Introduction

Pharmacology Basics is an important topic as medications have a great power to

both help patients (in terms of curing disease or infection, relieving symptoms such
as pain or nausea) and to harm patients (in terms of allergic reactions, overdoses,
adverse reactions, or administering the wrong medication to the wrong patient.) All
members of the healthcare team who deal, in any way with medications, should
respect the power of medications and act accordingly.

Receptors

The answer to the question in the introduction is that drugs are distributed
throughout the body by the blood and other fluids of distribution. Once they arrive
at the proper site of action, they act by binding to receptors, usually located on the
outer membrane of cells, or on enzymes located within the cell.

Receptors are like biological "light switches" which turn on and off when stimulated
by a drug, which binds to the receptor and activates it. For example, narcotic pain
relievers like morphine bind to receptors in the brain that sense pain and decrease
the intensity of that perception. Non-narcotic pain relievers like aspirin, Motrin
(ibuprofen) or Tylenol (acetaminophen) bind to an enzyme located in cells outside
of the brain close to where the pain is localized (i.e., hand, foot, low back, but not in
the brain) and decrease the formation of biologically-active substances known as
prostaglandins, which cause pain and inflammation. These "peripherally- acting"
(act outside of the central nervous system (CNS) analgesics may also decrease the
sensitivity of the local pain nerves causing fewer pain impulses to be sensed and
transmitted to the brain for appreciation.

In some instances, a drug's site of action or "receptor" may actually be something

that resides within the body, but is not anatomically a part of the body. For example,
when you take an antacid like Tums or Rolaids, the site of action is the acid in the
stomach that is chemically neutralized. However, if you take an over-the-counter
(OTC) medication that inhibits stomach acid production instead of just neutralizing
it (i.e., Tagamet (cimetidine) or Pepsid-AC (famotidine), these compounds bind to
and inhibit receptors in the stomach wall responsible for producing acid.

Another example of drugs, which bind to a receptor that is not part of your body, is
antibiotics. Antibiotics bind to portions of a bacterium that is living in your body and
making you sick. Most antibiotics inhibit an enzyme inside the bacteria that causes
the bacteria to either stop reproducing or to die from inhibition of a vital
biochemical process.

In many instances, the enzyme in the bacteria does not exist in humans, or the
human form of the enzyme does not bind the inhibiting drug to the same extent that
the bacterial enzyme does, thus providing what pharmacologists call ”Selective
Toxicity". Selective toxicity means that the drug is far more toxic to the sensitive
bacteria than it is to humans thus providing sick patients with a benefit that far
outweighs any risks of direct toxicity. Of course, this does not mean that certain
patients won't be allergic to certain drugs.

Penicillin is a good example of this. Although penicillin inhibits an enzyme found in

sensitive bacteria which helps to "build" part of the cell wall around the outside of
the bacteria, and this enzymatic process does not occur in human cells, some
patients develop an allergy to penicillin (and related cepahlosporin) antibiotics. This
allergy is different from a direct toxicity and demonstrates that certain people's
immune system become "sensitized" to some foreign drug molecules (xenobiotics),
which are not generally found in the body.

As medical science has learned more about how drugs act, pharmacologists have
discovered that the body is full of different types of receptors that respond to many
different types of drugs. Some receptors are very selective and specific, while others
lack such specificity and respond to several different types of drug molecules. To
date, receptors have been identified for the following common drugs, or
neurotransmitters found in the body: narcotics (morphine), benzodiazepines
(Valium, Xanax), acetylcholine (nicotinic and muscarinic cholinergic receptors),
dopamine, serotonin (5- hydroxytryptamine; 5-HT), epinephrine (adrenalin) and
norepinephrine (a and b adrenergic receptors), and many others.

Neurotransmitters are chemicals released from the end of one neuron (nerve cell)
that diffuse across the space between neurons called the synaptic cleft, and
stimulate an adjacent neuron to signal the transmission of information.

Pharmacokinetics

The next part of this course is designed to explain the complicated journey of a drug
through the body, which pharmacologists call pharmacokinetics. Pharmacokinetics
is the branch of pharmacology, which deals with determining the movement
(kinetics) of drugs into and out of the body. Experimentally, this is done by
administering the drug to a group of volunteer subjects or patients and obtaining
blood and urine specimens for subsequent quantitative (how much) analysis. When
the results of these analyses are plotted on graph paper with blood levels or urinary
excretion on the vertical axis and time on the horizontal axis, a blood level-time or
urinary excretion pattern is obtained. These graphs can be used to calculate the
rates of appearance and elimination of the drug in the bloodstream, the rates of
formation of the compounds into which the drugs are transformed in the liver
(metabolized), and finally the rates of elimination or excretion of the metabolites.

