STUDY GUIDE/LEARNING OBJECTIVES

NOTES
Autonomic Nervous System Pharmacology
Neuromuscular Junction Pharmacology

●Focus on underlying scientific principles relating to drug classifications and

pharmacotherapeutic decision making.
●Directed self study will focus on details regarding specific drugs. You may find
additional information in the course required textbooks.
●All study guide questions and learning objectives will be subject to exam questions
unless otherwise indicated. In other words, exam questions will be derived from material
in both video and directed self study.

Study guide Questions for Nervous System Pharmacology

Review the Following physiology.
1. What are the divisions of nervous system?
2. What are the neuroanatomical and chemical components of the autonomic
nervous system?
3. What is a synapse?
5. What is the Neuromuscular Junction (NMJ)?
The following will be discussed in the course.
4. What synapse anatomical locations are possible for drug pharmacodynamics?
6. What NMJ anatomical locations are possible for drug pharmacodynamics?
7. What are the common pharmacotherapeutic uses of the following ANS
classification of drugs?
antimuscarinic
parasympathomimetic
sympathomimetic
sympatholytic
8. What are the general side effects of the following ANS classification of drugs?
antimuscarinic
parasympathomimetic
sympathomimetic
sympatholytic
9. What is the general mechanism of action (Pharmacodynamics) of the following ANS
classification of drugs?
antimuscarinic
parasympathomimetic
sympathomimetic
sympatholytic
10. What is a ganglionic blocker?
11. What is a ganglionic stimulant?
12. Explain the following statement. “NMJ blocker drugs are not the same as skeletal
muscle relaxants.”

Please go to next page for question 13.

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13. For the following drugs, know the Classification, Pharmacotherapuetics and
pharmacodynamics.

For our purposes, the classification will be similar, if not identical to the
Pharmacodynamics (receptors affected) .

The primary sources can be the Woo and Robinson text book, the “drugs@FDA”
location on FDA web site, and Goodman and Gilman’s. Goodman and Gilman’s has
links to Pharmacy Access.

Dopamine Hydrochloride
Epinephrine
Norepinephrine Bitartrate
Dobutamine Hydrochloride
Isoproterenol Hydrochloride (One formulation available Isuprel trade name)
Phentolamine mesylate
Phenylephrine Hydrochloride
Propranolol Hydrochloride
Donepezil Hydrochloride
Neostigmine Methylsulfate
Bethanechol chloride (Urecholine)
Atropine (Atropen) or Atropine Sulfate Ansyr Plastic Syringe
Scopolamine
Nicotine
Pancuronium Bromide
Succinylcholine Chloride (Anectine, Quelicin)

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Why study the nervous system, especially the autonomic nervous
system separate from a pharmacotherapeutic discussion of
specific diseases?

Many persons are often frustrated with nervous system topics. The major reason,
is that recall of neuroanatomy and neurophysiology at the molecular and cellular level
is usually vague. This is not because the student is incapable, but rather due to fact the
material was most likely “inadequately” presented in previous academic experiences.
Therefore, I would like to offer some rationale for this lecture.
First, a very minimal overview of the nervous system and its subparts is
necessary. One needs to be familiar with the anatomical and physiological language of
the nervous system because it is used in the classification schemes of our nervous
system drugs.
Second, we need to review the components of neurotransmission (synapse and
neurotransmitters). Again, the language of such is used in the classification schemes of
the nervous system drugs. Equally as important, is the fact the pharmacodynamics
(recall: mechanism of action) of the majority of nervous system drugs occurs at the
synapse. The drugs can mimic, enhance, or block the action of the physiological
neurotransmitters.
Third, it is very important to study the autonomic nervous system (part of the
peripheral nervous system) by itself in detail. You will observe that most of our organ
systems are affected by the autonomic nervous system (ANS). As a result, many
pharmacotherapeutic strategies of organ system diseases utilizes drugs that affect the
autonomic nervous system. The downside to ANS pharmacotherapy, is that it is difficult
to isolate the action of a drug to a specific organ. A sound fundamental understanding of
the ANS will allow the practitioner to: 1.) better understand therapeutic action of ANS
drugs; 2.) predict side effects; 3.) predict drug-drug interactions; and 4.) select
appropriate drugs for diagnosis.
It is actually very efficient to evaluate the nature of ANS pharmacotherapy as the
large picture before attempting to discuss separate diseases. We can understand the
mechanisms of a large number of drugs quickly and then appreciate their significance
when we see them again.
Let me offer an example. Hypertension (HTN) is treated by about 16 categories
of drugs some of which include ANS drugs and other CNS drugs. Therefore, when we
get to issues of pharmacotherapy of hypertension, we can incorporate our basic
understanding of ANS pharmacology into the bigger picture of HTN without the need to
go off on a tangent.
Most people will not remember all of the details of receptor subtypes and ANS
regulation of organ systems. However, as a result of this presentation, you should be
able to logically ask the appropriate questions and know where to look for the answers
to make informed decisions.

