Pharmacology:

Fundamental Concepts
Pharmacology

● The study of drugs and their interactions with living systems.

● The study of biological effects of chemicals.
● It encompasses the study of physical and chemical properties of drugs as well
as their biochemical and physiologic effects.
● Also includes knowledge of history, sources, and uses of drugs as well as
knowledge of drug absorption, distribution, metabolism, and excretion.
Definition of Terms:

a. Drug - any chemical that can affect living processes.

b. Clinical pharmacology - also called as pharmacotherapeutics, branch of
pharmacology that uses drugs to treat, prevent, and diagnose disease. This
addresses 2 key concerns - the drug’s effect on the body and the body’s
response to the drug.
Sources of Drugs:

1. Natural Sources
a. Plants
b. Animal products
c. Inorganic compounds
2. Synthetic Sources
Drug Evaluation
Preclinical trials - chemicals that may have therapeutic value are tested on laboratory animals
for 2 main purposes:
1. To determine whether they have the presumed effects in living tissue
2. To evaluate any adverse effects
● At the end of these trials, some chemicals are discarded for the following reasons:
○ The chemical lacks therapeutic activity when used with living animals.
○ The chemical is too toxic to living animals to be worth the risk of developing into a
drug.
 ○ The chemical is highly teratogenic.
○ The safety margins are so small that the chemical would not be useful in the clinical
setting.

● Some chemicals, however, are found to have therapeutic effects and reasonable safety
margins. This means that the chemicals are therapeutic at doses that are reasonably
different from doses that cause toxic effects. Such chemicals will pass the preclinical trials
and advance to phase I studies.
Drug Evaluation

Phase I Studies - use human volunteers to test the drugs. These studies are more
tightly controlled than the preclinical trials and are performed by specially trained
clinical investigators.
● Usually the volunteers are healthy young men.
● Some chemicals are therapeutic in other animals but have no effects in
humans.
● Investigators scrutinize the drugs being tested. They also look for adverse
effects and toxicity.
● At the end of this phase, many chemicals are dropped from the process for the following
reasons:
○ Lack therapeutic effect in humans
○ Cause unacceptable adverse effects
○ Highly teratogenic
○ Too toxic
● Some chemicals move to the next stage of testing despite undesirable effects.
Drug Evaluation
Phase II Studies - allows clinical investigators to try out the drug in patients who have the
disease that the drug is designed for.
● Usually performed at various sites - in hospitals, clinics, doctors’ offices - and are
monitored by representatives of the pharmaceutical company studying the drug.
○ A drug may be removed from further investigation:
○ Less effective than anticipated
○ Too toxic when used with patients
○ Produces unacceptable adverse effects
 ○ Has a low benefit-to-risk ratio, the therapeutic benefit it provides does not outweigh
the risk of potential adverse effects that it causes.
○ No more effective than other drugs already on the market, making the cost of
continued research and production less attractive to the drug company.

● A drug continues to show promise as a therapeutic agent receives additional scrutiny in

phase III studies.
Drug Evaluation
Phase III Studies - involve use of the drug in a vast clinical market.
● Prescribers are informed of all the known reactions to the drug and precautions required
for its safe use.
● Patients are observed closely, monitored for adverse effects.
● Journals to record any symptoms experienced.
● Evaluation of effects whether they are caused by the disease or by the drug.
● Information will be collected by the drug company and shared with FDA (Food and Drug
Administration).
Drug Evaluation

Food and Drug Administration Approval - committees of experts familiar with

the specialty area in which the drugs will be used.
● Only those drugs that receive FDA committee approval may be marketed.
● An approved drug is given the brand name by the pharmaceutical company
that developed it.
● The entire drug development and approval process can take 5 to 6 years.
Drug Evaluation

Phase IV Studies - also Postmarketing Surveillance, continual evaluation.

● Prescribers are obligated to report to FDA any untoward or unexpected
adverse effects associated with the drugs.
● Some drugs cause unexpected effects that are not seen until wide distribution
occurs.
Three Types of Drug Names:
a. Generic Name - also Nonproprietary Name, original designation that the drug was given
when the drug company applied for the approval process.
b. Brand Name - also Trade or Proprietary Name, given by the pharmaceutical company
that developed the drug.
c. Chemical Names - reflect the chemical structure of a drug.
Randomized Controlled Trial (RCT)

● The most reliable way to objectively assess drug therapies.

