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

1. Benzyltetrahydroisoquinolines

H3C O H C O O CH3 3 H3C H + H3C H C O O H3C N O 3 OH H C 3 O O H3C

H H H + CH + N 3 O O N OH O CH3 N CH3 O O

O H3C O CH3 O CH3

tubocurarine atracurium ●used as besylate Tracrium ® inj. sol.

1. Benzyltetrahydroisoquinolines (continued)

H C H C 3 O 3 O H3C O O O H3C

O H O + H3C + H N CH3 N CH3 CH3 O O O

CH3 O O CH3 O CH3 O

CH3

mivacurium ●used as besylate Mivacron ® inj. sol.

2. Indole derivatives

R OH + N

O O H H H H N N H H H N H H H H N

+ N

R HO

●for comparison: strychnine R = -CH toxiferine C 3 ●from Strychnos nux vomica ●natural ●in small amounts as central analeptic R = -CH CH=CH alcuronium 2 2 (obsolete) ●as chloride 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

O H CH H C O 3 CH 3 O 3 H3C H H + CH3 H O + N CH3 + N O N H3C H H H C H CH H 3 3 H H N H3C O H H H H H H3C O H O

vecuronium pancuronium Norcuron ® inj. Pavulon ® inj. sol.

●as bromides

3. Steroids with basic substituents (continued)

H3C H3C H3C + H CH3 O N H3C O O CH3 H + H N H C O N 3 H H3C H O N H + O N H3C H H N CH H H 3 H H2C O H H CH3 H H HO H

rocuronium pipecuronium Esmeron ® inj. sol. Arduan ® inj. sicc. + solv. ●facilitation of tracheal intubation

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

H C 3 CH H3C + 3 O + N O N H C CH CH H3C 3 3 H3C 3 + + CH3 N N - - CH X H C CH3 3 X 3 - - O X X O

dekamethonium (halide) suxamethonium (halide) ●non-hydrolyzable syn. succinylcholine (halide) ●comparatively toxic ●hydrolyzable ●long effect ●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 M about 150, 000 r

●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

CH3 CH3 CH3 O O O NH O O O O CH3 H2N NH2 H2N O CH3 H3C

meprobamate carisoprodol ●myorelaxant, sedative, anxiolytic ●effectiveness unsure

Cl

NH2

O H

OH baclophene ●GABA derivative ●GABA receptor agonist B 2+ ●blocks voltage-gated input of Ca into CNS neurons Usage: spasmodic conditions (sclerosis multiplex, cramps in crucial region etc.)

O - + O N

NH N Cl NH

O N S N N

N thizanidine O ●myorelaxant, analgesic, antihypertensive N ●probably  receptors agonist O H 2 ●blocks release of excitation dantrolene transmitters (glutamate, ●hydantoine derivative aspartate) ●myorelaxant ●usage: eg. sclerosis ●Mode of action: directly to skeletal multiplex, ischias 2+ muscles; lowers Ca release