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Review the following Nervous System physiology on your own. PLEASE consult
with the course faculty if you have difficulty with these concepts.

NERVOUS SYSTEM
Draw boxes around and arrows connecting the parts in a manner that
demonstrates the organization!

Central nervous system (CNS) Peripheral nervous system (PNS)

spinal and peripheral nerves

Brain Spinal cord

afferent efferent
(sensory) (motor)
bodyCNS CNSbody

somatic autonomic
nervous nervous
system system
skeletal musc visceral org
tendons SM, CM,
joints glands

sympathetic parasympathetic
(adrenergic) (cholinergic)
thoracolumbar craniosacral
mobilize energy conserve energy

SYNAPSE: WHAT IS IT?

Anatomical structure that can be:

 nerve to nerve connection
 nerve to muscle (Neuromuscular junction NMJ)
 nerve to target end organ

No matter what type of structure, the major components are the same.
(Parts A, B, and C below.)
A. Presynapse (nerve that synthesizes, stores, and releases the neurotransmitter)
1. receptors for nerve autoregulation
2. drugs cross membrane and  or  neurotransmitter release
3. drugs cross membrane and affect enzymes of neurotransmitter
synthesis
B. Synaptic cleft (space between pre and post synapse)
1. drugs affect the enzymes that degrade the released neurotransmitter

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C. Postsynapse (location of receptor that neurotransmitter modulates)
1. Recall the types of synapses. Therefore the structure of postsynapse can be:
 nerve
 muscle (motor end plate)
 target end organ

OVERVIEW OF THE AUTONOMIC NERVOUS SYSTEM

Part of the efferent system of the PNS

The direction of information signal is from CNSbody

Autonomic nerve fibers

2. myelinated axon (preganglionic fiber)
(preganglionic neuron cell body in spinal cord)
2. unmyelinated postganglionic fiber
Special Synapse:
autonomic ganglion (synapse of pre and post ganglion nerve fibers)

NOTE: The number of nerve fibers between CNS and effector organ is 2 ( one
preganglionic and one postganglionic)

Autonomic nerve fiber neurotransmitters (NT)* and receptors

SYMPATHETIC PARASYMPATHETIC

Preganglionic fiber NT cholinergic fiber release cholinergic fiber release

Acetylcholine acteylcholine

ganglionic receptor nicotinic nicotinic

Postganglionic fiber NT adrenergic – release cholinergic – release

norepinephrine acetylcholine

Effector organ receptor  or  muscarinic

NOTE: Sympathetic system innervation of adrenal gland medulla is preganglionic fiber.

The cells release EPI and NE into blood circulation.

Receptors located on effector cell plasma membranes

What happens when the receptors are activated?

Please look at the the text book for tables of ANS innervation of various organ systems
and the resulting effects. Not all organs receive both parasympathetic and sympathetic.
However, when they do, the overall regulation is a balance between the two.

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There is always confusion of ANS regulation of arteries and veins. The following list is a
compilation of many resources.

