Chapter 1: Introduction to Pharmacology

What is homeostasis?

The maintenance of stable, normal conditions inside the body

(Homeostasis=keeping the body balanced)

What can happen when the body cannot maintain homeostasis?

Disease can occur

What is the desired purpose of a drug?

To restore and/or maintain homeostasis

What does it mean for a drug to maintain homeostasis?

It helps keep the body’s internal conditions stable

What happens when body temperature falls?

The body tries to conserve and generate heat to return toward normal temperature

What happens to blood vessels when body temperature falls?

They constrict to conserve heat

What does constrict mean?

To become narrower

Why does the body shiver when it gets cold?

Muscle contractions from shivering generate heat

What happens when body temperature rises?

The body tries to lose heat to return toward normal temperature

What happens to blood vessels when body temperature rises?

They dilate, which helps the body lose heat

What does dilate mean?

To become wider

How does sweating help restore normal body temperature?

Sweat evaporates, causing heat to be lost from the body

Memorize this chart

What is pharmacology?

The study of effects of drugs on the body

What does pharmacology study about drugs?

What effects drugs have on the body

What simple question can help you remember pharmacology?

“What does the drug do to the body”

What are the two main types of drugs listed on the slide?

• Small organic molecules

• Biologics

What are small organic molecule drugs?

Relatively small chemical compounds used as drugs

What type of drug makes up the vast majority of drugs currently on the market?

Small organic molecules

What are biologics?

Drugs made from biological molecules

What two types of biologics are listed on the slide?

• Peptides/proteins

• Oligonucleotides

What are examples of peptide or protein biologics?

Hormones and antibodies

What are examples of oligonucleotide biologics?

RNA and siRNA

What is an oligonucleotide?

A short sequence of nucleotides (a short sequence made from the building blocks or DNA or RNA)

What is the clinical pipeline?

All drugs currently under development or in clinical trials

About what percentage of drugs in the clinical pipeline are biologics?

About 55%

What is the difference between drugs on the market and drugs in the clinical pipeline?

Drugs on the market are already available, while drugs in the clinical pipeline are still under development or in clinical trials

How do drugs currently on the market compare to drugs in the clinical pipeline?

Drugs on the market are already available, while drugs in the clinical pipeline are still under development or in clinical trials

How do drugs on the market compare with drugs in the clinical pipeline?

The vast majority of drugs currently on the market are small organic molecules, while about 55% of drugs in the clinical pipeline are biologics

What are the four major targets of small organic molecule drugs?

• Receptors

• Ion channels

• Transport proteins

• Enzymes

What are receptors?

Proteins that bind and respond to endogenous (inside) chemical signals

What does endogenous mean?

Produced naturally within the body

What are the two types/locations of receptors listed on the slide?

• Membrane-bound receptors

• Intracellular receptors

What are two examples of membrane bound receptors?

• G-protein coupled receptors

• Receptor tyrosine kinases

What does intracellular mean?

Inside the cell

What type of receptor is a steroid hormone receptor?

An intracellular receptor

What are ion channels?

Proteins that allow ions to move across cell membranes

What are transport proteins?

Proteins that help move substances across membranes

What are enzymes?

Proteins that help speed up chemical reactions

What do peptide hormones bind to?

Receptors

What can antibodies bind to?

• Hormones

• Receptors

• Other structural proteins

What do oligonucleotides primarily bind to?

mRNA

Besides mRNA, what can some newer oligonucleotides bind to?

DNA, in a few newer cases

Connection card: Match each biologic with its target: peptide hormones, antibodies, and oligonucleotides

• Peptide hormones → receptors

• Antibodies → hormones, receptors, or structural proteins

• Oligonucleotides → mRNA (and sometimes DNA)

What are the major drug-target relationships from this slide?

• Small organic molecules → receptors, ion channels, transport proteins, & enzymes

• Biologics → specific targets depending on the type of biologic

Why do drugs affect cellular functions?

To help correct homeostatic imbalance

How do drugs affect cellular functions to correct homeostatic imbalance?

By modifying the activity of individual proteins

What are the four ways drugs can modify protein activity?

• Directly modify Activity

• Modify Transcription

• Modify Translation

• Increase degradation

What does it mean for a drug to directly modify protein activity

The drug increases or decreases the activity of a protein

What is an agonist?

