Autonomic Nervous System

Pharmacology

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 Organization of
Nervous System - Recall

Central Nervous System Peripheral Nervous System

“Brain and spinal cord”

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic Parasympathetic
“thoracolumbar” “craniosacral”
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Cranial nerves

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Olfactory nerve (I.): sense of smell

• It is a set of fine axons that run from the nasal

epithelium to the olfactory bulb so it is not
really a nerve, but part of the brain.
• Those axons run through the ethmoid bone
(cribriform plate).

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Optic nerve (II.): vision

• Grows out from retinal ganglion cells

(inner layer of the retina).

• Two optic nerves make optic chiasm.

• It is part of the brain.

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Oculomotor nerve (III.): eye movements,
pupillary constriction and
accommodation; muscles of eyelid
– Emerges from the interpeduncular fossa in
the midbrain (mesencephalon).
– Somatic motor component innervates
muscles of the eyeball and muscle that
elevates the eyelid.
– Visceral motor component is
parasympathetic preganglionic outflow
that is involved in constricting the pupil.
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Trochlear nerve (IV.): eye movements
(intorsion, downward gaze)

– Emerges from the dorsal aspect of the

brain stem (midbrain).
– It is only cranial nerve that exits on the
dorsal side of the central nervous system.
– It has only somatic motor outflow that
innervates superior oblique muscle of the
eyeball (inward and downward gaze).

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Trigeminal nerve (V.): motor and sensory,
somatic sensation from face, mouth and
cornea; muscles of mastication
– Only nerve emerging from the ventro-lateral
aspect of the pons.
– Branchial motor component is for muscles
of mastication.
– General somatic sensory component
for somatic sensation from face,
mouth and cornea.

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Abducens nerve (VI.): eye movements
(abduction or lateral movements)

– Emerges from the junctional region

between pons and medulla oblongata,
close to the midline.
– Single somatic motor output for lateral
rectus muscle of the eyeball.

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Facial nerve (VII.): controls the muscles of facial
expression, taste from anterior tongue, lacrimal
and salivary glands
– Emerges from the junctional region between pons and
medulla oblongata.
– Branchial motor component supplies the muscles of facial
expression.
– Parasympathetic outflow for the numerous glands in the
cranial region: lacrimal and salivary glands (exept for the
parotid gland).
– Special visceral outflow (sense of taste) from anterior two
thirds of the tongue.

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Vestibulocochlear nerve (VIII.): hearing,
sense of balance

– Emerges from the junctional region

between pons and medulla oblongata.
– It is the most lateral nerve emerging from the
junctional region.
– Special sensory nerve: hearing (cochlea)
and sense of balance (labyrinth).

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Glossopharyngeal nerve (IX.): sensation from posterior
tongue and pharynx, taste from posterior tongue,
carotid baroreceptors and chemoreceptors
– Emerges from the medulla oblongata.
– Branchial motor component for the innervation of the muscles
around the pharynx.
– Parasympathetic outflow for the parotid gland.
– Special visceral sense of taste from the posterior one third of the
tongue.
– General visceral sensory output from the carotid bodies which
are important for regulating blood pressure, cardiac output and
respiration rate.

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Vagus nerve (X.): autonomic functions of gut,
sensation from larynx and pharynx, muscles of
vocal cords, swallowing
– Emerges from the medulla oblongata.
– Branchial motor component provide innervation to muscles
of the posterior pharynx and the region of the larynx.
– Parasympathetic outflow for the viscera in the thorax and in the
upper part of the abdomen.
– Special visceral sensation of taste from some taste buds in the
posterior part of the oral cavity.
– Visceral sensory signal for regulation of cardiovascular system
(aortic arch).

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Spinal accessory nerve (XI.): shoulder
and neck muscles
– Emerges from the medulla oblongata.
– Branchial motor output for the upper part of the trapezius
muscle and the sternocleidomastoid muscle.

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Hypoglossal nerve (XII.): movements of
tongue

–Emerges from the medulla oblongata,

between medullary pyramid and olive.
–Somatic motor output for tongue muscles.

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Cranial nerves

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Spinal nerves

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Spinal nerves
• Spinal nerves are an integral part of the peripheral
nervous system (PNS).
• They are the structures through which the central
nervous system (CNS) receives sensory information
from the periphery, and through which the activity of
the trunk and the limbs is regulated. Also they
transmit the motor commands from the CNS to the
muscles of the periphery.
• They are composed of both motor and sensory
fibres, as well as autonomic fibres, and exist as 31
pairs of nerves emerging intermittently from
the spinal cord to exit the vertebral canal.

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Key Facts about spinal nerves
Origins Anterior (ventral) and posterior (dorsal) roots of
the spinal cord
Regional 8 cervical
divisions 12 thoracic
5 lumbar
5 sacral
1 coccygeal
Function Receive sensory information from the
periphery and pass them to the CNS
Receive motor information from the CNS and pass
them to the periphery

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 Spinal nerves
The human spinal column is made
up of 33 bones.
• 7 - cervical region
• 12 - thoracic region
• 5 - lumbar region
• 5 - sacral region
• 4 - coccygeal region

• There are 31 pairs of

spinal nerves
– 8 cervical
– 12 thoracic
– 5 lumbar
– 5 sacral
– 1 coccygeal 21
• Each spinal nerve contains a mixture of motor and sensory fibers. They begin
as nerve roots that emerge from a segment of the spinal cord at a specific
level.
• Each spinal cord segment has four roots:
an anterior (ventral) and posterior (dorsal) root on both right and left
sides.
• Each of these roots individually is composed of approximately eight nerve
rootlets.
• The rootlets unite to form an anterior (ventral) or posterior (dorsal) root of a
spinal nerve.
• The anterior/ventral root contains efferent nerve fibres, which carry stimuli
away from the CNS towards their target structures. The cell bodies of the
ventral roots are located in the central grey matter of the spinal cord.
Motor neurons controlling skeletal muscle, as well as preganglionic autonomic
neurons are located in the ventral roots.
• The posterior/dorsal root contains afferent nerve fibres, which return sensory
information from the trunk and limbs to the CNS. The cell bodies of the dorsal
roots are not located in the central grey matter in the spinal cord, but instead in
a structure called the dorsal root ganglion. The anterior and posterior roots join
to form the spinal nerve proper, containing a mixture of sensory, motor, and
autonomic fibers. 22
http://www.spinalhu
b.com.au

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 Organization of
Nervous System - Recall

Central Nervous System Peripheral Nervous System

“Brain and spinal cord”

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic Parasympathetic
“thoracolumbar” “craniosacral”
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Peripheral Nervous System
• Most of the nerves of the peripheral nervous system
are composed of sensory nerve fibres conveying
afferent impulses from sensory end organs to the
brain and motor nerve fibres conveying efferent
impulses from the brain through the spinal cord to
the effector organs.

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Somatic Nervous System
• The somatic nervous system (SNS or voluntary nervous
system) is the part of the peripheral nervous system.
• The somatic nervous system includes both sensory
(afferent nerves) and motor (efferent nerves) neurons.
• Sensory neurons convey input from receptors for somatic
senses (tactile, thermal, pain, and proprioceptive sensations)
and from receptors for the special senses (sight, hearing,
taste, smell, and equilibrium)

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Autonomic Nervous System
• The autonomic nervous system is involved in a
complex of reflex activities, which depend on
sensory input to the brain or spinal cord, and
on motor output.
• The majority of the organs of the body are
supplied by both sympathetic and
parasympathetic nerves which have opposite
effects that are finely balanced to ensure the
optimum functioning of the organ.

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Autonomic Nervous System
• The autonomic nervous system (ANS) is a complex set
of neurons that mediate internal homeostasis
without conscious intervention or voluntary control.
• The ANS maintains blood pressure, regulates the rate
of breathing, influences digestion, urination, and
modulates sexual arousal.
• There are two main branches to the ANS – the
sympathetic nervous system and the
parasympathetic nervous system.

The effects of autonomic control are rapid and essential for homeostasis

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Sympathetic nervous system
• Sympathetic nervous system otherwise called as
thoracolumbar system.
• Sympathetic stimulation prepares the body to deal
with exciting and stressful situations, e.g.
strengthening its defences in danger. sympathetic
stimulation mobilises the body for 'fight or flight'.
• Neurones convey impulses from their origin in the
hypothalamus, reticular formation and medulla
oblongata to effector organs and tissues. The first
neuron has its cell body in the brain and its fibre
extends into the spinal cord.
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Sympathetic nervous system

• Structure of the Sympathetic Division

– Pathway from Spinal Cord to Sympathetic Trunk
Ganglia
– Organization of Sympathetic Trunk Ganglia
– Pathways from Sympathetic Trunk Ganglia to
Visceral Effectors

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 Iris muscle: Pupil dilated

Salivary glands: Secretion inhibited

Blood vessels in heart : Vasoconstriction
Heart: Rate and force of contraction
increased

Trachea and bronchi: Bronchodilation

Liver: Glycogen glucose conversion increased

Stomach: Peristalsis reduced

Sphincters closed
Intestines: Peristalsis and tone decreased
Vasoconstriction

Kidney: Urine secretion decreased

Bladder: Smooth muscle wall relaxed

Sphincter closed
Sex organs: Generally Vasoconstriction
Structure of the sympathetic division of the autonomic nervoussystem 31
Parasympathetic nervous system

• Parasympathetic nervous system otherwise called as

craniosacral outflow.
• Parasympathetic stimulation has a tendency to slow
down body processes except digestion and
absorption of food and the functions of the
genitourinary systems. Its general effect is that of a
'peace maker' allowing restoration processes to occur
quietly and peacefully.
• Cell bodies of parasympathetic preganglionic neurons
are found in nuclei in the brain stem.

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Parasympathetic nervous system

• Structure of the Parasympathetic Division

– The cranial parasympathetic outflow consists of
preganglionic axons that extend from the brain
stem in four cranial nerves i.e. oculomotor, facial,
glossopharyngeal, and vagus nerves. The cranial
outflow has four pairs of ganglia and the ganglia
associated with the vagus (X) nerve.

