531 Lec 27

What neurotransmitters are in play in the adrenergic nervous system

What neurotransmitters are in play in the adrenergic nervous system

epinephrine or norepinephrine

Neurotransmission events at adrenergic receptor

1)Tyrosine is actively transported in to the neuron

2)Tyrosine is converted into L Dopa via tyrosine hydroxylase

3)L Dopa is converted into Dopamine via Aromatic L amino acid decarboxylase

4)Dopamine turns into NE via dopamine B hydroxylase in the storage vesicle

5. Calcium influx triggers release of NE from storage vesicles

What receptors are present in the synapase?

alpha1, alpha2, beta1, beta2

Where are alpha1, alpha2, beta1, beta2 receptors located in the synapse?

Alpha 2- Adrenergic neuron (autoreceptor)

Alpha1, B1, B2- Postsynaptic cell

what mechanisms are important to removing norepinephrine/epinephrine from the  synapse?

1. Ne can get reuptaken into the neuron via a NE transporter then it will a)get recycled into the vesicle and b) get degraded by MAO

2)NE can diffuse out of the synpase and get degraded by COMT and MAO

Norepinephrine Biosynthesis

•L tyrosine is hydroxylated by tyrosine hydroxylase into L-Dopa

•L Dopa is decarboxylated by Aromatic L amino acid with cofactor PLP decarboxylase turning it into dopamine

•Dopamine is actively transported into a storage vesicle

•Dopamine is turned into norepinephrine by dopamine hydoxylase

protonated state of epinephrine/norepinephrine at physiological pH

what enzymes are involved in the metabolic breakdown of norepinephrine/epinephrine.

COMT

MAO

Aldehyde reductase

Aldehyde dehydrogenase

What does COMT do

Recognizes catechols & converts one of the OHs to an ester

What does MAO do

Monoamine oxidase - oxidative enzyme that focuses on the amine functional group of  norepinephrine and drugs like it.

Turns amine into aldehyde

What kind of receptors are Adrenoreceptors

G protein coupled receptors

binding features of NE with its receptor-What residues are important and with what  functional groups of NE do they interact?

Serine interacts with the catechol

Aspartate interacts with the amine via charges

Asparagine interacts with OH

Phenylalanine interactions with the aromatic ring

Where are adrenergic alpha receptors found ?

alpha 1 & 2 on vascular smooth muscle

alpha 2 on presynaptic neuron

What is the role of alpha 2 receptors on the presynaptic neuron?

regulating NE release

What three second messengers are relevant in the stimulation of alpha-1 adrenergic receptors?

Stimulation results in increase in:

Inositol 3 phosphate (IP3)

1,2 diacylglycerol (DAG)

Calcium

what physiological effects result from stimulation of alpha-1 adrenergic receptors?

Vascular smooth muscle contraction

Vascular constriction

(antagonists used to treat hypertension)

Where are beta adrenergic receptors found

•Beta 1 reside mostly on cardiac tissue

•Beta 2 reside in lung tissue, liver, skeletal muscle blood vessels, intestine, uterus

what physiological effects result from stimulation of beta adrenergic receptors?

→Increased heart rate (B1)

→Dilation of bronchioles and skeletal muscle blood vessels (B2)

→Breakdown of glycogen to glucose (B2)

B1 antagonists used to treat hypertension

B2 agonists treat asthma or COPD

What are the relevant effector protein and second messengers in adrenergic beta receptor signaling?

Beta receptor stimulation:

Activates adenylate cyclase which converts ATP to cAMP → increased concen of cAMP → alters Ca2+ flux

B1 receptor stimulation

Resides mostly on cardiac tissue

Activates adenylate cyclase → increased concen of cAMP → increased protein kinase activity → phosphorylation of calcium channels →increased influx of calcium → increases association between actin and myosin→ increases contractive force and heart rate

Result: increased heart rate and contractile force

B1 antagonists treat

hypertension

B2 receptor stimulation

Reside in lung tissue, liver, skeletal muscle in blood vessels, intestine, uterus

Increased adenylate cyclase activity → increased cAMP production → myosin light chain kinase inhibition → increased calcium flux in opposite direction compared to B1 receptors→ reduced actin myosin interactions → smooth muscle relaxation in bronchioles

B2 agonists treat

Asthma or COPD

SAR for phenylethanolamines

1. Amine is separated by 2 carbons from a benzene ring

2)C1 is hydroxylated

3)Nature of substitution elsewhere affects selectivity and duration of action by augmenting lipophilicity or oral bioavailability

Why does NE have limited clinical use?

