Download Pharmacology

Introduction to Pharmacology
Pharmacology
2
Pharmacology
• Pharmacology – the study of drugs and their
interactions with living systems
– The study of physical and chemical properties of
drugs and their biochemical and physiologic
effects
– Knowledge of the history, sources, and uses of
drugs
3
What Do We Need to Know
About Drugs?
4
What Do We Need to Know About
Drugs?
• Pharmacokinetics
• Pharmacodynamics
5
Pharmacokinetics
6
Pharmacokinetics
• Pharmacokinetics - How a particular drug gets into
the body and is distributed throughout the body
• Determine how much of an administered dose
gets to its sites of action
• The impact of the body on drugs
• Components of pharmacokinetics
•
•
•
•
Absorption
Distribution
Metabolism
Excretion
7
Pharmacodynamics
8
Pharmacodynamics
• Pharmacodynamics: How a particular drug affects body processes
• The impact of the drug on the body
• Includes:
• Therapeutic or desirable effects
• Side or undesirable effects
• Steps in pharmacodynamics
• The initial step leading to a response is the binding of a drug to
its receptor
• The patient’s functional state has an influence
• Ex. tolerance, placebo
9
What Do You Need to Know About
How Drugs Interact with the
Patient?
10
What Do You Need to Know About
How Drugs Interact with the Patient?
• Patient-specific factors
• Alter the drug’s ability to produce its therapeutic
effects
• Increase the drug’s side effects
• Might cause an idiosyncratic reaction, like a drug
allergy, or other effect particular to that patient
• How to evaluate a patient to identify patient-specific
factors that will impinge on drug administration or
activity
– Ex. if the person is in a coma, you cannot give them a pill
11
Drug-Patient Interactions
12
Drug-Patient Interactions
•Other drugs that the patient is taking
•Sources of individual variation
•Particular characteristics of the patient
•Pregnancy
•Age
•Other characteristics that would affect that
patient’s ability to respond to a drug
13
Drug-Patient Interactions
Sources of Individual Variation
14
Drug-Patient Interactions
Sources of Individual Variation
• Physiologic variables
– Age, gender, weight
• Pathologic variables
– Diminished kidney function, diminished liver function
• Genetic variables
– Alter the metabolism of the drug and can predispose
the patient to unique drug reactions
15
Patient Evaluation
16
Patient Evaluation
 Health status, including cognitive function
 Life span and gender
 Lifestyle, diet and habits:
• Use of over-the-counter (OTC) medications, herbals, dietary substances
etc.
• Substance abuse.
• Health insurance/prescription drug coverage.
• Support system: family, significant other, etc
• Will affect their adherence to the drug regimen
 Environment:
• Occupational or other exposure to toxic substances.
• Setting in which the drug will be administered.
 Culture/Ethnicity:
• Some cultures have a negative view of taking medication
• Religious, social and ethnic background
• Genetic traits.
17
Where Does Patient Information
Come From?
18
Where Does Patient Information
Come From?
• Patient interview
• Observation of the patient
• History and physical examination
• Performed by you or another individual
• Medical record
• Lab values
• Family members, friends, etc.
19
The Nursing Process
Introduction
20
The Nursing Process
Introduction
• Assessment
• Diagnosis
• Planning
• Implementing
• Evaluation
21
The Nursing Process
Assessment
22
The Nursing Process
Assessment
• Includes patient factors and drug information
• Involves collecting data about the patient that is
used to identify actual and potential health
problems
• Establishes a database
23
The Nursing Process
Diagnosis
24
The Nursing Process
Diagnosis
• Identify deficits in patient, known as the
medical diagnosis
• Include a statement of the health
problem and of the problem’s probable
cause or risk factors
25
The Nursing Process
Planning
26
The Nursing Process
Planning
• Maximize therapeutic effects, minimize
adverse effects
• Include the patient/family in the planning
27
The Nursing Process
Implementing
28
The Nursing Process
Implementing
•
•
The rights of drug administration
–
–
–
–
–
Right route
Right patient
Right drug
Right dose
Right time
–
–
–
–
–
Right assessment
Right education
Right to refuse
Right documentation
Right situation/reason
Patient education must be a part of the intervention
• So that the patient understands why they are taking the
drug and why it is important
29
The Nursing Process
Evaluation
30
The Nursing Process
Evaluation
• Is the patient taking the drug as prescribed?
• Is the drug producing the effect it is supposed
to?
• Are the adverse effects acceptable?
• Should the dose be increased or decreased,
or a different drug substituted?
• Does the patient need to continue this
therapy?
31
Important Things to Know about
Drugs
32
Important Things to Know about
Drugs
• How drugs are named and classified
• How drugs are developed
• The legal requirements for drug
administration and dispensing
33
Naming and Classification of
Drugs
34
Naming and Classification of Drugs
•
Every drug has at least three names
•
Chemical Name
•
Generic Name
•
Trade Name
• This system is very confusing and could lead to the
patient receiving the same drug more than once
•
Patient knows the drug by two different names and do
not realize that it is the same drug
35
Chemical Name
36
Chemical Name
• Not used by health care providers
• Describes the chemical structure of the drug.
• This is usually irrelevant to health care
practitioners and patients because we want to
know what the drug does, not its structure.
• Drugs with different chemical structures can do the
same thing.
37
Generic Name
38
Generic Name
• Most important name
• Constant, printed on the label or bottle, not
capitalized
• Assigned to the drug when it is first given to humans.
• The drug is always known by this generic name.
• The generic name printed on a bottle or in an
advertisement might be in parentheses and is not
capitalized.
• Sometimes generic names are hard to say.