○ Use of Controls
○ Randomization
○ Blinding
● All these three serve to minimize the influence of personal bias on the
results.
Properties of an Ideal Drug

1. Effectiveness - drug that elicits the responses for which it is given. The most
important property a drug can have.
2. Safety - drug that cannot produce harmful effects, even if administered in
very high doses and for a very long time.
3. Selectivity - drug that elicits only the response for which it is given.
Additional Properties of an Ideal Drug

● Reversible action
● Predictability
● Ease of administration
● Freedom from drug interactions
● Low cost
● Chemical stability
● Possession of a simple generic name
No drug is ideal.
 Factors that Determine the Intensity of Drug Responses
● Administration - the drug dosage, route, and timing.
● Pharmacokinetics - determine how much of an administered drug gets to its sites
of action. The impact of the body on drugs.
A - Absorption
D - Distribution
M - Metabolism
E - Excretion
● Pharmacodynamics - determine the nature and intensity of the response. The
impact of drugs on the body.
● Sources of individual variation - characteristics unique to each patient can
influence pharmacokinetic and pharmacodynamic processes and, by doing
so, can help determine the patient's response to a drug.
○ Physiologic variables (age, gender, weight)
○ Pathologic variables (diminished functions of body)
○ Genetic variables
Legal Regulation of Drugs

FDA - regulates the development and sale of drugs. Local laws further regulate
the distribution and administration of drugs.
● Safety During Pregnancy - requirement of each new drug be assigned to a
pregnancy category. The categories indicate a drug’s potential or actual
teratogenic effects, thus offering guidelines for use of that particular drug in
pregnancy.
● Controlled Substances - drugs with abuse potential
● Generic Drugs - chemicals that are produced by companies involved solely
in the manufacturing of drugs.
● Orphan Drugs - drugs that have been discovered but are not financially
viable and therefore have not been “adopted” by any drug company.
● Over-the-Counter Drugs - products that are available without prescription
for self-treatment.
Nursing Considerations on OTC Drugs:
○ Taking these drugs could mask the signs and symptoms of underlying
disease, making diagnosis difficult.
○ Taking these drugs with prescription medications could result in drug
interactions and interfere drug therapy.
○ Not taking these drugs as directed could result in serious overdoses.
Sources of Drug Information

● Drug Labels - contain specific information that identifies a specific drug.

● Package Inserts - prepared by the manufacturer according to strict FDA
regulations. This contains all of the chemical and study information that led
to the drug’s approval.
● Journals - Medical Letter, American Journal of Nursing
● Internet Information
● Reference Books
○ Physician’s Desk Reference (PDR) - compilation of package insert
information of drugs
○ Drugs Facts and Comparisons
○ AMA Drug Evaluations
○ Nurses Drug Handbook - Lippincott’s Nursing Drug Guide
○ MIMS - Monthly Index of Medical Supplies
Pharmacokinetics
Pharmacokinetics

● Greek words: Pharmakon (drug or poison); kinesis (motion)

● Study of drug movement throughout the body.
● Also includes what happens to the drug as it makes this journey.
● The four basic processes: ADME
● Absorption - movement of a drug from its site of administration into the
blood.
● Distribution - drug movement from the blood to the interstitial space of
tissues and from there into cells.
● Metabolism - biotransformation, enzymatically mediated alteration of drug
structure.
● Excretion - movement of drugs and their metabolites out of the body.
Passage of Drugs Across Membranes

1. Channels and pores - very few drugs cross membranes via these.
2. Transport systems - carriers that can move drugs from one side of the cell
membrane to the other. Some requires energy. All are selective.
● P-Glycoprotein (PGP) or multidrug transporter protein
A transmembrane protein that transports a wide variety of drugs out
of cells.
3. Direct penetration of the membrane - most common - membranes are
primarily composed of lipids, a drug must be lipid-soluble (lipophilic) to
directly penetrate membranes.
A. Absorption

