PHARMACOLOGY of the

AUTONOMIC & somatic

nervous systems
Principles of Pharmacology of the ANS and/or SNS

SMS 371
Educational Goal

The student will understand the integrated

bodily response to drugs that interact with
segments of the autonomic and/or somatic
nervous systems.

SMS 371
2
 Objective 1: List Anatomical & Cellular
Components of the ANS & SNS
ANS
Ganglia
Subdivision
Sympathetic Parasympathetic

Thoracolumbar Craniosacral
Pre:Post short: long Long: short
Branched, neurohormone Discrete innervation
Diffuse response Discrete response

Somatic single nerve, no ganglia

Target Organs

SMS 371 3
 Objective 2: Key Biochemical
& Cellular events of
neurotransmission.
Nerve
Electrical stimulation
Transmitter release
Autoregulation
Target Organ
Termination of Signal
ACh destruction of transmitter - AChE
Noradrenaline reuptake of transmitter
Reuptake 1 transporter

SMS 371 4
Objective 3: Points of Pharmacological
Intervention

Adrenergic
Cholinergic
Synthesis Storage

Release
Receptor Binding
Termination

of the neurotransmitters

SMS 371 5
 Objective 4: Discuss Subtypes of Adrenergic and
Cholinergic Receptors

Adrenergic Cholinergic
Subtype: M N
Agonists :
Antagonists:
Location:
Importance:

SMS 371 6
Objective 5: Identify Prototype Drugs acting
to mimic, stimulate or block
Cholinergic
Adrenergic

Synthesis

Release
Receptor Binding
Termination

of the neurotransmitters at nerve terminals

SMS 371 7
 Integrated Response of
the ANS to either abrupt
or gradual s in
homeostasis
Example: Baroreceptor Reflex
BP

BP

SMS 371 8
 Objective 7: Recommend a
Strategy to Rx
pathological situations
involving the ANS
and/or
What general SNSusing agents that
strategy alter
either peripheral cholinergic or adrenergic nerves
or target organs could be used to:
Treat hypertension
Treat asthma
Treat myasthenia gravis

SMS 371 9
 Objective 8: Determine Probable Adverse
Responses

What adverse effects would you predict with:

Ganglionic blockade
Nicotinic agonist
Muscarinic antagonist
Adrenergic agonist
AChE inhibitor
Uptake I inhibitor

SMS 371 10
Nervous
System
Pharmacology

11
SMS 371
 Review the
Anatomy & functions of the peripheral nervous
system (somatic & autonomic)
Vocabulary used to describe the peripheral
nervous system
Basic actions of the two divisions of the autonomic
nervous system (sympathetic and
parasympathetic)
Principles of neurotransmission
Major neurotransmitters and their receptors

SMS 371
12
 The Nervous System

Nervous system

Peripheral
Central Nervous
Nervous
System
System

Efferent Afferent Brain Spinal Cord

Autonomic Somatic

Cholinergic Adrenergic

SMS 371 13
The Nervous System: A Review

Overall functions integration and homeostasis

Divisions CNS & PNS

CNS
consists of brain, brain stem, spinal cord
motor and sensory neurons
efferent fibers (exit CNS) & afferent fibers (enter CNS)

PNS
originates from hypothalamus, brain stem& spinal cord
nerve endings located outside the CNS
PNS: further divided into the Somatic NS & the Autonomic
NS

SMS 371
14
 In the ANS, one neuron leaves the CNS and connects
with a collection of nerve cells called a ganglion
First neuron which innervates the ganglion is the
preganglionic nerve
The neuron leaving the ganglion and innervating
the effector site is the postganglionic nerve
ending
In the somatic motor nervous system, the axon
leaves the CNS but does not connect with a ganglion
before innervating the effector cell

SMS 371
15
 Somatic Motor innervates one kind of
neuroeffector cell - skeletal muscle cell
ANS innervates three different neuroeffector
sites or cells
Smooth muscle
Cardiac muscle
Exocrine glands
Somatic motor nervous system differs from the
ANS in that the somatic is mainly under
voluntary control whereas ANS is mainly under
reflex control

SMS 371
16
 THE AUTONOMIC NERVOUS SYSTEM

TWO NEURON CHAINS

SYMPATHETIC
PARASYMPATHETIC

SMS 371
17
 18
SMS 371
 Sympathetic Autonomic NS
Has cell bodies of preganglionic neurons in the
thoracic and lumbar regions of the spinal cord
These nerve fibers leave the spinal cord and enter
the sympathetic ganglia

Acetylcholine: neurotransmitter between the pre- and

post-ganglionic neurons
Noradrenaline: neurotransmitter released by
postganglionic sympathetic fibers at the effector
organ

SMS 371 19
Sympathetic Autonomic NS

Sympathetic, unlike parasympathetic, is anatomically arranged

to produce diffuse activity
Sympathetic has its own neurohormones noradrenaline and
adrenaline which are released from adrenal medulla into the
circulation in response to sympathetic activation (ie "Fight or
flight response")
These neurohormones enable the sympathoadrenal system to
discharge as a unit

SMS 371 20
Parasympathetic Autonomic NS

GANGLION NEAR EFFECTOR ORGAN

LONG PREGANGLIONIC NEURONS
SHORT POSTGANGLIONIC NEURONS
POSTGANGLIONIC NEURONS ARE CHOLINERGIC
CRANIAL AND SACRAL NERVES

SMS 371 21
 Anatomical arrangement of
parasympathetic provides discrete
responses - doesn't discharge as a
unit
No neurohormone of its own

SMS 371 22
Parasympathetic Nervous System

Neurotransmitters:

Acetylcholine (ACh) is the neurotransmitter

released from all pre- and postganglionic
parasympathetic fibers (sites where ACh serves
as the neurotransmitter are called cholinergic)

Drugs can affect the biosynthesis, storage,

release and inactivation (hydrlysis) of ACh:

SMS 371 23
 DUAL INNERVATION OF MOST VISCERAL
ORGANS

MOST ORGANS ARE INNERVATED BY BOTH

SYSTEMS
EFFECTS ARE OPPOSITE IN MOST CASES
DOMINANT TONE

SMS 371 24
DUAL INNERVATION

SMS 371 25
 Functional and Anatomical Divisions of ANS

1.Sympathetic autonomic nervous

system
Tends to activate organ

2. Parasympathetic autonomic nervous

system
Tends to inactivate organ

SMS 371 26
Physiological functions controlled by the ANS

Both divisions help maintain homeostasis

General functions
Adjustment to stress
Preparation for combat
Adjustment to temp changes
Protection of eyes against bright light
Urination
Defecation
Digestion
Salivation
Accommodation for near vision
Maintenance of blood pressure at optimal level
Respiration

SMS 371 27
Comparison of FUNCTION
PARASYMPATHETIC NS SYMPATHETIC NS
H.R. , B.P. H.R. , B.P.
secretions secretions
eyes adjust for light (miosis - eyes adjust for dark (mydriasis -
constrict) dilate)
emptying of bowel digestion slowed
emptying of bladder
airways constrict airways opened

rest and digest response fight or flight response

SMS 371 28
 CHOLINERGIC PHARMACOLOGY

SMS 371 29
 Goals and objectives:
To know the biosynthesis, storage, release and hydrolysis of
acetylcholine

To know the types and locations of different acetylcholine

receptors

To know the effects of cholinergic agonists on tissues

To understand the relation between drug structure and function

3 vs. 4 drugs
To know major therapeutic indications and contraindications

SMS 371 30
Biosynthesis of Acetylcholine (Ach)

ACh is synthesized within cholinergic

neurons by the transference of an
acetyl group from Acetyl CoA to the
organic base choline.
The enzyme choline-O-
acetyltransferase (ChAT) catalyses the
reaction.

the enzyme choline-O-

aceltyltransferase (ChAT) exists in
multiple locations
cytosol,
surface of synaptic vesicles, and
inner face of plasma membrane).
(ChAT has been cloned)
31
SMS 371
Storage

The vesicles are mainly accumulated at

the nerve endings and inside these
vesicles the greater part of neuronal
Ach is stored.
The vesicles are about 300-600 A in
diameter and they combine with the
membranes of nerve endings to
discharge their content of Ach into the
synaptic cleft.

