Drug Acting on Peripheral

Nervous System

P-2

ANS Regulates Involuntary Functions

Blood pressure
Heart rate
Respiration
Body Temperature
Glandular Secretion
Digestion
Reproduction

Acetylcholine

Norepinephrine

Epinephrine

Site of release

All preganglionic
neurons of ANS; all
postganglionic neurons
of parasympathetic
system; Some
sympathetic
postganglionic neurons
to sweat glands

Most sympathetic
postganglionic
neurons; adrenal
medulla (20% of
secretion)

Adrenal medulla
(80 % of
secretion)

Receptor

Nicotinic (Nn or Nm),

Muscarinic (M1, M2,
M3, M4, M5) cholinergic

1, 2, 1 (adrenergic)

1, 2, 1, 2
(adrenergic)

Enzymatic degradation
by cholinesterase

Reuptake into nerve

terminals; diffusion of
synaptic cleft,
metabolic
transformation by
monoamine oxidase
(within nerve terminal)
or cahechol-O-methyltransferase within liver)

Metabolic
transformation by
catechol-Omethyltransferase within
liver

Termination of
activity

1. Mesentery

2. Outer longitudinal
muscle layer
3. Myenteric plexus
4. Peritoneum
and Serosa
6. Inner circular
muscle layer
5. Submucosa
7. Submucosal plexus
8. Mucosa
Subserosal plexus

P-3
Diarrhea / Vomiting / Intestinal colic
Constipation / Gastroparesis / Paralytic ileus
GERD (Could be due to a lax lower
esophageal sphincter)
Cholinergic and anti-cholinergic drugs
Opioid receptors inhibit acetylcholine
release
Antiemetic drugs

Central Autonomic
input
P-4

Periaqueductal
gray matter
Parabrachial
nucleus
Cortex
Dorsal motor vagal
nucleus

Amygdala
Hypothalamus
Nucleus Ambiguus
Ventrolateral medulla

Heart

Nucleus of the
solitary tract

Central Autonomic
Output

Periaqueductal
gray matter
Parabrachial
nucleus
Cortex
Dorsal motor vagal
nucleus

Amygdala

Hypothalamus
Nucleus Ambiguus
Parasympathetic
input

Nucleus of the
solitary tract
Ventrolateral
medulla
Sympathetic input

Heart
Intermediolateral cell column

P-6

Sympathetic System

Parasympathetic System

Originates in thoracic and lumbar regions of

the spinal cord (T1 L2)

Originates in brainstem (cranial nerves III, VII,

IX, and X) and sacral region of spinal cord
(S2 S4)

Ganglia located in paravertebral sympathetic

ganglion chain

Terminal ganglia located near or embedded

within target tissue

Short pre-ganglionic fibers

Long postganglionic fibers

Long pre-ganglionic fibers

Short postganglionic fibers

Ratio of pre-ganglionic fiber to postganglionic fibers is 1 : 20

Ratio of pre-ganglionic fibers to

postganglionic fibers is 1 : 3

Activity often involves mass discharge of

entire system

Activity normally to discrete organs

Primary neurotransmitter of postganglionic

neurons is norepinephrine

Primary neurotransmitter of postganglionic

neurons is acetylcholine

Predominates during emergency fight-orflight reactions and exercise

Predominates during quiet resting conditions

Divergence coordinates activity of neurons at

multiple levels of spinal cord

Limited divergence

Potential targets for drugs

Five key features of neurotransmitter function
provide potential targets for pharmacologic
therapy:
synthesis,
storage,
release,
termination of action of the transmitter,
functions of the receptor.

