Pharmac ology of drug acting on

Peripher al Nervous System

ORGANIZATION AND FUNCTION OF

AUTONOMIC NERVOUS SYSTEM

Points to be covered in this topic

; 1. Introductio n to PNS
--.....
; 2. Organizati on of ANS
..........
: 3. Functions of ANS
........

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DISCUSSION
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APP PHARMA EXAM PREPARATION
SIMPLIFIED
 □ INTRODUCTION TO PNS
• The nervous system is broadly classified as (fig. - 1)
✓ Central Nervous System (CNS)
✓ Peripheral Nervous System (PNS)
• The nervous system has an important role to
communicate information from outside the body;
process it and to take corrective action based on the
I ' ',' '

.I
received response. ~ \

NERVOUS SYSTEM

Central nervous system Peripheral nervous system

rvous system

:
Pilra.s~·m path e tic sys tem

t ..
Sym p .1 t hPt i c sy st e 111

•!• Peripheral Nervous System (PNS)

• The PNS includes all the neurons viz., afferent (sensory) neuron, efferent
(motor) neuron, and ganglia (found outside the CNS).
• Any sensory input or stimulus from the Afferent nerve

periphery to the CNS is carried by I

Skin
afferent neurons and modify motor
Spinal cord- ,.
output by the action of reflex arcs (fig. 2). Muscle

•!• Central Nervous System (CNS) t_. Efferent nerve

• The CNS covers the brain and the spinal cord.
• The CNS receives and processes incoming sensory information and
responds back by sending out signals which in turn activates or modifies
body processes.
❖ Ganglion
• Ganglia are structures containing a number of nerve cell bodies,
typically linked by synapses and often forming a swelling on nerve fibre.
• A ganglion is a collection of neuronal bodies found in voluntary and
autonomic branches of the peripheral nervous system (PNS).
• Ganglia can be thought of as synaptic relay stations between neurons.
• The information enters the ganglia ➔ excites the neuron in ganglia ➔

then exits.
❖ Autonomic nervous system (ANS)

• The autonomic nervous system is a component of the peripheral nervous

system that regulates involuntary physiologic processes including heart
rate, blood pressure, respiration, digestion, and sexual arousal
• It contains three anatomically distinct divisions:
✓ Sympathetic
✓ Parasympathetic
✓ Enteric

□ ORGANIZATION OF ANS
•!• Based on parts of the body which
responds, PNS is sub-divided into :-
✓ Somatic Nervous System
Somabe nM'OU$ s-,stem
✓ Autonomic nervous system (ANS).
•) Traditionally, the ANS and somatic
nervous system are usually described as
an output of efferent portion of PNS.

1. Somatic Nervous System

► The somatic nervous system consists of two types of neurons :-
✓ Sensory ➔ carry information from the skin and special sensory
receptors to the CNS.
✓ Motor ➔ conduct impulses from the CNS to skeletal muscles.
► Axons of somatic motor neurons extends fron1 CNS and are myelinated.
► The neurotransmitter release by somatic nerves at the Neuromuscular
Junction (NM)) is acetyl choline (ACh).
 _ . . direction ol
c:onducUon of
Motor neurone MNe impu9N
Carry Impulses from the CNS to
the effector or1ans (muscles/
glands)
c:.llbody

8eneo,y MWOM

Bring Impulses from the sense

~ L:.
Ci)
/ axon
organs or receptors Into the CNS
cell body

These receive Impulses from

sensory neurones or other
intermediate neurones and relay
them to motor neurones or other
intermediate neurones

□ Difference between sensory and motor neurons :-

SENSORY NEURON MOTOR NEURON
• They have short axon. • They have large axon.
• They have one long dendron. • They have many dendFons.
• They transmit impulses from • They transmit impulses from
receptors to CNS. CNS to receptors.
• They have dendrites located in • They have axon located in CNS
CNS and axons outside the CNS. and dendrites outside the CNS.

2. Autonomic Nervous System (ANS)

•!• In ANS, a nerve originating from brain/ spinal cord first enters
ganglia and then reaches the effector organ.
•!• The nerve-fibre coming up to ganglia is termed as pre-ganglionic fibre.
•!• Nerve coming from ganglia to effector organ is called as post-
ganglionic fibre.
•!• The part of the nervous system that controls muscles of internal
organs (such as the heart, blood vessels, lungs, stomach, and intestines)
and glands (such as salivary glands and sweat glands).
 ❖ The junction between pre & postgang)ionic fibres is known as a syn apse.
•:• A synaptic cleft refers to a small gap between two neurons.
❖ The preganglionic neuron has its origin in the CNS.

•:• It further passes out from the CNS to form ganglia at the synaptic
junction together with the postganglionic neuron.
❖ The postganglionic neuron thus arises from the ganglia. It supplies the

effector organs or tissues.

•:• The ANS consists of three main anatomical divisions:
✓ Parasympathetic Nervous System (PSNS) or (Cholinergic Division)
✓ Sympathetic Nervous System (SNS) or (Adrenergic Division)
✓ Enteric Nervous System (ENS)

PARASYMPATHETIC
PREGANGLIONIC PosTGANGLIONIC TARGET
NEQ _
N uR_o_N ~~
_ _ _ _ _ _ _ _ _N_E_

Acetylcholine Acetylcholine

SYMPATHETIC
fREGANGLIONIC fO5fGANGLIONIC
NEURON
TARGET
NEURON

A~ ylcholine ➔O .•
. hr1ne
NorepInep
•Exceptions:
1) Acetylcholine for sweat glands
2) Epinephrine for adrenal medulla

1. Parasympathetic Nervous System (PSNS) or (Cholinergic Division) :-

• The parasympathetic nervous system (PSNS) is one of the three divisions of
the autonomic nervous system.
• The parasympathetic system is responsible for stimulation of ttrest-and-
digest" or "feed and breed" activities that occur when body is at rest.
• It is active especially after eating, including sexual arousal, salivation,
lacrimation (tears), urination, digestion, and -defecation.
• Parasympathetic system is commonly referred to as "craniosacral outflow".
• The preganglionic fibres originate from the nuclei of the third, seventh ,
ninth and tenth cranial nerves (111, VII, IX, and X), and, the fourth sacral
segments (S 2 to S4) of the spinal cord.
• The parasympathetic nervous system has three parts:
i) Preganglionic Parasympathetic Fibres:
o These fibres are neuronal axons.

o These long sized fibres are present in the midbrain, brain stem, and
lateral funiculus of the sacral part of the spinal cord.
o They form the cranio-sacral outflow as they come out
✓ Either through some of cranial nerves such as Oculomotor (III), facial
(VII), glossopharyngeal (IX) and Vagus (X) or
✓ Through the 2nd, 3r~ and 4th sacral spinal nerves.
o They synapse with neurons of the parasympathetic ganglia.
ii) Parasympathetic Ganglia:
o These are either located inside the visceral organs, or close to them.
o Every ganglion is made up of a mass of neurons.
o The parasympathetic ganglia do not interlink to form a chain.
iii) Postganglionic Parasympathetic Fibres:
o These fibres are neuronal axons.
o These small-sized neurons supply the smooth muscles and glands of the
visceral organs.
o Acetylcholine is secreted by the nerve endings of these fibres therefore
these are lmown as cholinergic nerve fibres.
o The parasympathetic nervous system is involved in energy conservation
by feeling of comfort, relaxation, pleasure etc. at the time of rest.

2. Sympathetic Nervous System (SNS) or (Adrenergic Division)

• The sympathetic nervous system (SNS) is the another divisions ofANS.
• The sympathetic nervous system consists of many nerve cells found in
the peripheral and central nervous systems.
• This allows organisms the ability to activate many different responses at
once, leading to a coordinated flight or fight response.
• The Sympathetic Nervous System is made up of the following parts:
i) Sympathetic Trunks: These represent a pair of
long cords located on either side of vertebral
column that run from the base of the skull to
the coccyx.
\"1::1 ~ ~ ~ Sympathetic
ii) Preganglionic Sympathetic Fibres: These fibres Trunk

are sn,all sized neuronal axons located along

the lateral funiculus of spinal cord.
iii) Postganglionic Sympathetic Fibres: These fibres are long sized
neuronal axons of chain ganglia. Their effect is widespread as they
innervate smooth muscles and glands of visceral organs.
iv) Collateral Ganglia: Three collateral ganglia are present called
I

collateral ganglia coeliac ie, superior, mesenteric & inferior mesenteric

ganglia. Postganglionic fibres spread from neurons of collateral
ganglia to visceral organs.
□ Difference between Sympathetic & Parasympathetic
Nervous System
Parasympathetic Sympathetic

8LOCO \'ESSEts
CNillM.

\
\
"-.....
.
I
......
"-..) Da:STMl ~

~~1,
- r~ ,~
□ FUNCTGION OF ANS
•!• The principle functions of ANS are repairing of body tiss ues,
maintenance of a constant internal environment (homoeostasis), and
response to stress or emergencies.
•!• Special centres are present in CNS (in hypothalamus, brain stem, and the
spinal cord) to regulate the ANS.
•!• Autonontic Nervous System has the following functions :
1. Reflex Activities : The ANS is involved in complex reflex activities that
depend on sensory input to the CNS and on motor output.
2. Deals with Excitation and Stressed Conditions.
3. Slowing Down the Body Processes except digestion and absorption of
,
food and the genitourinary system.
4. Maintenance of Heartbeat.
 Pharmacology of drug acting on
Peripheral Nervous System
NEURO-HUMORAL TRANSMISSION, CO-
TRANSMISSION & CLASSIFICATION OF
NEUROTRANSMITTERS

Points to be covered in this topic

--•;_ 1. Neuro-humoral transmission
- ~...•. 2. Co-transmission
_ _..,.
. . 3. Functions ofNeurohumoral Transmitter
,...

..__..,....
.. 4. Neurotransmitters & its classification

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APP PHARMA EXAM PREPARATION

~ &,~lePlay SIMPLIFIED
 □ NEURO-HUMORAL TRANSMISSION
• The term neurohumoral transmission designates the transfer of a nerve
impulse from a presynaptic to a postsynaptic neuron by means of a humoral
agent e.g. a biogenic amine, an amino acid or a peptide.
• Neurohumoral transmission implies that nerves transmit their message
across synapses and neuroeffector junctions by the release of humora l
( chen1ical) 1nessengers.
• The transmission of an impulse along a nerve fibre 1s an electrical
phenomenon.
• Normally, a cell in resting condition is electronegative; indicating that
extracellular charge is negative and intracellular charge is positive in nature.
• At the nerve ending i.e. at synapses, the transmission is chemical in nature.
• A specialised chemical is secreted at the nerve ending. It is called as
neurohumoral transmission.

•!• Four processes occur in relation to nerve transmission in

CNS. They are as follows:
(i) Neurotransmission
o Neurotransmission occurs due to specialised chemicals called as
neurotransmitters.
o They are synthesised in pre-synaptic neurons and are released in to
synaptic cleft.
o They rapidly stimulate or inhibit post-synaptic neurons or effector
organs.
o Eg. -Acetyl choline, Dopamine, Nor-epinephrine/Epinephrine,
(ii) Neuromodulation
o The chemicals causing neuromodulation are called as neuromodulators.
o They are released by neurons and astrocytes to produce slower pre OR
post synaptic responses.
o Eg. - Carbon dioxide, Adenosine, some Purines.
(iii) Neuromediation
o Neuromediation is caused by neuromediators, which are second
messengers.
o They plays a crucial role in eliciting pos t-syna ptic respon ses caused by
neurotransmitters.
o Eg. - cAMP, cGMP and inositol phosphate.

(iv) Mediation through neurotropic factors

o Neurotropic factors are released by CNS neurons, astrocytes & microglia.
o They act longer than neuromodulators to regulate the growth and
morphology of neurons.
o It controls the long ,term changes in brain like synaptic plasticity,
remodelling, phenotype characteristics.
o Eg. - Cytokines, chemokines, growth factors etc.

•!• Steps in Neurohumo ral Transmission

o Neurohumoral transmission involves the following four steps :-
Step 1: Initiation of an Action Potential and Axonal Conduction
• During resting conditions, the membrane potential inside a typical axon
is -70mV with respect to exterior of axon.
• High concentration of K• intracellularly and low levels of Na• and c1-
extracellularly cause this difference in the resting membrane potential
• Special voltage-gated ion channels are present that respond to changes
in voltage across the cell membrane.
• When membrane of neurons becomes n
.... 1

more permeable to Na· ions it results "- - - ------~ ·+ + + -----

+++ ++++ + + + --- ---
+ +++ + + ++
in a rapid depolarisation. ....
t
'
....
• An energy-dependent active transport -----~ pollftled
~

dlpdwed rtpOllltad
pump (sodium pump) maintains these ffllfflbrane INllbrlnt memlnne
<
ionic gradients.
Step 2: Arrival of an AP a t nerve terminal resulting in release of
neuro·trans mitter
• Neurotransmitters are synthesised in the nerve terminal and are stored
within the synaptic vesicles.
• As the action potential arrives at nerve terminals, an influx of ca 2•
occurs to promote fusion of synaptic vesicles with adjacent axoplasmic
membrane.
• The vesicular contents are discharged (exocytosis) into the synaptic
cleft and formation of new vesicles is initiated by the adjacent sections of
the membrane.

Step 3: Events at the Synaptic Cleft and Post·junctional Sites

• Diffusion of the neurotransmitter thus occurs across the synaptic cleft.
• An interaction between postjunctional receptors and neurotransmitters
occurs resulting in either excitatory or inhibitory postjunctional effects.
• Excitatory Postsynaptic Potential (EPSP) occurs with the infl~ of Ca2 +.
• Inhibitory Postsynaptic Potential (IPSP) occurs with the influx of CJ · or
outflux of K+ resulting in hyperpolarisation.

Step 4 : Termination of Effect of Released Transmitter

• Metabolic inactivation of the neurotransmitter by an extremely efficient
enzyme, acetylcholinesterase (AChE) results in the termination at the
cholinergic sites.
• Major mechanisms involving inactivation of neurotransmitter by enzymes
Monoamine Oxidase (MAO) or catechol•o•methyl trans/erase (COMT) at
the adrenoceptor sites.
• Reuptake . of neurotransmitter into the nerve terminals causes
termination of neurotransmitter activity.
 UCO-TRANSMITTERS
• Co-transmitters ➔ Certain chemicals support
and augment action of neurotransmitters. They
are called as co-transmitters.
• Co-transmission can be more broadly defined as
the release of multiple neurotransmitters
from non-overlapping pools of synaptic vesicles.

• The co-transmitter is stored in prejunctional nerve terminal (in the figure)

along with primary transmitter, but in separate vesicles (in some cases in
same vesicle itself).
• Nerve impulse release9 both the transmitters concurrently.
• Eg. - In the ANS along with primary transmitters (ACH and NA), neurones
are found to release Adenosine, Nitric Oxide, Prostaglandins, etc. as co-
transmitters.

□ FUNCTIONS OF NEUROHUMORAL TRANSMITTERS

1) Functions of Neurotransmitters via Sympathetic Syst em:-

i. Sympathetic Control on Heart: When extra oxygen and
energy are required (e.g., by muscles), heart starts
pumping more blood under sympathetic control. UndUatedpuJlil

ii. Glycogenolysis and Lipolysis: If more energy is required,

stores of energy are mobilised.
DIJatedpapl
iii. Vasoconstriction and Vasodilation: Both events are
regulated by the sympathetic system.

~
iv. Dilation of Pupil: Pupil dilates to see better in dark
v. Dilation of other Body Muscles: \ I
✓ Dilatation of detrusor muscle of bladder
✓ Constriction of sphincter ( evacuation of bladder is not a
priority during emergency).
✓ Bronchodilation occurs which is a sympathetic function.
2. Functions of Neurotransmitte rs via Parasympathetic System:
i. GIT Motility and Secretion of Digestive Ju ices ➔ It helps in absorption of
nutrients and release of energy which is vital for survival.
ii. Actions Opposite to Sympathetic System: For example,
a) Conservation of energy by reducing heart rate.
b) Stimulate emptying of bowel and bladder.
c) Cause constriction of pupil to protect retina against extra light.
d) Functions like digestion, bladder emptying are not required continuously.

□ NEUROTRANSMITTERS & ITS CLASSIFICATION

• A neurotransmitter is a signalling molecule secreted by a neuron to affect
another cell across a synapse.
• They are made up of amino acids and some are hormones.
• They transmit information from one neuron to the other.
• Major body functions like movement, emotional response, and physical
ability to experience pleasure and pain are controlled by neurotransmitters.
• They are released by presynaptic terminals (nerve endings) into the
synaptic cleft in response to arrival of an action potential
• On the postsynaptic terminals the neurotransmitter binds to a specific
receptor which finally evokes a response.
• Substances acting as neurotransmitters are categorised into :-
[I) On the Basis of Chemical Nature:
1) Amino acids (primarily glutamic acid, Gamma-Aminobutyric Acid
(GABA), aspartic acid, and glycine).
2) Peptides (vasopressin, somatostatin, neurotensin, etc.).
3) Monoamines (NE, dopamine and serotonin) plus ACh.
[II] On the Basis of Secretion Site:
i) Neurotransmitters of Sympathetic Nervous System: In this two
neurotransmitters are present:
a) Acetylcholine (ACh) (liberated at the ganglion) acts as a
neurotransmitter for the preganglionic sympathetic nerves.
b) Nor-adrenaline (NA) acts as a neurotransmitter for the
postganglionic sympathetic nerves.
ii) Ne urotransmitters of Parasympathetic Nervous System:
Acetylcholine (ACh) also acts as neurotransmitter for postganglionic
parasympathetic nerves.
 Phannacology of drug acting on
Peripheral Nervous System . -. .... ,.. .

