of spinal cord. The kappa-opioid
receptor is synthesized and transported to the terminals of dopaminergic
neurons and there it reduces the release of dopamine. Kappa receptors seem to
be involved in analgesia, dysphoria (because of its blockade of dopamine
release), psychotomimetic effects, and mild respiratory depression.
Delta receptors are activated by endogenous
endorphins called enkephalins. They are involved in analgesia at both the
spinal and brain levels, and are found in the nucleus accumbens and limbic
system, possibly playing a role in emotional responses to opioids.
Pure agonists, e.g. morphine, fentanyl and methadone, are pure
agonists of mu receptors.
Pure antagonists, which have affinity for a receptor, but induce no
change in cellular functioning, WILL block access of both endogenous ligands
(e.g. endorphins) or exogenous drugs (morphine). An example is naltrexone, used
in treatment programs for heroin addicts.
Mixed Agonist-Antagonists will have an agonist effect at one receptor and an
antagonistic effect at another. Clinically useful ones are kappa agonists/weak
mu antagonists. These drugs cause a "ceiling" effect for analgesia.
Partial agonists will bind with receptors but have low intrinsic
activity, i e. low efficacy. These will also exert an analgesic effect, but
there is a ceiling.
Opioids can be administered orally, rectally,
by inhalation or by injection. Highly fat-soluble opioids such as fentanyl can
be readily absorbed from the oral mucosa and through the skin. They are used
directly into spinal canal to control pain of obstetric labor and delivery.
Opioids reach all body tissues, hence the fetus and nursing infants are
affected.
Of the two analgesics in opium, morphine is
more effective. No other drug is clinically superior for treating severe pain.
Morphine is less lipid-soluble than heroin, hence entry into brain is more
limited, therefore "rush" is less intense with morphine. Morphine is
metabolized by the liver to morphine-6-glucuronide, which is 10x to 20x more
potent than morphine itself. The half-lives of both morphine & its
metabolite is 3-4 hours.
The pharmacological effects of morphine are
mediated by its effects on mu receptors:
Analgesia: There is no loss of consciousness, nor does not
affect other modalities. The pain may persist, but it is more
"comfortable."
Euphoria: There is a strong feeling of contentment, well-being and lack of
concern, which is part of the affective, or reinforcing response of drug.
Opioid use becomes an acquired drive state that permeates all aspects of human
life, and is often described in ecstatic and sexual terms, although euphoria
declines with frequent use. The mechanism of morphine’s positive reinforcing
and euphoria-producing action probably involves more than mu receptors,
especially the dopaminergic neurons. In the ventral tegmental area, morphine
inhibits GABA neurons via mu-opioid receptors, thus disinhibiting dopaminergic
neurons and increasing dopamine input in the nucleus accumbens and in other
areas. This may be involved in the mechanism of reward.
Sedation and anxiolysis: Sedation is not as deep as that produced by CNS
depressants. "Mental clouding" is prominent, which is accompanied by
a lack of concentration, apathy, complacency, lethargy, reduced mentation, and
a sense of tranquility. These actions probably follow from mu receptor
inhibition of neuronal activity in the locus coeruleus, the principal
clustering of norepinephrine neurons in the brain.
Depression of Respiration: The use of morphine decreases the respiratory
center’s sensitivity to higher levels of carbon dioxide in blood. Respiratory
rate is depressed even at therapeutic doses, and the depression of respiration
can be fatal, especially if alcohol or other sedatives are taken
simultaneously.
Suppression of cough: The cough center is located in brain stem, and is
suppressed by opioids. Less addicting drugs are now used.
Pupillary Constriction
Nausea and vomiting: These symptoms may be unpleasant, but are not
life-threatening.
Gastrointestinal symptoms: Intestinal tone increases, motility decreases, feces
dehydrate, and intestinal spasms (cramping) occur. All this tends to constipate
people. Tolerance to the constipating qualities of opioids does not occur, so
drug-dependent individuals have a problem with constipation. Two opioids have
been developed that only VERY minimally cross blood-brain barrier, hence they
are very good opioid antidiarrheals with no analgesic action – Lomotil and
Imodium.
Tolerance and dependence are characteristic
of opioid use. The molecular basis of tolerance is unknown, but research
suggests possible desensitization of opioid receptor and involvement of
glutamate receptors and nitrous oxide (NO). The rate of tolerance development
also differs between users and type of opioid. Occasional, rare use rarely
generates tolerance, but frequent use can result in rapid tolerance. Cross
tolerance is characteristic.