Cholinergic nerve terminal

Neuromuscular
Blocking Drugs

Action
Potential
Arrives

Acetyl CoA + Choline

Cholineacetyl Transferase

ACh

Ca++
ACh
ACh

Potentiate
Transmission
Pyridostigmine
Neostigmine
Distigmine
edrophonium

Synaptic
Cleft

ACh

ACh
ACh
ACh

Vesamicol
ACh

ACh

Hemicholinium
Botulinum toxin
Aminoglycosides
2+ ions
Acetate Mg
ion2+,+CaCholine

Agents that reduce

ACh release

ACh

ACh

ACh

ACh

Competitive
Tubocurarine
Gallamine
Pancuronium
Vecuronium
Atracurium
Rocuronium
Depolarizing
Suxamethonium

Na+

Acetylcholinesterase
inhhbitors

G
P
C
R
Post-Synaptic
membrane

III

All preganglionic
nerves secrete Ach.
Ganglionic blocking
drugs block
transmission.
(e.g.Mecamylamine)

Ciliary

III

VII
VII

Pterygopalatine
VII

Submandibular
IX

IX

Otic
T1

T1
T2
T3

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

X Vagus

T2
T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

Nervi erigentes

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Radial muscles contract (1)

Sympathetic

Sympathetic

Parasympathetic

Circular muscles contract (M3)

Mydriatics and cycloplegics

Anticholinergics / antimuscarinics: Atropine, Scopolamine, Methylscopolamine,
cyclopentolate, Tropicamide
Sympathomimetics: Phenylephrine, Ephedrine, Ibopamine
P-16

Parasympathetic

P-23

Sympathetic

Lacrimal gland

Xerostomia:
Pilocarpine

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Superior (jugular)
ganglion of Vagus
nerve

Inferior (nodose)
ganglion of Vagus
nerve

Vagus nerve

Lacrimal gland

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Asthma / COPD:
Ipratropium
Beta blockers. NO
Pilocarpine. NO

Bronchoconstriction

Parasympathetic

Left vagus
Sympathetic trunk,
middle cervical
ganglion

Sympathetic
trunk, thoracic
ganglia

Thoracic aortic
plexus
Vagus nerve on
aortic arch

Cardiac
plexus

Lacrimal gland

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Autonomic drugs are very important in cardio-vascular system e.g.

hypertension, angina, stable cardiac failure, shock, postural hypotension

Sympathetic but cholinergic

Anhydrosis:
Neoplasms
Spinal cord
injuries
Lumbar
sympathectomy

Lacrimal gland

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Lacrimal gland

Pheochromacytoma:
Alpha blockers
Beta blockers ?

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Lacrimal gland

Glycogenolysis /
gluconeogenesis:
2 effects.
Beta blockers may
mask the effects of
anti-diabetic therapy

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Lacrimal gland

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

P
A
R
A
S
Y
M
P
A
T
H
E
T
I
C

S
Y
M
P
A
T
H
E
T
I
C

Lacrimal gland

Overflow
incontinence
Urge incontinence
Antimuscarinics

III

VII

IX

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

Parasympathetic

Premature
Labor:
2 receptors
cause
relaxation of
both pregnant
and non
pregnant uteri.
Beta agonists
e.g. ritodrine

Sympathetic

Pre-ganglionic
Blue
Post-ganglionic
Pink

Lacrimal gland

III

VII

IX

T1

T1

T2

T2

T3

T3

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2

S3

S3

S4

S4

Parasympathetic

Pre-ganglionic
Red
Post-ganglionic
Green

e.g. stimulating with insulin in type 2 diabetes

P-24

+++++++++++++++++++++++++

Cell
Receptor down-regulation

e.g. blocking with beta-blockers

- - - - - - - - - - - - - - - - - - - - - - - - -

Cell
Receptor up-regulation

P-24

Muscle Relaxant
A muscle relaxant is a drug which affects
skeletal muscle function and decreases the
muscle tone.
Neuromuscular blockers and spasmolytics are
often grouped together as muscle relaxants

Muscle Relaxants

They used for?

Facilitate intubation of the trachea
Facilitate mechanical ventilation
Optimized surgical working conditions
In intensive care and emergency medicine to cause
paralysis.
It may be used to alleviate symptoms such as muscle
spasms, pain & hyperreflexia .