• Only one per drug
39
Trade Name
40
Trade Name
• This name is given to the drug by the drug
company that markets it.
• If more than one drug company markets a
particular drug, it will have a different name
for each company.
• This name is capitalized.
41
Acetaminophen
42
Chemical Structure
Chemical Name
N-Acetyl-para-aminophenol
Generic Name
Acetaminophen
Trade Name
Acephen, Aceta, Anacin-3, Apacet, Arthritis Pain
Formula Aspirin Free, Aspirin Free Pain Relief,
Banesin, Bromo Seltzer, Dapa, Datril, Dolane,
Dorcol Children’s Fever & Pain Reducer, Feverall,
Genapap, Genebs, Halenol, Liquiprin Elixir, Meda
Tab, Myapap, Neopap, Oraphen-PD, Panadol,
Panex, Panex 500, Phenaphen Caplets, SnapletsFR Granules, St. Joseph Aspirin-Free for Children,
Suppap-325, Tapanol Extra Strength, Tempra,
Tylenol
Lehne, RA, Pharmacology for Nursing Care, 6th ed., 2007, Elsevier, p. 19
43
In the drugstore, you see pill bottles with the
following names:
1.
2.
3.
4.
Advil (ibuprofen) 200 mg
Ibuprofen, 200 mg
Motrin (ibuprofen) 200 mg
Nuprin (ibuprofen) 200 mg
Which of the following is true?
1.
2.
3.
4.
1.
2.
Advil (ibuprofen) 200 mg,
Ibuprofen, 200 mg
Motrin (ibuprofen) 200 mg
Nuprin (ibuprofen) 200 mg.
25% 25% 25% 25%
They all contain the same
drug.
People with muscle pain
should only take Motrin.
- Could take any of the medications
is
rin
up
N
ot
rin
...
fo
rh
on
ly
ge
ne
e
th
is
ith
w
le
op
Pe
ric
p.
..
cl
e
m
us
ta
in
on
al
lc
- Can be used for any type of pain
ey
Nuprin is only for headaches.
Th
4.
th
e.
..
- Motrin is the trade name
...
Motrin is the generic name
M
3.
Generic vs. Trade Names
46
Generic vs. Trade Names
• Generic names are international and avoid confusion.
• In clinical practice, trade names might be used but
you should always try to look at the generic name too.
• That way, you may avoid giving the same drug twice.
• In this course, we will try to stick to generic names,
although trade names may creep in.
47
Methods of Classifying Drugs
48
Methods of Classifying Drugs
• According to their use (antihypertensives, for instance):
• This may be confusing because many drugs have more than one
use.
• However, this is a classification system used by many people
• One of the most common ways to classify drugs
• According to their mechanism of action:
• This is the most useful classification since it explains all the
actions of the drug
• According to their chemical structure:
• This is of limited usefulness for health care providers
49
Advantages of Classifying According to Mechanism
of Action: Example of Calcium Channel Blockers
50
Advantages of Classifying According to Mechanism of
Action: Example of Calcium Channel Blockers
• Calcium channel blockers block calcium channels in smooth and
cardiac muscles
•When they block calcium channels in vascular smooth muscle, they
dilate vessels and reduce blood pressure.
•When they block calcium channels in the heart, they slow
conduction and so are used for cardiac arrhythmias.
• If we classified them based on their use, we would have to learn about
them at least twice.
•But if we classify them by their mechanism of action, we can learn
about them once and then apply that knowledge to different uses.
51
Classifying by Mechanism of
Action
52
Classifying by Mechanism of Action
• Classification by mechanism enables us to know what a new
drug will do
– Can put it into a class whose mechanism of action we
know
• Allows us to organize drugs in our head and understand what
they do
• Example - if a new calcium channel blocker were introduced,
you would know what it could be used for and what its side
effects might be because you already knew about other drugs
with that same mechanism of action
53
Classifying Drugs in the
Pathopharmacology Course
54
Classifying Drugs in the
Pathopharmacology Course
• We will use a “blend” of classification by use and
classification by mechanisms in this course
• The first time we encounter a particular drug, we will explain its
mechanism of action along with its use in relation to the body
system we are talking about
• If we encounter the same drug later, we will refer you back to its
mechanism and explain how that drug works in the new body
system
• Please read Lehne, p. 21: “What if peas were marketed like
drugs?”
55
Sources of Drug Information
Changes in Drugs
56
Sources of Drug Information
Changes in Drugs
• Drug information changes almost daily
• New drugs are constantly being introduced
• New dosage forms or routes of administration may be
approved for older drugs
• New adverse events may be uncovered and new
warnings may be issued
• Drugs may be taken off the market
57
Sources of Drug Information
58
Sources of Drug Information
1. Pharmacology book (Lehne)
- Goes into detail about the use and actions of the drug
2. Physicians’ Desk Reference (PDR) for prescription drugs and for OTC drugs
- Compendium of the prescribing information for each drug
- Written by lawyers who write it defensively
- All of the side effects of the drug are stated
- Includes only what the FDA has approved the drug company to say about the drug
3. Formularies
- In hospitals
- Includes drugs used in the agency
- Lists of drugs that are approved for use in the hospital and agency and include standards for how
they are to be used
4. Drug compendiums
- Quick and dirty reference
- Includes the dose, type of pills, strength
5. Web sites
- There are good and bad websites
- Example of a good website – NIH, CDC, FDA
- Example of a poor website – blogs
6. Drug companies
- Cannot tell you anything that has not been approved by their lawyers
7. People, such as health care personnel
59
How Drugs are Developed
60
How Drugs are Developed
•
In order to be marketed, a drug must be approved by the Food and Drug
Administration.
