Overview ANS

• 2 series of interconnected neuronal plexuses
• Regulated by local network reflexes
• Modulated by mostly PANS, some SANS

• to insular cortex
• PANS to right
• SANS to left

• Inhibit choline acetyl transferase (ChAT)
• No ACh synthesis

• choline acetyl transferase
• choline and acetyl CoA to ACh

• vesicular ACh transporter
• counter transports H+ with ACh and ATP to fill vesicles

• Inhibits VAT
• No filling vesicles with ACh (and ATP)

Inhibits SNARES (soluble attachment protein receptors)

• Acetyl-cholinesterase
• Degrades ACh to choline and acetyl coA
• Plasma version is butyrylcholinesterase
• Inhibit by AChEIs
• 2 binding sites (anionic and esteric) (both used by ACh)

• Inhibits choline transporter
• Choline can't be taken back up into presynaptic neuron

• Converts tyrosine to Dope (levodopa)
• Inhibited by metyrosine
• Rate limiting step
• Tetrahydropterin BH4 is co-factor

• Converts levodopa to dopamine
• Inhibited by carbidopa
• Vitamin B6 is cofactor

• Converts dopamine to norepinephrine
• localized in NE terminals

• Converts norepinephrine to epinephrine
• Present in adrenal medulla

• Vesicular NE transporter
• Counter-transports H+ with NE and ATP
• Inhibited by reserpine

• Inhibits VMAT
• No filling vesicles with NE

• Biotransforms NE
• Primary breakdown product is vanilla-mandelic acid (VMA)
• Located in membrane of target cell, liver cells, etc

• MAO
• Types A and B
• Primary breakdown product is vanilla-mandelic acid (VMA)
• Located in mitochondria within synapse, glia, etc

• Reuptake of NE into presynaptic neuron
• Inhibited by tyramine, amphetamine, cocaine

Circulates with epi and DA-beta-hydroxylase

• Cholinomimetic
• Quaternary amine
• Full M1-M3 agonist, little N effect
• increased secretions, sm m contraction, reduced heart rate
• Used for urinary retention
• Less affinity for AChE, so longer half time than ACh
• Toxicity: bronchospasm

• Bethanechol
• Carbechol
• Methacholine
• (used in urinary retention)

• Muscarine
• Pilocarpine

• Muscarinic cholinomimetics
• alkaloid
• quaternary
• in certain mushrooms
• very little N receptor activity
• Increased secretions, sm m contraction, reduced heart rate
• Used in glaucoma
• Toxicity: bronchospasm

• Nicotine
• Lobeline

• Specific N receptor cholinomimetic
• Lipophilic, crosses membranes readily
• Activates SANS and PANS and striated muscle
• Used in smoking cessation
• Increases dopamine via a4b2 nicotinic Nn receptors
• Toxicity: increase GI activity, nausea, vomiting, diarrhea, increased BP, potential for seizures

• Chantix
• Partial agonist of a4b2 nicotinic Nn receptor

• Primarily in limbic system
• Stimulated by nicotine and varenicline (chantix)
• Heteroreceptor presynaptically reducing further dopamine release

• =indirect-acting cholinomimetics
• 3 classes: alcohols, carbamates, organophosphates

• Edrophonium
• ACh competitive antagonist
• Hangs out in active site
• Reversible blockage lasts minutes

• Neostigmine and Physostigmine
• Processed like ACh but slower
• Reversible blockade lasts hours
• Overdose causes weakness by producing depolarization blockade

• AChE Inhibitor
• Echothiophate, Parathion, Malathion, Sarin, Soman, VX
• Phosphorylate esteric AChE site
• Irreversible after aged

• Specific AChEI for G1 and G4 isoenzyme
• Alzheimer's treatment
• Tacrine (comp, rev)
• Donepezil (non-comp, rev)
• Rivastigmine (comp, pseudorev)
• Galantamine (rev, low potency, also non comp Nn agonist)

• PANS effects
• Salivation
• Lacrimation
• Urination
• Defecation
• GI upset
• Emesis
• Miosis

• VIP
• Colacalized in PANS terminals, relseased with higher frequency stimulation

• Anti-immune modulator
• Applied topically to treat dry eye
• Reduces activation of immune cells and their production of pro-inflammatory cytokines in tear ducts

• PANS contracts detrusor by M3, M2 receptors inhibit NE release from SANS in detrusor
• SANS relax detrusor by beta

