A Brief History of Pharmacology as a Field

The earliest known written prescriptions are both found on a Sumerian cuneiform clay tablet dating back to 3,000 BC. But 2,000 years before that unknown doctor wrote these two prescriptions for an unknown ailment, there is archeological evidence of drug administration. [Time-Life Drugs pp. 10]  Long before doctors wrote prescriptions, there were male and female shamans mixing up herbal remedies for their tribe.  

The greatest advantage humans have over the animal kingdom is our ability to investigate, invent and adapt new practices based on our research. We learned to collect water in pots, create and wear clothes, grow crops and irrigate them. We also learned to eat small amount of sometimes poisonous substances to relieve our symptoms. 

The earliest drugs were most likely leaves plucked fresh and eaten on the spot. Later, the first herbalist collected these leaves, dried and preserved them. She experimented with dosages and solvents, and as she aged to preserve this knowledge, she began training her sons and daughters by moving about the forest touching and explaining each plant.  

One anthropologist following modern day primitive tribesmen in New Guinea has discovered that the average hunter-gather knows as many as 175 different plants in his environment. He knows the foods, the poisons and the medical herbs in his world. Furthermore, when anthropologists who research food production compare notes, they discover that in every part of the world, all early humans had exploited their particular environment to its fullest. Every grain that was capable of development as a food crop in that location was developed, every animal that could be tamed was domesticated and every herb with any medical use was explored. Europeans, Africans and Asians domesticated horses and cattle because they were in their environment.  Meso-Americans created corn with genetic manipulation because the undomesticated corn plant was found in their environment. (Guns, Germs and Steel) 

As humans collected into towns and then into cities, pharmacology and other sciences had to became more formal. Writing had to be invented to preserve knowledge and to circulate better. Formal schools were set up all over the ancient world. 

 

Sources of Drugs

While a lot of early drugs derived from plants, other came from minerals and animal sources; still others from human tissue.  In this current age, some of our newest drugs are artificial molecules that have never existed in nature. Newer drugs will be developed in outer space, because some substances cannot be created in the presence of gravity. 

Social Limitations on Pharmacology

As humans developed from tribes into states and empires, formal education became solidified as religion and custom constricted exploration. Some of this constriction, such as application of the 10 Commandments from the Judeo-Christian religions or the Greek philosophers’ Hippocratic Oath, created a moral base that modern medicine needed.  

But other constricts created serious limitations to tech0logical advances. While everyone is familiar with the Catholic Church’s sometimes baleful influence on science in Europe, we are less familiar with the education limitations placed by tradition-bound Confucian scholars that hampered education in the East in an identical manner, and in one case, the complete eradiation of all written material in China published before a certain date by the same despotic emperor who built the Wall of China.   

We are also less familiar with the limitations placed by autocratic social system on progress-- such as those that limited the great medical school of London which dominated 17^th and 18^th century medical science. The ‘best physicians’ in the British empire were trained in the excusive London school of medicine. These were the society physicians who demanded great salaries from great patrons. They moved about the drawing rooms and palaces as equals to the autocrats they treated. Highly respected gentleman from good families, they went to the right parties, and to the right church.  

In fact, this school was so exclusive that the more humble men who could not train in London had to make-d0 in faraway Glasgow, Scotland, a school that accepted men of other religions and classes. Time and time again, we discover that many of the great medical advances made in 1700s and 1800s in the British Empire happened at Glasgow-- not London. It is no surprise that American democracy spurred technical advances in the last century.

The apothecary or pharmacist industry didn’t help either. In an effort to control their trade, they deliberately limited the dissemination of drug knowledge. Not only ingredients, but ratios, solvents and measurements were kept from the competition by the creation of elaborate ciphers that rival the De Vinci Code for complexity. These hand-written books called pharmacopeias or formulary [recipe books] were closely guarded trade secrets written in Greek, Latin or even made-up words. Therefore, it is not surprising that apothecary measurements seem so illogical. For example: the symbol for “Drops” is “gtts.”  

Drug development has traditionally followed the money trail.  Paradoxically, this need for profit can trigger technology, but it can also hamper technology that is not cost effective.  For example: community-acquired pneumonias are caused by infections that affect everyone, so there is more research and development of antibiotics for these disorders than for some rare opportunist infections. Drugs for rare diseases affecting small numbers of persons need special funding to be studied.  

In recent years, federal funding for these ‘orphan drugs’ had to increase to allow drug development for rare disorders.    

