Drug Approval / Regulation
Pure food and Drug Act 1906—established government control of labeling medicines.
Food Drug and Cosmetic Act 1983 and amendments
o Thorough testing of drugs
o Proof of safety and efficacy of drugs
FDA must approve a drug before it may be marketed
o Black Box Warnings—created to regulate drugs with serious problems with potential for
causing serious injury or death
o FOUR STAGES OF APPROVAL:
1. Preclinical Investigation:
o
o
o
o
o
NO HUMANS
Lab research
Only on cells and animals
Determines drug-dose range
Examines adverse side effects
Inconclusive since cannot be tested on humans
2. Clinical Investigation
o In 3 different stages—clinical phase trials
o Longest part
o Evaluates human benefits ✓ HUMAN TRIALS BEGIN
o Tests healthy humans first
• Then on those with ailments
3. Review of New Drug Application (NDA)
o Applied if clinical investigations are positive—even if precautions are
o
o
o
o
noted
Avg 17-24months
Drug approved—processed continued
Drug rejected—suspended
Investigational New Drug Application (IND)
• Phase I clinical trials if there are significant therapeutic benefits
4. Post-marketing Surveillance
o Placed on market
o Surveyed for harmful effects in general population
o Annual public meetings
• Will withdraw if serious problems found
FDA Emergency Use Authorization (EUA)
o Used during public health emergencies (Covid-19 vaccines)
o Allows use of unapproved products to prevent life-threatening diseases/conditions with
no alternatives
o Potential benefits outweigh the risks
o Goal—more timely access for medical treatment
Controlled substances:
o Drugs with significant potential for abuse are placed into five categories called
schedules
o Schedule I (highest potential) Schedule V (lowest potential)
o US DRUG SCHEDULES BELOW
DRUG
SCHEDULE
Abuse
Potential
Potential for
PHYSICAL
Potential for
PHYSIOLOGICA
Therapeutic
Use
I
Highest
dependence
High
L dependence
High
II
High
High
High
III
Moderate
Moderate
High
IV
Lower
Lower
Lower
V
Lower
Lower
lower
Limited or
none
Limited or
none
Used with
prescription
Used with
prescription
Used without
prescription
PRINCIPALS OF PHARMACOLOGY ACROSS THE LIFESPAN
Pharmacokinetics
o Effects of the BODY on the drug
o Study of drugs movement through the body
o How the body handles the medications
o Understand/predicts actions and side effects
o Understands obstacles to target
Drugs in the Body –
The greatest barrier for a drug is CROSSING MEMBRANES – hence drugs
administer intravenously are most effective as they do not have any
membrane barrier to cross
Enteral drugs are broken down by the stomach acids and digestive enzymes
Organs attempt to excrete med
Phagocytes may attempt to remove as they are seen as foreign objects
ADME
ABSORPTION – HOW WILL IT GET IN?
o Movement of drug from site of admission to the bloodstream
o This is the PRIMARY PHARMOKINETIC FACTOR—determining the length of time it will
take to produce an effect
o Factors affecting
Formulation (enteric-coated pills may take longer for example)
Dose
Route
Size of drug molecule—smaller the easier
Surface area of absorption site—larger more difficult
Digestive motility
Blood flow – ↑profusion is favorable
Lipid soluability—these stay in our body longer
Water-soluble drugs excrete faster
Degree of ionization
Lipid soluble Nonionized easily absorbed by cell membranes
DO WELL IN ACIDIC
Water soluble ionized not as easily absorbed
DO WELL IN ALKALINE
pH of local environment
drug-drug and food-drug interactions
dietary/herbal product-drug interaction
Distribution – TRANSPORT/ WHERE WILL IT GO?
o TRANSPORT of the drug throughout the body/ movement into various tissues
o Process by which drug molecules will leave blood stream and are transported by bodily
fluids to site of action
o Simplest factor determining distribution is the amount of blood flow to body
tissues, also solubility of protein binding site. REMEMBER ↑profusion is always
our friend.
o Physical properties of drug have high influence
o DRUGS BIND WITH PLASMA PROTEINS:
o Drug can remain free or bind to plasma protein ( ie albumin)
o Many drugs form a drug-protein complex—binding and never reaching target
cells
Protein-binding may affect drug activity in one of two ways: either by
changing the effective concentration of the drug at its site of
action or by changing the rate at which the drug is eliminated, thus
affecting the length of time for which effective concentrations are
maintained.
Why is it important for the nurse to consider protein binding when giving
drugs?
This is important because it is the free drug that traverses cell
membranes and produces the desired effect. It is also important
because a protein-bound drug can act as a reservoir that releases
the drug slowly and thus prolongs its action.