Something that increases protein/receptor activity

What can directly decrease protein activity?

• Antagonists

• Inhibitors

• Antibodies

What is transcription?

The process of going from DNA→ mRNA

Can drugs increase or decrease transcription?

Yes. Drugs can modify transcription in either direction

What is translation?

The process of going from mRNA → Protein

Can drugs increase or decrease translation?

Yes. Drugs can modify translation ways

How can siRNA decrease protein production?

siRNA targets mRNA → decreases translation → less protein is produced

What drug is listed as an example of siRNA that decreases translation?

• Inclisiran

  • targets PCSK9

What does degradation mean?

Breakdown or destruction of something

What does increasing protein degradation do?

It causes more of the target protein to be broken down

What two binding sites are mentioned for proteins used to increase degredation?

A binding site for the target protein and a binding site for E3 ligase

What new drug target is mentioned in connection with degradation and pancreatic cancer treatment?

Ras

How are transcription and translation different?

• Transcription = DNA → mRNA

• Translation= mRNA → protein

At what four points can drugs alter protein function or amount?

• Existing protein activity → direct modification

• DNA→mRNA → modify transcription

• mRNA→protein→modify translation

• Existing protein → breakdown → increase degradation

What is specificity?

The ability of a drug to bind selectively to its target(s)

Where are a drug’s targets ideally found when the drug is specific?

Only on a subset of cells or tissues

What does selectively mean?

The drug preferentially binds to certain target(s) rather than everything

What is affinity?

The strength of binding between a drug and its receptor

What does high affinity mean?

The drug has a strong chemical attraction/binding to its receptor

What is efficacy?

The ability of a drug to produce a given physiological effect

What is another way to think about efficacy?

The effectiveness of a drug

What is potency?

The dose of a drug needed to produce a given physiological effect

If one drug requires a smaller dose than another to produce the same effect. which drug is more potent?

The drug requiring the smaller dose

When is potency relavent?

When comparing two or more drugs

What is the difference between affinity and efficacy?

• Affinity = strength of binding

• Efficacy= ability to produce an effect

What is the difference between efficacy and potency?

• Efficacy= ability to produce an effect

• Potency= Dose needed to produce a given effect

Match specificity, affinity, efficacy, and potency with their main question.

• Specificity → What does it target?

• Affinity → How strongly does it bind?

• Efficacy → How much dose is needed

What does efficacy represent on a dose-response graph?

The maximum effect/response a drug can produce

How do you compare efficacy on a dose-response graph?

Look at how high each curve reaches

Which drugs have the greatest efficacy on this graph?

X and Y

What is the efficacy ranking of X, Y, and Z

X= Y>Z

Why do X and Y have equal efficacy?

The both reach approximately the same maximum response (~100%)

Why does Z have a lower efficacy than X and Y?

Z reaches a lower maximum response

What does potency tell you?

How much drug is needed to produce a given effect

How do you compare potency on a dose-response graph?

Compare the curves left to right

What does a curve farther to the right indicate?

Lower potency

What is the potency ranking of X, Y, and Z?

X > Y > Z

How does efficacy and potency differ when reading a graph?

Efficacy → look at height

Potency → look left vs right

How do drugs X and Y compare in efficacy and potency?

• Efficacy: X = Y

• Potency: X > Y

They can produce the same maximum effect, but X requires less drug to produce a given effect

How does drug Z compare with X and Y?

Z has a lower efficacy and lower potency on the graph

Does a more potent drug automatically have greater efficacy?

No

What is generally more important to a practitioner? Efficacy or potency?

Efficacy

Why is efficacy generally more important than potency?

Because efficacy tells you the drug’s ability to produce the desired physiological effect

If choosing between two or more drugs with different efficacies, which should be used?

The more efficacious drug

When does potency become important when choosing between drugs?

When the drugs have equal efficacy

If two drugs have equal efficacy, which drug should be used according to the slide?

The more potent drug

Why would the more potent drug be chosen when efficacy is equal?

It can achieve the effect at a lower dose

What does greater potency mean about the dose needed?

A lower dose is needed to produce a given effect

What does “the poison is in the dose” mean?

A substance can become harmful/toxic depending on the dose

What is the therapeutic index?

The ratio of the amount of a drug that is harmful to the amount that is helpful

What is the formula for therapeutic index?

TI=LD₅₀/ED₅₀