• Vitamins and other dietary supplements are not drugs; they are foods
• They are approved in the same way as drugs
•
The drug company must show evidence of efficacy.
• Must show that the drug works in order to help a particular condition
• The development process can only be conducted with respect to one
particular condition or disease (indication)
• The drug company must have an indication – a disease or condition that the
drug is supposed to make better.
•
A particular drug might be good for more than one thing, but the drug company has to
choose for which use they want to seek approval.
• If the drug is ultimately approved, the approval will be for that indication only.
• Later, the FDA may approve the drug to treat a different indication after
conducting a second set of trials
61
Stages of Drug Development
62
Stages of Drug Development
-
Preclinical testing
-
-
Performed in animals
Drugs are tested for toxicity
May take one-five years
If successful, the drug is awarded new drug status and begins clinical testing
Clinical testing
- Performed in humans
- May take two-ten years
- Phase one
- Conducted in healthy volunteers
- Evaluate drug metabolism, pharmacokinetics, pharmacodynamics
- Aim to determine the maximum tolerated dose
- Phases two and three
- Tested in 500-5,000 patients
- Goal is to determine therapeutic effects, dosage range, safety, and effectiveness
- At the end, the drug company applies for conditional approval and begins phase four
- Phase four: postmarketing surveillance
- New drug is released for general use
- Observe the effects of the drug in the general population
63
Randomized Control Trial
64
Randomized Control Trial
• The development and testing of new drugs requires 612 years to complete
• Thousands of compounds undergo testing, a few enter
clinical trials, and 20% gain approval
• The cost of developing a new drug can exceed $800
million
• Testing can guarantee effectiveness but cannot
guarantee that a drug will be safe
– Adverse effects may appear after the drug has been
released for general use
• Randomized control trials (RCTs) are the most reliable
way to objectively assess all new drugs
65
Distinguishing Features of
Randomized Control Trials
66
Distinguishing Features of
Randomized Control Trials
• Use of controls
• Randomization
• Blinding
67
Off-Label Use
68
Off-Label Use
• Once a drug is approved for marketing, it can be prescribed for
anything by anyone authorized to prescribe drugs.
• Off-label use - if the prescriber gives a drug for a use for which it
is not approved
• There is nothing illegal about giving a drug for an off-label use,
but if an adverse event occurred, the provider could be sued for
malpractice.
• Typically, when drugs are prescribed off-label, there is evidence
in the literature that supports the off-label use so that an individual
provider can say that the use is supported.
69
Safety
Cost-Benefit Assessment
70
Safety
Cost-Benefit Assessment
• Drug companies must also provide evidence that the drug being
developed is safe, but there is no such thing as a completely safe
drug.
•Every drug possesses adverse effects
• The danger presented by the drug has to be balanced against the
benefits.
•We (and the FDA) are willing to compromise on safety if the
benefits are great.
•A life-saving drug that will cure cancer might have a lot of
adverse effects, but if your life were saved, it would be
worth it.
•We do not want a very dangerous drug for a trivial health
problem.
71
Safety
Long-term and Over-the-counter
Drugs
72
Safety
Long-term and Over-the-counter Drugs
• We would expect a drug that is to be taken for a
long period of time—such as an antihypertensive
drug—to be safer than one that would be taken
for a short time or only once.
• Over-the-counter drugs should be safer than
prescription drugs because we expect the
prescriber of a prescription drug to monitor the
patient, whereas this does not occur with overthe-counter drugs.
73
Pre-Clinical Studies
74
Pre-Clinical Studies
• Provide evidence of efficacy in the animal.
• Provide a rough idea of an effective dose that can be upscaled for
humans.
• In order to receive permission from the FDA to administer the drug
to humans in a clinical trial and garner data for safety and efficacy,
the drug company must have pre-clinical data.
• The drug will be given to animals
• There is an understanding that it is meant for eventual use in humans
(although it could also have veterinary use).
• Initial studies are often done in mice or rats, but sometimes in other
animals.
• Ex. you cannot test an anti-emetic drug in mice or rats, because they can’t
vomit; hence, cats, dogs, or ferrets are used in that case.
75
Safety Studies in Animals
76
Safety Studies in Animals
• Adverse effects
•Increasing doses of the drug
•How the drug is distributed in the body and how it is eliminated
•Blood, urine and organs
•Safety data of different time courses
•Short and long-term administration
•Animals on long-term administration are monitored for the
development of cancer
•Terotogenicity in pregnant animals
77
Use of Primates in Animal
Studies
78
Use of Primates in Animal Studies
• Primates may be given the drug to show that
effects in them are similar to smaller
(cheaper) animals.
• The use of primates in animal research is
becoming more rare; used only when necessary
• Ex. when a smaller animal does not have a disease
found in humans, such as HIV
79
Investigative New Drug (IND)
80
Investigative New Drug (IND)
• The drug company presents all this pre-clinical
data to the FDA in an IND application.
• The IND application is a request to the FDA for
approval to enter clinical trials on humans.
• The IND also includes a plan of how human
testing will be conducted.
81
Testing New Drugs in Humans
Phase I
82
Testing New Drugs in Humans
Phase I
• Determine the dose to be used in future studies.
• Normal people—not people with the condition that the drug is to be used
for—are used.
• The exception is for cancer and some AIDS drugs
•
Most Phase I trials have fewer than 50 subjects, sometimes only 10 or so.
•
A low dose is started and if the people tolerate it, the dose is increased.
• The dose is increased in a stepwise fashion until intolerable adverse
events occur – this is called the maximum tolerated dose (MTD).
•
Measurements of blood and urine are taken to determine how the drug is
distributed and eliminated.