– The sacral parasympathetic outflow consists of

preganglionic axons in anterior roots of the second
through fourth sacral spinal nerves.
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 Iris muscle: Pupil constricted

Salivary glands: Secretion increased

Heart: Rate and force of
contraction decreased

Trachea and bronchi:

Bronchoconstriction
Liver: Blood vessels dilated
Secretion of bile increased

Stomach: Secretion of gastric juice and

peristalsis increased
Intestines: Digestion and
absorption increased

Kidney: Urine secretion increased

Bladder: Muscle of wall contracted

Sphincters relaxed
Sex organs: Male: erection;
Female: variable
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Structure of the parasympathetic division of the autonomic nervous system
 Sympathetic Parasympathetic

Origin Thoraco-lumbar(T1-L3) Craniosacral (3,7,9,10;S2-4)

Distribution wide Head, neck and trunk

Ganglia Away from organs On or close to the organ

Post gangl fibre long short

Transmitter NA (major) Ach( minor) Ach

Stability of NA stable, diffuses for Ach-rapidly destroyed locally

transmitter wide action

Important Tackling Assimilation of food,

function stress and conservation of
emergency energy
“fight or flight” ”rest and digest” responses
responses
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Autonomic Motor Pathways

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ComparisonofSympathetic,Parasympathetic,andMotor Nerves

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Autonomic Motor Pathways
• Each division of the ANS has two motor neurons
(preganglionic and postganglionic neuron).
• Preganglionic Neurons
– In the sympathetic division (thoracolumbar division/
thoracolumbar outflow), the preganglionic neurons have
their cell bodies in the lateral horns of the gray matter in
the 12 thoracic segments and the first two (and sometimes
three) lumbar segments of the spinal cord.
– In the parasympathetic division (craniosacral division/
craniosacral outflow), the preganglionic neurons have their
cell bodies in in the nuclei of four cranial nerves in the brain
stem (III, VII, IX, and X) and in the lateral gray matter of the
second through fourth sacral segments of the spinal cord.
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 Autonomic Motor Pathways
Preganglionic Neurons
• Autonomic Ganglia
– There are two major groups of autonomic ganglia
• sympathetic ganglia
• parasympathetic ganglia
• Sympathetic Ganglia:
• The sympathetic ganglia are the sites of synapses between
sympathetic preganglionic and postganglionic neurons.
• Parasympathetic ganglia:
• Preganglionic axons of the parasympathetic division
synapse with postganglionic neurons in terminal ganglia.

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 Autonomic Motor Pathways
Postganglionic Neurons
• Once axons of sympathetic preganglionic
neurons pass to sympathetic trunk ganglia,
they may connect with postganglionic
neurons.
• A single sympathetic preganglionic fiber has
many axon collaterals (branches) and may
synapse with 20 or more postganglionic
neurons.

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 Autonomic Motor Pathways
Postganglionic Neurons
• Axons of preganglionic neurons of the
parasympathetic division pass to terminal
ganglia near or within a visceral effector. In the
ganglion, the presynaptic neuron usually
synapses with only four or five postsynaptic
neurons, all of which supply a single visceral
effector, allowing parasympathetic responses
to be localized to a single effector.

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Autonomic Receptors

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ANS Neurotransmitters and Receptors
ANS Receptor Receptor Sub-type
Parasympathetic Nicotinic cholinergic Nn, Nm
nervous system receptors
Muscarinic cholinergic M1, M2, M3, M4,
receptors M5
Sympathetic α adrenergic receptor α1, α2
nervous system β adrenergic receptor β1, β2, β3

Sympathetic nervous system Parasympathetic nervous system 43

Comparison of Somatic and
Autonomic Motor Neurons

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Comparison of Somatic and Autonomic Motor Neurons

Somatic Autonomic
Voluntary effectors: striated Involuntary effectors: smooth &
muscles cardiac muscles, glands
single motor neuron from usually 2 neurons with synapse
spinal cord to target organ (ganglion) between from spinal
cord to target organ
Neurotransmitter always Neurotransmitter stimulatory or
stimulatory inhibitory
ACh released at synapse ACh and NE released at synapses

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Comparison of Somatic and Autonomic Motor Neurons

Motor neuron pathways in the

(a) somatic nervous system and
(b) autonomic nervous system
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Autonomic Nervous System
Pharmacology

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 Goal !

To Learn about the drugs affecting the

autonomic nervous system

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Autonomic drugs are used
for the
treatment of Angina

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Autonomic drugs are used
for the
treatment of
Heart Failure

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Autonomic drugs are used for
the
treatment of High Blood
Pressure

•Autonomic drugs also used for

treatment of
- Anaphylactic shock
- Alzheimer’s disease
- Asthma

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Autonomic Pharmacology is Practical

Mimic transmitters

Nerves to organ O
release neurotransmitter N, Drug A enhances release
and N increases
the activity of organ O
+ of neurotransmitter N by
acting on receptors of N

Drug A increases
activity of
organ O
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 Autonomic Pharmacology

Block transmitters

Nerves to organ O
release neurotransmitter N, Drug A blocks
and N increases
the activity of organ O
+ receptors for
neurotransmitter N

Drug A decreases
activity of
organ O

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 Understanding actions of drugs that influence
the autonomic nervous system allows
prediction of their effects!

Parasympathetic nerves Atropine blocks

release Acetylcholine (Ach) muscarinic cholinergic
and increase
+ receptors
intestinal motility that respond to ACh

Atropine blocks Ach receptors (muscarinic)

and decreases intestinal motility

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 For a definite clinical outcome!

Sympathetic nerves Propranolol blocks

release Noradrenaline (NA) Receptors (β-adrenergic)
and increase
+ that respond to NA
Blood Pressure

Propranolol blocks β-adrenergic receptors

and decreases Blood Pressure

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 The autonomic nervous system maintains the
internal environment of the body –
HOMEOSTASIS
• Role of ANS in homeostasis links to specific target
organs - (Circulation, respiration, digestion,
temperature regulation and some endocrine
secretion)
• In contrast – endocrine system is more generalized
• ANS in periphery – nerve, ganglia and plexuses
innervates heart, glands, other smooth muscles and
visceral organs
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 Organization of
Nervous System - Recall

Central Nervous System Peripheral Nervous System

“Brain and spinal cord”

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic Parasympathetic
“thoracolumbar” “craniosacral”
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 AUTONOMIC NERVOUS SYSTEM
• SYMPATHETIC
– Fight or Flight

• PARASYMPATHETIC
– Rest and Digest

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Somatic Vs
Autonomic
Somatic Autonomic
1. Organ supplied Skeletal Muscle All other organs

2. Distal most synapse Within CNS Outside CNS in ganglia

3. Nerve fibres Myelinated Preganglionic – Myelinated

Postganglionic – Non-myelinated
4. Peripheral plexus Absent Present
formation
5. Efferent Transmitter Acetylcholine Acetylcholine and Noradrenaline

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 ANS Organization –
Autonomic afferents
• Afferent fibers from visceral structures – are the first link in the reflex arcs
of the autonomic system
• Most visceral reflexes are mediated through the CNS
• Information on the status of the visceral organs is transmitted to the CNS
through the cranial nerve (parasympathetic) visceral sensory system and
the spinal (sympathetic) visceral afferent system
• The cranial visceral sensory - mechanoreceptor and chemosensory
information
– 4 cranial nerves - V, VII, IX and X
– Carries from face, head, toungue, palate, carotid body, oesophagus,
thoracic and abdominal visceral organs except pelvic
• The spinal visceral system - temperature and tissue injury of mechanical,
chemical, or thermal origin:
– Sensory afferents from all viscera at thoracic level
– Muscle chemosensations – at all spinal level
• Pelvic sensory responses at S2-S4 level
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1. Afferent neuron
the neurons of which bring information from the periphery
to the CNS.
Afferent neurons provide sensory input to modulate the
function of the efferent division through reflex arcs.
2. Efferent neurons
carries nerve impulses from the CNS to the effector
organs by way of two types of efferent neurons (the
preganglionic neuron and the postganglionic neuron

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 Transmitters and Receptors - General
• Neurotransmitter
– All preganglionic and postganglionic Parasympathetic –
Acetylcholine
(Ach)
– Postganglionic sympathetics – norepinephrine (NE,
noradrenaline)
• Somatic: Nicotinic (NM) ACh type of receptor
– NM: musculoskeletal junction
• Autonomic:
1. Parasympathetic:
• Preganglionic: Nicotinic (NN) Ach
• Postganglionic: Muscarininic (M)
2. Sympathetic:
• Preganglionic: Nicotinic (NN) Ach
• Postganglionic : Noradrenergic (NA) - ɑ and ß (alpha and
beta)
• Adrenal medulla (NN) Preganglionic and Postganglionic -
Adrenaline in blood stream 65
NeurochemicalTransmission

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Neurotransmission
• Understanding the steps of chemical mediation of nerve
impulses is important – exploited pharmacologically
• Conduction refers to the passage of an impulse along an axon
or muscle fiber
• Transmission (Neurohumoral) transmission means the
transmission of message across synapse and neuroeffector
junctions by release of humoral (chemical) messages
• Initially junctional transmission was thought to be Electrical
• But, Dale (1914) and Otto Loewi (1921) provided direct proof
of humoral transmission
• Many Neurohumoral transmitters identified: Acetylcholine,
noradrenalin, Dopamine, 5-HT, GABA, Purines, Peptides etc.