Technical Limitations on Pharmacology 

The Roman Empire absorbed not only territory, but technology. The advances made by the Egyptians and the Greeks included medicine and surgical knowledge and this information was dispersed through out the empire [Europe and Middle East] by written accounts.  But most of this knowledge was lost when the Roman Empire fell. The few written accounts saved by Christian monks in distant places like Ireland were stored for centuries in monastery libraries. Unfortunately, this ancient knowledge was spotty and incomplete, but it was treasured. In the minds of the survivors of this lost age of greatness, the few classical tests that survived became sacred tests that could not be questioned. This attitude of reverence hampered the growth of pharmacology.

 In the beginning, drugs were simply crushed leaves or powered seeds but even a single leaf of tobacco contains more chemicals than nicotine. The major problem with early medicine was that the herbalist more often than not administrates more than one substance in his concoction. The active ingredient is the substance that actually interacts with the cells to create the action that is desired. This desired action is called the primary effect. Other substances in an herb or mineral may or may not add to the primary effect. Any affects that are not intended are called side effects. Some side effects are helpful, others harmful. Adverse side effects are side effects that are detrimental-- even dangerous. Any drug whose adverse side effects outweigh its primary effect may not be safe enough to use. The problem with crushed leaves is that the amount of the active ingredient varies from plant to plant and from one growing season to another. This was  technical hurdle to be overcome.

 

A Brief History of Drug Legislature in the USA 

After the Crusades introduced sophisticated Arab drug technology into the Europe of the 12^th century the apothecary [pharmacist] as a separate profession was created. These Middle Eastern innovations included drug distillation, fermentation and improved storage of liquids in non-porous porcelain containers. 

During the Middle Ages, the physician would meet his patient at the apothecary’s shop and the two would fine-tune a drug for their patient. People who could not afford a physician would bypass the middle man by dropping by the apothecary shop where he could be diagnosed and treated by the apothecary. [Time-Life Drugs pp. 16-21] Peasants, who could not afford the apothecary, would drop by the local witch [female herbalist] who would mix up an herbal concoction.

One of the goals of pharmacological research is the development of drugs with more specialized primary effects and to decrease—even to eliminate side effects. It took centuries for chemistry to develop the tools to break down, synthesize and concentrate active ingredients.  Poppy juice was used for centuries to relieve pain, but it was not until 1806 that a German apothecary isolated opium thus opening the flood gates for the creation of morphine and heroin. 

The scientific methods introduced in the age of Enlightenment changed the world and a new era of sharing information within the scientific community arose. In the 1880’s schools of medicine began to collect ‘recipes’ and print their own pharmacopeias. With increased knowledge of chemistry, some of these pharmacopeias were clearly better than others and they became popular with doctors everywhere in Canada and the USA.  

By the 1800s, pharmacology and medicine in general had become truly dangerous as more concentrated drugs became patented and sold in pharmacies all over Europe and the United States. Drug manufacturing became big business as it moved out of the doctor’s office and into the factories.  

There was little or no regulation on patent medicines and by 1900, the situation became critical. When selling drugs to the public, a manufacturer learns quickly that people want a drug that makes them feel better and feel better quick. Nothing made folks ‘feel better quicker’ than alcohol and opium based medicines, so most patent medicine contained one or the other or both of these sedatives. 

Click here to go to an example of pre-1914 pharmacopoeia belonging to a Waco, Texas vet  

A druggist could mix up root beer with morphine and alcohol, stick in a sprig of marijuana and call the drink a "cancer cure." He would sell it directly to the public under that label.  The country was full of opium addicts and alcoholics who did not even know they were addicted because they did not know what was in their medicines. 

The Patent Medicine Menace 

In mid-1800s, the temperance movement began to lobby Congress against alcohol but the same well-meaning men and women behind this movement were, sometimes, unknowingly addicted to alcohol or worse substances found in their patent medicine, even those prescribed by their physician.  

The druggist had no restraints on his rights to mix and sell drugs. There were no laws regarding labeling drugs. No one really knew what was inside his bottle of Pratt’s Healing Ointment or Kennedy’s Medical Discovery. No one knew that that the most popular patent medicines for TB and other pulmonary problems were merely cherry-flavored opium that depressed the cough-- but did nothing for the infection. 

