2. CONTENT
INTRODUCTION
CLASSIFICATION OF DRUGS
MECHANISM OF ACTION
CURARE ALKALOIDS AS A LEAD
OCCURRENCE
SYNTHETIC ANALOGUES OF TUBOCURARINE
1. PANCURONIUM
2. VENCURONIUM
3. ATRACURIUM
DEPOLARIZING BLOCKING AGENT
1. SUXAMETHONIUM
REFERENCE
3. • 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
These are of two types i.e.
1] Non-depolarizing agents.
2]Depolarizing agents.
Neuromuscular Blocking Agents-
5. Mechanism Of Action:
1. NON-DEPOLARISING AGENTS:
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 [figure01].
Their action is reversed by the anticholinesterase such as Neostigmine.
E.g. Tubocurarine, Pancuronium.
7. 2. DEPOLARISING AGENTS:
• These agents block the neuromuscular transmission by producing a partial depolarizing of
motor end plate which renders the tissues incapable of responding to acetylcholine [figure].
• E.g. Succinylcholine, Decamethonium.
8.
9. CURARE ALKALOIDS AS A LEAD-
• Initially, Curare was used by South American Indians as a arrow poison for killing wild
animals for food.
• Death of animals was due to paralysis of skeletal muscles.
• Sir Benjamin brodie was the first one to show that curare does not kill the animals and the
recovery is complete if the animal's is maintained artificially .
• In 1814, Charles Waterton, an eccentric explorer carried out experiment on female donkeys
with samples of curare by using the Sir Benjamin's theory-
(1) The first female donkey was injected with curare in the shoulder and died.
10. (2) The second had a tourniquet tied around its foreleg and curare was injected below the
tourniquet. The donkey died soon after the tourniquet was removed.
• In 1856, the Claude Bernard performed experiment on frogs. He showed that curare injected
into the limb prevented the muscle contraction and continue to respond when stimulate
directly. Curare when applied sciatic nerve failed to abolish the muscle contraction. This
shows that it acted at neuromuscular junction .
• The main active component that was responsible for activityof curare was Tubocurarine.
11. • Harold king isolated d-tubocurarine from sample of curare. He established that it was a bulky rigid
molecule has a bisbenzyl isoquinoline structure and two quaternary ammonium group with two
ether bridge.
[d-Tubocurarine]
12. OCCURRENCE-
• Curare or south American arrow poison in the dried crude extract, obtained mainly from
Chondrodendron tomentosum (Menispermaceae) and certain strychnos species (Loganiaceae)
• Curare contains several alkaloids (4-7%) the most important is d-Tubocurarine.
13. Structure Activity Relationship -
2CL-
• Contains at least one +ve charged quaternary amine [4 carbon attached to nitrogen ] like Acetylcholine
[Ach].
14. • Quaternary amine attracted to alpha subunit of Ach receptor [+ve charged].
• Tubocurine 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.
15. Mode of action
◦ Competitively binds with the nicotinic receptors N₁, to prevent the binding of Acetylcholine
and preventdepolarization of the muscle cell membrane and inhibit muscular contraction.
◦ Because these agents compete with Ach at the receptor without stimulating it, they are called
competitive blockers.
◦ Antagonism is surmountable so neostigmine, pyridostigmine can reverse the effect.
◦ Injected 0.1 to 0.3 mg/kg slow IV
◦ Long duration of action but more side effect so NOT used now!
16. SYNTHETIC ANALOGUES OF TUBOCURARINE
The synthetic derived compounds consist of either azasterodal or non steroidal nucleus.
Ex-Pancuronium ,
Atracuronium ,
Vencuronium ,
Metocurine iodide,
Suxamethonium .
17. PANCURONIUM
• More potent than curare (6 times)
• Acyl group are added to introduce the Ach skeleton.
• Faster onset than tubocurarine but slowerthan suxamethonium.
• Longer duration of action thansuxamethonium.
• Steroid acts as a spacer for the quaternarycentres (1.09nm)
Pancuronium
18. VECURONIUM
◦ Vecuronium is a demethylated product of pancuronium
◦ Savage recognized that the muscarinic receptor activity resided in the quaternary group at one
end and the neuromuscular blocking activity resided separately in the other quaternary group. By
demethylation of the A ring nitrogen Savage came up with vecuronium, a 'clean drug' devoid of
cardiac effects.
◦ Vecuronium had an intermediate duration of action and a slow onset.
Vecuronium
19. ATRACURIUM
◦ In 1981 Stenlake and colleagues, in a collaborative enterprise between the University of
Strathclyde and Wellcome Laboratories, synthesized atracurium, a benzyl isoquinoline molecule.
◦ .
Atracurium
20. ◦ Design based on tubocurarine and suxamethonium
◦ Rapidly broken down in blood both chemically and metabolically.
◦ Lifetime is 30 minutes.
◦ It has a 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. Administered as i.v. drip.
21. Depolarizing blocking agents
◦ Bovet was awarded the Nobel Prize for Medicine in 1957 for this discovery.
◦ It was realized that bulky molecules, the pachycurares, caused nondepolarizing block and
leptocurares, the slender molecules, caused depolarizing block.
◦ Suxamethonium, two molecules of acetylcholine ranged back to back, was the result
◦ By the end of the 1950s, d-tubocurarine and gallamine (the two nondepolarizers) and
suxamethonium (the depolarizer) were available.
SUXAMETHONIUM (SUCCINYLCHOLINE)
22. • 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 hyperkaliemia
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.
23. REFERENCE:
◦ 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-
◦ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC
◦ http://npharmacology.blogspot.com/2013/06/de polarizing-agents.html