CHOLINERGIC AND
ANTICHOLINERGIC DRUG

Points to be covered in this topic

............ 1. Intro. to Cholinergic system
____. 2. Biosynthesis, storage & release of ach
- .... 3. Cholinergic receptor
.---. 4. Parasympathomimetic dr ugs
■---.• 5. Parasympatholytic drugs
- .... 6. Chemistry of Parasympatholytics
_...._. 7. Anti-m~scarinicagents
---. 8. Anti-muscarinic poisoning & treatment
---. 9. Ganglionic stimulant drugs
GPATTM
.......... 10. Ganglionic blocker drugs D I SC U S SION
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APP PHARMA E XAM PR E PARAT ION

SIMP L I F I E D
GDC(ili't,,GJ
i\ AcvokltioNty ,,qy to A<.hic\'t
 l.J INTRODUCTION TO CHOLINERGIC SYSTEM
• Drugs related to autonomic nervous system (ANS) belong to two major
divisions of ANS: PSNS a nd SNS.
• Drugs mimicking the actions of ACh are called as parasympathomimetics.
• The drugs blocking actions of ACh are termed as parasympa tholytics.
• The drugs mimicking actions of nor-adrenalin/adrenalin are called as
syrnpathomimietics.
• The drugs antagonising a~ons of nor-adrenalin/ adrenalin are termed as
sympatholytics.

□ BIOSYNTHESIS, STORAGE & RELEASE OF Ach

• Acetyl choline, as such, is of no therapeutic use because of its ultra-short
action.
• Its half life is of few seconds only due to rapid hydrolysis by the enzyme
acetylcholinesterase.
• Chemically, ACh is the acetic ester of choline.

0
II
CH3 - C- 0- CH2 · N(CH3)3 Cl
Structure of acetylcholine chloride

•!• BIOSYNTHESIS
• Acetylcholine is synthesized from acetyl
lcCoA
CoA and choline. • O... - - - 10.-1
I OIAJ
IOI
• It reacts with acetyl CoA and reaction is .. ~A
I /ICi, •.

choline \PP.' .1
catalysed by an enzyme 7··
acetyltransferase.
• This ACh so formed is stored in small oval
...... .,
IOI l' ~

"°'
vesicles in the cholinergic nerve terminals. ~
•!• STORAGE
• ACh, formed by the process discussed above, is actively transported in to
vesicles by a transporter.
• This active vesicular uptake of ACh is selectively blocked by Vesamicol.
• This results in slow development of neuromuscular block.

•!• RELEASE
• Arrival of an action potential at the nerve terminal causes an influx of
calcium ions, which in turn triggers release of ACh by the process of
exocytosis.
• This mechanism involves interaction between proteins associated with
vesicles, called as synaptobrevin and the nerve ending membrane, called
as syntaxin.
• Botulinum toxin alters synaptobrevin to prevent release of ACh.

•!• METABOLISM
o ACh is hydrolysed by the enzyme called as acetyl cholinesterase to
choline and acetic acid. The hydrolysis terminates actions of ACh.
o It is the reason why duration of action of ACh is very less (few seconds).
o Cholinesterase enzyme (ChE) is of two types:
(i) True Acetylcholine Esterase:
✓ It is membrane bound enzyme located in cholinergic synaptic cleft.
✓ It is specific only to ACh and methacholine.
✓ It does not hydrolyse other esters of choline.
✓ It is mainly located in neuronal membrane, cholinergic synaptic cleft
and to a small extent in RBCs and placenta.
(ii) Plasma Choline Esterase (Pseudocholine esterase / Butyryl choline
esterase):
✓ It is synthesised in liver and found predominantly in plasma &
intestine.
✓ It is not located in membrane. It hydrolyses other esters of choline e.g.
succinyl choline, benzoyl choline and butyrl choline esters.
 U CHOLINERGIC RECEPTOR
o Actions of ACh are exhibited (Effects of parasympathetic stimulation)
through two types of receptors:
✓ Muscarinic
✓ Nicotinic.

I CHOLI NERG IC RErnPTORS I

, INirotink
11\i !'I
(N)I IMuscarinic (M) I

,i'l1j'1l\•l11
I ,.
I

,h 1;.,
N~ , . 1

N~i M1 ~ Ma
• Ganglia • Neuro-mus rular • Stomach • Heart • Bronchus
• Aa.:enalfoedulla junqtion • GIT
• Bladier
• Glands
• Eye

i. Muscarinic receptors ! . ·

: I I I I

• It is present in the heart, smooth muscles, glands, eyes and CNS.

• Five subtypes of muscari,~i} receptors, M1- M5 are recognise.
• Muscarinicreceptors are 1~IG~rotein coupled receptors.
TABLE - MuscariniciAcetylcholine Receptors Subtypes
M3 (Smooth
Characteristic M1 (Neural) M2 (cardiac)
Muscle)
I

Location CNS: cortex, smooth I

Heart, GI tract Exocrine gland,,.

muscle '· 1 1
eye, vessels
I ,I I.

Response 1· 1
1
CAMP inhibition.
I 1 1

ii .Ca 2+ conductance, IP3 stimulation_,,

IP3, DAG caa+
I
1

I,
1

, K• conductance
I ,

Nature a. proteln 'coupled · 1• .1, Q-,proteln coupled G-proteln couvled .

Agonlst: ACh Carbachol 1
As M1 AsM 1
Oxotremorlne
, '·'I.,
Antagonists: Atropine , '1 Aftr9pt11e Atropine
I I

Ipratropium Gallamlne Prire~zep,ine Dicycloverine

I I

I I 11,, i

r;Pxybutanln Ipratroplum . 1Iii Jp·~itr()plum

1

1
Tolterodine
2. Nicotinic receptors
• It is present in the neuromuscular junction, autonomic ganglia and
adrenal medulla.
• Nicotinic receptors are ion channels. Binding of acetylcholine to a-subunits
opens the channel allowing the e ntry of Na• into the cell.
• Two subtypes of nicotinic receptors are identified: NN& NM.
• NM receptors are present at skeletal muscle end plate and NN receptors at
the autonomic ganglia and adrenal medulla.
TABLE - Difference Between NM and NN
Characteristic
Location Neuromuscular junction Autonomic ganglia
Nature Intrinsic ion channel, Intrinsic ion channel,
pentamer pentamer
Transducer Opening of cation Opening of channel
mechanism (Na+, K•) (Na•, K+, Ca2•)
Agonists PTMA, Nicotine DMPP, Nicotine
Antagonists Tu bocurarine, Hexamethonium,
Bungarotoxin Trimethaphan

□ PARASYMPATHOMIMETIC DRUGS
•!• Parasympathomimetics are classified in two categories:
[I] Directly acting - Those drugs which act by their interaction directly
on receptors of ACh fall in this category.
[II] Indirectly acting - Drugs which inhibit enzyme cholinesterase and
thereby increase cone. of ACh fall in this category.

[I] Directly Acting Parasympathomimetics ➔ As mentioned earlier,

these drugs directly activate ACh receptor.
• It can causeACh-like action even after denervation (loss of PSNS nerves).
• They are sub-classified under three categories as follows:
1. Acetyl choline (ACh) : Prototype
2. Synthetic choline esters
3. Cholinomimetic alkaloids
 I CHOLINERG IC DRUGS

i
l
IDirectly acting I IIndirectly acting I
I (AntlcholJnesterase)
.. j,

!Choline esters I IAlkaloid I

• Acetyt:hollne • Pibauplne
• Bethanechol • Muscarine !
1-
~
• Methadlolinf • Arecolfne I Reverslblel lrreverslb.,
• Carbachol l - J
ILipid Soluble I + _b_le_l -
_ r_S_o-lu
_ a_te
I_W ---
l<>rganophospbate I l
~arbamatesl
• Physosttplne • Neostigmlne • Malathion • Carbaryt
• Thaine • Pyrtck>stigmine • Parathion • Propaxur
• Donepezil • F.droph on tum • Ecoth lophate • Aklcarb
• Rtvastigmine • Tabun}
• Gallan1amine • Sarin Netve gas
• Soman
• Diazoxide}
• Dytb5 Oraganophosphate
insedidde

1. Acetyl choline (ACh) : Prototype

• ACh is not used clinically because of its ultra-short action (few seconds).
• Mechanism of Action ➔ Cholinergic drugs act by various mechanisms
and responsible for a particular action.
• Muscarinic receptors are activated on the target cell, resulting in:
1) Increase in cGMP (second messenger) concentration, and
2) Decrease in cAMP concentration.
• Stimulated muscarinic receptors act on the channels within the cell
membrane and increase the flux of K+ion.
•!• Pharmacological actions of Acetylcholine
These actions result from the stimulation of the muscarinic receptors by
acetylcholine. These are all muscarinic action of acetylcholine.
1. Heart: The actions of acetylcholine are similar to that of vagal
stimulation. It depresses the SA node and thereby reduces the heart
rate and force of contraction.
ii. Blood vessels: ACh relaxes vascular smooth muscles & dilates blood
vessels of almost all vascular beds including pulmonary and coronary
vessels and of the skin ( causing flushing] and mucous membrane.
iii. Smooth muscle: ACh t tone of all other (nonvascular) smooth muscles.
• Gastrointestinal tract: Tone and peristalsis is enhanced, sphincters are
relaxed, resulting in rapid forward propulsion of intestinal contents.
• Urinary bladder: Detrusor contracts and trigonal sphincter relaxes-
promotes voiding of urine.
• Bronchial smooth muscle: Contracts resulting in bronchospasm
iv. Secretory gla nds: Acetylcholine increases the secretions of all glands; i.e.
salivary, lacrimal, nasopharyngeal, tracheobronchial, gastric & intestinal.
v. Eye: Cholinergic stimulation brings about constriction of pupil (miosis) by
contracting the circular ~muscles of the iris. Stimulation of muscarinic
receptors (M 3) presents in sphincter pupillae results in miosis.

❖ These are all nicotinic action of acetylcholine

i. NMJ: ACh brings about contraction of skeletal muscles by stimulating
the NM receptors present in the neuromuscular junction.
ii. Autonomic ganglia: ACh stimulates sympathetic & parasympathetic
ganglia and the adrenal medulla.
iii. CNS: ACh is a neurotransmitter at several sites in the CNS. ACh injected
IV cannot cross the BBB and has no central effects.
❖ Therapeutic Uses
• Acetylcholine is the prototype of the cholinergic group of drugs.
• It is therefore used in experimental studies, but limited clinical value
because of the following reasons:
1. It is rapidly hydrolyse·d by the pseudocholinesterases.
ii. It spreads widely and diffuses in a generalised manner and thus does ,
not produce a selective pharn1ac.:ological effect.
iii. It cannot be administered orally as it is immediately hydrolysed and
hence degraded by the gastric enzyn1es.
2. Synthetic choline esters
o They are also called ester of cholin.
o They are effective orally.
o Drug includes ➔ Carbachol, Bethanechol and Methacholine
i. Methacholine is resistant to pseudocholinesterase but is rarely used.
ii. Carbachol (eye drops) is used in glaucoma. Carbachol are resistant to
both cholinesterases and have a longer duration of action.
iii. Bethnechol
• They are resistant to both cholinesterases
Bladder In
• They have a longer duration of action. Amntlon

• Their muscarinic actions are prominent with a sustained

effect on GI smooth muscles and urinary bladder.
• Bethanechol n1ay be used in:
✓ Hypotonia of the bladder.
✓ Some cases of postoperative paralytic ileus.
✓ Urinary retention and neurogenic bladder.
✓ Xerostomia as an alternative to pilocarpine.
✓ Hypotonia of GI smooth muscles and in congenital megacolon.
• Precautions ➔ It should not be given by intravenous route. Sudden rise
in plasma concentration can cause cardiovascular collapse.
• Contra-indications and undesirable effects :
The contra-indications are as follows ➔

o Hyperthyroidism
o Bronchial asthma
o Peptic ulcer
o Myocardial infarction
• The undesirable effects include ➔ CNS stimulation, myosis, spasm of
accommodation for distant vision, broncho-constriction, abdominal
cramps, flushing, sweating and salivation.
• Disage ➔ Bethanechol is available as 2 5 mg tablet.

3. Cholinomimetic alkaloids ALKALOIDS

•!• Cholinomimetic alkaloid are categorized into :-
• Natural alkaloids - Pilocarpine, Muscari~e & Arecoline.
• Synthetic drug - Oxotremorine.
i. Natural alkaloids ➔
❖ Pilocarpine
o It is an alkaloid obtained from leaves of Pilocarpus microphyllus.
o Source of Pilocarpine ➔ obtained from shrubs of genus Pilocarpus,
cultivated in South America.
o It is a tertiary amine and crosses blood-brain barrier.
o It has a primary muscarinic action on M3 receptors.
o It has also a mild nicotinic action on NNreceptors of ganglia.
o It is too toxic for systemic use.
o Important adverse reactions of systemic use of it is pulmonary oedema.
o It has following therapeutic uses:-

✓ Ophthalmic use: As a 0.5-4% solution, it is instilled in to the eye, it is

used for initial treatment of open angle glaucoma. It reduces intra-

occular pressure within few minutes and lasts for 4-8 hours.
✓ Salivary secretion: It promotes salivary secretion and acts as
sialagogue. In oral dose of 5-10 mg, it can be used to stimulate salivary
secretions in patients after laryngeal surgery and to treat xerostomia
resulting after radiotherapy.
o Contraindications of Pilocarpine
✓ During pregnancy & lactation and in children because not clear safety.

✓ In geriatric patients complications such as diarrhoea, urinary frequency,

and dizziness during therapy.

o Drug Interactions of Pilocarpin e
✓ The efficacy of pilocarpine is reduced by J3-blockers, clindamycin,

aminoglycosides, colistin, cyclopropane and halogenated inhalational

anaesthetics, quinine, procainamide, and lithium.
✓ Pilocarpine prolongs the action of suxamethonium.

❖ Muscarine ➔ It is obtained from poisonous mushroom

(Amanita muscarica) Inocybe and Clitocybe.
o Muscarine produces only muscarinic effects.
o It has no beneficial therapeutic effects.
❖ Arecoline is obtained from betel nut (Areca catechu).
; ,, ._...

J;'\ H, .
o It produces muscarinic as well as nicotinic effects.
o On chewing, it causes salivation and slightly stimulates
, • JI ..L~,;
'
; ~J '
f/Ji-~ - -1 · . ·~
the skeletal muscles and the brain. '~ <!,)

o It has no therapeutic use and causes mild dependence. I

" ' ...
•. •.
- .
ii. Synthetic drug ➔ Oxotremorine, Tremorine.
• Tremorine and oxytremorine are synthetic tertiary amines.
• Oxotremorine is an active metabolite of tremorine.
I

• They are not used clinically.

• They are used as research tools to stimulate Parkinson-like
symptoms in animal models.

[II] Indirectly acting Parasympathomimetics

• These agents inhibit the enzyme acetyl cholinesterase (AChE), located
in synaptic cleft.
• The enzyme is responsible for rapid hydrolysis of ACh.
• As a result, these drugs prolong action and increase indirect availability
of ACh at muscarinic and/ or nicotinic receptors.
• These drugs are also called as anticholinesterase.
Ace~ n e y Anfl-ChE

Ct>Oltnastefose lllndng ,__..In~

Choine + Acehc acid

• The structure of AChE contains an anionic site and

an esteratic site.
• Reversible anticholinesterases except edrophonium
bind to both anionic and esteratic sites.
• Edrophonium binds only to anionic site and I
binding is quickly reversible in minutes, hence it is 1
very short acting.
• Organophosphates (OP) bind only to the esteratic
site but the enzyme is phosphorylated (by covalent
bonds) and the binding is stable.
 • Anticholinesterase may be reversible or irreversible.
• Reversible: Physostigmine, Neostigmine, Pyridostigmine, Tacrine,
Endrophonium.
• Irreversible : Dyflos, Echothiophate, Parathion, Tabun, Carbaryl
• Amongst these drugs, only Physostigmine is naturally occurring alkaloid.
• All other drugs are synthetic quarternary ammonium compounds.
• They exist in ionised form and do not cross blood-brain barrier.
, • As a result, synthetic drugs have very limited action on CNS.

•!• Reversible inhibitors of AChE

(i) Physostigmine {Eserine) ➔ It is an alkaloid obtained from the dried ripe
seeds of Physostigma venenosum.
• It is a tertiary amine; it is highly lipid soluble.
• It shows better absorption in the body and shows action even on CNS.
• It has marked muscarinic effects on M 1 and M 3 receptors and it also
stimulates ganglia. However, its nicotinic effects at NMJ are negligible.
• Uses
✓ Glaucoma: Physostigmine is used in glaucoma: It is used as eye drops
and on long-term use, retinal detachment & cataract.
✓ Belladona (atropine) poisoning: Physositgmine is a specific antidote
for atropine (datura) poisoning or for poisoning by any other
parasympatholytic/ anticholinergic drug.
(ii) Neostigmine:
• Neostigmine is a synthetic quaternary ammonium compound
poorly absorbed from the gut; it does not cross the BBB.
• Neostigmine enhances skeletal muscle strength and force of
contraction in myasthenia gravis - by anticholinesterase activity, by
direct stimulation of nicotinic NM receptors and by enhancing the amount
of ACh released during each action potential.
(iii) Pyridostigmine
• Similar to neostigmine but is longer acting & is used in myasthenia gravis.
• Dose: 60-180 mg TDS. MYESTIN 60 mg tab.
• Ambenonium is also a longer acting congener of neostigmine.
(iv) Edrophonium
• It is a quaternary ammonium compound and binds only to the anionic
site; it is rapid and short acting (10-20 mins).
• It is used in the diagnosis of myasthenia gravis and i. v. in snakebite and
in curare poisoning.
(v) Rivastigmine
• It is a longer acting carbamate that somewhat selectively binds to the
AChE in the brain.
• Being highly lipid soluble. rivastigmine is rapidly absorbed and reaches
the brain and augments cholinergic transmission in the brain.
• It is used in the treatment of mild to moderate Alzheimer's disease.
(vi) Donepezil
• It is another reversible anticholinesterase with longer duration of
action- given once daily.
• It was shown to produce improvement in symptom of Alzheimer's disease.