The situation became critical and in May of 1905, a series of inflammatory articles in Collier’s Magazine exposed both the food and drug industries as heartless death machines existing only to make money. The country was outraged and by 1906, Congress passed the Pure Food and Drug Act in which any drugs that contained opium or alcohol had to be labeled as such so that consumers could choice to buy these addictive drugs. The law did not discuss the safety or effectiveness of drugs being sold.  

Once the truth was out and the public was better informed, companies like Coca-Cola ^TM had to remove the cocaine from their products to keep sells up. Some companies removed the additive drugs or converted their patent medicine like Dr. Mile’s Compound into food condiments [catsup] to stay in business.  

In 1912 the Shirley Amendment prohibited fraudulent claims regarding therapeutic results.  

In 1914, after the well-publicized death of a popular movie star from heroin overdose, the Harrison Narcotics Act was passed to control opium-derived drugs.  

In 1938, after 100 people died from a new sulfa drug dissolved in diethylene glycol, [antifreeze,] Congress created the Food and Drug Administration [FDA] to over-see their demands that new drugs get toxicity testing before marketing.  

This act established the power of the FDA:  

1. to approve all drugs for safety if used in accordance with the manufactures’ guide lines. The FDA had the power to withdraw approval and prevent marketing if this was not done.  

2. Labeling rules became even stricter.

3. the US Pharmacopeias [USP] & the National Formulary [NF] were accepted as the official standards.  For example, if your drug contained “oxygen” the molecule had to be 02---not 0, or C02, or N20 but only 02. Albuterol USP means that the drug contains the molecules in the specific configuration as stated by the official recipe books the USP and the NF.

Go here for example of a company’s packet insert  

Albuterol Insert 

At this time, the drug company still didn’t have to prove the drug was effective-- only safe.  

Finally, in 1962, the Harris-Kefauver Amendment added efficacy to the FDA mandates. Now the pharmacological firms had to prove their drug was safe and effective before it could be marketed.

Every 5 years, the FDA reviews the new research and if a drug fails to prove effective for its stated indication,   the FDA can order the manufacture to update its product information, or the FDA can even remove the drug from the market. Note, the FDA will not pull an older drug off the market if a newer drug is better, only if the older drug is not effective. 

By 1952, the Durham-Humphrey Act listed the drugs that required a prescription to be sold by pharmacies, and by 1971, the Controlled Substance Acts were passed to control manufacturing and distribution of narcotics and other dangerous drugs. This act also defined scheduled drugs.

While the FDA is completely involved with drug development, its control over devices is spotty. In the last few years, the FDA has gotten a little more involved with the manufacture and sell of medical devices. Unsafe devices must be reported to the manufacturer in writing and if death occurred, the FDA must also be notified.

THIS MEANS YOU

                All persons who are qualified to operate this equipment are REQUIRED BY LAW to  report equipment malfunction (when used as directed) resulting in injury, to the manufacture, who in turn is required to keep ALL complaints on file for annual review by the FDA.  A health care professional is required to report deaths related to equipment malfunctions directly to the FDA.  

 

FDA FAQ's 

Equipment Malfunctions 

Example of a Respiratory Care Recall                

Naming Drugs 

A drug is a molecule which gains a chemical name based on its configuration. If the drug company that extracted or created the molecules wants to research it, the FDA gives the drug a code name, a combination of numbers and letters. This drug may now be studied only in animals for safety and possible clinical uses.

During this pre-clinical trial, the drug is studied for its pharmacokinetic [see pharmacokinetic below.] After about 5 years of animal research, the FDA assesses the data collected by the researchers. If the drug is still considered safe and potentially effective, the FDA gives the drug its generic name and the research now moves into the 3 phases of clinical trial by which the drug’s dose, frequency,  actual uses and safety are assessed first in healthy volunteers and then in sick patients.

Once the drug successfully passes these 3 research steps, the FDA lets the company use the trade name and market the drug. During these first few years, the FDA continues to monitor the drug’s safety during the Post-marketing Surveillance phase. At this point, because thousands of persons are now taking the drug, interactions with other drugs or food can now become evident. Serious hazards may come to light that weren’t evident during the more limited clinical trials.  

Labeling Drugs

All bottles of prescription drugs contain a packet insert. These inserts are written by the drug company under the supervision of the FDA as regards doses, indications, hazards and contraindications.  

The insert includes but is not limited to the following information:

1. the trade and generic names as well as the chemical name.