32
SMS 371
Release

Ca2+ is essential to ACh release but

exactly how it mediates release
remains to be determined
Drugs which chelate extracellular
Ca2+ and prevent its influx (ie
Aminoglycoside antibiotics) will
depress ACh release
ACh is probably released from synaptic
vesicles which are "docked" at the
plasma membrane and in position to
release it by exocytosis

33
SMS 371
Neurotransmission

Once released from

the nerve terminal,
ACh diffuses across
the synaptic junction
and acts on one post
junctional receptor
Activation of the
postjunctional
receptor leads to a
physiological response

34
SMS 371
Hydrolysis
Ach is degraded by the
enzyme
acetylcholinesterase (AChE)
to choline and acetate.
The choline derived from
the hydrolyzed ACh is
returned to the
prejunctional nerve terminal
by a Na+-dependent
transport process to form
ACh. (This carrier has recently
been cloned)

35
SMS 371
Hydrolysis
The acetate derived from
ACh breakdown in the
synaptic junction is also
returned to the nerve
terminal to form a portion
of the acetyl CoA used in
ACh formation.
The rate limiting step in
ACh metabolism is not
known with any certainty
and may differ depending
upon the circumstances
of the neuron (ie whether
neuron is stimulated or
not)

36
SMS 371
Hydrolysis
Some of the cholinergic drugs of clinical value act
as agonists at the receptor site whereas others
act as antagonists
Other drugs can act indirectly by inhibiting the
AChE and thereby building up the ACh in the
synaptic junction. This accumulation enables ACh
to bind to more than one receptor more than
one time
Most of the clinically useful cholinergic drugs act
postjunctionally, however, a couple (botulinium
toxin) act prejunctionally

SMS 371 37
Factors (Agents) affecting Ach synthesis, Release & Neurotransmission

The inhibitions are competitive.

Most of the drugs are NOT used
clinically- they are experimental
tools in studies concerned with the
mechanism of Ach synthesis in
cholinergic neurons.

38
SMS 371
 AGENTS AFFECTING CHOLINERGIC TRANSMISSION

Hemicholinium
- ketoacids,
naphthoquinones
Vesamicol
Latrotoxin
Botulinum toxin
Calcium
Physostigmine
Atropine
d-Tubocurarine

SMS 371 39
Agents affecting cholinergic transmission

Hemicholinium
blocks choline uptake, thereby
blocking synthesis of Ach.
-ketoacids,naphthoquinones
direct inhibition of the enzyme
ChAT
Vesamicol
blocks the specific transport
process of Ach into the vesicles so
there will not be vesicular release
of Ach.
These compounds are
poisonous and not used for
any therapeutic purpose
40
SMS 371
Agents affecting cholinergic transmission

Latrotoxin (a toxin from the

black widow spider)
produces an explosive release
of Ach, causing muscular
spasm.
Botulinum toxin ( a toxin
from Clostridium botulinum)
is able to bind to the neuron
and interferes with the
trafficking proteins as they
come together to promote the
fusing of the vesicles to the
membrane.

41
SMS 371
Agents affecting cholinergic transmission

Calcium
is involved in the vesicular
release. Its uptake is
important in the fusion of
vesicles to membrane of
neuron.

Physostigmine
inhibits acetylcholinesterase
causing Ach concentrations
in the synaptic cleft to
increase and rebind to
muscarinic and nicotinic
receptors.

42
SMS 371
Agents affecting cholinergic transmission

Atropine
blocks muscarinic actions of
Ach.
D-Tubocurarine
blocks the nicotinic actions,
which are primarily at the
endplate of the
neuromuscular junction.
Higher doses of this do tend
to block nicotinic receptors at
the autonomic ganglion.

43
SMS 371
 CHOLINESTERASE

SMS 371 44
CHOLINESTERASES
ChES are not used as drugs but they are important.
They interact with ACh.

The ChE are a group of enzymes which share a

common property of hydrolyzing ester bonds but they
differ in their substrate specificity.

The ChE found largely in the post synaptic membranes

at the cholinergic synapses is called
acetylcholinesterase (True or specific ChE)

The function it performs there is to rapidly hydrolyse

(terminate) the activity of Ach released from
cholinergic nerve endings. A rich source of ChE is the
RBC.

SMS 371 45
Cholinesterases

Another group of ChE that is collectively called non-specific or

pseudocholinesterase is found
in the plasma.
the intestine and
to a lesser extent in the liver.
Their function is not clear but where the intestine is concerned they are thought
to regulate the action of Ach in controlling muscular motility.

Amechol is hydrolysed by AchE but not pseudo-ChE where as a drug known as

succinylcholine (suxamethonium) is hydrolysed by pseudo-ChE but not by AchE.

SMS 371 46
 Autonomic Receptors

Two major types -

Cholinoceptors - receptors that respond to

ACh

Adrenoceptors - receptors that respond to

Noradrenaline and related compounds such
as Adrenaline and Dopamine

SMS 371 47
Types of cholinergic receptors-Cholinoceptors
Cholinergic receptors at organ cells are either nicotinic
(affects skeletal muscles) or muscarinic (stimulates smooth
muscle and slows the heart rate)

Two basic types -

Nicotinic (N)
Muscarinic(M)
Ach has both muscarinic and nicotinic activity

SMS 371 48
NICOTINIC RECEPTORS
Two subtypes
NN subtype is present on cell body of postganglionic
autonomic neuron
NM subtype is present at the endplate of the
neuromuscular junction

Differences?
Hexamethonium competitively blocks the action of ACh at the
ganglia but not at the NMJ
D-tubocurarine is more selective in blocking the action of ACh at
the NMJ.
Nicotinic receptors on adrenal medulla appear to be similar
to those at the autonomic ganglia

SMS 371 49
Basic functions of nicotinic receptors
Ligand gated ion channels and their activation causes a rapid increase
in cell permeability to Na+ and Ca2+
Nicotinic receptor activation produces short lived excitatory
responses
An excess of ACh or Nicotine (nicotinic agonist) at nicotinic receptor
can cause receptor desensitization
Receptor will no longer respond to agonist and physiological response does
not occur

SMS 371 50
MUSCARINIC RECEPTORS

Activated by ACETYLCHOLINE endogenously and MUSCARINE

exogenously
BLOCKED BY ATROPINE (non specific blocker)

Location
Smooth muscles
Glands
heart

SMS 371 51
MUSCARINIC RECEPTORS
subtypes
P/cologic types- M1,M2, M3,M4
Cloned receptors m1-m5

Pharmacologic receptors have been further

sub classified into
M1 (neural), -autonomic ganglia, CNS
M2 (cardiac), and
M3 (glandular)- peripheral gland tissue
eg pancreas and smooth muscle

SMS 371 52
 Basic functions of muscarinic receptors mediated by G-proteins

G-protein induced changes in membrane-bound

effector
Activation of certain muscarinic receptors activates a
G-protein for stimulation of phospholipase C (M1, M3
and M5)
Activation of other muscarinic receptors leads to an
inhibition of adenyl cyclase and activation of K+
channels (M2 and M4)
Muscarinic responses are typically slow, long lasting
and may be either inhibitory or excitatory

SMS 371 53
 The drugs atropine, hexamethonium, and d-
tubocurarine are all competitive antagonists to the
action of ACh at receptor sites
If ACh reaches a sufficiently high enough concentration in their
presence, it can override their blockade

One way of increasing amount of ACh in the synaptic

junction is to administer a drug which inhibits the
degradative enzyme AChE

SMS 371 54
CHOLINERGIC DRUGS

SMS 371 55
 Many cholinergic drugs are nonselective
Drugs that mimic the effect of Ach also known as
cholinergic agonists - initiate a cholinergic response
Cholinomimetics
Parasympathomimetics

SMS 371 56
Cholinergic Drugs

Action:
mimic the effects of stimulation of the
parasympathetic system
act on receptors that are activated by ACh in
smooth muscle, cardiac muscle, and some
glands - Direct acting

or inhibit the enzyme that breaks down

acetylcholine Indirect acting
little use in Emergency medicine
57
SMS 371
DIRECT-ACTING CHOLINERGIC DRUGS

Drugs in this group include

ACh,
Synthetic esters of choline
bethanechol,
carbachol,
methacholine and
Naturally occurring alkaloids such as
pilocarpine.