Withdrawal results from profound reduction in
release of dopamine in the nucleus accumbens, and reduction in the level of
dynorphin in the nucleus accumbens. Symptoms include restlessness, drug craving,
sweating, extreme anxiety, depression, irritability, dysphoria, fever, chills,
nausea and vomiting.
To help alleviate symptoms of acute
withdrawal, RAAD has been used, in which naloxone is given intravenously while
under anesthesia. After the procedure, patient is maintained on oral
naltrexone.
After acute withdrawal, focus is directed
toward the so-called protracted abstinence syndrome, which persists for ~ 6
months. It is characterized by depression, abnormal responses to stress, drug
hunger. Other psychiatric conditions complicate diagnosis and treatment of
syndrome.
Heroin is 3x more potent than morphine and is
produced from morphine. Heroin is more lipid-soluble, can be smoked or
injected, and is metabolized to monoacetylmorphine and morphine.
Codeine occurs naturally in opium, but is
1/10th as strong as morphine.
Other pure agonists include hydromorphone
(Dilaudid) and oxymorphone (Numorphan), which are structurally similar to
morphine. Demerol is a synthetic opioid whose structure is different from
morphine.
Methadone is a synthetic mu agonist opioid
whose pharmacological activity is very similar to that of morphine. It has a
very long half-life, and can be given orally, hence is a safe substitute for
heroin.
Partial agonist opioids include Buprenorphine (Buprenex) and Tramadol.
Buprenorphine has a ceiling effect, and at low doses, can substitute for
morphine.
Mixed Agonist-Antagonist Opioids bind with varying affinity to the mu and kappa
receptors, and include Pentazocine, Butorphanol, Nalbuphine, and Dezocine. All
of these drugs are weak mu agonists. Most analgesic effectiveness is from
stimulation of kappa receptors. Low doses provide moderate analgesia, and none
have much potential for respiratory depression or physical dependence.
Opioid Antagonists include Naloxone (Narcan), Naltrexone (Trexan), and
Nalmefene (Revex). All of these drugs are derivatives of oxymorphone. Naloxone
has no effect on nonopioid-dependent person, but will precipitate withdrawal
when injected into opioid-dependent persons. Naloxone is neither analgesic nor
subject to abuse, nor is it absorbed from GI tract. Naloxone is used to reverse
the respiratory depression that follows acute intoxication (overdoses) and to
reverse narcotic-induced respiratory depression in newborns born of
opioid-dependent mothers.
Naltrexone acts in a similar manner, but it
has longer half-life. Naltrexone is used to reduce the craving for alcohol and
or heroin. It is also used to treat autism and self-destructive behavior.
Pharmacotherapy of Opioid Dependence
It might not be a bad idea to give an opioid
addict his/her drug of choice in a carefully controlled therapeutic manner.
Unlike cocaine and amphetamines, which are power drugs, opioids cause
tranquility, analgesia, quieting. Violence is minimized if you just administer
what is needed, although it may have to be administered for a lifetime,
depending on addict’s personality and condition.
The hemp plant, <Cannabis sativa>, is the
source of marijuana.
The active ingredient in Cannabis sativa is delta-9-tetrahydrocannabinol
(THC). THC and other cannabinoids produce the characteristic motor, cognitive,
psychedelic, and motor effects of marijuana use. THC is concentrated in the
resin of the female plant, and the content of THC in plant tissue can vary from
2% to 20%, depending on the source and on the method of preparation.
THC can induce euphoria, hallucinations and
heightened sensations. It causes a disruption of attentive mechanisms,
impairment of memory, and analgesia. It suppresses the immune system, although
the clinical importance of this suppression is not known at this time. Because
it suppresses the sensation of nausea and increases appetite, THC may have
therapeutic applications for individuals who are undergoing chemotherapy or who
have AIDS.
The mechanism of action involves inhibition
of the cannabinoid receptor, a specific G-protein-coupled receptor that inhibits adenylate
cyclase. The receptor is now known to be a chain of 473 amino acids, with 7
hydrophobic domains. When THC binds to the outer portion of the receptor, the
nucleotide second-messenger system is activated to inhibit adenylate cylase. As
a result, potassium and calcium ion currents are regulated.
