The Autonomic Nervous System and Pharmokinetics Flashcards
What is the ANS comprised of?
A series of two neurones, one pre-ganglionic and one post-ganglionic
What is the ganglion?
The collection of cell bodies in the PNS
Where do the neurones in the ANS have their cell bodies?
One in the CNS, one in the PNS
What do neurones in the ANS exert action via?
Smooth muscle
Viscera
Secretory glands
What is the thoraco-lumbar outflow part of?
The sympathetic nervous system
Where do the nerve fibres that contribute to the thoraco-lumbar outflow have their cell bodies?
In all 12 thoracic sections and the first 2 lumbar sections
How long are the nerve fibres in the thoraco-lumbar outflow?
Short pre-ganglionic nerve fibre
Long post-ganglionic nerve fibre
Where can the nerve fibres synapse in the thoraco-lumbar outflow?
May synapse at the same level as origin (paravertebral origin)
May synapse at different level to origin
May not synapse in paravertebral chain
What kind of neurones are the pre-ganglionic in the thoraco-lumbar outflow?
Cholinergenic (ACh)
What do the post-ganglionic neurones in the thoraco-lumbar outflow express?
Nicotinic receptors
What kind of neurones are the post-ganglionic in the thoraco-lumbar outflow?
Noradrenergic (NA)
What are the classes of adrenoreceptors?
Alpha (1 and 2)
Beta (1 and 2)
What is the exception to the rules of the thoraco-lumbar rules?
Some synapses are cholinergic- perspiration and ejaculation pathways
What is the cranio-sacral outflow part of?
The parasympathetic nervous system
How long are the nerve fibres in the cranio-sacral outflow?
Long pre-ganglionic nerve fibre
Short post-ganglionic nerve fibre
What kind of neurones are the pre-ganglionic in the cranio-sacral outflow?
Cholinergic
What do the post-ganglionic neurones in the cranio-sacral outflow express?
Nicotinic receptors
What kind of neurones are the post-ganglionic in the cranio-sacral outflow?
Cholinergic
What synthesises acetylcholine?
The enzyme choline acetyltransferase (CAT)
What is acetylcholine synthesised from?
Choline and the metabolic intermediate Acetyl-CoA
Where is acetylcholine synthesised?
In the cytoplasm of cholinergic terminals
What happens to acetylcholine once synthesised?
Some is degraded by cytoplasmic cholinesterase
The majority is transported into synaptic vesicles by an indirect active transport mechanism
What do cholinergic terminals possess?
Numerous vesicles contain high concentrations (>100mM) of ACh
How can ACh be released from cholinergic terminal vesicles?
By Ca mediated exocytosis
What happens to released ACh?
It can interact with both pre- and postsynaptic cholinoreceptors
What is the opportunity for ACh to interact with receptors limited by?
ACh in the synaptic cleft being acted upon by cholinesterase, which rapidly degrades ACh to choline and acetate
Where is the activity of cholinesterase highest?
At fast (nicotinic) cholinergic synapses
What is the result of cholinesterase at cholinergic synapses?
The synaptic cleft half-life of ACh is only a few milliseconds
What recaptures most choline?
A choline transporter present in the synaptic terminal
What is noradrenaline synthesised from?
Tyrosine
Where is noradrenaline synthesised?
Within the nerve terminal
What is the rate limiting enzyme in noradrenaline synthesis?
Tyrosine hydroxylase
Where is the enzyme dopamine ß-hydroxylase located?
Within synaptic vesicles
What does dopamine ß-hydroxylase do?
Transports newly synthesised dopamine into the vesicle prior to its conversion to noradrenaline
What does dopamine ß-hydroxylase recognise?
Dopamine and noradrenaline
What does dopamine ß-hydroxylase recognising dopamine and noradrenaline allow for?
It’s recycling following release and reuptake
At what level is cytoplasmic NA concentration under most circumstances?
Low
At what level is intravesicular NA concentration under most circumstances?
Very high (0.5-1.0M)
Why is a very high intravesicular NA concentration possible?
Because the vesicular transporter exploits a H-ATPase-generated cytoplasm-vesicle H-gradient to move catecholamines against their concentration gradient
What is cytoplasmic NA susceptible?
Enzymatic breakdown by monoamine oxidase
How is tyrosine converted to noradrenaline?
