adrenoceptor pharmacology Flashcards
what is adrenaline and where is it released from?
a hormone released from chromaffin cells in the adrenal medulla
what is noradrenaline and where is it released from?
a neurotransmitter released by sympathetic nerve terminals in the central and autonomic nervous system
what is the significance of the pons?
contains more noradrenergic cell bodies than any other place in the nervous system
where do most noradrenergic projections originate? from?
the locus coerulus
outline how noradrenaline mediates post-ganglionic actions in the ANS
chromaffin cells receive a sympathetic pre-ganglionic innervation -> acetylcholine is released -> chromaffin cell depolarises -> adrenaline is released into the blood stream
what is a varicosity?
a region of the axon where neurotransmitter can be made and released, each contains everything required for synthesis and re-uptake of neurotransmitter
what is the role of the varicosity?
to mediate the level of NA in the body by synthesis and recycling existing NA depending on signal received from pre-junctional adrenoceptors
what is the role of pre-junctional adrenoceptors?
sensing how much NA is present outside the varicosity
other than NA regulation, what else is the noradrenergic varicosity responsible for?
co-release of mediators such as ATP and neuropeptide 7
what is the role of the sodium pump on the noradrenergic varicosity?
removes excess NA
outline the steps of synthesis of adrenaline
tyrosine hydroxylase converts dietary tyrosine to DOPA -> DOPA decarboxylase converts DOPA to dopamine -> dopamine-B-hydroxylase converts dopamine to noradrenaline -> phenylethanolamine N-methyltransferase converts noradrenaline to adrenaline
what are the stages in adrenergic transmission?
synthesis, storage/compartmentalisation, release, signal transmission, signal termination
what does the dopamine/noradrenaline transporter on noradrenergic terminal vesicles do?
uses transvesicular proton gradient as a driving force to allow accumulation of noradrenaline at very high concentrations (0.5-1M) inside vesicles
how does NA regulate its own release?
acts on pre-synaptic B2 receptors, receiving autoinhibitory feedback
what triggers NA release?
depolarisation of the nerve terminal. action potential causes voltage-gated calcium channels to open, allowing calcium flux into the vesicle and causes vesicle fusion
how is noradrenaline removed from the synaptic cleft?
cleared by a high affinity uptake mechanism ‘uptake 1/NET’, NA evading this mechanism is cleared by uptake 2
how is noradrenaline metabolised?
by monoamine oxidase (MAO) catechol O-methyltransferase (COMT) or aldehyde dehydrogenase/reductase
how much noradrenaline is repackaged and metabolised?
90% repackaged, 10% metabolised
what are MAO and COMT used for therapeutically?
treatment of parkinson’s disease by bolstering dopamine levels in the brain
what are MAO and COMT inhibitors used for therapeutically?
treatment of parkinson’s disease by bolstering dopamine levels in the brain
what is the primary ligand of the sympathetic ANS at the neuroeffector junction?
noradrenaline
what is the functional importance of packaging of noradrenaline inside varicosities?
it allows the autonomic nervous system to control activity of a vast area of smooth muscle in a highly coordinated way
how does a-methylnoradrenaline differ from noradrenaline?
1- more resistant to metabolism by MAO/COMT compared to noradrenaline (accumulates over time)
2- a-methylnoradrenaline is a selective agonist at some adrenoceptors
what is a-methyltyrosine?
an analogue of tyrosine that competitively inhibits tyrosine hydroxylase, this blocks de novo synthesis of noradrenaline