2. the primary and side effects are discussed and from these the indications, hazards and contraindications are listed. These hazards should be listed in order of frequency from the most common to the rarest. 

3. It will give the strength of the drug and dosage ranges. If the drug was studied in children, it should give the doses for children. If the drug’s not been studied in children, the insert will state this fact. Not studied in children under 12 years of age. 

4. Onset of action and duration of action are discussed. The onset of action is the time in minutes or hours that it takes for the drug to work. The duration of action is the time in minutes or hours that the drug’s primary action lasts. 

5. the pharmacokinetic action is discussed [see below] 

6. the pharmadynamic action is discussed [see below]

7. the tetragenic effects of the drug on the fetus are discussed. And the drug is rated by categories of its effects on w unborn babies [category A is safe, Category X proven risk to fetus] and ability to cross the placental barrier to harm the baby.

8. the carcinogenic effects of the drug- its ability to cause cancer is discussed 

9. Because most drugs are metabolized in the liver, a drug’s hepatotoxic effects must be discussed.

10. While any large molecule especially proteins] can cause allergic reactions, some drugs are more likely to cause them than others; this is discussed 

11. its drug interactions are discussed [see below] 

The PDR

The PDR or physician's desk reference is a compilation of these inserts into a single book. For a price the PDR is available online via Delmar Publishing 

Pharmacokinetic and Drug Levels 

Different drugs have variations in their pharmacokinetics-- which is their ability to be [1] absorbed into the cells they are to affect [2] ability to be distributed [3] ability to be metabolized in the liver and [4] eliminated by the body. 

 The effectiveness of a chemical on a substance in a Petri dish may be quite strong, but this effect can be lost when the drug comes into the body where it may not be absorbed into the cell membrane, or the drug’s distribution includes binding to serum proteins to become useless or it builds up in the fat stores of the body rather than moving out into the blood stream.  Some drugs don’t pass the blood-brain barrier and are useless to treat the brain and CNS, while other drugs may not pass the placental-fetal barrier to treat a sick fetus. 

The time a drug lasts in the body thus creating its primary and side effects can be influenced by the rate of metabolism in the liver or by its elimination from the body via the renal, GI tract, milk, respiratory tract or via the sweat.  

Metabolism & elimination can both be changed by illness or age. Drugs that work well with a 20-year-old may be useless with the elderly or the newborn.  An example: premature infants can metabolism a bronchodilator called theophylline into caffeine. As a systemic bronchodilator, theophylline is useless in this patient population.

When a drug’s rate of absorption exceeds its rate of metabolism or elimination, the amount available to the tissue becomes excessive. This effect is called CUMULATION because it accumulates in the tissue.  

These 4 factors give rise to several situations described by the following terms. These levels of drug are usually measured in the blood serum.

1. Therapeutic level: a measurable amount of active ingredient found in the tissue which is enough to cause the desire effect.

2. Toxic level: a measurable amount of active ingredient found in the tissue which exceeds the therapeutic level to the point that adverse hazards become more likely to occur.

3. Peak level: a measurement of the drug at the time interval in which it should be at its highest level.

4. Trough level: a measurement of the drug at a time interval just prior to the next scheduled dose. It should be the lowest level.

To optimize the safety and efficacy of a drug, the drug dosage should be adjusted to achieve a therapeutic level at all times, without reaching a toxic level. 

The half-life of a drug is the time it takes for half of the drug to be gone. 94% of drugs currently used are cleared from the body within 4.5 half-lives. 

Pharmacodynamics

All cells in the body are covered in a cell membrane which controls passage of substances in and out of the cell.  The cell membrane contains a phospholipid bi-layer that contains water and lip-soluble portions.  While some molecules such as water, and gases of metabolism diffuse based on concentration or osmotic pressures, other substances can enter the cell only under the right circumstances. 

These substances can pass via three mechanisms

1. Channels and Pores: usually only small ions such as calcium can cross these tiny pores

2. Transport Systems [active or passive]: based on a drug’s structure it might be carried into the cell by a transport system

3. Direct Penetration: a drug that is lipo- soluble or has electrical polarity can enter a cell by direct penetration. This penetration can altered by situations such as the pH of the tissue

Receptor Site Theory of Pharmacodynamics

Once a drug has reached the target organ and before the body metabolizes & eliminates it, a drug is available to the cells of the target organ. The surface of these cells has numerous RECEPTORS which act as locks. The drug is a key which fits this lock and turns it, or fits the lock and prevents some other chemicals from turning the lock. 