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 Axonal Conduction
• At rest, the interior of the typical
mammalian axon is ~70 mV negative to
the exterior
• These ionic gradients are maintained by
the Na+, K+-ATPase
• In response to depolarization to a
threshold level, an action potential (AP)
is initiated locally
• The AP consists of two phases:
• rapid increase in the permeability
of Na+
• rapid inactivation of the Na+ channel
and the delayed opening of a K+
channel

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 Junctional Transmission - Steps
• Arrival of the AP at the axonal terminals initiates a series of
events that trigger – transmission of excitatory or inhibitory:
1. Release of stored Transmitter (prejunctional regulation) –
• Cotransmission: enzymes, other proteins, and
cotransmitters (e.g., ATP, Neuropeptide Y)
• Receptors - M2 and M4 and ɑ2A, ɑ2B and ɑ2C
2. Combination of the transmitter with postjunctional
receptors and production of the postjunctional potential
• EPSP and IPSP
3. Initiation of postjunctional activity
4. Termination of transmitter action
– Nor epinephrine transporter, Serotonin transporter

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Junctional Transmission Steps - Image

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Steps Involved inNeurotransmission

• Impulse conduction

• Transmitter release

• Transmitter action on post junctional membrane

• Post junctional activity

• Termination of transmitter action

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1. Impulseconduction

RMP- -70 mV

Arrival of an electrical impulse  Na+conductance

Depolarization (+20mV)K + efflux repolarization

Blockers – Tetrodotoxin , Saxitoxin

Activators - Batrachotoxin

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2. Transmitterrelease

AP Release of transmitter stored in prejunctional nerve

endings within synaptic vesicles

Fusion of synaptic and vesicular

membranes

Ca 2+ entry exocytosis of all contents

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RELEASE MODULATED BY

1. Transmitter itself
2. Other agents through receptors located on pre junctional
membrane

NA release (-) by NA (α2),dopamine, adenosine, prostaglandins

Ach release at autonomic sites (-) α2 and muscarinic agonists

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3.Transmitter action on postjunctional membrane

Transmitter combines with receptor on post jnl membrane EPSP

or IPSP

EPSP  permeability to all cationsNa+ or Ca 2+ influx 

depolarization followed by K+ efflux

IPSP  permeability to smaller ions,

Cl- influx hyperpolarization

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Excitatory and inhibitory
neurohumoral transmission

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4. Post junctionalactivity
Suprathreshold EPSP propagated post junctional AP
nerve impulse/contraction/secretion

IPSP stabilizes the post junctional membrane , resists

depolarizing stimuli

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5. Termination of transmitteraction
1. Local degradation (Ach)
2.Reuptake (NA, GABA) Eg: Norepinephrine transporter,
dopamine transporter, Serotonin transporter

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Mechanisms of termination of
transmitter action

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Mechanisms of termination of
transmitter action

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Cotransmission
• On stimulation most peripheral and central neurons have been
shown to release more than one active substance

• Purines (ATP, adenosine)

• Peptides ( Vasoactive intestinal protein (VIP), Neuropeptide Y (NPY),
substance P)
•NO, prostaglandins
VIPAch
ATP Ach, NA
Vasc adrenergic nerves NPY

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Cotransmission

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Cholinergic Transmission

• All preganglionic nerve endings

• All parasympathetic postganglionic nerves

• Few sympathetic postganglionic nerves

• To the neuromuscular junction

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Synthesis ,storage and release of ACh
• Transport of Choline into the vesicle

• Synthesis of Acetyl choline from Acetyl CoA & Choline

• Transport of Acetyl choline into the vesicle

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VAT-Vescicular acetylcholine transporter
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SNAPS-Synaptosomal associated proteins
 CHEMICAL SIGNALING BETWEEN CELLS

Hormones - chemicals released into the bloodstream

 physiological effects on tissues - specific hormone
receptors.

Local mediators - Most cells in the body secrete

chemicals that act locally, and they don’t enter blood.
E.g, histamine and prostaglandins –

Neurotransmitters: A specific chemical signals,

released from the nerve terminals.
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Neurotransmitters

1. Norepinephrine and epinephrine - ANS

2. Acetylcholine - ANS
3. Dopamine - CNS
4. Serotonin - CNS
5. γ-aminobutyric acid (GABA)- CNS

 Co-transmitters, such as adenosine, often

accompany neurotransmitter on nerve
stimulation and modulate the transmission
process.

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Neurotransmitters of ANS

1. Acetylcholine (ACh) (cholinergic )

mediates the transmission of nerve impulses across:
autonomic ganglia in both sympathetic and
parasympathetic NS.
at adrenal medulla.
Transmission from the postganglionic nerves to the
effector organs in parasympathetic system,
 transmission at the neuromuscular junction
2. Norepinephrine (NE) and epinephrine (E) (adrenergic)
 Transmission from the postganglionic nerves to the
effector organs in sympathetic system

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Parasympathetic nervous system and effector organs

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Sympathetic nervous system and effector organs

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91
Neurotransmission in cholinergic neurons involves six steps:

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Cholinergic Transmission –
Synthesis:
•Cholinergic neurons contain large numbers
of small membrane-bound vesicles
(containing ACh) concentrated near the
synaptic portion of the cell membrane
•ACh is synthesized in the cytoplasm from
acetyl-CoA and choline by the catalytic
action of Choline acetyltransferase (ChAT)
•Acetyl-CoA is synthesized in
mitochondria, which are present in large
numbers in the nerve ending
•Choline is transported from the
extracellular fluid into the neuron terminal by
a sodium-dependent membrane carrier
(carrier A). This carrier can be blocked by a
group of drugs called hemicholiniums
The action of the choline
transporter is the rate-limiting step
in ACh synthesis

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Cholinergic Transmission –
Release:
•Synthesized, ACh is transported from the
cytoplasm into the vesicles by an antiporter that
removes protons (carrier B). This transporter
can be blocked by vesamicol
•Release is dependent on extracellular Ca2+
and occurs when an action potential reaches the
terminal and triggers sufficient influx of Ca2+
ions
•The increased Ca2+ concentration
"destabilizes" the storage vesicles by
interacting with special proteins associated with
the vesicular membrane (VAMPs-vescicle
associated membrane protein and SNAP-
synaptosome associated protein)
Fusion of the vesicular membranes with the
terminal membrane results in exocytotic
expulsion of ACh into the synaptic cleft
•The ACh vesicle release process is blocked by
botulinum toxin through the enzymatic removal
of two amino acids from one or more of the
fusion proteins.
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Cholinergic Transmission:
Destruction
•After release - ACh molecules may bind to
and activate an ACh receptor
(cholinoceptor)
•Eventually (and usually very rapidly), all of
the ACh released will diffuse within range of
an acetylcholinesterase (AChE) molecule
•AChE very efficiently splits ACh into
choline and acetate, neither of which has
significant transmitter effect, and thereby
terminates the action of the transmitter.
•Most cholinergic synapses are richly
supplied with AChE; the half-life of ACh in
the synapse is therefore very short.

•Another cholinesterase with a lower

specificity for ACh, butyrylcholinesterase
[pseudo cholinesterase], is found in blood
plasma, liver, glial, and many other tissues

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 Sites of Cholinergic Transmission
Acetylcholine (Ach) is major neurohumoral transmitter
at autonomic, somatic and central nervous system:
1. All preganglionic sites (Both Parasympathetic and
sympathetic)
2. All Postganglionic Parasympathetic sites and
sympathetic to sweat gland and some blood vessels
3. Skeletal Muscles
4. CNS: Cortex Basal ganglia, spinal chord and others
Parasympathetic Stimulation – Acetylcholine (Ach) release at neuroeffector
junction - biological effects
Sympathetic stimulation – Noradrenaline (NA) at neuroeffector junction -
biological effects

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Cholinergic receptors (CHOLINOCEPTORS)

A. Muscarinic receptors
 G protein–coupled receptors.
 Recognize muscarine, ACh, and weak affinity to
nicotine NT.
 five subclasses of muscarinic receptors:
M1, M2, M3, M4, and M5.
 Found on the effector organs of parasympathetic
such as the gastric (M1) , heart muscle (M2), bladder
and exocrine glands and smooth muscle (M3)
 When M receptor activated – G-protein – IP3 and
DAG - intracelluar Ca2+ - cause secretion, or
contract

97
Cholinergic receptors (CHOLINOCEPTORS)

98
Muscarinic receptors

99
Cholinergic receptors (CHOLINOCEPTORS)

B. Nicotinic receptors
 ligand-gated ion channel
 Recognize nicotine, ACh, and weak affinity
to muscarine NT.
 Two types : Nm and Nn
 Located in the CNS, adrenal medulla,
autonomic ganglia (called Nn), and the
neuromuscular junction (NMJ) called Nm

100
101
Nicotinic receptors

102
Adrenergic receptors

103
Adrenergic receptors

104
A. Cholinergic agonists
(parasympathomimetics)
ACh has both muscarinic and nicotinic
activity. Its actions include:
Decrease in heart rate and cardiac output
Decrease in blood pressure (VASODILATION)
Increases salivary secretion and intestinal secretions and
motility.
increases the tone of the detrusor urinae muscle, causing
expulsion of urine.
constriction of the pupillae sphincter muscle, causing
miosis (marked constriction of the pupil).