Two drugs can compete for plasma-protein binding sites
The drug with a higher affinity (likeness) will gain the site and
displace the other
Displaced drug can reach high levels & can produce adverse/toxic
effects
When two, highly protein-bound drugs (A and B) are added into the
same biological system it will lead to an initial small increase in
the concentration of free drug A (as drug B ejects some of the
drug A from its proteins).
o Blood-brain barrier and fetal-placenta barrier
Anatomic barrier that prevents many chemicals and medications from
entering
Makes brain tumors difficult to treat
Fetal-placental barrier protects the fetus
METABOLISM- HOW IS IT BROKEN DOWN?
o
o
o
o
Biotransformation
Chemically converts drug so it is easily excreted
Liver is the primary site of metabolism
Side chains—conjugates, makes drug more water soluble to be easily excreted by
kidneys
o METABOLISM IN THE LIVER
Accomplished by the Hepatic microsomal enzyme system
Primary action—to inactivate drugs and accelerate excretion
Pro-drugs have no pharmacological activity unless first metabolized to their
active form by the body
Changes in the function of the hepatic microsomal enzymes can signifigantly
affect drug metabolism
REMEMBER: Children immature liver | Older population deteriorating
liver | Hepatic failure med admin gets complicated
o Dosages should be reduced in patients with impaired
metabolic activity to prevent toxicity
Some drugs increase metabolic activity in the liver (enzyme induction)
o Enzyme induction could increase the metabolism and clearance
of a pharmacologically active drug leading to a reduction in
pharmacological activity
Some drugs reduce metabolic activity in the liver (enzyme inhibitors)
o Enzyme inhibition reduces metabolism
In general, the metabolism of a drug decreases its therapeutic effect
FIRST-PASS EFFECT—The first pass effect is a phenomenon in which a drug gets metabolized at a specific
location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the
systemic circulation.
EXCRETION- HOW DOES IT LEAVE YOUR BODY?
o Site of excretion KIDNEYS
o Easily excreted – easily filtered (glomerulus)
Free drugs remember those protein-binded drugs are locked up (NOT FREE)
therefore, they can be released late, and they cause ↑risk of toxicity – those
sneaky little criminals! Perhaps they will be overrun by a sneakier criminal for that
binding sites.. hint hint! if you don’t get it go back up and review this!!!
Water soluble agents think waters free movement
Electrolytes
Small molecules
o Secreted into distal tubule of nephron
Drug protein complexes
Large substances
o Secretion mechanism is LESS ACTIVE in infants and older adults
o pH of filtrate can INCREASE excretion
o FACTORS AFFECTING DRUG EXCRETION
Liver/kidney impairment
Blood flow remember a good flow is our FRIEND
Degree of ionization of drug
REMEMBER: ionized = water soluble and WE KNOW water soluble
is EASILY EXCRETED (DOSING CONSDERATION HERE)
Lipid solubility of drug
The key point to remember about metabolism is that it makes drugs
less lipid soluble, more water soluble, and therefore easier to
excrete from the body
Drug protein-complexes
Metabolic activity
the goal is to make the drug easier to excrete you need good hepatic
function to do so
SO REMEMBER TO KEEP SPECIAL CONSIDERATION WHEN
DELIVERING MEDS TO: infants, older adults, and those with hepatic
failure!
Acidity or alkalinity (pH)
In acidic urine, alkaline drugs are more readily ionized. Ionized
substances are more soluble in water so dissolve in the body
fluids more readily for excretion.
Respiratory, glandular, or biliary activity
Drugs are also excreted via lungs, sweat glands, skin, intestinal tract
and breastmilk—always consider this
Biliary excretion involves active secretion of drug molecules or their
metabolites from hepatocytes into the bile. The bile then transports
the drugs to the gut, where the drugs are excreted through
feces—sounds like you may want a functioning liver for this form of
excretion (CONSIDERATION!)
o RENAL FAILURE DIMINISHES EXCRETION
Drugs are retained for extended periods
Dosages must be reduced
LET’S TALK DIALYSIS—it’s an ARTIFICIAL KIDNEY
Rapidly flushes you out
Nursing consideration would be to HOLD meds until after dialysis to
preserve a therapeutic effect
o ENTEROHEPATIC RECIRCULATION
Enterohepatic recirculation is the process by which biliary excreted drug is
reabsorbed in the intestine instead of being removed from the body. This
can result in a lagging secondary absorption process and increases in drug
exposure.