SMS 371 58
Structure and mechanisms of cholinergic agonists

SMS 371 59
 Little is known about the physicochemical
nature of the muscarinic receptor.
It is thought that it is a water soluble protein
present in the outer lipoprotein layer of the
postsynaptic membrane and that its
combination with Ach involves:
spatial fit and
electrostatic attraction

SMS 371 60
Cholinesters

There are three main structural features of the choline ester

muscarinic agonists.

positively charged quaternary nitrogen N+.

the center of the cationic head and it is thought to fit into a
depression in the receptor surface called the anionic site.
Alterations in the molecule to reduce the charge on the
quartenary N or increase the size of the cationic head will
reduce the muscarinic receptor stimulating potency of the
molecule.
SMS 371 61
Structure and mechanisms of cholinergic agonists

SMS 371 62
Structure and mechanisms of cholinergic agonists
acetate ester (acetylcholine) or carbamate carbamylcholine
or bethanechol.
The ester group bears an overall negative charge. It fits
into a depression which bears a positive charge and is
called the esteratic site.
The ester group in acetylcholine is an excellent substrate
for cholinesterase enzymes so Ach is broken down very
quickly in vivo.
The carbamate is hydrolyzed very slowly so
carbamylcholine and bethanechol have much longer
durations of action.

SMS 371 63
Structure and mechanisms of cholinergic agonists
The alkyl chain provides a bridge of correct length
between the cationic head and the acetyl group of
the Ach molecule and hence allows simultaneous
attachment to the cationic head and ester (acetyl)
group to the muscarinic receptor site.
Shortening or lengthening it reduces the
potency of ACh molecule.
Apart from providing the correct length
between the ends of the Ach molecule the alkyl
chain also provides sites for formation of Van
der Waals forces between the molecule and the
receptor.

SMS 371 64
STRUCTURE-ACTIVITY-RELATIONSHIP

SMS 371 65
METHACHOLINE (Acetyl methylcholine)
Synthetic parasympathomimetic
Methyl substituent on carbon atom
Little effect on the muscarinic receptor
stimulating potency of the molecule
But abolishes (virtually) all the nicotinic
effects
More stable to hydrolysis by
cholinesterase
Virtually immune to hydrolysis by AchE
More prolonged effect than Ach and is
practically specific for muscarinic
receptors

66
SMS 371
CARBACHOL(Carbamylcholine)

Synthetic
Substitution of amide group on acyl carbon
atom
Renders carbachol immune to hydrolysis by
both AchE and pseudocholinesterase
Reduces its nicotinic potency
Does not affect its muscarinic stimulant
potency
More potent than acetylcholine
Longer duration of action
Administered orally
Most active nicotinic drug among the
commonly used parasympathomimetics
though its nicotinic activity is less than for
Ach.

67
SMS 371
BETHANECHOL (Carbamyl--methylcholine)

Has both amide group of carbachol and -

methyl group of amechol
Reduces the nicotinic potency of the drug
Immune to hydrolysis by AChE
Long acting muscarinic stimulant drug
almost devoid of nicotinic activity

68
SMS 371
ALKALOIDS--MUSCARINE
Muscarine mimics the actions of
acetylcholine at smooth muscles, cardiac
muscles, and glands
Muscarine is found in various mushrooms
Amanita muscaria: content of muscarine is
very low
Inocybe sp: content of muscarine is high
Clitocybe sp: content of muscarine is high

69
SMS 371
PILOCARPINE
Naturally occurring in the leaflets of a shrub Maranham jaborandi
Difficult to account for the muscarinic activity in terms of structure because
it bears no relationship to Ach
No quaternary N (a major active center for Ach) but tertiary amine
Has muscarinic receptor stimulating potency and much little nicotinic
activity
Particularly potent on glandular tissues e.g. sweat and salivary glands

SMS 371 70
PHYSIOLOGICAL RESPONSES

SMS 371 71
PHYSIOLOGICAL RESPONSES

Heart - The most prominent effect is bradycardia due to activation of the

SA node (pacemaker). This is mediated by a hyper polarization of SA node
cells by an M2-receptor-mediated increase in potassium currents. Also,
contractility in the atrium and conduction velocity in the AV node is
reduced.

GI tract - The GI tract is a major target of parasympathetic responses and

muscarinic cholinergic agonists. Effects include increased acid secretion in
the stomach and increased tone and, amplitude of contraction and
increased peristalsis in stomach and intestine.

SMS 371 72
PHYSIOLOGICAL RESPONSES

GU tract - A coordinated evacuation of the bladder

occurs due to contraction of the detrusor muscle and
relaxation of the sphincter.

Glands - Many glands in the body respond to

muscarinic stimulation. Lachrymal glands in the eye,
bronchial secretory glands, salivary glands (parotid,
etc.), pancreas, and sweat glands are all activated by
muscarinic agonists.

SMS 371 73
PHYSIOLOGICAL RESPONSES

Eye - Constriction of the pupil (miosis) and thickening of

the ocular lens (accommodation) occur in response to
muscarinic stimulation.

Bronchial smooth muscle - Contraction of bronchial

smooth muscle occurs and this can be very pronounced in
asthmatic patients.
The "methacholine challenge" test for asthma exploits this
phenomenon but must be done under carefully controlled
circumstances.

SMS 371 74
PHYSIOLOGICAL RESPONSES

Blood vessels
Vascular tissue represents a
pharmacological "oddity"" in that it is not
innervated by the parasympathetic
nervous system but it does contain
muscarinic receptors which are activated
by exogenous agonists.

The typical response is relaxation due to

release of NO (endothelial-derived
relaxing factor, EDRF) from endothelial
cells. When endothelium is damaged or
removed contraction is observed.

Ach acts at M3 site, causing activation of

nitric oxidase synthase. NO diffused to
smooth muscle activating guanyl cyclase
and changing GTP to cGMP to cause
vasodilation.
75
SMS 371
PHYSIOLOGICAL RESPONSES

CNS - Muscarinic receptors are very abundant

in the CNS and muscarinic agonists lead to
cortical arousal.
There is evidence for reversal of memory
deficits by muscarinic agonists or
anticholinesterase drugs.

SMS 371 76
PHARMACOKINETICS

SMS 371 77
Pharmacokinetics
Absorption - The quaternary choline esters are very poorly
absorbed and must be given parenterally. Due to the dramatic
cardiovascular effects of rapid bolus administration of choline
esters, they should never be given intravenously, with
subcutaneous administration being the preferred route.
Pilocarpine is much better absorbed and is given either orally
for systemic use or topically for ophthalmologic uses.

Distribution - As expected, pilocarpine will reach the CNS while

the quaternary choline esters have no CNS penetration.

Clearance - Acetylcholine is cleared within minutes due to the

activity of serum cholinesterase and its action is also reduced
dramatically by the acetylcholinesterase present at the synaptic
site of activity. Carbamylcholine and bethanechol are resistant
to the action of cholinesterases so their clearance is somewhat
slower though they are eliminated rapidly by the kidney t 1/2 < 1
hour. Pilocarpine has similar kinetics.

