1. Skeletal Muscle Relaxants
Relax skeletal muscle tone
Two types:
Spasmolytics
Reduce abnormally elevated tone caused by neurological or muscle endplate disease
Without paralysis
Neuromuscular blockers
Induce paralysis
Blockade at the motor end plate

2. Spasmolytics Relax painful contractions/spasm of skeletal muscles
During radicular syndrome, cerebral palsy, stroke, multiple sclerosis etc.
Most act in CNS
Benzodiazepines – tetrazepam, diazepam
GABAB agonists – baclofen
a2-agonists - tizanidine
Antiepileptics – gabapentin – relax in multiple sclerosis
??? - mephenoxalone, tolperison, carisoprodol
dantrolene
Exception – blockade of ryanodine receptor in muscles
reduces Ca release from sarcoplasmic reticulum
Emergeny – i.v. - malignant hyperthermia
Thiokolchikosid
Malignant hyperthermia – general anesthesia, succinylcholine or tubocurarine

3. a2 Glu a2 Action potentials
Postulated site of spasmolytic action of tizanidine (a2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord.
Inhibitory interneuron
Tizanidine
Corticospinal pathway
Baclofen a2
GABAB
Glu
GABA
Motor neuron
GABAB
AMPA a2
Muscle
GABAA
Dantrolene
Benzodiazepines
Action potentials
(according to Katzung BG et al: Basic and clinical pharmacology, 11th ed., 2009)

4. Inhibition of tonic output at spinal motoneurons
Baclofen
GABAB agonist
Presynaptically
Reduce Ca2+ influx – inhibition of glutamate release
reduce motor impulse transmission
Postsnaptically
Inhibition of AP generation??

5. Spasmolytics - AE Benzodiazepines Baclofen Tizanidine Sedation
Less sedative,
dependence – withdrawal syndrome !!
Reduce dose slowly after long term usage
Tizanidine
Dry mouth, hypotension, sedations
Cyklobenzaprin pro akutní podání - neregistrován

6. Neuromuscular blockers
Induce paralysis
for surgical procedures etc.
Skeletal muscle physiology
Cholinergic tranmission at the end plate
ACH released from presynaptic part
NM – Na+ channels – depolarization
NM blockade postsynaptic
Nondepolarizing type – curare
Depolarizing – succinylcholine
Presynaptic
Reduce ACH release
Botulinum toxin, aminoglycosides
some snake poisons - bungarotoxin

7. Nondepolarizing neuromuscular blocking drugs
Competitive (surmountable) antagonists of Ach at NM receptors
70-80% receptor blocked - effect
Cumulating ACH – reverses the blockade
ACHE inhibitors – antagonize effect of relaxants
Neostigmine, pyridostigmine
Larger muscles more resistant
Abdominal, diaphragm
Recover more rapidly than small (facial, hand etc)
kompetitivní antagonizmus vůči ACH na N receptorech - nedepolarizující, pachykurarové
antagonista obsadí receptor (má k receptoru afinitu), ale není schopen navodit depolarizaci (chybí mu vnitřní aktivita).
depolarizující, acetylcholine-like, leptokurarové.
suxamethonium

8. Nondepolarizing - Pharmacokinetics, classification
Large hydrophilic molecules
i.v. administration necessary
quarternary amonium bases – positive charged
Poor permeation (BBB, placenta, GIT)
Benzylisochinolines
d-tubokurarin, gallamin
mivacurium
atracurium, cisatracurium
Steroid molecule
pancuronium, piperuconium
rocuronium, vecuronium
Cumulation in muscles during prolonged administration
strukturou podobné Ach –

9. Nondepolarizing - Pharmacokinetics
Elimination
Unchanged by the kidneys (GF)
tubokurarine
Biotransformation in the liver  bile
vecuronium, rocuronium
Metabolized by pseudoChE in plasma
Mivacurium
Spontaneous decomposition in plasma
atracurium, cisatracurium (used more now)
!!! Elimination does not depend on function of liver or kidneys!!!

10. Nondepolarizing classification according duration of effect
Long acting (1-2 h)
tubokurarine, pancuronium a pipecuronium
Medium ( min)
rocuronium, vecuronium, (cis-)atracurium,
Short acting (< 15 min)
mivacuronium
Ultra-rapid onset of effect
rocuronium
Can replace succinylcholine
Nevýhodou tubokurarinu je jeho schopnost nesensibilisovanou cestou uvolňovat histamin s následnou bronchokonstrikcí a hypotenzí.

