A9-10: Catecholamines, Indirect Sympathomimetics, alpha agonists. Flashcards
What is the pathway for catecholamine synthesis (enzymes + intermediates)?
Most importantly, what is the rate limiting step?
Tyrosine → Tyrosine hydroxylase (rate limiting step) → DOPA → DOPA Decarboxylase → Dopamine → Dopamine B-Hydroxylase → NE → PNMT → E
What are the 3 endogenous catecholamines which can act on adrenergic receptors?
And the relative affinity of each one for the different types of adrenergic Rs?
(The presence of what functional group on one these catecholamines greatly changes its R affinity?)
- NE: α-1 or2 > β-1 >>> β-2
- E: β-1 or 2 > α-1 or 2
- Dopamine: dopamine Rs > β-1 > α-1
- (Methyl group on E’s amine shifts affinity from alpha to beta Rs. Synthetic isoproterenol has 2 methyls and thus no alpha + high beta affinity.)
Describe the mechanisms + transporters for catecholamine release, reuptake/recycling and degradation at nerve terminals.
(Can use NE as example … similar for DA and E)
- Ca-dependent exocytosis of NE from synaptic vesicles into synapse
- Reuptake by “NET” (NE transporter) back into pre-synaptic neuron (DAT, SERT for DA, 5-HT)
- Vesicular reuptake by VMAT (vesicular monoamine transporter)
- Degradation by MAO on mitochondria
What negative feedback mechanism is present on adrenergic neurons to regulate their catecholamine release?
presynaptic α2 receptors - act as a negative feedback “auto-receptor” to inhibit further release of NE from nerve terminals
Overview:
What are 5 mechanisms for pharmacological presynaptic stimulation of catecholamine activity?
- Precursors - e.g. levodopa
- Monoamine Releasers - amphetamines, etc.
- Reuptake Inhibitors - cocaine, etc.
- MAO-Is - selective or non-selective
- α2 inhibitors - inhibit negative auto-feedback
What is the main catecholamine precursor drug used in therapy? For what?
Why is a precursor used, rather than just the target catecholamine itself?
Levodopa (L-DOPA)
- used to increase DA levels in Parkinson’s
- DA doesn’t cross BBB but L-DOPA does
(may add more on this later, was all Kato said in class)
List the monoamine releasing drugs used for presynaptic adrenergic stimulating effects.
(3 categories, with several drugs in each)
- Amphetamines - MDMA, methamphetamine, methylphenidate
- Ephedrines - ephedrine, pseudoephedrine and norephedrine
- Tyramine - found in cheese, wine etc. as product of fermentation; metab’d by MAO-A; “cheese effect” if on MAOIs (htx crisis)
List 3 amphetamines, their mechanisms of action, indications + side effects.
- MDMA - prefers 5HT nerve endings; competitive reuptake inhibition at DAT/SERT/NET; taken up by VMAT and competes for vesicular space, forcing NTs into cytoplasm; causes calcium-independent exocytosis of NTs via NET/DAT etc.; inhibits MAO
- Methamphetamine - similar mechanisms, prefers DA nerve endings
- Methylphenidate - non-psychostimulant; used for ADHD and narcolepsy
- MDMA/Meth have no indications; previous use for meth was weight loss / short term memory enhancement, but it’s neurotoxic
- Overdose can cause arrhythmia, hyperthermia and psychosis
Other than tyramine and amphetamines…
what other group of compounds acts as a “monoamine releaser”?
Characteristics? Mechanism? Indications?
Ephedrine and its derivatives…
- alkaloid w/ high oral bioavailability, long duration, BBB penetration + mild stimulant effect
- acts by weak adrenergic receptor activation and NE release
- Pseudoephedrine used as nasal decongestant (via vasoconstr. effect) (also bronchodilates)
What chemical structure are most sympathomimetics based on?
And what other compound are some more specific adrenergic agonists based on? (With what specificity?)
Most are derivatives of phenylethylamine (img below)
Some alpha-1 agonists are based on imidazoline
Catecholamines all have what functional group substituted onto the benzene ring of their basic phenylethylamine* structure?
And how does this affect their action / kinetics?
(*picture on answer card)
all have 3,4-OH groups (one at C3, one at C4)
- makes them potent sympathomimetics, but results in poor kinetics (low absorption, distribution, duration) due to low lipophilicity
- also makes them a substrate of COMT, a catecholamine degradation enzyme
Other sympathomimetics have OHs at different positions on their benzene ring or none at all…
How does this affect their action / kinetics?
- 3-OH, 4-OH or 3,5-OH - weaker sympathomimetic but better kinetics; not COMT substrates; can be given orally (low bioavail.)
- No OHs - weak direct sympathomimetics / NE releasers; best kinetics / BBB penetration
What are 3 types/groups of reuptake inhibitors in presynaptic stimulation of noradrenergic function?
- Cocaine
- Tricyclic Antidepressants (TCA) and related drugs
-
SNRIs / NDRIs - serotonin-NE reuptake inhib. / NE-dopamine reuptake inhib.
- (Kato only listed bupropion, an NDRI; slides list SNRIs)
What is cocaine’s mechanism?
What is its one medical indication + why (based on mechanism)?
Why is it not more medically useful (aside from abuse/addiction potential)?
- blocks NAT/DAT for NE/DA reuptake; blocks Na channels
- used for local anesthesia due to its Na channel blockade effect
- No antidote exists so overdose can cause irreversible arrhythmia (NE effects)/ seizure (Na blockade)
What are TCAs? Their action and indications?
Complications?
(2 examples? Kato gave none, slide gave 2… maybe not important)
- Tricyclic antidepressants - older ADs with many side effects; block NE/5HT reuptake in CNS/PNS
- Complications: block alpha and muscarinic Rs > autonomic side fx; act like “class IA anti-arrhythmics” (block Na channels) so can cause adverse cardiac events
- Ex: desipramine, amitriptyline
Other than cocaine and TCAs…
what other drugs act as reuptake inhibitors in presynaptic adrenergic stimulation?
SNRIs and NDRIs
- SNRIs - ex: reboxetine, venlafaxine; inhibit 5HT/NE reuptake by SERT/NET; antidepressants; don’t block post-synaptic Rs like TCAs
- NDRIs - ex: bupropion (“Wellbutrin”) for depression/smoking cessation; blocks mostly NET, weakly DAT