– Pharmacokinetics
83
Testing New Drugs in Humans
Phase II
84
Testing New Drugs in Humans
Phase II
• Patients with the condition to be treated are used.
• Phase II trials typically include fewer than 50 subjects.
• At the end of Phase II, we would expect to know:
• A lot about drug distribution and elimination and
• A dosage range that is effective for the condition being treated.
• Blood and urine are taken to determine the distribution and
elimination.
• Dosages are adjusted based on response.
85
Testing New Drugs in Humans
Phase III
86
Testing New Drugs in Humans
Phase III
•
A large clinical trial is conducted with several hundred subjects who have the
condition
•
Demonstrate safety and efficacy of the drug in treating that indication
•
The drug must be compared with something – either a placebo, or if that is not
ethical, with the standard treatment for that condition.
•
•
Subjects are randomized to receive either the investigational drug or the comparator (placebo
or standard treatment).
The design is usually double blinded (neither the subject nor the person administering the
drug knows whether it is the experimental drug or the comparator).
• Randomized control trial
•
The trial may last several months or even years.
•
Subjects are monitored very carefully for progression of their disease and for
adverse events.
•
There may be more than one Phase III trial if the FDA thinks it is necessary.
•
If the drug company wants to market the drug for more than one indication, there would be a87
Phase III trial for each indication.
Phase III
Inclusion and Exclusion Criteria
88
Phase III
Inclusion and Exclusion Criteria
• Inclusion criteria for subjects
• Make sure that the subjects actually have the disease in
question
• Subjects are likely to be helped by the therapy
• Exclusion criteria exclude people likely to be harmed by the
therapy
• Ex. Pregnant women and people with serious
comorbidities.
• The problem with this is that it causes the research on the
effect of drugs on pregnant women and fetuses to be scant
89
Clinical Testing
90
Clinical Testing
• The FDA or the drug company can stop the
process at any time.
• At the end of the Phase III trials, the company
can submit a new drug application (NDA).
• Data from Phase I, Phase II and Phase III are
presented.
• A draft of the prescribing information is proposed—the
material to be published in the PDR and included on the
package insert.
• The drug company and the FDA negotiate the prescribing
information, warnings about particular adverse effects, etc.
• The prescribing information is a legal document
91
Testing New Drugs in Humans
Phase IV: Postmarketing Surveillance
92
Testing New Drugs in Humans
Phase IV: Postmarketing Surveillance
• It is imperative to continue surveillance after approval.
•
You could have a post-marketing study – this would be called a Phase IV
study. Most of the time, there is not a formal study.
• Usually is not done because it costs the drug company money
•
Unfortunately, post marketing surveillance relies on spontaneous reports
from practitioners or patients about adverse events.
•
A particular adverse event may not be attributed to a drug until the drug
has been on the market a number of years and a significant number of
people have taken the drug.
•
Since there is no control group, it is very hard to show that a particular
adverse event is due to the drug and is not just a coincidence.
93
New Drug Approvals
94
New Drug Approvals
• If all goes well, the company gets permission to market the drug
for the indication used in the clinical trials.
• In Phase I, Phase II, and Phase III, the drug may have been given
to fewer than 1000 people, maybe fewer than 500.
• When it is marketed, it may be given to millions of people.
• Since the drug was given to relatively few people before it was
approved, rare adverse events may not be evident before
approval.
• If an adverse effect has a one in a million chance, it may not
show up often or at all in the clinical trial but likely will when
it is marketed to the general public
95
In Which Stage of Drug
Development are Researchers
Concerned with the Drug’s
Maximum Tolerated Dose?
96
In which Stage of Drug Development are Researchers
Concerned with the Drug’s Maximum Tolerated Dose?
e
as
Ph
Ph
as
e
IV
.
II
Ph
as
e
e
as
25% 25%
III
25%
I
Phase I
Phase II
Phase III
Phase IV.
Ph
1.
2.
3.
4.
25%
Difference between Generic and
Brand Name Drugs
98
Difference between Generic and
Brand Name Drugs
• At this time, there is NO difference between
generic drugs and brand name drugs and NO
reason to buy the brand name over the
generic.
• The FDA has standards that force the company
marketing the generic to make sure the generic
drug is the same as the trade name drug in terms
of its activity and purity.
99
Patents
100
Patents
• When a drug is first approved, it is protected by a patent issued to the drug
company that developed it.
• No one else can produce the drug and they can charge whatever they
want
• The patent length is variable
• It is marketed under that company’s brand name with the generic name in
parenthesis.
•
After the patent expires, anyone can make the drug (as long as they satisfy
the FDA’s manufacturing standards).
• If the original drug company comes out with some improvement, however,
they can get a patent on the improvement and therefore extend their ability
to charge a high price for the drug.
• Example – long-acting preparations of short-acting medications can be eligible for a
new patent.
101
Drug Pricing
102
Drug Pricing
• The drug company typically charges a really high
price because they are trying to recoup their cost of
developing the drug.
• At that point, one or more other companies usually
make the drug available as a generic – it only has the
generic name and no trade name.
• Usually is much cheaper
103
Controlled Substances
104
Controlled Substances
•
Controlled substances are those that have a potential to be abused.
•
Controlled substances are regulated by the Drug Enforcement Administration,
NOT the FDA.
•
Each prescriber must have a DEA number that is on the prescription and every
prescriber must comply with DEA regulations. However, who can be a
prescriber is generally regulated by each state.
• Ex. NPs in most states can prescribe, but their limitations varies by state
•
Nurses, pharmacies and hospitals must also comply with DEA regulations to
handle controlled substances.
•
The regulations include keeping track of quantities of controlled substances and
who receives them.
