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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5484_Библиотеки_им_академика_М_И_Перельмана.pdf
Neuromuscular Blocking Agents 215
14
Neuromuscular Blocking Agents
14.1 INTRODUCTION
Neuromuscular blocking agents are also known as nicotinic receptor antagonists or peripherally
acting muscles relaxants. These agents are associated with that particular area of neuromuscular
contacts with weakened transmission from motor neuron ending to the membrane of skeletal muscles
cells. Neuromuscular blocking agents are subdivided into the depolarizing agents and antidepolarizing
agents. The neuromuscular blocking action is exhibited earlier in 1510 by the extract of curare d-
tubocurarine chloride it was the first neuromuscular blocking agent that had ability of the action
against nicotinic receptor antagonists. D-tubocurarine was isolated in 1935 as a pure alkaloid from
the tubecurare of unknown botanical region. It is characterized by quaternary ammonium salt
compound. Progress of research was of neuromuscular blocking agents are now based on quaternary
ammonium compounds.
14.2 MECHANISM OF ACTION
Neuromuscular blocking agents act by transmission blocked at the end of neuromuscular junction
by initiating an influx of Ca
++
that is caused by nerve impulse at the nerve terminal followed by
release of Ach from exocytic mechanism in synaptic vescicles. Release of Ach diffuses across the
synaptic cleft and binds to the nicotinic receptors located in motor end plates or may be hydrolysed
by Ach E enzyme. Binding of Ach to receptor causes opening of Na-K channel and thus cause
depolarization of end plates resulting in muscles contraction. Contraction of muscles can be countered
by two types of mechanism by non-depolarizing agents (tubocurarine and others) that prevent
depolarization by binding to nicotinic receptors. Others are depolarizing agents that mimic the action
of Ach and prevent muscle contraction. These types of agents are structurally similar to Ach and
cause relaxation of muscles.
216 A Textbook of Medicinal Chemistry
14.3 CLASSIFICATION
(I) Non-depolarizing muscle relaxants
1. Tubocurarine (Tubarine
®
):- (Tetrahydroisoquinoline derivatives) – (+)-Tubocuraranium, 7,12’-
dihydroxy-6,6’-methoxy-2-2’,-2’-trimethyl-chloride, hydrochloride penta-hydrate.
2Cl.5H O
2
–
N
O
HCO
3
H
H
CH
3
H
N
HC
3
CH
3
+
OCH
3
OH
O
HO
+
Fig. 14.1
2. Metocurine (Metubine
®
): (Tetrahydroisoquinoline Derivatives) Tubocuraranium, 6,6’,7’,12-
tetramethoxy-2,2’-2’-2’-tetramethyl-diiodide
2Cl
–
N
O
HCO
3
H
H
CH
3
N
HC
3
CH
3
+
OCH
3
OCH
3
HC
3
HCO
3
+
Fig. 14.2
3. Gallamine Triethiodide (Flaxedil
®
):- [Phenyl-tris-(oxyethylene)]-tris-[triethylammonium]-
triiodide (Trisquaternary Ether)
OCH CH — N — (C H )
22 253
OCH — CH — N (C H )
22 253
+
+
OCH CH — N — (C H )
22 253
+
3I
–
Fig. 14.3
Neuromuscular Blocking Agents 217
4. Pancuronium Bromide (Pavulon
®
) :- 1,1’-(3α-17β-dihydroxy-5α-androstane-2β-16β-ylene)-
bis-[1-methyl-piperidinium]-dibromidediacetate
(Aminosteroids Derivative)
H CCOO
3
N
CH
3
CH
3
CH
3
OCOCH
3
H
N
+
2Br
–
+
HC
3
Fig. 14.4
5. Hexafluronium Bromide (Mylaxen
®
):- Hexamethylene-bis [fluoren-9-yl-dimethyl ammonium]-
dibromide
CH
3
N
CH
3
(CH )
26
CH
3
N
HC
3
.2Br
–
+ +
Fig. 14.5
6. Dacuronium Bromide (Organon
®
):- 3α-17β-dihydroxy-5α-androstane-2β-16β-ylene)-bis-[1-
methyl-piperidinium]-dibromidediacetate.
