Neuromuscular blocking agents, Curare Alkaloids M.Pharmacy 1st Semester 2022 (2021-2022) Previous Year's Question Papers/Notes Download - HK Technical PGIMS

❖CONTENTS

➢INTERDUCTION
➢CLASSIFICATION OF NEUROMUSCULAR BLOCKING AGENTS

❑NON-DEPOLARISING AGENTS
❑DEPOLARISING AGENTS

➢CURARE ALKALIODS
➢SAR OF d-TUBOCURARINE
➢SAR OF SUCCINYLCHOLINE
➢REFERENCES

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖ NEUROMUSCULAR BLOCKING AGENTS

• These are the agents which relax the skeletal muscles by blocking
neuromuscular transmission at neuromuscular junction, causing
paralysis of the affected skeletal muscles
• These are generally used as adjuvants in surgical anesthesia to
produce muscle relaxation.
• Neuromuscular blocking agents are among the most commonly used
drugs during general anesthesia. They compete with acetylcholine and
interfere with the transmission of nerve impulses resulting in skeletal
muscle relaxation.
• These are of two types i.e. Non-depolarizing and Depolarizing agents.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖CLASSIFICATION OF NEUROMUSCULAR BLOCKING
AGENTS

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖ MECHANISM OF ACTION:

(1) NON-DEPOLARISING AGENTS: ( COMPETITIVE BLOCKERS )

• These are the agents which act by competing with the acetylcholine for the receptor sites on the
motor end plate , thus reducing their response to the neurotransmitter[figure].
• Produced by curare and related drugs.
• The competitive blockers have affinity for the nicotinic ( NM ) Cholinergic receptors at the muscle
end plate, but have no intrinsic activity.
• At very high concentration, curare like drugs enter the Na+ channels and directly block them and
Ach released from motor nerve ending is not able to combine with its receptors to generate end
plate potential (EPP).
• d- TC Thus reduces the frequency of channel opening.
• When the magnitude of EPP falls below a critical level, it is unable to trigger propagated muscle
action potential (MAP) and muscle fails to contract in response to nerve impulse.

• E.g. Tubocurarine, Pancuronium

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

(2) DEPOLARISING AGENTS:

• These agents block the neuromusculartransmissionby producing a partial
depolarising of motor end plate which renders the tissues incapable of responding
to acetylcholine[figure].
• Decamethonium and SCh have affinity as well as submaximal intrinsic activity at the
NM receptors.
• They induce prolonged partial depolarization of the region around the muscle end
plate ( do not dissociate rapidly from the receptor ), longer lasting depolarization
produces repetitive excitation of end plate. Ach released from motor nerve ending is
unable to generate propagated MAP.

E.g. Succinylcholine
Decamethonium.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖MECHANISM OF ACTION

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖CURARE ALKALIODS: INTRODUCTION

• Curare alkaloids are the neuromuscular blocking agent.
• Agents that block the transmission of Ach at the motor end plate.
• The therapeutic use of these compound is primarily as adjuvant in surgical
anaesthesia to obtain relaxation of skeletal muscles.
• Obtained from bark and steam of strychnos castelnoci and strychnos toxifera,
chondodendron tomentosum.
• South American Indians used curare as a very potent arrow poison.
• Early preparations:

• Calabash (gourd).
• Tube (bamboo).
• Pot curare (clay pot)
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖Curare Alkaliods:

• The development and use of muscle relaxants, to allow a reduction in the level of
anaesthesia during surgery, follows entirely from studies of south American
arrow poisons and particularly from the isolation of pure D- Tubocurarine in the
1930, from tube curare.
• Curare paralyzes skeletal muscle by antagonizing the effect of acetylcholine at the
neuromuscular junction.
• The muscle-paralyzing curare alkaloids are quaternary salts that are not absorbed
when take orally. For surgical procedures they must be administered by
intravenous injection which results in onset of paralysis in at most a few minutes.
• Curare contains several alkaloids (4-7) the most important is d-Tubocurarine.
• The methylation product of D-Tubocurarine, known as metocurine is a more
potent muscle relaxant.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖Physical Property of Tubocurarine.

White or yellowish white to greyish white.
• Odourless , Crystalline powder, Soluble in water.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖STRUCTURE ACTIVITY RELATIONSHIP
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖SAR OF TUBOCURARINE

• Tubocurarine contains atleast one +ve charged quaternary amine (4 carbon
attached to nitrogen) like Acetylcholine (Ach).
• Quaternary amine attracted to alpha subunit of Ach receptor (-ve charged).
• Tubocurarine consist of quaternary ammonium group and a tertiary nitrogen
which gets protonated at physiological pH and the interonium distance is must
for muscle relaxant activity.
• Methylation of phenolic hydroxyl group increases the activity whereas
ethylation or butylation decreases activity.
• Bridging structure in between two amines is lipophilic and determines potency.
• 10-12 carbon bridge between two nitrogen is optimal for maximal
neuromuscular blockade.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖USES OF TUBOCYRARINE

• As a Diagnosis agent for myasthenia gravis.
• Skeletal muscle relaxant.
• Adjuvant in surgical anaesthesia to obtain relaxation of skeletal
muscles.
• Control convulsions of strychnine poisoning and tetanus.
❖SIDE EFFECT
• Hypotension
• Bronchoconstriction
• Incidence of bone and spine fractures

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖ ATRACURIUM
• Design based on tubocurarine and suxamethonium.
• Rapidly broken down in blood both chemically and metabolically.
• Lifetime is 30 min.
• Its has slow onset and an intermediate duration of activity.
• Atracurium is a mixture of ten isomers and can release histamine.
• cis-Atracurium, an isomer of Atracurium, is a ‘cleaner’ molecule more potent than
Atracurium and does not release histamine.
• Administrated as I.V. drip.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖ Laudexium

The macro cyclic structure of tubocurarine is a difficult synthetic target, but
fortunately ring opened, such as Laudexium have high potency and relatively few
side effects.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖SUCCINYLCHOLINE (SUXAMETHONIUM)

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖SUCCINYLCHOLINE (SUXAMETHONIUM)
• Suxamethonium, two molecules of acetylcholine ranged back to back.
• Suxamethonium owes its short duration of action to its rapid enzymic
destruction by pseudocholinesterase.
• It is a depolarizing relaxant, acting in about 30 seconds and with a duration of
effect averaging three to five minutes.
• Occasionally SCh is used by continuous i.v. infusion for producing controlled
muscle relaxation of longer duration.
• It should be avoided in younger children unless absolutely necessary, because
risk of hyperkalaemia and cardiac arrhythmia is higher.
• d-Tubocurarine is not clinically used due to its histaminic effects
Suxamethonium do not produce histamine.
• All the nondepolarizing neuromuscular blocking drugs had a slow onset. The
only rapidly acting muscle relaxant was suxamethonium, a depolarizer, and it
had several undesirable effects.

Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

❖REFERENCES

• Burger’s Medicinal Chemistry and Drug Discovery, Volume-1 Drug
discovery, Edited by Donald J. Abraham, Sixth Edition, page no. 856-
858.
• https://bjanaesthesia.org/article/S0007- 0912(17)42829-7/pdf
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC 1279945/#ref24

• http://npharmacology.blogspot.com/2013/06/de polarizing-
agents.html