ANS and Pharmacokinetics -- 10.1 & 10.2

Question 1

Describe some characteristics of the parasympathetic nervous system

Answer 1

Long, myelinated pre-ganglionic neurones
Short unmyelinated post-ganglionic neurones
Oppose sympathetic actions
Originate in medulla and sacral regions
Ganglia located in tissue innervated by para. fibres

Question 2

Describe some characteristics of the sympathetic nervous system

Answer 2

Short, myelinated pre-ganglionic neurones
Long, unmyelinated post ganglionic neurones
Ganglia located close to spinal cord in paravertebral cord
Fight or flight response
Originate from lumbar and thoracic vertebrae

Question 3

What type of neurones are pre-ganglionic neurones?

Answer 3

Cholinergic

– ACh

Question 4

What type of neurones are parasympathetic post-ganglionic neurones?

Answer 4

Cholinergic with muscarinic AChR

G protein coupled

Question 5

What type of neurones are sympathetic post-ganglionic neurones?

Answer 5

Noradrenergic with alpha 1 and beta 1 adrenoceptors

G protein coupled

Question 6

Which receptors are G protein coupled?

Answer 6

M1, M2, M3, alpha1, alpha2, beta1, beta2, eta3

Question 7

What type of transmitters are used for sweat gland and follicle innervation?

Answer 7

Non-adrenergic, non-cholinergic transmitters (NANC) transmitters

e. g. nitric oxide, ATP, 5-hydroxytryptamine (seratonin)
- - Usually co-released with NA or ACh

Question 8

Describe the sympathetic innervation in adrenal glands

Answer 8

Have chromaffin cells
“postganglioninc sympathetic neurons that do not project to a target tissue”
Stimulated by nAChR which causes the release of adrenaline in to the bloodstream

Question 9

What is familial dysautonomia?

Answer 9

Autosomal, recessive disorder affecting the development and survival of
sensory, sympathetic and (some) parasympathetic neurones

Question 10

Symptoms of familial dysautonomia?

Answer 10

Dysautonomic crises - response to physical or emotional stress included vomiting, increased HR and BP, sweating and drooling
Spinal curvature
Poor growth
Cardiovascular and respiratory dysfunction
Altered sensory perception

Question 11

Why are cholinergic therapeutic interventions not commonly used?

Answer 11

The drugs are not very selective for their target receptors, so multiple side effects ail arise.

Question 12

What do acetylecholinesterase inhibitor do?

Answer 12

Enhance the effects of acetylcholine
e.g. pyridostigmine in myasthenia gravis
donepezil in Alzheimers

Question 13

What are some possible side effects for cholinergic drugs?

Answer 13

Bradycardia and decreased cardiac output
Increased bronchoconstriction in smooth muscle
Increased peristalsis
Increased sweating and salivation

Question 14

How are some cholinergic drugs used clinically?

Answer 14

Are administered locally in order to limit side effects and increase effectivity

Question 15

Describe some mAChR agonists

Answer 15

Pilocarpin and bethanechol for glaucoma and to stimulate bladder emptying

Question 16

Describe some mAChR antagonists

Answer 16

Ipratropium and tiotropium for asthma and COPD

Tolterodine for overactive bladder

Question 17

What type of receptors do you usually find in post-ganglioninc sympathetic neurones?

Answer 17

Noradrenergic

Question 18

What is a particular characteristic of innervation around smooth muscle?

Answer 18

A highly branched axonal network with variscosities (beads along axons) overlies the entirety of smooth muscle. These are specialised for Ca2+ dependent noradrenaline release

Question 19

How is noradrenaline synthesised?

Answer 19

Tyrosine to DOPA (tyrosine hydroxylase)
DOPA to dopamine (DOPA carbosylase)
Dopamine to noradrenaline (dopamine beta-hydroxylase)

Question 20

Where does noradrenaline synthesis take place?

Answer 20

Takes place in variscosities over smooth muscle cells. Tyrosine to dopamine stage takes place in cell cytosol whilst dopemine conversion to noradrenaline takes place in vesicles

Question 21

How is noradrenaline removed from post-synaptic adrenoceptors?

Answer 21

Noradrenaline transporter proteins

Question 22

What are the two methods of re-uptake of noradrenaline?

Answer 22

Uptake One
– uses Na+ dependent, high affinity transports to take NA back into presynaptic cells (takes place for majority of noradrenaline)
Uptake Two
– uses a lower affinity, non-neuronal mechanism for NA not taken up by uptake one, into the post-synaptic cells

Question 23

Describe NA metabolism

Answer 23

Some NA which has been brought back into the cell is taken up by vesicles.
The NA which has not been taken up by vesicles is metabolised by:
Monoamine oxidase (MAO)
Catechol-O-methyltransferase (COMT)

Question 24

What regulates the release of noradrenaline?

Answer 24

Inhibition and activation of Ca2+ dependent exocytosis
– inhibit VOCCs
less Ca2+ in the cell leads to less neurotransmitter release

Question 25

What are the classes of drugs that have an effect on adrenergic receptors?

Answer 25

Indirectly acting sympathomimetic agents and Uptake One inhibitors

Question 26

Describe "indirectly acting sympathomimetic agents"

Answer 26

The drug is taken up into the synaptic vesicles and cause NA to leak from those vesicles. NA then leaks into the synaptic cleft without being exocytosed. -- They mimic the actions of sympathetic transmitters (allows them to be taken up into vesicles) E.g. Tyramine, amphetamine (rapidly penetrates blood-brain barrier -- drug of abuse), ephedrine

Question 27

Describe "uptake one inhibitors"

Answer 27

Inhibit the re-uptake of noradrenaline into the pre-synaptic cells eg. Tricyclic antidepressants and selective noradrenaline re-uptake inhibitors

Question 28

Where do uptake one inhibitors have their main effect and what side effects can they causes? How can these side-effects be limited?

Answer 28

Mostly effect the CNS Can cause tachycardia and cardiac dysarrythmias -- minimised by the specific drug used and the therapeutic dose of the drug

Question 29

Name two beta2 selective agonists and describe what they do

Answer 29

Salbumatol and salbumetrol | Activate bronchodilation in the lungs by opposing bronchoconstriction

Question 30

What is the advantage of selectivity of drug for certain receptors?

Answer 30

Specificity of drug action to limit side effects in other parts of the body

Question 31

What is the purpose of alpha 1 selective and beta 1 selective antagonist?

Answer 31

Treat CVS disorders such as hypertension Alpha one -- doxazosin Beta one -- atenolol

Question 32

What drugs are usually combined to treat congestive heart failure?

Answer 32

``` Diuretic (lower blood volume & BP) ACE inhibitor (reduce fluid retention) Beta blocker (reduces force of contracion and cardiac output) ```