NS DIVISION

1. Central Nervous System (CNS) - brain, spinal cord

2. Peripheral Nervous System (PNS) - neurons outside the brain & spinal
cord
PNS DIVISION
A. Somatic - voluntary regulation of skeletal muscles
B. Autonomic - involuntary regulation of smooth muscle, cardiac muscle &
glands
I. Sympathetic
II. Parasympathetic
AUTONOMIC PHARMACOLOGY
-using drugs that mimic or block the actions of chemical transmitters to
selectively modify many autonomic functions
-- involve a variety of effector tissues (cardiac muscle, smooth muscle,
vascular endothelium, exocrine glands, and presynaptic nerve terminals)

AUTONOMIC NERVOUS SYSTEM

Anatomy
Roots
Location of Ganglia
Length of Fibers
Preganglionic
Postganglionic
Neurotransmitters
Preganglionic
Postganglionic
Receptor
Ganglia
Target Organ

SYMPATHETIC /
ADRENERGIC
(Fight, Flight,
Fright)
Thoracolumbar
(T1-T12, L1-L5)

PARASYMPATHETIC /
CHOLINERGIC
(Rest & Digest)
Craniosacral
(CN 3, 7, 9 & 10, S3-S4)

Near the spinal cord

Near the target organ

Short
Long

Long
Short

Acetylcholine
NE, Epinephrine,
Dopamine
Nicotinic
Alpha, Beta,
Dopamine

Acetylcholine
Acetylcholine
Nicotinic
Muscarinic, Nicotinic

SYMPATHETIC /
ADRENERGIC
(Fight, Flight,
Fright)
Dilation
(far vision)

Constriction
(near vision)

Bronchial smooth
muscle

Bronchodilation

Bronchoconstriction

Heart

(+) chronotropic
(+) inotropic

(-) chronotropic
(-) inotropic

Closed
motility

Opened
motility

Closed
Relaxation
Ejaculation

Opened
Contraction
Erection

Eye
Pupils
Ciliary muscle

GIT
Sphincters
Intestinal wall muscle
Secretions
Bladder
Sphincter
Wall muscles
Male genitalia

MATA | PHAR 140

PARASYMPATHETIC /
CHOLINERGIC
(Rest & Digest)

Uterus

Salivary glands
Lacrimal glands
Vascular smooth
muscle
Skin / gut
Skeletal muscle
Skin
Pilomotor muscles
Sweat glands
Metabolic fxns
Liver
Fat cells
Kidney

CHOLINERGIC RESPONSE
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction
Emesis
Lacrimation
Salivation
Sweating

Contraction

SYMPATHETIC /
ADRENERGIC
(Fight, Flight, Fright)
Thick, viscid secretion

Relaxation

PARASYMPATHETIC /
CHOLINERGIC
(Rest & Digest)
Copious, water
secretion
Secretion

Constriction
Dilation
Contraction
sweating
Gluconeogenesis
Glycogenolysis
Lipolysis
Renin release

ALICE IN WONDERLAND
Hot as a hare: hyperthermia, fever
Red as a beet: tachycardia,
vasodilation/flushing
Blind as a bat: blurring of vision, cycloplegia,
mydriasis
Mad as a hatter: delirium, hallucinations
Dry as a bone: decreased gland secretions

Autonomic Transmission
- involves two neurons:
1. Presynaptic neurons extend from the brain to autonomic ganglia
where they transmit CNS signals to postsynaptic neurons by releasing
acetylcholine into the synaptic cleft
2. Postsynaptic neurons subsequently transmit impulses to end organs
by releasing norepinephrine or acetylcholine

CHOLINERGIC TRANSMISSION
Synthesis
Molecules

Enzyme

Reaction
Storage
Carrier
Release

Receptor

Removal
Enzyme

DRUGS

Choline- outside cell

(transported by Na+-dependent
membrane
CHT) RLS
Acetyl CoA- mitochondria
Choline acetyltransferase
(ChAT)
Acetylation

