Catecholamines and adrenergic pharm I Flashcards
What are the three naturally occurring catecholamines in the body? Which two are associated with the sympathetic system?
norepinephrine, epinephrine, dopamine
NE and Epi are the sypathomimetic catecholamines
What are six sites where drugs that modulate the actions of the sympathetic nervous system act?
- catecholamine biosynthesis
- storage/uptake of catecholamines into synaptic vesicles
- catechoamine release
- catechoamine metabolism
- uptace of catecholamines into presynaptic nerve endings
- cabechoamine binding to receptors
Where is dopamine found?
brain and in some interneurons of the PNS
What are the two dopamine pathways in the body?
nigrostriatal: involved in motor control and lost in Parkinson’s disease
mesolimbirc: reward behavior and addiction
hypothalamus: controls pituitary gland function
Where is norepinephrine?
postganglionic sympathetic nerve terminals and CNS. esp. in the locus coeruleus. some in adrenal medulla.
Where is/what is epinephrine?
neurohormone from adrenal medulla and CNS neurotransmitter localized in branstem; also small nuclei in the hypothalamus
What is the role of tyrosine hydroxylase?
convert tyrosine to DOPA during catecholamine synthesis
What cofactors are required for tyrosine hydroxylase? Where in the cell is it found? what should I know about it (important)
this is usually RATE-LIMITING
found in cytosol
requires Fe2+ and tetrahydropteridine cofactor
Describe the synthesis of NE. 4 steps
- tyrosine hydroxylase converts tyrosine to L-DOPA
- DOPA goes to dopamine via enzyme called AADC.
- Dopamine taken into vesicles by a transporter called VMAT.
- Dopamine converted to NE in the vesicle via enzyme called DBH
What should I know about tyrosine hydroxylase? (4 facts)
- rate-limiting
- cytosolic
- marker for doamine in neurons
- inhibited by alpha-methyl-tyrosine
- very specifc (unique in NE synthesis)
What should I know about aromatic amino acid decarboxylase? (rxn, localization)
aka AADC
- cytosolic
- converts DOPA to dopamine
What should I know about DBH? (localization, what inhibits it)what does it do.
dopamine beta hydroxyase
1. inside synaptic vesicles
2. inhibited by disulfiram (copper chelator)
disulfiram also has other effects (prevents EtOH metab :-).
3, converts dopamine to NE
What should I know about PNMT? (all about location, what does it do)
phenylethanolamine N-methyltransferase
- cytosolic
- adrenal medulla
- makes epinephrine from NE
What 4 enzymes are involved in catecholamine synthesis?
- tyrosine hydroxylase
AADC (aromatic amino acid decarboxylase
DBH (dopamine beta hydroxyase)
PNMT (phenylethanolamine N-methyltransferase
What 2 enzymes are involved in catecholamine metabolism?
MAO (monoamine oxidase)
COMT (catecholamine O-methyltransferase)
What should I know about MAO? (what do they do, where are they found, what drugs affect MAO
- involved in catecholamine metabolism
- found on outer membrane of mitochondria
- metabolizes many drugs and dietary substances
- MAO inhibitors are effective antidepressants but have dangerous side effects/drug interactions
MAO inhibitors block the metab of serotonin, for example. this incr. cytosolic conc.; more serotonin in the vesicles, more serotonin release upon stimulation.
What should I know about COMT? (localization, role/job, what kinds of drugs target COMT?
catecholamine O-methyltransferase
- catecholamine metabolism, esp. extra neuronal monoamines in CNS and periphery
- cytoplasmic enzyme in organs, glial cells
- inhibitors + L-DOPA used to treat Parkinsons
How is degradation of catecholamines different from degradation of ACh?
slower
does NOT take place in the synaptic cleft
What is iproniazid? MOA, sideffects
MAO inhibitor
antidepressant
incr. in catecholamines in the nerve terminals: less catecholamine degradation!
side effects: hypotension
What is involved in catecholamine reuptake from the synapse?
NET: norepinephrine transporter
DAT (dopamine transporter) and serotonin transporter also related
How does NET work? features.
high affinity active transport that uses extracellular Na as a cosusbstrate. promiscuous.
Why is NET important in terms of catecholamine function?
it is the major mechanism for inactivation of synaptic NE
What is imipramine? MOA, uses
reuptake/ NETinhibitor. also blocks serotonin transporter.
antidepressant
What is the MOA of cocaine?
inhibitor of DAT (dopamine reuptake transporter). keeps dopamine around for longer –> dopamine related to pleasure and reward n brain (and addiction). also produces central stimulation (users are aroused, awake).
How does cocaine overdose lead to death?
overstim of the heart
cocaine, in low doses, is specific for dopamine (pleasure, CNS stim), but in high doses also blocks reuptake transporters of NE, so heart beats too too fast.
What are the 3 purposes of synaptic vesicles?
- store of neurotransmitter at high conc.
- protect neurotransmitter from degradation
- participate in exocytotic release
What is VMAT?
where is it found?
what does it do?
biochemical activity
vesicular monoamine transporter found in catecholamine and serotonin neurons
promiscuous
active transporter: transpots monamine sfrom cytosol to vesicle against huge conc. gradient. monoamine imported into vesicle; proton expelled from vesicle
VMAT activity coupled to proton-ATPase actively pumps huge amts of protons into the vesicle
What is reserpine? potential and real uses?
irreversible VMA inhibitor. depletes monoamines from brain and periphery.
antihypertensive: dopamine can’t get into vesicle and is degraded. w/o dopamine, we see less NE, and therefore less vasoconstriction and lower bps.
also used experimentally
What are the side effects of reserpine?
depression: less dopamine etc. in brain. sometimes we see suicidal ideation.
What are examples of NE transporter (or other catecholamine transporters)
imipramine, fluoxetine (Prozac), cocaine
How are COMT inhbitors used?
prevent L-DOPA breakdown: parkinson’s disease therapy.
tolcapone, entacapone
What is alpha-methyltyrosine?
inhibits tyrosine hydroxylase
prevents NE synthesis
treats pheochromocytomas (tumor in adrenal medulla- causes high bp, anxiety, weight loss).
What would be a potential use for the inhibition of NE release?
inhibition of sympathetic responses; treat emergency arrhythmias
