Autonomic - Sympathetic Nervous System

Cholinergic Nicotinic Systems: Sites & Actions:

Neuromuscular Junction (NMJ)

- skeletal muscle effector site in SNS
- ACh released from myelinated nerves
- muscle contraction with stimulation

Sympathetic System Terminology:

Agonists (direct/indirect/mixed) are also known as:

sympathomimetic
adrenergic

Sympathetic System Terminology:

Antagonists (direct/indirect; reversible/irreversible) are also known as

- sympatholytic
- α-blockers
- β-blockers

Nicotine - a drug of addiction and also a poison. Explain.

- Addiction (mesolimbic stimulation, ANS) : arousal at low doses, calming at high doses

- Poison (2 cigarettes ground up, 40mg lethal dose): sweating, hypertension, decreased GI activity, arrhythmia, tachycardia, flaccid paralysis, convulsions, vomiting

How is norepinephrine synthesized?

Tyr: tyrosine hydroxylase → DOPA: DOPA decarboxylase → DA (dopamine)[into vesicle]: dopamine-β-hydroxylase → norepinephrine (NE): phenylehtanolamine N-methyl transferase → epinephrine (E)

What is the key regulating step in sympathetic system? and Why?

NET transporter
- picks up NE and moves it into cell
-NE is metabolized inside the cell
- drug target

Norepinephrine

principal NT, precursor to E

Dopamine

Secondary, also precursor to NE

Epinephrine

secondary or circulating, adrenal medulla

Vesicle storage is complexed with:

- ATP (co-transmitter)
- Chromagranin A (stabilization)

Ways of releasing NE

- Exocytosis (Ca2+) driven
- Inhibitory Feedback via α2 & DA2, mAChR (↓ cAMP)
- Stimulatory Feedback via β2, AII receptors (↑ cAMP)

Monoamine Oxidase (MAO-A*, MAO-B#)

location and action?

- neurons and effector sites
- oxidizes NE & other amines (domaine, serotonin, epinephrine) -> replaces amine with aldehyde

Catechol-O-methyl-transferase (COMT)

location and action?

- effector sites
- may act in series with MAO
- adds methyl group to OH on phenyl ring

Why are MAO and COMT drug targets?

- inhibit = prevent breakdown of NE, elevated [NE] in cell = more release of NE
- indirect agonist, stronger SNS output

What is the overall effect of α1 type receptors?

- ↑ IP3, DAG
- diagnostic procedures and decongestant
- contractions

What is an agonist and antagonist for α1 type receptors?

Agonist: Phenylephrine
Antagonist: Prazosin

Where can α1 type receptors be found and what is the resulting action?

- Pupillary dilator muscle: contraction leading to dilation and ↑IOP

- Lacrimal Gland - secretion

What is the overall effect of α2 type receptors?

- ↓ cAMP

What is an agonist and antagonist for α2 type receptors?

Agonist: Clonidine
Antagonist: Yohimbine

Where can α2 type receptors be found and what is the resulting action?

- Ciliary epithelium
- vesicle fusion inhibition leading to decreased aqueous humor production causing a decrease in IOP

What is the overall effect of β-adrenergic receptors?

- ↑ cAMP
- overall relaxation except in β1 receptors in the heart where HR increases

What is an agonist and antagonist for general β type receptors?

Agonist: isoproterenol
Antagonist: propranolol

Where can β2 type receptors be found and what is the resulting action?

- ciliary epithelium → increase in aqueous humor production → increase in IOP

What disease can highly selective β2 agonists be used to treat?

Asthma
- ↓ cAMP → relaxation in smooth muscle

What is ephedra used for and why is it bad?

- Chinese herbal medicine for treatment of asthma (bronchodilation) and as a dietary supplement (appetite suppressant)

Problem: lasts for hours; not metabolized and as a result ↑ NE levels at junctions

What is Meridia (sibutramine)? and Why is it so bad?

- obesity drug; counterfeit weight loss product
- serotonin/norepinephrine uptake inhibitor (catecholamine transporter)
- increases serotonin level in brain and sympathetic tone, altering appetite (suppressing digestive activity) → flight or fight mode active for a long period of time

Possible Sites of Drug Interactions

Normal uptake of NE from synaptic cleft

- NE uptaken by active transport (NET)
- NET co-transporter is Na+
- either metabolized or stored in vesicle by active transport (VMAT)
- VMAT co-transporter is H+; requires ATP to create H+ gradient

What are some indirect antagonists for sympathetic system?

- Metyrosine
- Reserpine
- Bretylium, guanethidine
- blocking calcium signals

How does metyrosine act as indirect antagonist?

- mimics the structure of tyrosine
- reduces amount of NE synthesis

How does reserpine act as indirect antagonist?

- prevents packing of NE into vesicles
- NET transporter is still active and NE still being uptaken, but it can't be packaged into the vesicles.
- Eventually the vesicles will have less and less [NE]
- neurons rely on recycling NE into the vesicles
- sympathetic activity ↓

How does bretrylium/guanethidine act as indirect antagonist?

