Neuromuscular blocking agents and ganglionic blockers

Neuromuscular blocking agents and ganglionic blockers medicinal chemistry pharmacy

1. Neuromuscular
Blocking Agents

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2. INTRO

Defination:
- Agents that block the transmission of ACh at the motor
end plate are called neuromuscular blocking agents.

Effect :
- relaxation of skeletal muscle (syn. curariform or
curarimimetic activity )
example of:
- Nicotinic Antagonists (Nm antagonist)

Chemical nature:

- bis-quaternary ammonium compounds with varying numbers of
methylene groups separating the nitrogen atoms

Neuromuscular Blocking Agents

3. | CLASSIFICATIO |

Neuromuscular Blocking Agents

r 1
Nondepolarizing

Depolarizing
Blocking Agents Blocking Agents
r - 1 1. Succinylcholine
Curare Alkaloids Synthetic Compounds

1. (+)-tubocurarine

Tetrahydroisoquinoline
2. Metocurine

based agents

1. Atracurium
2. Mivacurium
3. Doxacurium

Steroid-based agents
1. Pancuronium
2. Vecuronium
3. Pipecurium
4. Rocuronium

Neuromuscular Blocking Agents _ AZC_2017 _ Medicinal Chemistry_ B. Pharm 3

4. | CLASSIFICATION |

Classification cum Mechanism
Non Depolarizing Blocking Agents
- drugs that compete with ACh for the recognition site on the nicotinic
receptor by preventing depolarization of the end plate by the ACh.
- This results in paralysis of neuromuscular transmission.

Depolarizing Blocking Agents

- depolarize (Na* Channel opening) the membrane of the muscle end
plate > blocks nervous transmission

- Agents do not rapidly dissociates from receptor > prolonged
polarization > Na* Channel get inactivated > muscle fails to
contract in response to nerve impulses

- This phenomenon is known as tachyphylaxis or desensitization

Neuromuscular Blocking Agents|AZG.Pu17 _. Medicinal’ Chen m 4

5. | CLASSIFICATION |

Curare Alkaloids

(1) d-Tubocurarine chloride

- Curare = potent arrow poison used
since early times by the South
American Indians

- (+)isomer

(2) Metocurine lodide

- 4 time more potent then d-tubocurarine

uu

Neuromuscular Blocking Agents B. Pharm.

6. | CLASSIFICATION |

Tetrahydroisoquinoline based agents

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Atracurium Besylate
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- 2.5 times more potent than
nore p O où
d-tubocurarine Doa o o o!
- Shorter DOA oe 7

10 stereoisomers

>o Ion À OW
- 4d pairs and two meso #

- trans isomers are active

Neuromuscular Blocking Agents _ AZC

cr 0.
(2) Doxacurium Chloride o \ OL 2
O o “oO 0

Chemistry_ B. Pharm 6

7. | CLASSIFICATION |

(3) Mivacurium Chloride

- is a mixture of three stereoisomers trans-trans, cis-trans, and cis-cis
diesters

- The drug is hydrolyzed by plasma esterases, and it is likely that
anticholinesterase agents used as antidotes could prolong rather than
reverse the effects of the drug.

B. Pharm.

8. | CLASSIFICATION |

Steroid-based agents
(1) Pancuronium bromide |
- 5 times that of (+)-tubocurarine chloride
- cardiovascular side effects , increases in heart rate and b.p.

(2) Vecuronium bromide

- 1s the monoquaternary analog of pancuronium bromide

- No cardiovascular side effects + No histamine release

- is hydrolyzed to the 3-hydroxy, 17-hydroxy, and 3,17-dihydroxy
metabolites, all of which are active. > Prologs DOA

(3) Pipecurium Bromide

- exhibits minimal cardiovascular effects

(4) Rocuronium Bromide

- does not appear to cause significant histamine release

Neuromuscular Blocking Agents _ AZC_2017 _ Medicinal Chemistry_ B rm 8

9. | CLASSIFICATION |

Steroid-based agents

Ra
= le]
Vecuronium Bromide N ) +N ) Br x À
Na, - + = o
Pancuronium Bromide -3-N » Br + ) Br ¿A
i N A a Br FN + - i
Pipecurium Bromide N_N TN No er adr
Rocuronium bromide -3-N © HD Se H

Neuromuscular Blocking Agents _ AZC_2017 _ Medicinal Chemistry_ B. Pharm

10. | CLASSIFICATION |

Depolarizing Blocking Agents
ie)

