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)
Imipramine
Tricyclic antidepressant Blocks NET (transporter mediating Uptake 1)
Amitryptaline
Tricyclic antidepressant Blocks NET (transporter mediating Uptake 1)
Clorgiline (Clorgyline)
Selective MAO-A inhibitor
Used in depression
Selegiline
Selective MAO-B inhibitor
Used in treatment of Parkinson’s Disease
Tranylcypromine
Non-selective irreversible inhibitor of MAO
Used in treatment of refractory depression
Entacapone
Inhibitor of COMT
Used in Parkinson’s disease.
MAO
Metabolises catecholamines
Occurs in outer membrane of mitochondrion.
In the liver: inactivates circulating monoamines e.g tyramine
In nerve endings: maintains low level of NA in cytoplasm.
Deaminates the side chain, produces the corresponding aldehyde.
2 isoforms (A and B) differ in distribution, substrate specificity & pharmacology.
MAO-A
Substrates: NA, Adr, 5-HT, DA
MAO-B
Substrates: DA (selective)
COMT
Metabolises catecholamines
Methylates one of the ring hydroxyls.
Found in the liver, widely distributed in neuronal & non-neuronal tissues
Often associated with Uptake 2 activity.
VMA
Metabolite of catecholamines found in the urine.
Originates from peripheral sources
MOPEG
Metabolite of catecholamines, found in the urine
Originates from CNS
