Pharmacodynamics

Question 1

Define pharmacodynamics.

Answer 1

Drug action at the molecular level.

Question 2

There are 4 classes of endogenous protein that drugs act on to mimic or influence NTs. What are they?

Answer 2

1. Enzymes
2. Receptors
3. Transporters
4. Ion channels

Question 3

What is Kd?

Answer 3

The disassociation constant.

Question 4

What does Kd tell us?

Answer 4

The concentration of drug required to fill 50% of the receptor sites at equilibrium.

Question 5

Thus if a drug has a low Kd value, what does it tell us?

Answer 5

The drug has a high affinity for its receptor, as a low concentration is needed to fill 50% of the receptor sites.

Question 6

What are dose-response curves used to show?

Answer 6

Drug potency.

Question 7

Define potency.

Answer 7

The ‘strength’ of a drug, essentially how efficiently it acts on its target

Question 8

What is potency measured by?

Answer 8

ED50.

Question 9

Define ED50.

Answer 9

The concentration of a drug required to produce 50% of the maximal response.

Question 10

If a drug is a partial agonist, but has a low Kd and low ED50 value, can it produce a maximal response?

Answer 10

No: even with high affinity and high potency a partial agonist can never produce a maximal response.

Question 11

With ligand-gated ion channels, the NT is the ligand. Describe the binding between the ligand and receptor.

Answer 11

It is weak, non-covalent association. Thus it is reversible, with rapid association and disassociation.

Question 12

Why do ligand-gated ion channels produce such fast responses?

Answer 12

Because the receptor IS the effector.

Question 13

Ligand-gated ion channels are monomeric and extrinsic. True or false?

Answer 13

False: they are multimeric and intrinsic.

Question 14

There are 3 classes of ligand-gated receptors. What are they?

Answer 14

1. Nicotinic
2. Glutamate receptors
3. GABA receptors

Question 15

a) which NT binds nicotinic receptors?

b) Describe what happens when this NT binds the receptor.

Answer 15

a) ACh

b) Causes a conformational change that allows Na+ to flood into the cell, producing an excitatory response.

Question 16

Describe what happens when glutamate binds its ligand-gated receptor.

Answer 16

Makes the cell permeable to Na+. This is the fastest mode of excitation (does not involve shape change).

Question 17

a) Which GABA receptor is the ligand-gated ion channel?

b) Describe what happens when glutamate binds this receptor.

Answer 17

a) GABA-A

b) Causes a conformational change that causes Cl- to flood in, causing an inhibitory response

Question 18

Which drugs target GABA-A receptors in the treatment of anxiety?

Answer 18

Benzodiazepines: they cause hypnotic, sedative, relaxant effects

Question 19

Nicotinic and GABA-A receptors are from the same receptor superfamily. Which superfamily is this?

Answer 19

The Cys-loop ligand-gated channel family

Question 20

Why are metabotropic receptors so slow?

Answer 20

They involve second messengers that activate ligand-gated ion channels.

Question 21

What is another name for metabotropic receptors and why?

Answer 21

GPCRs or G-protein coupled receptors: G-proteins are the second messengers.

Question 22

What happens to GPCRs when a ligand (NT) binds?

Answer 22

G-proteins are activated that act on a wide range of receptors.

Question 23

Describe what happens in G-protein activation.

Answer 23

GDP is bound to the alpha-subunit. This is phosphorylated to form GTP. Energy from phosphorylation activates the G-proteins. GTP is then hydrolysed back to GDP.

Question 24

Why can a single ligand binding a GPCR cause a huge response?

Answer 24

G-protein activation is a continuous cycle, so the effect of ligand binding is self-perpetuating.

Question 25

There are 7 transmembrane domains in a GPCR. These can act as independent monomers. True or false?

Answer 25

True.

Question 26

What is the a) extracellular and b) intracellular terminus of a GPCR?

Answer 26

a) Amino group

b) Carboxyl group

Question 27

There are 4 types of metabotropic receptor. What are they and what do they do?

Answer 27

1. Gs = stimulatory, these increase NT release.
2. Gi = inhibitory, these decrease NT release
3. Gq = activates phospholipase C
4. G12/13 = involved in cellular function

Question 28

How are Gs GPCRs stimulatory?

Answer 28

They activate adenylate cyclase.
Adenylate cyclase increases ATP hydrolysis.
This increases the levels of cAMP.
cAMP activates PKA.

Question 29

Why can the effects of Gs stimulation be long-lasting?

Answer 29

The catalytic subunit of PKA (5L) translocates to the nucleus and initiates gene transcription. This is involved in long-term memory.

Question 30

PKA has numerous effects. List some.

Answer 30

Involved in lipid, glycogen and glucose metabolism.

Involved in reward in the nucleus accumbens.

Question 31

Gs receptors are in a constant state of equilibrium. Even without the presence of NTs some are synthesising cAMP. Where does the equilibrium lie under normal conditions?

Answer 31

In favour of the receptors not producing cAMP.

Question 32

There are 3 ways in which drugs can affect Gs receptors. What are they?

Answer 32

1. Agonists: bind the receptors producing cAMP and shift the equilibrium in their favour.
2. Inverse agonists: binds the receptors not producing cAMP and shifts the equilibrium in their favour.
3. Antagonists: binds the receptors but cause no change to cAMP levels as antagonists do not cause a biological change.

Question 33

Gq is a lithium target. This is used to treat which disorders?

Answer 33

Bipolar and mania.

Question 34

G12/13 is involved in cellular processes. Which ones?

Answer 34

Proliferation, migration, embryogenesis and apoptosis.