Lecture 9.1: Pharmacology of the Autonomic Nervous System

Question 1

Basics Steps in Neurotransmission (10)

Answer 1

1) Uptake of precursors
2) Synthesis of transmitter
3) Vesicular storage of transmitter
4) Degradation of transmitter
5) Depolarisation by propagated action potential
6) Depolarisation-dependent influx of Ca2+
7) Exocytotic release of transmitter
8) Diffusion to post-synaptic membrane
9) Interaction with post-synaptic receptors
10) Inactivation of transmitter

Question 2

Acetylcholine Synthesis

Answer 2

• Acetyl CoA + choline —> acetylcholine + coenzyme A
• Facilitated by choline acetyltransferase (CAT)

Question 3

Acetylcholine Degradation

Answer 3

• Acetylcholine —> acetate + choline
• Facilitated by (acetyl) cholinesterase (AChE)

Question 4

Nicotinic acetylcholine receptors(nAChRs) at autonomic ganglia and the neuromuscular junction differ in structure, how is this clinically relevant?

Answer 4

Therefore, some drugs have actions selectively at autonomic ganglia (e.g. the ganglion-blocking drug
trimetaphan)

Question 5

What drugs can enhance the actions of endogenously released ACh?

Answer 5

• AChE inhibitor
• Pyridostigmine (used to treat myasthenia gravis)
• Neostigmine (to reverse muscle relaxation)
• Donepezil

Question 6

How many muscarinic acetylcholine receptor (mAChR)
subtypes are there?

Answer 6

• 5
• M1-M5

Question 7

A relative lack of selectivity of cholinergic drugs means that unwanted ‘side-effects’ often limit their usage, what side effects is a non-selective, muscarinic ACh receptor agonist is likely to cause?

Answer 7

• HEART: bradycardia, reduced cardiac output
• SMOOTH MUSCLE: bronchoconstriction, increased GI
  tract peristalsis
• EXOCRINE GLANDS: increased sweating & salivation

Question 8

mACh receptor agonists and antagonists have some
clinical uses, especially when they can be administered….?

Answer 8

locally rather than systemically

Question 9

What muscarinic ACh receptor agonist is used to treat glaucoma?

Answer 9

Pilocarpine

Question 10

What muscarinic ACh receptor agonist is used acutely to stimulate bladder emptying?

Answer 10

Bethanechol

Question 11

What muscarinic ACh receptor antagonists are used to treat some forms of asthma and COPD? (2)

Answer 11

• Ipratropium
• Tiotropium

Question 12

What muscarinic ACh receptor antagonists are used to treat an overactive bladder? (3)

Answer 12

• Tolterodine
• Darifenacin
• Oxybutynin

Question 13

What is an orthosteric binding site?

Answer 13

Active site

Question 14

What is an allosteric binding site?

Answer 14

Site elsewhere to active site

Question 15

How do benzodiazepines increase GABA(A) receptor/ion channel activity?

Answer 15

By acting as positive allosteric modulators(PAMs)

Question 16

The vast majority of post- ganglionic sympathetic neurons are ….?

Answer 16

Noradrenergic

Question 17

What are the Steps of Noradrenergic Transmission following Ca2+-dependent exocytotic release of NA?

Answer 17

1) NA diffuses across the synaptic cleft and interacts
with adrenoceptors in the post-synaptic membrane to
initiate signalling in the effector tissue
2) NA interacts with pre-synaptic adrenoceptors to
regulate processes within the nerve terminal e.g. NA
release
3) NA has only a very limited time in which to influence
pre- and post-synaptic adrenoceptors as it rapidly
removed from the synaptic cleft by noradrenaline
transporter proteins

Question 18

Noradrenergic Termination: Termination

Answer 18

• NA actions are terminated by re-uptake into the pre-
  synaptic terminal by a Na+- dependent, high affinity
  transporter
• NA not re-captured by Uptake 1 is taken up by a lower
  affinity, non-neuronal mechanism

Question 19

Noradrenergic Termination: Metabolism

Answer 19

• Within the pre-synaptic terminal NA not taken up into
  vesicles is susceptible to metabolism by two enzymes
• Monoamine oxidase (MAO)
• Catechol-O-methyltransferase (COMT)

Question 20

Presynaptic G protein-coupled receptors (e.g. the α2- adrenoceptor) can regulate neurotransmitter release by…?

Answer 20

inhibiting Ca2+-dependent exocytosis

Question 21

How do GPCRs inhibit Ca2+-dependent exocytosis?

Answer 21

G protein βγ subunits inhibit specific types of voltage- operated Ca2+ channels (VOCCs) reducing Ca2+-influx and neurotransmitter release

Question 22

Side Effects of Anticholinergic Drugs? (8)

Answer 22

• Dry Mouth
• Constipation
• Urinary Retention
• Bowel Obstruction
• Dilated Pupils
• Blurred Vision
• Tachycardia
• Decreased Sweating

Question 23

What type of drug is Atropine?

Answer 23

Anticholinergic, competitive antagonist

Question 24

What is Atropine used for?

Answer 24

Emergency bradycardia, it increases heart rate by blocking the inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate

Question 25

What is excess bronchoconstriction caused by?

Answer 25

• Increase parasympathetic tone (mAch receptors)
• Decreased sympathetic stimulation (β-adrenoceptors)