Muscle Relaxants
How skeletal muscle relaxation can be
achieved?
High doses of volatile anesthetics
Regional anesthesia
Administration of neuromuscular blocking agents

Muscle Relaxants
Muscle relaxants must not be given without
adequate dosage of analgesic and hypnotic
drugs
Inappropriately given : a patient is paralyzed
but not anesthetized

Muscle Relaxants (Neuromuscular blocking

drugs)
Muscle Relaxants (Neuromuscular blocking
drugs) are structural analogs of aceytylcholine ,
and act either as anatagonist ( non depolarizing
type) or agonist (depolarizing) at the receptors
on the end plate on the neuromuscular
junction.

Muscle Relaxants

(Neuromuscular blocking drugs)

How do they work?

Neuromuscular junction
Nerve terminal
Motor endplate of a muscle
Synaptic cleft

Nerve stimulation
Release of Acetylcholine (Ach)
Postsynaptic events

Muscle Relaxants (Neuromuscular blocking

drugs)
Neuromuscular blocking drugs block
cholinergic transmission between motor
nerve endings & the nicotinic receptors on
the neuromuscular end plate of skeletal
muscle.

Neuromuscular Junction (NMJ)

Binding of Ach to receptors on muscle end-plate

Central Muscle Relaxants

Used to control spastic muscle tone
- Diazepam: Binds at gamma-aminobutyric acid (GABA) receptors.
- Baclofen: Acts GABA receptors in the CNS
Directly acting muscle relaxants

- Dantrolene : Acts directly on muscle by interfering with the

release of calcium from the sarcoplasmic reticulum:

Muscle Relaxants
Depolarizing muscle relaxant
Succinylcholine

Nondepolarizing muscle relaxants

Short acting
Intermediate acting
Long acting

Depolarizing Muscle Relaxant

Succinylcholine
What is the mechanism of action?
Physically resemble Acetylcholine
Act as acetylcholine receptor agonist
Not metabolized locally at NMJ
Metabolized by pseudocholinesterase in plasma
Depolarizing action persists > Acetylcholine
Continuous end-plate depolarization causes muscle
relaxation

Depolarizing Muscle Relaxant

Succinylcholine

What is the clinical use of succinylcholine?

Most often used to facilitate intubation
Electroconvulsive therapy
What is intubating dose of succinylcholine?
1-1.5 mg/kg (Intravenous)
Onset 30-60 seconds, duration 5-10 minutes

Depolarizing Muscle Relaxant

Succinylcholine
Does it has side effects?

Cardiovascular
Fasciculation
Muscle pain
Increase intraocular pressure
Increase intragastric pressure
Increase intracranial pressure
Hyperkalemia
Malignant hyperthermia

Non depolarizing Muscle

Relaxants
(Competitive blockers)

What is the mechanism of action?

Compete with Acetylcholine at the binding sites
Do not depolarized the motor endplate
Act as competitive antagonist
Excessive concentration causing channel blockade
Act at presynaptic sites, prevent movement of
Acetylcholine to release sites

Nondepolarizing Muscle Relaxants

Long acting
Pancuronium

Intermediate acting
Atracurium

Short acting
Mivacurium

Nondepolarizing Muscle Relaxants

Pancuronium
Aminosteroid compound
Onset 3-5 minutes, duration 60-90 minutes
Intubating dose 0.08-0.12 mg/kg
Elimination mainly by kidney (85%), liver (15%)
Side effects : hypertension, tachycrdia, dysrhythmia,

Alteration of responses

Temperature
Acid-base balance
Electrolyte abnormality
Age
Concurrent diseases
Drug interactions

Alteration of responses
Concurrent diseases
Neurologic diseases
Muscular diseases
Myasthenia gravis
Myasthenic syndrome (Eaton-Lambert synrome)

Liver diseases
Kidney diseases

Alteration of responses
Drug interactions
Inhalation agents
Intravenous anesthetics
Local anesthetics
Neuromuscular locking drugs
Antibiotics
Anticonvulsants
Magnesium

Antagonism of Neuromuscular
Blockade
Effectiveness of anticholinesterases depends on the
degree of recovery present when they are
administered

Anticholinesterases
Neostigmine
Onset 3-5 minutes, elimination half life 77 minutes
Dose 0.04-0.07 mg/kg