- inhibits release of NE by reducing VAMPs and SNAPs

What are some indirect agonists acting on the sympathetic pathways?

- Cocaine, tricyclic antidepressants

How does cocaine act as a indirect agonist?

- blocks the NET transporter, increasing [NE] in the NMJ

What are the acute effects of Ephedrine as an indirect sympathomimetic?

- Ephedrine taken up by cell and competes with NE → displace NE from vesicle → higher [NE] in cytosol → NE flows out of cell due to concentration gradient → increased [NE] in synaptic cleft → stimulatory effect (not as dramatic as cocaine)

What are the chronic effects of Ephedrine as an indirect sympathomimetic?

- accumulation of NE in cytosol will lead to it being metabolized
- since Ephedrine displaced NE from vesicle, no new release of NE and overtime [NE] ↓ in the cleft → going from good highs to low. becomes inhibitory chronically

What are some other drugs that causes displacement from vesicles?

- Amphetamine
- Hydroxyamphetamine
- Tyramine
- Ephedrine
- Pseudoephedrine (highly effective decongestant)
- Methylphenidate (ADHD) [increases NE, serotonin, DA in brain]

Why is the sale of pseudoephedrine being restricted?

Precursor for synthesizing meth

What is tyramine?

- found in fermented foods (ex. cheese) catecholamine release, MAO inhibitors

- substrate for enzyme, enhancing effect of MAO inhibitor → net effect increase NE levels

- if pts are on MAO inhibitors, ↑ NE in cleft, with cheese, ↑↑NE in cleft

Neuronal effects on recycling

- Cocaine (topical anesthetic & drug of abuse)
- net effect = increase level of NE, DA, Serotonin (5HT), at neurojunctions

- Amphetamine (drug of abuse)
- inhibit uptake of NE, DA, 5HT

- Tricyclic antidepressants (TADs)
- desipramine
- imipramine

Extraneuronal effects on recycling

- corticosteroids
- ↓ rate of NE degradation = ↑ NE in cleft

- phenoxybenzamine (irreversible α-antagonist)
- ↑ NE in neurojunction

MAO inhibitors effect on metabolism

- depression, targeting mainly 5HT/DA.

- phenelzine: irreversible
- amphetamine
- clorgyline (MAO-A)
- selegiline (MAO-B)

PDE inhibitors effect on metabolism

- act on 2nd messengers: cAMP (also adenosine receptor antagonist)
- methylxanthines (caffein, theophylline)
- Caffeine ↑ cAMP by preventing breakdown of cAMP by PDE → more awake

COMT inhibitor effects on metabolism

- used for parkinson's disease
- entacapone
- trying to ↑ levels of 5HT/DA in system

Sildenafil (Viagra) also inhibits a PDE. How is it different from xanthines?

uses the cGMP pathway instead of cAMP

Directly acting α1 agonists we should know [[used for decongestant and mydriatics]]

phenylephrine
naphazoline
oxymetazoline
tetrahydrozoline

Directly acting α1 antagonist to recognize

prazosin
doxazosin
tetrazosin

Directly acting α2 agonists we should know [[used for glaucomarrrr]] ((↓ cAMP → ↓ AH → ↓ IOP))

aproclonidine
brimonidine

Directly acting α2 antagonist to recognize

yohimbine

Directly acting α1/α2 agonists to recognize

methoxamine

Directly acting α1/α2 antagonists to know [[reverse mydriasis]]

thymoxamine
dapiprazole

Directly acting β1 agonist to recognize

dobutamine

Directly acting β1 antagonist to know [[application for glaucomarrrr]] ((↓ cAMP → ↓ AH → ↓ IOP))

betaxolol
carteolol

Directly acting β2 agonists to know [[application for asthma, bronchodilator]] (↑ cAMP → bronchodilation but also ↑ heart contraction)

salbutamol
salmeterol

Directly acting β1/β2 agonist to know

ephedrine

Directly acting β1/β2 antagonist to know [[application for glaucomarrr]]

metipranolol
timolol
levobunolol

Would you give timolol to a patient with asthma, why or why not?

No because 80% of timolol is cleared systemically, blocking β1/β2 will make asthma worse.

Likely side effects of antagonists (peripheral, central/vascular)

α-blockers
• Orthostatic hypotension
• Tachycardia
• Vertigo
• Sexual dysfunction

β-blockers
• Drowsiness
• Fatigue
• Bradycardia • Hypotension

Likely side effects of agonists

adrenergic
• Cardiac arrhythmias
• Headache
• Hyperactivity
• Insomnia
• Nausea • Tremors

All drugs have more than one action

- phenyl: 10x-20x dose for diagnostic than you would give for decongestant action, don't want to give to someone with heart problems.

- E equally potent for β1/β2, NE less effect on bronchodilation, greater effect on heart
- anaphylactic shock → E binds to all receptors equally → epi-pen

- isoproterenol very potent for asthma, but increases HR as well