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Flashcards in SESSION 8 Deck (51):
1

What does the Autonomic Nervous System (ANS) do?

Conveys all of the central nervous system (CNS) efferent outputs
The ANS controls all involuntary functions
E.g. Heart rate, blood pressure and GI mobility

It is entirely efferent but is regulated by afferent inputs

2

What are the two anatomical divisions of the ANS?

- The sympathetic division
- The parasympathetic division

3

Define the sympathetic system

Responds to stressful situations
- fight or flight response
- results in an increased heart rate, increased blood pressure and increased force of contraction

4

Define the parasympathetic system

Regulates basal activities
- rest and digest

5

Describe the anatomical structure of the ANS
where the ANS originates from and specifically where the sympathetic/ parasympathetic nervous systems originate

The ANS conveys information from the CNS to the neuro-effector junction
The ANS originates in the central nervous system in particular different regions of the spinal column

The parasympathetic nervous system emerges either in cranial (brain- stem medullary) or sacral regions of the spinal column

The sympathetic nervous system originates in the thoracic and lumber regions of the spinal cord
Thoraco- lumbar fibres travels a short distance to the paravertable column where they form a synapse where another nerve emerges innovating the effector muscle

6

Describe the general structure of the ANS

Parasympathetic
- originate in the lateral horn of the medulla ad sacral spinal cord
- have long myelinated preganglionic fibres
- have short myelinated fibres
- ganglia are located within the innervated tissues
- have actions that oppose the sympathetic nervous system

Sympathetic nerves:
- originate in the lateral horn of the lumbar and thoracic spinal cord
- have short myelinated preganglionic fibres
- have long unmyelinated postganglionic fibres
- ganglia are located in the paravertebral chain close to the spinal cord
- have actions that oppose the parasympathetic nervous system

7

What are the principal neurotransmitters in the ANS?

- Acetylcholine
- Noradrenaline

All pre- ganglionic neurones are cholinergic
- they use ACh as the neurotransmitter
- activates post- ganglionic nicotinic ACh receptors
- nicotinic ACh receptors are ligand- gated ion channels

Parasympathetic post- ganglionic neurones are also cholinergic
- release ACh which acts of muscarinic ACh receptors in the effector
- muscarinic ACh receptors are G- protein coupled receptors

Sympathetic post ganglionic neurones are noradrenergic- use noradrenaline as the neurotransmitter
- 5 mACh receptor subtypes: M1, M2, M3, M4, M5
- Interacts with two major classes of adrenoreceptor: A and B
- undivided : a1, a2, B1, B2, B3
Exceptions that are cholinergic: sweat gland/ hair follicles

8

What other transmitters are found in the ANS other than ACh and NA?

Non- Adrenergic, Non- Cholinergic (NANC) transmitters

- they may be co- released by either NA or ACh
- effects still take place if NA or ACh are blocked as a result of NANC

NANC transmitters include:
- ATP
- nitric oxide (NO)
- serotonin


9

What is different about sympathetic postganglionic neurones in the adrenal glands?

They differentiate to form neurosecretory chromaffin cells

- Chromaffin cells are present in the adrenal medulla
- They can be considered as highly modifies postganglionic sympathetic neurones
- They do not project to a target tissue
- They release adrenaline into the bloodstream
- Chromaffin cells are innervated by pre- ganglionic sympathetic neurones

10

What are the physiological consequences of parasympathetic stimulation ?

Parasympathetic release of ACh causes:

Heart (M2):
- bradycardia
- reduced cardiac conduction velocity

Smooth muscle (M3):
- bronchioles contraction
- increased intestinal mobility
- bladder contraction/ relaxation
- penile erection
- ciliary muscle and iris sphincter contraction

Glandular (M1/ M3):
- increased sweat/ salivary/ lacrimal secretion

11

What are the physiological consequences of sympathetic stimulation ?

Sympathetic release of noradrenaline causes:

Heart (B1):
- tachycardia
- positive inotropy

Smooth muscle (a1/ B2):
- arteriolar contraction/ venous contraction
- bronchioles/ intestinal/ uterine relaxation
- bladder sphincter contraction
- radial muscle contraction

Glandular:
- increased viscous secretion

Kidney:
- renin release

12

Define dysautonomia and give examples

Distinct malfunctions of the ANS

- Catecholamine disorders
Pheochromocytoma- cancerous cells release NA/A constantly

- Central autonomic disorders
Multiple system atrophy- neurone degenerative disease

- Peripheral autonmic disorders
Guillian- barre syndrome

- orthostatic intolerance syndrome
POTS

13

Describe the basic steps in neurotransmission

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) exocytosis 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

Transmitter is usually in the cleft for a fraction of a second
- enzymes break down ACh very quickly (enzymatic degradation)
The majority of transmitter is recaptured, but some is degraded

