I. HISTORY OF THE USE OF DRUGS AND MEDICINES

1600 BC Egyptians codified forms of therapy for a variety of diseases-distinguished those   clinical conditions which could be successfully treated and those that could not.

1550 BC More than 700 remedies, procedures for their preparation and administration for   specific ailments were listed.

372-287BC  Theophrastus' "History of Plants" summarized all known medicinal
  properties of plants.

57 AD Dioscorides prepared a materia medica which classified 600 plants by substance   rather than disease.

131-201     Galen was one of the first true experimental physiologists.

1493-1541  Paracelsus-Grandfather of Pharmacology-developed many theories
  of pharmacology.

1660       Boyle demonstrated activity of drugs when administered by vein.

1776 Daries demonstrated the relationship between the amount of drug administered   and the magnitude of the resulting biological response.

1806       Serturner (German apothecary) isolated morphine from opium.

1841 Blake established the principle that the chemical structure of drugs determines   their effect on the body.

II. DEFINITIONS

PHARMACY - concerned with the preparing, compounding and dispensing of chemical agents  for therapeutic use.

PHARMACOLOGY - the unified study of the properties of chemicals and living organisms and   all of their interactions.

TOXICOLOGY - the study of the toxic or harmful effects of chemicals as well as of the    mechanisms and conditions of occurrence of these harmful effects.

DRUG - any substance, other than food, that by its chemical or physical nature changes or    enhances any physical or psychological function in the body.
PLACEBO EFFECT - The typical drug effects individuals can experience when they believe    they have taken a drug when actually they have not. A placebo is a      pharmacologically inert agent.

ACUTE EFFECT - A brief, intense or severe effect; having a rapid onset, a short course,     and pronounced symptoms (as opposed to chronic)
 CHRONIC EFFECT - Not severe, but continuing for a long time; of long duration.
 
DRUG DEPENDENCE - A term used to apply to all situations in which drug users     develop reliance - either physical or psychological - to drugs or medications.

PSYCHOLOGICAL DEPENDENCE - Effects produced by a drug, or the conditions     associated with its use, which are necessary to maintain an optimal state of well-   being; intensity can vary from occasional craving to compulsive use.

PHYSICAL DEPENDENCE - An altered physiological state produced by repeated     administration of a drug which necessitates the continued administration of the `   drug to prevent the withdrawal syndrome.

TOLERANCE - Develops when a drug must be taken in increasing amounts upon repeated    administration in order to derive the same degree of response.

ADDICTION - A state of periodic or chronic intoxication produced by repeated      consumption of a drug - involves tolerance, psychological dependence, usually    physical dependence, an overwhelming compulsion to continue using the drug.

HABITUATION - A condition resulting from the repeated consumption of a drug which    involves little or no evidence of tolerance, some psychological dependence, no   physical dependence, and a desire to continue taking the drug for the feeling of   well-being it engenders.
 

             physiological      compulsive           overwhelming
 occasional ==> frequent ==>  dependence   ==>  drug use   ==>     involvement
 use                  use              (habituation)      (preoccupation)        (ADDICTION)
                                           ;      mild to severe

Drugs are divided into two major groµps:

1. Nonprescription drugs - sold "over the counter" (OTC) judged safe for use without medical    supervision.

2. Prescription drugs - considered unsafe for use except under medical supervision-dispensed    only by the order of practitioners licensed by law (physicians, dentists,     veterinarians).

III. DRUG NOMENCLATURE
 Most drugs have three names: chemical name, non-proprietary (generic) name, and a proprietary (trade) name. Non-proprietary or generic names are the official names of drugs which are listed in the U.S. Pharmacopeia and National Formulary.

 U.S. Adopted Name Council consists of representatives of the American Medical Association, American Pharmaceutical Association, the U.S.  Pharmacopeial Convention and the Food and Drug Administration to establish principles for naming drugs generically.

 A generic name specifies a specific chemical structure. Generic names belong in the public domain. Proprietary or trade name specifies a particular formulation and manufacturer of a generic product.
 Manufacturers obtain patents for new drugs which protect the company for 17 years. The Patent Restoration Act states that the patent can be renewed up to 5 years from the time of patent issue to the date of FDA approval. Only that manufacturer, or those companies licensed by the original manufacturer, are allowed to market that drug. Trade names are copyrighted and belong to the holder indefinitely. This is the way that drug companies protect their investment. After the patent expires any company can manufacture and sell that drug, but not under the trade name assigned to the original manufacturer.