There are four scientific or pharmacokinetic processes to which every drug is

subject in the body:

1. Absorption 2. Distribution 3. Metabolism 4. Excretion

These four processes occur contemporaneously until, firstly, the entire drug is
absorbed from the GI tract, the muscle or subcutaneous tissue site into which it was
injected, and there is no more absorption phase; and, secondly, all of the drug has
been metabolized, and there is no more "parent" drug and it is no longer detectable
in the blood.

Absorption

Absorption is the process by which a drug is made available to the fluids of

distribution of the body (i.e., blood, plasma, serum, aqueous humor, lymph, etc.).

In the fasting state, most orally-administered drugs reach a maximum or "peak"

blood concentration within one to two hours. Intravenous (IV) administration is the
most rapid route of administration, with intra-nasal, smoking (inhalation),
sublingual (under the tongue), intra-muscular (IM), subcutaneous (i.e., under the
skin, SC or SQ), and percutaneous (through the skin) being the next most rapid.

The rate of absorption of orally-administered drugs and the subsequent appearance

of the drug in the blood is dependent on the following factors:

1. The rates of disintegration and dissolution of the pill or capsule in the stomach
or gastrointestinal (GI) tract.

2. The solubility of the drug in stomach or intestinal fluids (the more soluble, the
faster).

3. The molecular charge on the drug molecule (charged substances are soluble,
but don't pass through lipid (fat) soluble biologic membranes well). 


4. Aqueous (water) solubility vs. lipid (fat) solubility. Water-soluble drugs are
soluble but don't pass through lipid-soluble biologic membranes well. 


5. The presence or absence of food in the stomach (food delays the absorption
of some drugs and enhances the absorption of others). 


6. The presence of any concomitant medication(s) that can interfere with

gastrointestinal (GI) motility, i.e., Reglan increases GI motility, Aluminum
antacids slow, drugs like atropine or scopolamine used for ulcers or "queasy
stomachs" slow GI motility keeping some drugs in the stomach slowing
absorption, while drugs like Tagamet, Zantac and Prilosec (Pepcid-AC)
decrease gastric acid production increasing the rate of gastric emptying and
increasing the rate of absorption of some drugs. 


Distribution

Once a drug has been absorbed from the stomach and/or intestines (GI Tract) into
the blood, it is circulated to some degree to all areas of the body to which there is
blood flow. This is the process of distribution. Organs with high blood flow, i.e., brain,
heart, liver, etc. are the first to accumulate drugs, while connective tissue and lesser-
perfused organs are the last.

The pattern of distribution of drug molecules by different tissues after the chemical
enters the circulatory system varies. Because of differences in pH, lipid content, cell
membrane functions, and other individual tissue factors, most drugs are not
distributed equally in all parts of the body. For example, the acidity of aspirin
influences a distribution pattern that is different from that of an alkaline product
such as amphetamine.

Many drugs are bound to plasma proteins such as albumin. Since only drugs that are
not bound are free to exert a pharmacologic effect, the ratio of "free" to "bound"
drug is important in determining the onset and duration of action of drugs. Highly
bound drugs are distributed less extensively throughout the body and are slower to
act. By virtue of their high binding to plasma proteins, they also stay in the body for
longer periods of time because the binding sites act as a sort of "reservoir" for the
drug, releasing drug molecules slowly. One example of commonly used extended
release mediation is Effexor XR (an antidepressant medication.) Most extended
release mediations will have XR, ER or XL in their name.

Metabolism

Drugs in the blood and tissues must be inactivated and excreted from the body. This
process is initiated by altering the chemical structure of the drug in such a way as to
promote its excretion. The transformation of the drug molecule into a chemically
related substance that is more easily excreted from the body is called metabolism,
biotransformation or detoxification.

Drug metabolism is the process by which the body breaks down and converts
medication into active chemical substances. Drugs can interact with other drugs,
foods, and beverages. Interactions can lessen or magnify the desired therapeutic
effect of a drug, or may cause unwanted or unexpected side effects. There are
thousands of possible drug-to-drug and drug-to-food interactions, and many
medications and supplements are contraindicated (not recommended) under
certain conditions or in patients with specific diseases and disorders. This is why it
is imperative that patients always keep their physician fully informed about all
drugs and dietary supplements (including herbal remedies) they are taking.