ARTERIES/VEINS
ANS regulation

A. Coronary arteries
1. Predominant innervation is sympathetic
α1, α2 receptors – effect is constriction
β2 receptors – effect is dilation

2. Many references say that parasympathetic innervation is minimal or not at all.

The physiological parasympathetic role is therefore minor.

B. Veins in body
1. Predominant innervation is sympathetic
α1, α2 receptors – effect is constriction
β2 receptors – effect is dilation
2. No significant physiological parasympathetic innervation
C. Arteries in the body (peripheral)
1. Predominant innervation is sympathetic
α1, α2 receptors – effect is constriction
β2 receptors – effect is dilation

2. Minimal significant physiological parasympathetic innervation

SOMATIC NERVOUS SYSTEM

Part of the efferent system of the PNS

NMJ – Neuromuscular junction

One Somatic fiber from spinal cord that innervates the skeletal muscle
NT is acetylcholine; receptor is nicotinic

WHAT IS MEANT BY THE TERM “INNERVATION”?????!!!!!!!!

• Nerve connecting to something specific for purposes of regulation

COMPARE Parasympathetic Division of the ANS to the SOMATIC System

What is the same?
• Acetylcholine is the Neurotransmitter
What is different?
• ANS Parasympathetic Division has Muscarinic receptors on target organs/tissues
• SOMATIC has Nicotinic Receptor at the skeletal muscle

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 POSSIBLE DRUG ACTION AT SYNAPSE
 interfere with neurotransmitter(NT) synthesis
 metabolic transformation by same pathway as NT
 Block transport system of membrane of nerve terminal
 block transport system of granules
 Prevent release of NT
 Displace NT from axonal terminal
 mimic NT at postsynapse (agonist)
 Block NT at postsynapse (antagonist)
 inhibit enzyme breakdown of NT

DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM

Approach to analyzing, remembering, thinking about, etc:

1. What is the type of nerve stimulation to effector organ?
Parasympathetic or adrenergic
2. What is the effect nerve stimulation on the effector organ?
Excite or inhibit action
3. What type of receptor(s) is activated by neurotransmitter?
4. If a drug that mimics the normal action of the nerve stimulation (agonist of effector
receptor) is used, what is expected result on organ action?
5. If the drug blocks (antagonist) the action of the nerve on effector organ what would be
result?
Opposite of stimulation!
6. Side effects are dictated by the fact that agonists and antagonists can affect organs
other than the specific organ of therapeutic interest.
7. What is the major difference between the variety of drugs in a class???
Their pharmacokinetic and Pharmacodynamic properties !!!!!!

The following table illustrates the complexity of pharmacotherapeutics of ANS. Take a

few moments to closely examine. In the cases of organs that have BOTH
parasympathetic and sympathetic regulation, the following can occur:
Sympathetic agonist may have similar effects as antimuscarinic
Sympathetic antagonist may have similar effects as cholinergic agonist.
Please do not assume that the classes are interchangeable. There is usually a first
choice per diagnosis.

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Example of Autonomic innervation of Heart. Many, but not all tissues have both
sympathetic and parasympathetic control.

Symp- normal sympatho- sympatho- parasymp- normal parasymp antimusc-

Organ athetic physiologic mimetic lytic drug athetic physiologic athomim- arinic drug
recept ympathy drug effect effect receptor response etic drug effect
or type ympathy. (agonist) (antagonist type parasymp. effect (antagonist
Stimulation Stimulation (agonist)
HEART

SA node 1  HR  HR  HR Muscarinic  HR  HR  HR
Atria 1  contract.*  contract.  contract. none  contract.  contract  contract.
Ventricles 1  contract.  contract.  contract. Muscarinic None none None
Av node 1  conduct.  conduct.  conduct. none  conduct. conduct.  conduct.
Coronary 2 dilates Dilates Constrict none None None None
arteries