EXAMPLES:
 Generic Name Trade Name   Chemical Name
  diazepam  Valium®  7-chloro-1,3-dihydro-l-methy1-5-
     pheny1-2H-1,4-benzodiazepin-2-one
    propranolol           Inderal®  l-isopropylamino-3-1-naphthlyoxy-     2- propanol hydrochloride

Trade names are always capitalized, generic names capitalized only when starting a sentence.

Only Hofmann-LaRoche could sell Valium® until the patent expired. Now generic drug firms sell diazepam. The patent on Inderal recently expired.  Until that time only Ayerst could sell Inderal. Now generic drug firms can sell propranolol.

Trade name drugs are more expensive than generic drugs because the drug firm must protect its initial investment which went into the discovery of the new drug. Generic firms do not have to worry about the high costs of drug discovery so they can sell the drug cheaply.
EXAMPLE: The tranquilizer meprobamate (Miltown®) when sold under the trade name costs approximately $6.50/100 tablets while the generic form costs approximately $1.50/100.
Proprietary and Non-Proprietary Products
Example = ibuprofen is the generic or USAN name.
The chemical name for ibuprofen is 2-(p-isobutylphenyl)propionic acid
 The drug was originally discovered by Upjohn Laboratories who marketed it under the trade name Motrin®. Upjohn licensed the product to Boots who marketed ibuprofen under their trade name Rufen®. A few years ago the patent Upjohn held for ibuprofen expired. Other companies were then allowed to market ibuprofen generically or under their own trade name.  As a result there are a large number of different products available, by prescription or OTC, which contain the same chemical constituent, ibuprofen.

Prescription Products
 Trade Name  Company Product strength
 Motrin®   Upjohn 300, 400, 600 and 800 mg
 Rufen®   Boots 400 and 600 mg
 Ifen®   Everett 400 and 600 mg
 ibuprofen( generic)  Various 300, 400, 600 and 800 mg

OTC Formulations All contain 200 mg ibuprofen per tablet or capsule
 Trade Name  Company
 ibuprofen (generic)   Various
 Advil®   Whitehall
 Trendar®   Whitehall
 Haltran®   Upjohn
 Medipren®   McNeil
 Nuprin®   Bristol Myers
 Ibuprin®   Thompson Medical
 Pamprin-lB  Chattem
 ORIGIN OF TRADE NAMES
 

Towns: MILTOWN® Miltown, NJ

Places: FIORINAL® Clinical research at Montefiore
   Hospital, Bronx

Chem. Name: ALDOMET® Alpha-methyldopa
 TRIAMINIC® Contains 3 amines (2 antihistamines,
   one sympathomimetic)

Mode of Action: LORELCO® LOwer ELevated ChOlesterol

 LOPRESSOR® LOwer Blood Pressure

 BREVITAL® BRIEF-acting barbiturate

 CONRAY® CONtrast X-RAY agent

 CYTOXAN® CYTotoxic agent

 FEMINONE® FEMale sex hormONE-estrogen

 SKELAXIN® SKELetal Muscle RelAXANt

 SURFACAINE® Local anesthetic for sunburn

 SOLARCAINE® Local anesthetic for sunburn
 

Euphonies: PLACIDYL® Sedative

 TRANXENE® TRANquilizer

 ELAVIL® Mood ELEVATor
 

 IV. HOW DRUGS AFFECT THE BODY

 A drug can be effective only if it is delivered to those cells where the drug acts. Thus, in order to exert its effect the drug must get from the external world into the body and ultimately to a specific site within the body where it acts. This transportation is a complex process.

 Taking a drug involves:
 1. Absorption of that drug into the bloodstream.
 2. Distribution of the drug by the circulating blood to all regions of the body.
 3. The action of the drug itself.
 4. The eventual breakdown of the drug into an inactive compound (metabolism).
 5. Finally, the excretion of the drug (or the metabolite of the drug) into the external world.

