introduction to pharmacology. pharmacology 2 pharmacology – the study of drugs and their...

Introduction to Pharmacology

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

What Do We Need to Know About Drugs?

• Pharmacokinetics

• Pharmacodynamics

Pharmacokinetics

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

Pharmacodynamics

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

What Do You Need to Know About How Drugs Interact with the

Patient?

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

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

Drug-Patient Interactions

Drug-Patient InteractionsSources 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

Patient Evaluation

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.

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.

The Nursing ProcessIntroduction

• Assessment

• Diagnosis

• Planning

• Implementing

• Evaluation

The Nursing ProcessAssessment

• 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

The Nursing ProcessDiagnosis

• 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

The Nursing ProcessPlanning

• Maximize therapeutic effects, minimize adverse effects

• Include the patient/family in the planning

The Nursing ProcessImplementing

• 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

The Nursing ProcessEvaluation

• 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?

Important Things to Know about Drugs

• How drugs are named and classified

• How drugs are developed

• The legal requirements for drug administration and dispensing

Naming and Classification of Drugs

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

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.

Generic Name

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

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.

Acetaminophen

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, Snaplets-FR 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

In the drugstore, you see pill bottles with the following names:

1. Advil (ibuprofen) 200 mg2. Ibuprofen, 200 mg3. Motrin (ibuprofen) 200 mg4. Nuprin (ibuprofen) 200 mg

Which of the following is true?1. Advil (ibuprofen) 200 mg, 2. Ibuprofen, 200 mg 3. Motrin (ibuprofen) 200 mg 4. Nuprin (ibuprofen) 200 mg.

1. They all contain the same drug.

2. People with muscle pain should only take Motrin.

- Could take any of the medications3. Motrin is the generic name

- Motrin is the trade name4. Nuprin is only for headaches.

- Can be used for any type of pain T

Nuprin

nly fo

r h...

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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.

Generic vs. Trade Names

Methods of Classifying Drugs

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

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.

Classifying by Mechanism of Action

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

• 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

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?”

Sources of Drug InformationChanges 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

Sources of Drug Information

Sources of Drug Information1. Pharmacology book (Lehne)

- Goes into detail about the use and actions of the drug2. 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

How Drugs are Developed

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

Stages of Drug Development

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

Randomized Control Trial

Randomized Control Trial• The development and testing of new drugs requires 6-

12 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

Distinguishing Features of Randomized Control Trials

• Use of controls

• Randomization

• Blinding

Off-Label Use

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.

SafetyCost-Benefit Assessment

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.

SafetyLong-term and Over-the-counter

SafetyLong-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 over-the-counter drugs.

Pre-Clinical Studies

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.

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

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

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.

Testing New Drugs in HumansPhase 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

Testing New Drugs in HumansPhase 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.

Testing New Drugs in HumansPhase 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 a

Phase III trial for each indication. 87

Phase IIIInclusion 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

Clinical Testing

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

Testing New Drugs in HumansPhase IV: Postmarketing

Surveillance

Testing New Drugs in HumansPhase 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.

New Drug Approvals

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

In Which Stage of Drug Development are Researchers

Concerned with the Drug’s Maximum Tolerated Dose?

In which Stage of Drug Development are Researchers Concerned with the Drug’s Maximum Tolerated Dose?

1. Phase I2. Phase II3. Phase III4. Phase IV.

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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.

Patents

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.

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

Controlled Substances

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.

Drug Schedules

Drug SchedulesSchedule Abuse

PotentialDependence

LiabilityExamples 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

DefinitionPharmacology

The study of drugs and their interactions with living systems

DefinitionDrug

A drug is any chemical that can affect a living process.

Pharmacokinetics

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

Pharmacodynamics

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

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.

Drugs Cause Effects by Binding to Receptors

What Types of Physiologically Important Macromolecules Serve as Drug Receptors?

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, ionchannels, transport proteins, etc, can be drug receptors.

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

Classes of Macromolecules Defined as Receptors

Classical Receptors

Classes of Macromolecules Defined as ReceptorsClassical Receptors

• Membrane-bound enzymes with activating ligands.

• Ligand-gated ion channels

• G-protein coupled neurotransmitter receptors

• Transcription factors with activating ligands125

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.

128Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 48

Receptors with Endogenous Ligands

Four Primary Receptor Families

• Cell-membrane embedded enzymes

• Ligand gated ion channels

• G-Protein coupled receptor system

• Transcription factors

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

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

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

• 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)

Other Macromolecules that Drugs Can Bind to

• Enzymes

• Ribosomes

• Tubulin

• DNA or RNA

• Transporters

• Others141

Drug SpecificityBinding 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

Drug SpecificityBinding 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.

Dose-Response Curves

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 response is produced.

Basic Features of the Dose-Response 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

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

Simple Occupancy Theory

152Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 51

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

Simple Occupancy TheoryImportant 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)

Simple Occupancy Theory Things that are Not Explained

Simple Occupancy TheoryThings 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 place157

Efficacy vs. Potency

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.

Potency

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

Efficacy

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

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 activity2. Produce a lesser effect than the endogenous ligand

ex. pentazocine in the last diagram3. 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.

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

Modified Occupancy TheoryAffinity

• 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

Modified Occupancy TheoryIntrinsic 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

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

Intrinsic ActivityAntagonists

• 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

Noncompetitive vs. Competitive Antagonism

Competitive vs. Noncompetitive Antagonism

1. A competitive antagonist binds reversibly to the receptor such that bound drug is inequilibrium 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

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

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

Which of the Following Terms is Defined as “the Ability of a Drug

to Activate a Receptor upon Binding”?

Which of the Following Terms is Defined as “the Ability of a Drug to Activate a Receptor upon Binding”?

1. Affinity - the strength of the attraction between a drug and its receptor

2. Intrinsic activity3. Efficacy – maximum

effect of the drug4. Potency – dose of the

drug needed to elicit a response

25% 25%25%25%

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.

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.

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.

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

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.

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.

Frequency Distribution Curves

Frequency Distribution Curve

ED50= Effective Dose 50%

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

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.

Therapeutic Index

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

Therapeutic Index

LD50= Lethal Dose 50%

Therapeutic IndexMaximum 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.

DefinitionsUndesirable 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.

Choice of a particular drug is frequently dictated by side effects

Beetle BaileyBY MORT WALKER

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.

•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?

1. The curve will shift to the right (toward higher doses)

- Will make the response more difficult to obtain, so higher doses will be required

2. The curve will shift to the left (toward smaller doses.

3. The curve will not change.

4. The curve will broadenThe

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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

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?

introduction to pharmacology. pharmacology 2 pharmacology – the study of drugs and their...

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