(vii) Tacrine
• It is a lipophilic acridine, enhances ACh levels in the brain & has been
used in Alzheimer's disease.
• It is hepatotoxic, and therefore, not used.
(viii) Galantamine
• It similar to rivastigminewith good oral bioavailability- 90%.
• Dose - 8-16 mg BO in Alzheimer's disease.

•!• Uses of Reversible Anticholinesterase s :-

1. As a miotic (Physostigmine)
2. In glaucoma (Physostigmine)
3. Myasthenia gravis
4. Poisoning due to anticholinergic drugs
5. Curare poisoning
6. Postoperative paralytic ileus and urinary retention
7. Cobra bite
8. Alzheimer's disease
❖ Irreversible inhibitors of AChE
• Irreversible AChE blockers are organo-phosphorous compounds.
• They phosphorylate esteratic site of AChE irreversibly by form ing a
covalent bond.
• They have no clinical use.
• They are known for their toxicological effects and their toxicity is
treated by oximes.
• Drug includes ➔
o Organophosphates - Echothiophate, Malathion, Parathion, Dyflos,
1

Toxic nerve gases-Sarin, Ta bun

o Carbamate insecticides - Carbaryl (Sevin), Propoxure (Baygon).

□ Organophosphorus {OP) compounds are powerful inhibitors of AChE

enzyme; binding with the enzyme is stable by covalent bonds.
o They bind only the esteratic site and the enzyme is phosphorylated.
o Effects are similar to that of cholinergic stimulation as ACh
accumulates in the tissues.
o All organophosphates except echothiophate are highly lipid soluble
and hence are absorbed from all routes including intact skin.
o This makes OP poisoning possible even while insecticides are used for
spraying the plants.
o Drug of choice for Organophosphorus Poisoning is atropine IV 2 mg
every 10 minutes till pupil dilates.
o Cholinesterase reactivators: IAtro; lne I I Pralidoxlme (oxlmes) I
Pralidoxime, Obidoxime, Blocks muscarinic receptors Binds to ct!...terase

Diacetylmonoxime.
i organopholpha1e complex
Reverses musartnic ~
symptoms ele1N8SA949AI eholnesterase
R1n
o These oxime compounds
Note: ~
combine with cholinesterase • Life.saving ➔ therefore Choinesterase
DOC In OP poisoning degrades ACh
organophosphate complex, • Nlcotinlc symptoms not
reversed ~
release the binding and set I Reverses all symptoms I
Note:
free AChE enzyme. • To be started earty to avoid
ageing of complex
• Not useful in carbamate
poisoning
r,lrnroma Alzh rim rr !'I Hrll1do1u RP\'prr,.1I o f ~. J•;, 1,;t;1r • :; i l . · , ,, i',
Plbcarpine Tacnne poiso11i11r: 11111 sr!n r rl.i,.111 I:', ~eost1gmrne
Physostigtnmt:! Donepe2i l Physostigmine Neost igmine Py ndosogmme
Eci.:duophate Rlvasttgm ine Pyridos tig mine
Gilllantmun e
Sjog l'l'll Di.tgnosis of
Po sto pc>1-.1 t iYc>
s,11tlromc> umnc hi.ll hyper
Plbcirpme l'(l,lCtivi ty
Cevimeline Meth achol in e Edroponium ~eostigmm e
Pyndosag mme
(It , I' 't ', ·,·

Bethanechol Bethanechol
~eostimnine Neostigmine

□ PARASYMPATHOLYTIC DRUGS
• Drugs blocking muscarinic receptors are discussed in this sub-section.
• In addition, drugs which block nicotinic (NN) receptors are called as
ganglion blockers,
• While drugs blocking synaptic transmission at NMJ are called as
neuromuscular blocking drugs or skeletal muscle relaxants.
• Agents which block the effects of acetylcholine on cholinergic receptors
are referred to as anticholinergic drugs or cholinergic blockers.
AN TICHOLINERGIC DRUG
(Muscarinic antagonist Antrop ini c drugs,
para.s}'Dl patholyti cs)

Synthetic mmopunds
Atropine Atropine methonitrate
Hyosdn£ Hom.atropine
I (Scopobmine) Hyoscme butyl bromide
lpratropimn bromide
C}'C pentD IE Oxybutyrun Tnhayphemdyl
ncnopiwn bromide
Tropi cami de Fh,v~te (BenzhunJ)
Tolaucline Proqdidine
Darifenacin Biperidt:11
Solifmacin

[Antil«crdury-antispnmodics I
• ·-,,arr, m di
Propanlhehne
Oxyph en onium
Clidinium
Cim etmp ium brom de
lsop mp amide
~=1
,~
1
;~~me

Gl}Co pyrrol.ate
 U CHEMISTRY OF PARASYMPATHOLYTICS
• Atropine and Scopolamine are naturally existing alkaloids obtained from
the family of solanaceae plants.
• Atropine is obtained from Atropa belladonna or from Datura stramonium .
Naturally occurring atropine is L-hyoscyamin e but is racemised immediately
to D-hyoscyamine ( commercial atropine).
• The anti-n1uscarinic activity resides only in L-hyoscyamine.
• Scopolamine is obtained from Hyoscyamus niger and also from Scopolia
!

carniolica.
• Scopolamine is L-hyoscine and is several more potent than its D-isomer.

(Troplne) (Scopine)
N-CH3
N-CH3

CHiOH
7 CH20H I
I 0-CO-CH
0-CO-CH I
6 I CsHs
CsHs
Atropine Scopolamlne

N-CH{fropine)

<
~5
OCOC~CH~
OH
I C~s
0-CO-CH
I
CaHs
Hornatropine Dicyclomine
(Semi synthetic tertiary amine) (Semisynthetic tertiary amine)

~
COOCH2CH 2N
•t3H7 C3H7 Br
Propanthellne bromide CH3
(Synthetic quaternary derivative))
Chemical structures of some antimuscarinic drugs
(Parasympatholytics)
.J ANTI -MUSCARINIC AGENTS
The parasympatholytic/anticholinergic drugs that block the action of ACh
on muscarinic receptors are called as anti-muscarinic agents, muscarinic
receptor antagonist or atropinic agents.

1. ATROPINE
Atropine is obtained from the plant Atropa belladonna. Atropine and
scopolamine (hyoscine) are the Belladonna Alkaloids.
I

❖ Mechanism of Action
Atropine and related drugs compete with ACh or other muscarinic
agonists on the muscarinic receptor (M 1, M2, M 3). Thus, these drugs are
competitive antagonists of ACh.
•!• Pharmacological Action
• CNS: Atropine, in therapeutic doses results in mild stimulation of
nucleus of the vagus nerve. Higher doses of atropine may be toxic and
result in excitation of the brain that manifested as restlessness,
hallucination and delirium.
• Eye: The topical application of atropine on eyes gives following effects:

Pharmacology of atropine

I
I
Paralysis of constrictor pupillae
l
Paralysis of ciliary muscle
(blockade of M, receptors) (blockade of M3 receptors)

1
Passive mydriasis
1
Cycloplegia

• CVS: When administered in therapeutic doses, atropine causes

bradycardia initially but later tachycardia.
• Respiratory System: Atropine on systemic administration results in
decrease in glandular secretion and bronchodilation.
• Skin and Sweat Glands: The muscarinic receptors present on skin and
sweat glands are highly sensitive to atropine. Thus atropine acts on these
receptors and drastically reduces sweating.
• Secretion: Salivary glands are highly sensitive to atropine therefore its
administration causes dryness of mouth. Large doses of atropine are
required to inhibit the gastric secretion.
• Motility: Atropine causes significant decrease in motility of the GIT and
hence is used as an antispasmodic and an antidiarrheal drug.

❖ Pharmacokinetics
• On i.m. administration, atropine is absorbed very rapidly and efficiently.
• After absorption, it rapidly disappears from the blood and is distributed to
all the tissues and fluids of the body.
• In the liver, most of the drug is destroyed by enzymatic hydrolysis and
around 13-50% is excreted unchanged in the urine.
• Atropine is highly lipid soluble therefore can easily cross blood brain
barrier and placental barrier. Therefore, it must be avoided during
pregnancy as it enters foetal circulation.
❖ Therapeutic Uses
1) As Mydriatic and Cycloplegic: During refraction testing (or vision test)
atropine and its congeners ( e.g., homatropine, cyclopentolate) are
applied topically to bring mydriasis and cycloplegia.
2) As antispasmodics: In diarrhoea and dysentery, atropine relieves colic
and abdominal pain.
3) As pre-anesthetic medication: When administered 30 mins before
anesthesia, atropine reduces salivary and respiratory secretions and
prevents laryngospasm, bradycardia and aspiration pneumonia during
surgery. Its bronchodilator action is of additional value. Glycopyrrolate
is preferred for this use.
4) Labour: Hyoscine can also be used during labour to
produce sedation and amnesia (twilight sleep).
5) Motion sickness: Hyoscine given 30 minutes before ~ --0
the journey prevents travelling sickness.
6) In poisoning
• Organophosphorus poisoning: Atropine is lifesaving in OP poisoning.
• Mushroom po isoning: Atropine is used in poisoning due to some
mushrooms (lnocybe family).
• Atropine is used along with neostigmine in curare poisoning; Used to
block the muscarinic effects of neostigmine.
❖ Adverse effects: Adverse effects include blurring of vision, dry mouth,
dysphagia, dry skin, fever, constipation and urinary retention. Skin rashes
may appear

2. SCOPOLAMINE (HYOSCINE):
• Scopolamine is another tertiary amine and naturally occurring
belladonna alkaloid.
• All the actions of atropine are produced by scopolamine.
• The administratio n of scopolamine in therapeutic doses, depresses the
CNS significantly, along with producing sedation and amnesia.
• The duration of action of scopolamine is lesser than that of atropine.
• Scopolamine is drug of choice for motion sickness. It blocks cholinergic
activity prevents motion sickness
• Druglnteractions
i) Anticholinergic side effects may be potentiated by drugs such as H1 -
blockers, Tri cyclic Antidepressa nts (TCAs ), phenothiazines, etc., because
its action is similar to that of atropine, i.e., synergistic effects.
ii) Administration of atropine delays gastric emptying, thus it alters the
absorption of some drugs due to increased GI transit time like
absorption of tetracycline and digoxin is increased; at the same time, the
bioavailability oflevodopa is reduced.

3. PIRENZEPINE and TELENZEPINE:

• They are selective antagonists of M1 receptors.
• Affinity of telenzepine is far greater than that of pirenzepine.
• Pirenzepine inh ibits gastric secreti on without any 'typical' atropine side
effects because the M2 and M3 receptors are blocked by pirenzepine drug.
4. Dicyclomine:
• Dicyclomine is selective blocking (antagonist) to cholinergic receptors.
• It has antiemetic property and is indicated in motion sickness and morning
sickness.
• It is also used to treat irritable bowel syndrome and dysmenorrhoea.
• It directly relaxes smooth muscles and exerts weak anticholinergic action.

□ ANTI-MUSCARINIC POISONING & TREATMENT

•:• Consumption of excessive doses of belladonna alkaloids, synthetic
antimuscarinic drugs and drugs from other pharmacological groups having
significant antimuscarinic activity can cause anti-muscarinic poisoning.
❖ The following products may cause antimuscarinic poisoning:

1) Natural products (e.g., A. belladonna, D. stramonium),

2) Selective antimuscarinic drugs (e.g., atropine, scopolamine), and
3) Other dr ugs having marked anti-muscarinicproperties
( e.g., antihistamines, phenothiazines, tricyclic antidepressants).
❖ Symptoms:
1) Dry mouth,
2) Blurred vision,
3) Hyperthermia,
4) Photophobia (secondary to mydriasis),
5) Effects of CNS (such as hallucinations, delirium), and
6) Effects on skin (such as hot, dry, and flushed) .
❖ Treatment
1) To Reduce the Intestinal Absorption of Antimuscarinic Agent: This can
be done by intake of activated charcoal.
2) Removal of Absorbed Drug: For an adsorbed drug, universal antidote
(which contains animal charcoal 2 parts, tannic acid 1 part and
magnesium oxide 1 part) must be used.
3) Removal of Unabsorbed Drug: The unabsorbed drug is removed by
gastric lavage by potassium permanganate (for oxidation).
4. Controlling the Symptoms: Hyperpyrexi a can be controlled by using an
ice bag, cold sponging, artificial respiration, and oxygen delivered through a
face mask
5. Specific Treatment: To control excitement and convulsion 10mg diazepam
is given through IV route.
6. Antidote: Physostigmine is the most efficient antidote for treating
antimuscarin ic poisoning.

□ GANGLIONIC STIMULANT DRUGS

•!• Acetylcholine is the principal neurotransm itter at both the sympathetic
and parasympath etic ganglia.
❖ NN type of nicotinic receptors are abundant in ganglia.

❖ Ganglion stimulants:
• Nicotine, lobeline, acetylcholine and anticholinest erases can stimulate
the ganglia.
• Ganglion stimulants are of no therapeutic value.
• Tobacco alkaloid is used as transdermal patch to de-addict chronic
smokers.
•!• Pharmacolog ical Actions
1) Cardiovascu lar System: Nicotine produces effects on the cardiovascular
system which are similar to those seen after activation of the
sympathoadr enal system. The effects are comprised of a positive inotropic
and chronotropic effect on the myocardium as well as an increase in the
cardiac output.
2) Respiratory System: High doses of nicotine directly stimulate the
respiratory centres (inspiration and expiration centres). However, low
doses stimulate respiration by activation of chemorecept ors located in the
aortic arch and carotid bodies.
3) Central Nervous System: Nicotine produces a combination of stimulatory
and depressant effects on the CNS, which includes tremors, convulsions,
respiratory stimulation or depression,
4. Other Systems: Increase in secretion of gastric acid, increased tone, and
motility of GI tract are other effects of nicotine. These effects are result of
dominance of cholinergic input on the effector systems.

□ GANGLIONIC BLOCKER DRUGS

❖ Ganglionic blocking drugs or agents act by blocking the actions of ACh or
agonists at nicotinic receptors of both the parasympathetic autonomic
ganglia as well as sympathetic autonomic ganglia.
f

•!• In addition, some ganglionic blockers also block the nicotinic

cholinoceptor gated ionic channel.
❖ Classification of Ganglionic Blocker Drugs
1) Quaternary Ammonium Compounds: Hexamethonium, Pentolinium.
2) Secondary or Tertiary Amines: Mecamylamine, Pempidine.
3) Monosulphonium Compounds: Trimethaphan camsilate.
4) Persistent depolarising blocker: Nicotin,Anticholinesterases (large dose)
❖ Mechanism of Action
1) At presynaptic sites, they either affect nerve conduction or the
synthesis, release or re-uptake of neurotransmitter.
2) Post-junctionally, they may either affect the initiation of a propagated
action potential or the depolarisation of the ganglion cell or the
interaction between ACh and its receptor.
❖ Pharmacological Actions
1) CNS: The quaternary ammonium compounds and trimethaphan do not
cross blood brain barrier, the refore, they do not give central effects.
2) Eye: The ganglionic blockers act on them and cause cycloplegia along with
loss of accommodation.
3) Cardiovascular System: The ganglionic blockers cause a significant
decrease in arteriolar and venomotor tone because blood vessels are
supplied mainly by vasoconstrictor fibres of sympathetic nervous system.
4) Gastrointestinal Tract: Secretion and motility of all parts of GI tract are
inhibited thus resulting in severe constipation.
❖ Adverse Effects
1) Mild adverse effects
✓ Mydriasis,

✓ Difficulty in vision accommodation,

✓ Xerostomia (dry mouth),

✓Urinary hesitancy,
✓ Constipation, diarrhoea, abdominal discomfort
✓ Anorexia, and syncope.
2) Major adverse effects (o~cur less frequently)
✓ Hypotension
✓ Constipation
✓ Paralytic ileus, urinary retention
✓ Anginal pain
❖ Individual drug
1. Hexamethonium:
• Hexamethonium is a quaternary ammonium compound which was
popularly used for the management of hypertension.
• All the autonomic responses are blocked by these agents.
2. Trimethaphan (Arfonad) :
• The duration of action of this drug is very short.
• It is only used slowly as i.v. infusion of 3-4mg/min by IV route to achieve
controlled hypotension in surgeries.
• Cautiously used in allergic patients as it has histamine releasing property.
3. Mecamylamine (Inversirie):
• Chemically, it is secondary amine & absorbed fully when given orally.
• It can cross BBB to cause marked effects on CNS like tremor, confusion,
seizures, mania and depression.
• This drug is used in moderate to severe hypertension in case other drugs
are not efficient.
• The initial dose is 2.5mg twice a day and can be safely increased to 20-30
mg once a day.
• It undergoes excretion by the kidneys, in unchanged form.
 Pharmacology of drug acting on
Peripheral Nervous System
ADRENERGIC SYSTEM &
ADRENERGIC DRUGS

Points to be covered in this topic

---. 1. Intro. to Adrenergic system 1
. a ' GDC
......... 2. Biosynthesis of catecholamine = 1 -.

............ 3. Adrenergic transmitters

GPAT™
.......... 4. Adrenergicreceptor DISCUSSION
CENTER

........... 5. Adrenergic drugs & its classification

......... 6. IndividualAdrenergic drugs

~
NE NI!

