Drug-Receptor Interactions

Question 1

What are the two divisions of pharmacology?

Answer 1

Pharmacokinetics and Pharmacodynamics

Question 2

Define pharmacokinetics.

Answer 2

The effect that the body has on the drug (how the drug is absorbed, distributed, metabolised, excreted)

Question 3

Define pharmacodynamics.

Answer 3

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

Question 4

Define the word ‘drug’.

Answer 4

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

Question 5

State the four main target sites for drugs.

Answer 5

Receptors  
Ion Channels  
Transport Systems 
Enzymes
NOTE: all proteins

Question 6

What are receptors?

Answer 6

Proteins within cell membranes or within cells (steroid receptors)

Question 7

Give an example of a drug which targets receptors.

Answer 7

Atropine - muscarinic receptor antagonist; used as an anaesthetic premedication to dry up secretions (PNS promotes secretions
NOTE: ACh is not administered as a drug but it is a muscarinic agonist as it promotes receptor action (downstream response) when it binds

Question 8

What are ion channels?

Answer 8

Selective pores within lipid bilayers that allow the passage of ions in or out of the cell depending on the electrochemical gradient

Question 9

What are the two types of ion channels?

Answer 9

Voltage-Gated

Receptor Linked

Question 10

Give examples of the two types of ion channels

Answer 10

Voltage-gated - VGSC, VGCC

Receptor-linked - nicotinic ACh receptor

Question 11

Give an example of a group of drugs that act on ion channels.

Answer 11

Local anaesthetics

Calcium channel blockers

Question 12

How do local anaesthetics work?

Answer 12

Local anaesthetics – they block the VGSCs of nociceptor sensory axons by binding to prevent the conduction of pain signals to the CNS (prevents AP propagation along neurone to prevent pain sensation by actually binding inside the ion channel, blocking ion flow)
NOTE: nociceptor = type of sensory neurone (responds to ‘danger signals’)

Question 13

How do calcium channel blockers work?

Answer 13

The block VGCCs - used to treat cardiovascular conditions like hypertension (end in -dipine)
NOTE:
VGCCs required for excitation contraction coupling so by blocking these it can cause vasodilation, and reduce force of contraction
VGCCs also involved in cardiac APs so blockers also reduce HR

Question 14

What is a transport system?

Answer 14

Carrier which transports substances against their concentration gradients

Question 15

Give an example of a transport system.

Answer 15

Na+/K+ pump

NA uptake 1

Question 16

Give an example of a drug that acts on transport systems.

Answer 16

Tricyclic antidepressants (TCAs)
Cardiac glycosides

Question 17

How do TCAs work?

Answer 17

Block reuptake of certain neurotransmitters, e.g. serotonin and NA (block uptake 1), to increase their levels in brain (increase synaptic concentrations and neurotransmission) to improve mood

Question 18

How do cardiac glycosides work?

Answer 18

They slows down the Na+/K+ pump, which has a knock-on effect of increasing the intracellular calcium ion concentration (by reducing action of Na+/Ca2+ exchanger), which leads to an increased force of contraction of the heart

Question 19

What are the three ways in which drugs can interact with enzymes?

Answer 19

Enzyme inhibitors
False substrate
Prodrugs

Question 20

How do enzyme inhibitors work?

Answer 20

EXAMPLE: anticholinesterases (neostigmine)

Increases the concentration of acetylcholine in the synapse by decreasing the rate of breakdown of acetylcholine

Question 21

How do false substrates work?

Answer 21

EXAMPLE: methyldopa - hypertension treatment
Methyldopa will be taken up by the NA nerve terminal and it'll take the place of DOPA in the NA synthesis pathway so it'll reduce the amount of DOPA being converted to dopamine - you’ll produce methyl dopamine instead
Methyl noradrenaline (from methyl dopamine) is not as effective at causing vasoconstriction as NA on α1 receptors  so you get reduced TPR and hence reduced blood pressure

Question 22

How do prodrugs work?

Answer 22

EXAMPLE: chloral hydrate → tricholoethanol

Essentially the pro-drug is a precursor and needs to be converted into its active form by endogenous enzymes

Question 23

What is a common example of the unwanted effects of drug interaction with enzymes?

Answer 23

Paracetamol overdose – this will saturate the microsomal (ER vesicles) enzymes in the liver so the paracetamol is then broken down by another set of enzymes (P450) which generates toxic metabolites
Toxic metabolites causes hepatocyte damage (liver failure) and can also lead to other problems within the body (e.g. kidney failure)

Question 24

Name three groups of drugs that are exceptions to the four target site rule.