● The movement of a drug from its site of administration into the blood.
● The rate of absorption determines how soon effects will begin.
● The amount of absorption helps determine how intense effects will be.
Factors Affecting Drug Absorption
A. Rate of dissolution - before a drug can be absorbed, it must dissolve.
B. Surface area - the larger it is, the faster absorption will be.
C. Blood flow - the greater the concentration gradient, the more rapid absorption will
be.
D. Lipid solubility - “like dissolves like”
E. pH partitioning - Absorption will be enhanced when the difference between the
pH of plasma and the pH at the site of administration is such that drug molecules
will have a greater tendency to be ionized in the plasma.
Routes of Administration:
A. Enteral - via the GI tract
Oral, sublingual, buccal, rectal
A. Parenteral - injection
Intravenous, intramuscular, subcutaneous, intradermal
● Topical
● Inhalation
● Transdermal
● Vaginal
Pharmaceutical Preparations of Oral Drugs
1. Tablets - a mixture of a drug plus binders and fillers, all of which have been
compressed together. Tablets made by different manufacturers may differ in their
rates of disintegration and dissolution, causing differences in bioavailability
2. Enteric-coated - consist of drugs that have been covered with a material designed
to dissolve in the intestine but not the stomach.
a. To protect drugs from acid and pepsin in the stomach, and
b. To protect the stomach from drugs that can cause gastric discomfort.
3. Sustained-release - capsules filled with tiny spheres that contain the actual
drug; the individual spheres have coatings that dissolve at variable rates.
Because some spheres dissolve more slowly than others, the drug is released
steadily throughout the day.
B. Distribution

● Drug movement from the blood to the interstitial space of tissues and from
their into cells.
● Determined by 3 major factors:
a. Blood flow to tissues
b. Ability of a drug to exit the vascular system
c. Ability of a drug to enter cells
Blood Flow to Tissues
● Drugs are carried by the blood to the tissues and organs of the body.
● The rate of at which drugs are delivered to a particular tissue is determined by
blood flow to that tissue.
● Regional blood flow is rarely a limiting factor in drug distribution because most
tissues are well perfused.
● 2 pathologic conditions in which low regional blood flow can affect therapy:
1. Abscesses - no blood vessels inside
2. Tumors - limited blood supply
Exiting the Vascular System
● Typical Capillary Beds - drugs pass between capillary cells rather than through them.
● Blood-Brain Barrier (BBB) - unique anatomy of capillaries in the CNS. A drug must be
able to pass through cells of the capillary wall to reach sites of action within the brain.
Drugs that are lipid soluble or have a transport system can cross this to a significant
degree.
● Placental Drug Transfer - drugs must cross membranes of the maternal and fetal vascular
system. Lipid-soluble drugs can readily cross these membranes.
● Protein Binding - restriction of drug distribution. Because albumin is too large to leave
the bloodstream, drug molecules that are bound to albumin cannot leave either.
Entering Cells

● Drugs must enter cells to undergo metabolism and excretion.

● The factors that determine the ability of a drug to cross cell membranes are
the same factors that determine the passage of drugs across all other
membranes.
○ Lipid solubility
○ Transport system
C. Metabolism
● Biotransformation
● The chemical alteration of drug structure.
● Most drug metabolism takes place in the liver.
○ Hepatic Microsomal Enzyme System - also P450 System
■ 3 of this enzyme families metabolize drugs.
(CYP1, CYP2, CYP3)
Therapeutic Consequences of Drug Metabolism

● Accelerated renal excretion of drugs

● Drug inactivation
● Increased therapeutic action
● Activation of “prodrugs”
● Decreased toxicity
● Increased toxicity
Special Considerations in Drug Metabolism
● Age
● Induction and inhibition of drug-metabolizing enzymes
○ Substrate - drug metabolized by P450 enzymes
○ Inducer - drug that increase rate of metabolism
○ Inhibitor - drug that decrease rate of metabolism
● First-pass effect - rapid hepatic inactivation of certain oral drugs
● Nutritional status - lack of cofactors (vitamins, minerals)
● Competition between drugs
D. Excretion

● The removal of drugs from the body

● Drugs and their metabolites can exit the body in urine, bile, sweat, saliva,
breast milk, and expired air.
● The most important organ for drug excretion is the kidney.
● When kidneys are healthy, they serve to limit the duration of action of many
drugs.
● Conversely, renal failure may increase duration and intensity of drug
responses.
Renal Drug Excretion

1. Glomerular filtration - moves drugs from the blood into the tubular urine.
2. Passive tubular reabsorption - drugs that are lipid soluble undergo passive
reabsorption from the tubule back into the blood.
3. Active tubular secretion - active transport systems in the kidney tubules that
pump drugs from the blood to the tubular urine.
Non-Renal Routes of Drug Excretion

● Breastfeeding - lipid-soluble drugs have ready access to breast milk, whereas

drugs that are polar, ionized, or protein bound cannot enter in significant
amounts.
● Bile - secreted into the small intestine and then leaves the body in the feces.
● Lungs - volatile anesthetics are excreted.
● Sweat
● Saliva
Time Course of Drug Responses