A drug which fits the lock and turns it is called an AGONIST. An Agonist has affinity for the receptor that is--- it is attracted to it, it also has efficacy at that receptor site that is it turns the lock to create a specific effect. An example is Beta II bronchodilators that trigger bronchodilation. 

A drug which fits the lock but fails to turn it is called an ANTAGONIST. The drug has affinity for the receptor but no efficacy. This drugs action is in its ability to BLOCK the receptor from stimulation from an Agonist. An example is Atrovent, a cholinergic blocker that blocks the receptor for bronchoconstriction. 

Exactly How do These Receptors Work?

• The receptors on cell membranes act as the normal point of control for the cell’s activities

• These receptors are formed to interact with a single molecule that acts as a messenger to trigger or to stop one specific aspect of the cell’s activity

• There are hundreds of receptors for the same function on the surface

• There are also hundreds of receptors on the cell for other functions. All receptors respond only to their chemical messengers

• The chemical messenger lands on the receptor & if it fits [both physically and chemically] the receptor accepts it.

• Some receptors have better affinity for its chemical messengers than others, and in some cases this affinity can be increased. For Example: One of the ways steroids work is that, in addition to their own anti-inflammatory action, steroids also increase the Beta II receptor’s affinity for Beta II bronchodilators.

• Constant expose to some chemical messengers can result in a receptor losing its affinity, while with other chemical exposure the receptors becomes more responsive

• A drug can only mimic what the normal chemical signal was created to do

• With the exception of genetic alterations, a drug cannot force a cell to do what it is not designed to do

• So a drug is limited in its action by the ability of the drug to mimic the chemical, by the cell’s ability to perform the action, and by the number of open receptors for this action.

• A drug’s action on the cell assumes a sigmoid curve quite similar to the oxyhemoglobin curve.  As more receptors attach & react to the same chemical, the cell’s response rises until all the receptors are full. At this point more drug is useless-- because all the receptors are occupied.

Agonist and Antagonists

An agonist is a chemical that when it reaches the receptor will trigger a reaction, will activate the cell.  All hormones, neurotransmitters and other of the body’s regulators are agonists by definition.  A drug that mimics this activation is an agonist. Constant exposure to agonists tends to reduce affinity.

On the other hand, antagonists are more complex. An antagonist prevents the reaction caused by the agonists because it competes with the agonists for available receptor sites. It is also called a blocker. Needless to say, the number of agonist and antagonist present at the same time can determine what the cell actually does. If there are more agonists, more receptors get stimulated, if there are more antagonists present at the time, there are less open receptors that can be stimulated. 

 

Drugs are Not Involved in Receptor Stimulation or Blocking

A few drugs don’t occupy receptors. These drugs work by chemical reaction with substances. Anti-acids may buffer acids in the stomach. A drug could be used to reverse constipation by moving fecal material with increased osmotic pressure.  

Drug Interaction with Other Drugs

• Additive: An active drug which affects other drugs by an effect equal to the sum of double on or the other. 1 +1 =2.

• Synergism: Two active drugs which, when given together, have an effect greater than the sum of these two 1+1=3.

• Potentiation: An active drug is given more effectiveness by the addition of a drug which creates an effect greater than doubling the active drug. The difference between synergism and potentiation is that in this interaction is that only one drug is active.  The other, if given alone, doesn’t have the desired action but it increases the potential for the other drug. In potentiation  1+0=3.

• Antagonistic: Drugs which have opposite effects. So that they cancel out the other's effects. Obviously giving antidotes to overdoses could include drugs that are antagonistic to the poison. In this case  1+1=0.

Some drugs have a TOLERANCE problem, the longer a person takes the drug, higher doses must be given to get the same effect. Epinephrine [adrenaline] is famous for building up tolerance with in a few doses. 

If a person builds up tolerance to a drug in only one or two doses he has suffered from TACHYPHYLAXIS. Example:  crack cocaine is a tachyphylaxis drug; you are hopelessly addicted with one or two doses.                

Sometimes a person has an idiosyncratic reaction to a drug. The drug acts in a totally unexpected manner. This is seen often in children who will get jittery with a drug that should sedate them or become calm with a drug that should excite them. Some idiosyncratic reactions are based on genetics or gender. Only in the last few years are drug action differences between races being studied. In the case of gender, most drugs actions are well-known in adult men, but basically unknown in adult women because for years the FDA refused to study women of child-baring age.