(Aminosteroid Derivative)
HC—CO—O
3
N
HC
3
CH
3
HC
3
OH
H
N
.2Br
–
H
+
+
Fig. 14.6
218 A Textbook of Medicinal Chemistry
2. Depolarizing Muscles Relaxants
1. Suxamethonium Chloride (Acectine
®
):- Choline-chloride Succinate (2:1).
COOCH CH N — (CH )
22 33
(CH )
22
COOCH — CH N — (CH )
22 33
.2Cl
–
+
+
Fig. 14.7
2. Decamethonium Bromide (Syncurine
®
):- Decamethylenebis-[trimethylammonium]-dibromide.
(H C) — N — (CH ) — N —
33 210
+
+
CH
3
CH
3
CH
3
.2Br
–
Fig. 14.8
3. Suxethonium Chloride(Brevidil
®
):- Ethyl-(2-hydroxy ethyl)-dimethyl ammonium chloride.
.2Cl
–
(CH ) — N — (CH ) — OOC — (CH ) — COO (CH ) — N — (CH )
32 22 22 22 32
+
+
CH
25
CH
25
Fig. 14.9
4. Succinyl Choline (Listenon
®
):- 2,2’-[1,4-dioxo-1,4-butanediyl)bis-(oxy)]-bis-[N, N, N-
trimethylethanaminum-(diacetylcholine)] dichloride.
CH — C — O — CH — CH — N(CH )
22233
O
O
CH — C — O — CH — CH — N(CH )
22233
2Cl
–
+
+
Fig. 14.10
14.4 NON-DEPOLARIZING MUSCLE RELAXANTS
Non-depolarizing muscle relaxant agents are curare type agents (alkaloids) that contain two or more
quaternary nitrogen atoms which make the essential requirement to bind to nicotinic receptors.
Non-depolarizing muscle relaxants are required to used in surgical operation for skeletal muscles
relexants. They are used in trauma, in repositioning of broken bones and their clinical problems, for
relaxation of face and neck muscles as well as for respiratory muscles relaxation.
1. Tubocurarine (Tubarine
®
): Tubocurarine is synthesized from plant source extract of
“chondodendron”.
Neuromuscular Blocking Agents 219
Tubocurarine is used as myorelaxants, in surgical operation for prolonged muscle relaxation, in
endotracheal intubation, in orthopaedic surgery for repositioning of fractured bones.
2. Metocurine (Metubine
®
): Metocurine iodide is synthesized by the treatment of methyl iodide
with d-tubocurarine in the methylation process of two hydroxyl groups. Metocurine has threefold
potent action than d-tubocurarine and with longer duration of action.
3. Gallamine (Flaxedil
®
): Gallamine is used for the similar indication of d-tubocurarine further.
It is used in anaesthesiology for the muscle relaxation to facilitate surgical operation.
Synthesis:
OH
OH
+ Cl — CH — CH — N
22
CH
25
CH
25
OCH CH — N
22
OCH CH — N
22
OCH CH — N
22
CH
25
CH
25
CH
25
CH
25
CH
25
CH
25
Condensation
Gallamine triethiodioe
2-chloro-triethyl amine
Pyrogallol
C H I/Acetone
25
Fig. 14.11
4. Pancuronium (Pavlon®): Pancuronium is steroidal (cyclopetano perhydro phenenthrene ring
nucleus) muscle relaxant but it does not have hormonal pharmacological action. Pancuronium is a
potent muscle relaxant and is used as a relaxant in anaesthesiology, in cardiovascular disease, in
surgical operation for prolonged muscles relaxants, in ophthalmology, orthopaedic and in asthmatic
condition.
Synthesis:
Fig. 14.12
O—C—CH
3
O
3,17-bis-(acetoxy)-2,16-
5 -androstane
O—C—CH
3
O
O
O
HO
N
N
N
N
CH
3
CH
3
+
+
Bis-epoxy compound
1. NaBH
4
2. (CH CO) O
32
3. CH Br
3
3-chloroperbenzoic acid
(Pancuronium)
(Aminoketone)
H—N
HO
2
O
O—C—CH
3
O
(Piperidine)
2Br
–
HC—C—O
3
O
220 A Textbook of Medicinal Chemistry
5. Hexafluoronium (Mylaxen
®
): Hexafluoronium is a weak NMB (neuromuscular blocking agent).
