skeletal muscle relaxants acting on the neuromuscular junction Flashcards
Possibilities to relax skeletal
muscles
structure of skeletal muscle relaxants.
- Centrally acting muscle relaxants – decrease the tone of the skeletal muscles (spasmolytics)
- Peripheral muscle relaxants – paralyze the skeletal
muscles (total relaxation) - A. Presynaptically acting drugs
- A.A. Toxins: botulinumtoxin, -conotoxin (full relaxation)
- A.B. Certain antibiotics: aminoglycosides, tetracyclines.
2.B. Postsynaptically acting drugs
Curare derivatives
Depolarizing muscle relaxants
Ryanodine antagonists
Blockers act either as antagonists (non-depolarizing type of neurmuscular blockers) or as agonists (depolarizing type).
Structurally similar to Ach, and also contain 2 quaternary nitrogen which makes them pretty much impermeable to the CNS.
indications of peripheral muscle
relaxants
Indications of peripheral muscle
relaxants
1. Providing muscle ralxation during surgical narcosis
2. Relaxing the muscles of artificially respired patients (eg. severe COPD)
3. Electroshock
4. Intubation- very important
5.Tetanus
6. Epileptic seizure (convulsion) not responding to
antiepileptics
7. Intoxication (overdose) with certain medicines
(theophyllin, amphetamin)
Curare type peripheral muscle
relaxants
derivatives of d-tubocurare
Competitive antagonist of the NM acetylcholine
receptors in the neuromuscular junction
Structure: bisquaternary ammoniumbases (Ø
central effect!)
Intravenously administered.
Mechanism of action: The drug act predomininantly at the nicotinic receptor site by competing with acetylcholine, preventing binding of Ach and thus preventing depolarization of the muscle cell membrane.
Their action can be overcome by increasing the conc. of Ach in the synaptic clef (e.g. administration of AchE inhibitors such as pyridostigmine and neostigmine).
due to lack of selectivity the drug may also block prejuncitonal sodium channels, intefering with mobilization of acetylcholine at the nerve ending. They may also activate mast cells to release histamine-> vasodialation and bronchoconstriction.
Time order of the curare induced
muscle paralysis
Time order of the curare (d-tubocurarine) induced muscle paralysis Outer eye muscles Facial muscles Pharyngeal muscles Extremities Truncal muscles Respiratory muscles (diaphragm) Full paralysis within 2 to 6 minutes
the muscles recover in the reverse manner, with the diaphragm recovering first.
Structural classification of curare
drugs
Structural classification of curare drugs 1. Izoquinolines D-tubocurarine Doxacurium Atracurium Cisatracurium Mivacurium
2. Steroids Pancuronium Pipecuronium Vecuronium Rocuronium
mivacurium (isoquinolines)
short acting (15~mins)- Moderate histamine release. Eliminated by pseudocholinestrase. duration prolonged in imparied renal function.
Atracurium (Izoquinolines)
intermediate acting (20-35mins~).
slight histamine release.
elimination- spontaneous (Hoffmann-elimination)
metabolite may cross BBB and cause seizures.
Rocuronium (steroid)
intermediate acting (20-35mins~). (dose-dependent: 15-110 minutes) Metabolized mainly by liver.
Cisatracurium (isoquinoline)
Vecuronium (steroid)
Intermediate acting (20-40 minutes):
cisatracurium is metabolized spontaneously and vecuronium is metabolized by the liver.
Pancuronium
pipecuronium
both steroids
Long acting (60-180 minutes):
eliminated mainly by kidney
Doxacurium
long acting
Adverse effects of curare
derivatives
- Recurarization- After suspending the effect a reappearing muscle weakness (reason unknown)
2, Ganglion blockade (d-tubocurarine, pancuronium) - hypotension, tachycardia
- Histamine release (isoquinolines: atracurium, mivacurium)- leading to itching, bronchospasm, hypotension
- M2 receptor blockade (pancuronium) leading to tachycardia
- Norepinephrine releaser and re-uptake inhibitor (pancuronium)-> tachycardia
- The metabolite of atracurium (laudanosin) may cause
muscle spasm - convulsions
Suspending / terminating the curare effect
neostigmine/ pyridostigmine and sugammadex.
sugammadex is a selective relaxant binding agents which binds to rocuronium and vecuronium (chemical antagonist?)