105
 Cholinergic Drugs or
Cholinomimetic or
Parasympathomimetics
Drugs producing actions similar to Acetylcholine by –
1) interacting with Cholinergic receptors or 2)
increasing availability of Acetylcholine at these sites

106
 Classifiction - Direct-acting (receptor
agonists)
• Choline Esters
– Natural: Acetylcholine (Ach)
– Synthetic: Methacholine, Carbachol and
Bethanechol
• Alkaloids: Pilocarpine, Muscarine, Arecholine
– Synthetic: Oxotremorine

107
Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium
• Irreversible anticholinesterases:
1. Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion,
malathion, diazinon (insecticides and pesticides)
2. Tabun, sarin, soman (nerve gases in war)
3. Carbamate Esters: Carbaryl and Propoxur (Baygon)

108
109
110
111
ACh actions –
Muscarinic
1. Heart: M2
– SA node hyperpolarization (decrease in rate of diastolic
depolarizaton) - reduction in impulse generation and Bradycardia
– AVN and PF – RP is increased – slowing of conduction –
partial/complete heart block
– Atrial fibres: Reduction in force of contraction and RP in fibers
abbreviated
– Decrease in ventricular contractility (less prominent)
2. Blood Vessels: M3
– Cholinergic innervations is limited – skin of face and neck
– But, M3 present in all type blood vessel – Vasodilatation by Nitric
oxide (NO) release – fall in BP and flushing
– Penile erection

112
Muscarinic action
– contd.
3. Smooth Muscles: M3 - All are contracted
– Abdominal cramps, diarrhoea – due to increased peristalsis and
relaxed sphincters
– Voiding of Bladder
– Bronchial SM contraction – dyspnoea, attack of asthma etc.
4. Glands: M3
– Increased secretions: sweating, salivation, lacrimation,
tracheobronchial tree and gastric glands
– Pancreatic and intestinal glands – less prominent
5. Eye: M3
– Contraction of circular fibres of Iris – miosis
– Contraction of Ciliary muscles – spasm of accommodation,
increased outflow and reduction in IOP
– Stimulation of M3 receptors at lacrimal glands produce
lacrimation (due to vasodilation) 113
Ach actions –
Nicotinic
1. Autonomic ganglia:
– Both Sympathetic and parasympathetic ganglia are stimulated
– After atropine injection Ach causes tachycardia and rise in BP
2. Skeletal muscle
– IV injection – no effect
– Application causes contraction of skeletal muscle
3. CNS:
– Does not penetrate BBB
– Local injection in CNS – complex actions
(Acetylcholine is not used therapeutically – non specific)
Bethanecol Uses: Postoperative and postpartum urinary
obstruction, neurogenic bladder and GERD (10-40 mg oral)

114
 Pilocarpine
• Alkaloid from leaves of Jaborandi (Pilocarpus
jaborandi)
• Prominent muscarinic actions
• Profuse salivation, lacrimation, sweating
• Dilates blood vessels, causes hypotension
• High doses: Rise in BP and tachycardia (ganglionic action)
• On Eyes: produces miosis and spasm of
accommodation
• Lowers intraocular pressure (IOP) in Glaucoma when applied
as eye drops
• Too toxic for systemic use – CNS toxicity, pulmonary edema
115
 Pilocarpine – contd.
Ophthalmic use
1. Used as eye drops in treatment of wide
angle glaucoma to reduce IOP
2. To reverse mydriatic effect of atropine
3. To break adhesion between iris and
cornea/lens alternated with mydriatic
• Pilocarpine nitrate eye drops ( 1 to 4% )
Sialagogue
• Rarely, Pilocarpine (5-10 mg orally) is also
used to stimulate salivary secretions in
patient after laryngeal surgery

• Atropine used as antidote in acute

pilocarpine poisoning ( 1- 2 mg IV 8 hrly )
116
 Pilocarpine in Glaucoma
• Constriction of circular muscle of Iris
• Contraction of ciliary muscle
• Spasm of accomodation – fixed at near vision

117
 Muscarine
• Alkaloid from mushroom Amanita muscaria
• Only muscarinic actions
• No clinical use
• Mushroom poisoning due to ingestion of
poisonous mushroom
1. Early onset mushroom poisoning (Muscarine
type)
2. Late onset mushroom poisoning
3. Hallucinogenic type

118
Mushroom Poisoning

• Early Onset Mushroom Poisoning: Occurs ½ to 1 hour

– Symptoms are characteristic of Muscarinic actions
– Severe cholinergic symptoms like vomiting, salivation,
lacrimation, headache, bronchospasm, diarrhoea
bradycardia, dyspnoea, hypotension, weakness,
cardiovascular collapse, convulsions and coma
– Antidote is Atropine sulphate ( 2-3 mg IM every hrly till
improvement)
• Hallucinogenic type: due to Muscimol or ibotenic acid
present in A. muscria. Blocks muscarinic receptors in
brain and activate amino acid receptors. No specific
treatment – Atropine is contraindicated.
119
Late Onset Mushroom
Poisoning
• Occurs within 6 - 15 hours
• Amanita phylloides (deadly nightcap)– due to peptide
toxins – Inhibit RNA polymerase II and therefore mRNA
synthesis
• Irritability, restlessness, nausea, vomiting, bloody diarrhoea
ataxia, hallucination, delirium, sedation, drowsiness and
sleep – Kidney, liver and GIT mucosal damage
• Maintain blood pressure, respiration
• Inj. Diazepam 5 mg IM
• Atropine contraindicated as it may cause convulsions and
death
• Gastric lavage and activated charcoal
120
 Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium

• Irreversible anticholinesterases:
1. Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon
(insecticides and pesticides)
2. Tabun, sarin, soman (nerve gases in war)
3. Carbamate Esters: Carbaryl and Propoxur (Baygon)

121
 AChEs - MOA
• Normally Acetylcholinesterase (AchE)
hydrolyses Acetylcholine
• The active site of AChE is made up of
two subsites – anionic and esteratic
• The anionic site serves to bind a
molecule of ACh to the enzyme
• Once the ACh is bound, the hydrolytic
reaction occurs at a second region of the
active site called the esteratic subsite
• The AChE itself gets acetylated at
serine site
• Acetylated enzyme reacts + water =
acetic acid and choline
Tryptophan Glutamate and
• Choline - immediately taken up again histidine
by the high affinity choline uptake
system presynaptic membrane 122
 AChEs - MOA
• Anticholinesterases also react with the enzyme ChEs in similar
fashion like Acetylcholine

• Carbamates – carbamoylates the active site of the enzyme

• Phosphates – Phosphorylates the enzyme

• Both react similar fashion covalently with serine

123
Anticholinesterases – Individual Drugs

• 2 (two) important clinically used drugs –

– Physostigmine – lipid soluble, ganglion acting and
less action in skeletal muscle
– Neostigmine – lipid insoluble, skeletal muscle
acting

124
 Physostigmine
• Alkaloid from dried ripe seed (Calabar bean) of African plant
Physostigma venenosum
• Tertiary amine, lipid soluble, well absorbed orally and crosses
BBB
• Hydrolyzed in liver and plasma by esterases
• Long lasting action (4-8 hours)
• It indirectly prevents destruction of acetylcholine released
from cholinergic nerve endings and causes ACh accumulation
• Muscarinic action on eye causing miosis and spasm of
accommodation on local application
• Salivation, lacrimation, sweating and increased
tracheobronchial secretions
125
 Physostigmine - uses
1. Used as miotic drops to decrease IOP in Glaucoma
2. To antagonize mydriatic effect of atropine
3. To break adhesions between iris and cornea alternating
with mydriatic drops
4. Belladonna poisoning, TCAs & Phenothiazine poisoning
5. Atropine is antidote in physostigmine poisoning.

126
 Neostigmine
• Synthetic reversible anticholinesterase drug
• Quaternary ammonium compound and lipid insoluble
• Cannot cross BBB
• Hydrolysed by esterases in liver & plasma
• Short duration of action (3-5 hours)
• Direct action on nicotinic (NM) receptors present in
neuromuscular junction (motor end plate) of skeletal muscle
• Antagonises (reverses) skeletal muscle relaxation (paralysis)
caused by tubocurarine and other competitive neuromuscular
blockers
• No CNS effects

127
 Neostigmine – Uses and ADRs
• Used in the treatment of myasthenia gravis to increase
muscle strength
• Post-operative reversal of neuromuscular blockade
• Post-operative complications – gastric atony paralytic
ileus, urinary bladder atony
• Cobra snake bite
• Produces twitchings & fasciculations of muscles leading to
weakness
• Atropine is the antidote in acute neostigmine poisoning

128
 Physostigmine Vs Neostigmine
Physostigmine Neostigmine
Source Natural Synthetic
Chemistry Tertiary amine Quaternary ammonium
compound
Oral absorption Good Poor
CNS action Present Absent
Eye Penetrates cornea Poor penetration
Effect Ganglia Muscle
Uses Miotic Mysthenia gravis
Dose 0.5-1 mg 0.5-2.5 mg IM/SC
oral/parenteral 15-30 mg orally
0.1-1% eye drop
Duration of action 4-6 Hrs 3-4 Hrs

129
 Myasthenia gravis
• Autoimmune disorder affecting 1 in 10,000 population (?) –
reduction in number of NM receptors
• Causes: Development of antibodies directed to Nicotinic
receptors in muscle end plate – reduction in number by 1/3rd
of NM receptors
– Structural damage to NM junction
• Symptoms: Weakness and easy fatigability
• Treatment:
– Neostigmine – 15 to 30 mg. orally every 6 hrly
– Adjusted according to the response
– Pyridostigmine – less frequency of dosing
– Other drugs: Corticosteroids (prednisolone 30-60 mg /day)

130
 Myasthenia gravis (Myo + asthenia)
• Myasthenia gravis (MG) is a complex, autoimmune disorder
in which antibodies destroy neuromuscular connections.
• Causes problems with the nerves that communicate with
muscles.
• Affects the voluntary muscles of the body, especially the
eyes, mouth, throat, and limbs.
• Characterized by weakness and rapid fatigue of any of the
muscles under the voluntary control.
• The cause of myasthenia gravis is a breakdown in the
normal communication between nerves and muscles.
• No cure for myasthenia gravis, but treatment can help
relieve signs and symptoms – such as weakness of arm or
leg muscles, double vision, drooping eyelids, and difficulties
with speech, chewing, swallowing and breathing. 131
132
133
 TYPES OF MYASTHENIA GRAVIS
Three types of MG in children:
• Congenital MG - Very rare non-immune form of MG that is
inherited as an autosomal recessive disease.
• Symptoms of congenital MG usually begin in the baby's first
year and are life-long.
• Transient neonatal MG - Between 10 and 20 percent of
babies born to mothers with MG may have a temporary form
of MG.
• Neonatal MG usually lasts only a few weeks, and babies are
not at greater risk for developing MG later in life.
• Juvenile MG - This auto-immune disorder develops typically
in female adolescents.
• It is a life-long condition that may go in and out of remission.
About 10 percent of MG cases are juvenile-onset.
134
 SYMPTOMS
• Babies with neonatal MG may be weak, with a poor suck,
and may have respiratory difficulty. A few babies may need
the help of a mechanical breathing machine if their
respiratory muscles are too weak to breathe on their own.
• Congenital MG symptoms may begin in the first year, with
generalized weakness in the arms and legs, and delays in
motor skills such as crawling, sitting, and walking.
• Juvenile MG symptoms may begin gradually over weeks or
months. The child may become excessively tired after very
little activity, and begin to have problems chewing and
swallowing. Drooping eyelids may be so severe that the child
cannot see.