Tips: transmitters must be packaged appropriately otherwise degradation occurs

14

State the synthesis of acetylcholine

Acetyl CoA + choline --> acetylcholine + coenzyme A

Enzyme: choline acetyltransferase

Location: cytoplasm of cholinergic terminals

15

State the degradation of acetylcholine

Acetylcholine --> acetate + choline

Enzyme: acetylcholinesterase (AChE)

16

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

A non- selective, muscarinic ACh receptor agonist is likely cause autonomic side- effects

Heart:
Heart rate and cardiac output decrease

Smooth muscle:
Brochoconstriction and GI tract peristalsis increase - affecting existing respiratory illness

Exocrine glands:
Sweating and salvation increase

17

Define SLUDGE

SLUDGE- pathological indicative of massive discharge of the parasympathetic nervous system

Salvation- stimulation of the salivary
Lacrimation - stimulation of the lacrimal
Urination- relaxation of the urethral internal sphincter muscle and muscle contraction
Defection
Gastrointestinal upset- smooth muscle tone changes causing GI problems, including diarrhoea
Emissions- vomitting

18

When is SLUDGE usually encountered?

- drug overdose
- ingestion of 'magic mushrooms'
- exposure to organophosphorus insecticides' - modify acetylcholinesterase to irreversibly deactivate it and raise acetylcholine levels

SLUDGE is due o chronic stimulation of muscarinic acetylcholine receptors

19

How is SLUDGE treated?

Atropine
Pralidoxime
Other anti- cholinergic agents

20

Describe the cholinergic transition clinical uses

MACh receptor agonists and antagonists have clinical uses, when administered locally, rather than systematically

Agonists:
pilocarpine/ Bethanechol how - used to treat glaucoma and stimulate bladder emptying

Cholinesterase inhibitors:
- tacrine/ donepezil- treatment of the early ages of Alzheimer's disease

Antagonist:
- ipratropium/ tiotropium- used to treat COPD and asthma
- tolterodine/ oxybutynin - used to treat overactive bladder

21

Explain noradrenergic transmission

Majority of post- ganglionic sympatheticneurones are noradrenergic
Use noradrenaline as the transmitter

Post- ganglionic sympathetic neurones generally possess a highly branching axonal network with numerous varicosities
Varicosity- specialised site for Ca2+ dependent noradrenaline release

Following Ca2+ dependent exocytotic release of NA:
- NA diffuses across the synaptic cleft
- interacts with adrenoreceptors in the post- synaptic membrane
- initiate signalling in effector tissue

22

Describe the synthesis or noradrenaline

Cytosol of nerve terminal:
Tyrosine -->(tyrosine hydroxylase)
DOPA -->
Dopamine

Vesicle:
Dopamine ->
Noradrenaline

Adrenal medulla:
Noradrenaline -->
Adrenaline
Enzyme: phenylethanolamine N- methyltransferase

23

Explain the two types of termination of noradrenergic transmission

Uptake 1:
- NA actions terminated by re- uptake into pre- synaptic terminal by Na+ dependent symport - high affinity transporter
- vast majority 90% uptake

Uptake 2:
- NA not recaptured by uptake 1 is taken up by a lower affinity, non- neuronal mechanism
- two fates: re- vesiculated undergo further release or metabolised by MAO

24

NA not taken up into vesicles at the pre- synaptic terminal is susceptible to metabolism, by which two enzymes?

Monoamine oxidase (MAO)
Catechol -O- methyltransferase (COMT)

25

Explain the relevance of adrenoreceptor agonists in regards to pharmacy

Selective B1 agonist-dobutamine
Cause positive inotropic and chronotropic effects
Useful in treating circulating shock
Prone to causing cardia dysrhythmias

Selective B2 agonists- salbutamol
Highly effective in reversing bronchoconstriction

Selective a1 agonists- phenylephrine
Nasal decongestants
Conduction with a local anaesthetic to cause local vascoconsriction

Selective a2 agonists- clonidine
Anti-hypertensive agent
Decrease noradrenaline release

26

Define Inotropic

Modifying the force or speed of contraction of muscle

27

Define chronotropic

Change the heart rate and rhythm by affecting the electrical conduction system of the heart and the nerves that influence it

28

Explain the relevance of adrenoreceptor agonists in regards to pharmacy

A- adrenoreceptor antagonist- phentolamine and the irreversible blocker phenoxybenzamine
Cause peripheral vasodilation
Treats peripheral vascular disease

Selective a1- antagonist - prazosin
Treatment of hypertension
Postural hypotension and impotence are common side effects

B-adrenoreceptor antagonist - propranolol and atenolol
Treat hypertension, cardiac dysrhythmias, angina and myocardial infarction
Unwanted side effects: bronchoconstriction, bradycardia, cold extremities, insomnia and depression

29

Name some drugs acting on adrenergic nerve terminals

A- methyl- tyrosine
Inhibits hydroxylase - blocks synthesis of noradrenaline
Inhibit noradrenaline- secreting tumour

A- methyl- DOPA
Activates pre- synaptic a2- adrenoreceptors reducing transmitter release
Used to treat hypertension

CarbiDOPA
Treatment of Parkinson's

30

Asthma
What are the principle clinical/ pathological abnormalities in asthma?