Hemicholinuminhibits transport

ADRENERGIC TRANSMISSION
1. Tyrosine Dopa (RLS)
2. Dopa Dopamine (dopaminergic neurons)
3. Dopamine Norepinephrine (sympathetic
postganglionic neurons)
4. Norepinephrine Epinephrine (adrenal medulla)
1 Tyrosine hydroxylase (TH)
2 Dopa decarboxylase (DD)
3 Dopamine--hydroxylase (DH)
4 Phenylethanolamine-N-methyltransferase (PNMT)

Vesicle-associated transporter
(VAT)
Voltage-sensitive Ca+2 -channels
in the terminal membrane are
opened influx of Ca+2

DRUGS
Metyrosine/methyltyrosine- inhibits TH
Carbidopa- inhibits DD

Vesamicol- inhibits
transport

DA NE
Vesicular monoamine transporter (VMAT)

Reserpine-depletes
transmitter stores

-latrotoxinpromotes Ca+2
release
botulinum toxininhibits release

Action potential influx of Ca+2

Release of NE, cotransmitters, ATP and DH

Guanethidine, Bretyliumblocks release

Acetylcholine
receptor/Cholinoceptor

Acetylcholinesterase (AchE)
Hydrolysis Choline + Acetate

NE diffuses out of the cleft or is transported

into the cytoplasm of the terminal by the
norepinephrine transporter (NET)
Adrenoceptors

Monoamine oxidase (MAO)

Catechol-O-methyltransferase (COMT)
Oxidation (MAO)
Methylation (COMT)
Metabolites:
3-methoxy-4-hydroxy-mandelic acid / vanillylmandelic
acid (VMA)
metanephrine,
normetanephrine

Reaction

Amphetamines,
methamphetamines,
tyramine, ephedrine
- promote release
INCREASED NE ACTIVITY
Cocaine, TCA- blocks
reuptake INCREASED NE
ACTIVITY

CHOLINOCEPTORS
Muscarinic Receptors
Exocrine glands

secretion

Secretion

Smooth muscles

contraction

Autonomic
ganglia

seizure activity

Eye

Miosis, ocular
accommodation

CNS

cognitive and function

(learning and memory)

Blood vessels
(endothelium)

Vasodilation

Heart

Cardiac inhibition

CNS

CNS

Neural inhibition

M4

CNS

tremors; hypothermia;
analgesia

M5

CNS

Receptor

Location

M1

Exocrine glands

M2

Effect

M3

Enhanced locomotion

Salivary glands
Smooth muscle

contraction

Peripheral
nerves

Neural inhibition

Iris / ciliary muscle

ganglionic transmission

Nicotinic Receptors
Receptor
N1

Location

Effect

Ganglion

Stimulation

CNS

Neurotransmission

Skeletal muscle

Contraction

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CHOLINERGIC DRUGS/CHOLINOMIMETICS
1. Cholinergic Agonists
-Direct-acting- bind, activate receptor
-Indirect-acting- inhibit AChE ACh
2. Cholinergic Antagonists
DIRECT-ACTING CHOLINERGIC AGONISTS
- choline bound to an acetyl derivative by an ester bond
- poorly absorbed & poorly distributed into the CNS

DIRECT-ACTING CHOLINERGIC AGONISTS

Drug
Acetylcholine
(most potent)

Properties
-ester of acetic acid & choline, a
quaternary amino alcohol
-both muscarinic and nicotinic
(M1M5)
- prototype cholinergic agonist

Indication
Miotic agent in cataract
surgery (10 min)
*CARBACHOL long
duration (1 hr)

Bethanecol*

-strongly muscarinic
(M1-M3)

Acute non-obstructive
urinary retention
Increase intestinal motility
after surgery

MUSCARINIC
CHOLINOMIMETICS

mediate contraction of:

-pupillary constrictor muscle (miosis)
-ciliary muscle (accommodation of focus for near vision)
*puts tension on the trabecular meshwork, opening its pores & facilitating outflow of the aqueous humor into the canal of
Schlemm
-ester of carbamic acid
-open-angle glaucoma that is
Ophthalmic (topical,
More hydrolysis-resistant
-muscarinic & nicotinic activity
resistant to pilocarpine
intraocular)
(M1-M5)
Duration: 1 hr
-muscarinic & weak nicotinic
Dx of asthma (Methacholine
Inhalation
More hydrolysis-resistant
activity
challenge)
*give rapid-acting
bronchodilator after test
-Pilocarpus sp.
DOC for glaucoma
Ophthalmic drops-Unaffected by
-tertiary amine that crosses
-rapid miosis & contraction:
closed/narrow-angle
cholinesterases
membranes
Ciliary muscle
relatively easily
-stretches the trabecular
Gel/ time-release system-S/E: CNS disturbances (lipid-muscarinic activity
network, increasing its
open/wide-angle
soluble)
(M1-M3)
porosity & permeability to
-rapidly absorbed by the cornea
the outflow of fluid
of the eye
Iris sphincter
-can cross BBB
-pulls the peripheral iris away
from the trabecular
meshwork, thereby opening
the path for aqueous
outflow
-mushroom Amanita
No therapeutic use
S/E: nausea, vomiting,
muscaria
headache
-muscarinic activity
- causes diarrhea, sweating,
(M1-M3)
salivation, &
-some mushrooms of the genera
lacrimation
Inocybe,
*PARASYMPATHETIC
Clitocybe, &Omphalatus contain
OVERSTIMULATION- mushroom
significant amounts of muscarine
poisoning (DUMBBELSS)

Carbachol

Methacholine/
Provocholine*
Pilocarpine

Muscarine

Administration

PO, SC
Duration: 1 hr

Advantages/Disadvantages
Limited therapeutic use
1. Rapid hydrolysis
2. Lack of selectivity

More hydrolysis-resistant

INDIRECT-ACTING CHOLINERGIC AGONISTS/ CHOLINESTERASE INHIBITORS

1.
Reversible- Edrophonium, Carbamates
2.
Irreversible- Organophosphates
ORGANOPHOSPHATES
- highly lipid-soluble liquids
- bind to AChE forming covalent phosphorous- enzyme bond phosphorylated enzyme
- spontaneous hydrolysis of a phosphorylated enzyme is generally very slow
- phosphorylated enzyme complex ma undergo a process called aging
Aging
- involves the breaking of one of the oxygen-phosphorous bonds of the inhibitor & further strengthens the
phosphorous-enzyme bond
Isofluorophate
diisopropylfluorophosphate
Chronic treatment of openDuration: 1 week
(DFP)
angle glaucoma
Echothiophate
-phospholine iodide
Open-angle glaucoma
Duration: 100 hours
- highly polar
Malathion, Parathion
-thiophosphate prodrugs
- insecticides
active metabolites: malaoxon,
paraoxon
Tabun, Sarin, Soman
-nerve gases
-chemical warfare
ANTIDOTES
Cholinergic crisis

MATA | PHAR 140

Pralidoxime chloride (2-PAM)

*Pyridine-2-Aldoxime Methylchloride

- strong nucleophile
- quaternary amine
- able to break the
phosphorous-enzyme bond

Atropine

Anticholinergic agent
IV
Muscarinic blocker
-contain a tertiary or quaternary amine group that can bind noncovalently to the anionic site of the enzyme
carbamylated enzyme
-carbamylated enzyme undergoes hydrolysis much more slowly (30 minutes to 6 hours)

CARBAMATES

Physostigmine/Eserine

Neostigmine/Prostigmin

-alkaloid obtained from the

Calabar or ordeal
bean (Physostigma
venenosum)
-a tertiary amine of greater
lipid solubility

-quaternary ammonium
carbamate
- more polar & therefore does
not enter the CNS
-direct agonist activity at NM

Pyridostigmine/Mestinon

-quaternary ammonium
carbamate
- has direct agonist activity at
NM
Carbamate Insecticides: Carbaryl, Propoxur (Baygon), Aldicarb

