ANS

Question 1

What does the ANS do?

Answer 1

The ANS controls all vegetative (involuntary) functions. It is separate from the voluntary (somatic) motor system.
It is an entirely efferent system (but regulated by afferent outputs) so, goes from CNS to the periphery

Question 2

What are the two divisions of the ANS?

Answer 2

The sympathetic nervous system

The parasympathetic nervous system

Question 3

What does the sympathetic nervous system do?

Answer 3

In general, the sympathetic nervous system responds to stressful situations.
“Fight or flight” response.
Eg it raises heart rate, blood pressure and force of contraction of heart.

Question 4

What does the parasympathetic system do?

Answer 4

The parasympathetic nervous system Regulates basal activities (eg basal heart rate).
“Rest and digest”

Question 5

What is the structure of the parasympathetic nerves?

Answer 5

The originate in the lateral horn of the medulla (and sacral spinal cold)
They have long myelinated preganglionic fibres
They have short unmyelinated postganglionic fibres
Ganglia are located within the inner gated tissue
Have actions that oppose the sympathetic nervous system.

Question 6

What are the stucture of the sympathetic nerves?

Answer 6

Originate in the ,streak horn of the lumbar and thoracic spinal cold
They have short, myelinated preganglionic fibres
They have long, unmyelinated postganglionic fibres
Have actions that oppose the parasympathetic nervous system.

Question 7

What are the two main neurotransmitters I the ANS?

Answer 7

Acetylcholine and noradrenaline

Question 8

What neurotransmitter do all pre-ganglionic neurones use?

Answer 8

All preganglionic neurones are cholinergenic. 5is means that they use ACh as their neurotransmitter.

The preganglionic release of ACh results in the activation of the postganglionic nicotinic ACh receptors.

Nicotinic ACh receptors are ligand p-gated ion channels.

Question 9

What neurotransmitter do parasympathetic post-ganglionic neurones use?

Answer 9

These are also cholinergenic. This means they release ACh which acts in muscarinic ACh (nACh) receptors in the target effector tissue.
mACh receptors are G-Protein coupled receptors (GPCRs). There are five mACh receptor subtypes (M1-5)

Question 10

What neurotransmitter do most sympathetic post-ganglionic neurones use?

Answer 10

Noradrenaline. Noradrenaline interacts with one of two major classes of adrenoreceptors -the alpha and beta adrenoreceptors. These can be further subdivided into a1,a2,b1,b3,b3, all of which are G protein coupled receptors.

Question 11

What specialised sympathetic post ganglionic neurones are cholinergic rather than noradrenergic?

Answer 11

Those innervating sweat glands and hair follicles (piloerection)

Question 12

What other neurotransmitters can be found in the ANS?

Answer 12

these types of neurotransmitter are called non-adrenergic, non cholinergic (NANC) and may be co-released with either NA or ACh.
Examples include:
ATP (purinergic receptors)
Nitric oxide (NO)
5-hydroxytryptamine (5HT / serotonin)
Neuropeptides (eg VIP -vasoactive intestinal peptide, substance P)

Question 13

What is sometimes known as a third division of the autonomic nervous system? Why?

Answer 13

The enteric nervous system. This is the nervous system of your gut and, it can work independently of the CNS. For this reasons, some scientists classify it independently and others as a division of the ANS.

Question 14

How are sympathetic postganglionic neurones in the adrenal medulla different to those elsewhere?

Answer 14

This is because they differentiate to form neurosecretory chromaffin cells. These chromaffin cells can be considered post ganglionic sympathetic neurones that do not project to a target tissue. instead. upon synpathetic stimulation these cells release adrenaline into the blood stream.

Question 15

What are the 12 basic steps in neurotransmission?