The normal ligand for the cannabinoid
receptor was discovered in 1992 - anandamide. Anandamide is a derivative
of arachidonic acid and produces the behavioral, hypothermic, and analgesic
effects like the psychotropic cannabinoids. Both THC and anandamide inhibit the
presynaptic release of glutamate. This inhibition is consistent with the
marijuana-induced detrimental effects on cognitive functioning.
Anandamide receptors are concentrated in the
hippocampus, cerebral cortex, and cerebellum and basal ganglia, all of which
are structures involved in cognition and memory, mood and motor function. The
brain stem, lacking anandamide receptors, is unaffected.
THC is usually administered by inhalation.
The average marijuana cigarette (or joint) will have ~50 mg of THC. Social
smoking delivers 0.4 to 10 mg per cigarette. Absorption is rapid and complete.
The effects seldom lasts 3-4 hours, judgement will be impaired for hours longer
than the sensation of the "high". Furthermore, THC and its
metabolites will in blood and urine for days or weeks.
Low doses produce a sense of well-being, mild
euphoria, relaxation, and relief from anxiety. Higher doses yield mild sensory
distortion, hallucinations and paranoia. Learning, memory and attention will be
impaired, so that users are considerably more likely to be involved in serious
or fatal motor vehicle accidents.
Heavy marijuana use is associated with
multidrug use and an amotivational syndrome, in which they lose interest in
goal-oriented projects. It also inhibits secretion of sex hormones and
suppresses gamete formation in both males and females.
Children born to mothers who used marijuana
while they were pregnant display behavioral "increased behavioral problems
and decreased performance on visual perceptual tasks, language comprehension,
sustained attention and memory" when they reach the age of 4.
Psychedelic drugs induce visual and auditory
hallucinations. They may also disturb cognition and perception, and produce
behavior similar to that observed in psychotic patients. They can be divided
into 4 groups:
1. Anticholinergic psychedelics;
2. Catecholamine-like psychedelics;
3. Serotonin-like psychedelics;
4. Psychedelic anesthetics.
Anticholinergic psychedelic drugs
Scopolamine and atropine are examples of
anticholinergic psychedlics. Scopolamine is found in members of the plant
family Solanaceae, such as Atropa belladonna (deadly nightshade), Datura stramonium, (
Atropine is a poor psychedelic because it
does not cross the blood-brain barrier efficiently.
Catecholamine-like psychedelic drugs
These drug molecules are structurally similar
to norepinephrine, dopamine, and amphetamine. The difference is the addition of
methoxy groups to the carboxy ring structure. Methylation adds psychedelic
effects to the behavioral stimulant ones characteristic of the amphetamines.
This class of drugs includes mescaline, DOM, MDA, MDMA (ecstasy), MMDA, DMA, myristin,
and elemicin.
As a group, these drugs probably exert their
actions by augmentation of serotonin neurotransmission, which results in
LSD-like effects, and by release of dopamine, which accounts for stimulation
and reinforcement of the reward circuitry. The net results of usage include
sensory-perceptual distortions, altered perceptions of colors, shapes and
sounds, complex hallucinations and synesthesia, and depersonalization. The
catecholamine-like psychedelics selectively stimulate 5-HT2
receptors and dopaminergic systems including the nucleus accumbens.
Mescaline is the active compound found in
peyote cacti (Lophophora williamsii). The crown of the cactus is
cut from the root, dried, and eaten. The cactus is found in the southwest
Mescaline chemically resembles
norepinephrine. It is rapidly and completely absorbed, with significant concentrations
in the brain within 30-90 minutes. It produces unusual visual hallucinations,
consisting of brightly colored lights, geometric designs, animals, and
sometimes people. It will also cause anxiety, sympathomimetic effects,
hyperflexia of limbs and tremors. Effects will persist for ~10 hours.
The synthetic amphetamine derivatives include
DOM, MDA, DMA, MDE, and MDMA. They are structurally similar to mescaline and
methamphetamine.
DOM has effects similar to mescaline. Only
1-6 mg are required to produce euphoria and 6-8 hours of hallucinations. Its
potency is between that of mescaline and of LSD. It has a high incidence of
toxic overdose, so use is not widespread.
MDA is one of the "designer
psychedelics". It is a metabolite of MDMA, and its action reflects
catecholamine and serotonin interactions.
MDMA, also
known as "ecstasy" and "Adam", resembles MDA in structure,
but is less hallucinogenic. It releases serotonin and causes acute depletion of
serotonin from most axon terminals in the forebrain. It is known to cause
irreversible destruction of serotonin neurons in laboratory animals. The
symptoms of use include hyperthermia, tachycardia, disorientation, dilated
pupils, convulsions, rigidity, breakdown of skeletal muscle and kidney failure.
