SESSION 8 Flashcards
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
What are the two anatomical divisions of the ANS?
- The sympathetic division
- The parasympathetic division
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
Define the parasympathetic system
Regulates basal activities
- rest and digest
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
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
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
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
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
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
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
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
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
State the synthesis of acetylcholine
Acetyl CoA + choline –> acetylcholine + coenzyme A
Enzyme: choline acetyltransferase
Location: cytoplasm of cholinergic terminals
State the degradation of acetylcholine
Acetylcholine –> acetate + choline
Enzyme: acetylcholinesterase (AChE)
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
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
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
How is SLUDGE treated?
Atropine
Pralidoxime
Other anti- cholinergic agents
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
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
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
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
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)
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
Define Inotropic
Modifying the force or speed of contraction of muscle
Define chronotropic
Change the heart rate and rhythm by affecting the electrical conduction system of the heart and the nerves that influence it
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
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
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
Asthma
What are the consequences of increased parasympathetic drive?
Innervate airway smooth muscle
Release ACh on stimulation
Results in contraction
Lumen airways narrows- bronchoconstriction
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
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
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)
Asthma
Which drugs mimic the functions of the autonomic nervous system and how do they act at a cellular level?
B2 adrenoreceptors
Xanthine drugs
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
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
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
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
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
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
Thyrotoxicosis
What other treatments are used for Thyrotoxicosis?
Iodide
Thimides
Hypertension
What physiological reflexes are involved in the normal control of blood pressure?
Sympathetic nervous system
Renin angiotensin aldersterone system (RAAS).
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
Hypertension
What target sites for drug action ca you define to control abnormally elevated blood pressure?
Heart, smooth muscle, kidney
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
Hypertension
Does antagonism of these receptos explain the principal anti- hypertensive action of a- adrenoreceptor antagonists?
No vasodilation
Hypertension
What are the main unwanted side effects of use in a- adrenoceptor antagonists to treat hypertension?
Hypotension
Impotence
Diarrhoea
Arrhythiamus
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
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
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