Answer 15

1. Uptake of precursors
2. Synthesis of neurotransmitter
3. Vesicular storage of neurotransmitter (to prevent it being metabolised)
4. Degradation of transmitter
5. Depolarisation by propagated action potentials
6. Depolarisation-dependant influx of Ca2+
7. Exocytotic release of transmitter
8. Diffusion to post synaptic membrane
9. Interaction with post synaptic receptors
10. Inactivation of transmitter
11. Re-uptake of transmitter
12. Interaction with pre-synaptic receptors

4,9,10,11 and 12 are the steps that are interfered with pharmacologically.

Question 16

How is acetyl choline synthesised?

Answer 16

Acetyl CoA (pyruvate turns into AcoA) + choline (in diet) (using the enzyme choline acetyltransferase (CAT) which present in cholinergic synapses) makes acetylcholine and coenzyme A

Question 17

How is acetylcholine degraded?

Answer 17

Acetylcholine is degraded (using the enzyme acetylcholineesterase (AChE) into acetate (metabolised) + choline (recycled)

Question 18

How does cholinergic synaptic transmission work?

Answer 18

Acetylcholine is synthesied using CAT.
ACh then goes into vesicles.
These vesicles fuse with the membrane and ACh is released.
ACh is now susceptible to degradation suing AChE and, it binds to receptors on membrane.

Question 19

Where are nicotinic ACh receptors found?

Answer 19

Nicotinic ACh receptors are found in the autonomic ganglia. (At the sites between pre and post synaptic ganglion in both para and sympathetic nervous systems)

Question 20

Where are muscarinic ACh receptors found?

Answer 20

Muscarinic ACh receptors are found in post ganglionic synapses of the parasympathetic nervous system.

Question 21

What us trimethaphan used for?

Answer 21

Trimethaphan is used in hypertensive emergencies and to produce controlled hypertension during surgery.
This is the only ganglion-blocking drug that is widely used today.

Question 22

Is it possible to distinguish between muscarinic Ach receptor subtypes?

Answer 22

At the moment, No. Despite lots of research this has proved very difficult.
BUT, some newer agents do display limited tissue selectivity (eg the mAChR antagonist tolterodine which is used to treat an overactive bladder).
Allosteric agents are also being developed which may block some receptors -future development.

Question 23

Can cholinesterase activity be blocked? What happens when drugs do this?

Answer 23

When blocked, ACh increased in conc for a longer period if time. SO, more time to stimulate receptors in the system.
examples of AChE inhibitors include pyridostigmine which is used to treat myasthenia graves and dinepezil which is used to treat Alzheimers (limited success)

Question 24

What are some consequences of the lack of selectivity of cholinergic drugs?

Answer 24

This lack of selectivity means that unwanted side effects can limit their usage.
For example, a non selective muscarinic ACh receptor agonist is like cause autonomic side effects such as:
decrease heart rate and cardiac output (dangerous if already have heart problems)
Increase bronchoconstriction (make asthma worse) and GI tract peristalsis (might limit compliance)
Increased sweating and salivation. (limit compliance)

Question 25

What is SLUDGE?

Answer 25

SLUDGE is a mnemonic for the pathological effects indicative of massive discharge of the parasympathetic nervous system.
S stimulation of Salivary glands
L stimulation of Lacrimal glands
U Urination- relaxation of the urethral internal sphincter muscle and detrusor muscle contraction
D defecation
G gastrointestinal upset -smooth muscle tone changes causing GI problems inc diarrhoea
E Emesis -Vomiting

Question 26

When is SLUDGE syndrome usually encountered?

Answer 26

SLUDGE syndrome is usually encountered in cases of:

• Drug overdose
• Ingestion of magic mushrooms
• Exposure to organophosphorus insecticides (eg parathion) or nerve agents (eg sarin, VX-very very strong)

The latter agents (sarin and VX) covalently modify acetylcholinesterase to irreversibly deactivate the enzyme and raise acetylcholine.

Question 27

What causes SLUDGE symptoms?

Answer 27

SLUDGE symptoms are primarily due to chronic overstimulation of muscarinic acetylcholine receptors in muscles innervated by the parasympathetic nervous system

Question 28

How can SLUDGE be treated?

