From Physiological Systems To Molecular Drug Targets II Flashcards Preview

PM2C Autumn Amy L > From Physiological Systems To Molecular Drug Targets II > Flashcards

Flashcards in From Physiological Systems To Molecular Drug Targets II Deck (67):
1

Name the 3 locations where nicotinic ACh receptors are found

  1. Muscle (neuromuscular junctions)
  2. Ganglion
  3. CNS

2

What is the function of nicotinic ACh receptors?

Excitation

3

Name an agonist for nicotinic ACh receptors

Acetyl Choline

4

How many transmembrane domains does a subunit of a nAChR have?

4

5

How many subunits does a nicotinic receptor have?

5: alpha, alpha, beta, delta, gamma

6

What do the nicotinic receptor subunits come together to form?

An ion channel

7

What is a nicotinic receptor's ion channel permeable to?

Na+

8

How do nicotinic receptors cause excitation?

  1. 2 ACh molecules bind to the nAChR 
  2. Conformational change occurs
  3. Ion channel opens
  4. Na+ enters the cell causing an increase in positive charge inside of the cell
  5. This causes excitation

9

What acts as the receptor gate in a nicotinic receptor?

  • 2 alpha helices, 1 in each alpha subunit
  • Conformational change when ACh binds causes them to open the ion channel

10

What is an issue when synthesising drugs targeted at the ANS ganglia nAChRs?

The drugs do not discriminate between sympathetic and parasympathetic nerves

11

Where do neuromuscular blocking agents work?

Neuromuscular junction

12

Name 2 types of neuromuscular blocking agents

  1. Competitive blockers
  2. Depolarising blockers

13

What are competitive blockers?

Competitive antagonists of nAChRs

(Increase concentration of agonist = decrease power of antagonist)

14

What are depolarising blockers?

Agonists which cause a depolarising block of the muscle fibre endplate

15

How do depolarising blockers work?

  1. Switch the receptor on = increase in Na+ entering the cell
  2. Blocker stops channel from closing so sodium keeps coming into the cell
  3. Eventually too much sodium enters the cell and prevents further excitation
  4. Activation of receptor switched off

16

Give a use of competitive blockers

  • Muscle relaxants as an adjunct to anaesthesia
  • In particular in obstetrics as they do not cross into the placenta

17

Name 3 examples of a competitive blocker

  1. Tubocurarine
  2. Pancuronium
  3. Vecuronium

18

Why are competitive blockers used as muscle relaxants?

They selectively work on the nAChRs at the neuromuscular junction, rather than at the ganglia and the brain/CNS

19

Why are different competitive blockers used for minor vs major surgeries

Some have shorter half lives than others therefore work for shorter periods of time

20

Give an example of a use of depolarising blockers

Cause paralysis during anaesthesia

21

How do depolarising blockers cause paralysis?

  1. The muscle contracts due to maintained depolarisation
  2. Muscle cannot repolarise (relax)
  3. This causes loss of excitability (sodium channels cannot inactivate)
  4. Therefore the continual stimulation of the NMJ by DB's causes muscle paralysis

22

Name an example of a depolarising blocker

Succinylcholine (Suxamethonium)

Works on nAChRs

23

What is succinylcholine used for?

To cause paralysis during anaesthesia

Minor surgery

24

Why is suxamethonium so short acting? (10 mins)

Because it is rapidly hydrolysed by cholinesterases

25

What is the indication for Donepezil?

For the treatment of mild-moderate Alzheimer's Disease

26

What is the mechanism of action of Donepezil?

Anticholinesterase = inhibits ACh-esterase

27

How does botulinum toxin type A work?

It blocks vesicle docking/release and therefore prevents the release of ACh

28

How can botulinum toxin type A be deadly?

Can cause respiratory paralysis

29

Why is botulinum toxin type A so toxic?