Long term inflammatory disorder
Characterised by airway hyper- responsiveness
Variable and reversible airflow obstruction
Hyper-secretion of mucus
Release cytotoxic mediators

Triggers include: infections, allergens and air pollution

31

Asthma
What are the consequences of increased parasympathetic drive?

Innervate airway smooth muscle
Release ACh on stimulation
Results in contraction
Lumen airways narrows- bronchoconstriction

32

Asthma
There is a large population of adrenoreceptors in the airway
What subtype of adrenoreceptor are these, and where in the bronchial tree are they predominantly situated?

Large population of B2 adrenoreceptor airway smooth muscle
Density of receptors increase as diameter airway gets smaller

33

Asthma
What are the consequences of stimulating adrenoreceptors?
When might this occur in normal physiology?

Bronchodilation
Circulating adrenaline and noradrenaline in blood
Released adrenal medulla

34

Asthma
What are the main categories of drugs that are used to treat asthma?

Relievers- bronchodilators (B2 agonist, antichollinergics )

Preventers- anti- inflammatory ( glucocarticosterioids, lT receptor)

35

Asthma
Which drugs mimic the functions of the autonomic nervous system and how do they act at a cellular level?

B2 adrenoreceptors
Xanthine drugs

36

Asthma
A variety of adrenoreceptor agonists have been used to treat asthma-
Briefly discuss the advantages f using highly selective agents which display either short or long durations of action

Used acutely to counteract attack
Used during the night to prevent fall in peak flow in the morning

37

Asthma
Compared to muscarinic cholinoreceptor antagonists, adrenoreceptor agonists have a greater therapeutic benefit to asthmatic patients.
What advantage does adrenoceptor agonist therapy confer over the use of muscarinic cholinoceptor antagonists?

Adrenoceptor agonists cause brochodilation irrespective of reason behind bronchoconstriction
Muscarinic receptor antagonists inhibit action of parasympathetic nervous system

38

Thyrotoxicosis
What are the main symptoms and clinical signs in patients with Thyrotoxicosis?

High levels of thyroid hormone in the blood stream
Intolerance to heat
Increased sweating

39

Thyrotoxicosis
Compare and contrast the symptoms of thyrotoxicosis with those of simple anxiety

Some similar:
Palpitations, restlessness, increased bowel movement, tremor

Differences:
No goitre,may not have increased appetite/ weight loss

40

Thyrotoxicosis
Which of the symptoms are mediated by the autonomic nervous system? And why?

Thyroid hormones up-regulate the number of adrenoceptor in the body

41

Thyrotoxicosis
What drug targeted to the autonomic nervous system can be used for the treatment for thyrotoxicosis?
Why is this drug effective?

Non- selective B-adrenoceptor antagonists
Treatment often given to patients in IV, presenting acutely with thyroid crisis

42

Thyrotoxicosis
What other treatments are used for Thyrotoxicosis?

Iodide
Thimides

43

Hypertension
What physiological reflexes are involved in the normal control of blood pressure?

Sympathetic nervous system
Renin angiotensin aldersterone system (RAAS).

44

Hypertension
What is hypertension?
What are the clinical criteria for diagnosis?

Abnormally high blood pressure
- a state of great psychological stress

Normal blood pressure: 120/ 80mmHg
Hypertension: 140/ 90mmHg

Secondary effects: renal disease

45

Hypertension
What target sites for drug action ca you define to control abnormally elevated blood pressure?

Heart, smooth muscle, kidney

46

Hypertension
Explain what the main classes of drug currently used in the treatment of hypertension are

ACE inhibitors
Less effective in black people over 55-
Use calcium channel blockers

Diuretics
B-adrenoreceptor blockers

47

Hypertension
Does antagonism of these receptos explain the principal anti- hypertensive action of a- adrenoreceptor antagonists?

No vasodilation

48

Hypertension
What are the main unwanted side effects of use in a- adrenoceptor antagonists to treat hypertension?

Hypotension
Impotence
Diarrhoea
Arrhythiamus

49

Hypertension
B- adrenoceptor antagonists appear to exert their anti- hypertensive action through a number of possible mechanisms
Outline rationalise at least three of these

Reduced iconography
Reduced chronotrophy
Reduced renin release from kidneys

50

Hypertension
B- adrenoceptor antagonist also have unwanted side effects- what are these?

Bronchoconstriction in asthmatics
Cardiac failure in patients with pre- existing heart disease
Bradycardia
Physical fatigue
Impotence
Hypoglycaemia awareness

51

Hypertension
Why should so much consideration be given to side- effect profiles when treating hypertension?

Hypertension generally asymptomatic
Tablets have side effects
Don't like side effects
Poor compliance with patients