Drug-receptor interactions and mechanisms of drug action

Question 1

What is pharmacokinetics?

Answer 1

The effect of the body on the drug

E.g. ADME

Question 2

What is pharmacodynamics?

Answer 2

The effect of the drug on the body (responses produced, mechanism of action)

Question 3

What is a drug?

Answer 3

A chemical substance that interacts with a biological system to produce a physiological effect

Question 4

What are the 4 main drug target sites?

Answer 4

Receptors
Ion channels
Transport systems
Enzymes

Question 5

What is a receptor?

Answer 5

Protein molecules whose function it is to recognise and respond to endogenous chemical signals

Question 6

What is an ion channel?

Answer 6

Selective pore within membrane of lipid bilayer

Allows passage of ions depending on EC gradient

Question 7

What are the 2 types of ion channel?

Answer 7

Voltage-sensitive

Receptor-linked

Question 8

What are some drugs that interact with ion channels rather than with the receptors themselves?

Answer 8

Local anaesthetics - block VGSCs in sensory axons; fewer APs propagated; reduced perception of pain

Calcium channel blockers

• Usually end in -dipine
• Block VSCCs

Question 9

What is a transport system?

Answer 9

System of carriers that transport substances against their CG, e.g. glucose, ions, NTs

Show specificity for certain species
E.g. Na/K pump, NA uptake 1

Question 10

Why are transport systems not receptors?

Answer 10

Don’t mediate a response

Just allow NT to bind to protein and then move it somewhere else

Question 11

What are the 3 ways in which drugs interact with enzymes?

Answer 11

1. Enzyme inhibitors
2. False substrates
3. Prodrugs

Question 12

What are the exceptions to the 4 target site rule?

Answer 12

Some drugs produce responses due to the physiochemical properties

1. General anaesthetics dampen synaptic transmission but don’t interact with specific transport system or receptor
2. Antacids - reduces acidity of stomach contents - basic
3. Osmotic purgatives (laxatives) - stimulate voiding of gut contents - draw water into stomach contents - softens stool

Question 13

What is an agonist?

Answer 13

A molecule that binds to a receptor and stimulates it to generate a response

E.g. nicotine

Question 14

What is an antagonist?

Answer 14

A substance that interacts with and binds to a receptor but does NOT produce a response

Gets in the way of agonist

E.g. atropine

Question 15

Define potency

Answer 15

How powerful a drug is

Question 16

What does potency depend on?

Answer 16

Affinity

Efficacy

Question 17

What is affinity?

Answer 17

How willingly a drug binds to its receptor

Question 18

What is efficacy?

Answer 18

AKA intrinsic activity
Ability of a drug to generate a response once bound to receptor
Usually involves some sort of conformational change

Question 19

What is a full agonist?

Answer 19

An agonist that generates the maximal response

Question 20

What is a partial agonist?

Answer 20

An agonist that generates less than the maximal response

Question 21

What is selectivity?

Answer 21

When a drug prefers interacting with a particular receptor type

Question 22

Explain the log dose-response curve

Answer 22

Tissue response Y
Log [A] X

Full agonists with lower affinity with still generate a maximal response but needs much higher concentration

Partial agonist curve peaks before it gets anywhere near maximal tissue response

Question 23

Do antagonists have:

a) affinity?
b) efficacy?

Answer 23

Have affinity

No efficacy

Question 24

What are the 2 main types of antagonists?

Answer 24

1. Competitive

2. Irreversible

Question 25

How does a competitive antagonist work?

Answer 25

Binds to same site as agonist on receptor | Need higher agonist conc to generate maximal response

Question 26

Why are the responses of competitive antagonists surmountable?

Answer 26

They bind to same site as agonist on R | By increasing agonist concentration, you can overcome the effect of competitive antagonist

Question 27

How do competitive antagonists affect the log dose-response curve?

Answer 27

Shifts it RIGHT | Need higher [A] for same tissue response

Question 28

How do irreversible antagonists work?

Answer 28

Bind to same site as agonist but more tightly with covalent forces - can't be shifted OR Bind to different site --> insurmountable antagonism bc not competing

Question 29

What is receptor reserve? Advantages?

Answer 29

'Spare receptors' In some tissues, you don't have to occupy 100% of Rs to generate maximal response May be as low as 1% Advantage = increased sensitivity of tissue to agonist and increased speed of response

Question 30

How do irreversible antagonists affect the log dose-response curve?

Answer 30

Curve falls away and won't be able to generate maximal response regardless of [A]

Question 31

What are the 4 types of drug antagonism?