Cholinesterase regenerator
drug
* quaternary ammonium
group binds to the anionic
site of the enzyme & thereby
promotes dephosphorylation

IV
Should be given before
aging

-Intestinal & bladder atony

-Miotic agent for open-angle
glaucoma
- Tx of overdoses of drugs with
anticholinergic actions (Atropine,
TCA,
Phenothiazine)
Myasthenia gravis
-muscle weakness & rapid fatigue of
muscles during use
-affects skeletal muscle
neuromuscular junctions
- autoimmune process causes
production of
antibodies that bind to the
subunits of the
nicotinic receptor
-accelerated degradation of the
receptor
-blockage of acetylcholine binding to
receptors on
muscle end plates
- Myasthenia gravis
- Paralytic ileus or atony of the
urinary bladder
- Antidote for tubocurarine
poisoning & other competitive
neuromuscular blocking agents
-chronic management of myasthenia
gravis

-opthalmic, IV, IM
Duration: 0.5-2
hours

- does not cross the

blood-brain barrier
not useful for
reactivating
cholinesterases in
the CNS

-can enter & stimulate

the CNS
-can inhibit AChE in the
CNS
-stimulates not only
muscarinic & nicotinic
sites
of the ANS but also
the nicotinic receptors
of
the neuromuscular
junction

- PO, SC
- duration: 0.5-2
hours

- PO, IV, IM
- duration: 3-6
hours

QUATERNARY AMINE
Edrophonium/Tensilon

CHOLINERGIC ANTAGONISTS
-cholinergic blockers

MATA | PHAR 140

-reversibly bind
electrostatically & by hydrogen
bonds to the active site, thus
preventing
access of acetylcholine

-diagnosis of myasthenia gravis (Tensilon

Test)
1.

Obtain baseline measurements of

muscle strength
2. Initial Dose: 2mg IV
3. If no reaction occurs after 45
seconds, an additional 8mg may be
injected.
4. Observation: improvement in muscle
strength that lasts about 5 minutes
-DDx of MG and hypercholinergic crisis
(w/c produces depolarization blockade
of the NMJ)
- cholinergic crisis: further weakening of
muscles

Short duration of
action (5-15
minutes)

- anticholinergic drugs
- block the actions of ACh at muscarinic or nicotinic cholinoceptors
I. Muscarinic Blockers
II. Neuromuscular Blockers/Skeletal Muscle

III.

Ganglionic Blockers

Relaxants

CHOLINERGIC RESPONSE
Diarrhea
ALICE IN
Urination
WONDERLAND
Miosis
Hot as a hare:
Bradycardia
hyperthermia, fever
Bronchoconstriction
Red as a beet:
Emesis
tachycardia,
Lacrimation
vasodilation/flushing
Salivation
Blind as a bat: blurring
Sweating
of vision, cycloplegia,
mydriasis
Mad as a hatter:
delirium, hallucinations
Dry as a bone:
decreased gland
secretions

-block nicotinic receptors in muscles paralysis

Classification:
A. Nondepolarizing blockers
- competitive blockers
- combine with the nicotinic receptor & prevent
the binding of ACh
- prevent depolarization of the muscle cell
- membrane & inhibit muscular contraction
*Overcome by increasing the concentration of
ACh in the synaptic gap
ORDER OF PARALYSIS:
1 Face, eye, fingers
2 Limbs, neck, trunk
3 Intercostal & diaphragm muscles
B. Depolarizing blocker
MOA:
Phase I
- opening of the sodium channel associated
with the nicotinic receptors
- depolarization of the receptor
- fasciculations
Phase II
- gradual repolarization as the sodium
channel
closes or is blocked
- resistance to depolarization
- flaccid paralysis
ORDER OF PARALYSIS
1. Fasciculations in chest & abdomen
2. Neck, arms, legs
3. Facial, pharynx, larynx
4. Respiratory muscles