~
'V ... ~

NE NE
NOM---r- 'V ~ '
~ -.._/ Dexmedetomidlne
(lolliililw

Al ~or

--
- - --- Download
" GDC CLASSES" I inu~ to Sludv Snttu1
APP PHARMA EXAM PREPARATION

~ • ~ l e Play SIMPLIFIED ARe,•okltion.lr, wJy to ~ c

 --l INTRO. TO ADRENERGIC SYSTEM
•!• A part of nervous system using epinephrine and norepinephrine as
neurotransmitter is referred to as adrenergic system.
•!• The body is activated and prepared for vigorous muscular activity,
stress, and emergencies by the action of sympathetic nervous system.
•!• Drugs of this group are therapeutically used to combat life-threatening
disorders like bronchial asthma, shock, cardiac arrest & allergic reactions.
•!• Adrenergic drugs are also used as appetite suppressants and nasal
decongestants.

Sympathetic C ,..°"
Adi,..
Postgang · c ,!) Mydriasis
-- ct
NE Recepeo.,
Sympath ti in
(Ga
Docrnse Sallvallon

~ BronchodllltJon
~ (Mainly by Epinephrine)

ct TachYQrdla

-
t

.~ t_
Acetyl~oun,
' _._,,. );- •
♦ Ncnpinephri~
Epinephrine
~
I }g llecruH Dlgnllon
Decrease Urination
- Norepinephnne

□ BIOSYNTHESIS OF CATECHOLAM INE

•:• Nor-epinephrine/nor-adrenaline (NE/NA) is the major neurotransmitter
of SNS.
•) Epinephrine/adrenaline (E/A) is the primary hormone secreted by
adrenal medulla.
•:• Norepinephrine is precursor of epinephrine.
•:• Dopamine (DA) is the precursor of nor-epinephrine.
•:• All these three (epinephrine, nor-epinephrine and dopamine) together are
called as catecholamines.
❖ The steps in biosynthesis of dopamine, nor-adrenaline & adrenaline
r - - - - -- - - - - - -- - - -
are indicated below :-
HO_ r - \ _ CH-CH•NH
1. Biosynthesis of catecholamines ~ 2 booH 2
starts with the dietary amino PhenylalanJne
acid L-phenyl alanine which is l Hepatic hydroxytase

absorbed from GIT. Tyrosine

2. In liver phenyl alanine gets l Tyrosine hydroxylase

Dopa
oxidised by the enzyme
phenyl alanine hydroxylase
l L•Aromatic amil ~ decarboxytase
Dopamine
(hepatic hydroxylase) to form L-
tyrosine.
l Dopam~roxytase

Norepinephrine
3. The circulating L-tyrosine 1s
actively transported to 0
! Phenyle thanolamine N-methyt transferase

of nor-adrenergic H: ) ' - \ CH • CH2• ~-cH,

cytoplasm
~ - 1OH
neurons. Epinephrine

4. Within the neuronal cytoplasm, L-tyrosine is hydroxylated by enzyme

tyrosine hydroxy lase to I-dopa (dihydroxyphenyl alanine).
5. Conversion of tyrosine to dopa is the RATE LIMIT ING STEP in the
biosynthesis of nor-adrenaline.
•!• Storage
• The endogenous NE, located in the nerve terminal is stored in the synaptic
vesicles as a complex with ATP along with a soluble binding protein
called as chromograni~-A.
• Inside the storage vesicles, there is acidic pH which provides a positive
charge on amino group of NE preventing outside diffusion.
•!• Release ➔ In response to nerve impulse, NA is released into synaptic
cleft by a process called exocytosis. This NA binds to adrenergic
receptors located on postsynaptic membrane to produce the response.
•!• Metabolism CAs metabolized by the action of two enzymes: catechol-
➔

0 -methyltransferas e (COMT) and monoamine oxidase (MAO). Both

enzymes are widely distributed, with high concentrations in the liver,
brain, and sympathetic nervous tissue.
•!• Reuptake ➔ The uptake of the released NA takes place very
proficiently. The mechanism involves the following two steps:
1) Axonal Uptake: An active amine pump, Norepinephrine Transporter
(NE11 is present at neuronal membrane. A Na• ion coupled mechanism
transports NA inside the neurons via NET. This is identified as uptake 1.
The rate of uptake of NA occurs at a rate higher than Adr.
2) Vesicular Uptake: Another amine pump Vesicular Monoamine
Transporter (VMAT-2) is possessed by intracellular vesicles. This pump
transports CA from the cytoplasm to within the storage vesicle by the
mechanism of exchange with H• ions.
3) Extraneuronal uptake: Amine Transporter (ENT or OCT3) and other
Organic Cation Transporters (OCTl and OCT2) facilitate the uptake of
CA' s outside the neurons ( extraneuronal), i.e., into cells of other tissues.

Adrenergic
varicosity
e► Active transport
····-·· ► lnhibiUon

~ Nerve impulse
TYR ~ ~ - - - TYR
j
a M-p-Tyr - •·········► ! coupled release

Dopa
a M-Dopa • ---·-·······-· ··♦! .
Resorpine
Reserpine ••• ..

MAO-I ••, .. Guanethidine

Tyramine
+--DOMA+MOPEG
!
Cocaine

NMN ~

.-----VMA N
.---NA--.,- ~ - oo~.----<ID
Effector cell ·
...J ADRENE RGIC TRANSMITTERS
Adrenergic (or noradrenergic) transmission occurs only in the
sympathetic part of the autonomous nervous system and involves the
following three endogenous catecholamines (CAs):
1) Noradrenaline (NA): This neurotransmitter is fou nd on postgangJ ionic
sy1npathclic sites (except sweat glands, hair follicles and some
vasodilator fibres) and in some areas of brain.
2) Adrenaline {Adr): It is s~creted by the adrenal medulla and functions
as a neurotransmitter in the brain.
3) Dopamine (DA): It is the chief neurotransmitter of basal ganglia,
limbic system, CTZ, anterior pituitary, etc. In small concentration it is also
found in the periphery.

□ ADRENERGIC RECEPTOR
► Adrenergic receptors are membrane bound G-protein coupled
receptors which function primarily by increasing or decreasing the
intracellular production of second messengers cAMP or IP 3 /DAG.
► In some cases the activated G-protein itself operates K+ channels or
Ca 2 + channels, or increases prostaglandin production.
► Stimulation of presynaptic a 2 receptors inhibits the further release of NA
► Ahlquist classified adrenergic receptors into 2 types: a and f}.

ADRENERGIC
RECE P.IUR
•!• Physiological actions of Different Receptors

(A) Adrenerglc Receptora

Alpha-1 LAfpha-2 _J L Beta-1 ~

• i Heart Rate
l aeta-2
• vasoconstriction • lnhibHa Norepinephrine • Vasodllation
• f Peripheral Resjstance Release • i Lipolysis • J. Peripheral Resistance
(bk>od flow) • Inhibits Acetylcholtne • i Myocardial • Bronc:hodilation
• t BloOd Pressure Release Contractifity • i Gfycogenolysis
• Mydrialis • Inhibits Insulin • iRenin (muscle, liver)
• i Closure Bladder Refease • t Glucagon Release
Sphincters • Relaxes Uterine Smooth
Muscie

(B) Alpha-1 Alpha-2 Beta-1 Beta-2

NE >E E > NE E =NE E >>NE
NE = Noreplnephrine; E = Epinephrine

•!• Characteristics of adrenergic r eceptors

Receptor Second Selective Selective

Location Response
type I
messengers agonist antagonist

Vascular smooth
muscle Contraction
Phenylephrine
Gut Relaxation t IP3, DAG, Prazosin
Mephentermine
Genitourinary Contraction ca++ Terazosin
Methoxamine
smooth muscle Glycogenolysis
Liver
L
.J, Insulin
Pancreatic '3 cells
release
Platelets .J, cAMP Clonidine Yohimbine

L I Nerve terminals
Aggregation
J.NE release

~
t FOC, t HR Metoprolol,
Heart t cAMP Dobutamine
t AV cond. vel. Atenolol

Smooth muscle-

L:_ vascular
bronchial, gut and
Igenitourinary L
Relaxation
I t cAMP Salbutamol

l
Butoxamine

~
llpolysls
Adipose tissue
l:3ladder L:;trusor
atlon
l J.cAMP Mlrabegron
L l
+ Differences between a and p adrenergic receptors

S. No . Category _____ u J\
[Jlank order of
~ of aaonists ~ > NA

~ 10nist ~ opranolol
ins protein Gq/Gi/Go
Effector pathway IP3/ DAG't, cAMP '1-,, K• cAMP't, Ca2•
channel 1' channel 1'
• Thou1h lnh.,.ntly NA II equlpotant to Adr on Cl rwc•pton, In tat systems with
Intact nauronal rauptake, It appun leu potent due to faster rauptake.

•!• Differences between a 1 and a 2 receptors

i

S. No. Category a1 i a2

Prejunctional on nerve ending

(a2A), also postjunctional in
Post junctional on effector
1. Locatio n brain, pancreatic J3 cells and
organs
extrajunctional in certain
blood vessels, platelets

Inhibition of transmitter
GU Smooth mu scle- release
contraction Vasoconstriction
Function
2. Vasoconstriction Decreased central sympathetic
subserved
Gland-secretion flow
Gut-relaxation Decreased insulin release
Platelet aggregation

Selective
3. Phenylephrine Clonidine
agonist

Select ive
4. Prazosin Yohimbine, Rauwolscine
antagonist

Coupling
s. protein
Gq Gi/Go

cAMP '1-,
IP3/DAG 1'
Effector K• channel 1'
6. Phospholipase A2 1' - PG
ea 2• channel '1-, or 1'
pathway
release
IP3/DAG 1'
GU: Genitourinary
❖ Differences between 13 1 , 13 2 and 133 receptors

r S. No. r Cat. .ory r P, r P2

r P1
Heart, JG Bronchi, blood vessels, Adipose tissue,
1. Location cells in uterus, liver, g.i.t., Detrusor muscle of
kidney urinary tract, eye bladder

Selective
2. Dobutamine Salbutamol, terbutalin Mirabegron
agonist

Selective Metoprolol, 1(1118551 CGP 20712A (also t3 1)

3. 1
antagonist Atenolol a-methyl propranolol ICI 118551 (also f3 2)

Relative
4. potency of Adr ~ NA Adr >> NA NA>Adr
NA and Adr

□ ADRENERGIC DRUGS & ITS CLASSIFICATION

•!• These drugs mimic the actions of endogenous catecholamines and
hence it is called sympathomimetics.
•!• They are classified on the basis of :-
1. Mode of action

Ill CLASS DESCRIPTION

• These are drugs which act directly as agonists on a

or p or both a and p adrenoceptors
Directly acting
1. • E.g. Adr, NA, isoprenaline (Iso), phenylephrine,
sympathomimetics
methoxamine, salbutamol, xylometazoline & many
others.

• These drugs act on adrenergic neurone to release

Indirectly acting
2. NA, which then acts on the adrenoceptors,
sympathomimetics
• E.g. tyramine, amphetamine

Mixed action • These drugs act directly as well as indirectly-

3.
sympathomlmetlcs • E.g. - ephedrine, mephentermlne.

Catecholamine
4. • Atomoxettne, Reboxetine.. Duloxetine, Sibutramine
reuptake Inhibitors
2. Chemical classification - based on the presence/absence of catechol nucleus
S. No. CLASS DESCRIPTION

Noradrenaline, Adrenaline, Dopamine Synthetlc-

1. Catecholamines
lsoprenaline, Dobutarnine, Dopexamine, Dipivefrine

2. Non-catecholamines Ephedrine, Amphetamine

3. Therapeutic or clinical classification

Ill CLASS DESCRIPTION

Noradrenaline, Dopamine, Phenylephrt ne,

1. Vasopressors
Methoxamlne, Mephentennlne, Metaraminol

Adrenaline, Dopamine, Dopexamine,

Cardiac
2. Dobutarnine, Fenoldoparn, lsoprenaline,
stimulants
Ephedrine

3. CNS stimulants Amphetamine, Dexamphetarnlne, Ephedrine

Adrenaline, Isoprenaline, Salbutamol, Terbutaline,

4. Bronchodilators
Salmeterol, Perbuterol, Fenoterol, Formoterol

Ephedrine, Pseudoephedrl ne, Phenylpropanolarnine.,

Nasal
s. Naphazoline, Phenylephrine, Oxymetazoline,
decongestants
Xylometazoline.

Appetite
6. suppressants Fenflurarnine, Dexfenfluramine, Sibutramine (Banned)
(anorectics)

7. Uterine relaxants · Salbutarnol, Terbutaline, lsoxsuprine, Ritodrine

□ INDIVIDUAL ADRENERGIC DRUGS

[I] Directly acting sympathomimetics -
•!• They have following characteristics:
• They act directly on pre-and/ or post-synaptic a- and ~- adrenergic
receptors and produce various pharmacological effects.
• They can exhibit effects even after denervation of post ganglionic
adrenergic neurons.
• Repeated doses of these drugs do not lead to tachyphylaxis.
(1) Endogenous catecholamines
► Drugs in this category have foil owing characteristics:
• They have high potency.
• They are rapidly inactivated. Hence, a short duration of action.
• They are ineffective when given orally, because of being polar and
inactivation by metabolising enzymes.
• They have poor penetration in to CNS. However, they produce anxiety,
tremors and headache in high doses.
• Endogenous catecholaQtines - Epinephrine, Nor-epinephrine, Dopamine

(i) Epinephrine (Adrenaline)-

❖ Pharn1acological action :-
i. Cardiovascular system -
✓ Heart: Adrenaline is a powerful cardiac stimulant. Acting through ~1
receptors, it increases the heart rate, force of contraction, cardiac output
and conduction velocity.
✓ Blood vessels and BP: The effects on BP are complex as both a and~
receptors are stimulated by adrenaline.
✓ Other vascular beds: Adrenaline causes renal vasoconstriction resulting
in a fall in renal blood flow; it also causes pulmonary and mesenteric
vasoconstriction. Cerebral and coronary blood flow is enhanced.
ii. Smooth muscles
✓ Bronchi: Adrenaline is a powerful bronchodilator (activation of P2
receptors) and a weak respiratory stimulant
✓ Uterus - Non pregnant uterus - contracts. Last month of pregnancy ,
- relaxes.
✓ Gut: Smooth muscle is relaxed, but weak and transient action.
✓ Splenic capsule: Contracts resulting in the release of RBCs into the
circulation.
✓ Pilomotor muscles of the hair follicle contract
✓ Bladder: Detrusor is relaxed (p 3 receptors) while trigone is
contracted, thereby increasing.
 iii. Eye: Adrenaline causes mydriasis due to active contraction of the
radial muscles (al) of the iris-active mydriasis; it also reduces
intraocular pressure.
iv. Metabolic effects: Adrenaline increases the blood sugar level by
enhancing hepatic glycogenolysis. ltalso inhibits insulin release.
v. Skeletal muscles: Catecholamine's facilitate ne uromuscular
transmission by action on both a and 13 receptors, they enhance the
amount of ACh released.

❖ Pharmacokinetics - l ·NoradrenaUne I
✓ As catecholamine's are rapidly cow
inactivated in gut and liver, they are Metanephrine Nonnetanephrine

not given orally. MAO' / w.o

Vanilyt mandelic acid (VMA)
✓ Adrenaline and NA are metabolized by
COMT and MAO. !
Excreted In urine

❖ Therapeutic uses
► Allergy (anaphylactic shock) ➔ It is a drug of choice for type I
hypersensitivity reactions like acute anaphylactic attack It relieves
broncho-spasm, angioneurotic edema of larynx, prevents release of
histamine from mast cells and maintains BP in anaphylactic shock It is
given intra-muscularly as 0.3-0.5 ml; 1:1000 solution.
► Bronchial asthma - It causes broncho dilatation & decongestion of
bronchial mucosa. Given s.c. 0.3-0.5 ml as 1: 1000 solution as aerosol
► Cardiac resuscitation ➔ lntracardiac injection of 0.1 mg/ml adrenaline
can be used to reverse sudden cardiac arrests caused by drowning and
electrocution.
► To prolong duration of local anaesthetic (LA) action ➔ Adrenaline,
because of its vasoconstricting effect, antagonizes vasodilating effects
of LA and retards their systemic absorption from the site of injection.
> To control epistaxis (as a local hemostatic) ➔ It is used to control
bleeding as in epistaxis and in ENT surgery. It is used as a spray to have
clear vision.
❖ Adverse effects
• Increase in BP can lead to cerebral hemorrhage.
• Increase in card iac work and contractility may lead to coronary
insufficiency-Adrenaline may cause pulmonary edema.
• CNS side effects may include tremors, anxiety and headache.
❖ Contra-indications and interactions
• Hyperthyroidism: Due to up-regulation of a-receptors on the vessels and
P-receptors in heart, a patient with hyperthyroidism may become hyper-
responsive to adrenaline. In such cases, dose of adrenalin should be
reduced.
• Angina and hypertension.
• Tricyclic anti-depressants like Imipramine prevent re-uptake of
adrenaline & action of adrenaline may be excessively enhanced.
• Anaesthetics like Halothane increase the sensitivity of myocardium
towards catecholamines.
• Inhibitors of MAO increase concentration and availability of adrenaline.
Hence, its effects are excessively enhanced.