105
Drug Schedules
106
Drug Schedules
Schedule
Abuse
Potential
Dependence
Liability
Examples
Rules
I
High
Severe
Heroin, LSD
No acceptable use
Research only
II
High
Severe
Amphetamines, some
opioids
Triplicate prescriptions, no
refills, limit the quantity of
drugs/number of pills,
typed or ink-written
prescriptions
III
Moderate Moderate
Some opioids, some
stimulants, anabolic
steroids
Written or telephone
prescription every 6
months, up to five refills
allowed
IV
Low
Limited
Tranquilizers, weak
opioids ex. valum
Same as schedule III
V
Limited
Lowest
Antidiarrheals
(Lomodium) drugs
that contain small
amounts of opioid in
a medication mixture
Many OTC
107
Definition
Pharmacology
108
Definition
Pharmacology
The study of drugs and their
interactions with living systems
109
Definition
Drug
110
Definition
Drug
A drug is any chemical that can
affect a living process.
111
Pharmacokinetics
112
Pharmacokinetics:
- The effect of the body on the drug
1. The study of how a drug gets to its receptor in the
body. This is broken down into absorption and
distribution.
2. The study of how a drug is changed or excreted by
body processes. This is called elimination.
- Includes metabolism and elimination
113
Pharmacodynamics
114
Pharmacodynamics:
The study of the interaction
between a drug and its receptor to
produce an effect.
-What drugs do in the body
-The effect of the drug on the
body
115
Receptor Theory
116
Receptor Theory
1. Drugs interact with the receptors,
which are physiologically important
macromolecules.
2. Drugs alter the rate – either up or
down – of the natural function of the
macromolecule.
117
Drugs Cause Effects by Binding to
Receptors
118
Drugs Cause Effects by Binding to
Receptors
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 50
119
What Types of Physiologically
Important Macromolecules Serve
as Drug Receptors?
120
What Types of Physiologically Important
Macromolecules Serve as Drug Receptors
•Almost any molecule in the body can serve
as a drug receptor.
•Ex. enzymes, neurotransmitter receptors, ion
channels, transport proteins, etc, can be
drug receptors.
121
Use of the Term “Receptor” by
Pharmacologists
122
Use of the Term “Receptor” by Pharmacologists
• Receptor - a macromolecule with an
endogenous ligand
• Ligand - a chemical that binds to a receptor
and activates it, causing some change to
occur
• Ex. in the previous slide, acetylcholine is the
ligand
• There are four classes of macromolecule
that are usually defined as receptors
123
Classes of Macromolecules Defined
as Receptors
Classical Receptors
124
Classes of Macromolecules Defined as Receptors
Classical Receptors
• Membrane-bound enzymes with activating
ligands.
• Ligand-gated ion channels
• G-protein coupled neurotransmitter receptors
• Transcription factors with activating ligands
125
Examples of Endogenous Ligands
126
Examples of Endogenous Ligands
• Neurotransmitters bind to neurotransmitter
receptors, which can be of several types.
•Ex. norepinephrine binds to the beta-1
receptor and acts as an agonist, causing
effects
•Causes the heart to speed up
• Steroids
bind to their respective receptors
which are transcription factors.
127
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 48
128
Receptors with Endogenous Ligands
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 49
129
Four Primary Receptor Families
130
Four Primary Receptor Families
• Cell-membrane embedded enzymes
• Ligand gated ion channels
• G-Protein coupled receptor system
• Transcription factors
131
Cell-membrane Embedded
Enzymes
132
Cell-membrane Embedded
Enzymes
• Cell membrane-embedded enzymes span the cell membrane
• The ligand-binding domain is located on the cell surface
• The enzyme’s catalytic site is located inside
– Binding of an endogenous regulatory molecule or agonist drug (one
that mimics the action of the endogenous regulatory molecule)
activates the enzyme, thereby increasing its catalytic activity
• Responses to activation of these receptors occur in seconds
• Ex. insulin is an endogenous ligand that acts through this type of
receptor
133
Ligand Gated Ion Channels
134
Ligand Gated Ion Channels
• Span the cell membrane
• Function to regulate the flow of ions into and out of
cells
– Each ligand-gated channel is specific for a particular ion
• When an endogenous ligand or agonist binds the
receptor, the channel opens, allowing ions to flow
inward or outward
– The direction of flow is determined by the concentration
gradient of the ion across the membrane
• Responses to activation of the channel are extremely
fast, occurring in milliseconds
• Ex. neurotransmitters, such as GABA
135
G-Protein Coupled Receptor System
136
G-Protein Coupled Receptor
System
• Possess three components
– The receptor itself
– G protein (named because it binds GTP)
– An effector (typically an ion channel or an enzyme)
• Binding of an endogenous ligand or agonist drug activates the receptor,
which in turn activates G protein, which in turn activates the effector
• Responses develop rapidly
• Ex. many endogenous ligands act through G protein-couples receptor
systems, such as NE, serotonin, histamine, and many peptide hormones
• The receptors that couple to G proteins are serpentine structures that
traverse the cell membrane seven times
– The ligand-binding domain may be on the cell surface or located in a pocket
accessible from the cell surface
137
Transcription Factors
138
Transcription Factors
• Differences from other receptors
– Found within the cell rather than on the surface
• Situated on the DNA in the cell nucleus
– Responses to activation are delayed – may take several hours to days
• Transcription factors function to regulate protein synthesis
• Activation by endogenous ligands or by agonist drugs stimulates
transcription of messenger RNA molecules, which then act as templates
for synthesis of specific proteins
• Because transcription factors are intracellular, they can only be activated
by ligands that are sufficiently lipid soluble to cross the cell membrane
• Ex. thyroid hormone, steroid hormones (progesterone, cortisol,
testosterone)
139
Other Macromolecules that
Drugs Can Bind to
140
Other Macromolecules that Drugs
Can Bind to
• Enzymes
• Ribosomes
• Tubulin
• DNA or RNA
• Transporters
• Others
141
Drug Specificity
Binding to One Receptor
142
Drug Specificity
Binding to One Receptor
• If a drug only binds to one receptor type, it will be very specific
in its effects.