A. Administration of Drugs

 When administering any drug three factors must be considered since they affect the ability of the drug to reach its site of action in the desired effective concentration:
 1. Route of administration
 2. Dose of the drug
 3. The dosage form

The administration of drugs is normally achieved by the following routes:
 1. Local
 2. Enteral - drug is placed into the gastrointestinal tract
  a. Oral - drug placed in mouth and swallowed
  b. Sublingual - drug placed beneath tongue
  c. Rectal - drug placed in rectal cavity
 3. Parenteral - does not involve placing drug in G.I. tract
  a. Intravenous - injection directly into a vein
  b. Subcutaneous - injection beneath skin
  c. Intramuscular - injection into muscle
  d. Intradermal - injection within substance of the skin
  e. Intrathecal - injection into fluid beneath spinal membranes
  f. Inhalation - drawing drug into lungs

B. Absorption of Drugs

 1. ORAL

 In order for most drugs to be effective by mouth they must:
  a) be soluble in stomach fluid
  b) be carried to the intestine
  c) penetrate the lining of the intestine
  d) pass into the bloodstream

 Some drugs are absorbed directly from the stomach. A common example is alcohol. The effects of alcohol are noted quickly for this reason. On an empty stomach alcohol is absorbed quickly. On a full stomach it may dissolve in ingested foods and pass into the intestine where absorption is slower and effects are noted more slowly.
  Drugs given as liquids tend to be more rapidly absorbed than drugs given as tablets or capsules since they are already in solution. Drugs in solid form have to dissolve thus absorption is slower. Poorly manufactured drugs may fail to dissolve and the drug not absorbed-or absorbed to a lesser extent.

The major problems with oral administration are:
 1. Stomach distress may result
 2. One cannot always accurately predict how much of the drug in the tablet or capsule     actually gets into the bloodstream. Different brands of the same drug may be absorbed    at different rates
 3. Some drugs are destroyed by stomach acids and are thus ineffective. A good example of    this is insulin.
 
  2. INJECTION

 Administration of drugs by injection usually results in a much faster onset of action of the drug. There are some problems, however. If an overdose of a drug is given orally it can usually be recalled by inducing vomiting or by administering gastric lavage. This is not possible when a drug is given by injection. Also, sterile conditions are required.
 

  Intravenous - directly into a vein- rapid drug effects noted.

  Intramuscular - directly into muscle- effects are noted faster than oral administration but        slower than intravenous.

  Subcutaneously - just under the skin

C. Distribution of Drugs

a) Blood-Brain Barrier

 In order for drugs to reach the central nervous system (brain) the drug must cross the so-called blood-brain barrier (BBB). The BBB consists of fat-covered membranes that surround capillaries in the brain. In order to cross this barrier the drug must generally be fat soluble, as opposed to water soluble.

 Drug in Salt Form <=========> Drug in Free-Form
   Water-soluble       Fat Soluble

 Drugs are often administered as salts since they are water soluble and are often more stable to heat, light and moisture.

b) Placental Barrier

 The placenta is a spongy network of blood vessels and structures in the uterus through which the fetus derives its nourishment. These capillaries are more easily penetrated by fat-soluble substances. In actuality, almost all of the dugs that enter the mother's blood supply (and substances other than drugs) will cross over into the unborn's circulation.
 D. Excretion of Drugs

 The final step in the fate of administered drugs is elimination of the drug from the body along one or more of five possible pathways:

  a) Through the urine
  b) In the feces by way of the bile
  c) Exhalation through the breath
  d) In perspiration, saliva or milk
  e) Regurgitation

 The most common route of excretion is through the urine. In order to be eliminated through the urine the drug must be water soluble. While some drugs are already water soluble most drugs must be converted to forms which are water-soluble, or more water soluble than the administered drug. The mechanism the body has of converting fat-soluble drugs to water-soluble drugs is called metabolism.

 The major organ in the body responsible for metabolism is the liver. Also of importance in metabolism are the G.I.tract, the kidneys, and blood plasma.

 The liver contains structures called microsomes which contain enzymes which carry out the chemical conversions required to make a water-soluble drug from a fat-soluble one. Depending on the state of these enzymes in the liver (from either genetic or disease factors) individuals vary in the way they metabolize drugs.

 Also, some drugs affect the way the liver metabolizes other drugs, or the drug itself by either inducing or inhibiting these liver microsomal enzymes.  For example, one reason individuals can develop tolerance to drugs such as phenobarbital is because phenobarbital has the ability to induce is own metabolism. Thus, on continued use higher and higher doses become necessary.