(ii) Nor-epinephrine (Nor-adrenaline) (NE/NA)

•!• Endogenous NE is the 1-isomerwhich is more potent than d-isomer.
•!• NE predominantly acts on a-receptors with relative receptor affinity as a 1
= a2>~1>>~2-
•!• It also possesses significant ~3 actions. -= •
-..... ~
~~
---

•!• Cardiovascular actions r EN_:. . ~ , c~

✓ NE raises both systolic and diastolic BP, due ~ ~ ca. ;

1
~
to cardiac stimulation (~ 1) and rise in cAMP ATP
A
peripheral vascular resistance (a 1). ~
✓ Cardiac output is unchanged.
✓ Reflex bradycardia is caused, secondary to hypertension.
✓ The coronary blood flow increases due to rise in mean arterial pressure.
✓ NE has predominant a-action and does not exhibit Dale's vasomotor
reversal.
❖ Therapeutic uses
o It is carefully used to treat cardiogenic shock, since the shock increases
vascular resistance and decreases blood flow to vital organs.
o Dopamine is preferred in this condition, since it does not reduce blood
flow to kidney.
o It is not suitable for s.c., i.m. or undiluted IV injection because of possibility
of necrosis at the site of action.
o Vasoconstriction is the cause of necrosis.
❖ Adverse effects, precauti9ns and contraindications
o These are similar to that of adrenaline.
o Infusions of NE should be tapered off gradually to avoid sudden fall in BP.
o Extravasation into s.c. tissue should be carefully watched to avoid tissue
necrosis at the site of infusion.
(iii) Dopamine is the precursor of NA.
• It acts on dopaminergic and adrenergic receptors.
• There are 5 subtypes of dopamine receptors: D 1-D 5.
• Dopamine is a central neurotransmitter.
• Low doses stimulate vascular D1 receptor in renal, mesenteric and
coronary beds causing vasodilatation in these vessels.
• D2 receptor stin1ulation in syn1pathetic nerve terminals and in
cardiovascular centres also results in renal vasodilation. Hence, renal
blood flow and GFR increase.
• Higher doses cause cardiac stimulation through ~1 receptors resulting
in ant in force of contraction with relatively minor t in heart rate.
• In high doses a 1 receptors activated resulting in vasoconstriction and iBP.
• Dopamine does not cross BBB, hence it has no CNS effects. It is given Iv.
• It is short acting. Dopamine is metabolised by COMT and MAO.
• Epinine (Ibopamine) is an ester of methyldopamine which acts like
dopamine.
•!• Adverse effects:
✓ Nausea ✓ Headache
✓ Vomiting ✓ angina and sudden rise in BP may occur.
✓ Palpitation
❖ Uses: Dopamine is used in the treatment of :· I
o Shock - cardiogenic, hypovolaemic and septic.
o It is specially useful when there is renal dysfunction and low cardiac
output because
a. DA trenal blood flow and therebyGFR
b. DA stimulates the heart -tFOC, t cardiac output and BP.
c. DA is short-acting and therefore the response can be easily
controlled by modifying the infusion rate.
4

2. Synthetic catecholamines
Drug includes ➔ lsoprenaline Dipivefrine Dobutamine Dopexamine
(i) Isoprena line ➔

•!• It predominantly stimulates P1 - and Pi-adrenoceptors. It has negligible a-

receptor action. The structure of isoprenaline is shown.
❖ Pharmacological / Cardiovascular effects -

• It exerts positive ionotropic and chronotropic

effect on heart causing an increase in cardiac
output (P1-effect).
• It dilates arterioles of skeletal muscle (Pi-effect) resulting in
decreased peripheral resistance.
• lsoprenaline relaxes bronchial & GIT smooth muscles.
• It relieves bronchoconstrictio n mainly due to stimulation of Pi-
receptor and partly due to inhibition of induced histamine release.
❖ Pharmacokinetics
• It is readily absorbed when given parenterally or as an aerosol.
• It is stable to MAO degradation; but it is metabolised by COMT
present in liver and other tissues.
❖ Therapeutic uses ➔ Used only in emergency situations tot heart rate in
patients with bradycardia/heart block, prior to insertion of an pace maker.
❖ Adverse effects ➔ Its cardiac stimulant actions can lead to
✓ Pa lpitations, ✓ Sinus tachycardia ✓ Even seriou s a rrhythmias.
(ii) Dipivefrine
• It is a pro-drug for epinephrine with enhanced corneal permeability.
• 0.1 % solution is used for the treatment of glaucoma.
• Ocular side effects includes photosensitivity & conjunctiva} hyperaemia.
(iii) Dobuta mine
• It is used clinically as a racemic mixture of two enantiomers.
• The I-form is a potent agonist of al-receptor while d-form is a potent
antagonist of al and also powerful agonist of Pl-receptor. As a result, the
net cardiovascular effects of dobutamine are mixed.
• On heart it has more selective ionotropic than chronotropic effects
without any significant change in peripheral vascular resistance and BP.
• It t cardiac output & stroke volume without affecting heart rate, peripheral
resistance or blood pressure.
• Its half-life is about 2 minutes; hence it is given as a IV infusion.
•!• Therapeutic uses ➔ It is used as IV infusion in a dose of 2-5 µg/kg/min to
treat patients of heart failure associated with myocardial infarction, cardiac
surgery and for short term management of acute congestive heart failure.
•!• Adverse effects ➔
• There is a sharp rise in BP and heart rate in patients with hypertension.
• Being an ionotropic agent, myocardial oxygen demand t and hence
angina may be precipitated or myocardial infarction may be aggravated
• Tolerance may develop on prolonged use. Since it t AV conduction, it
should be used with caution in atrial fibrillation.

(iv) Dopexamine
• It stimulates (32 receptors and peripheral dopamine receptors and it
inhibits neuronal uptake of NE.
• It results in t cardiac output, peripheral vasodilatation and t in renal and
mesenteric blood flow.
• It is used to provide haemodynamic support in patient with CHF & shock
• Side effect ➔ tachycardia, transient hypotension & dyspnoea. Avoided in
phaeochromocytoma.
 3. Non -catecholamines
(i) a 1 -agonist drugs
► Phenylephrine and methoxamine are two prototype drugs in this
category.
► Other drug are - Methoxamine, MidodrineNaphazoline, Oxymetazoline,
Pseudoephedrine, Phenylpropanolamine
(a) Phenylephrine
• It is a a 1-selective agonist. It lacks -OH group on benzene; hence it is a
non-catecholamine.
• It is not metabolised by COMT and hence has got a relatively longer
duration of action.
• Activation of a 1-receptor results in t peripheral vascular resistance & BP;
which is associated with reflex bradycardia.
• It is used as nasal decongestant & mydriatic and in patients with
hypotension or shock

(ii) a r agonist drugs

•:• «i-receptors are located pre-synaptically on sympathetic post-ganglionic
neuron and post-synaptically on blood vessels and brain.
•:• Stimulation of a 2 receptor by NE or any aragonists t further release of NE.
•:• In brain, stimulation of «rreceptors i central sympathetic outflow.
•:• Hence, they are primarily used for hypertension.
•:• Drug includes - clonidine and methyldopa
(a) Clonidine
► It belongs to imidazoline group chemically.

► It causes the effect by following mechanisms:

✓ It stimulates a 2 -receptors present at vasomotor centre causing reduction in

central syn1pathetic outflow thereby fall in BP & heart rate.

✓ Clonidine also activates pre-synaptic a 2 -receptors on postganglionic neurons

and suppresses further release of NE from nerve endings.

✓ Pharmacokineti~ ➔ It is well absorbed after oral administration with a
bioavailability of 100%.
 ► Therapeutic uses
✓ Moderate hypertension
✓ To control diarrhoea in diabetic patients with autonomic neuropathy
✓ Prophylaxis of migraine
✓ Management of Nicotine, Alcohol and Opiate withdrawal
✓ Pre-anaesthetic medication
✓ Menopausal hot flushes

► Adverse effects : Major adverse effects are as follows:

✓ Rebound hypertension after abrupt withdrawal
✓ Dry mouth
✓ Sedation
✓ Nasal stuffiness
✓ Constipation
✓ Impotence
✓ Contact dermatitis, when used as a trans-dermal patch

(b) a -methyldopa
• It is a centrally acting anti-hypertensive drug.
• It exerts its action through a metabolite, a-methyl NE.
• It has two major advantages:
✓ It reduces renal vascular resistance. Hence, useful in hypertensive
patients with renal insufficiency.
✓ It reduces ventricular hypertrophy.
• Due to potential adverse reactions, immunological and hepatotoxicity, it is
no longer a drug of choice for long term management of HTN
• It is used only for hyp~rtension during pregnancy. It is safe both for
mother as well as foetus.
• Adversereactions
✓ It causes sedation, dryness of mouth, involuntary movements,
✓ Gynaecomastia in males and galactorrhoea in females due to
interference with dopaminergic suppression of prolactin release.
✓ Hepatotoxicity is associated with fever.
(iii) Non-catecholamine Pi-selective agonists
o They are administered by inhalation, in the form of aerosol, leading to
effective activation of ~i-receptors in bronchi.
o There is less potential to stimulate Pi- receptors in ske leta l muscle.
o They activate Pi-receptors located on airway smooth muscle and enhance
the release of cAMP by activating the enzyme adenylyl cyclise.
o They exert foil owing actions:
✓ Relax airway smooth muscle.
✓ Inhibit release of bronchoconstricting mediators from mast cells.

✓Inhibit micro-vascular leakage.

✓ Increase the mucociliary transport by increasing the ciliary activity.
o The drugs under this category are as follows: Salbutamol, Terbutaline,
Metaproterenol, Bambuterol, Salmeterol, Formoterol, etc.

(a) Salbutamol
• It is fairly selective Pz-agonist with relaxant effects on smooth muscles
of bronchi and uterus.
• It has minimal cardiac stimulant effects. It is not metabolised by COMT
and exhibits longer duration of action as compared to isoprenaline.
• For immediate relief of asthma, it is given by oral inhalation from a
metered dose inhaler (100 µg/dose).
• It can also be given orally (2-4 mg TDS), i.m. or by slow i.v. injection.
• Side effect ➔
✓ Nausea and vomiting.w ith a risk of developing pulmonary edema.

✓ Other side effects are tremors in hands, palpitation, headache and

hypokalaemia (after large doses).

(b) Terbutaline
• It is a resorcinol derivative.
• It is not metabolised by COMT and hence has longer duration of action.
• It is effective when given orally, s.c. or by inha lation.
• It is used to relieve acute bronchospasm in asthma, as a metered dose
aerosol whenever required.
(II] Indirectly Acting Sympathomimetic
• They do not have direct stimulant effect on adrenoceptors.
• They are taken up by neuronal membranes; they displace NE from their
stores. The displaced NE causes pharmacological actions.
• Denervation of post-ganglionic adrenergic neuron prevents their action.
• Repeated dosing at short intervals leads to tachyphylaxis due to depletion
of stores of NE.
• It replace catecholamine's from the storage site.
• They cross blood-brain barrier and have notable effects on CNS.
• Drugs in this category are as follows: Tyramine, Amphetamine,
Methamphetamine, Methylphenidate, Pamoline, Modafanil.
• Therapeutic uses
✓ Narcolepsy

✓ Attention Deficit Hyperactivity Disorder (ADHD)

• Adverse effects
✓ Restlessness, tremors, hyperactive reflexes, irritability,
✓ Insomnia, euphoria, hallucinations and sweating, Palpitation, headache
✓ Arrhythmia, Dry mouth, metallic taste, anorexia
✓ Abdominal cramps & difficulty in micturition, dependence & tolerance.
[III] Mixed Action Sympathomimetics
•!• Drug in this category includes ➔ Ephedrine, Pseudoephedrine,
Mephentermine
1. Ephedrine
• It is a non-catecholamine alkaloid obtained from Ephedra vulgaris.
• Its racemic form is used clinically & has direct action on a & P-receptors.
• In addition, it enhances release of NE from sympathetic neuron.
• It is not destroyed by MAO and COMT and therefore it has longer
duration of action than E and NE.
• It crosses blood-brain barrier and has a powerful stimulant action on
CNS. It increases heart rate, cardiac output and BP.
• Adverse effects ➔ Hypertension, when given parenterally cause insomnia
and tachycardia. Repeated doses at short intervals produce tachyphylaxis.
 Pharmac ology of drug acting on
Peripher al Nervous System
, -~"" ·-;;-•~1,-·r
-

ANTI-ADRENERGIC DRUGS

Points to be covered in this topic

........... 1. Intro. to Anti-Adrene rgic drugs
.......... 2. Classificatio n of Anti-Adrene rgic drugs
.......... 3. a -Adrenocep tor Blocking Drugs
........... 4. fJ-Adrenergi c Blocking drugs
i..r.o
(dale
~)

IYIIPATHVlC

~ GDC
GPAT™ , _ _;.
DISCUSSION
CENTER
Sciwwll
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0■
c..-,
I --U

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.J INTRO. TO ANTI -ADRE E •• __ :,:,:ad;},$.',.

► Anti-adrenergic drugs are also called Adrenoceptor antagonists or

adrenergic blocking agents or antiadrenergic drugs
► These are drugs which antagonize the r eceptor a ction of a drenaline
and related drugs.
► They are competitive antagonists at a/P or both a and P adrenergic
receptors.
► Adrenergic blockers bind to adrenergic receptors and prevent the action
of adrenergic drugs. They may block a or J3 receptors or both.
► The action of sympathomimetic amines is selectively blocked.
► It brings about opposite effects of catecholamine's that facilitated
through the a- or J3-receptors.

□ CLASSIFICATION OF ANTI-ADR.EN ·RGI£:. ·

DRUGS
Antiadrene,gc Orugs
J,
+ + +
Aarenergic
,ecepco,
antagonists
Drugs inhibiting
NE synthesis
e .g . (i) Metnyldopa
"
Orugs Inhibiting
NE Sk>rage
e.g. (i) Rese,p.ne
Drugs int11t)iling
NE rtleaM
e.g. (i) Bretyfium
(II) Cart>ldopa (M) Guanelhidlne

I
(ill) a•methyl•P·tyrOStne

.,.,ec:eptor +
Both a and JJ ~IOr ant&goniats *
P•recept1.01
antagonists e.g. (i) Labatalol an1agon111s
(Ii)_Medro•alol

+
I· (Iii) BudnGOIOI

NonMlec1,w
e.g. (i) Pnenoxyoenza.mine
00 PhenlOlemlne
Oil) TOINOline
a, +anragonlsta a ,+~
e.g. (I) Prazoa1n e.g. (i) ~ifflbln•
CM Dibtnarnine (Ii) Te,1zolln (11) Allpamezole
(bl) lnmalOkl (111) lduolcan

·~
(1V)OOICuot1n

+
Nonalleotiw
+
e.g . Ci) PropranOIOI
01) NadOlol +
/Ji anlllgonlata
• +
Iii...,,_
(Ul) Tlmotol
e.g. (I) MelOC)IOIOI e.g. (I) 8U1011111W1e
(IY) P1ndo1Qt
(IQ AlenOIOI
(v) Pllnbulok>I
M ) 0a•ltOIOI ('a) Ac«)u10IOI
(Iv) Prec101o1
M EtfflOIOI
❖ The antiadrenergic agents can be divided into the following two
classes depending on the receptors with which they interact:
1) a-Adrenoceptor Blocking Drugs: The effects of catecholamine
facilitated via a receptors are blocked by these agents. Furthermore,
depending on the ability of these drugs to dissociate from the receptors,
they may either be reversible or irreversible.
2) P-Adrenoceptor Blocking Drugs: The effects of catecholamine
facilitated via the P-adrenoceptors are blocked by ~-adrenoceptor
blocking drugs. They can further be categorised as selective or non-
selective P-adrenoceptor blocking agents.

•!• a. receptor antagonists block the adrenergic responses mediated through

a adrenergic receptors.
•!• Some of them have selectivity for a. 1 or a. 2 receptors.
•!• a. receptor antagonists are classified as :-

\I> I I '-. I

Nonequlllbri um ~'Pe F.quiUbrium type

(Competitive a.nragonists)

~ haloa lkyla m in e
Ph enm~.-ybenzam:in e I I I
j Non selective I a. 1 Selective a. 2 Selective
I Prazosin Yohimbine
I I I Terazosin
Ergot alkaloids lmidazoline I Miscellaneous Doxazosin
AHuzosin
Ph entoJami ne
I

· Ergo1amine 1

Chlorproma'Tine 1

Tamsulosin
Ergoaxine
Silodosin

Hydrogenated ergot alkaloids

Dihydroergo1amine (DHE)
Dihydroergotnxine
( Codergocrine)
(i) Reversible non -selective a -blockers
•!• These drugs are competitive antagonists at a-adrenergic receptors
and have similar affinities for al- and a2-receptors.
❖ Two drugs of this class are - Phentolamine and Tolazoline.
1. Phentolamine
► Pharmacological action ➔ Cardiovascular effects
• Blockade of vasoconstrictor a 1-receptors in the periphery by
Phentolamine leads to vasodilatation, decrease in peripheral vascular
1

resistance leading to hypotension.

• The resultant fall in BP stimulates baroreceptor reflex causing
sympathetic discharge. Since a 1-receptors are blocked, the sympathetic
discharge stimulates P1-receptors on the heart producing tachycardia.
• Being non-selective, it also blocks pre-synaptic a 2-receptors limiting
neuronal release of NE to produce more tachycardia and palpitation.
• The patients may suffer from events of postural hypotension.
o Nasal stuffiness results due to vasodilatation and congestion of nasal
mucosa.
o Myosis, due to loss of tone of radial muscles of iris and unopposed
contraction of circular muscle.
o Improved urine flow rates due to relaxation of smooth muscles of
urinary bladder neck and prostate.
o Failure of ejaculation and impotence due to inhibition of contractions of
vas deferens and ejaculatory ducts.
o Nausea, vomiting and diarrhoea due . to partial inhibition of relaxant
sympathetic influences on GIT, and increase in gastric secretiom due to
agonistic action on histamine H2 receptors.
> Pharmacokinetics ➔

✓ It is poorly absorbed from GIT.