SMS 371 78
CLINICAL USES OF MUSCARINIC AGONISTS

SMS 371 79
CLINICAL USES OF MUSCARINIC AGONISTS

Muscarinic agonists have relatively limited clinical

utility at present with ophthalmic uses being the most
significant.
However, knowledge of the actions of muscarinic
agonists is important for the understanding of the
actions of antagonists and in the understanding of
pathophysiological processes mediated by over
activity of parasympathetic responses.
Glaucoma
Gastric atony/Paralytic ileus
Bladder dysfunction -nonobstructive
Xerostomia

SMS 371 80
CONTRA-INDICATIONS
ASTHMA hyperactive airways
CORONARY INSUFFICIENCY drugs can cause fall in peripheral
resistance, compounding the problem
PEPTIC ULCER HCl secretion would be increased
ORGANIC OBSTRUCTION IN BLADDER OR G.I. TRACT cant
force contraction of smooth muscle if something is present
HYPERTHYROIDISM may cause arrthymia

SMS 371 81
SIDE EFFECTS
The side effects are mainly predictable based on the
physiological function of acetylcholine and the
parasympathetic nervous system.
Cardiovascular effects of hypotension and
bradycardia are common with systemic
administration.
Bronchoconstriction and wheezing
Flushing, sweating, abdominal cramps, blurred
vision, and salivation

SMS 371 82
Drug interactions
Cholinesterase inhibitors greatly increase the duration and
effect of acetylcholine & the muscarinic agonists

SMS 371 83
Synthetic acetylcholine analogs
DISADVANTAGES OF ACh AS A CHOLINOMIMETIC DRUG
- Pharmacodynamic: also acts at nicotinic
receptors USES:
- Pharmacokinetic: rapidly metabolized by
cholinesterases (acetylcholinesterase, Bethanechol - GI stimulation or
butyrylcholinesterase, others) treatment of urinary retention

Acetylcholine or Carbachol - ocular

(surgery, glaucoma)

Methacholine - provocative test for

hyperreactive airways

Rarely used because of

Potential for disaster
1. Cardiovascular
2. Respiratory

CONTRAINDICATIONS
Asthma
Peptic Ulcer
Coronary Insufficiency

* NEVER GIVE I.V. OR I.M.!

acute respiratory distress
cardiac arrest/CV collapse
SMS 371 84
Symptoms of
Fast Mushroom Poisoning:

Bradycardia
Nausea, cramps, vomiting,
diarrhoea
Bronchoconstriction
Salivation
Sweating
Hypotension*

* uninnervated muscarinic receptors in

all blood vessels mediate vasodilation via NO

85
SMS 371
CHOLINERGIC PHARMACOLOGY
Muscarinic Nicotinic
Agonists Agonists
Acetylcholine Acetylcholine
Carbamylcholine Nicotine
Bethanechol - Carbamylcholine
Muscarine
Antagonists
Pilocarpine
Trimethaphan ganglionic blocker
Antagonists
Succinylcholine - depolarizing
Atropine
Hyoscine
Tubocurarine - non-depolarizing
Pirenzepine Pancuronium
Ipratropium bromide Atracurium
Cholinesterase Mivacurium
Inhibitors Muscle relaxants
Physostigmine , Neostigmine Baclofen, Diazepam,Dantrolene
Edrophonium Drugs interacting with cholinergic agents
Sarin
Reactivator
Amitriptyline
Pralidoxime Diphenhydramine
Isoflurane

SMS 371 86
SMS 371 87
 Anticholinergic drugs

Antimuscarinic Antinicotinic

M - selective Nonselective Ganglion Neuromuscular

blockers blockers

These drugs are pharmacological

antagonists

Acetylcholinesterase inhibitors?
SMS 371 88
CONCEPTS

The cholinoceptor antagonists are grouped

into subclasses on the basis of their
spectrum of action :
whether the receptors they block are
muscarinic or
nicotinic.

SMS 371 89
SMS 371
Goals and objectives
To understand the relation between drug
structure and function - 3 vs. 4
To know the key clinical uses of antimuscarinic
drugs
Side effects
a) To know side effects of specific
antimuscarinic drugs
b) To recognize other drugs with
anticholinergic side effects

SMS 371 91
Classification

A. Muscarinic antagonists can be subdivided according to their

selectivity for Muscarinic (M) receptors

Pirenzepine / Telenzepine
Gallamine

SMS 371 92
Classification

B. They can be divided into 2 groups according to their origin:

Naturally occuring compounds:

Atropine and its congeners
tertiary ammonium alkaloid esters of tropic acid.

SMS 371 93
 Semisynthetic and synthetic antimuscarinic agents:

Tertiary amines:
homatropine (mandelic acid ester of tropine),
cyclopentolate hydrochloride
tropicamide
benztropine
trihexyphenidyl

Quarternary ammonium agents

have been developed to produce more peripheral effects with
reduced central nervous system effects.

They also have ganglion-blocking properties - anticholinergic.

SMS 371 94
Definition: Antimuscarinic drugs

Drugs that selectively antagonise (block) the effects

produced by either ACh or any other drug that stimulates
ACh receptors of the muscarinic type.

SMS 371 95
ACETYLCHOLINE IS AN AGONIST AT BOTH MUSCARINIC AND NICOTINIC RECEPTORS

M N

SMS 371 96
THE NICOTINIC ACTIONS OF ACETYLCHOLINE REMAIN WHEN MUSCARINIC RECEPTORS ARE
BLOCKED

Muscarinic receptor
blockade does not
interfere with transmission
at autonomic ganglionic
sites, the adrenal medulla,
or skeletal muscle fibers.
M
X N
Sympathetic adrenergic
functions are not affected

In dual innervated organs,

muscarinic receptor
blockade allows
sympathetic dominance

97
SMS 371
Structure and pharmacological specificity

5 subtypes muscarinic acetylcholine receptors

M1 and M3 couple to PLC activation via a Gq family G
protein
M2 and M4 inhibit AC and cardiac K+ channels via Gj
family G protein
blockade caused by antimuscarinics is selective for
muscarinic receptors: nicotinic receptors are not
blocked, nor are adrenergic receptors
blockade is competitive

SMS 371 98
Structure and pharmacological specificity

most currently used muscarinic blockers are Non-selective

M1 selective compound Pirenzepine is used clinically for reducing acid
secretion in PUD disease
other differences among muscarinic blockers mostly derive from
pharmacokinetic differences
quaternary ammonium compounds (poor absorption)e.g. Ipratropium bromide and
propantheline
tertiary compounds (well absorbed and easily penetrate the bbb) e.g. hyoscine

SMS 371 99
Pharmacological actions

SMS 371 100

Pharmacological actions

largely predicted from the physiology of the

PNS and the effects of muscarinic agonists
Inhibit acetylcholine by occupying the
muscarinic receptor sites
By blocking the parasympathetic nerves, the
sympathetic nervous system is allowed to
dominate
anticholinergic and adrenergic drugs
produce many of the same responses

SMS 371 101

SALIVARY GLANDS RESPIRATORY TRACT
salivation secretions
bronchodilatation
CVS
primary expected effect is GI TRACT
reversal of vagal tone and motility (smooth muscle
acceleration of heart rate relaxation)
At low doses (0.5mg) acid secretion
paradoxical slowing of heart rate other mediators prevent full
due to inhibition of M1 receptors inhibition of these processes
in sympathetic ganglion or CNS
effects
A-V impulse conduction GU TRACT
contractile force micturition speed and urinary
retention at higher doses

SMS 371 102

EYE CNS
dilatation of pupil excitation leading to
(mydriasis)
restlessness and
paralysis of accomodation hallucinations (moderate
(cycloplegia) doses)
lachrymal secretions
generalized depression and
coma (high doses)
SWEAT GLANDS
inhibition of sweating can
lead to increased core
temp.

SMS 371 103

Prototype:Atropine

SMS 371 104

A lesson from the Mona Lisa...

Atropine is found in the Atropa Belladonna

plant (deadly nightshade) and in Datura
stramonium (thorn apple).
Bella donna = Italian for beautiful lady

Scopolamine occurs in Hyosciamus niger

(henbane).

105
SMS 371
Pharmacokinetics of Atropine and other tertiary amines

Atropine is relatively lipid soluble and readily crosses membrane

barriers.
The drug is well distributed into the CNS and other organs and is
eliminated partially by metabolism in the liver and partially by renal
excretion.
The elimination half-life is approximately 2 hours, and the duration of
action of normal doses is 4-8 hours
In the eye, effects last for 72 hours or longer (7dys).
shorter acting agents for diagnostic dilatation e.g. Tropicamide
MYDRIACYL

Other tertiary amines are able to enter the eye after conjunctival
administration.
Similar ability to cross lipid bariers is important for the agents used in
Parkinsonism.