Despite these serious consequences, people still use it because of its intense
euphoric high.
Myristin and elemicin are found in
nutmeg and mace. A tea is brewed from the leaves, and it will produce euphoria,
visual hallucinations, acute psychotic reactions, feelings of impending doom,
depersonalization, and unreality within 2-5 hours of ingestion. Both compounds
induce vomiting, nausea, and tremors, so continued use is uncommon.
Serotonin-like psychedelic drugs
This group includes LSD, psilocybin and
psilocin, DMT, and bufotenine. They interrupt "informational
filtering" by the pontine raphe, so a surge of sensory data
overloads brain circuitry.
The most potent is LSD, lysergic acid
diethylamide. Only 25 to 50 micrograms are required to induce a whole
cascade of psychological effects, including alterations in perception,
thinking, emotion, arousal, and self-image. Time is distorted, and visual
images are seen. In fact, "colors can be heard and sounds may be
seen." As the "trip" continues, fear, tension and anxiety may
occur. It is rapidly absorbed when taken orally, with peak blood levels in 3
hours. The usual duration of action is 6-8 hours. Tolerance and dependence are
readily induced, although tolerance is lost within several days after
cessation. Cross-tolerance to other psychedelic drugs also occurs, but physical
dependence does not. Adverse reactions may continue long after cessation of
use. Chronic or intermittent psychotic states may persist, and there may be
exacerbation of existing psychiatric illness or flashbacks.
Other serotonin-like hallucinogens include
DMT, bufotenine, psilocybin and psilocin.
DMT, dimethyl tryptamine, occurs naturally
and is short acting. It is structurally similar to serotonin and its effects
are similar to LSD. It must be smoked or sniffed, and it is metabolized by MAO,
monoamine oxidase. Its physiological effects include the elevation of body
temperature and heart rate, the dilation of the pupils, and the increase of
endorphins and hormones in the blood.
Bufotenine is derived from skin secretions of
Bufo, a genus of toads. Its half-life is ~2 hours, and is metabolized by
MAO. Its presence in urine has been documented among autistic,
autistic-epileptic, and schizophrenic patients. It has also been found in the
urine among Finnish male violent offenders. Its presence indicates a marker for
psychiatric disorders and may therefore have diagnostic value.
Psilocybin and psilocin are
found in many genera of mushrooms, including Psilocybe, Panaeolus,
Copelandia, and Conocybe. These genera are found in
Ololiuqui are morning glory seeds which are
ingested by Central and South American natives as an intoxicant and a
hallucinogen. The active ingredient in these seeds is lysergic acid amide,
which is very similar to LSD. Side effects include nausea, vomiting, headache,
increased blood pressure, dilation of pupils and sleepiness.
Harmine is obtained from Peganum
harmala, Syrian rue, a plant native to the
Psychedelic anesthetics
Phencyclidine, also known as "PCP"
and "angel dust" was developed as an analgesic-amnestic-anesthetic.
It is now considered too harmful for human use because of agitation,
hallucinations and psychotic behavior it produces, but it is still used as a
veterinary anesthetic. Usually, it is smoked, but it can be eaten, snorted, or
injected.
PCP is readily absorbed whether it is smoked
or ingested. Its peak effects occur within 15 minutes, although blood levels
don't peak until 2 hours post-ingestion. Its half-life is extremely long (11 -
51 hours) because of enterohepatic recirculation.
PCP binds to NMDA receptors, and is
classified as an NMDA receptor antagonist. Its mode of action is to bind with
and occlude the central pore of NMDA receptors, whose normal ligand is
glutamate. NMDA receptors are located in the anterior forebrain (neocortex and
olfactory structures), dentate gyrus, hippocampus, and the dorsal horns of the
spinal cord. NMDA receptors are involved in synaptic plasticity and in long-term
enhancement of synaptic efficacy, which are processes involved in learning and
memory.
When ingested, PCP dissociates individuals
from themselves an the environment. It then induces an unresponsive state with
intense analgesia and amnesia. Low doses produce mild agitation, euphoria,
disinhibition and excitement, but higher doses will induce coma and stupor.
Confusion may last up to 72 hours. PCP is psychologically addicting, and has
been found to stimulate brain award areas.