- Ng antagonists
- block nicotinic receptors in both sympathetic &
parasympathetic ganglia
*ACh: neurotransmitter in all sympathetic &
parasympathetic ganglia
- reduce the effects of whichever system is
predominant
- seldom used clinically
Sympathetic blocking effects
Arterioles
Dilate, high flow,
hypotension
Veins
Dilate, pool blood, low
return, low cardiac
output
Parasympathetic blocking effects
Heart
Tachycardia
Iris
Mydriasis
Ciliary muscle
Cycloplegia
GI tract
Low tone, low
motility, constipation
Bladder
Urine retention
Salivary glands
Xerostomia
Sympathetic (cholinergic)
Sweat glands
anhidrosis

MUSCARINIC BLOCKERS
Drug
Atropine/Hyoscyamine

Scopolamine/Hyoscine

MATA | PHAR 140

Properties
-prototype
alkaloid from deadly
nightshade (Atropa
belladonna) & Jimson weed
(Datur stramonium)
- central & peripheral
muscarinic blocker
( M1-M5)

-alkaloid from henbane

(Hyoscyamus niger)
- M1, M2, M3 blocker
- produces peripheral effects
similar to those of
atropine
- has greater action on the

Indication
-irritable bowel syndrome
-mild diarrhea
-GIT & bladder spasms
-enuresis
-bradycardia
-bronchospasm
-reduces glandular & bronchiolar
secretions before anesthesia
-treats intoxication by cholinergic
agonists or
by acute mushroom poisoning
-produces mydriasis & cycloplegia
(ophthalmoscopic examination)

-prevents motion sickness

(transdermal)
- blocks short-term memory
- produces amnesia & sedation
(obstetrics with
morphine)

Contraindication
CI:
-glaucoma
-prostatic
hypertrophy
-heart disease
-obstructive bowel
disease

Adverse Effects/Other Notes

Eye
- mydriasis
- cycloplegia
- outflow resistance
GIT
- reduces activity of the GIT
- motility
- secretion of pepsin & acid
Urinary system
- constriction of sphincter
- relaxation of detrusor
Glands
- salivary, sweat, & lacrimal gland
secretions
Cardiovascular
- bradycardia (low dose)
block presynaptic muscarinic
receptors that
normally provide feedback
inhibition of the release of ACh
- tachycardia (higher dose)
Adverse effect: reverse
DUMBBELSS
Adverse effects:
-more CNS depression at low doses
tha atropine
- similar to atropine at high doses

CNS
- longer duration of action
than atropine
Homatropine
Cyclopentolate
Tropicamide
Ipratropium bromide

Pirenzepine

Benztropine,
Trihexyphenidyl,
Oxybutynin
Dicyclomine

Ophthalmoscopic examination
(produce mydriasis & cycloplegia)
-M1, M2, M3, M4 blocker
- more peripheral effects,
less CNS effects

-M1 blocker
-selective for muscarinic
receptor in the stomach
- poorly absorbed, thus high
concentration in gut
-- secretion of acid &
pepsin
M1, M2, M3 blockers

Asthma & chronic obstructive

pulmonary disease (COPD)
Tiotropium (Spiriva)
- treatment for COPD
Peptic ulcers

Adverse effects:
few, relatively specific for
gastric secretions

Parkinsons disease, extrapyramidal

disorders

M1, M2*, M3 blocker

*hypermotility of the bowel
Propantheline
-M1, M2, M3 blocker
adjunct for peptic ulcers
- reduces GI smooth-muscle
spasms [M2 (contraction),
M3]
Other Drugs That Have Anticholinergic Effects:
1. Antihistamines 2. Antipsychotics 3. Tricyclic antidepressants (TCAs) 4. Opioids

*Adjunct- supporting
*Adjuvant-additional

Neuromuscular Blockers/Skeletal Muscle Relaxants: NON-DEPOLARIZING BLOCKERS

Drug
Vecuronium

Properties

Indication
Adjunct to anesthesia:
-muscle relaxant
-eases intubation & ventilation
-eases orthopedic manipulation
-controls respiration during chest
surgery

