Mechanisms of Drug-Receptor Interaction

Question 1

What does pharmacology include?

Answer 1

There are two main domains of pharmacology: medical pharmacology and toxicology, and environmental toxicology.
Medical pharmacology and toxicology can be further divided into pharmacokinetics (PK) and pharmacodynamics (PD)

Question 2

Describe the history of pharmacology

Answer 2

Our first drugs most likely came from roots, berries, leaves and tree bark, etc. as evidenced by ancient well drawings and carvings.
We learned through trial and error.
Now we have evidence-based medicine (controlled clinical trials)

Question 3

What is a drug?

Answer 3

Drug defined as any substance that brings about a change in biologic function through its chemical actions

Question 4

What’s a substance?

Answer 4

A chemical species, pure element or species of matter

Question 5

Describe the naming convention of drugs

Answer 5

Chemical name: e.g., acetylsalicylic acid
Code name: short hand method for defining a drug
Generic name: given by the government (Health Canada, FDA)
Trade/Brand name: given by the company

Question 6

What is pharmacodynamics?

Answer 6

The actions of the drug on the body

Drug-receptor interaction

Question 7

What is pharmacokinetic?

Answer 7

The actions of the body on the drug

ADME (main pillars of PK)

Question 8

What are the two main mechanisms of drug action?

Answer 8

Non-receptor mechanisms (e.g., anti-infectives)
Receptor mechanisms (e.g., NDMA)

Question 9

What are 3 characteristics of a receptor?

Answer 9

1. They determine the relationship between dose and effect
2. Receptors are responsible for selectivity (if it’s not selective, you’re going to have all these other, most likely unwanted, biological responses)
3. Receptors are responsible for the agonist or antagonist activity

Question 10

What are the classifications of receptors?

Answer 10

Ion channels
G-protein-coupled receptors
Enzyme-linked receptors
Steroid receptors

Question 11

Describe ion channel receptors

Answer 11

There’s a receptor that goes through the lipid bilayer. It’s selective as to what can pass through it. Most ion channel receptors have a gaiting mechanism (they only open when stimulated). E.g., NMDA is closed by the presence of Mg ion. When activated, the Mg ion dissociates and the receptor opens, allowing calcium to flow through

Question 12

Describe G-protein-coupled receptors

Answer 12

When a ligand binds to the receptor, this causes the activation of a G-protein. The alpha subunit of the G-protein acts on the effector protein, causing a change in the cell

Question 13

What are the three subtypes of enzyme-linked receptors?

Answer 13

Guanylyl cyclase
Tyrosine kinase receptors
Tyrosine kinase-associated receptors

Question 14

Describe guanylyl cyclase

Answer 14

The receptor is located within the cell (not in the lipid bilayer) which means the drug has to get passed the lipid membrane (filtering process). It binds to the binding domain and the catalytic domain has some enzymatic conversion

Question 15

Describe tyrosine kinase receptors

Answer 15

The span the membrane

Activation causes phosphorylation of a Tyr residue on a second messenger

Question 16

Describe tyrosine kinase-associated receptors

Answer 16

Drug binds to a receptor that then activates a tyrosine kinase (common in the immune system)

Question 17

Describe steroid (nuclear) receptors

Answer 17

The drug has to cross the membrane AND enter the nucleus (via nuclear pores).
This type of receptor is involved in DNA transcription (and gene expression)

Question 18

Explain the duration of effect of activated receptors

Answer 18

The effect typically only lasts as long as the drug is bound to the receptor. So if the drug dissociates from the receptors, the process is terminated. There are, however, examples where the effect might continue to last

Question 19

How do enantiomers affect the binding of drugs?

Answer 19

The + form might bind better than the - form just because of the chiral molecule is a little different (affects affinity). This can change the potency and effectiveness

Question 20

What are the factors determining drug properties?

Answer 20

Affinity - the degree of attraction between drug and receptor
Efficacy - maximal response

Question 21

What is an agonist?

Answer 21

Drugs that bind to activate the receptor

Question 22

What is a partial agonist? Describe them

Answer 22

Drugs that bind to the same receptors and activate them in the same way with a lower response.
They have affinity for the receptor but have low efficacy

Question 23

What is an antagonist?

Answer 23

Drugs that bind to the receptor, compete with and prevent binding by other molecules

Question 24

What is a competitive inhibitor?

Answer 24

It binds to the active site of a receptor, blocking other molecules from binding

Question 25

What is an allosteric activator/inhibitor?

Answer 25

It binds to a site other than the active site. This often causes conformational change leading to increased activation/inhibition

Question 26

What is the law of mass action?

Answer 26

When a drug combines with a receptor, it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor.

Question 27

What is the EC50?

Answer 27

The concentration of drug that causes 50% of its maximum effect. To determine the EC50, we often log transform the ligand concentration to give a sigmoidal relationship

Question 28

What does effect equal, mathematically?

Answer 28

Effect = Emax x D/(D+EC50)

Question 29

What is potency?

Answer 29

Potency refers to the concentration or dose of a drug required to produce maximal effect (x axis)

Question 30

What is an inverse agonist?

Answer 30

Causes the efficacy to reduce (creates a new response in the opposite direction

Question 31

What happens when you administer a partial agonist?

Answer 31

When administered alone, partial agonists activate the receptor
When administered in the presence of a full agonist, the partial agonist reduces the effects of the full agonist

Question 32

Name the different types of antagonists

Answer 32

Competitive reversible antagonists
Irreversible antagonists
Physiological "antagonists"
Chemical "antagonists"
Allosteric modulators

Question 33

How do competitive reversible antagonists work?

Answer 33

They make the drugs less potent. The EC50 is shifted to the right. Emax doesn’t change.

Question 34

How do irreversible antagonists work?

Answer 34

Via covalent bonds, they diminish the number of receptors available. The Emax is reduced

Question 35

How do physiological “antagonists” work?

Answer 35

The effects of one agonist counteracts the effects of another agonist (no drug-receptor interactions)

Question 36

How do chemical “antagonists” work?

Answer 36

A chemical interaction reduces the effect of the agonist (the effect of the drug is lost).
No receptors are involved

Question 37

How do allosteric modulators work?

Answer 37

They do not bind to the agonist binding site of the receptor
They do not compete with the agonist for binding; they do not interfere with agonist binding
Allosteric modulators may increase or decrease agonist-induced response

Question 38

What is desensitization?

Answer 38

Receptor response to agonist wanes over time. Response recovers after wash-out of agonist. The process is turned off because of a lysosomal interaction

Question 39

What is tachyphylaxis?

Answer 39

Tissue response to agonist wanes over time