Week 2: Autonomic Nervous System Drugs

Sympathetic or thoracolumbar division

Arises from neurons located in the thoracic and upper lumbar regions of the SC

Parasympathetic or craniosacral division

Composed of neurons originating in the midbrain, brainstem, and sacral region of the SC

Preganglionic neurons

* First neuron (CNS to synapse)
* Type B myelinated fibers
* Tend to be short (sympathetic division)
* Long (parasympathetic division)

Postganglionic neurons

* Synapse to destination (target tissue)
* Small, unmyelinated type C fibers
* Long (sympathetic division)
* Short (parasympathetic)

intermediolateral gray columns of the thoracic and upper lumbar
spinal cord

cell bodies for the sympathetic preganglionic fibers arise from

1. **Paired paravertebra**l, or chain, **ganglia**, which lie bilaterally on either side of the vertebral column
2. A group of **unpaired prevertebral ganglia**, which lie anterior to the aorta (e.g., the celiac plexus, the superior and inferior mesenteric ganglia)
3. A small number of **terminal ganglia**, which lie directly in the tissue that is innervated (e.g., the bladder and rectum)

Sympathetic preganglionic fibers leave the spinal cord via the ventral root of the spinal nerve and end in a sympathetic ganglion located in 3 areas

Parasympathetic and sympathetic

two areas of ANS

thoracolumbar division

Sympathetic

craniosacral

Parasympathetic

Preganglionic and Postganglionic neurons

two neurons in sequence to reach from the CNS to the peripheral organ or tissue.

cranial nerves III, VII, IX, and X

Neurons comprising the cranial portion of the parasympathetics exit the CNS via

Cranial nerve X (vagus nerve)

particularly significant because it contains approximately **75 percent** of the __efferent__ component of the entire parasympathetic division

ventral root of the spinal nerve; sympathetic ganglion

Sympathetic preganglionic fibers leave the spinal cord via the _________ and end in a _________

pelvic splanchnic nerves

Preganglionic fibers of the sacral portion exit the spinal cord via the

terminal ganglia

Synapse usually takes place in a ____________ located directly in the organ or tissue

1:15-20

sympathetic synapse

1:1

parasympathetic synapse

S:

Increased heart rate (beta-1, -2) Increased contractility (beta-1, -2)

\
P:

Decreased heart rate (M2)

Slight decrease in atrial contractility (M2)

heart

S:

Vasoconstriction of skin and viscera (alpha-1, -2)

Vasodilation of skeletal muscle and liver (beta-2)

\
P:

No parasympathetic innervation

No parasympathetic innervation

arterioles

S: Bronchodilation (beta-2)

P: Bronchoconstriction (M3)

airway smooth muscle

S: Increased secretion (beta-2); decreased secretion (alpha-1)

\
P: Increased secretion (M2)

Bronchial secretions

S: Contraction (alpha-1)

P: No parasympathetic innervation

radial muscle of iris

S: No sympathetic innervation

P: Contraction (M3)

circular muscle of iris

S: Relaxation (beta-2)

P: Contraction (M3)

ciliary muscle

S: Decreased motility and secretions (alpha-1, -2; beta-1, -2)

P: Increased motility and secretion (M3)

GI function

S: Increased renin secretion (beta-1)

P: No parasympathetic innervation

kidney

S: Relaxation (beta-2)

P: Contraction (M3)

Detrusor

S: Contraction (alpha-1)

P: Relaxation (M3)

Trigone and sphincter

S: Increased secretion (M‡)

P: No parasympathetic innervation

Sweat glands

S: Glycogenolysis and gluconeogenesis (alpha-1, beta-2)

P: No parasympathetic innervation

Liver

S: Lipolysis (alpha-2, beta-1, -2, -3)

P: No parasympathetic innervation

Fat cells

sympathetic division

mobilize body energy, massive reaction

fight or flight reaction

not always stimulatory

parasympathetic division

conserve and store energy

rest and digest reaction

affect only one tissue

not always inhibitory

* Synthesizes and secretes **norepinephrine** (20%) and **epinephrine** (80%) directly into the bloodstream
* Innervated by sympathetic
* Release by stress
* Fight or flight reaction

adrenal medulla

Nicotinic and Muscarinic

Cholinergic subtypes

L:

* CNS
* Visceral and bronchiole smooth muscle
* Cardiac muscle
* Exocrine glands (salivary, intestinal, lacrimal)
* Sweat glands

\
R:

* Mediate effects of acetylcholine in various parts of brain (M1–M5)
* Contraction (generally) (M2, M3)
* Decreased heart rate (M2)
* Increased secretion (M1, M3)
* Increased secretion (M)†

Muscarinic

L: Autonomic ganglia

R: Mediate transmission to postganglionic neuron (NN)

Nicotinic

Cholinergic Receptor

called because the neurotransmitter is more on acetylcholine

* Alpha-1


* Alpha-2
* Beta-1
* Beta-2
* Beta-3

Adrenergic subtypes

L:

* Vascular smooth muscle
* Intestinal smooth muscle
* Radial muscle iris
* Ureters
* Urinary sphincter
* Spleen capsule

\
R:

* Contraction
* Relaxation
* Contraction (mydriasis)
* Increased motility
* Contraction
* Contraction

Alpha-1

L:

* CNS inhibitory synapses
* Presynaptic terminal at peripheral adrenergic synapses
* GI tract
* Pancreatic islet cells
* Some arterioles (skeletal muscle, liver, kidneys)

\
R:

* Decreased sympathetic discharge from CNS
* Decreased norepinephrine release
* Decreased motility and secretion
* Decreased insulin secretion
* Vasoconstriction

Alpha-2

L:

* Cardiac muscle
* Kidney
* Fat cells

\
R:

* Increased heart rate and contractility
* Increased renin secretion

* Increased lipolysis

Beta-1

L:

* Bronchiole smooth muscle
* Some arterioles (skeletal muscle, liver)
* GI smooth muscle
* Skeletal muscle and liver cells
* Uterus Gallbladder

\
R:

* Relaxation (bronchodilation)
* Vasodilation
* Decreased motility
* Increased cellular metabolism
* Relaxation
* Relaxation

Beta-2

L:

* Fat cells
* Bladder
* Heart

\
R:

* Increased lipolysis
* Decreased contraction of detrusor muscle
* Decreased contractility

Beta-3

1. Sympathetic - between pre and postganglionic neurons
2. Parasympathetic - pre & postganglionic neurons
3. Synapse between sympathetic ganglion and effector cell
4. Parasympathetic postganglionic -effector cell synapse N.B. ALL. preganglionic neurons and parasympathetic

4 sites of synaptic transmission in efferent limb of ANS:

1. Adenosine
2. ATP
3. Substance P
4. Vasoactive intestinal Polypeptides

Other neurotransmitters:

Cholinergic stimulants and Anticholinergic Drugs

2 General Categories of Cholinergic Drugs

Muscarinic Receptors

Peripheral tissues supplied by parasympathetic postganglionic neurons

Nicotinic Receptors

Autonomic ganglia, type 1 or Nn

* Increase activity at acetylcholine synapse
* Many drugs are capable of potently and effectively stimulating cholinergic activity but few are relatively safe and specific

cholinergic stimulants

* Bind directly to receptors, activates it and initiates a cellular response e.g. acetylcholine
* Greater specificity for muscarinic receptors better

direct acting cholinergic stimulants

* Betanechol - Bladder Dysfunction
* Carbachol/ Pilocarpine - Glaucoma
* Methacholine - Inhalation test for asthma

Few agents are suitable for clinical use:

Betanechol

Bladder Dysfunction

Carbachol/ Pilocarpine

Glaucoma

Methacholine

Inhalation test for asthma

* Increase activity at cholinergic synapses by inhibiting the acetylcholinesterase enzyme; decreased degradation
* Cholinesterase inhibitors or anticholinesterase agents
* Lacks specificity; acts more on peripheral tissues
* Neostigmine / Pyridostigmine
* Used for treatment of Myasthenia gravis and glaucoma

indirect acting cholinergic stimulants

* Bethanechol
* Carbachol
* Methacholine
* Pilocarpine

Direct-Acting (Cholinergic Agonists)

* Duvoid, Urecholine
* Postoperative GI and urinary atony

Bethanechol

* Carboptic, Isopto Carbachol
* Glaucoma

Carbachol

* Provocholine
* Diagnose asthma (used to test for airway hyper-responsiveness)

Methacholine

* Pilocar, Isopto Carpine, many others
* Glaucoma

Pilocarpine

* Ambenonium
* Donepezil
* Echothiophate
* Edrophonium
* Galantamine
* Isoflurophate
* Neostigmine
* Physostigmine
* Pyridostigmine
* Rivastigmine
* Tacrine

Indirect-Acting (Cholinesterase Inhibitors)