SMS 371 106

Pharmacokinetics of quarternary
amines
In contrast, charged molecules are more polar and therefore
less likely to penetrate a lipid barrier like the blood-brain barrier or the
cornea of the eye.
Only 10-30 % of a dose is absorbed after oral administration.
If an intense effect is needed they should be administered parenterally.

These drugs are used for their antisecretory or antispastic actions in the
gut (anticholinergic action) and the bronchi.
Ipratropium bromide (ATROVENT ) used by inhalation for bronchial
dilatation
propantheline bromide (PROBANTHINE ) are given orally where
limited systemic absorption is desirable

SMS 371 107

Clinical indications

SMS 371 108

HEART EYE
Atropine & hyoscine - mainly used for
premedication to general ophthalmologic diagnostic
anaesthesia (prevent dilatation (homatropine
preferred?)
excessive vagal slowing of
heart rate)
reduce the risk of cardiac GIT
arrest hyper-motility syndromes
(not common diarrhoea)-
treat vagal syncope spasms of the pylorus and
bile
peptic ulcer disease

SMS 371 109

CNS (BRAIN)
Treatment of Parkinsons disease
objective- (Ach and dopamine)

dystonias from antipsychotics

use of synthetics- little side effects

treatment of maniac states

(withdrawal of drugs of
dependence or alcoholism)
hyoscine preferred?

Motion sickness

SMS 371 110

EXOCRINE GLANDS
adjunct to anaesthesia ( salivation)- hyoscine
preferred?

ANTICHOLINESTERASE & MUSHROOM

POISONING

SMS 371 111

SMS 371 112
TIOTROPIUM - new longer acting analog
(not yet available in U.S.)

SMS 371 113

Oxybutinin (DITROPAN) - similar profile and use but not as selective for bladder

SMS 371 114

Side effects and Adverse Rxns to
Anticholinergics

SMS 371 115

Side effects and Adverse Reactions to Anticholinergics

Think opposite of SLUDGE / DUMBELS

Dry mouth
Dry skin
Decreased perspiration
Blurred vision
Tachycardia
Constipation
Urinary retention
Photophobia (day blindness from dilated pupil)
Seizures
Delirium
Abdominal distention

SMS 371 116

 TOXICITY:
Antimuscarinic (Atropine) Poisoning

SMS 371 117

1. PERIPHERAL (AUTONOMIC) SIGNS &
SYMPTOMS
Dry as a bone
absence of secretions, no defecation or urination
Red as a beet (the atropine flush)
reflects vasodilatation
Blind as a bat
cycloplegia, inability of eye to focus near as if you
only have eyes for seeing far away

SMS 371 118

2. CENTRAL (CNS;brain) RESPONSES

Mad as hatter
hallucinations, disorientation etc

Hot as a furnace
fever can be severe

SMS 371 119

Rx : Atropine Poisoning

SMS 371 120

Treatment of Atropine Poisoning

a) Physostigmine (Neostigmine?)
b) Symptomatic/supportive care
c) No Antipyretic (fever reducing) drug should be used

SMS 371 121

Contra-indications

SMS 371 122

contra-indication

Glaucoma
Prostate hypertrophy

SMS 371 123

Drugs with atropine-like actions, SE, & CI

SMS 371 124

Drugs with atropine-like actions, SE, & CI

Many older antihistamines

Diphenhydramine (Benadryl)
Antipsychotics
Chlorpromazine (Largactil )
Older antidepressants
Imipramine (Tofranil )
Some anti-Parkinson drugs
Benztropine (Cogentin )
Some benzodiazepines
Diazepam (Valium )

SMS 371 125

INDIRECT ACTING CHOLINOMIMETICS

SMS 371 126

SMS 371
Goals and objectives

To understand the relation between drug structure

and function
a) 3 vs. 4 drugs
b) Organophosphate vs. carbamate vs. alcohol
drugs
To know the mechanism of inhibition by different drug
classes
To know therapeutic uses of the different types of
cholinesterase inhibitors

SMS 371 128

These are drugs, which prevent the hydrolysis of
ACh by cholinesterase
Anti-cholinesterases by delaying the destruction of
ACh produce widespread effects in the body.
These drugs modify transmission in:
Autonomic ganglia
Post-ganglionic parasympathetic nerve
endings (neuroeffector junction)
Neuromuscular junction
Cholinergic synapses in the CNS

SMS 371 129

MECHANISM

Covalently modify an active serine in the

enzyme catalytic site with
carbamate group or
an organophosphorus

which is more slowly, hydrolysed leading to

enzyme inhibition.

SMS 371 130

CLASSIFICATION

SMS 371 131

1.REVERSIBLE Anticholinesterase

Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Ambenonium
Distigmine

SMS 371 132

2. IRREVERSIBLE - Organophosphates

Echothiophate (PHOSPHOLINE)

Di-isopropylfluorophosphate (DFP)

SMS 371 133

Pharmacological actions

SMS 371 134

 Actions of anticholinesterases are like the combined
action of nicotinic and muscarinic stimulation

Muscarinic -. There is massive activation of

parasympathetic target organs, which has been described
as the SLUDGE syndrome: Salivation, Lacrymation,
Urination, Diarrhoea, etc.

Nicotinic - The nicotinic effects of cholinesterase

inhibitors are complex and may show an initial activation
of nicotinic receptors - with muscle tremors or
fasciculations - followed by paralysis due to
desensitization of the nicotinic receptors.
The primary mode of death in poisoning by cholinesterase
inhibitors is due to respiratory paralysis.
SMS 371 135
Objective for Use of
Anti-cholinesterases

SMS 371 136

 One of the clinical
uses is based on their
actions in increasing
the effect produced
by parasympathetic
stimulation.

The other main use of

the anti-ChE is based
on their effects in
inhibiting AChE at the
neuromuscular
junction.
At the NMJ the anti-ChE are
used to antagonize the
effect of neuromuscular
blocking drugs such as d-
tubocurarine (d-TC)
137
SMS 371
Therapeutic uses of Reversible
cholinesterase inhibitors

Paralytic ileus or bladder atony

(Neostigmine preferred?)
Glaucoma
Alzheimer's disease
Myasthenia gravis
Atropine poisoning (physostigmine
preferred?)

SMS 371 138

Myasthenia Gravis
Progressive autoimmune disorder that blocks the ACh
receptors at the neuromuscular junction
The more receptors are damaged the weaker the muscle
(as the disease progresses).
More common in women 20 to 40 with possible line to
thymus gland tumors
Begins with double vision & swallowing difficulties &
progresses to paralysis of respiratory muscles
Treatment includes steroids that reduce antibodies that
bind to ACh receptors and acetylcholinesterase
inhibitors

SMS 371 139

Irreversible anti-cholinesterases

SMS 371 140

 The irreversible anti-ChEs
R2
are mainly compounds of O

organic sources and they P

contain pentavalent R1 X

phosphorus.

R1/R2-alkyl chains
X=halogen (Cl,F,Br,I)

141
SMS 371
Mechanism
The reaction between the irreversible anti-ChE and
the enzyme ChE is similar to the reaction between
the reversible anti-ChE and the enzyme.
The only difference is that many of the
organophosphorus compounds do not have a
quaternary N atom and for this reason cannot react
with the cationic site of the enzyme. They react only
with the esteratic site of the enzyme.

SMS 371 142

 Initially the irreversible anti-chE reacts with the enzyme to form a
complex, which is capable of dissociation at the initial stage.
The X in the molecule is split off from the inhibitor-
organophosphorus complex
what is left is extremely stable so that the removal of the
phosphoryl group from the complex may take several weeks or
months
for practical purposes the reaction is regarded as irreversible.

