The Autonomic Nervous System and Pharmokinetics

Question 1

What is the ANS comprised of?

Answer 1

A series of two neurones, one pre-ganglionic and one post-ganglionic

Question 2

What is the ganglion?

Answer 2

The collection of cell bodies in the PNS

Question 3

Where do the neurones in the ANS have their cell bodies?

Answer 3

One in the CNS, one in the PNS

Question 4

What do neurones in the ANS exert action via?

Answer 4

Smooth muscle
Viscera
Secretory glands

Question 5

What is the thoraco-lumbar outflow part of?

Answer 5

The sympathetic nervous system

Question 6

Where do the nerve fibres that contribute to the thoraco-lumbar outflow have their cell bodies?

Answer 6

In all 12 thoracic sections and the first 2 lumbar sections

Question 7

How long are the nerve fibres in the thoraco-lumbar outflow?

Answer 7

Short pre-ganglionic nerve fibre

Long post-ganglionic nerve fibre

Question 8

Where can the nerve fibres synapse in the thoraco-lumbar outflow?

Answer 8

May synapse at the same level as origin (paravertebral origin)
May synapse at different level to origin
May not synapse in paravertebral chain

Question 9

What kind of neurones are the pre-ganglionic in the thoraco-lumbar outflow?

Answer 9

Cholinergenic (ACh)

Question 10

What do the post-ganglionic neurones in the thoraco-lumbar outflow express?

Answer 10

Nicotinic receptors

Question 11

What kind of neurones are the post-ganglionic in the thoraco-lumbar outflow?

Answer 11

Noradrenergic (NA)

Question 12

What are the classes of adrenoreceptors?

Answer 12

Alpha (1 and 2)

Beta (1 and 2)

Question 13

What is the exception to the rules of the thoraco-lumbar rules?

Answer 13

Some synapses are cholinergic- perspiration and ejaculation pathways

Question 14

What is the cranio-sacral outflow part of?

Answer 14

The parasympathetic nervous system

Question 15

How long are the nerve fibres in the cranio-sacral outflow?

Answer 15

Long pre-ganglionic nerve fibre

Short post-ganglionic nerve fibre

Question 16

What kind of neurones are the pre-ganglionic in the cranio-sacral outflow?

Answer 16

Cholinergic

Question 17

What do the post-ganglionic neurones in the cranio-sacral outflow express?

Answer 17

Nicotinic receptors

Question 18

What kind of neurones are the post-ganglionic in the cranio-sacral outflow?

Answer 18

Cholinergic

Question 19

What synthesises acetylcholine?

Answer 19

The enzyme choline acetyltransferase (CAT)

Question 20

What is acetylcholine synthesised from?

Answer 20

Choline and the metabolic intermediate Acetyl-CoA

Question 21

Where is acetylcholine synthesised?

Answer 21

In the cytoplasm of cholinergic terminals

Question 22

What happens to acetylcholine once synthesised?

Answer 22

Some is degraded by cytoplasmic cholinesterase

The majority is transported into synaptic vesicles by an indirect active transport mechanism

Question 23

What do cholinergic terminals possess?

Answer 23

Numerous vesicles contain high concentrations (>100mM) of ACh

Question 24

How can ACh be released from cholinergic terminal vesicles?

Answer 24

By Ca mediated exocytosis

Question 25

What happens to released ACh?

Answer 25

It can interact with both pre- and postsynaptic cholinoreceptors

Question 26

What is the opportunity for ACh to interact with receptors limited by?

Answer 26

ACh in the synaptic cleft being acted upon by cholinesterase, which rapidly degrades ACh to choline and acetate

Question 27

Where is the activity of cholinesterase highest?

Answer 27

At fast (nicotinic) cholinergic synapses

Question 28

What is the result of cholinesterase at cholinergic synapses?

Answer 28

The synaptic cleft half-life of ACh is only a few milliseconds

Question 29

What recaptures most choline?

Answer 29

A choline transporter present in the synaptic terminal

Question 30

What is noradrenaline synthesised from?

Answer 30

Tyrosine

Question 31

Where is noradrenaline synthesised?

Answer 31

Within the nerve terminal

Question 32

What is the rate limiting enzyme in noradrenaline synthesis?

Answer 32

Tyrosine hydroxylase

Question 33

Where is the enzyme dopamine ß-hydroxylase located?

Answer 33

Within synaptic vesicles

Question 34

What does dopamine ß-hydroxylase do?

Answer 34

Transports newly synthesised dopamine into the vesicle prior to its conversion to noradrenaline

Question 35

What does dopamine ß-hydroxylase recognise?

Answer 35

Dopamine and noradrenaline

Question 36

What does dopamine ß-hydroxylase recognising dopamine and noradrenaline allow for?

Answer 36

It's recycling following release and reuptake

Question 37

At what level is cytoplasmic NA concentration under most circumstances?

Answer 37

Low

Question 38

At what level is intravesicular NA concentration under most circumstances?

Answer 38

Very high (0.5-1.0M)

Question 39

Why is a very high intravesicular NA concentration possible?

Answer 39

Because the vesicular transporter exploits a H-ATPase-generated cytoplasm-vesicle H-gradient to move catecholamines against their concentration gradient

Question 40

What is cytoplasmic NA susceptible?

Answer 40

Enzymatic breakdown by monoamine oxidase

Question 41

How is tyrosine converted to noradrenaline?