Acetylcholinesterase inhibitors
neostigmine, distigmine
Coadministered with atropin in order to
antgonize their parasympathomimetic effects
Sugammadex
Neutralizes the steroid structures in the plasma
Factors infulencing the curare
effects
Enhancing the effects 1. General anesthetics - important 2/ Aminoglycosides, tetracyclines 3/ Local anesthetics 4/ Myasthenia gravis (autoimmune disease, antibodies against the NMJ)
Attenuating the effetcs
- Acetylcholinesterase inhibitors
- Motoneuron lesions
depolarizing skeletal muscle agents
Depolarize the NM similar to Ach but are more resistant to degradation by AchE and can thus more persistenly depolarize the muscle fibers.
Succynylcholine (suxamethonium)
MEchanism: Provides depolarizing blockade that cannot be antagonized by acetylcholinesterase inhibiotors
Kinetics:
Duration of action: after iv. admnistration 5 to 10 minutes
Metabolism: pseudocholinesterase in the blood then in the liver.
Indications: short surgical interventions; intubation;
electroshock; short, invasive diagnostic procedures (e.g. bronchoscopy). Important in the induction of anesthesia when rapid endotracheal intubation is required.
mechanism of succynylcholine
phase 1: attaches to nicotinic receptor-> membrane depo-> initial discharge that produces transient fasciulations followed by flaccid paralysis (voltage gated Na remains in the inactive state.
phase 2: membrane repolarizes but receptor is desensitized to the effect of Ach.
lecture:
In the beginning short time muscle fasciculations
Due to the longer stimulus of the receptor Na+
influx is higher resulting the depolarization of the surrounding membrane
In the surrounding depolarized membrane the voltage gated Na+ -channels cannot return to the resting closed state instead they remain in inactive state
action potential generation stops, the muscle becomes paralyzed
This paralysis cannot be antagonized by acetylcholiesterase inhibors in the beginning.
2nd phase: desensitization block
Succynylcholine diffuses quckly out of the NMJ
continous receptor stimulation ends
The muscle restores the normal ion balance
(see Na+ /K+ -ATP-ase)
The muscle can be stimulated with high amount
of acetylcholine for a while
Reason: desensitization of the NM receptors
Adverse effects of succynylcholine
Muscle pain (postoperative, fatigue fever like
pain – muscle strain)
Arrythmia – mainly bradycardia.
Hyperkalemia – nicotinic receptor conducts
outward K+ current-> K efflux from the cell.
Vomiting
Higher intraocular pressure (contraction of the
myofibers or dilation of choroidal vessels)
MALIGNANT HYPERTHERMIA!!!-> treat with dantrolene quickly.
Malignant hyperthermia: reason
and symptoms
Genetic disorder – affects ryanodin receptors
For unknown reason (idiosynchrasia)
succynilcholine makes ryanodin activation
permanent, continously high amount of Ca++
flows out of the sarcoplasmic reticule
Continuous muscle shivering heat production
hyperthermia
Lactacidosis
Myoglobinaemia, myoglobinuria, acute renal
failure
teatment to malignant hyperthermia
Treatment of malignant hyperthermia
– dantrolene
Dantrolene
Ryanodin receptor antagonist, inhibits Ca++
release in the skeletal muscle
Main indication: malignant hyperthermia
Most dangerous side effect: hepatotoxicity (1- 2%), when develops lethality is 20-30%
Other
Bicarbonate infusion to acidosis
Physical cooling of the patient
adverse effects of muscle relaxants:
Recurarization
