Drugs and ANS

Question 1

Where can we pharmacologically intervene to alter ANS activity?

Answer 1

At the points of chemical communication

Question 2

Describe the successful ways in which we can target neurotransmission

Answer 2

We can design drugs that interfere with:

• Interaction with Presynaptic receptors
• Interaction with Post synaptic receptors
• Inactivation of transmitter
• Degradation of transmitter
• Reuptake of transmitter (neuronal)

Question 3

Steps of neurotransmission

Answer 3

Question 4

What is Acetylcholine synthesised from?

Answer 4

Acetyl Co A + Choline = acetylcholine (+co enzyme A)

Question 5

Enzyme used to synthesise Ach

Answer 5

Choline acetyltransferase (CAT)

Question 6

Acetylcholine degradation

Answer 6

acetylcholine –> acetate + choline

Question 7

Enzyme used for acetylcholine degradation

Answer 7

(acetyl)cholinesterase (AchE)

Question 8

How are drugs targeted to cholinergic sites? (3)

Answer 8

• nAchR at autonomic ganglia is different to nAchR at somatic neuromuscular junction (they differ in structure)
• Thus, some drugs have actions selective to autonomic ganglia
• You can get ganglion-blocking drugs

Question 9

Name a ganglion blocking drug and state its use

Answer 9

Trimethaphan

• Used in hypertensive emergencies
• Used to produce controlled hypotension in surgery

Question 10

How can endogenoulsly released Ach action be enhanced?

Answer 10

Using AchE inhibitors - acetylcholinesterase inhibitors

Question 11

Give 2 examples of acetylcholinesterase inhibitors and describe their uses

Answer 11

Pyridostigmine for Myasthenia Gravis

Donepezil for Alzheimers

Question 12

Problem with mAchR agonists/antagonists (4)

Answer 12

• There are 5 muscarinic acetylcholine receptor subtypes M1-M5
• At present, there are few subtype selective mAChR agonists or antagonists that are clinically available
• Not many selective ones
• Most effect all subtypes (M1-M5) so side effects limit use

Question 13

What are the dangers of a non-selective, muscarinic ACH receptor agonists? (3)

Answer 13

Autonomic side effects:

Heart - Increase in Heart rate and cardiac output (ie could be an issue for an elderly patient in an early stage of heart failure)

Smooth muscle - Increase in bronchoconstriction and GI tract peristalsis

Endocrine gland - Increase in sweating and salivation

Question 14

What is SLUDGE?

Answer 14

• A mneumonic for the pathological effects indicative of a massive discharge of the PNS

Question 15

What is SLUDGE syndrome?

Answer 15

Parasympathetic mAchR system overly stimulated 
Salivation
Lacrimation
Urination
Defectation
GI upset (ie diarrhoea)
Emesis (vomitting)

Question 16

Causes of SLUDGE (4)

Answer 16

- Drug overdose
- Ingestion of Magic mushrooms
- Exposure to Organophosphorous insecticides (parathion)
- Exposure to Nerve agents (e.g. sarin, VX,novichok)

Question 17

What do organophosphate poisoning and nerve agents do? (3)

Answer 17

• Covalently modify acetylcholinesterase
• To irreversibly deactivate the enzyme
• Ach levels rise = continued stimulation of mAchR

Question 18

Sludge treatment

Answer 18

Atropine
Pralidoxime

Or other anti-cholinergic agents

Question 19

Name 2 mAchR agonists and state their uses

Answer 19

Pilocarpine (treat glaucome)

Bethanechol (stimulate bladder emptying)

Question 20

Name 2 mAchR antagonists and state their uses

Answer 20

• Ipratropium
• Tiotropium

Used to treat some forms of asthma and COPD

Question 21

mAchR antagonists for overactive bladder

Answer 21

Tolterodine
Darifenacin
Oxybutynin

Question 22

mAchR antagonists for IBS/post op nausea

Answer 22

Hyoscine (aka Scopolamine)

Question 23

Sympathetic neuroeffector junction

Answer 23

postganglionic neurones = branches axonal network with bulges (VARICOSITIES)
These are specialised site for Ca2+ dependent release of noradrenaline from vesicles

Question 24

Noradrenaline synthesis

Answer 24

Tyrosine –> DOPA –> dopamine –> Noradrenaline

Question 25

What happens in adrenal medulla to noradrenaline?

Answer 25

Converted to adrenaline via phenylethanolamine N-methyltransferase)

Question 26

How is noradrenaline released?

Answer 26

Ca2+ dependent exocytosis

Question 27

What does noradrenaline do once released?

Answer 27

interacts with post-synaptic adrenoreceptors to signal effector tissue
Interacts with pre-synaptic adrenoreceptors to provide negative feedback to stop release

Question 28

How is NA removed from cleft?

Answer 28

By high affinity Na+ dependent transporter (NET aka Uptake 1) back to presynaptic terminal
If not recaptured by Uptake 1:
Uptake 2 = low affinity, non neuronal mechanism

Question 29

What happens to NA once back in presynaptic terminal?

Answer 29

Packaged back into vesicles
Any not packaged metabolised by:
- monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)

Question 30

B2 receptor agonists

Answer 30

Salbutamol 
treat asthma (reverse bronchoconstriction)

Question 31

Why is B2 selectivity important?

Answer 31

if just broad beta receptor agonist there are possible cardiovascular side effects (+ve inotropic and chronotropic)

Question 32

Drugs for hypertension

Answer 32

a1 adrenoreceptor antagonist (Doxazosin)

B1 adrenoreceptor antagonist (atenolol)