Muscle relaxant
Muscle relaxants (also: muscle relaxants, myotonolytics, often muscle relaxants; singular: muscle relaxant , myotonolytic, muscle relaxant) are substances that cause a reversible (temporary) relaxation of the skeletal muscles . According to their mechanism of action, a distinction between the right at the neuromuscular junction of the muscle attacking peripheral muscle and central muscle relaxants , in the central nervous system reduce the muscle tone. Many muscle relaxant substances as drugs used: peripheral muscle relaxants are used to carry out anesthesia as part of operations used to the tonus of skeletal muscle to reduce or completely abolish, central muscle relaxants for the treatment of spinal induced spasms or local muscle spasms .
Peripheral muscle relaxants
Peripheral muscle relaxants block the neuromuscular transmission of stimuli to the motor endplates, which causes reversible paralysis, which the organism breaks down on its own. The duration for this depends on the dosage. The administration of antagonists ( neostigmine , sugammadex ) can actively cancel the effect, e.g. B. at the end of an operation or problems with securing the airway . With the routine use of relaxometry , a relaxation overhang after anesthesia is almost impossible.
Mode of action
Motorized end plate
Muscle relaxants are inhibitors of neuromuscular transmission at the motor endplate . This is the place where the excitation is transmitted from a nerve cell to the muscle fiber .
When the nerve cell is excited, the messenger substance acetylcholine is released from vesicles via the axonal release points into the synaptic cleft. The acetylcholine diffuses to the receptors of the muscle cell, binds there and, by changing the allosteric configuration of the receptor molecules, leads to an influx of sodium ions into the muscle cell. This leads to a depolarization of the membrane potential for excitation and contraction of the muscle cell.
Acetylcholine is quickly removed from the synaptic cleft by diffusion and enzymatic breakdown ( acetylcholinesterase ). This leaves the binding sites on the receptor free and available for renewed excitation.
Effect of muscle relaxants
The substances attach to the nicotinic acetylcholine receptors of a muscle cell. When a motor nerve cell is excited, the neurotransmitter acetylcholine is released, but this messenger substance cannot work adequately because of the blocked receptors on the assigned muscle cells. The control of muscle contractions by nerve impulses is interrupted. The muscle is temporarily paralyzed and active movements are excluded.
Non-depolarizing
Non-depolarizing muscle relaxants bind as competitive antagonists (inhibitory) to the receptor without triggering a depolarization of the muscle cell membrane. The blockage prevents the acetylcholine from working. The effect can be broken by increasing the acetylcholine concentration. Cholinesterase inhibitors such as neostigmine are usually used, which, however, also require the administration of a vagolytic, as they do not specifically attack the motor endplate. Recently there is also a chelating agent called sugammadex , whose high specificity has so far produced promising results.
Depolarizing
Depolarizing muscle relaxants act as agonists (exciting) at the receptor, they trigger a long-lasting depolarization. In the beginning, they lead to a brief contraction of the muscles, which is observed in the patient as fasciculation (uncoordinated muscle tremors), and then turn into flaccid paralysis. The persistent depolarization prevents a renewed excitation by acetylcholine, the muscle is inexcitable. The effect cannot be canceled by other drugs (can be antagonized). The only active ingredient approved for humans is succinylcholine , which is easy to control because it has a short-term effect .
Active ingredients
Apart from minor and rare side effects, preferred muscle relaxants have a quick onset of action and a short duration of action in the sense of easy controllability of their action. All non-depolarizing muscle relaxants ( NDMR ) can release histamines to varying degrees and allergic reactions have been described for all of them.
From a structural point of view, the benzylisoquinolines ( atracurium , cisatracurium , mivacurium ) and the steroid derivatives pancuronium , rocuronium , vecuronium , pipecuronium and rapacuronium (the latter two are no longer available) are distinguished. In general, benzylisoquinolines are more prone to histamine liberation than the group of steroid derivatives. The names of the benzylisoquinolone derivatives end with -urium , the steroids with -uronium .
