Muscle relaxants
●cause relaxation of striated (voluntary skeletal) musculature (in contrast to spasmolytics
which relax unstriped musculature)
Classification of myorelaxants
1. Neuromuscular blocking drugs
●periferial (direct) myorelaxants: interact with acetylcholine nicotinic (N) receptors of skeletal
musculature
a) stabilizing myorelaxants – N-receptors antagonists
b) depolarizing myorelaxants – N-receptors agonists
●
continuous N-receptors stimulation  depolarization of cells  functional antagonism:
further leading of impulses imposible, no muscle contraction
c) indirect myorelaxants: botulinum toxin
●irreversibly inhibits acetycholine releasing
2. Central muscle relaxants
●acts in CNS
●structurally heterogenic group
●compounds with various mechanisms of action
Stabilizing myorelaxants
●N-receptors antagonists in skeletal muscle cells
●usage: surgical operative measures (often as a part of some form of anaesthesia)
●structures derived from curare alkaloids
Curare: arrow poison of South American Indians
●preparation from various plants
●contained a complex mixture of alkaloids
Curare classification: according to preparation and package in which it was shipped to Europe
1. Tubocurare: in hollow bamboo rods
2. Calebase curare: in bottle-shaped cucurbits (gourds, calabashes - from plants of genus Strychnos)
3. Pot curare: in ceramic vessels
Structural types:
1. Benzyltetrahydroisoquinolines: tubocurarine (from tubocurare)
atracurium besylate (synthetic)
mivacurium besylate (synthetic) etc.
2. Indole derivatives: toxiferine C
alcuronium chloride
3. Steroids with basic substituents: vecuronium bromide
pancuronium bromide
rocuronium bromide
CH3
CH3
CH3
CH3
CH3
N
N
+
OH
OH
O
O
O
O
H
H
O
CH3
OCH3
N
+
H
O
CH3
O
CH3
OON
+
H
O
CH3
O
CH3
OCH3 O
CH3
CH3
O O
CH3
1. Benzyltetrahydroisoquinolines
tubocurarine atracurium
●used as besylate
Tracrium ® inj. sol.
1. Benzyltetrahydroisoquinolines (continued)
O
CH3
O
CH3
H N
+
CH3
O
O
O
N
+
H
O
CH3
O
CH3
O
CH3
O CH3
O
CH3
CH3
O
O
CH3
O CH3
O
CH3
mivacurium
●used as besylate
Mivacron ® inj. sol.
2. Indole derivatives
H
N
+
R
H
N
H
H
H
N
H
N
+
OH
R
OH
H
H
H
O
H
N
O
N
H
R = -CH3
toxiferine C
●natural
R = -CH2
CH=CH2
alcuronium
●as chloride
●for comparison: strychnine
●from Strychnos nux vomica
●in small amounts as central analeptic
(obsolete)
Stereochemistry: „playing cards symmetry“
toxiferin C
alcuronium chloride
●structure similarity with strychnine, both indole alcaloids
●dimer
●2x pentacyclic system
●2 quarternary ammonium moieties
Stereochemistry:
●chiral
●contain C2 symmetry axis: „playing cards symmetry“
Effects of alcuronium chloride
●more active than tubocurarine
●relatively short time of action
●not absorbed from GIT
●very stable, excreted in unchanged form
Preparation:
●partial synthesis from strychnine
3. Steroids with basic substituents
HH
H
H
H
O
CH3
O
H
N
CH3
H
H
O
CH3
O
N
+
CH3
CH3
HH
H
HH
OCH3
O
H
N
+ CH3
CH3
H
O
CH3
O
H
N
+
CH3
CH3
vecuronium
Norcuron ® inj.
pancuronium
Pavulon ® inj. sol.
●as bromides
3. Steroids with basic substituents (continued)
N
+
H
H
H
H
H
H
H
NO
H
OH
CH3
CH3
O
CH3
O
CH2
H
H
H
HH
O
CH3
O
H
N
N
+CH3
CH3
CH3
H
O
CH3
O
H
N
N
+
CH3
CH3
CH3
rocuronium
Esmeron ® inj. sol.
●facilitation of tracheal intubation
pipecuronium
Arduan ® inj. sicc. + solv.
Depolarizing myorelaxants
●agonist of N-receptor
●continuous depolarization leads to muscules slack
Usage: introduction into general anaesthesia (intubation)
Compounds: synthetic bis-quarternary ammonium salts
●originated by simplifying of tubocurarine structure
N
+ N
+
CH3
CH3
CH3
CH3
CH3
CH3
X
-
X
-
N
+
O
O
O
O
N
+
CH3
CH3CH3
CH3
CH3
CH3
X
-
X
dekamethonium
(halide)
●non-hydrolyzable
●comparatively toxic
●long effect
suxamethonium (halide)
syn. succinylcholine (halide)
●hydrolyzable
●
fast cleft by esterases  short effect
Succinylcholinjodid Valeant ® inj. plv. sol.
Comparison of molecule sizes of direct
muscule relaxants
Indirect myorelaxants
Botulinum toxin
●protein with Mr
about 150, 000
●product of anaerobic bacterium Clostridium botulinum (serotypes A – G: A –
Botox infusion; B - Neurobloc infusion)
●extremely toxic (food poisoning, potential biologic weapons)
Indications: cervical dystonia, facial spasms, writer's cramp and other spasms
●in cosmetics for smoothing of wrinkles – very hazardous
●irreversibly inhibits acetylcholin release
●local injection into the particular muscle
●blocks transfer of impulse by means of acetylcholine to the muscle
●muscle paralysis
●to hands of qualified physicians only
●by no means can reach bloodstream
●new injection is possible after 3 – 4 months (the effect is poorly estimable in
shorter intervals due to possible formation of antibodies)
Central muscle relaxants (myotonolytics)
Using: painful spasms of skeletal muscles (not in surgical measures)
Structures: heterogenic group
Mechanisms of action: various, not perfectly known in every case
●im most they act sedatively in high doses
Central muscle relaxants (myotonolytics)
Carbamates derived from diols
O
NH2
O
O
NH2
O
CH3
CH3
NH2
O
O O
NH
CH3
CH3
O
CH3
CH3
meprobamate
carisoprodol
●myorelaxant, sedative, anxiolytic
●effectiveness unsure
baclophene
●GABA derivative
●GABAB
receptor agonist
●blocks voltage-gated input of Ca2+
into CNS neurons
Usage: spasmodic conditions (sclerosis multiplex, cramps in crucial region etc.)
H
OH
O
NH2
Cl
N
+
O
O
-
O
N
N
O
N
H
O
NH
NH
N
N
S
N
Cl
dantrolene
●hydantoine derivative
●myorelaxant
●Mode of action: directly to skeletal
muscles; lowers Ca2+
release
thizanidine
●myorelaxant, analgesic,
antihypertensive
●probably 2
receptors agonist
●blocks release of excitation
transmitters (glutamate,
aspartate)
●usage: eg. sclerosis
multiplex, ischias