135
136
 Eye muscles
In more than half the people who develop MG, their
first signs and symptoms involve eye problems:
• Drooping of one or both eyelids (ptosis)
• Double vision (diplopia), which may be horizontal or
vertical
• Blurred vision, which may come and go

137
 Face and throat muscles
In about 15 percent of people with myasthenia gravis, the first
symptoms involve face and throat muscles, which can cause
difficulties with:
• Speaking. The speech may be very soft or sound nasal,
depending upon which muscles have been affected.
• Swallowing. May choke very easily, which makes it difficult to
eat, drink or take pills. In some cases, liquids may come out of
the nose.
• Chewing. The muscles used for chewing may wear out
halfway through a meal, particularly if eating
something hard to chew, such as sugarcane.
• Facial expressions. Family members may
note "lost smile" if the muscles that control
facial expressions are affected.
138
Arm and leg muscles
• Myasthenia gravis can cause weakness in arms
and legs, but this usually happens in conjunction
with muscle weakness in other parts of the body –
such as eyes, face or throat.
• The disorder usually affects arms more often than
legs.
• If it affects legs, may waddle when walking.

Normal dumbbell Weakness dumbbell

139
CAUSES
• Myasthenia gravis may be inherited, genetic disease,
acquired by babies born to mothers with MG
• Nerves communicate with the muscles by releasing
chemicals, called neurotransmitters, which fit
precisely into receptor sites on the muscle cells.
• In myasthenia gravis, immune system produces
antibodies that block or destroy many of the muscles
receptor sites for a neurotransmitter called
acetylcholine.
• With fewer receptor sites available, muscles receive
fewer nerve signals, resulting in weakness.

140
Chemicals messengers, called neurotransmitters, fit
precisely into receptor sites on your muscle cells. In
myasthenia gravis, certain receptor sites are blocked
or destroyed, causing muscle weakness.
141
• It's believed that the thymus gland, a part of the
immune system located in the upper chest beneath
the breastbone, may trigger or maintain the
production of these antibodies.
• Large in infancy, the thymus is small in healthy
adults. But, in some adults with myasthenia gravis,
the thymus is abnormally large.
• Some people also have tumors of the thymus.
• Usually, thymus gland tumors are noncancerous.

142
Thymus gland, a part of your immune system located
in the upper chest beneath the breastbone, may
trigger or maintain the production of antibodies that
result in the muscle weakness common in MG. 143
 Treatments & Drugs
• Specific treatment to age, overall health, and
medical history and extent of the condition
• No cure for MG, but the symptoms can be
controlled.
• MG is a life-long medical condition and the key to
medically managing MG is early detection.
• The goal of treatment is to prevent respiratory
problems and provide adequate nutritional care to
the child since the swallowing and breathing
muscles are affected by this condition.

144
 Medications
• Cholinesterase inhibitors. Drugs like Neostigmine,
pyridostigmine enhance communication between
nerves and muscles. These drugs don't cure, but
improves muscle contraction and strength.
• Corticosteroids. Like prednisolone. These types of
drugs inhibit the immune system, limiting antibody
production. Prolonged use of corticosteroids, can
lead to serious side effects, like bone thinning, weight
gain, diabetes, increased risk of some infections, and
increase and redistribution of body fat.
• Immunosuppressants. Doctor may also prescribe
other medications that alter immune system, like
azathioprine, cyclosporine, or mycophenolate.

145
Overall Therapeutic Uses – cholinergic drugs

1. Myasthenia gravis: Neostigmine,

Pyridostigmine & Distigmine to treat
2. To stimulate bladder & bowel after surgery:
– Bethanechol, Carbachol, Distigmine.

3. To lower IOP in chronic simple glaucoma:

– Pilocarpine, Physostigmine
4. Physostigmine in Belladonna poisoning
5. Cobra Bite

146
Pharmacotherapy of Organophosphate Poisoning

• Signs and symptoms:

1. Irritationof eye, lacrmation, salivation, tracheo-bronchial
secretions, colic, blurring of vision, defaecation and
urination
2. Fall in BP, tachy or bradycardia and CVS collapse
3. Muscular fasciculations, weakness, and respiratory
paralysis
4. Excitement, tremor, convulsins and coma
• Treatment:
– Decontamination – gastric lavage if needed
– Airway maintenance
– Supportive measures – for BP/fluid and electrolyte
– Specifc antidote – Atropine – 2 mg IV every 10 minutes till
dryness of mouth or atropinization (upto 200 mg/day)
147
148
ANTICHOLINERGIC DRUGS

149
 ANTICHOLINERGIC DRUGS
• Which block the actions of Ach on autonomic
effectors and in the CNS; exerted through
muscarinic receptors.
• Nicotinic antagonists are referred to as ganglion
blockers and neuromuscular blockers.
• Prototype is ATROPINE
• Highly selective for muscarinic receptors.
• Synthetic substitutes possess nicotinic blocking
property also.

150
Classification
• Natural Alkaloids – Atropine, Hyoscine (Scopolamine).
• Semisynthetic derivatives - Homatropine, Atropine methonitrate,
Hyoscine butyl bromide, ipratropium bromide
• Synthetic Compounds –
• Mydriatics – Cyclopentolate, Tropicamide.
• Antisecretory-antispasmodics :
A) Quarternary compounds:
Propantheline, Oxyphenonium, Clidinium, Pipenzolate methyl
bromide, Isopropamide, Glycopyrrolate.
B) Tertiary amines : Dicyclomine, Oxybutynin, Flevoxate,
Pirenzepine, Telenzipine.
• Antiparkinsonian : Trihexyphenidyl, Procyclidine, Biperiden,
Benztropine.

151
MUSCARINIC RECEPTORS SUBTYPES & ANTAGONISTS

• M1 Antagonists –
Pirenzepine, Telenzepine, dicyclomine,
trihexyphenidyl
• M2 Antagonists –
Gallamine, methoctramine
• M3 Antagonists –
Darifenacin, solifenacin, oxybutynin,
tolterodine

152
Pharmacological actions
Prototype is ATROPINE

• CNS –
Atropine- less entry → stimulation of CNS
High dose- excitation, disorientation, hallucination
Synthetic – Antiparkinsonian drugs

• Scopolamine has more marked central effects,

producing drowsiness and amnesia.
• In toxic doses, scopolamine and to a lesser degree
atropine can cause excitement, agitation, hallucinations
and coma.

153
154
• Parkinson’s disease –
• It blocks the relative cholinergic overactivity in basal
ganglia and suppresses tremor and rigidity of
parkinsonism.
• A combination of an anti-muscarinic and dopamine
precursor.
• Vestibular disturbances-
• Especially motion sickness, involves muscarinic
cholinergic transmission.
• Scopolamine (l-hyoscine) effective in preventing or
reversing these disturbances.

155
EYE
A) Muscarinic cholinoreceptor
stimulation cause
• Pupillary constrictor muscle
Stimulation
• Blocked by topical atropine
• Due to unopposed sympathetic dilator
activity-mydriasis
B) Weakening of contraction of ciliary
muscle
• Cycloplegia
• Loss of accomodation
• Can’t focus for near vision
C) Decrease in lacrimal secretions - Dry
or sandy eyes
156
CVS
• Blockade of vagal slowing
• Relative tachycardia
• Due to M2 blockage

157
 Respiratory System

• Smooth muscles & secretory glands of airway

receive vagal innervation & contain muscarinic
receptors.
• Receptor blockade leads to Bronchodilatation &
decrease in secretions.
• For COPD or Asthma - antimuscarinic drugs are
effective .
158
Gastrointestinal tract
• Marked effect on salivary secretions- Dry mouth.
• Gastric secretions affected less.
Pirenzepine & Telenzepine - decrease gastric secretion with
lesser side effects.
• Motility of GIT smooth muscles decreases.
Walls of viscera relaxed.
Tone and propulsive movements decrease.
Gastric emptying time – Prolonged
Diarrhoea due to over dosage of parasympathetic
agents – Stopped
• Spasmolytic activity in some synthetic antimuscarinic
agents.
159
Genitourinary tract
• Smooth muscles of ureters and bladder wall –
relaxed – voiding is slowed.

• Useful in treatment of spasm by mild inflammatory

conditions and neurologic conditions.

• But precipitation of urinary retention in elderly men

with prostatic hyperplasia, So contraindicated.

160
Glands
• Decrease sweat, salivary, tracheobronchial and
lacrimal secretion (M3 blockage)
• Skin and eyes become dry
• Talking and swallowing may be difficult.
• Decrease secretion of acid, pepsin and mucus in
the stomach.

161
Body temperature
• Rise in body temperature occurs at higher doses. It
is due to both inhibition of sweating as well as well
as stimulation of temperature regulating center in
the hypothalamus.

162
Action of anticholinergic

1. mydriasis (dilation of the pupil)

2. antispasmodic (reduce
motility of the GI tract)
3. Reduce Hypermotility states of
the urinary bladder.
4. blocks the salivary glands
secretion (xerostomia).

163
Mechanism Of Action
• Atropine causes reversible blockade of the
cholinomimetic actions at muscarinic receptors –
• Blockade by a small dose of atropine can be
overcome by a large concentration of Ach or similar
drug.
• Atropine prevents actions such as release of
inositol triphosphate(IP3) and the inhibition of
adenylyl cyclase that are caused by muscarinic
agonists.
• Highly selective for muscarinic receptors .

164
 Pharmakokinetics
• Atropine is readily absorbed from gut and
conjuctival membranes.
• Scopolamine is absorbed across the skin,
(Transdermal route).
• Partially metabolised by the liver.
• Eliminated primarily in the urine.
• Half life of about 4 hours.

165
Uses
A. For Central action-

• Parkinson’s disease –

• Benztropine, Biperiden, Procyclidine & Trihexyphenidyl

used as adjunctive therapy.

• Motion sickness -

• Scopolamine – one of the oldest drug for sea sickness.

