Peripheral neural transmission: Noradrenergic transmission Flashcards
α β γ
α-methyltyrosine [methyltyrosine]
Used?
Competitive inhibitor of TOH
Used experimentally to reduce NA production (only effective way of reducing amount of transmitter produced)
Not v useful clinically, v large doses needed to lower blood pressure.
Occasionally used in malignant phaeochromocytoma
Tyrosine hydroxylase (TOH)
Rate limiting step in catecholamine synthesis
Converts Tyrosine -> DOPA
Carbidopa
Inhibits DDC
‘Peripheral decarboxylase inhibitor’- does not cross BBB.
Given with L-DOPA to reduce its peripheral side effects (which arise due to increased DA and NA in the periphery. L-DOPA can cross the BBB)
Dopa decarboxylase (DDC)
Converts DOPA -> dopamine in catecholamine synthesis
Not v selective, also decarboxylates many aromatic L-amino acids including tryptophan to make 5-HT.
Disulfiram
Uses?
Inhibits DBH.
May act by chelating the Cu2+ ion (which is essential for enzyme function) or by attacking the sulphur-handling system for the methyl donor, S-adenosyl methionine
Used in treatment of alcohol abuse: inhibits aldehyde dehydrogenase, probably by sulfhydryl interaction, which causes acetaldehyde (metabolite of ethanol) to build up when alcohol is imbibed -> causes vomiting
Methyldopa (α-methyldopa)
Taken into noradrenergic nerve endings, converted successively by DDC and DBH -> α-methyldopamine and α-methylnoradrenaline (a false transmitter)
α-methylnoradrenaline
Active product of methyldopa, acts as a ‘false transmitter’: stored in vesicles, released in place of some NA.
Is less active than NA at α1 receptors but more active at α2 -> less vasoconstriction following sympathetic nerve stimulation. (due to decreased α1 mediated smooth muscle contraction & increased negative feedback on NA release)
Primary site of action as an antihypertensive is in the CNS.
VMAT2
Transports NA and DA into synaptic vessels.
AKA SLC18A2
Uses a proton gradient as its energy source (2 H+ extruded for each amine molecule taken into vesicle), set up by an ATP-dependent proton pump.
Reserpine
Inhibits VMAT2
Binds v tightly to amine binding site. Recovery from blockade requires synthesis of new vesicles.
Leads to block of uptake, & long-lasting depletion of stored NA (and 5-HT) in the brain, as vesicles do allow leakage of stored amine into cytoplasm, where it is metabolised by presynaptic MAO.
Actions in periphery & brain
Use as antihypertensive discontinued because could cause profound depression (resulting mainly from 5-HT depletion?)
Indirectly acting sympathomimetic amines
Examples:
Transported into nerve endings & storage vesicles
Displace NA from the vesicle:
- some metabolised by MAO in cytoplasm
- some NA escapes metabolism & reaches extracellular space to activate the local adrenoceptors
Tachyphylaxis: repeated administration produces less & less response, because drug action is dependent on presence of NA in vesicles.
Effects can be abolished by destruction of transmitter stores with reserpine.
e.g tyramine, ephedrine (used as a nasal decongestant because produces NA mediated vasoconstriction in nasal vasculature), dexamfetamine
Tyramine
Indirectly acting sympathomimetic amine.
Found in a variety of foodstuffs: cheese, red wines, picked herring, yeast extracts, soya beans.
Transported into presynaptic terminal by uptake 1
‘Cheese effect’: large amount of tyramine ingested- can be sufficient to cause widespread vasoconstriction & large increase in BP.
People taking MAOI warned to avoid tyramine rich food.
Dexamfetamine (D-amphetamine)
Indirectly acting sympathomimetic amine.
Transported into presynaptic terminal by uptake 1
Has an α-methyl group -> not metabolised by MAO, weakly inhibits the enzyme.
Taken up into storage vesicles, & because it is a weak base, reduces the pH gradient & thus the packaging of amines.
MAO inhibitors (MAOI)
Increased risk of ‘cheese effect’ - warned to avoid tyramine rich foods.
Patients may often have lowered blood pressure as a result of reduced NA release resulting from the conversion of some of the normal dietary amounts of tyramine into octopamine, a false transmitter.
Guanethidine
Blocks release of NA.
Taken up into nerve by Uptake 1- so competes with NA. Can therefore potentiate exogenously applied NA.
Mechanism unknown:
- repeated low doses/ in the aftermath of a large dose, block release of NA evoked by action potentials
- spontaneous release is unaffected (therefore vesicle release processes are intact)
- Bretylium, a similar drug, appears to act after increasing [Ca2+]i in the nerve terminals.
Cocaine
Blocks NET (transporter mediating Uptake 1)
