Lecture 2 - Drug-Receptor Interactions

Question 1

What is meant by the term “pharmacokinetics”?

Answer 1

The effect of the body on the drug e.g. absorption, metabolism, distribution, excretion

Question 2

What is meant by the term “pharmacodynamics”?

Answer 2

The effect of the drug on the body e.g. responses produced, mechanism of action

Question 3

What is the definition of a drug?

Answer 3

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

Question 4

What are the four main target sites of drugs?

Answer 4

These are all proteins

1) Receptors
2) Ion channels
3) Transport systems
4) Enzymes

Question 5

What is a receptor, what types of substances are they activated by, and what are they defined by?

Answer 5

A receptor is a membrane-bound protein or intracellular steroid receptor.
They are activated by neurotransmitters or hormones.
A particular receptor is usually defined by the particular agonists and antagonists that interact with it.

Question 6

What is an example of a drug that targets a receptor?

Answer 6

Atropine - targets muscarinic cholinoceptors (acetylcholine) as an ANTAGONIST, anaesthetic premedication.

Question 7

What is an ion channel, how do they work, and what are the two types?

Answer 7

These are selective pores that allow the passage of ions in or out of the cell depending on the electrochemical gradient. (facilitated diffusion)
The 2 types are Voltage-Sensitive (e.g. VGSC) and Receptor-Linked (nicotinic acetylcholine receptor)

Question 8

What are 2 examples of drugs that targets ion channels and how do they work?

Answer 8

Local anaesthetic - blocks sodium channels in the sensory axons, blocking of these channels means fewer action potentials are propagated so the perception of pain is less.
Calcium channel blockers - block calcium channels (usually end in -dipine)

Question 9

What are transport systems, what do they show specificity for, what are they NOT, and what are examples of transport systems?

Answer 9

Systems of carriers that transport substances against their concentration e.g. glucose ions and neurotransmitters
They show specificity for certain species
They are NOT receptors, they don’t mediate the response they just allow the NT to bind to a protein and then move the complex somewhere else
Examples include Na+/K+ pump and Noradrenaline uptake 1.

Question 10

What are 2 examples of drugs that target transport systems?

Answer 10

Tricyclic antidepressants (TCAs)
Cardiac Glycosides - cardiac stimulant drugs (digoxin)

Question 11

How does digoxin (cardiac glycoside) work?

Answer 11

Slows down the patient’s Na+/K+ pump
Knock-on effect means intracellular calcium concentration increases
This increases force of contraction
So digoxin = increased cardiac contractility

Question 12

What are the 3 types of drugs that interact with enzymes?

Answer 12

Enzyme inhibitors
False substrates
Prodrugs

Question 13

How do enzyme inhibitors work and what is an example of one?

Answer 13

Neostigmine (anticholinesterase)

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

Question 14

How do drugs work as false substrates and what is an example of one?

Answer 14

Methyldopa (antihypertensive)
- Takes the place of DOPA in production of noradrenaline. Produces methylnoradrenaline which is worse at causing vasoconstriction than NA so reduced TPR and hence reduced BP.

Question 15

How do drugs work as prodrugs and what is an example of one?

Answer 15

Chloral hydrate (treatment of insomnia)

• Chloral hydrate heads to the liver and is metabolised to trochloroethanol before it is effective
• Prodrug must interact with enzyme system before effective drug form released

Question 16

What is an unwanted effect with enzymes with regards to paracetamol consumption? Is it reversible or irreversible?

Answer 16

If you overdose then you saturate the liver’s microsomal enzymes that usually metabolise the paracetamol. Once saturated, the liver uses a different set of enzymes to metabolise it but this produces different metabolites which can interact with the liver and the kidney
These effects are irreversible

Question 17

What is non-specific drug action and what are 3 examples of types of drugs that use this?

Answer 17

These are drugs that produce responses due to the physicochemical properties rather than binding to a specific site.

1) General anaesthetics dampen synaptic transmission but do not interact with a specific transport system or receptor.
2) Antacids reduce the acidity of stomach contents as they are basic compounds that neutralise the stomach acid.
3) Osmotic purgatives stimulate the voiding of gut contents by drawing water into the gut contents, softening the stool and increasing gut volume which stimulates voiding.

