BIOL 103: BIOLOGY OF ADDICTION  -- Lecture Notes
Stan Eisen
Biology Department
Christian Brothers University
650 East Parkway South
Memphis, TN 38104

Mail To:
seisen@cbu.edu
(901) 321-3447

(Updated January 6, 2006)

Some Useful Web Addresses:

The National Institute on Alcohol Abuse and Alcoholism -

http://www.niaaa.nih.gov/

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

Addiction defined

          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 Entry I. Oral administration

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.

Modes of Entry II. Inhalation

          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.

 

Average lung capacities for normal 20-year old males and females

Measured in milliliters

 

Parameter

Males

Females

Tidal volume (TV)

500

500

Inspiratory Reserve (IR)

3000

2100

Expiratory Reserve (ER)

1200

800

Vital Capacity (VC=TV+IR+ ER)

4700

3400

Residual (RE)

1200

1000

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.

Modes of Entry III. Injection

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:

 

Characteristics and Functions of Leukocytes

 

Type

Percentage

Function

Neutrophils

70%

Principal phagocytic cells in the blood -- they detect and ingest bacteria.

Eosinophils

1-3%

Detoxify foreign proteins and other substances --numbers increase during allergic reactions and in response to certain parasitic infections

Lymphocytes

25-35%

Produce antibodies and destroy foreign or cancerous cells -- specific immunity

Monocytes

6%

Leave the bloodstream to differentiate into macrophages which attack pathogens

          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)

 

 

At rest

During exercise

Cardiac output

5,400

17,500

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.

Termination of Drug Action

          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.  

Structure of neurons

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:

          Campbell, N. 1996. Biology, edition 4. Benjamin Cummings.

How neurotransmitters work

          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.

Types of neurotransmitters

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.

On the use of depressants

          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 U.S. It is also considered a food and has an enormous effect on nutritional status. It is soluble in both water and oil, and is rapidly and completely absorbed by the GI tract. Maximum blood concentration is 30-90 minutes past the last drink, although fatty foods and milk will slow absorption.

Alcohol equivalents include the following:

 

Ounces/standard serving

Average alcohol content/volume

Pure alcohol/standard serving


Liquor (88 calories)

1.25 x

40.0%

.50


Beer (148 calories)

12 x

4.5%

.54


Wine (114 calories)

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 ę î

 

í í
ę ę

ę ę
ę ę

î î
ę ę

 

(Meos) Microsomal ethanol oxidizing dehydrogenase
î

(ADH) Hepatic ethanol dehydrogenase
ę

 

Catalase (H2O2)
í

 

 

 

Acetaldehyde
ę î

 

 

 

 

Via Hepatic Acetaldehyde Dehydrogenase
ę
Acetate
ę
Acetyl CoA
ę
CO2 + H2O

Neurotransmitters

ę
ę
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

Reproductive System

(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 genetics of alcoholism

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. Helsinki: Finnish Foundation for Alcohol Studies.

          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 United States, the Food and Drug Administration (FDA) is the agency which approves drugs. A pharmaceutical company will initially submit preclinical data to the FDA in a document called an Investigational New Drug (INA). The FDA will then give or withhold permission to initiate clinical trials in humans. The pharmaceutical company will then inform the FDA of progress, and when Phase III trials are completed, the company will submit all preclinical and clinical data to the FDA in a New Drug Application (NDA). The FDA reviews the data and decides whether they provide adequate documentation of safety and efficacy. Part of the approval process consists of writing a "label", which includes the following information:

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 United States and have a high abuse potential. Some examples are Heroin, Marijuana, LSD, Peyote, Mescaline, Psilocybin, Tetrahydrocannabinols, Ketobemidone, Benzylmorphine, Dihydromorphine, and Morphine methylsulfonate. 

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

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.

 NS depressants

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

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.

Psychostimulants I: Cocaine

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 Peru and Bolivia. It is used by natives as an endurant, with a daily dose of ~200 mg. In 1885, cocaine was added, along with caffeine, at a serving dose of 60 mg. The present use of free-base or crack cocaine involves high doses, leading to toxicity and rapid dependency.

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 University of Pennsylvania's School of Medicine.

"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 University of North Carolina in Chapel Hill.

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 Emory University in Atlanta, called the research "a technical tour de force" that will refine models of how the brain acts in cocaine addicts.

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.

Caffeine

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.)

  

Caffeine content (mg)

 Item

Average

Range

Beverages (8 fluid ounces)

Coffee (5-ounce cup)
Tea (5-ounce cup)
Cocoa (5-ounce cup)
Red Fusion
Mountain
Dew
dnL
Pepsi
Pepsi Blue Berry Cola Fusion
Coca-Cola Classic
Vanilla Coke
Barq's Famous Olde Tyme Root Beer
Starbucks Coffee Frappuccino
AMP Energy Drink
Red Bull Energy Drink
Elements Atomic Jacked Apple Juice Drink
Sobe Energy Citrus Flavored Beverage

 

160
80
8
38
37
27
27
26
24
21
15
83
77
70
33
25

 

50-100
25-90
2-20

Snacks

Starbucks Coffee Java Chip Ice Cream (1/2 cup)
Haagen-Dazs Coffee Ice Cream, 1/2 cup
M&M's Milk Chocolate Candies, 1/4 cup

 

28
24
8

 

Over-the-Counter (OTC) Medicines

Stimulants, e.g. No Doz
Analgesics, e.g. Excedrin

 

65
30

 

 

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

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

 

 

In terms of:

 

 

 

Dependence among users

nicotine>heroin>cocaine>

alcohol>caffeine

 

 

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.)

 

 

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

Antidepressants

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

Opioids

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 US, morphine and opium were widely used during 19th century. The invention of hypodermic needle in 1856 created a new type of user - intravenous.

 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.

Marijuana

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.

Psychedelics

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, (Jamestown weed), and Mandragora officinarum (Mandrake). Topical application of scopolamine on the eyes will cause dilation of pupils. Within the central nervous system, scopolamine is the primary intoxicant, inducing drowsiness, euphoria, profound amnesia, fatigue, delirium, mental confusion, dreamless sleep and loss of attention. At higher doses, a behavioral state resembling psychosis occurs, manifested by delirium, mental confusion and sedation. The effects on the peripheral nervous system include tachycardia, blurred vision, urinary retention, and dry mouth.

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 USA and Mexico, and is legally used as a sacrament by members of the Native American Church.

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 Thailand, the Venezuelan Andes, Central America and northwest USA. These compounds are weaker than LSD, and their effects last 6-10 hours.

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 Middle East. It has been used as an intoxicant for centuries. The visual distortions are similar to those associated with LSD. Intoxication is accompanied by nausea, vomiting, sedation, and finally sleep. Intoxication is accompanied by nausea, vomiting, sedation and sleep. Visual distortions are similar to those of LSD.

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 United States and have a high abuse potential. Some examples are Heroin, Marijuana, LSD, Peyote, Mescaline, Psilocybin, Tetrahydrocannabinols, Ketobemidone, Benzylmorphine, Dihydromorphine, and Morphine methylsulfonate. 

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.