SMS 371 143

Organophosphate Inhibitors of AchE

Their action promoting accumulation of ACh

at the NM nicotinic receptor is the basis
for their toxicity,
but actions at muscarinic receptors
contribute to their toxic actions as well

SMS 371 144

 Organophosphate Inhibitors of AchE

Their action promoting accumulation of ACh at

the nicotinc and muscarinic receptor of the ciliary
muscle is the basis of their therapeutic
effectiveness in open angle glaucoma
Only two of these agents are used
Echothiophate therapeutic glaucoma
Diisopropylflurophosphate (DFP)
Except for echothiophate, these agents are
extremely lipid soluble, and some are very volatile.

SMS 371 145

Uses of Irreversible anti-chE
The very long duration of action of these compounds
together with their high potency makes them extremely
toxic substances.
Their toxicity is further increased by the fact that they are
lipid soluble and therefore they can be absorbed by
inhalation and even by contact with the skin.
Their lipid solubility makes them easily penetrate the CNS.
In general they are too toxic for use as therapeutic agents
but occasionally their long duration of action is desirable
for the treatment of conditions such as glaucoma.

SMS 371 146

 TOXICITY OF ORGANOPHOSPHATE
CHOLINESTERASE INHIBITORS IN MAN

SMS 371 147

TOXICITY

While cholinesterase inhibitors have some

clinical uses they are of major toxicological
importance
Both insecticides and chemical warfare agents
(humanicides) often contain the highly
irreversible organophosphorus type of
cholinesterase inhibitor.

SMS 371 148

 A. Nicotinic receptors - DEPOLARIZING BLOCKADE
TARGET: Neuromuscular junction
muscle weakness ,respiratory failure , DEATH

B. Muscarinic receptors - HYPERACTIVITY

TARGET 1: peripheral parasympathetic nervous system
bradycardia , arrhythmias/arrest , DEATH
excessive airway secretion/constriction , asphyxiation , DEATH

TARGET 2: central nervous system

decreased respiratory drive , respiratory failure , DEATH
generalized seizures , convulsions , DEATH
SMS 371 149
SMS 371 150
USES OF ORGANOPHOSPHATE CHOLINESTERASE INHIBITORS BASED
UPON TOXIC EFFECTS

1. Cholinesterase inhibitors ARE designed to be

deadly = NERVE GAS(Military)
e.g., soman, sarin, tabun, VX

2. Insecticides
e.g., diazinon (SPECTRACIDE), chlorpyrifos
(DURSBAN), parathion, malathion

SMS 371 151

ORGANOPHOSPHATES AS NERVE GAS AGENTS IN CHEMICAL WARFARE

Extremely volatile agents such as sarin, tabun, soman, and agent VX may
be used as nerve agents in chemical warfare.
Accumulation of ACh at cholinergic receptors produces effects reflecting
stimulation of cardiac muscle, smooth muscles and glands. Such effects
would be identical to those caused by muscarine poisoning.
Bradycardia and hypotension occurs. However, in some cases, tachycardia
may be observed, due to intense sympathetic discharge in response severe
hypoxemia.
Irreversible inhibition of acetylcholinesterase by these agents produces
accumulation of ACh at the end plate of skeletal muscle fibers. This in turn
leads to depolarizing blockade of the NM nicotinic receptor. Skeletal muscle
paralysis occurs. Movement is impossible. The diaphragm is also paralyzed.
The individual eventually dies due to respiratory paralysis.
Persian gulf war syndrome

SMS 371 152

Potential Agents
Nerve Agents GA,GB,GD,VX
Blister Agents HD,HN,H,CX,L
Choking Agents CG,CL,PS
Blood Agents AC,CK
Incapacitating Agents BZ

SMS 371 153

Mustard - Skin

SMS 371 154

What is the Threat?

SMS 371 155

Chemical Terrorism

SMS 371 156

 Aum Shinrikyo Cult
March 20, 1995
11 bags Sarin
5500 patients, 550
Treated, 12 dead

SMS 371 157

Autoinjectors

SMS 371 158

 Questions?

SMS 371 159

Rx: ANTI-CHE POISONING

SMS 371 160

Treatment of Anti-ChE poisoning

Reversible anti-ChE,

Autonomic effects can be controlled by using

atropine.

SMS 371 161

organophosphorus anti-ChE

can be treated with substances that are able to

regenerate the inhibited cholinesterase by removing
the phosphoryl group.
These compounds are strongly basic and have
positively charged quaternary N atom.
The best known of these compounds is Pralidoxime
(Pyridine-2-aldoxime methiode (P-2-Am) and it is
generally called REACTIVATOR
Other oximes :Obidoxime, HI6

SMS 371 162

 Pralidoxime was designed to optimally reactivate
acetylcholinesterase by incorporating the positive charge in
the ring along with the highly nucleophillic oxime to displace
the covalently bound organophosphorus inhibitor.

Early treatment is essential as aging of the enzyme-

inhibitor complex renders pralidoxime ineffective.
Inhibition by agents that undergo rapid aging is not
reversed.

Atropine can be used to take care of the autonomic effects

of organophosphorus poisoning.

SMS 371 163

 Benzodiazepines -prevents
protracted seizure activity

Phenobarbitone
Inhaled -agonists

SMS 371 164

SMS 371 165
Goals and objectives:
Ganglion stimulants & blockers
1. Describe ganglionic transmission and the respective roles of the
nicotinic, muscarinic and dopaminergic receptors at certain ganglia.
2. State that nicotine stimulates ganglionic transmission at low doses
and inhibits it at high doses.
3. Summarize nicotine toxicity and how to treat it.
4. State which division of the ANS dominates over the other in
controlling a particular body function.

SMS 371 166

Drugs Which Affect Autonomic Ganglia

Ganglionic Transmission
Primary Pathway
Mediated by nicotinic receptors on ganglia-activation leads to a fast excitatory
potential
Classical ganglionic blocker is hexamethonium (C-6) - competitive antagonist
All clinically useful ganglionic blockers act at nicotinic receptor
Secondary Pathways
Slow excitatory potential produced by action of ACh on M1 receptor

SMS 371 167

GANGLION STIMULANTS

SMS 371 168

GANGLION STIMULANTS

These have no therapeutic uses but have useful pharmacological

activities.

SMS 371 169

 NICOTINE

SMS 371 170

 alkaloid obtained from
Nicotina tobaccum CVS
produces a variety of blood pressure
pharmacological effects in the
body and most of these
effects are antagonistic to Respiratory System
each other and therefore the
effects of nicotine are respiration
generally very difficult to
analyze
it is a partial agonist Neuromuscular junction
exhibits tachyphylaxis stimulates the neuromuscular
Central effects junction
Can cause emesis by acting at GIT
chemoreceptor trigger zone G.I. tract motility and HCl
ADH release release

SMS 371 171

TOXIC EFFECTS OF NICOTINE
Rapidly absorbed through skin and can enter placenta
readily
Kills by causing respiratory arrest
In high doses it desensitizes nicotinic receptors at medulla
oblongata to stop breathing
Desensitizes nicotinic receptors at motor endplate region
to cause paralysis of diaphragm and intercostal muscles
Treatment?

SMS 371 172

Nicotine is a tertiary amine that can act as an agonist at nicotinic receptors

1. in autonomic ganglia including the adrenal medulla

2. at the neuromuscular junction

3. on sensory nerve endings

4. in the CNS

Effects of nicotine receptor agonists may reflect stimulation or blockade*

EFFECTS SEEN IN HUMANS WITH SYSTEMIC NICOTINE

CNS: STIMULATION
VOMITING
ADH RELEASE

CARDIOVASCULAR: MOSTLY STIMULATES SNS

i HR, i BP

GI, GLANDS: PSNS STIMULATION, THEN BLOCK

NMJ: MOSTLY BLOCKS

*ACUTE NICOTINE TOXICITY - CONVULSIONS AND COMA, HYPERTENSION AND ARRHYTHMIAS,

NEUROMUSCULAR FAILURE

SMS 371 173

Other stimulants
Tetramethyl ammonium (TMA)
Dimethylphenylpiperazinium (DMPP)

SMS 371 174

GANGLION BLOCKERS

SMS 371 175

Goals and objectives:
Understand the consequences of using a ganglionic
blocker.
Justify why ganglionic blockers are rarely used today.
Be able to list the various ganglionic blockers:
Hexamethonium (C6) prototype but rarely used, and
Mecamylamine.
List the various side effects caused by chronic treatment
with ganglionic blockers such as impotence and
orthostatic hypotension and describe how ganglionic
blockers impair the body's ability to maintain
homeostasis.