Pertains to IV administration
DRUG PLASMA CONCENTRATION & THERAPEUTIC RESPONSE
Concentration of med in target tissue is not easy to measure so it must be measured in
plasma:
o Minimum effective concentration—amt required to produce therapeutic effect
o Toxic concentration—level that would result in serious adverse effects
o Therapeutic ranges—concentration between minimum
effective concentration and toxic concentration
Onset of drug action—time takes to produce therapeutic event
Peak plasma level—when med reaches its highest concentration in blood
Duration of drug action—amt of time drug maintains a therapeutic effect
Plasma Half-Life (t½) – USED FOR Dosing & Frequency
Time takes for drug to decrease by 50%
Metabolism/excretions determines
Greater the half-life, the longer it takes to excrete
Doesn’t change with dose
How does a drug reach and maintain its therapeutic effect?
Repeated doses
Drug accumulates in blood
Plateau is reached
Amount administered = amount excreted
STEADY STATE— Amount administered = amount excreted
A stable/consistent level
Takes approximately 5 half-lives to reach
LOADING DOSE
Single large dose used to raise plasma concentration to a therapeutic level
Higher amt given
Plateau reached faster
MAINTENANCE DOSE - Keeps plasma concentration @ therapeutic level
SERUM DRUG LEVELS:
Peak level—highest plasma concentration
Trough level—drug at its lowest level—30 min before next dose given
Therapeutic range—results show if patient has correct/therapeutic amt of drug
FIVE RIGHTS OF ADMINISTRATION:
1. Right person
2. Right med
THREE CHECKS—checks with MAR when
1. Removing from drawer
2. When preparing med
3. Right before administering
3. Right dose
4. Right Route
5. Right time
ALWAYS CHECK ALLERGIES
BEFORE
Pharmacodynamics
Frequency Distribution Curve
How a medication changes the body
Helps predict the change in a person
Helps determine safe/effective treatment
MEDIAN EFFECTIVE DOSE
o Middle of curve
o Produces therapeutic effect in 50% of a group
o Called average or standard dose
o Many pts require less or more
MEDIAN LETHAL DOSE
o Asses safety
o Shown on curve
o Determined in preclinical trials
o In 50% of group of animals
o NOT ON HUMANS
THERAPEUTIC INDEX
o Measure of drugs safety margin
o THE HIGHER THE VALUE – SAFER THE DRUG
o TI = Median lethal dose
Median effective dose
MEDIAN TOXICITY LEVEL
o Toxicity in 50% of group
From animal data
Adverse effects from clinical trials
o THIS IS NEEDED BECAUSE LETHAL DOSES CAN NOT BE TESTED ON HUMANS
TWO WAYS TO COMPARE MEDICATIONS:
1. Potency – a higher potency produces a therapeutic effect with a smaller dose
2. Efficacy – capacity to produce an effect – efficacy is always more important than potency
RECEPTOR SITE: The better the fit of a receptor site and a drug molecule = better response
Intrinsic activity Ability to activate the receptor
Affinity – likeness
o Strength of a drugs binding ability
o High affinity = strongly attracted to receptor sites, usually potent drugs
o Low affinity = less attracted, weaker drugs
Types of Drug-Receptor Interactions:
Agonist—drug molecule attaches to receptor
o Promotes a function/promotes the same type of response as endogenous substance
o Sometimes produces greater maximal response
o Affinity and intrinsic acidity
Partial agonist—medication that produces a weaker response than agonist
Antagonist
o Affinity for receptor
o No intrinsic activity
o Prevents/blocks a response from happening
ADVERSE EVENT (AE)—Unintended
Anaphylaxis—severe
massive histamine response, you can see:
• Hypotension
• Tachycardia
• Dyspnea
Teratogenic effects—causes harm to fetus
Idiosyncratic response—an unexplained drug reaction
Carcinogenic—potential cause of cancer
TOXICITIES
Neurotoxicity (CNS)
• Drowsiness
• Auditory/visual disturbances
• Seizures
Hepatotoxicity (liver)
• Drug will not be metabolized efficiently
Nephrotoxicity (kidneys)
• Decreased urine output
• ↑ blood urea nitrogen
• ↑ serum creatinine
• Altered acid-base balance
• Electrolyte imbalance
Ototoxicity (8th cranial nerve)
• Tinnitus
• Hearing loss
• Light-headed
• Vertigo
• Nausea
Cardiotoxicity (heart)
• Irregularities in conduction
• HF
• Damage to myocardium
Immunotoxicity (immune system)
Immunosuppression
PATIENT
Infant(birth-12m)
RELATED VARIABLE
Primary goal—administer full dose without spitting out
Held and cuddled
Allow to swallow before administering more w/ syringe
Insert into buccal cavity
Toddler(1-3y)
Preschool(3-5y)
School-aged(5-12y)
Adolescent(13-16y)
Young adulthood18-40y)
Middle aged adults
Older adults(65+)
Immature hepatic function alters metabolism