The primary site of drug metabolism is the liver, the organ that plays a major role in
metabolism, digestion, detoxification, and elimination of substances from the body.
Enzymes in the liver are responsible for chemically changing drug components into
substances known as metabolites. Metabolites are then bound to other substances
for excretion through the lungs, or bodily fluids such as saliva, sweat, breast milk,
and urine, or through reabsorption by the intestines. The primary mode of excretion
is through the kidneys and will be described further in the next section.

The family of liver isoenzymes known as cytochrome P-450 are crucial to drug
metabolism. These enzymes (labeled CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4) have a catabolic action on substances, breaking them down into
metabolites. Consequently, they also act to lower the concentration of medication in
the bloodstream.

Drug interactions can occur when one drug inhibits or induces a P-450 that acts on
another drug. An example is nicotine, a drug contained in tobacco, and known to
induce P-450s. Individuals with liver disease (i.e., cirrhosis) may also have
insufficient levels of P-450 enzymes. As a result, the concentration of drugs
metabolized by these enzymes (i.e., amprenavir and other protease inhibitors)
remains high and can build up to toxic levels in the bloodstream. In addition, certain
medications and foods, such as grapefruit juice, can inactivate or lessen the
metabolic activity of P-450s. Changing the drug dosage can alleviate the problem in
some cases.

The metabolic rate can vary significantly from person to person, and drug dosages
that work quickly and effectively in one individual may not work well for another.
Factors such as genetics, environment, nutrition, and age also influence drug
metabolism; infants and elderly patients may have a reduced capacity to metabolize
certain drugs, and may require adjustments in dosage.

In the case of ethanol, the alcohol molecule is metabolized in the liver by the enzyme
alcohol dehydrogenase, to acetaldehyde that causes dilatation of the blood vessels
and, after accumulation, is responsible for the subsequent hangover that ensues.
The acetaldehyde is subsequently metabolized by the enzyme aldehyde
dehydrogenase to acetate, a substance very similar to acetic acid or vinegar.

Therapeutic agents like antibiotics and drugs used for the treatment of high blood
pressure, epilepsy (i.e., phenobarbital, Dilantin), pain (i.e., morphine, codeine),
anxiety (i.e., Valium, Xanax) are also metabolized to chemically- related compounds
called metabolites, which are then excreted in the urine.

Drugs that commonly interact with other medications include the following
categories:

Diuretics: 
Diuretics such as hydrochlorothiazide can

reduce serum potassium and sodium electrolyte levels when taken with
digoxin and lithium, respectively. 


Monoamine oxidase inhibitors (MAOIs): 
MAOI

antidepressants can cause convulsions and other serious side effects when
used with tricyclic antidepressants (i.e., Imipramine, Nortriptyline), selective
serotonin reuptake inhibitors (SSRIs), or sympathomimetic drugs (i.e.,
amphetamines). 


Antibiotics:
Antibiotics may reduce the efficiency of oral

contraceptives. 

 Metals: 
Medications containing metals, such as antacids
with aluminum additives and iron supplements, can reduce the absorption of
tetracyclines and fluoroquinolones. 
Drugs that inhibit liver enzyme
function: 
Drugs that slow drug metabolism include ciprofloxacin,
erythromycin, fluoxetine, nefazodone, paroxetine, and ritonavir. The
therapeutic effect of other medications taken with these drugs may be
amplified. Warfarin, a blood thinner, should be used with great caution in
individuals taking these drugs. 


Foods and beverages that may interact with drugs include:

Grapefruit juice: 
Grapefruit juice inhibits the metabolism

of many medications, including cyclosporine, felodipine, nifedipine,
nitrendipine, nisoldipine, carbamazepine, triazolam, and midazolam. 


Foods and beverages with tyramines: 
Red wine, malted

beers, smoked foods (i.e., fish and meats), dried fruits, and aged cheeses may
contain tyramines, and can cause a severe and dangerous elevation in blood
pressure when taken with MAOI inhibitors (a class of antidepressants). 


Dairy products: 
Milk, cream, and other dairy products

containing calcium can prevention the absorption of antibiotics such as
tetracycline, doxycycline, and ciprofloxacin when they are taken with the
drug. In addition, whole milk with vitamin D can cause milk-alkali syndrome
in patients taking aluminum hydroxide antacids. 