•Will only cause an effect in places in the body where the
specific receptor is located
143
Drug Specificity
Binding to Multiple Receptor
144
Drug Specificity
Binding to Multiple Receptor
• Many drugs bind to more than one receptor type and
have effects due to activity at all those receptors.
• If a drug has activity at more than one receptor, that might
be good --- for instance a drug that blocks both β and α
receptors might be a good anti-hypertensive agent.
• For instance, many beta blockers bind to both β1 and β2 receptors.
These drugs can cause bronchiolar constriction at beta-2 receptors
in the bronchi as well as slowing of heart rate at beta-1 receptors
at the SA node in the heart.
•
Conversely, activity at a second receptor might be
undesired—for instance a β blocker might also block
serotonin receptors and cause bad dreams.
145
Dose-Response Curves
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 47
146
Dose-Response Curve
1. Before the threshold, few receptors are bound by drug
and such a small response is produced, it is not
detectable in a whole animal or person.
Threshold occurs between phase one and phase two
2. After the threshold is reached and a response can be
detected, more drug produces a bigger effect because
more receptors are bound.
3. At the plateau, all receptors are bound by drug, and no
matter how much more drug is given, no additional
147
response is produced.
Basic Features of the DoseResponse Curve
148
Basic Features of the DoseResponse Curve
• Dose-response relationship – the relationship between the
size of an administered dose and the intensity of the
response produced
• The dose-response relationship is graded
• As the dosage increases, the response becomes
progressively larger
• To tailor treatment to a patient, need to raise or lower the
dosage until a response of the desired intensity is achieved
149
Phases of the Dose-Response
Curve
150
Phases of the Dose-Response
Curve
• Phase I occurs at low doses
– The curve is flat during this phase because doses are too low to elicit a
measurable response
• Phase II
– An increase in dose elicits a corresponding increase in the response
– The phase during which the dose-response relationship is graded
• Phase III
– The curve flattens out again
– Point where an increase in dose is unable to elicit a further increase in
response
151
Simple Occupancy Theory
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 51
152
Simple Occupancy Theory
• The intensity of the response to a drug is
proportional to the number of receptors
occupied by that drug
– Presumably, all receptors are occupied when the
dose-response curve starts to level off
– A maximal response will occur when all available
receptors have been occupied
153
Simple Occupancy Theory
Important Points
154
Simple Occupancy Theory
Important Points
• The receptors through which drugs act are
normal points of control of physiologic processes
• Under physiologic conditions, receptor function is
regulated by molecules supplied by the body
• All that drugs can do at receptors is mimic or
block the action of the body’s own regulatory
molecules
• Drugs cannot give cells new functions, but rather
can only alter the rate of pre-existing processes
(except with gene therapy)
155
Simple Occupancy Theory
Things that are Not Explained
156
Simple Occupancy Theory
Things that are Not Explained
• Things that are not explained
– Why one drug is more potent than another drug
– How one drug can have higher maximal efficacy
than another
• Assumes that all drugs acting at a particular
receptor are identical with respect to
– The ability to bind to the receptor
– The ability to influence receptor function once
binding has taken place
157
Efficacy vs. Potency
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 47
158
Potency vs. Efficacy Explanation
159
Potency vs. Efficacy Explanation
1. A more potent drug binds the receptors more
avidly, so that a high proportion of receptors are
bound with drug even at low doses. This
produces a response at low doses.
2. The second drug that is less potent is not
attracted to the receptors to the same extent and
it takes higher doses to produce the same degree
of receptor occupancy.
160
Potency
161
Potency
• Potency – the amount of drug necessary in order to produce an effect
– Indicated by the relative position of the dose-response curve along the x
(dose) axis
– The closer to 0 on the axis, the more potent the drug
– A more potent drug produces its effects at low doses
• In diagram B, both drugs are 100% efficacious because they produce the
same effect, but morphine is more potent because it produces it at a
lower dose
• Potency refers to the dose, while efficacy refers to the maximal effect
• Potency is rarely an important characteristic of a drug
• Potency does not make a drug superior; it only means that the drug can be
given in smaller doses
162
Efficacy
163
Efficacy
• Efficacy- the ability of a drug to produce an effect
• In diagram A, the maximum effect of meperidine is much
higher than that of pentazocine so it is more efficacious
– They are equally potent but not equally efficacious
• Maiximal efficacy – the largest effect that a drug can
produce
– Indicated by the height of the dose-response curve
• A drug with very high maximal efficacy is not always more
desirable than a drug with a lower maximal efficacy
164
Modified Occupancy Theory
165
Modified Occupancy Theory
• Modified occupancy theory takes into account that a drug
binding to a particular receptor may:
1. Mimic the endogenous ligand’s activity at that receptor to produce
activity
2. Produce a lesser effect than the endogenous ligand
ex. pentazocine in the last diagram
3. Produce no effect.
• A drug that produces no effect at the receptor will produce
an effect in the body by preventing the binding of the
endogenous ligand.