✓ It is administered intravenously.
✓ It has an immediate onset and shorter duration of action.
► Therapeutic uses
• For diagnosis and management of Phaeochromocytoma.
• For peripheral vascular d isorders : It is used to treat Raynaud's
syndrome and frostbite.
• To prevent dermal necrosis: It is used sub-cutaneously to prevent
dermal necrosis after incidental extravasation of NE from intravenous
infusion.
• To prevent hypertensive eris is following abrupt withdrawal of Cioni dine
and those resulting from ingestion of tyramine-containing food with MAO
inhibitors.

2. Tolazoline
o It is similar to Phentolamine; but it is less potent.
o It is better absorbed from GIT.
o It is rarely used.

(ii) Irreversible non-selective a -blockers ➔ The only drug in this

category is Phenoxybenzamine.

1. Phenoxybenzamine
► Phenoxybenzamine binds covalently to a -receptors causing
irreversible blockade or non-equilibrium type of blockade.
► Given Iv, blood pressure gradually falls over 1-2 hours and is
associated with tachycardia and tco.
► The BP reduction is more in patients with increased sympathetic tone.
► The action lasts for 3-4 days. It also blocks histamine, 5-HT and
cholinergic receptors.
► Phenoxybenzamine can b e give n orally but absorption is incomplete;
should not be given by IM and SC route as injections are painful.
► Adverse effects ➔ postural hypotension, palpitation, nasal stuffiness,
inhibition of ejaculation and depression, hence started with a low dose
and gradually increased.
► Usage ➔ It is used in the treatment of pheochron1ocytoma.
(iii) Reversible, selective a 1 -blo cke r s
❖ The primary drug in this category is Prazosin. Few derivatives of
Prazosin are also available.
❖ Other drugs are ➔ Terazosin and Doxazosin Bunazosin and Alfuzosin
Tamsulosin and Silodosin
1. Prazosin
• It is a selective a 1-receptor antagonist.
• It causes periphera l vasodilatation and a fa ll in arterial pressure with
lesser tachycardia probably because of lack of arreceptor blocking
actions, limiting release of NE.
• It also J.. cardiac preload & it suppresses sympathetic outflow from CNS.
• It is potent inhibitor of enzyme cyclic PDE leading to t in cAMP.
• It also causes rise in cone. of HDL and J.. in LDL and triglycerides.
• It relaxes smooth muscles of urinary bladder neck, prostate capsule and
prostatic urethra leading to improvement of urine flow in cases of BPH.
❖ Pharmacokinetics
o It is well absorbed after oral administraton.
o Its plasma half-life is about 4 hours.
•!• Therapeutic uses
o Treatment of hypertension
o In the treatment of benign prostatic hyperplagia (BPH).
o In patients of Raynaud's disease, calcium channel blockers are preferred
over Prazosin.
•!• Adverse effects
o The major adverse effect is postural hypotension (Syncopal attack).
o Impotence
o Nasal congestion,
o GIT upset,
o Sodium and water retention
~

•
21!!)
.,
./
-I
d
2. Te razosin & Doxazosin
✓ Both are a 1-blockers like Prazosin but have longer duration of action.

✓ Both are well absorbed after oral administration.

✓ Plasma half-life of Tetrazosin is 12 hrs; and Doxasosin is 20 hrs.
✓ Once daily dose is preferred for treatment of hypertension and BPH.
✓ Terazosin in a dose of 2-5 mg or Doxazosin in a dose of 1-4 mg, once
daily is useful to improve urine flow.
(iv) a 2-receptor blockers - The only drug in this categoryisYohimbine.
1. Yohimbine
• It is a natural alkaloid available from Pausinystaliayohimbe.
• It is lipid soluble. It crosses blood-brain barrier.
• It has antagonistic action to 5-HT. They treat autonomic insufficiency by
promoting NE release by blocking pre-synaptic arreceptor.
• It can also be used to treat male sexual dysfunction and to treat diabetic
neuropathy and postural hypotension.
• It can abruptly reverse anti-hypertensive effect of clonidine, which is a
notable drug interaction. Its clinical role needs to be established.

, ,:,
Yohimbe

-\ ~

~ Pausinystaliayohimbe

I?.·"
(v) Miscellaneous non-selective a -blockers
1. Ergot alkaloids ➔ Alkaloids from ergot like Dihydroergotamine &
Ergotamine exhibit complex pharmacological actions.
• They block both a 1 - and «r receptors.
• In addition, they act as partial agonists to a-receptors and 5-HT2
receptors. Some of them are Oxytocics anp dopamine receptor agonists.
• Methysergide, a synthetic compound is related to ergot alkaloids.
• It is a potent 5-HT antagonist and was used for migraine
prophylaxis.
• Ergonovine/Ergon1etrine is an ergot alkaloid.
• Its derivatives n1e thyl-ergonovine a nd dihyd roergonovine
are used for their uterine relaxant (tocolytic) action.
Ergot Alkaloid

■ , .,• ; : , su,, .am~

•!• These drugs block JJ 1 or JJ 2 receptors & antagonise effects of
catecholamine's which are mediated through the receptors.
•!• In addition, some of these drugs also exert membrane stabilising effect
leading to local anaesthetic action.
•!• Some of them have intrinsic sympathomimetic activity.
•!• Based on their selectivity towards receptors, they can be classified as:

P-Blockers

Non-selective Selective Mixed

(~ 1 and Jli blockers) (a and Jl blockers)
• Propranolol • Labetalol
•Timolol • Carvedilol
•Sotalol
•Nadolol P1 blocker P2 blocker
•Pindolol • Metaprolol • Butoxamine
• Oxprenolol • Atenolol
•Esmolol
• Acebutalol
• Celiprolol
• Betaxolol
• Bisoprolol
• Nebivolol

(i) Non-selective P-blockers

(a) Propranolol is the prototype drug in this category.
•!• It is a non-selective P-antagonist. OH CH
1
rA1A( OCHi ). "HiNH(?I
❖ It is primarily used to treat hypertensiop ~ T 'CH,

•!• Also used in ischaemic heart disease. Structure of propranolol

❖ Pharmacological Actions
1. CVS
• Heart: p blockers decrease heart r a te, force of contractio n and cardiac
output Blood pressure falls.
✓ AV conduction delayed due to blockade of J3 receptors in AV node.

✓ High doses produce membrane-stabilizing activity like quinidine,

causing direct depression of the heart.

• Blood vessels - J3-blockers reduce BP. On long-term use, ~blockers
reduce peripheral vascular resistance in hypertensive patients.
2. Respiratory tract: Blockade of P2 receptors in bronchial smooth muscle
causes an increase in airway resistance may precipitate acute attack in
asthmatics.
3. Eye: Many J3-blockers reduce in traocular pressure by decreased
secretion of aqueous humour.
4 . Metabolic: J3-antagonists block Iipolysis & glycogenolysis (J3 2 mediated)
induced by sympathetic stimulation.
5. Other effects: Many J3-blockers in higher doses block sodium channels
and have a local anesthetic effect- membrane-stabilizing effect.

❖ Pharmacokinetics
• Though well absorbed on oral administration (propranolol almost
completely absorbed).
• Undergo extensive first pass metabolism which reduces the
bioavailabilityto ,v25%; food improves bioavailability of propranolol.
• Most of the J3-blockers have short t1/2 and are metabolised in the liver. T

❖ Adverse Reactions
1. Bradycardia is common. Patients with AV conduction defects may
develop arrhythmias and heart block with P-blockers.
2. CCF: P-blockade eliminates compensatory effect and may precipitate
CCF and acute puhnonary oedema.
3. Cold extremities -seen especially in patients with peripheral vascular
disease.
4. P-blockers can precipitate acute asthmatic attack in asthmatics and is
contraindicated in them. They can worsen COPD.
5. CNS: Insomnia, depression and rarely hallucinations can follow the use of ~-
blockers.
6. Fatigue due to decreased blood flow to the muscles during exercise and
reduced cardiac output.
7. Metabolic effects: Weakness, reduced exercise capacity may be seen due to
its metabolic effects. Carbohydrate tolerance may be impaired in diabetics.
Plasma levels of triglycerides and LDL cholesterol may rise while HDL
cholesterol may decrease with non-selective J3-blockers.

❖ Some important drug interactions

1 . Propranolol + insulin: When diabetics on insulin also receive
propranolol:
t. J3-blockade masks tachycardia which is the first warning signal of
hypoglycemia.
tt. J3-blockade delays the recovery from hypoglycaemia by preventing

glycogenolysis induced by sympathetic stimulation (acting through f32

receptors). This may be avoided by using a J3 l -selective blocker.
2 . Propranolol + verapamil: Since both cause myocardiac depression,
profound depression may result when both are used together. Hence, the
combination should be avoided.
3. fl-blockers + catecholamines: In patients on non-selective J3-blockers,
blockade of vascular J3·receptors could predispose peripheral vessels to
intense vasoconstriction (receptor upregulation) from even small doses of
adrenaline used with LAs. Hence, it is safer to use plain local anaesthesia
in such patients.
4. fl-blockers, digitalis and verapamil: All cause depression of AV
conduction and together may cause cardiac arrest.
5. Enzyme inducers: Like rifampicin can hasten the metabolism and reduce
the plasma levels of propranolol.
6 . NSAIDs counter the antihypertensive effects of J3-blockers.
lb) Timolol
o Timolol is orally absorbed.
o It shows moderate first-pass metabolism.
o It crosses blood brain barrier.
o It's uses and side effects are similar to that of propranolol.
o Therapeutic uses
✓ It is used as eye drops to decrease raised intraoccular pressure, in
case of wide angle glaucoma.
✓ It is devoid of membrane stabilising activity.
✓ From ocular formulations, some amount may be absorbed systemically
to exhibit side effects.
( c) Sotalol
o Sotalol has low lipid solubility.
o It shows lesser CNS effects and has negligible first-pass metabolism.
o Its uses and side effects are similar to that of propranolol.
o It has K• channel blocking activity and anti-arrhythmic activity also.
o Its oral dose is 80-320 mg twice a day.
(d) Nadolol
o Nadolol has longer plasma half-life (20 hours).
o It does not cross blood-brain barrier.
o It has least first-pass metabolism.
o Its dose is 40 mg once daily.
o Its effects are similar to that of propranolol.

(ii) Cardio-s elective P1-blockers

•!• These drugs are more selective towards heart & exert lesser side
effects on respiratory system.
•!• Examples ➔ Metoprolol, Atenolol, Blisoprolol, Nebivolol, Esmolol and
Betaxolol
•!• Advantages over non-selective II-blockers
✓ They are safer in asthmatic patients in comparison to Propranolol.
✓ They have less adverse effects on lipid profile.
 ✓ They are safer in diabetes since they cause less inhibition of
glycogenolysis during hypoglycaemia. Tachycardia in response to
hypoglycaemia is blocked.
✓ They are safer in patients with peripheral vascular disease since
they do not cause ~rblockade.
•:• Disadvantages
✓ They cause rebound hypertension after abrupt withdrawal.
✓ They are ineffective in controlling essential tremors.

la) Metoprolol
o It is completely absorbed after oral administration.
o Due to first-pass metabolism, its bioavailability is low.
o Its plasma half-life is 4 hours.
o For treating hypertension, usual dose is 50-100 mg daily.
o Extended release formulations are available for once daily administration.
o Its uses are similar to that of Propranolol.
(b) Atenolol
o It does not cross blood-brain barrier.
o It has relatively longer half-life in comparison to Metaprolol.
o It can be given once daily in dose of 25-50 mg.
o Its uses are similar to that of Metoprolol.
(c) Bisoprolol
o It is commonly used for hypertension and angina.
o Its dose is 2.5-10 mg once daily.
o When used with ACE inhibitors, it lowers mortality in CHF.
(d) Nebivolol
o It enhances production & release of NO in addition to P-blockade.
o It lowers arterial BP & peripheral vascular resistance.
o It is used for treating hypertension.
o Usual oral dose is 5-10 mg once daily.
( c ) Es1nolol
o It is an ultra-short acting P1 -antagonist.
o It has a plasma half-life of 8-10 minutes.
o It is given i.v. in conditions to terminate supra-ventricular tachycardia,
episodes of atrial fibrillation.
o It also control heart rate and blood pressure during surgery or in
critically ill patients in whom the drug can be withdrawn immediately.
o Adverse effects include bradycardia, hypotension and heart failure.
(f) Betaxolol
o It is less effective than Timolol because 80% of P-receptors on ciliary
body epithelium are of P2 sub-type.
o It is better tolerated. It has no membrane stabilising (LA) effect.
o It has cyto-protective action on retinal neurons.
o It is safer in asthmatic and diabetic patients.
o Oral formulations are used for hypertension and angina.
o It facilitates drainage of aqueous humour.
(iii) Non-selective P-blockers with intrinsic sympathomimetic activity
•:• Drugs under this category possess some intrinsic sympathomimetic
activity on (3 1 and P2 receptors in addition to non-selective P-blockade.
•:• Drugs under this category are: Pindolol and Oxprenolol.
(a) Pindolo I and Oxprenolol ➔ Daily doses are 10 mg for Pindolol, once
daily and 20 mg twice or thrice a day for Oxprenolol.
❖ Advantages:
• They cause lesser bradycardia and myocardial depression.
• Relatively better in patients of asthma because of ~i-agonistic action.
• Rebound hypertension after withdrawal is less likely.
• Lipid profile is less worsened in comparison to Propranolol.
•!• Disadvantages:
• These drugs cannot be used in migraine prophylaxis since P2 agonistic
activity dilates cerebral blood vessels.
• It is less suitable for secondary prophylaxis of myocardial infarction.
(iv) Selective pt-blockers with intrinsic sympathomimeti c activity
o Drugs of this category offer additive advantages of Pindolol & Atenolol.
o They also have membrane stabilising action.
o Drugs under this category are Acebutolol and Celiprolol.
(a) Acebutolol
o It is well absorbed orally.
o It undergoes first-pass metabolism
o It is converted to an active metabolite, called dia cetolol which has a
longer half-life (10-12 hrs).
o It is given as a single oral dose of 400 mg/ day.
o It is used for treating ventricular arrhythmia.
(b) Celeprolol
o It is well absorbed with a bioavailability of75%.
o It has partial agonistic action on Pr receptors.
o It also causes some direct vasodilatation by releasing nitric oxide (NO).
o Pref erre d for hypertensive patients with asthma in an oral dose of
200-400 mg once a day.
(v) Mixed ( a + P) antagonists ➔ Drugs under this category block a- and P-
receptors. The examples are Labetalol and Carvedilol.
(a) Labetalol
•:• It acts as competitive antagonist at both a 1 & P-adrenergic receptors.
•:♦ It exhibits optical isomerisn1 and has four diastereomers.

•!• The racemic mixure exhibits following activities:

✓ Selective blockade of al-adrenergic receptors,
✓ Blockade of P1-receptors,
✓ Blockade of P2-receptors, and
✓ Partial agonistic activity at Pi-receptors.
•:• The a 1- and ~1-blocking actions of Labetolol lead to fall in BP.
•:♦ The intrinsic sympathomimetic activity (ISA) at Pi-receptor causes
peripheral vaso & bronchodilatation. Heart rate remains unaffected.
•:• It is also useful in phaeochromocyto ma.
•!• Postural hyp e rte nsion and he patotoxicity are main adverse reactions.
(b) Carvedilol
o It is orally effective.
o It undergoes significant first-pass effect with 30% bioavailability.
o It has a half-life of 6-8 hours. It is a P1-, Pr and a 1 -adrenoceptor blocker.
o Its p1 & P2 receptor blocking actions more prominent than a 1 - actions.
o It is used to treat essential hypertension.
o Useful to reduce mortality in myocardial infarction (with conventional
therapy).
o For hypertension/angi na, usual oral dose is 6.25 mg twice a day which is
increased to 12.5 mg if needed.

CLINICAL PHARMACOLOGY
• While administ.ering J3-blockers, watch for bradycardia especially, if
the patient is on digoxin or amiodarone.
• Atenolol, propranolol, metoprolol are commonly used ~-blockers
while esmolol (IV) is used in eme rgencies.
• J3-blockers even as eye drops (timolol) can precipitat e
bronchospasm in asthmatics.
• J3-blockers reduce the hepatic blood flow by about 30%- and thereby
delay the hepatic metabolism of some drugs.
• Postural hypotension and sexual dysfunction may reduce the utility
of a blockers but these effects are milder with a 1 -selective blockers.
• As per JNC recommendation, P-blockers are mainstay as anti-HTN.
• P-blockers, particularly metoprolol and carvedilol use, have shown
reduced morbidity and 1nortality in CCF.
• Most P-blockers do not block the J} 3 receptors and thereby have no
significant effect on lipolysis.
 Pharmacology of drug acting on
Peripheral Nervous System
SKELETAL MUSCLE RELAXANT &
NEUROMUSCULAR BLOCKING AGENT

Points to be cOvered in this topic

: 1. Introduction to SMR
- -..
---.. : 2. NeuromuscularBlock ingAgents
: 3. Classification of SMR
..........
: 4. Peripherally acting SMR
............
: 5. Directly acting muscle relaxants
............
: 6. Drug interaction
..........

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 □ INTRODUCTION TO SKELETAL MUSCLE
RELAXANT
❖ Skeletal muscle relaxants (SMRs) are drugs that reduce the muscle
tone either :-
i. By acting peripherally at the neuromuscular junction (neuromuscular
blockers)
ii. By centrally acting in the cerebrospinal axis, OR
j

iii. Directly acting on the contractile mechanism.

• They reduce the spasticity in a variety of

neurological conditions and are also useful
in surgeries.
• They relax skeletal muscles, particularly of abdominal wall and lower
limbs so that operative manipulations become easier.

• This situation minimises the risk of respiratory and cardiovascular

depression and also reduce post anaesthetic recovery period.
• The drugs block post-synaptic actions of ACh at motor end plate.