SMS 371 176

pharmacology
These are drugs used in the treatment of hypertension.
Their uses have been replaced by other drugs and are now widely used in
experimental pharmacology.
These drugs produce blockade without stimulating the ganglia.
Since ganglion blockers inhibit both sympathetic and parasympathetic
output the major factor that determines the net effect of a ganglion
blocker is the predominant tone in the tissue affected.

SMS 371 177

HEXAMETHONIUM (C6)

SMS 371 178

 CVS effects effects on the heart are
BP by preventing the passage variable and depend on the
of nerve impulses across initial level of the vagal tone.
sympathetic ganglia If the initial rate is high then
these drugs will reduce the
fall in BP is mainly due to heart rate.
reduced peripheral resistance
the more usual effects are
Cardiac output bradycardia.
produce variable effects but reduce BP better in the upright
generally they lower the cardiac position cause orthosthatic
output because they reduce hypotension
venous return
produce postural hypotension

SMS 371 179

ADVERSE EFFECTS

All the ganglion blocking drugs block both the sympathetic and
parasympathetic ganglia equally and therefore the unwanted effects
of these drugs are on peripheral smooth muscle containing tissues.
Most are quaternary compounds and do not easily penetrate the
CNS, a few are not quaternary and exhibit both peripheral and central
effects)

SMS 371 180

 Eye
Incomplete mydriasis secretions of digestive
blockade of sympathetic
and parasympathetic
nerve supply to the iris
Cause partial paralysis of
accommodation and so
patients may suffer from
blurred vision and
difficulty in focusing the
eye
SMS 371
Glandular secretions
juices from the stomach
and intestine by blocking
the parasympathetic
ganglion
saliva and sweat and
therefore patients may
complain of dry mouth
181
GIT Sex organs
tone and motility on all parts of Serious consequence in
the git
results in slowing of gastric
the sexual performance
emptying after meals of the male, often
constipation producing complete
paralytic ileus in very high doses impotence ejaculation
and erection are affected
Urinary bladder
Blockade of the
parasympathetic ganglia
produce difficulty in
emptying of the bladder
and this may lead to serious
urinary retention

SMS 371 182

USES OF GANGLION BLOCKERS

SMS 371 183

 Treatment of hypertension (rarely used)
Produce controlled hypotension during surgery in order
to reduce bleeding
In bloodless field surgery

SMS 371 184

Other Blockers
Mecamylamine (Inversine)
Pentolinium
Pempidine
Trimethaphan

SMS 371 185

SMS 371 186
Important note

SMS 371 187

 Structures innervated by the ANS can function on their own at some
level of activity, without any innervation (or when the receptors
involved in their activation are blocked).

Skeletal muscles cannot.

Over stimulate the muscle (leads to fatigue)
or
block the ability of Ach to stimulate the nicotinic receptors, and
the skeletal muscle is inactive totally.

SMS 371 188

Learning Objectives
Describe neurotransmission at the neuromuscular
junction.

State that there are two distinct types of neuromuscular

blocking agents which are used as surgical adjuncts during
general anaesthesia to produce skeletal muscle relaxation
-competitive antagonists which compete with endogenous ACh and
include d-tubocurarine (prototype), Pancuronium and Vecuronium.
-persistent blockers eg succinylcholine (suxamethonium)

SMS 371 189

Recognize that these agents primarily differ in how they
affect the cardiovascular system and how much histamine
they release.

Assess how various drugs such as aminoglycoside

antibiotics and certain general anaesthetics can interact
with competitive neuromuscular blockers.

List the particular reversible AChE inhibitors used to treat

an overdose of a competitive blocking drug.

SMS 371 190

Specify that the drug Dantrolene acts directly on skeletal
muscle to produce relaxation; also, that it is used to treat
malignant hyperthermia, multiple sclerosis and stroke.

Cite that the cholinergic toxin (botulinum toxin) is now used

to treat blepharospasm and to cosmetically reduce facial
aging and to treat cerebral palsy spasms.

Recognize that the centrally acting drug cyclobenzaprine is

used to treat muscle spasms and may have a lower abuse
potential than other drugs used to treat muscle spasms.

SMS 371 191

Why Neuromuscular blockers?

SMS 371 192

Neuromuscular blocking drugs are used
to induce complete skeletal muscle
relaxation in surgery

SMS 371 193

Physiology of Neurotransmission

SMS 371 194

Physiology of Neurotransmission

An action potential sweeps down motor nerve

terminal and its propagation is dependent on
Na+ influx
Arrival of action potential at nerve terminal
enhances Ca2+ influx through channel which in
some unknown way triggers ACh release from
synaptic vesicles
ACh diffuses across synaptic junction and acts
on a nicotinic receptor to open channels to
positively charged ions for a particular period
of time
SMS 371 195
 An increased influx of Na+ and K+ leads to
muscle action potential
Excitation in muscle tissue spreads via a
transverse tubular system.
Actin Myosin filaments slide together with the
help of Ca2+ released from the sarcoplasmic
reticulum to cause muscle contraction

SMS 371 196

General properties of neuromuscular
blockers

SMS 371 197

 paralyze skeletal muscle by interfering with the
normal skeletal muscle activation or
reactivation (i.e. depolarization by Ach and /or
subsequent depolarization) via the nicotinic
receptors found on skeletal muscle at the
neuromuscular junction.
are used specifically (and commonly) to
paralyze skeletal muscle e.g. for surgery, some
diagnostic procedures.
virtually all skeletal muscles in the body are
paralyzed when therapeutic doses are given

SMS 371 198

 do not affect sensory function/sensory nerves
(e.g. sensation of pain), nicotinic receptors in
autonomic ganglia, or muscarinic receptors on
any structures
have no major direct autonomic effects (they
act only on structures innervated by the
somatic nervous system)
do not affect the CNS or alter level of
consciousness (assuming patients ventilation,
cardiovascular functions are supported at
normal levels)
SMS 371 199
 1 cause of death from over dosage or improper
use is ventilatory impairment/apnoea
(asphyxiation),

1 treatment for (and prevention of) this is

mechanical support of ventilation(+
cardiovascular function as needed)

All of these drugs can have an adverse effect on

respiration.

SMS 371 200

 Can cause respiratory paralysis by either
antagonizing action of ACh at motor endplate
region of diaphragm and intercostal muscles or
by causing receptor desensitization.

Those that release histamine such as d-

tubocurarine and succinylcholine are
dangerous to use in asthmatics

SMS 371 201

Important note

SMS 371 202

 Structures innervated by the ANS can function on their own at some
level of activity, without any innervation (or when the receptors
involved in their activation are blocked).

Skeletal muscles cannot.

Over stimulate the muscle (leads to fatigue)
or
block the ability of Ach to stimulate the nicotinic receptors, and
the skeletal muscle is inactive totally.

SMS 371 203

 Be clear that these drugs act on nicotinic
receptors at the skeletal-somatic nerve
junction (neuromuscular junction).

They do not act on nicotinic receptors found

at the autonomic ganglia.

They do not act on muscarinic receptors (or

any other kind of receptors for that matter).