* contractility;  conduction

CLASSIFICATION OF DRUGS AFFECTING THE

AUTONOMIC NERVOUS SYSTEM

I. Classification of drugs affecting the parasympathetic nervous system

ANTIMUSCARINIC DRUGS (M receptor antagonists)

Atropine Sulfate [prototype]
Scopolamine Hydrobromide (Transderm Scop)
Glycopyrrolate
Dicyclomine Hydrochloride

PARASYMPATHOMIMETIC (agonist to M receptor)

1. Direct acting
Acetylcholine Chloride [prototype] One opthamalic formulation on market
Bethanechol Chloride (Urecholine)
Carbachol (ophthalmic use)
2. Indirect acting (cholinesterase inhibitors)
Drugs for alzhiemer’s type dementia
Donepezil Hydrochloride(Aricept)
Galantamine Hydrobromide (Razadyne)
Tacrine HCl (Cognex) Discontinued in USA
Rivastigmine Tartrate (Exelon)
Older drugs for conditions such as myasthenia gravis
Neostigmine metylsulfate [prototype]
Pyridostigmine bromide (Mestinon)
Ambenonium Cl (Mytelase) FDA web site states “discontinued”

Note:The following ganglionic classification in the Parasympathetic seems like an

anomaly. The following two are sometimes put in a class of their own. In reality, both the
Sympathetic and Parasympathetic systems have ganglions. So, the blockers and
stimulants are not perfectly selective.

C. Ganglionic blockers
Mecamylamine Hydrochloride is on FDA web site as available.
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 D. Ganglionic stimulants
Nicotine [prototype]

II. Classification of drugs affecting the sympathetic nervous system

Sympathomimetic drugs (Adrenergic agonists)

1. Direct acting nonselective ( or )
Epinephrine [prototype] (1, 1, 1 or 2)
Dopamine Hydrochloride (Low doses:D and ; higher doses D and 1;
large doses D and 1 and  ) (Goodman and Gilman’s)
Norepinephrine Bitartrate (1, 2 or 1)
2. Direct acting nonselective  agonist
Isoproterenol hydrochloride (Isuprel) [prototype] (1 or 2)
3. Direct acting selective 1 agonist
Phenylephrine hydrochloride [prototype]
Metaraminol Bitartrate Discontinued in USA
4. Direct acting selective 2 agonist
Clonidine is central acting 2 agonist
5. Direct acting selective 1 agonist
Dopamine Hydrochloride (dose dependent- see above)
Dobutamine Hydrochloride (if the +racemic enantiomer on cardiovascular
tissue. See below for more explanation)*
6. Direct acting selective 2 agonist
Albuterol sulfate (Proventil-HFA) [prototype]

7. Indirect nonselective agonist

Amphetamines are thought to block the reuptake of nor epinephrine and dopamine into the presynaptic neuron and
increase the release of these mnoamines into the extraneuronal space.
Amphetamine (Adderall XR) Has 4 mixed salts including Dextroamphetamine
8. Mixed action nonselective agonist
direct alpha and beta R stimulation
indirect release of NE from nerves
Ephedrine [prototype] (1, 1, 1 or 2 and releasing agent)

(Goodman and Gilman’s) “lower doses produce renal and mesenteric vasodilation, higher doses also produce
cardiac stimulation and renal vasodilation; large doses stimulate alpha-adrenergic receptors.”
Hilal-Dandan R, Brunton LL. Adrenergic Agonists and Antagonists. In: Hilal-Dandan R, Brunton LL. eds.
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e. New York, NY: McGraw-Hill; 2016.
http://0-accesspharmacy.mhmedical.com.carlson.utoledo.edu/content.aspx?bookid=1810&sectionid=124490379.
Accessed February 12, 2017.