□ NEUROMUSCULAR BLOCKING AGENTS

•:• Neuromuscular blocking agents act peripherally at neuromuscular
junction or muscle fibre· itself or centrally on cerebrospinal axis to reduce
muscle tone and/ or cause paralysis. Neuromuscular Junction
•) These drugs are also termed as
skeletal muscle relaxants because
these drugs are used to reduce
unwanted spasm, spasticity, and
to cause paralysis of the skeletal
muscle without interfering with
consciousness.
□ CLASSIFICATION OF SMR
❖ The classification of muscle relaxants is based on their mode of
action, duration of action, and site of action, which is as follows:
t) Drugs Acting Peripherally at the Neuromuscular Junction : These drugs
are further categorised into the following sub-classes:
i) Competitive Blockers or Non-Depolarising Blockers: They may be:
a) Long Acting (60-120 Minutes) : Doxacurium, Pancuronium,
Pipecuronium and Veruronium.
b) Intermediate Acting (20-50 Minutes) : Atracurium & Rocuronium.
c) Short Acting (10-20 Minutes) : Mivacurium.
ii) Depolarising Blockers: Succinylcholine.
iii) Inhibition of Release of Acetylcholine: Botulinum toxins type A and 13-
Bungarotoxin.
2) Drugs Acting Centrally: Diazepam, Baclofen, and Mephenesin.
3) Drugs Acting Directly on Muscle: Dantrolene.

□ PERIPHERALLY ACTING SMR

► Muscle relaxants reduce muscle tone and influence the functions of
skeletal muscles.
► Symptoms like pain, muscle spasm, and hyper-reflexia are relieved by
using peripheral muscle relaxants.
► Muscle relaxants refer to two primary therapeutic groups, i.e.,
neuromuscular blockers and spasn10Iytics.
► The neuromuscular blockers act by interfering in the transmission at the
neuromuscular end plate.
► They do not act on the CNS.
► Spasmolytic acts by supressing the n1uscle spasm.
► They are sub-classified in to two sub-categories:
1. Non-depolarising blockers (competitiye blockers)
ii. Depolarising blockers (persistent depolarisers).
1. NON-DEPOLARISING BLOCKERS
• The first NMJ blocker was curare, which native hunters of Sou th
America were using for paralysing an animal before hunting.
• Curare was a plant extract and d-Tubocura rin e (d-TC) was isolated and
used in clinical practice from 1940s.
• Structure of d -TC and related derivative
are depicted below. There are several
derivatives of d-TC.
• Sonte are lo ng acting e.g. Metocurine, Doxacurium, Pancuronium and
Pipecuronium
• Son1e others are short acting e.g. Atracurium, Cis-atracurium,
Mivacurium, Vecuronium, Rocuronium and Rapacuronium.
• MOA ➔ Non-depolarising blockers bind to NM nicotinic receptors on the
motor end plate and block the actions of Ach by competitive blockade.
• These compounds slowly dissociate from the receptors and
transmission is gradually restored. Thus, the action of d-TC is reversible

Tubocurarine
dTc

:>ACh N',coti me
. Binds to and blocks N11 receptors
- ~

:>ACh
· receptors
!
Competitively blocks the action of acetylcholine
~
ACh: Acetylcholine ISkeletal muscle relaxation I
• Phannacokinetics
✓ These drugs are not absorbed orally. They are given i.v. route.
✓ They have relatively small volume of distribution (Vd). None of them cross
blood brain barrier. Hence, they do not produce CNS toxicity.
✓ These drugs do not cross placental barrier.

✓ Drugs excreted by kidney have longer duration of action.

✓ Drugs eliminated by liver have intermediate duration of action.
✓ Drugs inactivated by plas1na cholin esterase have short duration of action.
• Pharmacological Actions
i. Skeletal muscle: On parenteral administration, TC initially causes
muscular weakness followed by flaccid paralysis.
ii. Autonomic ganglia: In high doses TC can block autonomic ganglia and
adrenal medulla resulting in hypotension.
iii. Histamine release: TC can cause histamine release from the mast cells
leading to bronchospasm, increased tracheobronchial and gastric
secretions. May also contributes to hypotension.
• Adverse Reactions
✓ Respiratory paralysis and prolonged apnoea.
✓ Hypotension is due to ganglion blockade and histamine release.
✓ Flushing and bronchospasm due to histamine release
2. DEPOIARISING BLOCKERS {PERSISTENT DEPOIARISERS):
• Succinyl Choline (SCh) is the only one depolarising
neuromuscular blocker is available in clinical practice.
• Succinylcholine (SCh, suxamethonium) is a quaternary
ammonium compound with the structure resembling two
molecules of acetylcholine joined together. ISucclnylchollne I
• MOA - SCh stimulates N'.\1 nicotinic receptors and ! tMrm
Nicotinic receptors
depolarises the skeletal muscle membrane. (at motor end plate)

• Pharmacokinetics - ~
Membrane depolali11l cc,
(clinicaly fasciculations)
✓ Succinylcholine is rapidly hydrolysed by ~
pseudocholinesterase, hence it 1s short-acting Persistentdapolansation

✓
(about 5 minutes).
It is not absorbed orally and does not cross bold-
*
!Flacdd pan1ys1s j

brain barrier or placental barrier. Higher doses-- dual block

Phase I block
✓ It is administered i.v. in a dose of 0.75-1.5 mg/kg. (Depolarising. rapid onset.
polentiated by
antichcli 18Statases)
• Pharmacological Actions
!
1. Skeletal . muscle ➔ Initial transient muscular Phase II block
(non-depolarisil.
fasciculations & - twitching, mostly · in chest & slow onset.
reversed by
antichollnesterases)
stomach regions, followed by skeletal muscle paralysis.
2. CVS:
✓ Initially hypotension a nd bradycardia may result from stimulation of
vagal ganglia.
✓ This is fo llowed by hyperte nsion a nd tachycardia due to stimulation
of sympathetic ganglia.
✓ Higher doses can cause cardiac arrhythmias.
• Adverse effect
1. Postoperative muscle pain: is a common adverse effect of SCh.
2. Hyperkalemia: Sch can cause hyperkalemia due to sudden release of K•
from the intracellular sites which could be due to fasciculation's.
3. Cardiac arrhythmias: SCh can cause cardiac arrhythmias. It stimulates
the nicotinic receptors in the ganglia and cardiac muscarinic receptors.
4. Malignant hyperthermia is a rare genetically determined condition
where there is a sudden increase in the body temperature and
severe muscle spasm due to release of intracellular Ca++ from the
sarcoplasmic reticulum.

•!• USES OF PERIPHERALLY ACTING SMR :-

1. Adjuvant to general anaesthesia
• All NMJ blockers (d-TC like drugs and SCh) are used to provide skeletal
muscle relaxation during abdominal or thoracic surgery and for
endotracheal intubation.
• They are also used to counteract laryngospasm during barbiturate
anaesthesia.
• They are also used to prevent muscle contractions during surgery.

2. To prevent trauma during electro-convulsive therapy {ECT) ➔ SCh

with Diazepam is used to prevent injuries or fractures due to excessive
convulsions caused by ECT.
3. In minor procedures: SMRs are also useful in laryngoscopy,
bronchoscopy, oesophagoscopy, trache~ intubation and in orthopedic
procedures like reduction of fractures and dislocations.
4. In electroconvulsive therapy: SMRs protect the patient from convulsions
and trauma during ECT.
5. In spastic disorders: SM Rs are used to overcome the spasm of tetanus
and athetosis.
6. In status epilepticus: When convulsions cannot be controlled by
anticonvulsants alone, sometimes a NMB is used to control the muscular
component of convulsions. However, they do not cross the BBB and have
no central effects.
7. In patients on ventilator: To reduce the resistance of the chest wall and
enhance thoracic compliance and to facilitate artificial ventilation, NMBs
are used in intensive care units

•!• OTHER DRUGS ACTING AT NMJ

1. Botulinum toxin
• It is produced by the anaerobic bacterium Clostridium botulinum.
• The toxin inhibits the release of acetylcholine at the cholinergic
synapses resulting in flaccid paralysis of skeletal muscles.
• Botulinum toxin is useful (local injection) in the treatment of dystonias,
including sports or writer's cramps, muscle spasms, tremors, cerebral
palsy and in rigidity seen in extra pyramidal disorders.
• It is commonly used to relieve blepharospasm.
• Botulinum toxin is also gaining popularity in cosmetic therapy for the
removal of facial lines and wrinkles by local injection.

□ DIRECTLY ACTING MUSCLE RELAXANTS

1. Dantrolene
► It is a phenytoin analogue that acts directly on the --- + OlntroltM,

Binds~ ,ac:epeo, dlannel

skeletal muscle.
► Mechanism of Action ➔ Dantrolene directly affects
+
8locb.,. dwlnel

the skeletal muscle contractile mechanism. +

C... ,.....
Inhibits from SR

► It inhibits the muscle contraction by preventing the +

lnNbill,... corlhdion

calcium release from the sarcoplasmic reticulum

Sktlttal
+
fflUldt Nlaution
through ryanodine receptors (RyR1) channel.
► Adverse effects
✓ Drowsiness, dizziness, fatigue
✓ Diarrhoea, muscle weakness
✓ Rarely hepatotoxicity (Liver function tests should be done to look for
hepatotoxicity).
► Uses
• Dantrolene is used in spastic disorders like hemiplegia and paraplegia,
multiple sclerosis and spinal cord injury.
• Dantrolene is the drug of choice in malignant hyperthermia.
• Dantrolene is also useful in n1alignant neuroleptic syndrome.

2. Quinine:
• The antimalarial quinine is a skeletal muscle relaxant.
• It is a Na• channel blocker & it reduces the excitability of motor end plate.
• Quinine is used in myotonia congenita and in nocturnal muscle cramps.

□ DRUG INTERACTIONS
1) Thiopentone Sodium: Succinylcholine and thiopentone sodium must not
be mixed in the same syringe as they result in a potential harm.
2) General Anaesthetics: These agents potentiate competitive blocking
agents. Non-depolarising blocking agents are also intensified by
ketamine.
3) Anticholinesterases: The actions of competitive blockers is reversed by
the administration of anticholinesterases.
4) Aminoglycoside antibiotics decrease the release of ACh from
prejunctional nerve endings by competing with Ca 2• ions.
5) Calcium Channel Blockers: Like verapamil potentiates both, the
competitive as well as depolarising neuromuscular blocking agents.
6) Diuretics: Causes hypokalaemia which in turn improves the activity of
competitive blockers.
7) Diazepam, Propranolol, and Quinidine: -Administration of these agents
intensifies th e compe titive blocking by muscle relaxants.
, Pharmacology of drug acti ng on
Peripheral Nervous System
;- - - - - . .

LOCAL ANAESTHETICS AGENT

Points to be covered in this topic

---. 1. Introduction
---.. 2. Classification of local anesthetics
___... 3. Mechanism of action of LA
........... 4 . Pharmacokinetics of LA
_.._.. 5. Therapeutic uses of LA
6. Pharmacological action of LA
7. Adverse effects of LA GDC:@fr,,19
_ ..... 8. Drug interactions of LA A~w:yto ~

---...... 9. Individual drugs of LA

- ..... 10. Pre-anaesthetic agent
Do~nluad
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SIMPLIFIED
CE N TE R
 U INTRODUCTION
• Local anaesthetics (LA) are drugs that block nerve
conduction when applied locally to nerve tissue in
appropriate concentrations.
• Their action is completely reversible.
• They act on every type of nerve fibre and can cause both sensory and
n1otor paralysis in the innervated area.
• Cocaine was the first agent to be isolated by Niemann in 1860.
• Unlike general anaesthetics, they neither cause a loss of consciousness,
nor need a proper maintenance of vital functions during surgery.

□ CLASSIFICATION OF LOCAL ANESTHETICS

[I] According to clinical use -

CIASSES SUB-CLASSES f DRUGS
Low potency, short Procaine, Chloroprocaine
duration
Injectable Intermed iate potency Lidocaine (Lignocaine),
anaesthetic and duration
-
Prilocaine
---
High potency, Long Tetracaine, Bupivacaine,
duration Ropivacaine, Dibucaine
Soluble Cocaine, lignocaine, Tetracaine
Surface
anaesthetic Insoluble benzocaine,
1 Butylaminobenzoate

[II] According to structure -

CLASSES DRUGS

Esters Cocaine, procaine, benzocaine, tetracaine

Amide Lignocaine, Bupivacaine, Dibucaine, prilocaine, Ropivacaine

❖ ADVANTAGESOFAMIDESOVERESTERS
• Produce more intense and longer lasting anaesthesia.
• Cause less hype rse nsitiv ity reaction.
• Produce longer lasting anaesthesia as they are not hydrolysed by esterase.

□ MECHANISM OF ACTION OF LA
• The primary mechanism is blockade of voltage-gated sodium chann e l,.
• LA diffuses through cell membrane and bind to voltage-sensitive sodium
channels from inner side of the cell membrane.
• They prevent the increase in permeability to Na• and gradually raise the
threshold for excitation.
• With t concentration, impulse conduction Jr, rate of rise of a ction
potential {AP) ..i.
Local anaesthetic are weak base

D,
Partly un ionized

Penetrate nerve membrane

Enter the axon (axonal pH is Io,v)

Local anaesthetic block the ,·oltage gated Na· ions into

the neurons ➔ No depolarization

No generation of action potential

No generation and conduction of in1pulse to CNS

Local anaesthesia
 B1 ·~I i11 · 1
')
,\1 I I\ .111 d I 11 . I ( I i ·•. I I I I I
0 0
EFC
' ' j
- t 1 i C

f1l)011;,·li.
i 1 ) • I
I ' . 1

"·, ;I li I I )1II 1111)111;

1 ' ! • • ' \ ' .. t I i. , t I ~

ICF
Slow
Activation gate IL1pid
do~inr,
hLtct iv.1t ion :~;1t <' O(H'llill:~
tr·in~ered
m1 er·ed
tr i IM>
at I hreshold
at thn·shold

I
□ PHARMACOKINETICS OF LA

► The presence of ester or amide bond in a LA molecule governs its

biotransformation and possibility of causing hypersensitivity reactions.
, ► The ester-type LAs ( e.g. Tetracaine, Chloroprocaine) are usually
hydrolysed by pseudo cholinesterase or by liver esterase 's.
► Hypersensitivity reactions are common with ester type of LAs; because
they are hydrolysed to para-amino-benzoic acid (PABA) that are known
to be potential allergens.
► The amide type of LAs (Lidocaine, Bupivacaine) are degraded by
hepatic microsomes. As a result they have a longer duration of action.

□ THERAPEUTIC USES OF LA
•:• The local anaesthesia induced by LA is designated according to the
technique or anatomical site where it is injected or applied.
•!• Thus, it is sub-classified in to following fwe types:
i. Topical anaesthesia -
✓ It is also termed as surface anaesthesia. ·
✓ It is restricted to mucus membranes, damaged skin surface or burn s.
 ✓ Corneal surface, mucosa of mouth, nose, pha rynx, trachea and
urethra are easily anaesthetised.
✓ Surface anaesthetics can also be used to facilitate endoscopic
procedures and to reduce pain of haemorrhoids or anal fissures.
✓ The names of topical/surface anaesthetics & their concentrations :-
• Tctracaine: AMETHOCAINE, ANETHANE (2%),
• Lidocaine (2-5%),
• Benzocaine: MUCOPAIN, ZOKEN (5%),
• Dycyclonine (0.5-1 %),
• Proparacaine (0.5-1 %)
• Eutectic mixture of Lidocaine (2.5%) & Prilocaine (2.5%)
(ii) Infiltration anaesthesia -
•:• In this case, the dilute solution of LA is injected under the skin to reach
sensory nerve terminals.
•:• Infiltration is used for m inor surgical proce d ures like incisions or
excisions.
•:• The available preparations are: Lidocaine (1-2%): LIGNOCAINE,
GESICAINE, XYLOCAINE, Bupivacaine (0.25%): MARCAIN, BUPIVAN,
Ropivacaine (0.5-1 %), Mepivacaine (1-3%) and Prilocaine (1-4%):
PRILOX, ASTHESIA.

(iii) Conduction block anaesthesia -

•:• In this case, LA is injected around the nerve trunk so that distal area
around the site of injection gets anaesthetized.
•!• It is of two types: Field block or Nerve block
(a) In case of field block, the LA is injected sub-cutaneously in the
surrounding area of the nerve so that all other nerves coming to a ,
particular field are blocked. Field blocks are applied to the scalp and ,
interior abdominal walls.
(b) In case of nerve block, the LA is injected around anatomically
localised nerve trunks i.e. close to ·the mixed nerve. Nerve block
lasts longer than field block or infiltration anaesthesia.
(iv) Central nerve block anaesthesia -
❖ Available preparations are Lidocaine (3-5%), Tetracaine (0.3-0.5%) or
Bupivacaine (0.5- 0.7%).
•!• It is further divided in to epidural and spinal block anaesthesia.
(a) Epidural block anaesthesia
• It is also named as peri-dural block and widely used to provide
analgesia or anaesthesia in surgical or obstetric practice.
• It involves injecting a LA like Lidocaine, Bupivacaine or Ropivacaine
either alone or in combination with a small dose of opioid analgesic
in to the epidural space in lumbar, thoracic or cervical regions to
provide segmental analgesia.
• One of these types is called as Caudal block which is administered in
the caudal (sacral) region.
(b) Spinal block anaesthesia
• It is also named as sub-arachnoid or intra-thecal block anaesthesia
• It can also be used as spinal analgesia.
• It is produced by injecting suitable LA in the spinal sub-arachnoid space
between L2 and L3 or L3 and L4•
• It is used to anaesthetise lower abdomen and hand limbs.

