Neuropharm of Catecholamines Flashcards
Sympathetics use catecholamines with one exception. What’s the exception?
Sweat gland innervation uses Ach (not important for this class, but relevant for boards)
What 4 primary neurotransmittters are used in the sympathetic nervous system (SNS)?
Epinephrine, NE, dopamine, 5-HT
we don’t know if dopamine and 5-HT are really involved in the SNS, though
What are 3 contransmitters in the SNS?
ATP, Galanin, and Neuropeptide Y
Review: What are the 4 defining properties of a neurotransmitter?
Specific synthesis mechanism.
Mechanism to store and release.
Recognition site.
Inactivation process.
From what amino acid are epinephrine and norepinephrine synthesized?
Tyrosine.
What are the intermediates between tyrosine and epinephrine?
Tyrosine -> Dopa -> Dopamine -> Norepinephrine -> Epinephrine
What enzyme converts tyrosine to dopa?
Tyrosine hydroxylase (don’t confuse with tryptophan hydroxylase)
What enzyme converts Dopa to dopamine?
L-aromatic amino acid decarboxylase (LAAD)
What enzyme converts dopamine to norepinephrine?
Dopamine beta-hydroxylase
What enzyme converts norepinephrine to epinephrine?
Phenylethanolamine N-methyltransfersase (PNMT)
What’s the rate-limiting step for getting from tyrosine to NE? Enzyme used?
Conversion of Tyr to Dopa by Tyrosine hydroxylase.
What enzymes does the substantia nigra lack?
The substantia nigra wants this pathway to stop at dopamine, so it won’t have Dopamine beta-hydoxylase and PNMT.
How does stress affect Tyrosine hydroxylase?
Stress leads to upregulation of the gene that encodes the enzyme.
What do biosynthetic vesicles for catecholamines contain? (5 things)
Catecholamines, ATP, Dopamine beta-hydroxylase, ascorbic acid, and NPY.
What sort of negative feedback fro catecholamine synthesis is there?
Dopamine inhibits Tyrosine hydroxylase.
How does the adrenal medulla produce both epinephrine and NE?
2 different cell types. One of them doesn’t have PNMT, one does.
How does stress affect PMNT?
Stress, specifically cortisol, leads to increased transcription of the gene for PNMT.
How do catecholamines get into vesicles for storage/secretion?
VMAT (vesicle monoamine transporter) - recall that this is also used for 5-HT.
Review?: What does Ca++ specifically interact with on vesicles to trigger fusion and release?
VAMPs (vesicle-associated membrane proteins)
What are the 2 different autoreceptors for catecholamines on the presynaptic nerve terminal? What effect does each have?
alpha 2 adrenergic: inhibitory for NE release
beta adrenergic: stimulatory for NE release
(i.e. both negative and positive feedback)
Review: What second messengers do Gs, Gi, and Gq use?
Gs: increase cAMP
Gi: decrease cAMP
Gq: increase cytosolic Ca++
Review: What class of receptors are adrenoreceptors?
GPCRs
What type of G protein do alpha-1 receptors have? What catecholamine(s) do they bind?
Gq
Bind both NE and Epi
What type of G protein do alpha-2 adrenoeceptors have? What catecholamine(s) do they bind?
Gi
Bind both NE and Epi
What type of G protein do both beta-1 and beta-2 adrenoreceptors have? What catecholamine(s) do they bind?
Both use Gs.
Beta-1 binds both NE and Epi
Beta-2 only binds Epi
Which adrenoreceptor only binds epinephrine (and not NE)?
Beta-2
What are the 2 major systems for neurotransmitter reuptake? Briefly describe them. (Where? How fast? Capacity?)
Uptake 1: Uptake into nerve terminals. Fast (high affintiy), low capacity.
Uptake 2: Extra-neuronal uptake. Slow (low-affinity), high capacity.
Which neurotransmitters does MAO A break down?
5-HT, NE, and Tryptamine
Which neurotransmitters does MAO B break down?
Dopamine and Tryptamine
In what cells are MAO A and MAO B?
All of them.
Where is MAO within a cell?
On the outer mitochondrial membrane.
Is MAO the only way to degrade neuroamines?
Nope, but don’t worry about the other degradation mechanisms.
What breaks down monoamines in extra-neuronal sites?
Still MAO A and MAO B.
What are 4 pharmacological mechanisms by which you can turn down the SNS?
Inhibit catecholamine synthesis.
Block vesicular transporters.
Block release.
Antagonize adrenergic receptors.
What are 4 pharmacological mechanisms by which you can turn up the SNS?
Adrenergic agonists.
Promote release.
Inhibit reuptake.
Inhibit catabolism.
Why don’t you inhibit the rate limiting step in catecholamine synthesis to turn down the SNS?
Because it’s not selective. If you inhibit tyrosine hydroxylase, you’ll knock down dopamine, NE, and epi.
What does alpha-methyldopa do? What is it used for?
Inhibits LAAD.(which converts Dopa to Dopamine).
Hypertension - the MoA is weird, don’t worry about it.
What does carbidopa do? What is it used for?
Inihbits LAAD just in the periphery.
Used in PD with L-dopa to make sure more L-dopa makes it to the CNS.
What does tetraethylthiuram (disulfiram) do? What is it used for?
Inhibits dopamine beta-hydroxylase (which converts dopamine to NE).
Used for alcoholism - because it also inhibits acetylaldhyde dehydrogenase.
(more important for other lectures)
What does reserpine do? What is it used for? Why is it a terrible drug?
Inhibits VMAT.
Used for hypertension (and snakebite!).
Causes big reduction in NE, epi (and some dopamine) -> profound drop in BP, and causes depression.
What does bretylium do?
What is it used for?
Problem with it?
Blocks vesicular release of NE (after initially causing NE release).
Used for ventricular fibrillation.
It’s non-specific.
What does guanethidine do?
What is it used for?
Problem with it?
Inhibits NE release.
It’s a powerful antihypertensive.
Leads to catecholamine depletion / nerve ending degradation.
What two drugs block NE release?
Bretylium and guanethidine.
What happens when you give someone dopamine? What is it used for?
Agonizes alpha and beta-1 adrenoreceptors in the periphery (doesn’t cross the BBB).
Used for management of shock, hypovolemia.
She notes that it’s “inotropic.”
What does dobutamine do?
What is it used for?
Beta-1 adrenoreceptor agonist (more specific than dopamine).
Used in congestive heart failure.
What does bromocriptine do?
What is it used for?
Trivia about it?
Selective D2 receptor agonist.
Used for Parkinson’s disease.
It’s an LSD derivative.
What’s an important feature of amphetamine kinetics?
They resist MAO degradation.
How do cocaine and tricyclic antidepressants work?
They inhibit reuptake.
How does selegiline work?
What is it used for?
Inhibits MAO B (which breaks down dopamine and tryptamine) -maybe.
It’s used for PD (as adjunct) and as an antidepressant.
(despite us thinking that it acts on MAO B, it also appears to affect NE and 5-HTergic neurons)
What are the 2 major systems for neurotransmitter reuptake? Briefly describe them. (Where? How fast? Capacity?)
Uptake 1: Uptake into nerve terminals. Fast (high affintiy), low capacity.
Uptake 2: Extra-neuronal uptake. Slow (low-affinity), high capacity.
What does reserpine do? What is it used for? Why is it a terrible drug?
Inhibits VMAT.
Used for hypertension (and snakebite!).
Causes big reduction in NE, epi (and some dopamine) -> profound drop in BP, and causes depression.
