Session 6+7 - Noradrenaline Flashcards
Where is Noradrenaline released in the body?
In the post ganglionic neurones of the sympathetic nervous system
Are there any post ganglionic synapses in which noradrenaline is not the transmitter?
Sweat glands
- ACh (nicotinic receptors)
Ejaculation
What are the “biogenic amines”? What is the synthetic pathway?
Biological compounds containing NH2 synthesized from tyrosine
Tryosine –> (tryosine hydroxylase) DOPA –> (DOPA decarboxylase) Dopamine –> (dopamine b-hydroxylase) Noradrenaline
Where does the synthetic production of biogenic amines take place?
The sympathetic nerve axon
Tryosine –> DOPA –> Dopamine in cytoplasm
Dopamine - Noradrenaline in synaptic vesicle
What determines whether a nerve terminal is dopaminergic or noadrenergic?
The presence of DBH, which converts dopamine to noradrenaline
How is noradrenaline packaged for release?
Packaged into synaptic vesicles, which actively take up noradrenaline via vesicular catecholamine pump
Outline the key events of post-ganglionic sympathetic innervation of target tissues
- Actions potential travels down axon and reaches pre-synaptic knob
- Voltage gates calcium ion channels open and Calcium flows in
- Calcium binds to synaptotagmin
- Vesicle containing noradrenaline brought close to membrane
- Snare complex makes a fusion pore
- Noradrenaline is released into synaptic cleft
- Binds to adrenergic receptors
- Causes influx of Na+ ions into effector organ
- Action potential generated in effector organ
List five sites of sympathetic innervation
The heart Skeletal muscle Smooth muscles Adipose tissue Glands (not sweat glands)
What is positive chronotrophy in heart rate?
Increase in HR
What is positive intropy in the heart?
Increase in force of contraction
Explain the anatomical basis for positive chronotrophy due to NA
- Right sympathetic nerve acts on the B1 adrenoreceptors of the SA node
- B1 adreno receptors activate adenylyl cylcase
- Causes increase in rate of AP generation
Explain the anatomical basis for positive inotrophy due to NA
NA acts on B1 receptors, increase in Ca2+ influx in ventricular cardiomyocyte.
For each receptor subtype, give the G protein, effector and whether in activates or inhibits
a1
Gq
Activates phospholipase C, producing secondary messenger IP3. IP3 interacts with IP3 sensitive calcium channels in sarcoplasmic reticulum
For each receptor subtype, give the G protein, effector and whether in activates or inhibits
a2
Gi
Inhibits adenylyl cyclase
Inhibits calcium channels, activates potassium channels
For each receptor subtype, give the G protein, effector and whether in activates or inhibits
B1 + B2
Gs
Stimulate adenylyl cyclase causing increase cAMP
Causes opening of calcium channels
B1 - in heart increase in force and rate of contraction
B2 In smooth muscle, causes relaxation
How are extracellular noradrenaline levells decreased?
- Noradrenaline can be taken up by noradrenaline transporter and repackaged into vesicles in presynaptic neuron
- Norepinephrine transporter
Na+ Cl- dependent reuptake
Uses Na+ gradient to move into cells - Vesicular Monoamine Transporter
Repackage into vesicles
Uses proton gradient
Name two enzymes which degrade noradrenaline
Monoamine oxidase
Catechol-O-methyltransferase
What do enzymes degrade NA into?
Its aldehyde derivative by O-methylation which can be excreted in the urine
Which products of metabolism can be measured in the blood or urine as an indirect index of sympathetic activity?
VMA and MHPG are metabolites of noradrenaline
Can be measured in urin
High levels indicative of adrean or sympathetic nervous system tumour
What are the adrenoreceptors and physiological response of liver cells?
A1, B2
Increased glycogenolysis, increased gluconeogenesis
What are the adrenoreceptors and physiological response of vascular smooth muscles?
a1 - constrict
a2 - constrict/dilate
b2 - dilate
What are the adrenoreceptors and physiological response of airways (bronchi)
a1 - constrict
b2 - dilate
What are the adrenoreceptors and physiological response of GI tract
a1 - relax
a2 - relax
b3 - relax
What are the adrenoreceptors and physiological response of the SA node of the heart
B1 - increased heart rate
What are the adrenoreceptors and physiological response of ventricle of the heart
B1 - force of contraction increased
What are the adrenoreceptors and physiological response of skeletal muscle
B2 - Tremor, increased muscle mass and speed of contraction and glycogenolysis
B3 - thermogenesis
What are the adrenoreceptors and physiological response of adipose tissue
B1, B3 - Increased lipolysis
What are the adrenoreceptors and physiological response of the iris?