166
Characteristics of the Modified
Occupancy Theory
167
Characteristics of the Modified
Occupancy Theory
• The intensity of the response is related to the number
of receptors occupied, but also to the ability of the
drug to activate receptors once bound to them
• Explains observations that cannot be explained by the
simple occupancy theory
• Components of the modified occupancy theory
– Affinity
– Intrinsic activity
168
Modified Occupancy Theory
Affinity
169
Modified Occupancy Theory
Affinity
• Affinity – the strength of the attraction between a
drug and its receptor
– The higher the affinity, the stronger the attraction to
the receptors
• The affinity of a drug for its receptors is reflected
in its potency
• Drugs with high affinity can bind to their
receptors when present in low concentrations
and have greater potency
170
Modified Occupancy Theory
Intrinsic Activity
171
Modified Occupancy Theory
Intrinsic Activity
• Intrinsic activity – the ability of a drug to activate the
receptor following binding
– Drugs with high intrinsic activity cause intense receptor
activation
• The intrinsic activity of a drug is reflected in its
maximal efficacy
• Drugs with high intrinsic activity have high maximal
efficacy because they are able to cause intense
responses by causing intense receptor activation
172
Intrinsic Activity
Agonists and Partial Agonists
173
Intrinsic Activity
Agonists and Partial Agonists
• Intrinsic activity- The ability of a drug to activate a particular
receptor when bound to it.
• Endogenous ligands have full (100%) intrinsic activity.
• Full agonists mimic the endogenous ligand and have full
intrinsic activity.
• Ex. meperidine in the previous example
• Partial agonists have less than full intrinsic activity (they are
less efficacious than full agonists).
• Ex. pentazocine
174
Intrinsic Activity
Antagonists
175
Intrinsic Activity
Antagonists
• Antagonists have no intrinsic activity.
• Antagonists block the activity of the endogenous ligand by
occupying the receptor and preventing the endogenous ligand
from binding
• The effect of an antagonist depends on the concentration of
agonist (endogenous ligand) present.
• If there is no agonist present, administration of an antagonist
will have no observable effects
• The drug will bind to its receptors but nothing will happen
• *If receptors are undergoing activation by agonists,
administration of an antagonist will shut the effects of the
agonist down by blocking the receptor sites for the agonist
• The effect of a competitive antagonist can be overcome by
increasing the concentration of an agonist
176
Noncompetitive vs. Competitive Antagonism
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 53
177
Competitive vs. Noncompetitive
Antagonism
1. A competitive antagonist binds reversibly to the receptor such that bound drug is in
equilibrium with unbound drug.
- The binding between an antagonist and the receptor in competitive binding is
electrostatic and thus is reversible
2. As a given molecule of drug unbinds from the receptor, its place may be taken by
another molecule of the same drug, or it may be taken by a molecule of the
endogenous ligand.
3. If we’re trying to overcome the effect of the 1st drug (an antagonist), we could give a
2nd drug (an agonist) in high dose, increasing the chance that a vacant receptor
will be occupied by the 2nd agonist drug in place of the 1st antagonist drug.
- Can compete with a competitive antagonist by adding more agonist
4. At high enough concentrations of the agonist, we “win the competition”, ensuring
that vacant receptors will always bind agonist.
- The same maximum effect occurs because all of the receptors are bound
178
Competitive (Surmountable)
Antagonism
179
Competitive (Surmountable)
Antagonism
• More common type of antagonist
• Bind reversibly to receptors
– Produce receptor blockage by competing with
agonists for receptor binding
• If an agonist and an antagonist have equal
affinity for a receptor, it will occupied by
whichever is in a higher concentration
• Because binding is reversible, the inhibition
that competitive antagonists cause can be
surmountable by adding more agonists
180
Noncompetitive
(Insurmountable) Antagonism
181
Noncompetitive (Insurmountable)
Antagonism
• Bind irreversibly to receptors
– Reduces the total number of receptors available for
activation by an agonist
• Reduces the maximal response that an agonist can elicit
• Because the binding of noncompetitive antagonists is
irreversible, inhibition by these agents cannot be
overcome, no matter how much agonist is given
• Noncompetitive antagonists are rarely used
therapeutically because they are irreversible
• The effects of noncompetitive antagonists wear off as
the receptors to which they are bound are replaced
• The effects may subside in a few days
182
Which of the Following Terms is
Defined as “the Ability of a Drug
to Activate a Receptor upon
Binding”?
183
Which of the Following Terms is Defined as “the Ability of
a Drug to Activate a Receptor upon Binding”?
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1. Affinity - the strength of
the attraction between
a drug and its receptor
2. Intrinsic activity
3. Efficacy – maximum
effect of the drug
4. Potency – dose of the
drug needed to elicit a
response
ity
25% 25% 25% 25%
Regulation of Receptor
Sensitivity
185
Regulation of Receptor Sensitivity
• Receptors continually exposed to agonist may
downregulate their response.
• Rapid downregulation: tachyphylaxis or
desensitization.
• Slower, more permanent downregulation:
tolerance or tachyphylaxis.
186
Example of Downregulation or
Tolerance
187
Example of Downregulation or Tolerance
•Opioid tolerance - people who take opioid
drugs for chronic pain gradually have to
increase the dose because the dose they are
taking becomes ineffective in relieving their
pain.
• Ultimately, they may be taking doses that will
cause a respiratory arrest in a drug-naïve person.
•They are able to remain active and alert
because they have tolerance to the drug.
188
Other Causes of Decreased Drug
Effect
189
Other Causes of Decreased Drug
Effect
•Receptor downregulation is not the only reason
for loss of drug effect.
•Anything that speeds up the elimination of the
drug from the body will result in lower drug
levels and less effect.
190
Receptor Upregulation
191
Receptor Upregulation
• If a person takes an antagonist for a prolonged period, receptors
may be upregulated so there are more of them per cell.
•Increase in receptor number in order to have more receptors
available for the agonist
• The antagonist still has an effect if it is present in high enough
concentration.