It has significant anaesthetic properties and used muscles relaxation. It antagonizes the action of
Decamethonium. It exhibits synergistic effect with suxamethonium chloride and prolong the action.
Synthesis:
HC
3
N — (CH ) — N
26
HC
3
CH
3
CH
3
+ 2Br
Tetramethyl-1, 6
-hexane diamine
9-bromofluorene
Quaternization
N
CH
3
CH
3
(CH )
26
N
CH
3
CH
3
+
+
2Br
–
Fig. 14.13
14.5 STRUCTURAL ACTIVITY RELATIONSHIP OF AMINOSTEROIDS NMB AGENTS
H
H
H
R
2
R
1
R
3
R
4
H
2
3
10
1
9
8
4
5
6
7
11
12
13
14
15
16
17
Ring B
Ring C
Ring D
Ring A
Fig. 14.14
Hexafluoronium
Neuromuscular Blocking Agents 221
Substitution
Derivatives R
1
R
2
R
3
R
4
1. Pancuronium (Pavvlon®)
N
CH
3
+
CH
3
COO —
N
HC
3
+
— OOCCH
3
2. Vecuoronium (Norcuron®)
N
CH
3
COO —
N
CH
3
+
— OOCCH
3
3. Rocuronium (Zemuron®)
O
N
OH —
N
+
4. Repacuronium (Newer)
N
CH
3
COO === (double band) — OOCCH
2
CH
\3
5. Pipecuronium (Arduan®)
N
N
+
HC
3
HC
3
CH
3\
COO —
N
N
+
HC
3
CH
3
— OOCCH
3
1. Presence of steroid muscles provides a rigidity of bulky structural base.
2. Presence of two Ach moiety of Pancuronium at Ring A make the compound trans in geometry
while ring D is Cis in nature. Hence, Pancuronium and Vancuronium are equipotent, their
NMB action may be attributed to their common Cis-D-ring Ach moiety.
3. Beta surface of the molecules is crowded with substituents (R
1
and two methyl groups, R
3
and R
4
) are essential for NMB activity.
4. Replacement by larger groups with R
3
or R
4
in place of methyl groups decrease the potency.
5. Introduction of bis quaternary with dimethypiperazinium moiety at ring A and D makes the
compound more potent, e.g., Pipecuronium.
6. Repacuronium is the newer agent it has 16-N-propenyl and 17-propionyloxy (C
2
H
5
— COO
—) groups. It is more than 10 times weaker than vecuronium.
7. 10 Atoms-rules: Ten atoms (C or O) separates the quaternary N-atoms of C
10
with onion
heads are interconnected. This imparts the greatest NMB activity, e.g., in Pancuronium, 10
atoms along with one path or another from N to the other atoms therefore is called rules for
NMB activity.
222 A Textbook of Medicinal Chemistry
14.6 SAR OF TETRAHYDROISOQUINOLINE DERIVATIVES
HCO
3
N
+
N
+
X
HCO
3
CH
3
HC
3
R
2
HCO
3
HCO
3
R
1
R
2
R
1
OCH
3
OCH
3
Onium head
CH
3
CH
3
Fig. 14.15
Derivatives Substitution
YR
1
R
2
1. Atracurium
(Tracrium
®
)
— (CH ) — C — O — (CH ) — C — O — (CH ) —
22 25 22
O
O
HH
2. Mivacurium
(Mivacron
®
)
— (CH ) — O — OC — (CH ) — CH CH — (CH ) — C — O — (CH ) —
23 22 22 23
O
— OCH
3
H
3. Doxacurim
(Nuromax
®
)
— (CH ) — O — OCCH — CH — C — O — (CH ) —
23 2 2 23
O
— OCH
3
— OCH
3
1. Presence of methoxymoeity at position 4,5,6 on benzylisoquinolium heads are essential for
NMB activity and reduce the side effects.
2. Presence of onium heads connecting chain(X) exhibit increase in NMB activity as indicated
in the same order.