• Injection, oral or transdermal (patch behind the pinna ,
prophylactically 4 hrs before journey, effect persists for 3
days ).
166
Uses
• As Antisecretory-
• Preanesthetic medication-
When irritant General anesthetic (GA) is used, before
their administration anticholinergics given to
decrease salivary and tracheobronchial secretion.
• Peptic Ulcer
• Decrease gastric acid secretion

167
Uses
• As Antispasmodic
• Intestinal and renal colic - abdominal cramps
• In the treatment of traveller’s diarrhoea, drug induced
diarrhoea.
• To relieve urinary frequency and urgency.
• Enuresis in children.
• Oxybutinin - to relieve bladder spasm after urologic surgery
e.g. prostatectomy.

168
 Respiratory disorders –
• Hyperactive neural bronchoconstrictor reflex in asthma,
mediated by vagus, acting on muscarinic receptors on
bronchial smooth muscle cells.
• Ipratropium bromide - A synthetic analogue of atropine,
used as inhalational drug in asthma. Aerosole route –
Maximal conc. at bronchial target with reduced systemic
effects.
• COPD patients – Chronic smokers, older patients.
. Tiotropium bromide - A long acting quaternary aerosol
anti-muscarinic drug, can be given once daily.
169
Ophthalmological disorders-
• Accurate measurement of refractive error in
uncooperative patients, young children require ciliary
paralysis (have high ciliary tone).
• Retinal examination - when mydriasis is required , so for
complete examination, eye drops or ointment. (less
systemic absorbtion of ointment form by passage through
naso-lacrimal duct)
• Shorter acting anti-muscarinics (Cyclopentolate and
tropicamide) have largely replaced atropine due to
prolonged mydriasis observed with atropine (7-10 days
verses 6-24 hours with other agents like tropicamide).

170
CVS
• To counteract bradycardia and partial heart block in
selected patients where increased vagal tone is
responsible.
• digitalis toxicity .

171
POISONINGS
• Organophosphate poisoning : 1-2 mg i.v. atropine
sulfate every 5-15 min until signs of dry mouth, reversal of
miosis occurs.
• Some type of mushroom poisoning-
• Massive doses of antagonist may be required over a long
period of time to counteract the poisons.
• Also blocks the effects of excess Ach resulting from
cholinesterase inhibitors, such as physostigmine.

172
Adverse effects
Dry mouth, mydriasis, blurred vision, tachycardia, dry
eyes, Body temp. increases, constipation,
hallucinations, agitation, delirium which may progress
to depression, collapse of circulatory and respiratory
system, coma and death.

173
Atropine poisoning
Treatment
• Temperature control with cooling blankets and
seizure control with diazepam .
• Physostigmine – small doses given slowly i.v.
• To manage ganglionic blockade with marked
orthostatic hypotension, give symatho-mimetic
agents –phenylepherine,

174
Contraindications
• Glaucoma patients esp. angle closure.
• Systemic use of moderate doses may ppt. angle
closure.
• In elderly men with caution. Avoided in those with a
history of prostatic hyperplasia.
• Slow gastric emptying may increase symptoms
in patients with gastric ulcer.
• Nonselective anti-muscarinic agents should never
be used to treat acid-peptic disease.

175
 OTHER DRUGS
Homatropine
Cyclopentolate Ophthalmic
Tropicamide
Hyoscine Butyl Br:- G .I. smooth muscles
Atropine Methonitrate:- Oral
Methantheline:- Oral, long duration
Ganglion block→ postural hypo.
Urinary retn, impotence.
Propantheline:- Less S/E
Oxyphenonium:- Potent antispasmodic
Pirenzepine:- M1 selective (Telenzepine)

176
 OTHER DRUGS (contd.)
Dicyclomine :- Direct relaxant also + antiemetic
Oxybutynin :- Urinary bladder & salivation
Glycopyrrolate:- Potent, rapid
Flavoxate:- Analgesic, L.A. & Anticholinergic
urinary pathologies
Clidinium:- With chlordiazepoxide
Isopropamide:- Long duration
Ipratropium:- Bronchi (inhalation)
Tiotropium
Drotavarine:- Selective PDE4

177
II. Neuromuscular-blocking drugs nicotinic
receptors antagonist

1. Nondepolarizing blockers
Tubocurarine is the prototype agent in this class
interact with the nicotinic receptors to prevent the binding of
Ach --- inhibit muscular contraction
Therapeutic uses:
as adjuvant drugs in anesthesia during surgery to relax skeletal
muscle and to facilitate intubation

2. Depolarizing agents
Succinylcholine
rapid onset and short duration of action, useful when rapid
endotracheal intubation is required 178
179
 Cholinergic receptors - 2 types

• Muscarinic (M) and Nicotinic (N):

Nicotinic (N) –
Muscarinic ligand gated
(M) - GPCR

180
Muscarinic Receptors ??

1. Selectively stimulated by Muscarine and blocked by

Atropine – all are G-protein coupled receptors
2. Primarily located in heart, eye, smooth muscles and
glands of GIT
3. Subsidiary M receptors are also present in ganglia for
modulation – long lasting late EPSP
4. Autoreceptors (M type) are present in prejunctional
cholinergic Nerve endings
– also in adrenergic nerve terminals leading to vasodilatation
when Ach is injected
5. Blood vessels: All blood vessels have muscarninc receptors
although no cholinergic innervations

181
 Muscarinic Receptors - Subtypes
• Pharmacologically - M1, M2, M3, M4 and M5
• M4 and M5 are present in certain areas of Brain and
regulate other neurotransmitters
• M1, M3 and M5 fall in one class, while M2 and M4 in
another class
• However - M1, M2 and M3 are major ones and present
in effector cell and prejunctional nerve endings in CNS
• All subtypes have little agonist selectivity but selective
antagonist selectivity
• Most organs usually have more than one subtype but
one subtype predominates in a tissue

182
 Muscarinic Receptors - Location
• M1: Ganglion Cells and Central Neurons (cortex,
hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid secretion and
relaxation of LES (vagal)
• Learning, memory and motor functions
• M2: Cardiac Muscarinic receptors
– Mediate vagal bradycardia
– Also auto receptors in cholinergic nerve endings
• M3: Visceral smooth muscles, glands and vascular
endothelium. Also Iris and Ciliary muscles

183
 Muscarinic Receptor Subtypes
M1 M2 M3
Location Autonomic ganglia, Heart and CNS SMs of Viscera,
Gastric glands and Eye, exocrine
CNS glands and
endothelium
Functions EPSP & Histamine Less impulse Visceral SM
release & acid generation, less velocity contraction,
secretion with CNS of conduction, Constriction of
learning and motor decreased contractility, pupil, contraction
functions less Ach release of Cilliary muscle
and vasodilatation
Agonists Oxotremorine Methacholine Bethanechol

Antagonists Pirenzepine Methoctramine & Darifenacin

Triptramine
Transducer IP3/DAG and PLA2 K+ channel opening and IP3/DAG and PLA2
increase – Ca++ and decresed cAMP increase – Ca++
PG and PG

184
 Acetylcholine (cholinergic receptors)
– Muscarinic Receptors

• Selectively stimulated by Muscarine and

blocked by Atropine

M1 M2 M3

Ganglia Heart Glands and

and CNS Smooth Muscles

185
Nicotinic (N) Receptors

• Nicotinic receptors: nicotinic actions of ACh are

those that can be reproduced by the injection of
Nicotine (Nicotiana tabacum)
– Can be blocked by tubocurarine and
hexamethonium
• ligand-gated ion channels
– activation results in a rapid increase in cellular
permeability to Na+ and Ca++ resulting -
depolarization and initiation of action potential

186
 Nicotinic Receptors - NM Vs NN
NM (Muscle type) NN (Ganglion type)
1. Location: Skeletal Muscle 1. Location: In autonomic ganglia of
all type (ganglion type) –
end plates Sympathetic, Parasympathetic and
2. Function: Stimulate skeletal also Adrenal Medulla
2. Function: Depolarization and
muscle (contraction) postganglionic impulse – stimulate
3. MOA: Postsynaptic and all autonomic ganglia
Excitatory (increases Na+ and 3. MOA: Excitatory – Na+, K+ and
K+ permeability) Ca+ channel opening
4. Agonists: ACh, CCh, nicotine
4. Agonists: ACh, carbachol – Selectively stimulated by
(CCh), suxamethonium Dimethyl phenyl piperazinium
– Selective stimulation by phenyl (DMPP)
trimethyl ammonium (PTMA) 5. Antagonists: Trimethaphan,
5. Antagonists: tubocurarine, Mecamylamine and
Hexamethonium
Atracurium, vecuronium and
pancuronium

187
Adrenergic and antiadrenergic drugs

188
DOPA is
decarboxylated
to form
dopamine

Dopamine is
hydroxylated
to form
norepinephrine

189
190
191
 α-Adrenergic Receptors
α1 α2

Location Postsynaptic ‐Presynaptic neuron membrane:

membrane of the sympathatic and parasympathatic
effector organs ‐Pancreas β cells
‐At certain vascular smooth muscle
cells
Binding to Adrenergic effect Feedback inhibition:
agonist ↓‐-sympathatic output
↓‐-cholinergic output (minimal(

Effect Classic adrenergic ‐Control adrenergic neuromediator

effect (e.g. ‐Control insulin output
Contraction of the
smooth muscles( 192
193
194
β-Adrenergic Receptors
• β receptors: β1, β2 and β3
• Different locations, hence, functions
• β1 : more predominant at Heart
• β2: more predominant smooth muscle (blood vessel and
bronchi)
• Β3 and little β1 are located in adipose tissue lipolysis
• Drugs differ in affinity to β receptors
β1 receptors have approximately equal affinities for
epinephrine and norepinephrine,
β2 receptors have a higher affinity for epinephrine than
for norepinephrine
195
196
197
198
 Adrenergic Agonists (Sympathomimetic)
They are classified according to their structure:
A. Catecholamines
such as epinephrine, norepinephrine, isoproterenol, and
dopamine
show highest potency in activating α or β receptors.
Rapid inactivation: metabolized by COMT and MAO
Short t1/2
Poor penetration into the CNS: polar
Only parenterally (not effective orally)

