ANS Overview

ANS Anatomy

• ANS is subdivided into sympathetic and parasympathetic neurons
• Sympathetic innervations branch from T1-L2 and the sympathetic ganglia lie along both sides of the spinal cord (but the ganglia are higher and lower then the branches innervating them)
• Parasympathetic innervations branch from the brainstem and sacral spine
• All preganglionic neurons utilize acetylcholine
• Sympathetic presynaptic neurons are short, meeting the ganglia near the spinal cord, and have long post-ganglionic neurons. Post-ganglionic neurons from a single ganglion can innervate multiple neurons, and utilize NE as their neurotransmitter
• Parasympathetic preganglionic neurons are long, meeting the ganglia which rest near their target organ. The postganglionic neurons are short, innervate a single organ, and utilize ACh.

Unique ANS Innervations

• Sweat Glands
  • Post-ganglionic sympathetic neurons secrete ACh to stimulate sweating
• Kidneys
  • Sympathetic innervations of renal vasculature secrete dopamine to cause vasodilation
• Adrenal Glands
  • The adrenal glands act as sympathetic ganglion, i.e. preganglionic neurons release ACh onto nicotinic receptors in the gland, leading to epinephrine and norepinephrine release into systemic circulation

ANS Receptors

Receptor	Signaling Pathway
Nicotinic Receptor	Na Influx
M1,3,5	Gq
M2,4	GI/O
α1	Gq
α2	Gi
β	GS

Physiologic Parameter	Symp. Receptor	Effect	Para. Receptor	Effect
Chronotropy	β1>2	Increase	M2	Decrease
Inotropy	β1>2	Increase	M2	Decrease
Arteries (most)	α1	Constrict
Veins	α1,2	Constrict
Skeletal Muscle Vessels	β2	Dilate
Endothelium			M3	Release EDRF (minimal vascular relaxation)
Bronchioles	β2	Dilate	M3>2	Constrict
Bladder Wall	β2	Relax	M3	Constrict
Ureter	α1	Contract	M3	Relax
Urinary Sphincter	α1	Contract	M3	Relax
Uterus	β2 α1	Relax Contract	M3	Variable
Penis/Vas Deferens	α1	Ejaculation	M3	Erection
Salivary Glands	α1	Increase Secretion	M3	Increase Secretion
GI Walls	α2, β2	Relax	M2,3	Contraction
GI Sphincters	α1	Contract	M2,3	Relaxation
GI Secretions	α2	Inhibit Secretion	M2,3	Increase Secretion
Skin Follicle Muscles	α1	Contraction and Piloerection
Thermoregulatory Sweating	M3	Increase Secretion
Stress (Apocrine) Sweating	α1	Increase Secretion
Iris Radial Muscle	α1	Contract
Iris Circular Muscle			M3	Contract
Ciliary Muscle	β2	Minor Relaxation	M3	Contract
Ciliary Epithelium	β2	Increase Aqueous Humor Secretion
Liver	α1, β2	Gluconeogenesis and Glycogenolysis
Adipose Tissue	α1, β1,2,3 (if it exists)	Lipolysis
Kidney	β1	Increase Renin Release
Pancreas	α2	Decrease insulin release

Sympathomimetics

Drug	Receptor Specificity	Notes
Norepinephrine	α, β	Inopressor
Epinephrine	α, β	Inopressor, anaphylaxis, cardiac arrest, vasoconstrictor
Phenylephrine	α1	Mydriasis w/o cycloplegia, push-dose pressor, decongestant
Naphazoline Tetrahydrozoline Oxymetazoline	α1 partial agonist	Nasal and ophthalmic decongestant / vasoconstrictor Tachyphylaxis
Methyldopa (prodrug) Clonidine Guanabenz Guanfacine Apraclonidine Tizanidine	α2	HTN, vasomotor menopausal SSx, and many psychiatric uses Inhibit preganglionic innervation of heart, kidney, and vascular α1 causing bradycardia, decreased renin release, and inhibition of vasoconstriction Apraclonidine is used primarily for glaucoma Tizanidine is primarily used for muscle spasticity
Isoproteronol	β	Used in Asthma, COPD, and as an inotrope
Metaproterenol Terbutaline Albuterol Salmeterol Formoterol -erols	β2	Bronchodilator Terbutaline can be used as a tocolytic in premature labor
Dobutamine	β	Dopamine derivative Inotrope w/ little chronotropic activity due to enantiomers’ competing chronotropic actions
Amphetamines	Inhibition of VMAT leading to reversal of DAT, NET, and SERT	Indirect sympathomimetic Used in ADHD, narcolepsy, obesity, and ephedrine and pseudoephedrine are decongestants Ephedrine is unique and is a direct adrenergic agonist
Cocaine	NERT, DAT, and SERT Inhibitor
Phenelzine Selegiline	MAOIs	NE, Epi, Phenylephrine are sensitive

SEs

• α₂ Agonists
  • Dry Mouth
  • Increased aldosterone release
  • Sedation
  • Rebound Tachycardia

Sympatholytics

α-Blockers

Drug	Receptor Selectivity	Notes
Phenoxybenzamine	α1,2, Histamine, ACh, 5HT (Irreversible)	Useful in HTN crisis and pheochromocytomas
Phentolamine	α1,2	IV only, useful in HTN crisis and pheochromocytomas
Prazosin	α1	BPH, HTN t1/2: 3hr
Terazosin	α1	BPH, HTN t1/2: 12hr
Doxazosin	α1	BPH, HTN t1/2: 20hr

