Mechanism of Drug Action

Question 1

Where is the GABAa receptor found?

Answer 1

On neurons in the amygdala and hypothalamus in the brain

Question 2

What type of receptor is GABAa?

Answer 2

Ligand-gated ion channel for Cl- ions

Question 3

What amino acids are the M2 helix of GABA rich in?

Answer 3

Positive amino acids, arg and lys

Question 4

What effect does GABA have when binding to GABAa and why?

Answer 4

Sedative effect, when it binds, Cl- ions flow into the cell, hyperpolarizing the membrane making the neuron less likely to fire an action potential

Question 5

What class of drugs also bind to GABAa and what is their indication?

Answer 5

Benzodiazepines e.g diazepan (Valium)

Short term treatment of anxiety

Question 6

How do benzodiazepines help with anxiety?

Answer 6

They enhance the effect of GABA binding to GABAa

Question 7

What also enhances the binding of GABA to GABAa receptors resulting in a sedative effect as well as benzodiazepines?

Answer 7

Alcohol

Question 8

What is the role of oestrogen?

Answer 8

To control when cells grow

Question 9

Give an example of when oestrogen is beneficial and when it can be harmful

Answer 9

It is important for bone growth and prevents osteoporosis

It an also enhance the unnatural growth of tumours

Question 10

What drug is used to treat cancer through blocking oestrogen?

Answer 10

Tamoxifen

Question 11

Describe how tamoxifen works for treatment of cancer

Answer 11

It mimics the shape of oestrogen and binds tightly to the oestrogen receptor, changing the shape of the signalling loop, preventing the binding of transactivation proteins and RNA polymerase

Question 12

What type of receptor is oestrogen receptor?

Answer 12

DNA-binding receptor

Question 13

How are tyrosine kinase receptors linked to cancer and give an example?

Answer 13

In cancer cells, mutated tyrosine kinases are over active leading to more transcription and therefore excessive growth
E.g Leukaemia

Question 14

Describe the mutation in cancerous tyrosine kinase receptors

Answer 14

There is a translocation mutation of one of the genes resulting in the loss of the region which codes the the regulatory region for ligand binding resulting in the receptor always being in the active form, Bcr-Abl kinase

Question 15

What is Bcr-Abl tyrosine kinase?

Answer 15

The mutated form of tyrosine kinase which is always in the active form and results in excessive growth

Question 16

What drug is used aginst Bcr-Abl tyrosine kinase?

Answer 16

Imatinib (Gleevec), 90% of patients respond well to it

Question 17

Describe how Gleevec works against Bcr-Abl tyrosine kinase

Answer 17

It mimics ATP and binds to the ATP site on the binding site in the c terminus, blocking the binding of ATP and phosphorylation and no binding site for proteins is exposed and so no transcription of proteins

Question 18

What type of receptors do beta-blockers target?

Answer 18

GPCRs

Question 19

Which domains of GPCRs are most important in binding to adrenaline?

Answer 19

M3, M6, M5

Question 20

What type of ligands are beta blockers?

Answer 20

Antagonists

Question 21

Give 2 examples of beta-blockers

Answer 21

Propranolol, atenolol

Question 22

How do beta-blockers work?

Answer 22

They mimic the shape of adrenaline and bind to the the pocket in the receptor but do not activate the receptor and so block the following processes that normally happen that lead to heart contraction

Question 23

How were beta-blocker drugs synthesised?

Answer 23

By chemical modification of adrenaline

Question 24

Which 3 regions on adrenaline are also found in beta-blockers?

Answer 24

Benzene ring, OH and NH

Question 25

When are beta-blockers more effective?

Answer 25

During exercise, stress or excitement since they block pathways stimulated by adrenaline

Question 26

What class of drugs lower lipid levels in the blood?

Answer 26

Fibrates

Question 27

How do fibrates reduce the lipid levels in the blood?