Antagonism of Neuromuscular
Blockade
What is the mechanism of action?
Inhibiting activity of acetylcholineesterase
More Ach available at NMJ, compete for sites on
nicotinic cholinergic receptors
Action at muscarinic cholinergic receptor
Bradycardia
Hypersecretion
Increased intestinal tone

Antagonism of Neuromuscular
Blockade
Muscarinic side effects are minimized by
anticholinergic agents
Atropine
Dose 0.01-0.02 mg/kg

Scopolamine
glycopyrrolate

Reversal of Neuromuscular
Blockade
Goal : re-establishment of spontaneous
respiration and the ability to protect
airway from aspiration

Local Anesthetics
All local anesthetics in current use are derivatives
or analogues of cocaine, a drug extracted from
coca leave

South American Indians for thousands of years

who chewed the leaves to relieve fatigue in the
harsh climate.
Its numbing effect was utilized in Europe to
relieve pain in surgical procedures

Mode of action
Na+ channels exist in three states resting, open
and inactivated.
The inactivated state occurs after the open state
when the membrane is repolarising and this
discourages premature activation until the next
action potential arrives.
Local anaesthetics bind most strongly to Na+
channels in the inactivated state thus contributing to
the blocking effect.

Local anaesthetics block conduction primarily in

the small diameter afferent Ad and C nerve fibres
rather than the larger motor neurons.
This means that motor control is less affected than
pain perception
Some loss of motor function occurs depending on
procedure and dose

Properties that govern clinical

effect
Potency
Lipophilicity
Ionization (all are weak bases)
Rate of metabolism

Acute toxicity
Main concern is CNS and cardiac toxicity
CNS
Tinnitus, dizziness, lightheadedness are early signs
Anxiety disorientation loss of consciousness
seizures respiratory arrest

Cardiac
Hypotension
All local anesthetics are negative inotropes
PVC wide QRS Multiform vtach vfib, or
Pattern with bupivacaine
Bradycardia asystole
Pattern with bupivacaine + lidocaine

Acute Toxicity
With most drugs, CNS toxicity proceeds cardiac
toxicity, providing a warning of impending disaster.
Key response: maintain oxygenation and normal CO2!

With bupivacaine, CNS toxicity rapidly progresses to

cardiovascular collapse.
Pregnancy enhances the risk of cardiac toxicity.

Acute toxicity
Risk of seizure and/or cardiovascular collapse
is increased by:
Cold temperature (slows metabolism)
Metabolic or respiratory acidosis
Hypoxia

Treatment of overdose
Airway:
100% oxygen
Intubate if necessary to ventilate

CNS:
Break seizure with propofol, thiopental, or midazolam

Cardiovascular
Amiodarone has demonstrated efficacy. Use 300 mg
Lidocaine would be a particularly poor choice!
Resuscitation difficult with bupivacaine, more frequently
successful in animal studies following ropivacaine and
levobupivacaine overdose.

Allergies
Amides
True allergies to amide
anesthetics are
EXCEEDINGLY rare

Esters
Uncommon
Allergic reactions
probably
related
PABA.
Common ingredient
sun-screen.

are
to
in

May also be related to

topical
benzocaine
exposure.

Allergies
Allergies to local anesthetics are commonly reported
by patients.
True allergies to local anesthetics of either class are
rare.
Most allergic responses that have been carefully
evaluated are:
Psychogenic
Reactions to preservatives (e.g., metabisulfite) or latex
cardiovascular response to epinephrine.

The exception is long-term exposure to benzocaine in

topical preparations, which has resulted in numerous
reports of contact dermatitis.

Methemoglobinemia
10%: clinical anoxia
60%: stupor, coma, and death.
Documented with benzocaine, prilocaine

Associated with benzocaine and prilocaine

Treat with methylene blue, 1-2 mg/kg given
over 5 minutes
Faster
administration
methemoglobinemia

may

exacerbate

Drug Interactions
Esters
are
pseudocholinesterase

metabolized

by

Compete with succinylcholine for metabolism, so when

given together each lasts longer
Metabolism
slowed
by
administration
of
anticholinesterase (e.g., neostigmine)