Answer 41

Tyrosine -> dopa -> dopamine -> noradrenaline

Question 42

How is NA released?

Answer 42

Ca mediated exocytosis

Question 43

What can released noradrenaline interact with?

Answer 43

Both pre- and postsynaptic adrenoreceptors

Question 44

What is the opportunity for noradrenaline to interact with adrenoreceptors limited by?

Answer 44

A high affinity reuptake system, Uptake 1

Question 45

What does uptake 1 act to do?

Answer 45

Rapidly remove NA from the synaptic cleft, rapidly decreasing the localised concentration and terminating its actions

Question 46

What happens to any NA escaping from the synaptic cleft?

Answer 46

It is removed from the extracellular space by another, widespread, lower affinity reuptake system, uptake 2

Question 47

What is ACh and NA release triggered by?

Answer 47

Depolarisation of the nerve terminal membrane, Ca entry, and fusion of vesicles with the pre synaptic membrane (Ca mediated exocytosis)

Question 48

What drugs act on cholinergic nerve terminals?

Answer 48

Nicotinic cholinoceptor antagonists Muscarinic cholioceptor agonists Muscarinic cholinoceptor antagonists Cholinesterase inhibitors

Question 49

How do agents that interfere with cholinergic transmission and are of therapeutic use generally act?

Answer 49

By interaction with cholinoceptors

Question 50

What is the exception to agents interfering with cholinergic transmission acting by interaction with cholinoceptors?

Answer 50

Cholinesterase inhibitors

Question 51

How are cholinesterase inhibitors used therapeutically?

Answer 51

They decrease the rate of ACh degradation, and so prolong the lifetime of ACh within the synaptic cleft

Question 52

What drugs act on adrenergic nerve terminals?

Answer 52

``` α-methyl-tyrosine α-methyl-DOPA CarbiDOPA Adrenergic blocking drugs Indirectly-acting sympathomimetic agents (IASAs) Uptake 1 inhibitors ```

Question 53

What does α-methyl-tyrosine do?

Answer 53

Completely inhibits tyrosine hydroxylase, and therefore blocks de novo synthesis of noradrenaline

Question 54

What is the clinical use of α-methyl-tyrosine?

Answer 54

Inhibits NA synthesis in pheochromocytoma

Question 55

What is α-methyl-DOPA taken up by?

Answer 55

Adrenergic neurones

Question 56

What happens do α-methyl-DOPA when taken up by adrenergic neurones?

Answer 56

It is converted to α-methyl-noradrenaline

Question 57

How is α-methyl-DOPA differ from a true neurotransmitter?

Answer 57

It is poorly metabolised

Question 58

What is the result of α-methyl-DOPA being poorly metabolised?

Answer 58

It accumulates in the synaptic vesicles of noradrenergic terminals

Question 59

How is α-methyl-DOPA released from synaptic vesicles?

Answer 59

Ca mediated exocytosis

Question 60

What happens when α-methyl-DOPA is released from synaptic vesicles?

Answer 60

It preferentially activates pre-synaptic α2 receptors

Question 61

What happens when α-methyl-DOPA activates pre-synaptic α2 receptors?

Answer 61

The ßγ subunit of the α2 receptor inhibits the VOCC, reducing Ca mediated neurotransmitter release

Question 62

What does carbiDOPA do?

Answer 62

Inhibits DOPA decarboxylase in the periphery, but not in the CNS

Question 63

Why does carbiDOPA not inhibit DOPA decarboxylase in the CNS?

Answer 63

It does not cross the BBB

Question 64

What is carbiDOPA used for?

Answer 64

In combination with L-DOPA in the treatment of Parkinson's disease

Question 65

Where are adrenergic blocking drugs selectively concentrated?

Answer 65

In terminals

Question 66

How are adrenergic blocking drugs selectively concentrated in terminals?

Answer 66

By uptake 1

Question 67

How do adrenergic blocking drugs act?

Answer 67

Via a variety of mechanisms, including a local anaesthetic action reducing impulse conduction and Ca mediated exocytosis and repletion of NA from synaptic vesicles

Question 68

Why are adrenergic blocking drugs rarely used therapeutically?

Answer 68

Because of their severe side effects, including postural hypotension

Question 69

What are IASAs structurally related to?

Answer 69

NA

Question 70

Why are IASAs though to exert their actions by additional/other methods to NA?

Answer 70

Because they are only weak agonists at adrenoreceptors

Question 71

What happens to IASAs?

Answer 71

They are recognised and transported into the adrenergic terminal by Uptake 1 and taken up into the synaptic vesicles

Question 72

What happens to NA displaced by IASAs?

Answer 72

It can leak into the synaptic cleft, by a mechanism unrelated to Ca mediated exocytosis

Question 73

What is the extent to which NA leaks into the synaptic cleft greatly enhanced by?

Answer 73

The inhibition of the NA-degrading enzyme MAO

Question 74

What do uptake 1 inhibitors comprise?

Answer 74

An important class of therapeutic agents, the tricyclic antidepressants

Question 75

How do uptake 1 inhibitors exert their therapeutic action?

Answer 75

Centrally

Question 76

What are the unwanted side effects of tricylic antidepressants?

Answer 76

Their possible peripheral actions, e.g. tachycardia and cardiac dysrhythmias