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
What are the indications of clonidine?
- Mild to Moderate Hypertension
- Minimize symptoms of withdrawal from opiates, tobacco, alcohol, or nicotine
- Glaucoma
- Perianesthesia
- Sedation in intensive care, adjuvant to analgesia
- Diarrhea in diabetics
- ADHD
Note that like many anti-hypertensive drugs, abrupt withdrawal of clonidine from a person who takes it chronically can -> hypertensive crisis. Has to be taken off gradually.
What are clonidine’s 3 mechanisms of action?
(Bonus: what base molecule is it a derivative of? what was its original pharmacological purpose?)
- Enhanced Negative Feedback - as agonist at presynaptic α2
- Central α2 Effects - medullary postsynaptic α2 agonism > ↓ symp. + ↑ vagal tone
- Imidazoline I1-R Agonism - medullary imidazoline receptor agonism also ↓ sympathetic vasomotor effects
(is an imidazoline derivative; originally developed for nasal decongestion)
What are some of clonidine’s side effects?
They seem counter-intuitive, considering its action as a sympatholytic agent. What is the possible explanation?
- sedation, dry mouth, constipation (parasympatholytic-like sx)
- may be due to alpha-2 Rs also present on cholinergic presynaptic neurons having an inhibitory effect
What are two (more minor) alpha-2 agonists used as non-first line anti-htx agents?
Hint: they stimulate a unique receptor that clonidine also stimulates … though that probably won’t help you with their names, sorry : P
-
Moxonidine and Rilmenidine
- both stimulate imidazoline R w/ greater affin. than alpha-2
What presynaptic catecholaminergic inhibition drug can be considered a “false transmitter”?
Mechanism? Side effect? Unique advantage?
- alpha-methyl DOPA - converted to alpha-methyl-NE which has no alpha 1 but sustained alpha 2 affinity > ↓ vasoconstriction
- side effects: similar to clonidine = sedation, dry mouth, constipation
- advantage: NOT contraindicated in pregnancy
What are the 3 major categories of drugs in postsynaptic stimulation of catecholaminergic transmission?
- Natural Catecholamines - DA, NE, E
- Synthetic Catecholamines - isoprenaline, dobutamine
- Non-Catecholamine Postsynaptic Stimulators - selective or non-selective
At physiological concentrations, what determines epinephrine’s local effect on blood pressure? What is its systemic effect on BP?
Effects other than BP?
- Organ-specific receptor distribution affects local BP (E’s affinity is beta 1,2 > alpha 1,2)
- if mostly beta2 (muscle, brain, heart) dilation
- alpha1 (skin, GI, kidney) constrictition vessel
- overall, systemic BP is barely changed
- Bronchodilates + hepatic glycogen mobilization (beta2); Positive ino-/chronotrope (beta1)
At medical doses (higher than physio), how does epinephrine’s effect change?
Indications? Admin + distribution?
- At higher doses, affects more alpha1 Rs, causing systemic BP increase
- indications: anaphylactic shock; acute, but not chronic asthma tx; cardiac arrest (intracardial injection); glaucoma (ciliary body vasoconstr. ↓ humor production); perianesthetically (↓ local flow, ↓ systemic abs. of anesthetic)
- parenteral admin (IM or SC); doesn’t cross BBB
What is norepinephrine’s systemic effect on BP?
Other effects?
Indications (1 main, 1 minor)?
How is it administered?
- Raises BP systemically (alpha1 Rs on vessels; low beta2 dilator effect)
- Positive chrono-/inotrope (but compensatory vagal reflexes sometimes mean it causes bradycardia in vivo!)
- Indications: shock (neurogenic, septic, cardiogenic; for pressor effect); local blood flow decrease (surgery)
- Parenteral administration
How does dose affect the action of dopamine?
Indications?
Complications?
- low dose = D1 selectivity > vasodilation > ↑RBF
- medium = acts on beta1 > positive inotrope
- high = no selectivity, also affects alpha1
- indications: poor renal blood flow (“shock kidney”); decompensated CHF; cardiogenic shock; acute HF
- complications: tachycardia, tolerance, bad kinetics
What synthetic catecholamine is often used instead of dopamine for similar indications?
What is its selectivity? Indications? Complications?
Dobutamine
- beta1 selective
- used in acute HF + decompensated chronic CHF
- tolerance develops via receptor downreg., tachycardia (same as DA)
What is isoprenaline / isoproterenol (same thing)?
Actions? Indications?
- A catecholamine with two methyl grps on its amine –> high beta selectivity, no alpha action
- Positive ino-/chronotrope; broncho- and vasodilator (↓ BPdiastolic and MAP)
- Indications: bradycardia + AV blocks
- (Not used much anymore; is precursor structure for many modern β agonists + blockers)
How does the use of alpha agonists differ between local and systemic administration?
- Local - for local vasoconstriction (nasal decongestion) and pupillary dilation (ophth. exam / glaucoma); α1/α2 selectivity unimportant
- Systemic - for increase (α1) or decrease (α2) of sympathetic tone, to ↑/↓ blood pressure; (so obviously α selectivity is essential)
What are the common indications for local non-selective α agonist use as nasal drops/spray?
Examples of drugs?
Side effects?
- Nasal congestion assoc. with hay fever / common cold
- Naphazoline, xylometazoline, oxymetazoline**
- Side effects: rebound hyperemia; mucosal ischemia; swallowing of nasal drip containing drug may cause systemic effects (so α selectivity can actually be important!); (oxymetazoline has high alpha1A affin. so worse BPH-stimulating side effects)
Give 3 indications for local α agonist use in eyedrop form.
(And drugs for each?)
- Decongestion - phenylephrine (i guess congestion of aqueous humor?)
- Mydriasis - AKA pupil dilation, for examination; also phenylephrine
- Glaucoma - reduces aq. humor production by ciliary body; (apraclonidine, brimonidine … maybe less important)
Give 3 examples of α-1 selective agonists which would might be used to increase vascular tone / blood pressure.
(1 is most important, 2 are minor; give the important one’s other more common indications, complications etc.)
- phenylephrine
- midodrine
- methoxamine
- indications: nasal decongestant; pupil dilator; systemic vasopressor in septic shock
- complications: nasal mucosa atrophy; rebound hyperemia; can worsen BPH via α-1 in prostate