• Miosis, accomodation, glaucoma
• M3 mediates smooth muscle contraction to contract iris and ciliary muscle, opens angle of schlemm
• M2 mediates NE release reduction

• vasoconstriction from circulating ACh
• No ANS innervation

M3 mediated smooth muscle contraction adn induced secretions

• Atropine
• Scopolamine
• Ipratropium
• Oxybutynin
• Tolterodine
• Darifenacin, solifenacin, fesoterodine
• Glycopyrrolate

• Surmountable antagoinis of all M receptors
• Used to reduce airway secretions in surgery
• Used after mushroom poisoning/insecticide exposure

• Anti motion sickness and to reduce airway secretions in surgery
• Anti M with some anti Nn

• COPD, asthma treatment
• Anti M with some anti Nn

• M3 prefering antagonist
• Manage bladder control
• Short half life --> frequent dosing

• M3 preferring antagonists
• Manage bladder control

• Reduce PANS
• Sweat and salivary glands most affected and GI activity
• CV effects compensated by reflexes

• Hot as a hare: inability to swear - hot, dry skin
• Blind as a stone: absence of accommodation
• Mad as a hatter: CNS toxidrome - delusions with hallucinations
• Dry to the bone: no bowel sounds, no spit, no tears, no sweat

• Glaucoma
• Obstructive GI and urinary systems
• Intestinal atony
• Dementia

• Nm antagonists
• d-tubocurarine
• Atracurium
• Pancuronium
• Rocuronium
• Lead to weakness and eventually flaccid paralysis with increase dose

• Non-depolarizing NMJ blocker
• Nm antagonist
• Stimulates release of histamine

• 2 ACh molecules
• Full, specific Nn receptor agonist
• First occupies receptor then desensitizes
• Can release histamine and cause hypotension
• Releases K+ from several sites leading to hyperkalemia
• Broken down only by buyrylylcholinesterase

• a-Bungarotoxin (inhibits NMJ like curare)
• a-latrotoxin (black widow spiders) (produces presynaptic relsease of neurotransmitters)
• tick venoms (induce synaptic vesicle fusion)

• Relatively specific to Nn
• Block all ANS outlfow
• Limited clinical efficacy
• Mecamylamine
• Heexamethonium
• Trimethaphan

• short acting ganglionic blocker
• blocks Nn receptors
• water soluble

a1 = a2 > b1 >>> b2

b1 = b2 > a1 = a2

• vasodilates renal arterioles
• direct inotropic effects
• in chain ganglia small intensely fluorescent cells, regulates ACh release

• enhance intracellular Ca
• Regulate IP3 and DAG

• enhance intracellular Ca
• regulate IP3 and DAG

• opens K+ channels
• inhibits adenyulyl cyclase

ionotropic, increasing Na+ channel conductance

• Increase intracellular Ca
• regulates IP3 and DAG via Gq
• Vascular sm m contraction, mydriasis, positive inotropy, bladder trigone and sphincter contraction, ENS sphincter contraction, arrector pili contraction, apocrine gland secretion, ejaculation

• Autoreceptor reducing future release of NE
• Inhibits adenylyl cyclase via Gi

• Enhances adenylyl cyclase
• HEART

• enchances adenylyl cyclase
• can activate Gi
• bronchioles, arterioles, liver

• enhances andenylyl cyclase
• LIPOCYTES

• Selectivity: preference for one R over another
• Specificity: 1000 fold higher affinity

Desensitization that occurs over a periord of time

• GRK
• Phosphorylates G-protein receptor after G-protein component has left
• Then beta arrestins can jump on and target the receptor for internalization

• Phenylephrine
• Pseudoephedrine
• Midodrine
• Methoxamine

• Clonidine
• Methyldopa
• Guanfacine
• Guanabenz

Isoproterenol

Dobutamine

• Albuterol
• Terbutaline
• Metaproterenol
• Pirbuterol
• Salmeterol
• Formoterol

• Alpha-1 selective agonist
• smooth muscle contraction
• used as decongestant, hypertensive, resolve priapism, induce mydriasis
• Toxicity - hypertension issues, seizures
• Significant first pass due to MAO-A

• Alpha-1 selective agonist
• More CNS effects than phenylephrine

• Alpha-1 selective agonist
• Prodrug to des-glymidodrine
• Treats hypotension

• Alpha-1 selective agonist
• Similar to phenylephrine
• Used for hypotension

• Alpha-2 selective agonist
• sympatholytic effects
• reduces NE release which can lead to hypotension
• Used for AD/HD, CNS anxiety after opiate withdrawal, anti-hypertensive, sedative