Anabolic-Androgenic Steroids
(AAS)
Hormones are compounds released into the
bloodstream by glands or glandular tissue and affect target organs elsewhere in
the body. Typically, negative feedback mechanisms regulate the concentrations
of hormones in the blood. For example, the control of both endocrine
and reproductive systems is mediated by the hypothalamus. Cells in the
hypothalamus monitor the concentration of testosterone in the blood. When testosterone
levels decrease sufficiently, the hypothalamus secretes gonadotropin
releasing factor (GRF), which, in turn, stimulates the pituitary gland to
secrete follicle stimulating hormone (FSH) and luteinizing hormone
(LH). The target for FSH and LH are the gonads. In males, FSH
stimulates the production of sperm (spermatogenesis), while LH
stimulates the production of testosterone. When males ingest exogenous
testosterone or testosterone-like drugs, abnormally high levels shut off
production of FSH, LH, and GRF, and decrease the rate of spermatogenesis.
In females, FSH
stimulates the maturation of ova, while LH stimulates ovulation.
Anabolic-androgenic steroids are used in this
manner in order to increase body mass, to improve athletic performance, and
enhance physical appearance. The increase in body mass is partially caused by
A-ASs blocking the action of natural cortisone, a hormone which normally
functions to regulate the breakdown of amino acids from protein. It is also
caused by the increased transcription and translation of genes coding for
muscle proteins.
Side effects are associated with the use of
AAS's by both males and females. Males experience an increase in cardiac risk
factors due to an increase in the LDL/HDL ratio, elevated liver enzymes,
increased likelihood of liver tumors, testicular atrophy and transient
infertility. Females experience a masculinizing of their body, as shown in an
increase in body and facial hair, disruption of their menstrual cycle, and an
enlarged clitoris.
Both males and females report a significant
increase in aggression, mood swing, psychotic episodes and depression. In fact,
the psychological condition associated with long-term use of anabolic steroids
is "roid rage". It is now well established that areas of the brain
that influence mood and judgement, such as the hypothalamus and limbic regions,
are endowed with steroid receptors. The delay in the onset of unpleasant or
unwanted side effects masks seriousness and harm of androgenic-anabolic
steroids.
Schedules of controlled
substances
The Controlled Substances Act of 1996 empowers the Drug Enforcement Administration (DEA) to
administer the regulations and to govern the export of narcotic and
non-narcotic substances. Controlled substances are divided into 5 schedules,
depending on their therapeutic application and on their abuse potential. These
schedules include the following:
Substance I
Substances
Drugs in this schedule are those that have no
accepted medical use in the
Substance II
Substances
Drugs in this schedule have a high abuse
potential with severe psychic or physical dependence liability. Schedule II
controlled substances consist of certain narcotic drugs, and drugs containing
amphetamines or methamphetamines as the single active ingredient, or in
combination with each other. Examples of Schedule II controlled substances are:
opium, morphine, codeine hydromorphone (Dilaudid), methadone (Dolophine),
Meperdine (Demerol), Cocaine, Oxycodone (Percodan), and straight Amphetamines
and Methamphetamines. Also in Schedule II are Methylphenidate (Ritalin),
Amobarbital, Pentobarbital, Secobarbital, Phencyclidine, and Methaqualone.
Schedule III
Substances
These drugs have an abuse potential less than
those in Schedules I and II, and include compounds containing limited
quantities of certain narcotic drugs, and non-narcotic drugs such as:
derivatives of barbituric acid except those that are listed in another
Schedule, such as Glutethimide (Doriden), Methyprylon (Noludar),
Sulfondiethylmethane, Sulfonmenthane, Nalorphine, Benzphetamine, Mazindol, and
Paregoric.
Schedule IV
Substances
The drugs in this schedule have an abuse
potential less than those listed in Schedule III and include such drugs as:
Barbital, Phenobarbital, Methylphenobarbital, Chloral Betaine (Beta Chlor),
Chloral Hydrate, Ethchlorvynol (Placidyl), Ethinamate (Valmid), Meprobamate
(Equanil, Miltown), Paraldehyde, Pentaerythritol Chloral (Petrichloral),
Fenfluramine, Diethylpropion, and Phentermine.
Schedule V
Substances
The drugs in this schedule have an abuse potential
less than those listed in Schedule IV and consist of preparations containing
moderate, limited quantities of certain narcotic drugs generally for
antitussive and antidiarrheal purposes, which may be distributed without a
prescription order.
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Questions? Comments? Please let me know. Mail
to: seisen@cbu.edu or call 1-901-321-3447.