(1) Succinylcholine eo.
ÓN a

lo)

Succinylcholine

- It is stable in acidic solutions but unstable in alkali. (should not be used
with thiopental sodium because of the high alkalinity)

- very short duration of action and a quick recovery because of its rapid
hydrolysis by esterase

- Large doses may cause temporary respiratory depression
- anticholinesterase drugs actually prolong the action of drug

Neuromuscular Blocking Agents _ AZC_2017 _ Medicinal Chemistry_ B. Pharm. 10

11. Therapeutic Application

- as an adjunct to general anesthesia (reduce the depth requirement for
general anesthetics;)

- They produce skeletal muscle relaxation that facilitates operative
procedures such as abdominal surgery.

- used in the correction of dislocations and the realignment of fractures.

neuromuscular blocking agents (at excess dose )poisoning

- Antidote > administration of AChE inhibitors

- Exceptional drugs for antidote
Mivacurium Chloride
Succinylcholine Chloride

11

Neuromuscular Blocking Agents

12. GANGLIONIC

Blocking Agents

13. INTRO

Defination:
- Agents that inhibits neuronal transmission between pre- and post -
ganglionic neurons in the ANS.

Effect :
- blockade of ganglionic transmission

example of:
- Nicotinic Antagonists (N2 antagonist)

13

Ganglionic Blocking Agents _ AZG

14. - Competitive ganglionic blocking agents possess the necessary affinity
to attach to the nicotinic receptor sites

- Bloks N: nicotinic receptors of the neuronal membrane.

- Prevent ACh - N2 receptor intraction and hence prevent neuronal
transmission from pre to post synaptic neurons.

- Noncompetitive ganglionic blocking agents produce their effect not at
the specific ACh receptor site but at some point farther along the chain of
events that is necessary for transmission of the nerve impulse.

14

slionic Blocking Agents _ AZC_201

15. GANGLION BLOCKING AGENTS

A. Competitive blockers
Quaternary ammonium compounds
Hexamethonium, Pentolinium

Amines (secondary/tertiary)
Mecamylamine, Pempidine

Monosulfonium compound
Trimethaphan camforsulfonate

B. Persistent depolarising blockers
Nicotine (large dose)
Anticholinesterases (large dose)

15

Ganglionic Blocking Agents _ AZC_2017 _

16. | Classification |

+ AY DI | +
+
N > Q
Hexamethonium Pentolinium
H,C
| ‘ sr
N CH,
CH,
CH,
Pempidine Mecamylamine

is dual noncompetitive & competitive blocking
agent.

B. Pharm. 16

Ganglionic Blocking Agents _ AZC 2017 _ Medic

17. Classification

o
OSO 4
> bl
N
3 ar de
Nicotine
Trimethaphan

camforsulfonate

-
Ganglionic Blocking Agents _ AZC_2017 _ Medicinal Chemistry_ B. Pharm. | i

18. Action TABLE Results of Ganglionic Blockers on Organs
Results of
Predominant Ganglionic
Organ System Blockade
Cardiovascular system
Heart Parasympathetic Tachycardia
Arterioles Sympathetic Vasodilation
Veins Sympathetic Dilation
Eye
Iris Parasympathetic Mydriasis
Ciliary muscle Parasympathetic Cycloplegia
Gl tract Parasympathetic Relaxation
Urinary bladder Parasympathetic Urinary
retention
Salivary glands Parasympathetic Dry mouth
Sweat glands Sympathetic? Anhidrosis

18

Ganglionic Blocking Agents

7 _ Medicinal Chemistr

19. | Action |

Use:

- The principal therapeutic application has been in the treatment of
hypertension through blockade of the sympathetic pathways.

Side effect: (because of nonspecific action)

- visual disturbances, dryness of the mouth, impotence, urinary
retention, and constipation.

Ganglionic Blocking Agents _ AZC_2017

20. End

of the topic

Reference:
Textbook of org. medi. and ph'cal chem. - Wilson and Giswolds
Principles of medicinal chemistry - W. C. Foye
Essentials of Medical Ph'cology - KD Tripathi

21. | Questions |

1. SN on Neuromuscular Blocking Agents [win16, win15, win11]
[sum16, sum15,sum14, sum13, sum12]

2 Write a note on Neuromuscular blocking agents and ganglionic
blockers [win14] [sum16]