• Non-specific beta receptor agonist
• Asthma/COPD
• High doses cause big BP increase

• Beta-1 selective agonist
• racemic mix complicates things

• Beta-2 selective agonist
• like terbutaline, metaproterenol, and pirbuterol
• R isomer is active
• Vasodilate muscle arterioles, decreasing TPR and BP
• ASTHMA, COPD
• Tolerance issues

• Beta-2 selective agonists
• durations of actions up to 12 hours

• Beta-2 Selective agonist
• acute sc injection for ER treatment of asthma

• NE and DA re-uptake inhibitor
• Substrate for NET, can result in ca-indep release
• Blocks MAO

• Increase HR and TPR
• CNS effects
• Effects of inc synaptic NE, DA, 5HT

• Used as anorexient, AD/HD, narcolepsy, abuse
• Dependence issues
• Ceiling effect

• Methamphetamine
• Ephedrine
• Psudoephedrine
• Phenylpropanolamine
• Phenmetrazine
• Methylphenidate
• Modafinil
• Tyramine

• Non-competitive inhibition of NET
• (No Ca-indep release)
• Caine properties

like drugs: atomoxetine

• Phenoxybenzamine
• Phentolamine

• Prazosin
• Tramsulosin

Yohimbine

• Propranolol
• Nadolol
• Pindolol
• Sotolol
• Carvedilol
• Timolol

• Metaprolol
• Atenolol
• Esmolol

• Guanethidine
• Reserpine

• Long acting non-spec alpha antagonist
• Covalent binding alpha 1>>alpha 2
• Significant orthostatic hypotension
• Adverse effects: HR/CO up, nasal stuffiness, inhibit ejaculation
• Used to manage pheochromocytoma

• Reversible, short acting non-specific alpha antagonist
• alpha 1 = alpha 2
• less sedation than phenoxybenzamine
• used for surgical procedures for pheochromocytoma

• Alpha-1 selective drug
• Profound vascular blocking effects leading to orthostatic hypotension
• Like Tamsulosin, terazosin, doxazosin
• Used to manage hypertension and for benign prostatic hyperplasia

• Alpha-2 sselective drugs
• Increase SANS activity during SANS activation
• Treats orthostatic hypotension

• Non-specific beta blockers
• Treat hypertension, angina, chf, glaucoma
• Beta-1 blockade reduces renin release
• Beta-2 blockade prevents skel m vasodilation, bronchiole relax, glycogenolysis in liver
• Beta-3 blockade prevents lipolysis
• Watch out with asthmatics and type 1 diabetics

• Beta-1 selective antagonist
• some beta-2 antag activity
• Safer than non-spec to treat hypertension

• Beta-1 selective antagonist
• ultrashort acting
• used in icu to manage arrhythmias

• Partial non-specific agonist
• Mildly reduces beta tone

• Mixed antagonist
• Used to manage CHF

• NE depletor
• Ligand for NET and VAT
• Used as antihypertensive

PANS

• Liquid tears
• Antibiotics
• Cycosporine

• M3 agonists increase aqueous outflow
• Alpha-1 agonists induce mydriasis with facilitates aqueous humor outflow
• Alpha-2 agonists reduce production of aquous humor
• Beta blockers reduce production of aqueous humor
• Carbonic anhydrase inhibitor reduces production of aqueous humor
• PGF2a analogs facilite outflow

• Carbonic anhydrase inhibitor
• Treats open and closed angle glaucoma by reducing aq humor production

Use an alpha-1 agonist to induce vasoconstriction and reduce secretions

• PANS
• Dry mouth can be from lack of PANS secretions or too much SANS creating thick mucous

Beta-2 receptors increase mucous clearance by increasing cliliary beat frequency

Bronchiole smooth muscle is SANS controlled by Epi

• Cardica is primarily PANS
• Vessels = SANS (alpha-1 agonists increase tone, increasing TPR)(Beta-2 agonists reduce BP)

• Eccrine sweat glands are SANS
• ACh and M3 receptors

• Viagra
• Blocks PDE-5 so cGMP sticks around and erection stays

Erection is PANS - ACh/M3 inc NO, act guanylate cyclase, making cGMP --> erection

Ejaculation is SANS - alpha-1