Flashcards in Session 10 & 11 Deck (10):
What is the name given to other transmitters that can be co-released alongside ACh and NA?
Non-adrenergic non-cholinergic transmitters (NANC). Examples include ATP, serotonin, NO and neuropeptides.
Outline the basic steps in neurotransmission and indicate with a * the common sites for drug action
Uptake of precursors
Synthesis of transmitter
Vesicular storage of transmitter
Degradation of transmitter*
Depolarisation by propagated action potential
Entry of Ca2+ through VOCCs
Exocytotic release of neurotransmitter
Diffusion to post synaptic membrane
Interaction with post synaptic receptors*
Inactivation of transmitter*
Re uptake of transmitter*
Interaction with pre synaptic receptors*
Explain how acetylcholine is synthesised and terminated
It is synthesised by the enzyme choline acyltransferase from choline (from the diet) and acetyl-CoA in the cytoplasm of cholinergic terminals.
Most choline is recaptured by a choline transporter in the synaptic terminal and the remainder is degraded to choline and acetate by cholinesterase in the synaptic cleft.
Explain how noradrenaline is synthesised and terminated
In nerve terminals:
Tyrosine -> DOPA -> dopamine (-> noradrenaline)
()= in synaptic vesicles.
The rate limiting enzyme is tyrosine hydroxylase. Cytoplasmic NA is susceptible to breakdown by monoamine oxidase (MAO).
The activity of NA released into the synaptic cleft is limited by a high affinity reuptake system, uptake 1. Any remaining NA is taken up by a lower affinity system called uptake 2.
Recaptured NA is either revesiculated or metabolised by MAO.
Why is the usage of cholinergic drugs limited?
They have a relative lack of selectivity so develop unwanted side effects.
What are the major drug classes that act on cholinergic nerve terminals and what can they be used for?
Nicotinic cholinergic antagonists - tubocurarine for muscle paralysis during anaesthia
Muscarinic cholinergic antagonists - used to treat bronchoconstriction in asthmatics
Muscarinic cholinergic agonists - pilocarpine for glaucoma, increasing GI motility, stimulating bladder emptying, treating tachycardia
Cholinesterase inhibitors - used to treat myasthenia gravis and Alzheimer's (donepezil)
What can lead to tachphylaxis or supra-sensitivity?
Tachphylaxis - excessive exposure to agonist (reduced sensitivity)
Supra-sensitivity - agonist deprivation or excess exposure to an antagonist
What factors can result in a change in receptor number?
Change in receptor number
Change in receptor coupling to second messengers
Change in availability of second messengers
Change in cell responsiveness
What is pheochromocytoma and why doesn't it cause tachyphalaxis?
Tumour of the adrenal gland that causes INTERMITTENT increase in the secretion of catecholamines which can be found in the blood and urine. Presents with intermittent sweating, anxiety and increased BP.
Tachyphalaxis does not develop because of the intermittent release so symptoms get worse.
Treated with A/B blockers