SEs α₁ Blockade

• Orthostatic Hypotension
• Inhibition of Ejaculation
• Congestion
• Reflex Tachycardia

β-Blockers

Drug	Receptor Selectivity	ISA	Usual Maintenance Dose	Notes
Acebutolol	β1	+	200-600mg BID
Atenolol	β1	0	50-100mg QD
Betaxolol	β1	0	10-20mg QD
Bisoprolol	β1	0	5-10mg QD	Approved for CHF
Carteolol	β1, β2	++	2.5-10mg QD	Partial Agonist
Carvedilol	β1, β2, α1	0	25-50mg BID	Approved for CHF
Esmolol	β1	0	HTN Emergency: 500-1000mcg/kg over 1min 50-200mcg/kg/min	IV Only t1/2: 9min Incompatible w/ Bicarb Useful for rapid HR and BP control as a drip
Labetalol	β1, β2, α1	0	200-400mg BID	Enantiomers possess different properties
Metoprolol Tartrate	β1	0	50-100mg BID
Metoprolol Succinate	β1	0	100-200mg QD	Approved for CHF
Nebivolol	β1	0	5-40mg QD	Increases NO production
Nadolol	β1, β2	0	40-80mg QD	t1/2: 20hr
Penbutolol	β1, β2	+	20mg QD
Pindolol	β1, β2	+++	5-20mg BID	Partial Agonist
Propranolol	β1, β2	0	Variable	Lipophilic Reduces Renin Release
Propranolol LA	β1, β2	0	80-160mg QD
Timolol	β1, β2	0	10-20mg BID	PO and Ophthalmic (Glaucoma)

SEs

• Bronchoconstriction (particularly those with β₂ activity)
• Bradycardia / AV Block
• Difficulty identifying Hypoglycemia
• Withdrawal can cause HTN Crisis
• Fatigue
• Depression
• Nightmares
• Sexual dysfunction

Catecholamine Depleters

• Reserpine
  • Blocks VMAT inhibiting vesicular loading
  • Lasts for weeks

Cholinergics

Cholinergic Toxidrome

SLUD

• Salivation
• Lacrimation
• Urination
• Defecation
• Sweating
• Pupil constriction
• Hallucinations
• Bradycardia

Direct Cholinergic Agents

• Acetylcholine
• Carbachol
• Methacholine
• Bethanechol (Muscharinic Agonist)
• Muscarine
• Nicotine
• Pilocarpine (Muscharinic Agonist)
• Varenicline (Partial Nicotinic Agonist)

Cholinesterase Inhibitors

• Reversible
  • Edrophonium
    • Dx of Myasthenia Gravis (SSx will resolve almost immediately)
  • Neostigmine
  • Pyridostigmine
  • Physostigmine
    • Anticholinergic antidote
  • Tacrine
  • Donepezil
  • Rivastigmine
  • Galantamine
  • Memantine
• Irreversible
  • Organophosphates
  • Isoflurophate
  • Echothiophate
  • Sarin
  • Soman
  • Malathion
  • Diazinon

Treatment of Anticholinesterase Inhibitor Poisoning

• 2-PAM (Pralidoximine, 2-pyridine aldoxime methyl chloride)
• Organophosphate Poisoning IV: 30 mg/kg (Max 2g) then 8-10 mg/kg/hr (Max 650 mg/hr)
• Organophosphate Poisoning IM
  • Mild: 600mg IM repeat q15min PRN NTE 1800mg
  • Severe: 600mg IM rapid repeat NTE 1800mg
  • Persistent: May repeat 1800mg series q1h
• Reversible Anticholinesterase Inhibitors: 2-PAM or Anticholinergic agents
  • 2-PAM: 1-2g IV then 250mg q5min PRN

Anticholinergics

• Atropine
  • 0.5mg: Slight cardiac slowing, some oral dryness, and inhibition of sweating
  • 1mg: Tachycardia, mild mydriasis, oral dryness
  • 2mg: Tachycardia / palpitations, mydriasis, blurring of near vision, oral dryness
  • 5mg: All above SSx marked, difficulty speaking / swallowing, HA, hot / dry skin
  • ≥ 10mg: All above SSx, iris obliterated, vision very blurry, hallucinations, coma, ataxia
• Ipratroprium
  • COPD
• Scopolamine
  • Motion Sickness
  • Highest CNS penetration
• Homatropine
  • Cycloplegia and Mydriasis
• Tropicamide
  • Cycloplegia and Mydriasis
• Benztropine
  • PD and EPS
• Glycopyrrolate
  • GI Disorders (charged, won’t enter CNS)
• Propantheline
  • GI Disorders (charged, won’t enter CNS)

Paralytics

DO NOT ADMINISTER A PARALYTIC WITHOUT SUFFICIENT OPIOID ANALGESIA OR SIGNIFICANT SEDATION (Propofol, Ketamine, Etomidate, Volatile Anesthetics, etc)

• Succinylcholine
  • 1-2 mg/kg IV or 4-5 mg/kg IM
  • Depolarizing blocker
  • Causes hyperkalemia
  • Short acting (effect ends in ≈5 min)
• Non-Depolarizing
  • Vecuronium
    • 0.1 mg/kg
    • Lasts 30-60min
  • Pancuronium
    • 0.1 mg/kg
    • 45-90 min
  • Rocuronium
    • 0.8-1 mg/kg (30-45 min)