199
 Adrenergic Agonists Sympathomimetic
They are classified according to their structure:
B. Noncatecholamines
include phenylephrine, ephedrine, and amphetamine
Low potency
have longer half-lives, because they are not inactivated by
COMT.
Greater access to the CNS.
Oral and parenterally

200
 Catecholamines Noncatecholamines
Drugs Epinephrine, Norepinephrine, Phenylephrine,
Isoproterenol, Dopamine Ephedrine,
Amphetamine
Potency in activating High Less
adrenergic receptors
Inactivation Rapid (shorter T)1/2 Slower (longer T)1/2
(metabolism) rate
Inactivation enzymes COMT No effect of COMT
MAO Poor effect of MAO

Oral Ineffective effective

CNS penetration Poor, but have effect High
(e.g. anxiety, headache
and tremor(
201
202
203
 Epinephrine Norepinephrine
Release Adrenal medulla Major: postganglionic sympathatic
neurons
Minor: adrenal medulla
Adrenergic receptor Low dose: β effect Mainly α effect (vasoconstriction)
(vasodilation(
High dose: α effect
(vasoconstriction(
Cardiovascular and +ve inotropic (contractility) and 1)Vasoconstriction for all blood
kidney Effect chronotropic (heart rate) vessels and vasodilation of certain
action vessels
2)Increase renin release 2)Initially: +ive inotropic
vasoconstriction 3) ↑Systolic & ↑diastolic BP
3)Vasoconstriction and
vasodilation of certain vessels
4)Decrease in renal blood flow
5) ↑Systolic & ↓diastolic BP

Duration of action Short Very short

204
I. Direct-acting adrenergic agonist
1. Epinephrine: Action
II. CVS effect:
strengthens the contractility of the myocardium (positive
inotropic) and increases its rate of contraction (positive
chronotropic).
Activates β1 receptors on the kidney to cause renin release
---- angiotensin II --- a potent vasoconstrictor.
constricts arterioles in the skin, mucous membranes, and
viscera (α effects).
 Therefore, the cumulative effect is an increase in systolic
blood pressure

205
Respiratory:
causes powerful bronchodilation by acting directly on bronchial smooth
muscle (β2 action).
Hyperglycemia:
increased glycogenolysis in the liver (β2 effect),
increased release of glucagon (β2 effect),
decreased release of insulin (α2 effect).
Therapeutic uses
1. Treatment of acute asthma and anaphylactic shock, epinephrine is the
drug of choice
2. Anaphylactic shock
3. Cardiac arrest
Side effect:
1. Anxiety, fear, tension and tremors
2. Cerebral haemorrhage
3. Cardiac arrhythmias

206
 I. Direct-acting adrenergic agonist
2. Norepinephrine
Norepinephrine causes a rise in peripheral resistance
due to intense vasoconstriction (α1 effect) of most
vascular beds (including kidney)
Both systolic and diastolic blood pressures increase
Norepinephrine is used to treat cardiogenic shock

207
I. Direct-acting adrenergic agonist
3. Dopamine

Dopamine stimulates: α1 & β1 adrenergic, D1 & D2

activate dopaminergic receptors, thereby increasing blood
flow to the kidneys
Dopamine actions:
Cardiovascular: +ive inotropic and chronotropic effect (β1
effect)
vasoconstriction (high dose at α1)
Renal and visceral: vasodilation (dopaminergic receptor
effect)

Uses: Dopamine is the drug of choice for cardiogenic shock

208
 I. Direct-acting adrenergic agonist
4. Dobutamine
β1-receptor agonist ! ↑ heart rate without affecting blood
vessels
Therapeutic use: in congestive heart failure
S.E: atrial fibrillation

5. Clonidine
α2-receptor agonist.
Acts centrally by decreasing sympathatic outflow ! lower BP

209
I. Direct-acting adrenergic agonist
Short acting: Albuterol , terbutaline
Long acting: Salmeterol and formoterol
β2 agonists used primarily as bronchodilators
administered by inhaler for asthma
Fast onset of action

210
I. Direct-acting adrenergic agonist
Phenylephrine and Oxymetazoline:
α1-receptor agonist
Used locally to induce vasoconstriction:
Nasal spray: decongestant (may cause
burning of the mucosa and sneezing)

211
 II. Indirect-acting adrenergic agonists
1. Amphetamine stimulants of the CNS
MOA:
Blockade of norepinephrine uptake and enhances its release !
indirect stimulate α1 and β1 receptor agonist
Centrally: stimulatory action !
increase blood pressure significantly by α1-
agonist
β-stimulatory effects on the heart.

212
II. Indirect-acting adrenergic agonists

2. Cocaine
MOA:
Blockade of norepinephrine uptake !
sympathatic activity by working indirectly on α1 and
β receptor agonist
Centrally: stimulatory action ! drug abuse
So: prolongs the CNS and cause intense euphoria

213
III. MIXED-ACTION ADRENERGIC AGONISTS
Ephedrine and pseudoephedrine
MOA: release stored norepinephrine from
nerve endings
directly stimulate both α and β receptors.
α1-agonist that constricts the nasal mucosa,
thereby decreasing airway resistance.
Used as a nasal decongestant

214
215
216
217
 Anti-adrenergic Drugs/Sympatholytics

• These are the drugs that antagonize the

action of adrenaline & related drugs.
• They are competitive antagonist of α or β or
both receptors.
• Classification:

Alpha (α) Beta (β) blocker

blocker •Nonselective
•α1 selective •Cardioselective
•α2 selective )β1)
•Nonselective 218
 Alpha (α) blockers
α1 selective Prazosin, Terazosin,
Doxazosin, Tamsulosin
α2 selective Yohimbine, Idazoxan,
Atipamezole
Non- selective α blocker Phenoxybenzamine,
Phentolamine,
tolazoline, ergotamine,
ergotoxine,
chlorpromazine
219
Actions:
• Vasodilation (venous):- Fall in BP
• Reflex tachycardia
• Nasal congestion
• Miosis
• Increase intestinal motility
• Trigone, sphincter & prostate tone is
reduced:- Improve urine flow
• Inhibit ejaculation:- Impotence

220
Prazosin, Terzosin, Doxazosin & Tamsulosin
• These are selective competitive blockers of the
α1 receptor.
• Prazosin, Terazosin & Doxazosin are useful in
the treatment of hypertension as they cause
dilation of artery. They are orally effective with
high plasma protein bound, metabolised in liver
& excreted from bile.
• Tamsulosin is uroselective )α1A & α1D) indicated
for the treatment of benign prostatic hypertrophy
(BPH).
• Uses: Pheochromocytoma, Hypertension,
Benign prostrate hypertrophy, Raynaud’s
disease (Fingers and toes —numbness and cold) 221
• Yohimbine is a selective competitive α2
blocker. It is found as a component of the
bark of the yohimbe tree.
• It directly blocks α2 receptors and has been
used to relieve vasoconstriction associated
with Raynaud disease.
• Yohimbine is contraindicated in CNS and
cardiovascular conditions because it is a
CNS and cardiovascular stimulant.

222
• Phenoxybenzamine is nonselective, linking
covalently to both α1 and α2 receptors. The
actions of phenoxybenzamine last about 24
hours after a single administration.
• Dose: 20-60mg/day oral
• Phentolamine produces a competitive block of α1
and α2 receptors. This drug’s action lasts for
approximately 4 hours after a single
administration.
• Dose: 5mg i.v. repeated as required
• Uses:
• Pheochromocytoma
• Hypertension
• Benign prostatic hypertrophy
• Peripheral vascular disease
223
 Beta (β)-blockers
Non-selective β-blocker Propanolol, sotalol,
timolol, pindolol,
labetalol,
carvedilol
Cardioselective )β1) Atenolol, Metoprolol,
Acebutol, Esmolol

224
Propanolol
• Propanolol is the β-adrenergic antagonist and
blocks both β1 and β2 receptors with equal affinity.

Pharmacological Actions:
1. Cardio Vascular System (CVS)
• Heart: HR, Force of contraction, A-V conduction
• Fall in BP
2. Respiratory Tract
• Increased bronchial resistance )β2 blockade)
3. Metabolic
• Blocks adrenergically mediated lipolysis
• Inhibits glygenolysis in heart, skeletal muscles, liver
• May reduce carbohydrate tolerance (decreased insulin release)

225
4. Skeletal muscle
• Inhibits adrenergically provoked tremor )β2
blockade)
6. Eye
• Reduced secretion of aqueous humor and intra
ocular tension
7. Uterus
• Relaxant activity of β agonists blocked

• Dose: 10mg BD to 160mg QID oral, 2-5mg i.v.

parenteral

226
Timolol
• Timolol blocks β1 and β2 adrenoceptors and is
more potent than propranolol.
• Timolol reduces the production of aqueous humor
in the eye. It is used topically in the treatment of
chronic open-angle glaucoma and occasionally
for systemic treatment of hypertension. (0.25-5%
eyedrops)
Labetalol and carvedilol
• Labetalol and carvedilol are β blockers with
additional α1 blocking actions that produce
peripheral vasodilation, thereby reducing blood
pressure.
• It is useful in treating hypertensive patients with
increased peripheral vascular resistance. 227
Acebutolol, Atenolol, Metoprolol & Esmolol
• Cardioselective β blockers, such as acebutolol,
atenolol, and metoprolol antagonize β1 receptors.
This cardio selectivity is pronounced at low doses.
• These drugs lower blood pressure in hypertension
and increase exercise tolerance in angina.
• Esmolol has a very short lifetime due to metabolism
of an ester linkage. It is only given intravenously if
required during surgery or diagnostic procedures.
• The cardiospecific blockers have relatively little effect
on pulmonary function, peripheral resistance, and
carbohydrate metabolism.
• Dose: Acebutolol 200-400mg OD, Atenolol 12.5-50mg
OD
228
Uses
• Hypertension
• Stable Angina
• Cardiac arrhythmias
• Myocardial infarction
• Pheochromocytoma
• Thyrotoxicosis
• Migraine
• Anxiety
• Tremor
• Glaucoma

229
Adverse Effects:
• Can accentuate myocardial insufficiency and
precipitate CHF/edema
• Bradycardia
• Exacerbates variant angina
• Impaired Carbohydrate tolerance
• Altered plasma lipid profile
• Tiredness and reduced exercise capacity
• Cold hands and feet
• Others: G.I. upset, lack of drive, nightmares,
forgetfulness, hallucinations, sexual distress in male
Contraindications:
• Sudden withdrawal : rebound hypertension, worsening
of angina, sudden death
• Worsens COPD; can produce acute Bronchial asthma
• Partial or complete heart block
230
231
Skeletal Muscle Relaxants and
Neuromuscular blocking drugs

232
Skeletal Muscle Relaxants
Definition
Skeletal Muscle Relaxants are the drugs that act
peripherally at neuromuscular junction or muscle fiber
itself or in cerebrospinal axis to reduce muscle tone and
cause muscle paralysis.