Answer 31

Receptor blockade Physiological antagonism Chemical antagonism Pharmacokinetic antagonism

Question 32

Explain receptor blockade

Answer 32

Antagonist binds to receptor and prevents binding of agonist

Question 33

What is use dependency? Give an example

Answer 33

- Refers to ion channel blockers - The more active the target tissue, the more effective the blocker E.g. normal neurones fire at a relatively low rate Put local anaesthetic on them --> relatively low blockage Nociceptor neurones fire rapidly and bc APs are generated rapidly, ion channels are open more often LAs work by binding to inside of ion channels after they open – channels open more often --> more chance for blockage Gives LAs a selective action on nociceptor neurones - act on pain conducting fibres more specifically than normal neurones

Question 34

Explain physiological antagonism and give an example

Answer 34

2 drugs act at different receptors to have opposite effects in same tissue E.g. NA on vasculature binds to adrenoceptors --> vasoconstriction Coadminister histamine - acts on different Rs to cause vasodilation

Question 35

Explain chemical antagonism and give an example

Answer 35

Interaction of drugs in solution E.g. dimercaprol is a chelating agent - forms heavy metal complexes which are more rapidly excreted by kidneys - reverses lead poisoning

Question 36

Explain pharmacokinetic antagonsim and give an example

Answer 36

One drug reduces concentration of another drug at the site of its action by reducing absorption, increasing metabolism or increasing excretion of the other drug Must be aware of this so you don’t administer two drugs that interfere with each other E.g. repeatedly administering barbiturates increases production of microsomal enzymes Administering another drug metabolised by same enzymes --> metabolised more quickly --> reduced effect

Question 37

What is drug tolerance?

Answer 37

Gradual decrease in responsiveness to a drug with repeated administration

Question 38

What can cause drug tolerance?

Answer 38

``` Pharmacokinetic factors Loss of receptors Change in receptors Exhaustion of mediator stores Physiological adaptation ```

Question 39

How can pharmacokinetic factors cause drug tolerance?

Answer 39

Metabolism of drug increases when given repeatedly over time E.g. barbiturates and alcohol

Question 40

How can loss of receptors cause drug tolerance?

Answer 40

If cell is repeatedly stimulated by an agonist, cell will endocytose some receptors so there are fewer available on cell surface = receptor downregulation Beta adrenoceptors are susceptible to this

Question 41

How can change in receptors cause drug tolerance?

Answer 41

No. of receptors on cell surface stays same but Rs themselves undergo desensitisation Trigger = continued stimulation over long period of time Involves conformational change Proportion of Rs are no longer effective

Question 42

How can exhaustion of mediator stores cause drug tolerance?

Answer 42

Happens with amphetamines Amphetamine = CNS stimulant - gets into BS, crosses BBB into brain and acts on noradrenergic neurones Amphetamine binds to uptake 1 protein - taken into central NA synthesis system - replaces NA in vesicles - big increase in NA production 2nd dose - less severe response due to exhausted NA stores - no more NA unless de novo synthesis

Question 43

How can physiological adaptation cause drug tolerance?

Answer 43

Like a homeostatic response | Body attempts to maintain a stable internal environment

Question 44

What are the 4 receptor families?

Answer 44

Type 1 - ionotropic Type 2 - G-protein coupled Type 3 - tyrosine kinase-linked Type 4 - intracellular steroid type

Question 45

Describe type 1 ionotropic receptors and give 2 examples

Answer 45

Ion channel linked Mediate very fast responses - milliseconds 4 or 5 subunits Defining feature: transmembrane alpha helices External binding domain - stimulates and opens ion channel E.g. nicotinic ACh R and GABA

Question 46

Describe type 2 G-protein coupled receptors and give an example

Answer 46

``` Must first link to a G protein before it can mediate a response Much slower - seconds 1 subunit 7 transmembrane alpha helices E.g. b1 adrenoceptors in heart ```

Question 47

Describe type 3 tyrosine kinase linked receptors and give 2 examples

Answer 47

``` Single protein 1 transmembrane domain When agonist stimulates R, activates catalyst inside cell and stimulates kinase activity of R --> phosphorylation of IC proteins --> response E.g. insulin receptor, GF receptor Minutes ```

Question 48

Describe type 4 intracellular steroid type receptors

Answer 48

Activated by steroids and thyroid hormones Regulate DNA transcription Drug must pass through cell membrane and into nucleus before effect R stimulates --> zinc fingers uncovered --> DNA binding --> increased transcription Hours

Question 49

What is a drug target site?

Answer 49

Anything to which a drug is directed and/or binds, resulting in a change in its behaviour or function