NEUROMUSCULAR
BLOCKING
AGENTS :CURARE
ALKLOIDS
Strychnos toxifera
CONTENTS:1. Neuromuscular Blocking Agents
2. Classification of Neuromuscular
Blocking Agents
3. Curare Alkaloids
4. Extraction of Curare Alkaloid
5. S.A.R of Curare Alkaloid
6. Mechanism of Action Curare
Alkaloid
7. Isolation of Curare Alkaloid
8. Analogue of Tubocurarine
derivatives
9. Uses of curare alkaloids
NEUROMUSCULAR BLOCKING AGENTS :-
These are the agents which relax
the skeletal muscle by blocking
the neuromuscular transmission
at neuromuscular junction , by
causing paralysis of affected
skeletal muscle.
Non- Depolarising
Agents :These are the agents which acts
by
competing
with
the
acetylcholine for the receptor
sites on the motor end plates
,thus reducing their responce to
the transmitter.
Their action can be reversed by
the anticholinesterase such as
neostigmine.
Ex. Tubocurarine,Pancuronium
Depolarising Agents :These
agents
block
the
neuromuscular transmission by
producing a partial depolarising
motor end plate which renders
the
tissues
incapable
of
responding to the acetylcholine.
They act as agonists at the
acetylcholine receptor, meaning
they bind to the receptor and
trigger a response, unlike nondepolarizing blockers which act
as antagonists.
Ex.
Succinylcholine,
Decamethonium
CURARE ALKALOIDS
Curare alkaloids are the group of
chemical that acts as a paralysing
agents. they are used to relax
muscle and acts as therapeutic
agents .
Curare alkaloids blocks the
neuromuscular transmission of
impulses especially in skeletal
muscles.
1.
Tubocurarine is a nondepolarizing
neuromuscular
blocking agent and the first
identified curare alkaloid.
2. Dried extract from the bark and
stems of Strychnos species
e.g., S. castelnaei, S. toxifera, S.
crevauxii
3. Family- Loganiaceae and from
Chondodendron species,
Family- Menispermaceae. •
4.
Curare
contains
several
alkaloids, the most important
is
d-tubocurarine
(quaternary
ammonium structure with two ether
bridges).
SAR of Curare Alkaloid:1. D-tubocurarine is a bisbenzylisoquinoline derivative
and shares this stuctural
backbone.
2. The presence of quaternary
ammonium group targets the
activity of neuromuscular
receptor blockage.
3. Tetrahydro-isoquinoline
derivative.
4. Quaternary ammonium tertiary
amine in acidosis (+ charge)
increase potency.
5. Two quaternary centres at
specific separation ( 1.15 nm)
6. Bis-quaternary ammonium
compound having two
quaternary ammonium salts
separated by 10-12 carbon
atom was required for
neuromuscular blocking
activity.
7. 10-12 carbon bridge between
2 nitrogen max.
Neuromuscular blockade.
Extraction and Isolation of Curare Alkaloids
Collection of Curare Plant Material
Drying & Grinding into Powder
Powered drug containing Alkaloids
Defatted If
Necessary
Moisten and render with
alkaline solution like Na2CO3,Lime,etc..
Obtained Alkaloidal mixture
Exhaust with organic solvents like
CHCl3 , Ether
Extract containing Alkaloidal mixture
Extract containing Alkaloidal mixture
Add and shake with dil. H2SO4
Aq. Acidic solution
( Acidic Alkaloidal Sulphate )
Make the mixed
aqueous liquid
alkaline with ammonia
Collect the ppt of Alkaloids
Residual Organic solution
( Pigments,fats,and weak bases and
Chloroform soluble substances )
Collect the ppt of Alkaloids
Concentration (Evaporation)
Fractionation (Column Chromatography
Purification (Recrystallization, HPLC)
Identification (UV, IR, NMR, MS)
Pure Alkaloids.
Stage1: -Powdered material is moistened with water and mixed with alkali like
sodium & potassium carbonate, ammonia, lime. Make a paste with water, dry,
repowder.
Concept: -Lime (calcium hydroxide), combines with acid, tannins, and other
phenolic substances and sets free alkaloids.
Stage2: - extract the free alkaloids by hot continuous percolation with chloroform
or any other organic solvents.
Concept: -the free alkaloids dissolve together with other substances soluble in
solvent.
Stage3: - agitate the chloroform soln. With successive portion of dil. sulphuric
acid separating the aqueous layer before adding the next portion of acid.
Concept: -the alkaloids are converted into alkaloidal sulphates, which being
soluble in water, pass into aqueous layer.
Stage4: - Make the mixed aqueous liquid alkaline with ammonia, collect the
precipitate that forms, wash with water and dry.
Concept: - Ammonia decomposes the alkaloidal sulphates forming ammonium
sulphates, soluble in water, and the free alkaloid which being practically insoluble
in water is precipitated.
Mechanism of action of Tubocurarine:Tubocurarine
Binds to and blocks the Nm receptor
Competitively blocks the action of
Acetylcholine
Skeletal muscle relaxation
D-tubocurarine is a long acting; competitive neuromuscular blocker
competes with acetylcholine for receptor sites at the motor end plate,
thereby reducing the response of the end plate to acetylcholine. This results
the skeletal muscle relaxation.
Synthetic Analogue of Tubocurarine
The synthetic derived compound consist of either azasteroidal or
non-steroidal nucleus,
Ex,
1. Pancuronium
2. Atracuronium
3. Vencuronium
4. Metocurine Iodide
Pancuronium
• More potent than curare
(6 times)
• Acyl group are added to
introduce the Ach skeleton.
• Faster
onset
than
tubocurarine but slower than
suxamethonium.
• Longer duration of action
than suxamethonium.
Vecuronium
• Vecuronium
demethylated
pancuronium
is
product
a
of
• Vecuronium
had
intermediate
duration
action and a slow onset.
an
of
Atracurium
• Design based on tubocurarine
and suxamethonium.
• Rapidly broken down in blood
both chemically and metabolically
.
• Lifetime is 30 minute.
• It has a slow onset and an
intermediate duration of activity
Atracurium is a mixture of ten
isomers and can release histamine.
• Cis-atracurum, an isomer of
atracurium, is a cleaner molecule
more potent than atracurium and
does not release histamine.
Administered as i.e drip.
Metocurine Iodide
• (+)-O,Odimethylchondrocurarine diodide.
• Prepared
curare.
from
natural
crude
• By extracting the curare with
methanolic pot. Hydroxide.
• MOA same as a d-tubocurarine.
• More potent than d-tubocurarine.
Uses of Curare Alkaloids:1.
2.
3.
4.
It is a non-depolarizing neuromuscular blocking agent,
employed IM and IV as a skeletal muscle relaxant to secure
muscle relaxation in surgical procedures.
It is used to control and reduce convulsions of strychnine
poisoning and of tetanus.
It is used as a diagnostic aid in myasthenia gravis
Use as spider bite treatment.