Patient: Channels, receptors and enzymes as drug targets

Question 1

Define pharmacokinetics

Answer 1

What the body does to a drug

Question 2

Define pharmacotherapeutics

Answer 2

The use of drugs to prevent and treat disease

Question 3

Define pharmacodynamics

Answer 3

What the drugs does to the body

Question 4

How does a drug produce an effect?

Answer 4

A drug interacts with (binds to) its target usually in/on a cell. Targets forms tight bonds with the drug dependent on the size, shape and stereo-specificity.

Question 5

When a drug produces a response, what is it dependent on?

Answer 5

The type of target and what the target is linked to
Affinity - degree of attraction
Efficacy (intrinsic activity) ability to change target in a way that produces an effect

Question 6

Target interaction is due to what 3 types of charge distribution?

Answer 6

ions
dipoles
van der Waals forces

Question 7

What are ionic bonds dependent on?

Answer 7

Related to drugs being weak acids or bases

pH and pKa influence the degree of ionisation

Question 8

What are dipoles due to?

Answer 8

Uneven distribution of electrons between atoms in molecules

Question 9

What are van der Waals forces due to?

Answer 9

flexible movement of charge (electrons) through chemical groups

Question 10

What are the 3 types of agonist?

Answer 10

Full, partial and inverse

Question 11

What do agonists do?

Answer 11

They have affinity and they have efficacy

All bind to the binding site/active site

Question 12

Name the 3 types of allosteric modulators

Answer 12

Positive, negative and neutral

Question 13

What do allosteric modulators do and how do they do it?

Answer 13

Indirectly influence the binding of an agonist
Alter affinity and efficacy
Binds to a different site on receptor compared to the agonist

Question 14

What do antagonists do?

Answer 14

They prevent agonist binding

Question 15

Name the 4 types of binding of anatagonists

Answer 15

competitive
non-competitive
reversible (always competitive)
irreversible (competitive or non-competitive)

Question 16

Reversible antagonists have what kind of bonds?

Answer 16

Short lived bonds - dissociates easily

Question 17

Irreversible anatagonists have what kind of bonds?

Answer 17

Strong (covalent) bonds - does not dissociate

Question 18

Name 4 types of target receptor

Answer 18

Ion channels
G-proteins
Protein kinases
Cytoplasmic/nuclear receptor

Question 19

Opening of Na+ or Ca2+ ion channel causes…

Answer 19

the opening of Na+/Ca2+ channels cause further depolarisation
Ca2+ channels open
Increase in Ca2+
Hence increase in cellular activity

Question 20

Opening of K+ channels causes…

Answer 20

hyperpolarisation
Ca2+ channels close
Decrease in Ca2+
Hence decrease in cellular activity

Question 21

What does GTP stand for?

Answer 21

Guanosine triphosphate

Question 22

How many lipophilic membrane domains does a GTP receptor have?

Answer 22

7

Question 23

Describe how GTP coupled receptors work

Answer 23

Ligand binds to exterior section of the receptor
Interior section linked to G-protein
ligand binding changes conformation activates G-protein
G-protein linked to enzyme systems or ion channels

Question 24

Describe how GTP coupled receptors work in terms of alpha, beta and gamma subunits

Answer 24

Receptor occupied by agonist
GTP hydrolysed to GDP
causes alpha and beta-gamma subunits to dissociate
alpha one binds to target 1
beta-gamma one binds to target 2
effect repeats if presence of drug still there

Question 25

Describe how adenylyl cyclase works with G proteins

Answer 25

ATP becomes cAMP (catalysed by adenylyl cyclase)
cAMP can become 5’AMP via a phosphodiesterase
OR
cAMP can activate protein kinase A
this then leads to protein phosphorlyation and a change in Ca2+ concentration
Which then leads to biological response
OR the phosphorylated protein can be dephosphorylated by phosphatase enzyme

Question 26

Give an example of a G-protein receptor

Gs-GTP

Answer 26

beta-adrenoreceptors

Question 27

Differentiate Gs-GTP and Gi-GTP

Answer 27

Gs-GTP = stimulatory (activates adenylyl cyclase)
Gi-GTP = inhibitory (inhibits adenylyl cyclase)

Question 28

Give an example of a G-protein receptor

Gi-GTP

Answer 28

opiod receptors

Question 29

What about Gq-GTP?

Answer 29

Different enzyme - activates phospholipase C (PLC)
PLC–>inositol triphosphate (IP3)–>change in Ca2+ conc
then biological response
OR
PLC–>diacylgylcerol (DAG)–>activates protein kinase C–>protein phosphorylation–>biological response

Question 30

Give an example of a Gq-GTP receptors

Answer 30

muscarnic receptors and alpha-adrenoceptors

Question 31

Describe the Na+/K+ ATPase (Na+ pump)

Answer 31

3Na+ out of cell
2K+ into cell
Powered by ATP hydrolysis
Contributes to resting membrane potential

Question 32

What kind of drug is digoxin?

Answer 32

cardiotonic

used in heart failure

Question 33

How does digoxin work?

Answer 33

Blocks Na+/K+ ATPase 
Increase in intracellular Na 
Na+/Ca2+ exchanger stimulated 
Increase in Ca2+ 
Increase in force of contractions

Question 34

Give an example of a tyrosine kinase receptor

Answer 34

Insulin receptor

Question 35

How does a tyrosine kinase receptor work?

Answer 35

Signal molecule binds
Dimerisation of receptor
Activate of tyrosine-kinase regions and phosphorlyation of the dimer.
Dimer goes on to phosphorlyate tyrosine molecules and activate inactive relay proteins via this mechanism

Question 36

Give examples of nuclear receptor drugs

Answer 36

steroids and thyroid hormones (lipophilic drugs)

Question 37

Name some illnesses associated with malfunctioning nuclear receptors

Answer 37

inflammartion, cancer, diabetes, cardiovascular disease, obestiy and reproductive disorders

Question 38

describe speed of:
ligand gated ion channels 
g protein coupled receptors
kinase-linked receptors
Nuclear receptors

Answer 38

Milliseconds
seconds
hours
hours-days

Question 39

Look at dose response curves!

Answer 39

Okay