Answer 27

They reduce the concentration of VLDL which contains triacylglycerols by rapidly increasing the number (proliferate) of peroxisomes in a cell

Question 28

Give an example of a fibrate

Answer 28

Clofibrate

Question 29

What receptors do fibrates bind to?

Answer 29

PPARs (peroxisome proliferator activated receptors)

Question 30

What are PPARs?

Answer 30

Peroxisome proliferated activated receptors, they are nuclear receptors that are also specific transcription factors

Question 31

Describe the mechanism of fibrates binding to PPARs

Answer 31

Fibrates bind to the PPARa isoform causing a conformational change which promotes dimerisation with RXR. This complex binds to PPARa Response Element (PPRE) in the promoter region of the target gene. This complex then recruits the TFs (e.g TFIID) and RNA polymerase II to activate transcription of the target gene

Question 32

What in target genes that contain PPRE makes them effective at lowering lipid levels?

Answer 32

They contain genes that encode for proteins that remove VLDL triacylglycerol from the plasma and destroy it by oxidation

Question 33

Which part of the protein structure on an antibody contains the binding site for the antigen?

Answer 33

Tertiary structure, at the tips of the heavy and light chains

Question 34

What are the 2 major therapeutic uses of antibodies?

Answer 34

Vaccines and monoclonal antibodies

Question 35

What is an attenuated vaccine?

Answer 35

A vaccine that contains a weakened version of the virus/bacteria which cannot cause disease

Question 36

What is an inactivated vaccine?

Answer 36

A vaccine that contains dead virus

Question 37

What are subunit vaccines?

Answer 37

Vaccines that only use one viral/bacterial protein (purified pathogen)

Question 38

Describe the general idea behind vaccines

Answer 38

When injected, the body begins to make B-lymphocytes which are specific to the antigen, after a few doses, the body contains a sufficient supply of "memory" B-lymphocytes so that a future immune response is faster

Question 39

Describe the mechanism behind the Covid vaccine

Answer 39

One of the transmembrane proteins on SARS-Cov-2 is S1, this protein binds to ACE2 using RBD in humans to initiate a response. Antibodies that are produced in response to the vaccine bind to this same protein, inhibiting RBD from binding to ACE2

Question 40

How are antibodies produced in scientific research?

Answer 40

Repeated immunisation of a suitable animal, their blood is then taken and a serum is prepared the the peak of antibody production

Question 41

What is the epitope?

Answer 41

The region on the antigen which is recognised by antibodies

Question 42

What is the difference between polyclonal and monoclonal antibodies?

Answer 42

Polyclonal antibodies are released from different B-cells but attach to the same antigen if the antigen is large and has different epitopes Monoclonal antibodies are released from one B-cell and attach to the only epitope on an antigen

Question 43

Which gene is a key factor in breast cancer?

Answer 43

HER2 gene (human epidermal growth factor receptor 2 gene), over expression by tumour cells was found in patients with breast cancer

Question 44

What type of receptor is HER2

Answer 44

Tyrosine kinase

Question 45

What is the role of HER2?

Answer 45

It transmits the epidermal growth factor extracellular signal that controls cell growth and division

Question 46

What causes overexpression of HER2?

Answer 46

Gene amplification, more copies of the gene for HER2 are found in a tumour cell resulting in more transcription and synthesis of the receptors

Question 47

What is Herceptin?

Answer 47

A monoclonal antibody that was produced using a mouse B cell where 95% of it was genetically engineered to look like a human cell to reduce chances of rejection

Question 48

How are monoclonal antibodies synthesised in a lab?

Answer 48

They are produced by cells obtained from immunised animals

Question 49

Describe how Herceptin works

Answer 49

It reacts with cancer cells that have increased HER2 on their surface by binding to the receptor resulting in the growth signals normally released to be prevented i.e through EGFs

Question 50

What is the ADCC mechanism

Answer 50

Antibody-dependent cellular cytotoxicity, the immune system destroys cells that are labelled with antibodies