* Mytelase
* Myasthenia gravis

Ambenonium

* Aricept
* Alzheimer-type dementia

Donepezil

* Phospholine Iodide
* Glaucoma

Echothiophate

* Enlon, Reversol, Tensilon
* Myasthenia gravis, reversal of neuromuscular blocking drugs

Edrophonium

* Razadyne, Reminyl
* Alzheimer-type dementia

Galantamine

* Diflupyl
* Glaucoma

Isoflurophate

* Prostigmin
* Postoperative GI and urinary atony, myasthenia gravis, reversal of neuromuscular blocking drugs

Neostigmine

* Antilirium, Eserine Opht
* Glaucoma, reversal of CNS toxicity caused by anticholinergic drugs

Physostigmine

* Mestinon, Regonol
* Myasthenia gravis, reversal of neuromuscular blocking drugs

Pyridostigmine

* Exelon
* Dementia of the Alzheimer’s type

Rivastigmine

* Cognex
* Alzheimer-type dementia

Tacrine

Alzheimer’s Disease

Tacrine (Cognex), Donepezil (Aricept), Galantamine (Reminyl), and Rvastigmine (Exelon)

GI & Bladder Atony

Bethanechol - Direct

Neostigmine - Indirect

Glaucoma

Cholinergic stimulation via the parasympathetic supply to the eye increases the outflow of aqueous humor, thus preventing excessive accumulation

Myasthenia Gravis

* Characterized by skeletal muscle weakness and profound fatigability
* No cure is available but Neostigmine and Pyridostigmine can help as they inhibit enzyme

Reversal of Neuromuscular Blockade

* Curarelike Drugs
* Often used during general anesthesia (GA) during surgery
* Indirect acting cholinergic stimulants inhibit acetylcholinesterase enzyme to permit

Reversal of anticholinergic-induced CNS Toxicity

* Anticholinergic drugs Toxic CNS effects; delirium, hallucination and coma
* Indirect-acting stimulants (physostigmine) enable endogenous Acetylcholine to overcome anticholinergic drug effects

○ GI distress
○ Inc salivation
○ Bronchoconstriction
○ Bradycardia
○ Difficulty of visual accommodation
○ Inc sweating
○ Vasodilation of facial blood vessels

Adverse effects of cholinergic stimulants: exaggerated parasympathetic responses

Anticholinergic drugs

* Competitive antagonists of the postsynaptic cholinergic receptors
* Cause reversible binding
* Cause receptor blockade

1. Antimuscarinic
2. Antinicotinic

Classification of anticholinergic drugs

autonomic ganglia

Type I

neuromuscular junction

Type II

atropine

* prototype
* came from a plant–belladonna & jimson weed
* MOA: block synaptic cholinergic muscarinic receptors c some degree of specificity
* Receptors:
* M1
* M2
* M3

Atropine

* AtroPen
* Peptic ulcer, IBS, neurogenic bladder, bronchospasm, preoperative antisecretory agent, cardiac arrhythmias (e.g., sinus bradycardia, postmyocardial infarction, asystole), reversal of neuromuscular blockade, antidote to cholinesterase inhibitor poisoning

Belladonna

* Generic
* Peptic ulcer, IBS, dysmenorrhea, nocturnal enuresis, antivertigo

Clidinium

* Quarzan
* Peptic ulcer, IBS

Cyclopentolate

* Ocu-Pentolate, Cyclogyl, others
* Induces mydriasis for ophthalmologic procedures

Darifenacin

* Enablex
* Overactive bladder

Dicyclomine

* Bentyl, others
* IBS

Fesoterodine

* Toviaz
* Overactive bladder

Glycopyrrolate

* Cuvposa, Robinul
* Peptic ulcer, preoperative antisecretory agent, reversal of neuromus- cular blockade, prevent excessive drooling

Homatropine

* Isopto Homapin
* Induces mydriasis for ophthalmologic procedures

Hyoscyamine

* Cystospaz, Levsin, others
* Peptic ulcer, IBS, urinary bladder hypermotility, preoperative antisecretory agent

Ipratropium

* Atrovent
* Bronchodilator

Mepenzolate

* Cantil
* Peptic ulcer

Oxybutynin

* Ditropan, Oxytrol
* Neurogenic or overactive bladder

Methscopolamine

* Pamine
* Peptic ulcer

Propantheline

* Pro-Banthine, Probanthel
* Peptic ulcer, IBS, urinary incontinence