A1 - Radial muscle contracts
B2 - cillary muscle relax
Does adrenaline contribute to or exert the predominant effects of any of the receptors we have so far talked about?
Smooth muscle relaxation in airways
Smooth muscle contraction in most arteries
Major bronchiodilatory used to treat asthma
Skeletal muscle affected buy far less than the heart
What is an adrenoreceptor agonist?
Agents which mimic the actions of noradrenaline/adrenaline
What would the advantage be of synthesizing an adrenoreceptor agonist which only interacts with particular receptor subtypes?
- Increase specificity
- Pevents additional side effect
- Greater efficacy, so lower dose required
- Can clearly predict clinical effects
Outline the type of adrenoreceptor agonist used to reverse bronchoconstriction in asthmatics
Salbutamol, B2 agonist
Outline the type of adrenoreceptor agonist used to aid decongestion o nasal passages
Oxymetazoline
A1 and partial a2 agonist
Outline the type of adrenoreceptor agonist used to prolong the action of local anaesthetic
A2 agonist
Clonidine
What is an adrenoreceptor antagonist?
One which prevents the actions of catecholamins
Give an example of the clinical use of an a adrenoreceptor antagonist
Prazosin
Treats high blood pressure, anxiety and panic disorder
Give an example of the clinical use of a b adrenoreceptor antagonist
Beta blockers
Used for management of cardiac arrythmias, preventing the heart from hypertension MI
What unwanted side effects limit the usefulness of prazosin?
Syncope, hallucination, vivid dreams
What unwanted side effects limit the usefulness of beta blockers?
Nausea, insomnia, bronchospasm
Which enzyme is specifically inhibited by a methyltyrosine? Why is this important with respect to noradrenaline synthesis? What particular cancer is treated by this drug?
Tyrosine hydroxylase
Inhibits the first step of noradrenaline synthesis.
Important in treating pheochromocytoma (a neuroendocrine tumour of the adrenal medulla.
What is an adrenoreceptor agonist?
Agents which mimic the actions of noradrenaline/adrenaline
What would the advantage be of synthesizing an adrenoreceptor agonist which only interacts with particular receptor subtypes?
- Increase specificity
- Pevents additional side effect
- Greater efficacy, so lower dose required
- Can clearly predict clinical effects
Outline the type of adrenoreceptor agonist used to reverse bronchoconstriction in asthmatics
Salbutamol, B2 agonist
Outline the type of adrenoreceptor agonist used to aid decongestion o nasal passages
Oxymetazoline
A1 and partial a2 agonist
Outline the type of adrenoreceptor agonist used to prolong the action of local anaesthetic
A2 agonist
Clonidine
What is an adrenoreceptor antagonist?
One which prevents the actions of catecholamins
Give an example of the clinical use of an a adrenoreceptor antagonist
Prazosin
Treats high blood pressure, anxiety and panic disorder
Give an example of the clinical use of a b adrenoreceptor antagonist
Beta blockers
Used for management of cardiac arrythmias, preventing the heart from hypertension MI
What unwanted side effects limit the usefulness of prazosin?
Syncope, hallucination, vivid dreams
What unwanted side effects limit the usefulness of beta blockers?
Nausea, insomnia, bronchospasm
Alpha-methyl DOPA acts as a competitive inhibtor for which enzyme?
DOPA decarboxylase
What product of alpha-methyl DOPA metabolism accumulates in noradrenergic terminals?
It is converted to alpha-methylnoadrenaline by dopame beta-hydroxylase
If released, what is the major action of alpha-methyl DOPA?
Agonist for adrenergic terminals
How is alpha-methyl DOPA used to treat hypertension?
alpha-methylnoadrenaline causes inhibition of sympathetic nervous system and decreases blood pressure. This is achieved by activating alpha-2-adrenergic receptors in the brainstem
How does guanethidine inhibit noradrenaline release?
Competes with NA for uptake into presynaptic terminal.
Becomes concentrated in NA transmitter vesicles, causing gradual depletion.
Blocks release NA
What is guanethidine used as?
An anti-hypertensive
What side effects does guanethidine cause?
Causes postural hypotension, failure of ejaculation, fluid retention and diarrhoea
Why are adrenoreceptor agonists and antagonists the drugs of choice?
Mimic, block or reduce effects
Focused response