SMS 371 204

Classification

SMS 371 205

PERSISTENT DEPOLARIZATION BLOCKERS
(Prototype-Succinylcholine)

Mechanism of action:
These drugs produce contraction of skeletal muscles
(Quickly, intensely activates nicotinic receptors on skeletal
muscles by acting sort of like a super Ach)
but they are not destroyed immediately as Ach is and
therefore the depolarization persists
and it is this persistent depolarization that blocks the
neuromuscular junction
(agonists which initially cause persistent depolarization
followed by receptor desensitization )

SMS 371 206

Effects NOT surmountable:
cannot overcome or reverse effects (paralysis) i.e. administering
AchE-Inhibitor does not reverse drug effects and may actually
prolong/intensify them.
Normal muscle function restored naturally and rapidly as
effects of drug wear off due to metabolism by plasma
ChE.
When used clinically, they initially produce muscle
fasciculation prior to muscle relaxation
These drugs elevate plasma K+ levels

SMS 371 207

SUCCINYLCHOLINE
(Succinyldiacetylcholine
Suxamethonium) Anectine
short acting depolarization neuromuscular
blocker
typical dose of 1mg/kg iv produces complete
neuromuscular blockade. Occasionally it may be
given im/sc
50% blockade recovery occurs within 10min
muscle fasciculation occurs prior to paralysis

SMS 371 208

 patients receiving drug often complain of
muscular pain about 1-3 days after the
operation (because of the intense contractile
effects of the drug)
intra ocular pressure
a second dose of suxamethonium inj. shortly
after the fist dose leads to bradycardia or even
cardiac arrest mainly due to vagal stimulation.
Atropine can prevent/block this cardiac arrest

SMS 371 209

 Pharmacokinetics

rapidly eliminated by metabolism via plasma ChE. (-ChE

within 1hr)
for normal person 2 other routes are important:
alkaline hydrolysis - 5% inj. drug destroyed in 1 hr
renal excretion 2% excreted unchanged

SMS 371 210

 patients with genetic deficiency of ChE have these 2
other routes as the only means of eliminating the
drug and in such patients the duration of action of the
drug is very much prolonged.
If the duration of action lasts for hours, there is no
effective way of eliminating the drug and hence
artificial respiration or passive pressure ventilation is
initiated.
The diaphragm is the last skeletal muscle to be
attacked by the drug

SMS 371 211

 muscle relaxation is first seen in the eyelids of
patients
paralysis in normal patients lasts for about 2-6
min
AntiChE e.g. Tacrine is used to potentiate the
effect of suxamethonium
Mainly used for short-term procedures such as
endotracheal intubation and to protect skeletal
muscle during electroshock therapy

SMS 371 212

 TOXICITY

SMS 371 213

Important adverse reactions & other
considerations

Contra-indicated when there is ocular trauma

or glaucoma risk of damage to the eye
Succinylcholine can elevate intraocular
pressure and should not be used in patients
with narrow-angle glaucoma
High plasma K + - develop dysrrhythmia

SMS 371 214

 malignant hyperthermia rapidly developing
and worsening intense muscle contractures-
tightening contraction of muscles without
intervening relaxation Ca2+ levels greatly
elevated more prone to cause malignant
hyperthermia than other skeletal muscle
relaxants
rapidly developing very high fever (intense
muscle contractions generate lots of metabolic
heat)

SMS 371 215

 death mainly from ventilatory failure
complicated by cardiac arrhythmias from hyperkalaemia
intense muscle contractions damage muscle cells which
then leak large amounts of K+ in circulation
Succinylcholine releases vasodilator histamine and tends
to slow heart rate.
May be unwise to use in patients taking digitalis-like drugs
that compete with K+ to increase ventricular contraction
or diuretics that lower plasma K+ levels

SMS 371 216

 Mainly used for short-term procedures such as
endotracheal intubation and to protect
skeletal muscle during electroshock therapy
Releases histamine so will reduce blood
pressure
No drug antidote for succinylcholine overdose

SMS 371 217

 Management

SMS 371 218

 anticipate potential for reaction monitor closely
body temp. must be reduced with physical means NOT
with antipyretics toxic if high doses are used in attempt
to lower temp.
administer Dantrolene helps to restore normal skeletal
muscle function (blocks Ca2+ release from the SR, reduces
heat production and muscular tone)
Symptomatic/support- focus on ventilation, CV status,
correct electrolyte imbalance.

SMS 371 219

others
Deccamethonium

SMS 371 220

 NON-DEPOLARIZATION (Competitive, Curare inhibitors) BLOCKERS
Prototype- d-tubocurarine

Mechanism of action
Competitively block nicotinic receptors on skeletal muscle that are normally activated by
Ach released from the somatic nerve.
This prevents depolarization (activation) of skeletal muscle cells by Ach and leads to
paralysis (compete with ACh at nicotinic receptor and act strictly as ACh antagonists when
producing skeletal muscle relaxation
These drugs have affinity for the receptor sites at the motor end plate and they bind to
the receptor loosely.
Since these drugs dont have intrinsic activity they dont stimulate the muscle
Release of Ach goes on normally but the released Ach comes to find the receptor site
already occupied.

SMS 371 221

 Effects are surmountable: can overcome effects
(paralysis) and restore normal muscle function (before
effects of the blocker wear off normally) by making more
Ach available to activate the nicotinic receptors.-
clinically accomplished by injecting ChE-inhibitor e.g.
neostigmine or edrophonium
just before receiving AchE-I, patient is pretreated with
atropine to prevent unwanted parasympathomimetic
effects of AchE-I that will arise due to stimulation of
muscarinic receptors simultaneously by Ach.

SMS 371 222

D-TUBOCURARINE (CURARE, d-TC)

no CNS effect
rarely used because it causes more cardiovascular difficulties than others
and also releases more histamine
is broken down if given orally
only used as a surgical adjunct during general anesthesia
reversed by anti-ChE
onset of action not preceded by muscle fasciculation

SMS 371 223

 when inj. effect is maximal in about 4min
has some ganglion blocking activity
hypotension follows the inj of the drug d-
tubocurarine lowers b.p. by releasing histamine and
causing some blockade of ganglionic transmission
through sympathetic division of ANS
effect on muscle is entirely peripheral

SMS 371 224

Pharmacokinetics

principal route of excretion by kidney

(unmetabolized drug). Liver and biliary systems
provide alternate route of excretion (important
in renal failure)
does not affect the foetus and can therefore be
used in caesarean sections
given im/iv (may be dissolved in oil and given
by deep im to prolong the effect of the drug.
usual iv dose 30mg produces muscle paralysis
lasting for about 30 min

SMS 371 225

others
GALLAMINE (Flaxedil)
PANCURONIUM (Pavulon)
VECURONIUM
ALCURONIUM (Alloferin)

SMS 371 226

DRUG INTERACTIONS

SMS 371 227

 Certain general anesthetics stabilize postjunctional
membrane (i.e., halothane) and make depolarization at
nicotinic receptor more difficult.
Therefore, dose of a d-tubocurarine-like competitive
blocker should be reduced when using one of these
anaesthetics
Aminoglycoside antibiotics (i.e., neomycin, kanamycin)
and tetracycline reduce prejunctional release of ACh by
chelating Ca2+.
Less ACh arrives at nicotinic receptor for d-
tubocurarine-like drug to block.
Reduce dose of competitive blocker

SMS 371 228

CONTRA-INDICATIONS

SMS 371 229

 Asthma - d-tubocurarine and succinylcholine
Narrow-angle glaucoma - succinylcholine
Hyperthyroid condition - d-tubocurarine and
vecuronium
hyperkalaemia

SMS 371 230

Distinction between the 2 classes

SMS 371 231

 Avian skeletal muscle (Day old chick)
Results
Spastic paralysis Persistent blockers
Flaccid paralysis Competitive blockers

SMS 371 232

Other skeletal muscle relaxants& Mode of action

SMS 371 233

 Drugs Acting directly on Skeletal Muscle to
Produce Relaxation
Dantrolene
Chelates Ca2+ in sarcoplasmic reticulum
postjunctionally to produce skeletal muscle
relaxation

SMS 371 234

 Drugs that Act Prejunctionally to Reduce ACh
Release
Botulinum Toxin

Drugs Acting Centrally to Produce Skeletal

Muscle Relaxation
Cyclobenzaprine (Flexeril)

SMS 371 235

 CAUTION

SMS 371 236

 Neuromuscular blockers should NEVER be
administered for any reason, by anyone who is
not extremely familiar with their safe use and
who can provide rapid intervention in case
something wrong occurs.
-only anaesthesiologists and nurse
anaesthetists not the average doctor or nurse

SMS 371 237