It has a very low LD50 value

LD50 = 10ng/kg

30

List 3 therapeutic indications for botulinum toxin

  1. Excessive muscle spasm - can result from stroke, brain or spinal cord injury, CP
  2. Migraine/headache treatment - facial muscle contraction stimulates headaches
  3. Excessive secretion - severe underarm sweating or salivation

31

What receptors does noradrenaline act on?

α or β-adrenoceptors

32

What is noradrenaline release regulated by?

Inhibitory presynaptic α2-adrenoceptors

33

What are β​-blockers?

Blockers of the β-adrenoceptors

34

How is adrenaline released into the bloodstream?

It is secreted from the adrenal gland

35

What is dopamine?

A precursor for noradrenaline and adrenaline

And a CNS transmitter

36

Which amino acid are adrenaline, noradrenaline and dopamine generated from?

Tyrosine

37

Describe the biogenic amine synthesis process

Tyrosine --> DOPA --> Dopamine --> Noradrenaline --> Adrenaline

38

How can one of the substances in biogenic amine synthesis build up?

If the enzyme which converts the substance into something else becomes inhibited

39

What acts as negative feedback in biogenic amine synthesis?

  • Build up of noradrenaline
  • Negative feedback on to tyrosine hydroxylase (converts Tyrosine to DOPA)

40

How many subtypes of adrenoceptor are there?

5: α1 α2 β1 β2 β3

41

Where is the β1-adrenoceptor located?

Heart

42

Where is the β2-adrenoceptor located?

Smooth muscle

43

Where is the α1-adrenoceptor located?

Smooth muscle

44

Where is the α2-adrenoceptor located?

Smooth muscle

45

What type of G protein is the α1-adrenoceptor coupled to?

q

46

What type of G protein does the α2-adrenoceptor couple to?

Gα​i/o

47

What type of G protein do the β-adrenoceptors couple to?

s

48

What response does the α1-adrenoceptor cause when its G protein is bound?

Increase in IP3

49

What response does the α2-adrenoceptor cause when bound to its G protein?

Decrease in cAMP

50

What response do the β-adrenoceptors cause when their G protein is bound?

Increase in cAMP

51

Name the enzyme that s (with β​1/2/3 adrenoceptors) stimulates

Adenylate cyclase

52

What process does adenylate cyclase carry out?

Converts ATP --> cAMP

53

What effect does increased cAMP have?

Increased protein phosphorylation

54

What would be the agonist of choice to activate the α1-adrenoceptor

Noradrenaline

55

What would be the agonist of choice to activate the α2-adrenoceptor

Adrenaline

56

What would be the agonist of choice to activate the β-adrenoceptors

Isoprenaline

57

What effect does NA cause when bound to an α1 receptor

(α selective)

  • Vasoconstriction
  • This causes reflex bradycardia due to baroreceptor response
  • ACh release = slows vagal nerve 
  • Overall increase in BP

58

What effect does isoprenaline have when it binds to β adrenoceptors? (β- selective)

Causes vasodilation (β2) and tachycardia (β1) Overall decrease in BP

59

What effect does adrenaline have when it binds to a β or α-adenoceptor?

Higher affinity for β receptor but can still bind to α 

Slight increase in BP

60

What are adrenergic synapses also known as?

Varicosities (= swelling)

61

How do sympathomimetics work?

Mimic CNS

62

What is the indication for salbutamol?

Asthma treatment

63

What is the mechanism of action for salbutamol?

Selective β2 adrenoceptor agonist

Causes bronchodilation

64

What is the indication for atenolol?

Hypertension

65

What is the mechanism of action of atenolol?

Cardioselective β1 adrenoceptor antagonist

(= β​ blocker)

66

What is the indication of pseudoephedrine?

Nasal decongestion

67

What is the mechanism of action of pseudoephedrine? (Sudafed)

Substrate for biogenic amine uptake system = sympathomimetic

  1. Mimics NA and gets taken up by uptake system
  2. Therefore NA displaced from vesicles
  3. Released NA builds up in synapatic cleft = vasoconstriction of mucosal blood vessels (α1 adrenoceptors)
  4. This reduces fluid build up in the nose