Plasma drug levels

a. Minimum effective concentration (MEC) - plasma drug level below which
therapeutic effects will not occur. Hence, to be of benefit, a drug must be
present in concentrations at or above the MEC.
b. Toxic concentration - plasma drug levels climb too high at which toxic
effects begin.
Therapeutic range - a range of plasma drug levels, falling between the MEC and
the toxic concentration. When plasma levels are within the range, there is enough
drug present to produce therapeutic responses but not so much that toxicity
results.
● The objective of drug dosing is to maintain plasma drug levels within the
therapeutic range.
● Drugs with a narrow range are more dangerous than drugs with a wide range.
Time Course of Drug Responses

Single-Dose Time Course

- Shows how plasma drug
levels change over time
after a single dose of a
medication.
Time Course of Drug Responses

Drug Half-Life - the time required for the amount of drug in the body to decrease
by 50%.
● It is an index of just how rapidly that decline occurs.
● This determines the dosing interval (how much time separates each dose)
● Drugs with short half-life, dosing interval is short.
● Drugs with long half-life, long time interval.
Pharmacodynamics
Pharmacodynamics

● The study of the biochemical and physiologic effects of drugs on the body
and the molecular mechanisms by which those effects are produced.
● The study of the interactions between the chemical components of living
systems and the foreign chemicals, including drugs, that enter those systems.
● The study of what drugs do to the body and how they do it.
Drugs usually work in one of four ways:

1. To replace or act as substitutes for missing chemicals. (Insulin, vitamin B12)

2. To increase or stimulate certain cellular activities. (Caffeine)
3. To depress or slow cellular activities. (Diazepam, beta blockers)
4. To interfere with the functioning of foreign cells, such as invading
microorganisms or neoplasms. (Antibiotics, chemotherapeutic agents)
Dose-Response Relationship
● The relationship between the size of an administered dose and the intensity
of the response produced determines the minimum amount of drug needed to
elicit, and how much to increase the dosage to produce the desired increase
in response.
The dose-response relationship is graded.

● That is, as the dosage increases, the response becomes progressively larger.
● Because drug responses are graded, therapeutic effects can be adjusted to fit
the needs of each patient by raising or lowering the dosage until a response
of the desired intensity is achieved.
Drug-Receptor Interactions
● The only way drugs can produce their effects is by interacting with other chemicals.
● Receptors are the special chemical sites in the body that most drugs interact with to
produce effects.
● Receptor - any functional macromolecule in a cell to which a drug binds to
produce its effects.
● The body’s own receptors for hormones, neurotransmitters, and other regulatory
molecules.
● Other macromolecules to which drugs bind, such as enzymes and ribosomes, can be
thought of simply as target molecules, rather than as true receptors.
Receptor Sites
● Many drugs are thought to act at specific areas on cell membranes’ receptor
sites.
● They react with certain chemicals to cause an effect within the cell.
● Nearby enzymes break down the reacting chemicals and open the receptor
site for further stimulation.
● The activated enzyme systems then produce certain effects, such as increased
or decreased cellular activity, changes in cell membrane permeability, or
alterations in cellular metabolism.
● Agonists - drugs that interact directly with receptor sites to cause the same
activity that natural chemicals would cause at the site.
Example: Insulin (reacts with specific insulin-receptor sites to change
cell membrane permeability, thus promoting the movement of glucose
into the cell)
● Antagonists - drugs that act to prevent the breakdown of natural chemicals
that are stimulating the receptor site.
Example: Monoamine oxidase inhibitors (block the breakdown of
norepinephrine by the enzyme MAO)
Drug-Enzyme Interactions
● Interference of drugs with the enzyme systems that act as catalysts for
various chemical reactions.
● Enzyme systems work in a cascade fashion, with one enzyme activating
another, and then that enzyme activating another, until a cellular reaction
eventually occurs. If a single step in one of the many enzyme systems is
blocked, normal cell function is disrupted.
● Example: Acetazolamide - diuretic (that blocks the enzyme carbonic
anhydrase, which subsequently causes alterations in the hydrogen ion and
water exchange system in the kidney, as well as in the eye.)
Selective Toxicity
● The ability of a drug to attack only those systems found in foreign cells.
● Example: Penicillin (It affects an enzyme system unique to bacteria, causing
bacterial cell death without disrupting normal human cell functioning.)
Unfortunately, most other chemotherapeutic agents also destroy normal human
cells, causing many of the adverse effects associated with antipathogen and
antineoplastic chemotherapy.