3. α-tubocurarine is not like the atracurium, mivacurium or doxacurium. However, it is benzyl
isoquinolinium compound. Its onium heads are interconnected with ether linkage.
4. Both hydroxyl groups of d-tubocurarine (d-tc) are methylated in metocurine (mtc) while
metocurine has four methoxy groups. Mtc has 3-fold activity than d-tubocurarine.
14.7 DEPOLARIZING MUSCLE RELAXANTS (DPR)
Depolarizing muscle relaxant are not competitive antagonists like undepolarizing agents. They are
based on structurally similarity of Ach and are considered more stable than Ach. DPR have prolonged
duration of action than Ach. DPR acts on same receptors as Ach with longer action in the synapse
and cause more stable depolarization that is positive symptom of muscles relaxants by blocking of
receptor repolarization in order to accept new stimuli.
1. Suxamethonium Chloride (Acectine
®
): Ethanaminium, 2,2’-[1,4-dioxo-1,4-butanediyl)-bis-
(oxy]-bis [N,N,N-trimethyl]-dichloride
Neuromuscular Blocking Agents 223
Suxamethonium chloride is a potent depolarizing neuromusclar blocking agent. Because of its
rapid hydrolysis by cholinesterase, its blocking effect is very limited. It has significant properties to
relax the muscles. It is used in orthopaedic problems, endotracheal intubation, in laryngospasm, in
electroconvulsion therapy.
Synthesis:
CH COCl
2
CH COCl
2
+ 2HO CH CH — N
22
CH
3
CH
3
(i) Condensation
(ii) CH Cl
3
COOCHCHN
22
(CH )
22
COOCHCHN
22
CH
3
CH
3
CH
3
CH
3
+
+
Succinyl
chloride
b-Dimethylamino
ethanol
2Cl
–
Fig. 14.16
2. Succinylcholine (Listenone®):
Succinylcholine is a potent depolarizing muscle relaxant. It has longer duration of action than Ach
and it is more stable agonist rather than Ach. It causes more stable depolarization and blocks
repolarization state, results in relaxation of skeletal muscles. Succinylcholine is therapeutically used
in the treatment of muscles spasm, in operation, intubation of trachea, etc.
Synthesis:
CH —C—Cl
3
CH – COCl
3
+ 2HO — CH CH — N
22
CH
3
CH
3
Succinic acid
dichloride
2-Dimethylamino
ethanol
(i) Condensation
(ii) CH Cl
3
O
CH —C—O—(CH )—N—
22
CH —C—(CH )—N—
22
CH
3
CH
3
CH
3
CH
3
+
+
O
O
CH
3
CH
3
2
Fig. 14.17
3. Decamethonium Bromide (Syncurine
®
):
Decamethonium was one of the first NMB agents which was synthesized. Decamethonium exhibits
the primary action on nicotinic receptors as depolarization at the motor end plate membrane. It is
used in the surgical operation for relaxation of skeletal muscles.
Suxamethonium
chloride
Succinylcholine
224 A Textbook of Medicinal Chemistry
Synthesis:
CH
3
CH
3
Br — (CH ) — Br + 2N(CH )
210 33
H C — N — (CH ) — N — CH
3 2 10 3
CH
3
HC
3
1, 10-Decamethylene
dibromide
Trimethyl-amine
.2Br
–
+ +
Fig. 14.18
14.8 SAR OF DEPOLARIZING MUSCLE RELAXANTS
(1) In the series of bis-quaternary ammonium compounds with varying number of methylene
groups (10,12), separating the nitrogen atoms enhances the NMB activity.
(2) Alteration of NMB activity by increasing or decreasing the number of carbon atoms.
(3) All the compounds in this series show depolarizing activity at the post junctional motor end
plate membrane.
(4) Decamethonium prefers the straight conformation while Ach and succinyl choline prefers
the bent geometry due to electrostatic interaction between the functional groups. (Methonium
head, carbonyl group and estero atom.)
C
O
O
N
HC
3
+
N
+
O
O
N
O
Ach
Succinyl choline
N
+
N
(Bent Geometry)
Decamethonium
(Straight conformation)
+
+
Fig. 14.19
Methonium Head — (CH
2
)
n
— Methonium Head
Where n = 10 to 12
Decamethonium
Bromide