Caffeinated beverages:
The caffeine contained in coffee and

colas can influence drug 
metabolism. 


Alcohol: 
Alcohol is a central nervous system depressant,

and should not be taken with other CNS depressants (i.e., antipsychotics, 


antihistamines). In addition, certain fermented beverages may contain tyramines.

This list is not all-inclusive and individuals should always let their doctor and
pharmacist know when they are taking other medications, herbal remedies, or
dietary supplements. Anyone who experiences a serious reaction to a drug that is
not consistent with its product labeling should report the event to their doctor
and/or the MedWatch adverse event reporting system of the United States Food and
Drug Administration (FDA).

Excretion

Excretion is the process by which a drug is eliminated from the body. Drugs can be
excreted by various organs including the kidney and lungs, and found in many
biological fluids like: bile, sweat, hair, breast milk, or tears. However, the most
common fluid in which to look for drugs is the urine.
In order to determine the rate of excretion of any drug from blood, one must first be
certain that the entire drug in the subject's GI tract has been absorbed. If not,
calculation of a rate of excretion would be confounded be the ongoing absorption of
more drug. Once the entire drug has been absorbed, this is called the post-
absorbtive, or distributive stage. At this time, serial (multiple) blood level
determinations should show a decline with time. The amount of time required to
eliminate half of the drug from the body is called the half-life.

Generally, it takes six half-lives to rid the body of 98% of a drug and 10 half-lives to
completely eliminate the drug from the body. Using these mathematical
relationships allows pharmacologists to determine how often a therapeutic drug
should be administered to a patient or toxicologists to determine a time interval
within which one would test positive for drugs of abuse.

Drug Nomenclature

A medication will have a generic name and one or more trade names. The generic
name usually signifies the medication’s chemical derivation. However, this may not
always be the case, at times generic names are either determined by the company
that first developed the drug, or a by the U.S. Adopted Name Council. Generic names
are written beginning with a lower case (small) letter.

The trade name is a name chosen by a pharmaceutical company for purposes of

marketing or to identify the company responsible for manufacturing the drug. The
trade name may also represent some property of the drug. Trade Names usually
begin with a capital letter and may be followed by a Trademark. A single drug may
have many different trade names.

Examples of generic and trade names are listed in the table below.

Generic Trade

Ibuprofen Motrin®

Acetaminophen Tylenol®

benzoyl peroxide Oxy10®

Drug Classifications

Drugs are classified into different groups according to their chemical characteristics,
structure and how they are used to treat specific diseases. One way to classify
medications is as controlled versus non-controlled. Non- controlled medication is
medication that is not considered to be a depressant or a stimulant and is not
considered addictive or with a potential for abuse. Non-controlled medication may
include over-the-counter medication or prescription medication. Controlled
medications are divided into five schedules based on their potential for abuse and
physical and psychological dependence.

1. Schedule I:

Drugs that currently do not have accepted medical use, have a high potential for
abuse, and lack accepted safety measures for use (i.e., LSD, peyote, heroin).

2. Schedule II:

Drugs that have medical use and a high potential for abuse; those that tend to cause
severe dependence (i.e., morphine, secobarbital, amphetamines (Ritalin),
methadone).

3. Schedule III:

Drugs used in medical practice with less potential for abuse than schedule II drugs;
those that tend to cause moderate or low physical dependence or high psychological
dependence (i.e., nalorphine, drug combinations containing small amounts of
narcotics such as codeine).

4. Schedule IV: 
Drugs that have medical use and lower potential for abuse than
schedule III drugs; those that tend to cause limited physical or psychological
dependence (i.e., meprobamate, chlordiazepoxide, diazepam). 


5. Schedule V: 
Drugs that have medical use and lower potential for abuse than
schedule IV drugs; those that tend to cause less physical or psychological
dependence (i.e., mixtures of limited quantities of narcotics such as cough syrups
containing codeine). 


Medications may be classified or categorized in a number of other ways.

Medications may be classified by function or use. For example, an anti- anxiety
medication is used to treat anxiety, tension and nervousness. An antidepressant
treats depression by elevating the mood. Medication may also be classified by the
body system that it affects. Cardiovascular drugs work on the heart and blood
systems. Gastrointestinal medicines work on the stomach and intestinal tract.