Noradrenaline synthesis, release and degradation Flashcards
what processes are regulated by the autonomic nervous system?
Smooth muscle tone
Cardiac rate and force
Secretion (all exo/ some endocrine)
certain metabolic processes
What neurotransmitters are released from sympathetic post ganglionic neurones?
Noradrenaline
ATP
What neurotransmitters are released from parasympathetic post ganglionic neurones?
ACh
Nitric Oxide
how can we interfere with adrenergic pharmacology?
By interrupting the synthesis of adrenaline and noradrenaline.
Drugs that inhibit enzymes that help create intermediates in their synthesis.
What is the rate limiting step in noradrenaline synthesis?
Tyrosine Hydroxylase
Modifying this allows us to have the greatest control on the rest of the metabolic synthesis so this is often the target for drugs
What drug inhibits tyrosine hydroxylase?
alpha-methyltryosine
What drug inhibits DOPA decarboxylase?
Carbidopa
drug used to treat Parkinson’s disease
Where are adrenaline and noradrenaline stored in the body?
Stored in subcellular membrane limited particles (chromaffin granules) within the adrenal glands.
what is the main enzyme that packages noradrenaline into vesicles?
VMAT - Vesicular monoamine transporter
what drug inhibits the VMAT transporter?
Reserpine
Inhibits VMAT
Not in use today due to having many side effects.
what are varicosities?
Point at which neurotransmitters are released from their vesicles
How are neurotransmitters released from sympathetic nerves by exocytosis?
Arrival of action potential causes depolarisation of varicosity
This results in opening of voltage-gated Ca2+ channels Ca2+ entry causes an increase in the concentration of free Ca2+ in the varicosity
This activates Ca2+-sensitive proteins that initiate the process of exocytosis
explain the autoinhibition of noradrenaline release?
Noradrenaline, released from sympathetic varicosities, can act locally on presynaptic receptors to inhibit its own release, and also that of ATP
Noradrenaline acts on the alpha2- adrenoreceptors
What other mediators can affect noradrenaline release?
ACh - inhibits release via muscarinic receptors, facilitates nicotinic receptors
Adenosine - Inhibits release (A1 receptors)
Opioids - Inhibits release (u-receptors)
Angiotensin II - facilitates release via AT1 receptors
What is morphine??
Important analgesic with important autonomic side effects - constipation, pupillary dilation.
These autonomic side effects are through the prejunctional inhibition of neurotransmitter release
how is noradrenaline terminated after release?
- uptake into sympathetic nerve terminals or other cells.
2. Degradation by intracellular enzymes
What are the processes used in uptake of noradrenaline for its termination?
Neuronal
Non-neuronal
How does neuronal uptake 1 work?
due to the secondary active transporter NAT.
High affinity for noradrenaline, and relatively selective.
Cotransports Na, Cl and catecholamine.
What drugs inhibit neuronal uptake transporters?
cocaine
Tricyclic antidepressants (desipramine)
Phenoxybenzamine
What effect do NAT inhibitors have?
enhance sympathetic activity,
Desipramine:
major action on CNS.
adverse effects - tachycardia, dysrhythmia
Cocaine:
euphoria and excitement (CNS action)
acts as a local anaesthetic
Tachycardia and increased BP
What are the autonomic effects of taking cocaine?
increased heart rate
Increased blood pressure
Local vasocontriction (could lead to infarction)
How are catecholamines degraded?
via intracellular enzymes monamine oxidase (MAO) Catechol-O-methyl transferase (COMT)
What are monoamine oxidase inhibitors used for and how do they work?
Used to treat depression
They work by blocking MAO irreversibly leading to increased noradrenaline, dopamine and 5-HT in the brain and peripheral tissues
What are COMT inhibitors used for?
Treatment of Parkinson’s disease
what do noradrenergic neuron blocking drugs do?
inhibit noradrenaline release from sympathetic nerve terminals.
What are indirectly acting sympathetic amines?
eg. amphetamine, ephedrine, tyramine
act by displacing noradrenaline which leaks out via NAT.
How does non-neuronal uptake of catecholamines work?
Non-neuronal - smooth/cardiac muscle. endothelium
Low affinity for NAd
High maximal rate of uptake
What substances inhibit non-neuronal uptake?
normetanephrine
steroid hormones
phenoxybenzamine
What is the process of synthesis of Adrenaline?
Tryosine DOPA Dopamine Noradrenaline Adrenaline
