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
What are the 2 subtypes of MAO and their substrate specificities?
- MAO-A - serotonin, melatonin, NE and E mostly by MAO-A
- MAO-B - phenylethylamine (catecholamine “backbone” compound)
- Dopamine and tyramine broken down by both equally … so only non-selective MAOIs tend to cause “cheese effect”
What are 3 categories of MAOI drugs effective in presynaptic catecholaminergic stimulation?
Give 1 example from each of the 2 categories still used.
- Irreversible Non-Selective - inhibit both MAO-A and B; older antidepressants no longer used due to cheese effect
- Reversible MAO-A - ex: moclobemid; used for depression
- Irreversible MAO-B - ex: selegiline; used to treat Parkinson’s
Other than precursors, monoamine releasers, reuptake inhibitors, and MAOIs…
what is the final mechanism / category of presynaptic catecholaminergic stimulators?
Examples? (I think these are less important for now)
- Alpha-2 Inhibitors - block negative feedback “autoinhibitory” effect of alpha-2 R on presynaptic neuron
- Mirtazapine - an atypical anti-depressant
- Mianserine - another atypical AD
- Yohimbine - plant alkaloid; small dose inhibits alpha2 only, large dose also alpha1; no indications
What are the 6 mechanisms / classes of drugs for presynaptic inhibition of catecholaminergic transmission?
- Tyrosine OHase inhibition - alpha methyl tyrosine
- DOPA Decarboxylase Inhibitors - carbidopa / benserazide
- NT Storage Inhibition - reserpine inhibits VMAT
- Adrenergic Neuron Blockers - guanethidine etc. inhibit NT release
- α-2 Agonists - presynaptic negative feedback
- False Transmitters - alpha-methyl DOPA
Which drugs (3) inhibit enzymes (2) in NT synthesis for presynaptic inhibition of catecholaminergic transmission?
Indications?
- Tyrosine OHase inhibitor - alpha-methyl tyrosine inhibits synth of all CAs; old, unused tx for htx (many side effects)
- DOPA decarboxylase inhibitors - carbidopa / benserazide inhibit only peripherally; used to prevent peripheral conversion of levodopa + spare it for CNS entry / dopamine synth in Parkinson’s
Give an example of a vesicular uptake inhibitor in presynaptic catecholaminergic inhibition.
Its indications, side effects, etc?
(not much info other than name and mechanism on slides, so rest may be unimportant for now)
Reserpine - blocks VMAT (keeping NTs in cytoplasm for breakdown by MAO / COMT)
- used as anti-psychotic / anti-htx med in past, but less so now
- DA blocking effect can cause depression + Parkinson-like symptoms
What are the adrenergic neuron blockers acting in presynaptic inhibition of catecholaminergic transmission?
(3, with mechanism + indication)
- All compete with NE for space in vesicles + inhibit Ca-dependent exocytosis, causing first a transiet BP ↑ and then long duration (2 wk) ↓ in BP
- Were used as anti-htx med, not anymore
- Debrisoquine
- Guanethidine
- Bretylium - also inhibs K+ channels (class III AA)
(Say this to yourself in a Mexican accent: “Deborah is a queen, Juan is the dean, and then there is Bret y Liam” and remember forever…)
Give 3 examples of α-2 selective agonists used systemically to decrease blood pressure.
What counter-intuitive effect might they have at certain doses and why?
(Only 1 drug here is very important, Kato just mentioned the other 2’s names)
- clonidine (and guanfacine / guanabenz)
- Normally act on pre-synaptic inhibitory α2 and central α2 that decrease vascular tone, but at high systemic concentration may affect post-synaptic α2 on vessels and cause transient BP increase