The Autonomic System

Messages are sent through the body by the secretion of hormones and neurotransmitters. Cells will react to these substances.  Most cells of the body are controlled by some chemical that lands on the cell membrane and initiates a specific change within the cell.  Chemicals that land on muscle cells are part of this system.  Muscle cells can constrict for muscle action or relax.  Skeletal muscles found in the body react to certain chemicals, while smooth muscle cells in the body react to other chemicals.  Myocardial cells react to still other chemicals. 

The chemoreceptors on these various muscle cells generally have a “yes” or “no” response.  Each target organ can have chemoreceptors for yes and other chemoreceptors for no.  For instance, if one chemical message landing on the cell membrane causes a “yes” response, that muscle cell may contract,  while another chemical which initiates a “no” response will result in relaxation. One could say that the binary system used to make computers work was first worked out at the cellular level throughout the entire body.   

 The autonomic nervous system is concerned with the involuntary control of the body. These are the daily operations for which we don’t need to decide to perform for them to happen. While we may decide to eat, we don’t decide to digest this food. 

This involuntary action works by manipulation of the sympathetic and the parasympathetic nerves going to various target organs. These nerve endings secrete neurotransmitters that trigger chemoreceptors on a target organ.

Because there are both yes and no responses, obviously if sympathetic triggers ‘yes’ on one chemoreceptor, the parasympathetic must trigger a ‘no’ response on that same target organ. 

Sympathetic Nervous System                 

                One of the functions of the sympathetic system is to initiate the FIGHT OR FLIGHT reactions. To kill or be killed involves some rapid movements that must have increased blood flow to the peripheral skeletal muscles. This must happen in seconds. These extremes of behavior must also subside quickly or the organism will die. 

                To perform "FIGHT OR FLIGHT" one must:  

• Increase the Cardiac Output by raising the Heart Rate and the Stroke Volume. This will raise the blood pressure.

• The skeletal muscle's deeper vasculature will vasodilatation, so blood flow to legs and arms going through the lower resistant vessels increases blood flow to the legs.   

• At the same time the skin and the mucosa will vasoconstrict, so that their unneeded blood flow can be shunted to the skeletal muscles.  This is called dermal vasoconstriction.

• To assist the increased myocardial work the coronary arteries vasodilate to receive more blood with less   resistance, so that heart itself is perfused better.

• To assist the massive increase in minute ventilation that will be needed, the bronchial smooth muscles dilate to allow more air into the lungs. This bronchodilation reduces airway resistance to a faster flow rate.

 

How Does This Happen? 

The neurotransmitter for the sympathetic system is stored in the sympathetic neuron in the form of tyrosine. After enzyme activation, the tyrosine converts to dopa which in turn converts to dopamine. 

The dopamine is stored in storage vesicles near the presynaptic terminal. When neurotransmitter is needed at the junction, the dopamine quickly converts into NOREPINEPHRINE. 

To bridge the gap between sympathetic nerve and the target organ, the NOREPINEPHRINE must be released in to the synaptic gap. The NOREPINEPHRINE attaches to the ADRENERGIC RECEPTORS found on the target organ. It is important to remember than any given cell is responsive to the stimulation-- only if it has the proper receptors on its membrane to react to norepinephrine. 

The resulting action depends on several factors. (1). the neurotransmitter must be released, (2) the appropriate receptors must be present and (3.) the receptor must not be currently occupied. 

To start the overwhelming FIGHT OR FLIGHT action of sympathetic stimulation, the release of NOR-EPINEPHRINE into the synapses results in some norepinephrine converting into epinephrine. Some of this epinephrine [and nor-epinephrine] enter into the blood stream. When the blood-borne epinephrine or nor-epinephrine gets to the adrenal gland, it stimulates that gland to dump even more epinephrine into the blood stream. Thus the term ADRENERGIC (of the adrenal gland) is used to describe drugs which mimic epinephrine or receptors which respond to epinephrine or norepinephrine. 

Due to the adrenal gland's action of dumping epinephrine into the blood stream, all of the sympathetic system's target organs' receptors receive stimulation at the same time. The result is a body-wide reaction. FIGHT OR FLIGHT.

However, the release of any neurotransmitter results in action, only if the target organ possesses the appropriate receptor to respond to the neurotransmitter. A catecholamine such as epinephrine or norepinephrine will stimulate its target organ only as much as the presence of adrenergic receptors will allow.