(v) Intravenous regional anaesthesia

✓ It is also named as Bier's block.
✓ It is mainly used for the upper limb and for orthopaedic procedures.
✓ Available preparations are Lidocaine (0.5%) and Prilocaine (0.5%).

□ PHARMACOLOGICAL ACTION OF LA
► Depending on concentration attained in the plasma_. any LA can
produce systemic effects.
► CNS, autonomic ganglia, NM) and all muscles are affected.
1. CNS: Local anaesthetics depress the cortical inhibitory pathway
thereby allowing unopposed activity of excitatory components. The
central stimulation is followed by generalised CNS depression and
death may result from respiratory failure.
2. CVS: The primary site of action is the myocardium- Lignocaine
decreases excitability, conduction rate and force of contraction
(quinidine like effects). Bupivacaine is more cardiotoxic than other LAs.
3. Blood vessels: LAs cause hypotension which is due to sympathetic
blockade. They also cause arteriolar dilatation.
4. Smooth muscle: LAs depress contractions in the intact bowel. They
also relax vascular and bronchial smooth muscles.
5. Local actions: On local administration, LAs bring about reversible loss of
sensation as already discussed.

□ ADVERSE EFFECTS OF LA
► In general, adverse effects of all types of LAs are similar. They are
mentioned below:
1. Allergic reactions
• The ester type of LAs are metabolised to PABA or lts derivatives,
which cause allergic reactions.
• The result is contact dermatitis, rashes and asthma.
• Amide group of LAs do not cause allergic reactions.
2.CVS
• LAs block sodium channels and depress abnormal cardiac pace-
maker activity, excitability and conduction.
• Most LAs produce hypotension.
• Bupivacaine is cardiotoxic, cause ventricular tachycardia & fibrillation.
• Lignocaine has a quinidine-like action on heart and is used in the
treatment of cardiac arrhythmia.
 3. Blood
• Large doses of Prilocaine cause accumulation of its metabolite called
orthotoluidine, which oxidises haemoglobin to methaemoglobin.
• Higher levels of methaentoglobin can cause cyanosis.
• Methylene blue or ascorbic acid can be used to restore haemoglobin.
4.CNS
• At low doses, LAs cause tongue numbness, sleepiness, mild headache,
visual and auditory disturbances.
• At high dose, they cause nystagmus and muscular twitching.

0 DRUG INTERACTIONS & PRECAUTION OF LA

❖· Before injecting the LA, aspirate lightly to avoid intravascular injection.
•!• Inject the LA slowly and take care not to exceed the maximum safe dose,
especially in children.
❖ Propranolol (other beta blocker) also may reduce metabolism of
Lidocain & other amide Local anaesthetic by reducing hepatic blood flow.
•!• Vasoconstrictor (adrenaline) containing Local anaesthetic should be
I

avoided for patient with :-

✓ Ischemia heart disease,
✓ Cardiac arrhythmias,
✓ Thyrotoxicosis,
✓ Uncontrolled hypertension
✓ Those receiving ~-blocker or Tri cyclic arrhythmias.

□ INDIVIDUAL DRUGS OF LA
1. Lignocaine
• It is the most widely used LA. It is fast and long-acting. Lignocaine
• It is useful for all types of blocks, Hydrochloride
Injection IP
• Maximum anaesthetic effect is seen in 2-5 minutes and Xylocailt• a
I
~

lasts for 30..:.45 minutes. ·---- 30ml

I I •

• In contrast to other LAs, lignoea.ine tauses drowsiness and.

mental clouding.
2. Bupivacaine HCI
• It is n1ore potent and longer acting than lignocaine-it is µ
widely used.
• But it can cause more cardiotoxicity than others.
( __ :]
0 It "'•
BUPIVACAINl J
Levobupivacaine HCI is a derivative of bupivacaine that seems
I -:.".~....~· ~.
~ 111P..J!_,_J.!!._

to be less neurotoxic and less cardiotoxic than bupivacaine.

3. Cocaine:
t J
• It is a benzoyl methylecgonine hydrochloride (an ester of benzoic acid).
• It is an alkaloid extracted from the leaves of coca tree (E,ythroxylum coca).
• Pharmacological Actions
i. It stimulates CNS & causes restlessness, excitement,
euphoria, tachycardia, tachypnea, and hypertension.
ii. It also stimulates respiratory, vasomotor &
vomiting centres.
iii. It has a direct toxic effect on myocardium.
iv. In small doses it causes bradycardia due to central Coeain
vagal stimulation.
v. In larger dose it causes sympathetic stimulation
resulting in tachycardia, peripheral vasoconstriction,
hypertension, and ventricular fibrillation.
• Pharmacokinetics:
1. Cocaine undergoes slow absorption from mucous membrane due to

its vasoconstriction.
ii. It gets eliminated slowly so toxic symptoms easily occur.
iii. It is mostly detoxicated in the liver and a small unchanged quantity is
excreted via kidneys.
• Adverse effect
✓ Cocaine is unique among drugs of abuse.
✓ Cocaine also stimulates vagal centre ➔ bradycardia
✓ Vasomotorcentre ➔ rise in BP;
✓ Vomiting centre ➔ nausea & vomiting
✓ Temperature regulating centre ➔ pyrexia
4. Tetracaine (amethocaine)
• It is a PABA derivative
• It is I O tintcs rnorc toxic and more active than procaine.
• It is used on the eye as 0.5% drops, ointments 0.5% and cream 1 % for
topical use.
5. Procaine
• It is hydrolysed to PABA which interferes with the action of sulphonamides.
• It is rapidly absorbed following parenteral administration.
• It is ineffective when applied topically because it is poorly absorbed from
the mucous membranes-thus not useful as a surface anaesthetic.

6 . Chloroprocaine HCI potency is twice that of procaine and its toxicity is

lower because of its more rapid metabolism.
7. Etidocaine HCl: Its analgesic action lasts 2- 3 times longer. It is used for
epidural (1 %) and all types of infiltration and regional anaesthesia
8 . Mepivacaine: Action is more rapid in onset and more prolonged than that of
lignocaine.

•!· COM PARISON BETWEEN GENERAL AND LOCAL ANAESTHETIC

GENERAL LOCAL
FEATURES
ANAESTHETIC A NA ESTHETIC

• • I • •

Area of body involved Whole body Restricted area

Consciousness Lost Unaltered
Care of vital function Essential Usually not needed
Physiological trespass High Low
Poor health patient Risky Safer
- -t

Use in non-cooperative patient Possible Not possible

- -- - -
Major surgery
----+-------
Preferred Cannot be used
Minor surgery
----4----------,
Not preferred Preferred
 Pharmacology of drug acting on
Peripheral Nervous System
.
DRUG USED IN MYASTHENIA GRAVIS
AND GLAUCOMA

Points to be covered in this topic

; 1. Introduction to myasthenia gravis
.........
; 2. Etiology and Symptoms
..........
; 3. Diagnosis
- ....
; 4. Treatment of Myasthenia Gravis
..........
: 5. Drugs Causing Myasthenia Gravis
..........
: 6. Introduction to Glaucoma
; 7. Types of Glaucoma
...........
; 8. Drug acting on Glaucoma
~
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GDC(illti 119
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SIMPLIFIED
 □ INTRODUCTION TO MYASTHENIA GRAVIS
• Myasthenia Gravis (MG) is a n a utoin11nune di sord e r, in which antibodies
are produced at n e uron1uscular junction (NMJJ against the NMreceptors,
so, it results in decrease in the number of NM receptors.
M'f ASTl-\€N \~
• This prevents nerve impulses from
W \J\S
lriggcfing ,uuscle contractions. Pi'b~•~ ,.,... ()N

• Patients with thymoma show an more risk

of development of myasthenia gravis.
~.... ~
. 1,J&~ l)SOJtJI
~..w;.1\()-..j
,./

□ ETIOLOGY AND SYMPTOMS

❖ ETIOLOGY
• Myasthenia gravis is an acquired auto-immune disorder causing fatigue
and wealmess of skeletal muscles. I I

• The disease is associated !with production of IgG type of antibodies t o

ACh receptors (NM) at th~ po:s t-junctional motor end plate.

❖ SYMPTOMS I ,c
I : !

• In early stages of disease, , the fast moving muscles are affected first.
, I

Followed by :- 1

✓ Ptosis,

<es >
II ~
✓ Diplopia, I '-
I

✓
I ,

Opthalmoplegia I I
I I I

✓ Weakness of muscle I I J, I ' 11

✓ Fatigue which worsens after exercise but goes off after rest.
I
I

✓ Slurring of speech,
I'
✓ Difficulty in swallowing.
✓ Subsequently, all
I

muscles are progressively affected including I I •

respiratory muscles.
LJ DIAGNOSIS
• Also called Ameliorative test

• Initially edrophonium 2 mg is injected I.V.

as a test dose.
EDROPHONIUM TEST • If patient shows improvement in muscles
power ➔ myasthenia gravis

• In muscular wealmess deteriorates ➔

cholinergic crisis
• Detection of circulating antibodies to NM
receptors like anti-AChR antibodies,
ANTIBODY TEST
antiMuSK antibodies, anti-striational
antibodies
• Repetitive Nerve Stimulation (RNS) and
Single Fibre Electromyography (SFEMG)
NEUROPHYSIOLOGICAL
TESTS are most commonly used for
neurophysiological tests.

□ TREATMENT OF MYASTHENIA GRAVIS

► Any reversible anti-AChE drug of intermediate duration of action is
useful for treatment of myasthenia gravis.
► Initially Neostigmine is given in a oral dose of 15-30 mg/day in divided
doses or 0.5-2.5 mg as i.m. or s.c. injection with gradual increment till
therapeutic goals are achieved.
► Alternatively oral Pyridostigmine 60 mg three times a day is followed by
gradual increase till satisfactory response ..
► Another alternative is oral Ambenonium 2.5-5 mg, every 6 hours.
► Drug used in the treatment of Myasthenia Gravis are :-

TREATMENT

The neuromuscular transmission is modulated by

Modulation of administration of anticholinesterases
Neuromuscular (cholinesterase inhibitors) such as :-
Transmission 1. Pyridostigrnine bro1nide (mestinon)

11. Neostigmine bromide (Prostigmin).

1. Plasma Exchange: It helps to remove abnormal

antibodies.
11. Intravenous Immune Globulin (IVIG): It
Immunomodulation : brings about down-regulation of antibodies
Modulation of the directed against AChR
immune system is iii. lmmunoadsorption : This procedure helps to
brought about by - remove anti-AChR antibodies.
iv. lmn1unosuppression: Corticosteroids (e.g.,
prednisone ), Azathioprine, Cyclosporin,
Mycophenolate Mofetil & Tacrolimus.

□ DRUGS 'CAUSING' MYASTHENIA GRAVIS

• Doses of these drugs should be reduced or these drugs may be withdrawn
during treatment of myasthenia gravis.
• Following drugs are lmown to aggravate myasthenia gravis.

CATEGORY OF EXAMPLES
DRUG ~

1. Antibiotics Aminoglycosides (Streptomycin, Gentamycin),

Polymixins, Colistin
2. Anti-arrbythmics Procainamide, Quinidine and Propranolol

3. CNS depressants Morphine (respiratory depression)

4. Miscellaneous d-TC, Quinine, Methoxyflurane and Lithium

[□ INTRODUCTION TO GLA
❖ Glaucoma is defined as a progressive optic neuropathy causing
damage to optic nerves that result in visual field defects.

NORMALEYE GLAUCOMA

C0MIA
''
'

'' ' '.,

'/ \
TRABICULAR
MalHWOIU(
'\
',
~·--
',
'\

'
TRAIIECULNt ,
MUHWORK ,'

'
ISUILDU~OP
1
'
'' ~~~..!-~~ I
''
AQUEOUS HUMOR FLUID
I
I
DAIIAO&TO
I

TH8 OPTIC NIIIVa

AQUIOUS HUMOR
PLUID

• The disorder is progressive in nature and is usually associated with

increase in intraocular pressure (normal intraocular pressure ranges
from 10- 20mmHg).
• Therefore, management of glaucoma aims at decreasing the raised
intraocular pressure which can be achieved either by reducing
aqueous humour formation (formed by ciliary process) or improving
the drainage.

[□ 1YPES OF GLAUCOMA, ]
•) There are three types of glaucoma:
✓ Primary, Secondary and Congenital.

•!• Treatment is available for primary glaucoma and certain types of secondary
glaucoma (after trauma or after cataract operation).
•!• There is no treatment for congenital glaucoma.

1. Primary gl~ucoma
• It is associated with direct disturbance in-outflow of aqueous humour.
• Divided into two sub-types: Narrow Angle and Wide Angle Glaucoma.
(i) Narrow angle glaucoma
o Also called + Closed angle, acute congestive or angle closure glaucoma.
o In this case, the pressure fro m the posterior chamber pushes the iris
foiward, closing the ocular angle and preventing the drainage of
aqueous humour.
o The iris may also physically block the passage of aqueous humour
through the canal of Schlemm.

Wide Narrow
angle angle
glaucoma glaucoma

(ii) Wide angle glaucoma

o Also called + Open angle, chronic simple glaucoma
o In this case, the ocular angle remains wide but the trabecular mesh work
starts losing patency due to progressive degeneration.
o As a result, the outflow of aqueous humour gets impeded. In this type,
the surgical intervention is not much helpful.
o Control of IOP is usually dependent on long range drug therapy.

2. Secondary glaucoma refers to any form of glaucoma in which there is an

identifiable cause of increased eye pressure, resulting in optic nerve
damage and vision loss. secondary to some eye diseases.

3. Chronic Simple Glaucoma: It is a genetic disorder, characterised by a

gradual increase in the intraocular pressure. In this condition, the potency
of trabecular meshwork is affected.
4. Acute Congestive Glaucoma: It is generally seen in patients having a
shallow anterior chamber and a narrow iridocorneal angle, who use
mydriatics (eye drops bringing about dilation of the pupil). This condition, if
once under control is treated either surgically or by laser iridotomy.
[□ DRUG ACTING ON
•:• Drugs used for treating glaucoma are :-
ACUTE CONGESTIVE (NARROW• CHRONIC SIMPLE (WIDE-ANGI.E)
ANGLE) GLAUCOMA GLAUCOMA

Ji-Blockers
Osmotic Agents
1) Tlmolol (0.25%)
1) Mannitol (20%) IV
2) Betaxolol (0.25%)
2) Glycerol (50%) oral
3) Carteolol (1%), topical

Carbonic Anhydrase Inhibitors Prostaglandlns

Acetazolamide, J.v. & Oral Latanoprost (0.005%), topical

Carbonic Anhydrase Inhibitors

P-Blockers 1) Dorzolamide (2%), topical
Timolol (0.5%), topical 2) Brinzolamide, topical
3) Acetazolamide, oral

a.-Adrenel'lf c Agonlsts
Miotics
1) Dipivefrine (0.1 %), topical
Pilocarpine (2%), topical
2) Apraclonidine (1%), topical

Prostagland.ins Miotics
Latanoprost (0.005%), topical Pilocarpine (0.5%), topical

•!• Following drugs are used for the treatment of glaucoma :-

1. Osmotic Agents:
o These agents reduce the intraocular pressure by I Clrbonic anti,dl . . lntlllllla •
(iCNZOUmidt, dorzolamlde)
i
~
drawing fluid from the eye into the circulation via II.,.._
I

of ClltJonk lnftiion
osmotic effect.
f
!
Ebrt>ol••
o 20% Mannitol OR 10% Glycerol injected IV exert
osmotic effects and draw fluid from the eye. l aFb
I l Produdloaol lqlMOUI lulot
2. Carbonic Anhydrase Inhibitors:
o These agents include Acetazolamide ( oral, IV), Dorzolamide (topical),
and Brinzolamide (topical).
o They act to reduce the intraocular pressure by decreasing the
formation of aqueous humour.
o They inhibit the enzyme carbonic anhydrase non-competitively.
3. f}·Adrenergic Blockers:
► These agents include Timolol, Betaxolol, Levobunolol, Carteolol, and

Metipranolol administered topically.

► For treating patients with glaucoma, Timolol is widely used because:
i. It lacks properties of a partial agonist or a local anaesthetic.
ii. It has no effect on the size·of the pupil or accommodation.
iii. Its action lasts for a longer duration.
iv. It is easily tolerable.
v. Its topical preparation is safe and very effective.
► f3-blockers should be used cautiously or contraindicated in bronchial

asthma and heart failure.

4. Prostaglandins {PGS):
► For the initial treatment of open-angle glaucoma, topical PGs like
Latanoprostand Bimatoprost (PGF 2a analogues) are preferred.
► These agents have longer duration of action, high efficacy and low
incidence of systemic toxicity.
► These agents are also used for treating acute congestive glaucoma.
► They facilitate uveoscleral outflow and thus reduce intraocular pressure.
5. Miotics:
► These are used to treat acute congestive and open angle glaucoma.
► Pilocarpine, a tertiary amine is used as a mitotic agent.
► It is administered topically and is absorbed well through the cornea.
► It decreases intraocular pressure by the drainage of aqueous humour.

6. a-Adrenergic Agonists
i) Apraclonidine.
• It is used topically as an adjunctive therapy, in patients with glaucoma.
• It is advantageous because it does not cross BBB & has no hypotensive
effect.

Apraclonidine } Reduc~ formation

Bn·mon1·d1·ne + .a.2-Agonists + of aqueous humor
+ Decrease IOP
ii) Dipivefrine
• It is another a.-adrenergic agonist.
• It is a prodrug of adrenaline and acts by penetrating the cornea.
• It is converted into adrenaline via the action of esterases.
• It is better tolerated & longer acting than adrenaline - used as adjuvant.

iii) Brimonidine
• It is more a. 2 selective and has higher lipophilicity than Apraclonidine.
• Ocular side effects (a. 1) are milder.
• Used as an alternative to other drugs and as an adjuvant.