Nonselective agonist

Is NE an oral drug?

IV only- No oral bioavailability

What is NE used for? What adrenergic receptors are relevant to its clinical use?

Hypotensive crisis (sudden drop in BP)

alpha activity raises BP

B activity stimulates heart

What uses does epinephrine have clinically? What adrenergic receptors are relevant to those  uses?

Hypotensive crisis (IV) - alpha activity raises BP, B activity stimulates heart

Asthma (inhaler)- relieves bronchoconstriction (B2)

Allergic emergency (Anaphylaxis

Is epinephrine an oral drug?

No- no oral bioavailability due to rapid metabolism

Selective alpha 1 adrenergic agonists- phenylethanolamines

Phenylephrine

Metaraminol

Methoxamine

why phenylethanolamines phenylephrine, metaraminol and methoxamine have longer  duration of action compared to NE?

No COMT liability leads to longer duration of action

why phenylethanolamines phenylephrine, metaraminol and methoxamine have limited  cardiac stimulatory effects compared to NE?

No beta 1 activity

physiological effects of using phenylephrine, metaraminol and methoxamine and  why/how they are used clinically?

Strong vasoconstrictors

Use: Hypotension during surgery or accompanying shock

Phenylephrine use: nasal decongestant

Selective alpha 1 agonists- 2 arylimidazolines

Xylometazoline

Oxymetazoline

Tetrahydrozoline

Naphazoline

how the 2-arylimidazolines xylometazoline, oxymetazoline, tetrahydrozoline, and  naphazoline are used clinically and with what receptor(s) they interact preferentially.

Alpha 1 agonists

Use: eye drops to treat red eye and topical nasal decongestants

Alpha 2 agonist

Brimonidine

Brimonidine

Use: Glaucoma

Side effects: fatigue/drowsiness

Isoproterenol

1st B agonist discovered

Non selective

Not orally active bc catechol is metabolized by COMT

Colterol

(One more methyl group than isoproterenol)

selective B2 agonist

Not orally active bc caetchol is metabolized by COMT

Albuterol

Selective B2 agonist

Orally active

Altered catechol is not a substrate for COMT

Short acting B2 agonists

Albuterol

Pirbuterol

Airsupra

what albuterol and pirbuterol are used for clinically.

Bronchodilator

the structural difference between albuterol and pirbuterol?

Pirbuterol has an N in the aromatic ring

What side effect profile albuterol that might make pirbuterol a better patient choice?

Racing heart beat

Airsupra

Albuterol + Budesonide

Rescue inhaler

Use: Asthma and associated exacerbations in adults over 18

MOA: Bronchodilator (albuterol) + anti inflammatory (budesonide)

Side effects: headache, oral candidiasis, cough, hoarseness

Long acting B2 agonists

Salmeterol

Indacaterol

Symbicort

Advair

Trelegy

Breztri

Salmeterol

Inhaler

Long acting Beta2 agonist

Use: Severe persistent asthma following treatment with short acting B agonist

Duration: 12 hours

Longer duration due to anchoring of long side chain phenyl group to B2 receptor

Indacaterol

Long acting Selective B2 agonist

Zwitterionic character promotes membrane interactions → longer duration

Duration: 24 hour

Use: Bronchodilator for COPD

Symbicort

Long-acting B2 agonist

Formoterol + Budesonide

Inhaler

Use: reduce exacerbations of asthma, COPD

Wash mouth after use to avoid thrush (budesonide steroid)

Advair

LABA

Fluticasone (corticosteroid) + Salmeterol

use: severe persistent asthma following treatment with short acting B agonist, COPD

Wash out moth after to avoid oral flush

Trelegy

LABA

Fluticasone (Corticosteroid) + Vilanterol (Ulta LABA) +Umeclidinium Bromide(long acting muscarinic antagonist

1)Open airways

2)Keep airways open

3)Reduce inflammation

Use: Asthma and COPD

Does not replace rescue inhaler

Breztri

Budesonide (corticosteroid), Formoterol (LABA), Glycopyrrolate (long acting muscarinic antagonist)

1)Open airways

2)Keep airways open

3)Reduce inflammation

Use: COPD ONLY

Does not replace rescue inhaler