Week 5

Question 1

Agonists

Answer 1

A chemical that binds to receptor and activates the receptor to produce a biological response
e.g. Opiate receptor = Morphine

Question 2

Antagonists

Answer 2

Locks or dampens a biological response by binding to and blocking a receptor rather than activating it. e.g. Opiate receptor = Naloxone

Question 3

Blockers

Answer 3

Block the ion channel e.g. VG Na Channels = Local Anaesthetic

Question 4

Enzyme inhibitors

Answer 4

Competitive or non-competitive
or
False substrates - Drug converted into abnormal product that disrupts the normal metabolic pathway

Question 5

Beta-blockers

Answer 5

antagonist
Used in cardiovascular diseas.
- Heart failure, hypertension coronary artery disease
-Block signalling through the B adrenal-receptor (antagonist)

Question 6

B1

Answer 6

G-protein coupled receptor -
Increase in cardiac rate and force
Gene = ADBR1

Question 7

B2

Answer 7

G-protein coupled receptors
Bronchodialation, vasodialation
Gene = ADBR2

Question 8

ADBR1 - What are the two variants and how do they similar?

Answer 8

Two common variants
p.Arg389Gly
p.Ser49Gly
Both variants result in hyper functional receptor that are less responsive to blockade that wild type

Question 9

Malignant hyperthermia (MH)

Answer 9

Autosomal dominant, disorder of skeletal muscle
MH is triggered by volatile anaesthetics and depolarising muscle relaxants.
Muscle rigidity and a hyper-metabolic state (high temperature)
Can cause death if not treated promptly

Question 10

Muscle biopsy - MH

Answer 10

Expose it too halothane and caffeine, the contraction can be measured, caffeine will cause the muscle to contract more than normal because of the sensitivity.

Question 11

Muscle biopsy - MH

Answer 11

Expose it too halothane and caffeine, the contraction can be measured, caffeine will cause the muscle to contract more than normal because of the sensitivity.

Question 12

What do Statins do?

Answer 12

Lipid lower drug 
Example = simvastatin, atorvastatin 
Pharmacokinetic 
SLCO1B1 - Transporters 
Pharmacodynamic 
HMGCR - Enzymes

Question 13

SLCO1B1 encodes OATP1B1, What is it?

Answer 13

Membrane-bound sodium-independent organic anion transporter which uptakes many statins into hepatocyte

Question 14

What do drugs mainly act on (RICE)?

Answer 14

Receptors
Ion Channels
Carrier molecules
Enzymes

Question 15

What can polymorphisms effect?

Answer 15

Drug target can effect - pharmacodynamics
Drug transporters - Both
Drug Metabolising enzymes -Pharmacokinetics

Question 16

ADBR1 - What is the p.Arg389Gly variant and how does it differ?

Answer 16

• Reduced response to receptor activation by agonists

- Reduced response to receptor blockage by antagonists

Question 17

ADBR1 - What is the p.Ser49Gly variant and how does it differ?

Answer 17

• Increased receptor desensitisation after prolonged activation by an agonist

Question 18

What happens when someone with high blood pressure has a variation in ADBR1?(shown in a study)

Answer 18

There is no significant change in blood pressure after using beta-blockade, however there is other outcomes of studies which could be related to other variants.

Question 19

What is the genetic cause of Malignant Hyperthermia?

Answer 19

50-70% of cases is due to variation in the ryanodine receptor.

Question 20

What is the symptoms of a being triggered with Malignant Hyperthermia?

Answer 20

Increased Heart Rate 
Elevated ETCO2
Decreased oxygen saturation 
Increased temperature 
Muscle Rigidity 
Arrhythmias

Question 21

Biochemical and genetic basis of Malignant Hyperthermia

Answer 21

Mutation in the RYR1 gene
Altered calcium channel protein
Mutated channel opens more easily and stays open longer, thus flooding the cytosol with calcium
High intracellular levels of calcium stimulate sustained muscle contraction; high ca also stimulated breakdown of glycogen, glycolysis, and aerobic metabolism (resulting In excessive heat)

Question 22

Why does local aesthetics cause uncontrolled myoplasmic calcium release in patients with malignant hyperthermia?

Answer 22

The aesthetic acts on the Ryanodine receptor
Normally - Magnesium is bound keeping the channel shut, then the succinylcholine causes the channel to open - causing depolarisation
Mutated - The Magnesium is not keeping the channel shut properly so when Succinylcholine is added, there is a weaker depolarisation, because they are hypersensitive.

Question 23

How do statins work?

Answer 23

Statins form a substrate for the organic OATP transporter, which allows the transcellular movement of statin dugs inside the liver or the hepatic cell.
Statins are a HMG-CoA reductase inhibitor, which stops HMG-CoA producing Mevalonic acid, which inhibits cholesterol production.

Question 24

What do variants in the SLCO1B1 cause?

Answer 24

The transport which takes statin up into the liver cell
- toxicity occurs when the transporter does not work as well when there is a variant.
Causing muscle degradation and kidney damage/ achy muscles

Question 25

What do variants in the HMGCR (HMGCoA Reductase) cause?

Answer 25

Target for statins however variant in the non-coding region cause decreased response to statins.

Question 26

What does HMGCR do?

Answer 26

It catalyses the NADP-dependent conversion of HMG-CoA to mevalonate in the rate limiting step of cholesterol production.

Question 27

Modulators

Answer 27

Modulators - increased/decreased opening probability

e.g. VG Na channels = Veratridine

Question 28

What is NAT2 in tuberculosis?

Answer 28

• Highly polymorphic phase 2 metabolic enzyme

- Add to aromatic amine drugs with acetyl-groups