*Mechanism of Action For Dobutamine

“Dobutamine, a racemic mixture, stimulates myocardial beta1-adrenergic receptors primarily by
the (+) enantiomer and some alpha1 receptor agonism by the (-) enantiomer, resulting in
increased contractility and heart rate, and stimulates both beta2- and alpha1-receptors in the
vasculature. Although beta2 and alpha1 adrenergic receptors are also activated, the effects of
beta2 receptor activation may equally offset or be slightly greater than the effects of alpha1
stimulation, resulting in some vasodilation in addition to the inotropic and chronotropic actions

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(Leier 1988; Majerus 1989; Ruffolo 1987). Lowers central venous pressure and wedge pressure,
but has little effect on pulmonary vascular resistance (Leier 1977; Leier 1978). “
The McGraw-Hill Education logo, AccessPharmacy, and related trade dress are trademarks or registered
trademarks of McGraw-Hill Education. Through the electronic online license of the University of Toledo Library on
February 12, 2017. For this course only. Not to be copied and used for other purposes.

Sympatholytic (antagonists)
1. Noncompetitive long acting  antagonist
Phenoxybenzamine Hydrochloride (Dibenzyline) [prototype]
Doxazosin (Cardura)
2. Competitive short acting 1 antagonist
Phentolamine mesylate [prototype]
Tamsulosin (Flomax)
3. Ergotamine group
Ergotamine tartrate [prototype]
prevent NE from activating  receptors; competitive inhibition
Dihydroergotamine (DHE-45)
4.  Blockers
Propranolol Hydrochloride [prototype]

TERMINOLOGY DESCRIBING ANS DRUG ACTION

The various terms can lead to confusion because they are interchangeably used.

PARASYMAPATHETIC ANS

ANS Division PHARMACODYNAMIC TERMS

Parasympathomimetic (agonists)
Antimuscarinic (Antagonists)
FUNCTIONAL AGONIST TERMS
Cholinergic
FUNCTIONAL ANTAGONIST TERMS
Anticholingergic
Antimuscarinic
Anticholinesterase
Cholinesterase inhibitor

SYMPATHETIC ANS

ANS Division PHARMACODYNAMIC TERMS

Sympathomimetic (Agonist)
Sympatholytic (Antagonist)
FUNCTIONAL AGONIST TERMS
Adrenergic
alpha agonist
beta agonist
FUNCTIONAL ANTAGONIST TERMS
Antiadrenergic
alpha blocker
beta blocker

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 PARASYMPATHOMIMETIC DRUGS
(Cholinergic drugs)
 Pharmacotherapeutics
urinary retention
gastroesophageal reflux disease
mild to moderate Alzheimer's type dementia
visual decrease miosis
 Pharmacodynamics
indirect or direct stimulation of cholinergic nicotinic or muscarinic receptors
 Adverse effects
"extensions of agonist effects"
GI and urinary problems
urgency, nausea, vomiting, salivation, abdominal cramps, diarrhea, headache,
syncope, heart block

GANGLIONIC BLOCKERS
limited use, lack of selectivity
Mecamylamine Hydrochloride is on FDA web site as available. Year 2019
GANGLIONIC STIMULANTS
most have little or none clinical value
Nicotine

ANTIMUSCARINIC DRUGS
(Anticholinergic drugs)
 Pharmacotherapeutics
treatment of bradycardia and bradyarrhythmias
preop decrease of secretions and vagal reflex
adjunct in peptic ulcer disease
irritable bowel syndrome
nausea
motion sickness
Parkinson's disease
visual disorders - cause mydriasis
 Pharmacodynamics
-block effect of endogenous acetylcholine on nicotinic or muscarinic receptors
-Anticholinergic “Drying effects” are dose dependent- Decreased secretion of
salivary glands, sweat glands, bronchial glands
-Decreased GI motility and tone
-Dilation of bronchial smooth muscle
-Increase heart rate
 Adverse effects
many: cardiac increase heart rate, GI constipation, dilated pupils, urinary
retention, Dryness of secretions, asthma