Answer 24

General anaesthetics – reduce synaptic transmission without interacting with transport systems or receptors  
Antacids – these are basic so they simply neutralize some of the stomach acid  
Osmotic purgatives (laxative) – draw water into the bowel due to its physicochemical properties (high osmolarity substance which softens stool to allow easier voiding)

Question 25

What is the relationship between drugs and plasma binding proteins?

Answer 25

drugs bind to plasma proteins but this does NOT generate a response so it is not a drug target site - it is just a reservoir of the drug

Question 26

Define potency. What is it dependent on?

Answer 26

How powerful the drug is (i.e. more potent you can use a lower concentration to get the same level of response)
It depends on affinity AND efficacy

Question 27

What is affinity?

Answer 27

How strongly the drug binds to its receptor

Question 28

What is efficacy?

Answer 28

The ability of a drug to generate a response once it has bound to its receptor - usually involves some sort of conformational change of receptor (this determines downstream signalling)

Question 29

Define agonist.

Answer 29

A molecule that binds to a receptor and generates a response (e.g. nicotine, ACh)

Question 30

Define antagonist.

Answer 30

A molecule that binds to a receptor but does NOT generate a response (get in the way of the agonist; inhibitor - e.g. atropine)

Question 31

What is a full agonist?

Answer 31

An agonist that generates a maximum response

Question 32

What is a partial agonist?

Answer 32

An agonist that generates a less than maximum response
NOTE: probably because it has a different structure/properties so doesn’t cause the same conformational change of receptor; different/less downstream signalling means reduced response

Question 33

What happens if you administer a full agonist with a partial agonist?

Answer 33

if you administer a partial agonist with a full agonist you will get an effect similar to an antagonist
Not all receptors occupied by full agonist, some are occupied by partial agonist instead
Therefore, you have a reduced response as the partial agonist has a lower efficacy
Reduced response means antagonist-like activity by the partial agonist

Question 34

What is the difference between full agonists with a high affinity and full agonists with a lower affinity?

Answer 34

Full agonists with a lower affinity can still generate a maximum response but requires a higher dose than the full agonist with lower affinity

Question 35

True or false: full agonists that are selective for a given receptor will have the same efficacy.

Answer 35

True

They are full agonists so they all elicit a maximum response hence they have the same efficacy

Question 36

What is selectivity?

Answer 36

Drugs have a preference for binding to certain receptors (drugs are rarely specific to just one receptor – they normally bind to a few different ones)

Question 37

What is structure-activity relationship?

Answer 37

Emphasises the relationship between the structure of the drug and its activity - a small structural change can turn an agonist into a partial agonist or antagonist
Analogy - lock and key - key has a very specific structure which is required to fit in the lock (i.e. for full efficacy)

Question 38

Describe antagonists in terms of affinity and efficacy.

Answer 38

Antagonists have affinity but NO efficacy

Question 39

What are the two types of antagonist?

Answer 39

Competitive

Irreversible

Question 40

How does a competitive antagonist work?

Answer 40

Binds to the same site as the agonist on the receptor - surmountable (i.e. by increasing the concentration of the agonist, you can overcome the effect of the competitive antagonist)

Question 41

How does an irreversible antagonist work?

Answer 41

Could bind to the same site as the agonist but will bind more tightly with covalent forces so that they can’t be moved
Some irreversible antagonists will bind to sites different to the site that the agonist binds to – insurmountable (i.e. inhibition cannot be overcome as it is not competing with the agonist)

Question 42

Give an example of a competitive antagonist.

Answer 42

Atropine - competitive muscarinic cholinoceptor antagonist

Propranolol - competitive beta blocker (blocks beta adrenergic receptor)

Question 43

What effect do these two types of antagonist have on dose-response curves?

Answer 43

Competitive – shifts the D-R curve to the RIGHT (higher concentration of agonist needed to generate a maximal response)
Irreversible – shifts the D-R curve to the RIGHT and LOWERS the response elicited (you won’t have the max number of receptors available for max response to be generated )

Question 43

Give an example of an irreversible antagonist.

Answer 43

Hexamethonium - irreversible nicotinic cholinoceptor antagonist (it waits until the ion channel is open and then blocks the ion channel rather than just blocking a receptor – so binds to a different site from the agonist; insurmountable antagonism)

Question 45

What is receptor reserve?

Answer 45

Essentially means when ‘spare receptors’ are present
In some tissues, not all the receptors need to be stimulated to generate a maximum response (sometimes as little as 1% of receptors may need to be activated)
This increases the sensitivity of the tissue to the agonist

Question 46

What is sensitivity in the context of drugs?

Answer 46

How strong the drug dose needs to be (i.e. drug concentration) before the tissue responds to it)
Lower drug dose needed to generate tissue response → more sensitive tissue