Answer 28

SLUDGE can be treated with atropine, pralidoxine or other anti-cholinergic agents.

Question 29

What are clinical uses of mscarinic ACh receptor agonists?

Answer 29

pilocarpine and bethanechol are respectively used to treat glaucoma and acutely to stimulate bladder emptying.

Question 30

What are clinical uses of mscarinic ACh receptor antagonists?

Answer 30

ipatropium and tiotropium are used to treat some forms of asthma and COPD
Tolterodine, darifenacin and oxybutynin are used to treat overactive bladder.

Question 31

What is the structure of post ganglionic sympathetic neurones?

Answer 31

They are long and they innervate a large variety of tissues using noradrenaline as the neurotransmitter.
They generally possess a highly branching axonal network with numerous varicosities, each of which is a specialised side for Ca2+ dependent noradrenaline release.

Question 32

What is a varicosity?

Answer 32

This is where noradrenaline is synthesised, stored in vesicles and released to the synaptic cleft. Noradrenaline is then recaptured by an uptake mechanism. This recaptured noradrenaline is either repackaged or metabolised. Because some noradrenaline is constantly metabolised (no system is perfect) there is a requirement for constant synthesis.

Question 33

How is noradrenaline synthesised?

Answer 33

Tyrosine (precursor) is taken up by a noradrenaline varicosity and then converted, via two other molecules, into noradrenaline.
Tyrosine is first converted into DOPA and then into dopamine which is then converted into noradrenaline. This process uses different enzymes and produces noradrenaline in very high levels.

Question 34

How is synthesis of noradrenaline different in the adrenal medulla?

Answer 34

In the adrenal medulla (in chromaffin cells), noradrenaline is converted to adrenaline (by adding a methyl group). This means that adrenaline will accumulate in high levels in vesicles in the adrenal medulla so that, upon command, it can be released by chromaffin cells.

Question 35

What happens after Ca2+ dependant exocytosis release of noradrenaline?

Answer 35

NA diffuses across the synaptic cleft and it interacts with the adrenoreceptos in the post synaptic membrane to initiate signalling in the effector tissue.
NA then interacts with the pre-synaptic adrenoreceptors to regulate processes within the nerve terminal eg NA release.

Question 36

Why does noradrenaline have a very limited time frame in which to interact with the per and post synaptic adrenoreceptors?

Answer 36

Noradrenaline works within 100s ms because it is rapidly removed from the synaptic cleft by noradrenaline transporter proteins.

Question 37

How is noradrenergic transmission terminated?

Answer 37

Uptake 1 / NET- NA actions are terminated by re-uptake into the pre-synaptic terminal by Na+ dependant hight affinity transporter. This captures 90-95% of NA

Uptake 2- NA is not recaptures re-captures by uptake 1 so, it is taken up by a lower affinity, non neuronal mechanism.

Question 38

What happens when he NA is recaptured?

Answer 38

It is reused or metabolised.
There are a number of enzymes that metabolised NA eg monoamine oxidases and catechol-O-methyltransfrases. There are clinically useful inhibitors of both of these enzymes.

Question 39

Can you create receptor specific drugs?

Answer 39

YES! it is much easier to create drugs specific to specific types of adrenal receptors or b1 specific rectors.

Question 40

How do adrenoceptor agonists work?

Answer 40

These are specific to one type of adredoceptor and will stimulate this receptor more.
For example, B2 adrenoceptor selective agonists (eg salbutamol) are used in asthma to reverse or oppose bronchoconstriction.. The B2 adrenoceptor selectivity of such agents is important because it limits possible cardiovascular side-effects.

Question 41

What do adrenoceptor antagonists used for?

Answer 41

These block the effects of receptors to prevent the NA from binding.These are more clinically useful than agonists. Eg a1 adrenoreceptor antagonists (eg doxazosin and b1 adrenoceptor selective antagonists (eg atenolol are used to treat a number of cardiovascular disorders inc hypertension.