Neuromuscular blocking drugs: These are agents that act

peripherally at neuromuscular junction/muscle fibre
itself to block neuromuscular transmission.

233
234
Classification

235
236
 Acetylcholine
• Acetylcholine is a major neurohumoral transmitter
at autonomic, somatic and central nervous
system:
1. All preganglionic sites (Both Parasympathetic and
sympathetic)
2. Skeletal Muscles
3. CNS: Cortex Basal ganglia, spinal cord and others
Parasympathetic Stimulation – Acetylcholine (ACh)
release at neuroeffector junction – biological
effects
Sympathetic stimulation – Nonadrenaline (NA) at
neuroeffector junction – biological effects
237
Acetylcholine

238
Neuromuscular Junction (NMJ)

239
Physiology of Skeletal Muscle Contraction

240
241
 Peripherally acting: Neuromuscular Blockers

• Depolarizing Blockers – mimic the action of

acetylcholine (ACh)
– Agonists
– Succinylcholine (SCh) is the only drug used clinically

• Non-Depolarizing – interferes with the action of ACh

– Competitive Blockers (Antagonist)
– Further divided into short, intermediate and long acting non-
depolarizing drugs

242
 Depolarizing Block - Succinylcholine
• Succinylcholine have affinity and sub-maximal
intrinsic activity at Nm receptor.

• It acts on sodium channels, open them and

causes initial twitching and fasciculation.

• It does not dissociate rapidly from the receptors

resulting in prolonged depolarization and
inactivation of Na+ channels.

243
Mechanism of Action: Succinylcholine

244
 Succinylcholine acts on the Nicotinic receptors of
the muscles, stimulates them and ultimately cause
their relaxation.
This process occur in two phases :
Phase I: During Phase I (depolarizing phase), they
cause muscular fasciculations while they are
depolarizing the muscle fibers.

Phase II: After sufficient depolarization has occurred,

phase II (desensitized phase) sets and the muscle is
no longer responsive to Ach released by the nerve
endings.

245
246
 Succinylcholine
Advantages:
•Most commonly used for Tracheal intubation
•Rapid onset (1-2 min)
•Good intubation conditions – relax jaw, separated vocal chords with immobility, no
diaphargmatic movements
•Short duration of action (5-10 minutes)
•Dose 1-1.5mg/kg
•Used as continuous infusion occasionally

Disadvantages:
•Cardiovascular: unpredictable BP, heart rate and arrhythmias
•Fasciculation
•Muscle pain
•Increased intraocular pressure
•Increased intracranial pressure
•Hyperkelemia: k+ efflux from muscles, life threatening in Cardiac Heart Failure,
patient with diuretics etc

247
 Non-Depolarising Drugs
• Competitive Blockers having no intrinsic activity
(antagonist)
• These are of 3 types based on their activity:
– Long Acting : d-TC, Pancuronium,
Pipecuronium, Gallamine (Kidney Excretion)
– Intermediate : Vecuronium, Rocuronium,
Atracuronium (eliminated by liver)
– Short Acting : Mivacuronium, Ropcacuronium
(inactivated by plasma cholinesterase)

248
 Mechanism of Action:
Non-depolarizing Block in Muscles

249
 Mechanism of Action

• They have affinity but no intrinsic activity for Nicotinic receptors

(Antagonist)
• They are quaternary N+ compounds that contain cationic head
that act only on closed Na+ channels – No action on already
opened Na+ channels
• The cationic head binds to the anionic ACh binding site at the α –
subunit of the Nm receptor but cannot bring conformational
change & Na+ channels remians closed
• No End Plate Potential generation in nerve endings
• Muscle Action Potential decreases
• Action can be overcome by increased ACh concentration or
blocking of acetylcholinesterase
• They also block prejunctional ACh receptors on motor nerve
endings – FADE PHENOMENON 250
251
 Effects of Non-depolarizing blockers
• Low Doses:
– Competitive antagonists of ACh
– Action reversed by ACh ecterase inhibitors

• Large Doses:
– Ion Channel is blocked
– More weakness of neuromuscular transmission
– Action could not be reversed by ACh esterase
inhibitors

• Other actions:
– Can block pre-junctional Na+ channels and interfere
with mobilization of ACh at nerve endings

252
Non-depolarizing Drug: d-Tubocurarine
• 1st agent to undergo clinical investigation
• purified curare – Chondodendrom tomentosum
• ED95= 0.5mg/kg
• undergoes minimal metabolism- is excreted
- 10% in urine
- 45% in bile
• excretion impaired in Renal Failure

253
CVS
Effects:
 Hypotension frequently even at doses < ED50
 histamine released (skin flushing frequently)
 autonomic ganglionic blockade- manifests as
hypotension

254
 Non-depolarizing Drugs
• Gallamine
– Less potent than curare
– Tachycardia
• D-Tubocurarine
– 1-2 hr duration of action
– Histamine releaser (Brochospasm,
hypotension)
– Blocks autonomic ganglia (Hypotension)
• Atracurium
– Rapid recovery
– Safe in hepatic & renal impairment
– Spontaneous inactivation to laudanosine
(seizures)
255
 Non-depolarizing Drugs
• Mivacurium
– Metabolized by pseudocholinesterase
– Fast onset and short duration

• Pencuronium
– Long duration of action
– Tachycardia

• Vecuronium
– Intermediate duration of action
– Fewer side effects (no histamine release, no
ganglion blockade, no antimuscarinic action)

256
257
 Other Actions of Nm Blockers
• Automic ganglia:
 Partial blockage of ganglia (Nm type of receptor)
 Results in fall in BP and tachycardia
• Histamine release:
 Hypotension
 Bronchospasm, excess bronchial and salivary
secretion
• Cardiovascular: Fall in BP due to
 Ganglion blockage, histamine release and reduced
venous return
 Succinylcholine may cause cardiac arrhythmias
• GIT: Paralytic ileus
258
Drug treatment in Glaucoma

259
 Glaucoma
•Glaucoma is an eye disease that is associated with
increased intraocular pressure, in which damage to the eye
(optic) nerve can lead to loss of vision and even blindness.
• It can be open angle glaucoma & angle closure glaucoma.

Drugs for Glaucoma:

1. Beta blockers: Timolol, Betaxolol, Levobunolol
2. Alpha agonists: Dipivefrine, Apraclonidine,
Brimonidine
3. Prostaglandin analogues: Latanoprost, Travoprost
4. Carbonic anhydrase inhibitors: Acetazolamide,
Dorzolamide
5. Anticholinesterase/Miotics: Pilocarpine
260
261
1. Beta (β) blockers: Timolol, Betaxolol, Levobunolol
Topical β blockers have been the first line drugs in treatment
of glaucoma. They lower i.o.t. by reducing aqueous
formation. Ocular β blockers are lipophilic with high ocular
penetration.

2. Alpha (α) agonists: Dipivefrine, Apraclonidine

Dipivefrine is a prodrug of Adrenaline that penetrates
cornea. The released Adr (from dipivefrine) lowers i.o.t. by
augmenting uveoscleral outflow, β2 receptor mediated
increase in hydraulic conductivity of trabecular filtering cells
as well as by reducing aqueous humor formation (α1 + α2
mediated).
Apraclonidine is a polar clonidine congener which does not
cross blood brain barrier, but applied topically (0.5%-1%)
that lowers i.o.t. by 25%.

262
3. Prostaglandin analogues: Latanoprost, Travoprost
Prostaglandins at low concentration lowers i.o.t without
inducing ocular inflammation. It acts by increasing
uveoscleral outflow, increasing permeability of tissues in
ciliary muscle or by an action on episcleral vessels. Ciliary
body COX-2 has been found to be down regulated in wide
angle glaucoma indicating a physiological role of PGs in
aqueous humor dynamics.

4. Carbonic anhydrase inhibitors: Acetazolamide,

Dorzolamide
Oral treatment with acetazolamide (0.25 g 6–12 hourly)
reduces aqueous formation by limiting generation of
bicarbonate ion in the ciliary epithelium. It is used to
supplement ocular hypotensive drugs for short term
indications like angle closure, before and after ocular
surgery/laser therapy. 263
5. Anticholinesterase/Miotics: Pilocarpine
• Pilocarpine is used to treat glaucoma and is the drug of choice in the
emergency lowering of intraocular pressure of both narrow- angle (or
closed-angle) and wide-angle (also called open-angle) glaucoma.
• It is extremely effective in opening the trabecular meshwork around
Schlemm’s canal, causing an immediate drop in intraocular pressure as
a result of the increased drainage of aqueous humour. (action within few
minutes, lasts 4-8 hours)
• Mechanism of action: Pilocarpine produces rapid miosis, contraction
of the ciliary muscle & fall in intraocular pressure. It acts through direct
stimulation of muscarinic receptors and smooth muscle such as the iris
and secretory glands.
• It is used as 0.5-4% eye drop.
• Adverse effects: Pilocarpine can enter the brain and cause CNS
disturbances, sweating & salivation.
• Nursing Management: Parenteral atropine 2mg is administered to
counteract the toxicity of pilocarpine 264