The receptors for epinephrine and for norepinephrine (called endogenous catecholamines) are called the Alpha, Beta I, and Beta II receptors.  

• The Alpha receptors constrict pre-capillary sphincters. 

• The Beta I receptors found on the myocardium will stimulate increased rate and force of the myocardial contraction.

• Beta II receptors are found in great numbers on the bronchial smooth muscle. Stimulation of the Beta II receptors will result in bronchodilation.

 

The release of epinephrine into the body can cause seemingly opposite effects on the same type of tissue. For example, epinephrine can increase blood flow to deep vessels, in the leg--- but at the same time, this same drug constricts the mucosal capillaries. This seeming contradiction is made possible due to the presence of alpha receptors in the mucosa, which constrict when stimulated by  the epinephrine.  On the other hand, the vasodilatation at the skeletal muscle level is mediated by the stimulation of the Beta II receptors found on the pre-capillary sphincters found in the leg's muscle bed.  

Adrenergic drugs are categorized by the specificity of their stimulation of receptor sites. Epinephrine is non-specific; it stimulates Alpha and Beta I and II. Other drugs may be Alpha specific or Beta I or II specific. The more specific an adrenergic drug is in it's stimulation of ADRENERGIC RECEPTORS, the less side effects occur with the administration of these drugs. 

Because the effect of FIGHT OR FLIGHT is so dramatic, the body would not live long in a state of sustained sympathetic stimulation so the body quickly breaks down the nor-epinephrine and the epinephrine. The chemicals which break these down are two enzymes called MAO (monoamine oxidase)  and COMT (catechol-o-methyl transferase).  

Both MAO and COMT degrade the epinephrine so that it no longer bridges the synaptic gap. Furthermore, large amounts of MAO are found in the GI tract. This gastric MAO tends to degrade exogenous catecholamines as they enter the body. The presence of MAO in the GI tract will dictate that the routes of catecholamine administration will not include the oral one. Catecholamine drugs must be inhaled, given by shot—but are never active as oral drugs. 

 

Parasympathetic System 

The parasympathetic system is that portion of the autonomic system which controls the action of the day to day involuntary actions of the body. In contrast to the SYMPATHETIC SYSTEM which responds in a body-wide short-term burst of energy, the parasympathetic system is fine-tuned to stimulate action in only one organ, or in only one gland, or it will act on only one set of involuntary muscles. 

This specific action is due to the proximity of the parasympathetic nerve fiber to the target organ. Also release of the neurotransmitter does not trigger a glandular release such as happens with the adrenal gland in the presences of epinephrine.          

The FUNCTION of the parasympathetic system is glandular secretion, digestion, urinary elimination, and bowel movements.  

Because the parasympathetic system tries to conserve energy it tends to keep the heart rate down, via vagal nerve stimulation.  

Parasympathetic stimulation of the bronchial smooth muscle tends to result in bronchospasm, and stimulation of the respiratory system’s submucosal glands results in increased airway secretions. 

Stimulation of the tear glands results in crying, and parasympathetic stimulation of the proper glands results in sweating and saliva production. 

The parasympathetic system stimulates increased intestinal mobility to move the bowels, and the parasympathetic system increases urinary output by relaxation of the bladder sphincters. 

The neurotransmitter for the parasympathetic system is acetylcholine which is also the neurotransmitter for the voluntary skeletal muscles. 

These are collective known as the CHOLINERGIC receptors. The receptor sites on the target organs are of two types:

• the muscarinic because these were triggered by a poison mushroom

• the nicotinic receptors because these were triggered by nicotine.  

Cholinergic receptors are found in great numbers in the bronchial smooth muscles, on the submucosal glands, and they are found on the surface of the mast cells.  Stimulation of these cholinergic receptors results in bronchospasm, increased secretion and mast cell rupture. 

There are larger numbers of cholinergic receptors in the central airways than in the smaller more peripheral airways.               

When the body is done with a particular parasympathetic action, the action of the acetylcholine is stopped by the presence of the enzyme, CHOLINESTERASE. This enzyme is secreted by the target organ after the cholinergic receptor has been stimulated to halt the transmission of the parasympathetic nerve impulse. 

Inhibition of the cholinesterase would increase the duration of the parasympathetic stimulation. As the acetylcholine accumulates at the junction, the affects on the cholinergic receptors is enhanced.