Tyrosine -> dopa -> dopamine -> noradrenaline
How is NA released?
Ca mediated exocytosis
What can released noradrenaline interact with?
Both pre- and postsynaptic adrenoreceptors
What is the opportunity for noradrenaline to interact with adrenoreceptors limited by?
A high affinity reuptake system, Uptake 1
What does uptake 1 act to do?
Rapidly remove NA from the synaptic cleft, rapidly decreasing the localised concentration and terminating its actions
What happens to any NA escaping from the synaptic cleft?
It is removed from the extracellular space by another, widespread, lower affinity reuptake system, uptake 2
What is ACh and NA release triggered by?
Depolarisation of the nerve terminal membrane, Ca entry, and fusion of vesicles with the pre synaptic membrane (Ca mediated exocytosis)
What drugs act on cholinergic nerve terminals?
Nicotinic cholinoceptor antagonists
Muscarinic cholioceptor agonists
Muscarinic cholinoceptor antagonists
Cholinesterase inhibitors
How do agents that interfere with cholinergic transmission and are of therapeutic use generally act?
By interaction with cholinoceptors
What is the exception to agents interfering with cholinergic transmission acting by interaction with cholinoceptors?
Cholinesterase inhibitors
How are cholinesterase inhibitors used therapeutically?
They decrease the rate of ACh degradation, and so prolong the lifetime of ACh within the synaptic cleft
What drugs act on adrenergic nerve terminals?
α-methyl-tyrosine α-methyl-DOPA CarbiDOPA Adrenergic blocking drugs Indirectly-acting sympathomimetic agents (IASAs) Uptake 1 inhibitors
What does α-methyl-tyrosine do?
Completely inhibits tyrosine hydroxylase, and therefore blocks de novo synthesis of noradrenaline
What is the clinical use of α-methyl-tyrosine?
Inhibits NA synthesis in pheochromocytoma
What is α-methyl-DOPA taken up by?
Adrenergic neurones
What happens do α-methyl-DOPA when taken up by adrenergic neurones?
It is converted to α-methyl-noradrenaline
How is α-methyl-DOPA differ from a true neurotransmitter?
It is poorly metabolised
What is the result of α-methyl-DOPA being poorly metabolised?
It accumulates in the synaptic vesicles of noradrenergic terminals
How is α-methyl-DOPA released from synaptic vesicles?
Ca mediated exocytosis
What happens when α-methyl-DOPA is released from synaptic vesicles?
It preferentially activates pre-synaptic α2 receptors
What happens when α-methyl-DOPA activates pre-synaptic α2 receptors?
The ßγ subunit of the α2 receptor inhibits the VOCC, reducing Ca mediated neurotransmitter release
What does carbiDOPA do?
Inhibits DOPA decarboxylase in the periphery, but not in the CNS
Why does carbiDOPA not inhibit DOPA decarboxylase in the CNS?
It does not cross the BBB
What is carbiDOPA used for?
In combination with L-DOPA in the treatment of Parkinson’s disease
Where are adrenergic blocking drugs selectively concentrated?
In terminals
How are adrenergic blocking drugs selectively concentrated in terminals?
By uptake 1
How do adrenergic blocking drugs act?
Via a variety of mechanisms, including a local anaesthetic action reducing impulse conduction and Ca mediated exocytosis and repletion of NA from synaptic vesicles
Why are adrenergic blocking drugs rarely used therapeutically?
Because of their severe side effects, including postural hypotension
What are IASAs structurally related to?
NA
Why are IASAs though to exert their actions by additional/other methods to NA?
Because they are only weak agonists at adrenoreceptors
What happens to IASAs?
They are recognised and transported into the adrenergic terminal by Uptake 1 and taken up into the synaptic vesicles
What happens to NA displaced by IASAs?
It can leak into the synaptic cleft, by a mechanism unrelated to Ca mediated exocytosis
What is the extent to which NA leaks into the synaptic cleft greatly enhanced by?
The inhibition of the NA-degrading enzyme MAO
What do uptake 1 inhibitors comprise?
An important class of therapeutic agents, the tricyclic antidepressants
How do uptake 1 inhibitors exert their therapeutic action?
Centrally
What are the unwanted side effects of tricylic antidepressants?
Their possible peripheral actions, e.g. tachycardia and cardiac dysrhythmias