•Supersensitivity - the problem comes when the person stops
taking the antagonist—since there are more receptors, the
endogenous agonist will have a pronounced effect.
•Need to slowly lower the level of antagonist being taken
192
Receptor Regulation
193
Receptor Regulation
• Sudden discontinuation of the drug allows the
endogenous agonist to have access to the receptor.
• In the case of desensitization following prolonged agonist
administration, the endogenous agonist may have little
effect, thereby producing a deficiency state.
• In the case of increased sensitization following prolonged
antagonist administration, the endogenous agonist may
produce greatly exaggerated effects.
194
Patient Variability in Drug
Responses
195
Patient Variability in Drug Responses
• Up until now, the dose-response curves I
have shown you were obtained in one
animal or one person.
• Drug response varies between individuals.
• Frequency distribution curves show us
how a population responds to a drug.
196
Frequency Distribution Curves
197
Frequency Distribution Curve
ED50= Effective Dose 50%
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 54
198
How to Determine a Frequency
Distribution Curve
199
How to Determine a Frequency
Distribution Curve
-
Begin with a number of people who are receiving the drug
-
Define a response
-
This is an important step
Need to have at least the response in order to qualify
-
Give a dose of drug and see how many people responded to that drug
-
Give the remaining people a higher dose of the drug (after the previous dose is
eliminated from the body)
-
Continue increasing the dose until all individuals respond to the dose
-
People respond at varying doses
-
At the peak of the frequency distribution curve is the ED50, the effective dose 50%
- 50% of the people responded with that dose
200
Frequency Distribution Curve
Explanation
201
Frequency Distribution Curve Explanation
1.
A response is strictly defined. For instance, it might be defined as a 10%
reduction in BP for an antihypertensive.
2.
If a low dose is given, a few people (2 in the example) will exhibit a response.
(That doesn’t mean that the other people will have no change. It just means
that the degree of change doesn’t meet the definition of a response.) The
responders are removed from the mix.
3.
As the dose is increased, more and more people will achieve the response.
4.
At some dose, all of the subjects will achieve the response.
5.
When the curve is plotted, there will be some dose at which 50% of the
population tested will have achieved a response. This dose is called the
“effective dose 50%” or ED50.
202
Therapeutic Index
203
Therapeutic Index
• Therapeutic index – a measure of the drug’s safety
– The ratio of a drug’s LD50 to its ED50 (therapeutic dose)
• Average lethal dose – the dose that is lethal to 50% of the animals
treated
– The lethal dose is only tested in animals
– A large therapeutic index indicates that a drug is relatively
safe
– LD50/ED50
• When there is overlap between the ED curve and the LD
curve, it shows that the high dose needed to produce
therapeutic effects in some people may be large enough to
cause death in others
• The larger the therapeutic index, the greater the space
between the therapeutic dose and the lethal dose
204
Therapeutic Index
LD50= Lethal Dose 50%
Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 55
205
Therapeutic Index
Maximum Tolerated Dose
206
Therapeutic Index
Maximum Tolerated Dose
• We
do not usually determine LD50 in
animals, but instead determine the maximum
tolerated dose in humans.
• Numerical values for TI are rarely spoken
about, but the concept of a large therapeutic
index being associated with a safer drug is
frequently used.
207
Definitions
Undesirable Drug Responses
208
Definitions
Undesirable Drug Responses
•Toxicity: an undesirable or dangerous effect of a
drug brought about by high drug levels.
•Side effect: an undesirable effect of a drug that occurs
at therapeutic levels of the drug and is the result of the
interaction of the drug with a receptor.
•Allergic response: a response to a drug that is
mediated by the immune system.
209
Choice of a particular drug is frequently
dictated by side effects
Beetle Bailey
BY MORT WALKER
© Copyright 2007 King Features Syndicate. All Rights Reserved
Allergic Responses
211
Allergic Responses
•Anaphylaxis, rashes, hives, etc, produced by the immune
system interacting with the drug.
•Patients who have allergic symptoms due to a drug should
discontinue that drug right away.
•The patient could be given another drug (usually from a
different class or with a distinctly different chemical
structure) that produced the same therapeutic effect in the
hope that he/she would not be allergic to the new drug.
•An exception to this is allergic reactions to nonsteroidal
anti-inflammatory agents (NSAIDs), such as aspirin or
ibuprofen.
212
•Will have allergic responses to all NSAIDs
A frequency distribution curve for an
antihypertensive agent shows an
ED50 of 10 mg when the response is
defined as a 10% lowering of blood
pressure. What would happen if the
response definition were changed to
a 25% lowering of blood pressure?
213
A frequency distribution curve for an antihypertensive agent
shows an ED50 of 10 mg when the response is defined as a 10%
lowering of blood pressure. What would happen if the response
definition were changed to a 25% lowering of blood pressure?
The curve will shift to
the right (toward higher
doses)
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The curve will shift to
the left (toward smaller
doses.
The curve will not
change.
The curve will broaden
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Will make the response
more difficult to obtain,
so higher doses will be
required
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1.
Things to Look Up
• Slide 176 - If receptors are undergoing activation by
agonists, administration of an antagonist will shut
the effects of the agonist down by blocking the
receptor sites for the agonist
• Slide 178 – competitive vs. noncompetitive
antagonism
215
Things to Ask
• Slide 176 - If receptors are undergoing activation by
agonists, administration of an antagonist will shut
the effects of the agonist down by blocking the
receptor sites for the agonist
• Slide 178 – competitive vs. noncompetitive
antagonism
• Slide 192 - What determines whether a drug will
result in receptor downregulation or upregulation?
216