11. AE – Nondepolarizing Respiratory paralysis
Mechanical ventilation always required
Histamine release from mast cells
Especially benzylisochinoline congeners – mivacurium, atracurium
Also succinylcholine
bronchospasm, ↓ BP
Autonomic ganglion blockade
↓ BP, tachycardia, prolong GIT atonia – tubocurarine – ex now
Prolongation of myorelaxation during liver or renal impairment
Better start with short acting drug
Antidote:
AChE inhibitor (neostigmin, i.v.) + atropin
M- receptor antagonits to block neoastigmin AE

12. Depolarizing suxamethonium (succinylcholine)
Partial agonist at NM receptors
Effect – two phases
1st phase – depolarization
NM receptor stimulation  depolarization of end plate
contraction/fasciculations immediately after adm
AChE inhibitors may potentiate
Also decrease degradation of the drug
2nd phase – desenzitization - Depolarizing blockade
loss of electric excitability of membrane
Na+ channels blocked despite partial repolarization
Mucsle relaxation
Blockade may by alleviated (možné zmírnění inhibitory AChesterasy)...pachy

13. repolarizace nervosvalové ploténky
depolarizace
kontrakce
repolarizace nervosvalové ploténky
trvalá depolarizace nervosvalové ploténky
rychlé štěpení Ach acetylcholinesterasou
sukcinylcholin se acetylcholinesterasou nerozkládá
může vzniknout nový AP a kontrakce
vznik AP a kontrakce nejsou možné
Sukcinylcholin
buňka koster. svalu
šíření akčního potenciálu

14. Suxamethonium Duration of effect - 5-10 min idiosyncrasy
mtb pseudocholinesterase
idiosyncrasy
Even 3-6 h paralysis
Genetically reduced activity – 1:2500
Therapy – fresh frosen plasma
10 donors – contain pseudocholinesterase
ventilation
O depolarisaci svědčí počáteční svalové fascikulace – dlouhodobě depolarizovaná postsynaptická membrána přestane reagovat (důvod nejasný) na přítomnost molekul ACH, což má za následek myorelaxaci.
lze také vyčkat na spontánní odeznění myorelaxace za podpory umělé plicní ventilace

15. Suxamethonium - AE Acute Asphyxia/apnea - respiratory muscle paralysis
Ventilation required
? Genetic cause?
Prolonged paralysis
Idiosyncrasy, newborns, liver diseases
Prolonged postoperative muscle pain
Sceletal muscle impairment – myoglobin release – due to fasciculation during 1st phase
hyperkalemia  arrhythmias or even cardiac arrest
Risk patients – with burns, injuries, sepsis, kidney failure, hypercalemia drugs
Leak of K+ through ion channels from depolarized muscles
bradycardia:
Direct effect on M receptors
↑ intracranial, intraoccular pressure (KI: glaucoma), or intraabdominal
↑ risk of vomiting
Malignant hyperpyrrexia
caution: combination with halothane
th: cooling, dantrolene
K jejich prevenci je možno zvolit metodu prekurarisace, jež spočívá v podání malé dávky nedepolarisujícího myorelaxancia 3-5 min před aplikací suxamethonia.

16. Muscle relaxants - interactions
AChE inhibitors
slows degradation of suxamethonium  prolongation of effect
Local anesthetics
and antiarrhythmics of I. class
In large doses they inhibit neuromuscular conduction
Ca2+ channel blockers
↑ skeletal muscle blockade
Amidoglykosides, magnesium salts
Inhibition of Ach release
Block Ca2+ entrance to presynaptic part
th: administration of Ca2+
General anesthetic
Potentiation by stabilization of membranes
th: dosage correction
prokain (kompetice o AChE)

17. Myorelaxants - clinics
Nondepolarizing
surgery
After general anesthesia induction, ventilation required
↓ consuption of general anesthetics – reduced AE
Depolarizing
Rapid and short myorelaxation (3-5 min)
Intubation, endoscopy, orthopedic manipulation, cesarean section
Introduction to general anesthesia with consequent nondepolarizing myorelaxation
Seizures/Jerks, th of intoxication with increased muscle tone etc.
myastenia gravis diagnosis - nondepolarizing

18. Botulotoxine A Contains neurotoxin A Inhibits release of ACH
Protein complex from Cl. botulinum
Contains neurotoxin A
Penetrate by endocytosis to nerv endings
Increases proteasome degradation of SNAP25 – syntaxin complex
botulotoxin B inhibits synaptobrevin (vesicular protein)
Inhibits release of ACH
Impairs attachement of vesicles to membrane
Duration – weeks or even 3 M
Function is restored by synthesis of new membrane proteins
PK – slow absorption to circulation
excretion by kidneys – without systemic effect
I: blepharospasm, hemifacial spasm, tortikolis, reactive bladder, cosmetics
i.m. or s.c. administration to site of action/spasms

19. Suxametonium - SPC výkony vyžadující krátkodobou relaxaci
Tracheální intubace, zejména k tzv. bleskové intubaci,
nekrvavé repozice, divulze análního svěrače,
usnadnění sutury peritonea, laryngospazmus,
relaxace při císařském řezu do vybavení plodu,
kardioverze