Never give IM into gluteal—causes permanent damage to sciatic nerve
Always putting things in mouth, major med safety concern at home
Parent education—lock meds up
Flavored elixir’s
never tell a child meds are candy
May need help restraining for IV or injections
May start to understand the need
Safe storage of meds
Can begin to help with administration
Briefly explain that the med will help them feel better
Mixing with food/beverage
After walking you may use ventrogluteal as IM site
More detailed explanation is reasonable
Let them choose a drink they like
Make them feel like a participant in the healthcare team
Independence leads to self-administration of meds
Parents should be educated and aware of recreational use
Most common: for skin, headaches, contraceptives, alcohol/tobacco,
sport related injuries
Privacy is key, talk to them like an adult
Often embarrassed in front of peers which can impact taking
medications at school
Need support, approval, and presence
Educate about: Hazards of tobacco and substance abuse, Sexual
intercourse, Eating disorders
Generally good health
ADME at their PEAK
Medical adherence and compliance is usually good
18-24 there is concern for illicit drug use
Health remains the same as young adult until 45y
Numerous transitions occur
Begin to look for: hypotension, obesity, arthritis, cancer, and anxiety
Diabetic screening begins
Age related change—response to medications
Absorption—decreased gastric motility/increased pH
Distribution—aging liver produces less albumin (protein-binding) which
increased higher level of free drugs
Metabolism—again liver results in first-pass metabolism
MATERNITY
CHANGED IN PREGNANCY
ABSORPTION
Hormonal changes
affect absorption
Inhaled drugs may be
absorbed faster
Teratogen
A substance, organism, or physical agent to
which an embryo or fetus is exposed that
causes permanent abnormality in
structure or function and causes
retardation or death
No absolute teratogens: risk increases with
dose
Current FDA Pregnancy Category
Category
A
Interpretation
Drug
Adequate, well-controlled studies in pregnant women
Have not shown an increased risk of fetal abnormalities to
the fetus in any trimester of pregnancy
Animal studies have revealed no evidence of harm to
the fetus; however, there are no adequate and wellcontrolled studies in pregnant women.
Animal studies have shown an adverse effect, but adequate
and well-controlled studies in pregnant women have
failed to demonstrate risk to the fetus in any trimester.
Prenatal multivitamins, insulin,
thyroxine, folic acid
C
Animal studies have shown an adverse effect and there
are no adequate and well-controlled studies in pregnant
women.
OR No animal studies have been conducted and there are
no adequate and well-controlled studies in pregnant women.
Most prescription medicines;
antimicrobials such as clarithromycin,
fluoroquinolones, and Bactrim;
selective serotonin reuptake inhibitors
(SSRIs); corticosteroids; and most
antihypertensives
D
Adequate well-controlled or observational studies in
pregnant women have demonstrated a risk to the fetus.
However, the benefits of therapy may outweigh the potential
risk.
Alcohol, ACE inhibitors, angiotensin
receptor blockers (ARBs) in the
second and third trimesters,
gentamicin, carbamazepine,
cyclophosphamide, lithium carbonate,
methimazole, mitomycin, nicotine,
nonsteroidal anti-inflammatory
drugs (NSAIDs) in the third
trimester, phenytoin, propylthiouracil,
streptomycin, tetracyclines, valproic
acid
X
Adequate well-controlled or observational studies in animals
or pregnant women have demonstrated positive evidence of
fetal abnormalities or risks. The use of the product is
contraindicated in women who are or may become pregnant.
There is no indication for use in pregnancy
B
Penicillin, cephalosporins,
azithromycin, acetaminophen,
ibuprofen in the first and second
trimesters
Clomiphene, fluorouracil, isotretinoin,
leuprolide, menotropins, methotrexate,
misoprostol, nafarelin, oral
contraceptives, raloxifene, ribavirin,
statins, temazepam, testosterone and
thalidomide, and warfarin
Drugs Secreted into Breast Milk
Fortunately, few instances of harm to infant
Dangerous drugs usually have safe alternatives
Drugs with high protein-binding ability are less likely to enter breast milk
Mother should check all medications with OB MD during lactation
Factors That Affect Drug Exposure Through Lactation
Time between drug administration and breast feeding
Mother's use of illicit drugs
Amount of drug administered
Amount that reaches fetus tissue
Infant's ability to metabolize drug