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 SYMPATHOMIMETIC DRUGS
(Adrenergic drugs)

 mimic flight or fight response

 Pharmacotherapeutics - heart, lung, vessels
heart disorders
blood vessel disorders
bronchial respiratory disorders
acute shock
reduce bleeding
hypoglycemia (Epi antagonize insulin- blood CHO)
allergies/anaphylaxis
allergic rhinitis
uterine muscle relaxation

Emergency use
Epinephrine
anaphylactic shock
bronchial constriction
complete heart block
cardiac arrest
isoproterenol
cardiac failure
status asthmaticus
 Pharmacodynamics
direct or indirect stimulation of  or  receptors
1. Stimulate alpha1 receptors
mydriasis (pupil dilation)
vasoconstriction
hemostasis (arrest of bleeding or circulation)
nasal decongestion
elevation of systemic BP
2. Stimulate beta1 receptors
cardiac arrest
Atrioventricular block
shock
3. Stimulate beta2 receptors
uterus - delay premature labor
lungs - bronchodilation
 Adverse effects
"extensions of their pharmacotherapeutic effects"
nervousness, restlessness, insomnia, tremors,
headache
 decrease BP (OD), dizziness, tachycardia, hyperglycemia, hypokalemia,
seizures, more
 Contraindications
 narrow angle glaucoma, cerebrovascular disesase, hyperthyroidism,
arrhythmias, hypertension, angina pectoris

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 SYMPATHOLYTIC DRUGS
(Antiadrenergic drugs)

 Pharmacotherapeutics - heart and blood vessels

heart rate
cerebral circulation
some hypertension
benign prostate hyperplasia
migraine headaches
 Pharmacodynamics
block the action of endogenous neurotransmitters on adrenergic receptors
 Adverse effects
tachycardia, arrhythmias, angina, abdominal pain, nausea, vomiting, nasal
stuffiness, dizziness, cerebrovascular spasm, hypotension, MI
POSTGANGLIONIC BLOCKERS
Reserpine (Novo-Reserpine)

PHARMACOTHERAPEUTICS
alternative drugs for hypertension
PHARMACODYNAMICS
reserpine: deplete postganglionic catecholamine
inhibit reuptake of DA
suppress NE synthesis
antag. 5HT bind

SOMATIC SYSTEM
NEUROMUSCULAR BLOCKING DRUGS

 not same as skeletal muscle relaxant classification

 Pharmacotherapeutics
adjunct to anesthesia to facilitate endotrachial intubation and as skeletal
muscle relaxant
 Pharmacodynamics
neuromuscular junction
depolarize or nondepolarize at motor end plate acetylcholine receptors (nicotinic)
 Adverse effects
cardiovascular and respiratory depression
effect ANS ganglion nicotinic receptors

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS

General pharamacodynamics
Compete with ACh for nicotinic binding sites on the motor end plate
Blocks stimulation of receptor - muscle relaxes

Prototype – Pancuronium Bromide

(like the older discontinued TUBOCURARINE HYDROCHLORIDE- Experimental use)
Pharmacokinetics
IV, onset 1 min, duration action 30-60 min, recovery hours

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Pharmacotherapeutics
muscle relaxation for endotracheal intubation
facilitate mechanical ventilation
electroconvulsive shock therapy
Dx Myasthenia Gravis
management of tetanus
Undesired clinical results
respiratory failure
Other drugs in category
differ in potency and duration of action
Special considerations
atropine will block and reduce muscarinic effects
admin of acetylcholinesterase inhibitor reverses

DEPOLARIZING NEUROMUSCULAR BLOCKERS

General Pharmacodynamics
bind to nicotinic (N2) receptors on motor end plate and causes depolarization of
muscle fiber
stays bound to N2 and prevents repolarization
Prototype - SUCCINYLCHOLINE

Pharmacokinetics
IV, onset < 30sec, duration 4 - 10 min
(ultra short-acting)
Pharmacotherapeutics
surgery
electroshock Tx
Biotransformation - pseudocholinesterase
Undesired clinical responses
Paralysis prolonged
malignant hyperthermia
postop muscle pain
Life span considerations
FDA Pregnancy Category C

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