Question 18

What is plasma protein binding with regards to drugs?

Answer 18

This is where the drug molecules bind to plasma proteins (mostly albumin) and move around the body in circulation as an inactive molecule. They then unbind to become active but it allows for the drug to be transported.

Question 19

What is an agonist?

Answer 19

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

Question 20

What is an antagonist?

Answer 20

A molecule that interacts and binds to receptors with generally higher affinity than its corresponding agonist but do NOT produce a response and instead simply block the agonist from binding

Question 21

What is meant by potency and what is it dependent on?

Answer 21

How powerful the drug is, dependent on the affinity and the efficacy of the drug

Question 22

What is meant by the affinity of a drug?

Answer 22

The avidity with which the drug binds to its target

Question 23

What is meant by the efficacy (a.k.a. intrinsic activity) of a drug?

Answer 23

The ability of a drug to generate a response once it has bound

Question 24

What is meant by a full and partial agonist?

Answer 24

A full agonist is an agonist that generates the maximal response once the concentration is high enough.
A partial agonist is an agonist that, no matter how high the concentration, produces less than the maximal response.

Question 25

What happens when you co-administer a partial agonist with a full agonist?

Answer 25

The partial agonist acts as an antagonist as it interferes with the full agonist’s ability to produce the maximal response

Question 26

What is meant by selectivity regarding drugs?

Answer 26

If a drug has selectivity then it means it has a preference for interacting with a particular receptor type

Question 27

What is the structure-activity relationship and why is it important?

Answer 27

The structure of the drug and its activity are very closely linked.
Small changes in the structure in the drug can produce enormous changes in the effectiveness of the drug.
Some pharm companies can take an agonist and make a small structural change to make it an antagonist.

Question 28

What would a dose-response curve look like for a full and partial agonist?

Answer 28

Full agonist - curve extending up and to the right from 0 with decreasing gradient plateauing at maximal response once concentration high enough.
Partial agonist - same type of curve but plateaus at some <100% percentage of maximal response.

Question 29

What is the shape of the log dose-response curve of full and partial agonist? Which way does the curve move if the affinity is lower?

Answer 29

Sigmoid shape
Tapers off at the maximal response for full agonist, tapers off earlier for partial agonist.
Curve moves to the right the lower the affinity.

Question 30

How much affinity and efficacy do antagonists have?

Answer 30

Antagonists have high affinity but NO efficacy as they don’t produce a response.

Question 31

What are the two types of antagonist and how do they work?

Answer 31

Competitive and Irreversible

• Competitive bind to the same site as the agonist on the receptor. These are surmountable antagonists as increasing the concentration of the agonist can overcome the antagonist action (shifts D-R curve to the right)
• Irreversible, some bind to same site as agonist more tightly with covalent forces so they can’t be shifted by agonist molecules, some bind to a different site from the agonist and causes insurmountable antagonism as the agonist cannot outcompete the antagonist.

Question 32

What are examples of competitive and irreversible antagonists?

Answer 32

Competitive - atropine (competitive muscarinic cholinoceptor antagonist), propranolol (competitive non-selective beta blocker, covers beta 1 and 2 receptors)
Irreversible - hexamethonium (irreversible nicotinic cholinoceptor antagonist, waits for channel to open then blocks the channel).

Question 33

What is the concept of “receptor reserve” and how does sensitivity differ in different tissues?

Answer 33

These are ‘spare receptors’ from those needed for maximal response. E.g. if a tissue only requires occupation of 50% of receptors for maximal response, the other 50% are spare receptors.
The sensitivity of the tissue to the agonist is dependent on the % of receptors that need to be activated for a maximal response. The smaller % of receptors that need to be activated for maximal response, the faster the response is induced by the agonist.

Question 34

What are the effects of competitive and irreversible antagonists and how would these appear when plotted on a D-R curve?

Answer 34

Competitive - surmountable antagonism, just means higher concentration of agonist required for same level of response so curve maintains shape but shifts to the right.
Irreversible - insurmountable (in some cases), curve only reaches maybe half the height of the original D-R curve and will be unable to generate the maximal response regardless of the concentration of agonist.