Administration
-IV
Short duration of action (25-40
min.)
-suitable for short surgical
procedures

Atracurium

useful in mechanical
ventilation of critically
ill
patients

patients with kidney & liver failure

*also Cisatracurium (administer
slowly due to HA release)

short duration of action (20-45

min.)
-suitable for short surgical
procedures

Pancuronium

vagolytic actions
(increases HR)

Used when elevated heart rate is

desired

Tubocurarine

-from Curare
(Strychnos sp.) used as
arrow poison in South
America
-hydrolyzed by plasma
cholinesterase

Prevents the fasciculations

associated with succinylcholine
administration

IV

Short surgical procedures

short duration of action (15-20

min.)
more rapid recovery from blockade

Rocuronium

For tracheal intubation in patients

with gastric contents

rapid onset of action (1-3 min.)

minimal cardiovascular effect

Pipecuronium,
Doxacurium

adjunct to anesthesia in long surgery

cases

long duration in patients with renal

dysfunction

minimal cardiovascular effect

prolonged neuromuscular
blockade

Mivacurium

heart rate
no histamine release

DRUG INTERACTIONS
I. Cholinesterase Inhibitors
- Neostigmine, Physostigmine, Edrophonium
- can overcome the action of nondepolarizing blockers

III. Aminoglycoside Antibiotics

- inhibit ACh release from cholinergic nerves by
competing with calcium ions

II. Halogenated Hydrocarbon Anesthetics

- enhance neuromuscular blockade by exerting
a stabilizing action at the neuromuscular junction

IV. Calcium Channel Blockers

- may increase the neuromuscular block of nondepolarizing & depolarizing blockers

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Adverse Effects/Other Notes

Adverse effects:
- usually cardiac stable, but
induces:
*severe tachycardia
*bradycardia
*AV block or CHF complications
-Very little histamine release
Adverse effect:
Moderate histamine release

hypotension (histamine)
bronchospasm (ganglionic
blockade)

Neuromuscular Blockers/Skeletal Muscle Relaxants: DEPOLARIZING BLOCKERS

Succinylcholine

rapid hydrolysis by
acetylcholinesterase &
plasma
pseudocholinesterase

Reversing Neuromuscular Blockade

Pre-reversal:
- Atropine or Glycopyrrolate
- administered prior to reversing agents to
prevent bradycardia, salivation & other
muscarinic effects

Used when rapid

endotracheal intubation is
required during the
induction of anesthesia

-IV, IM
rapid onset (30-60
sec.)
short duration (3-5
min.)

intraocular & gastric pressures

- dysrhythmias
- post-operative muscle pain
- apnea
- malignant hyperthermia
*muscle rigidity & hyperpyrexia
- treatment:
-rapidly cooling the patient
-Dantrolene - blocks release of calcium from the
sarcoplasmic reticulum of muscle cells

Reversal:
- cholinesterase inhibitors
- increased ACh concentration competes with
neuromuscular blockers

GANGLIONIC BLOCKERS
Drug
Nicotine

Properties
active ingredient in tobacco

Indication
smoking cessation therapy

Administration
transdermal patch,
chewing gum

Adverse Effects/Other Notes

Low dose: causes ganglionic stimulation by
depolarization
blood pressure & heart rate
motor activity of the bowel
High dose: causes ganglionic blockade
blood pressure
activity both in the GIT & bladder musculature
ceases
Adverse Effects:
- irritability
- tremors
- intestinal cramps
- diarrhea
- heart rate & blood pressure

Hexamethonium

Trimethaphan

Mecamylamine

MATA | PHAR 140

-produces most of its

blockade by occupying
sites in or on the nicotinic
ion channel, not by
occupying the cholinoceptor
itself
short-acting, competitive
nicotinic ganglionic
blocker
competitive nicotinic
ganglionic blocker

introduced clinically as the first

drug effective for
management of hypertension

treatment of hypertensive
emergencies caused by
pulmonary edema or dissecting
aortic aneurysm
treatment of moderately
severe to severe hypertension

short-acting