| Surname | Wirkungs- occurs |
Duration of action |
Side effects | Remarks |
|---|---|---|---|---|
| Pancuronium | 3-5 min | 70-120 min | Irregular heartbeat, especially an increase in heart rate ( tachycardia ) | Cardiovascular interactions with imipramine described |
| Pipecuronium | 3-5 min | 90-120 min | very long duration of action. No longer in trade. | |
| Vecuronium | 3-4 min | 35-45 min | low | |
| Rocuronium | 45 sec-3 min | 30-40 min | low, only non-depolarizing MR for modified Rapid Sequence Induction (= RSI) | |
| Rapacuronium | 60-90 s | 15-25 min | Increased heart rate, ventilation disorders described. | was withdrawn from the market in 2001. |
| Atracurium | 3-4 min | 35-45 min | Increase in heart rate, bronchospasm | Hofmann elimination , therefore the degradation is independent of liver and kidney function |
| Cisatracurium | 4-6 min | 40-50 min | Hofmann elimination | |
| Mivacurium | 3-5 min | 10-25 min | Histamine release (flush) up to slight anaphylactic reactions , especially if the injection is too fast | short duration of action, prolonged action in the case of cholinesterase deficiency. |
| Alcuronium | 3-5 min | 60-80 min | Bronchospasm , cardiac arrhythmias , histamine release | is hardly used anymore |
| Surname | Wirkungs- occurs |
Duration of action |
unwanted effects | Remarks |
|---|---|---|---|---|
| Suxamethonium / succinylcholine | 35-90 s | 3-5 min | Cardiac arrhythmias, hyperkalemia, myoclonus , trigger substance for malignant hyperthermia , greatly prolonged duration of action in the case of a lack of pseudocholinesterase | the only depolarization blocker used in humans, due to its side effects increasingly only standard for rapid sequence induction in emergency anesthesia; newer alternative: Rocuronium |
| Decamethonium | 10 min | not used in human medicine |
| Surname | Duration of action |
unwanted effects | Remarks |
|---|---|---|---|
| Dantrolene | Half-life 7 hours | Anaphylactic and allergic reactions, neurological disorders | The drug of choice for malignant hyperthermia |
| Surname | origin | Mechanism of action | application |
|---|---|---|---|
| Botulinum toxin | Clostridium botulinum | inhibit the fusion of the membrane with acetylcholine-containing vesicles | for eyelid cramps |
application areas
The surgeon Arthur Läwen had already used "Curarin" in 1912 to supplement the anesthesia during operations. The worldwide use of muscle relaxants in anesthesia began with Harold R. Griffith and G. Enid Johnson's application of Tubocurare and Tubocurarine ( Intocostrin ) during appendix removal under cyclopropanic anesthesia on January 23, 1942 . Muscle relaxants are required in the context of open or minimally invasive operations of the abdominal cavity ( laparotomy , laparoscopy ) and the chest ( thoracotomy , thoracoscopy ) in order to reduce the muscle tone of the skeletal muscles ( muscle relaxation ), since otherwise there are no adequate visibility and operating conditions. Using the example of laparoscopic gallbladder removal, a double-blind examination clearly showed that deep relaxation is necessary for certain operations in order to prevent problems during the operation. For example, the abdomen often couldn't be inflated far enough without relaxation, and at the end of the operation the gall bladder couldn't be pulled out through the small incision in the abdomen.
Another indication is endotracheal intubation . The lack of defensive movements reduces the risk of injury and improves the visibility of the vocal folds and the passage of the latter. The risk of hoarseness and / or damage to the vocal cords with intubation without relaxation is approximately three times higher than with the use of relaxation.
Monitoring of neuromuscular function
As Relaxometry or neuromuscular monitoring refers to the monitoring of the neuromuscular stimulus transmission at the neuromuscular junction in the use of muscle relaxants. A peripheral nerve is stimulated by the relaxometer by means of two electrodes and the resulting muscle response is measured quantitatively. Based on these values, the anesthetist can assess the effect of the muscle relaxants and control their dosage accordingly.
Antagonization
The effect of non-depolarizing muscle relaxants can be neutralized ( antagonized ) via two principles .
The administration of cholinesterase inhibitors such as neostigmine reduces the effect of acetylcholinesterase , which means that acetylcholine, the activating messenger substance on the muscular endplate, is less broken down. By shifting the quantitative ratio, it displaces the relaxant from the nicotinic acetylcholine receptors and thus neutralizes its effect. The side effects on the parasympathetic nervous system , which are mediated by muscarinic acetylcholine receptors and which lead to an increase in the parasympathetic tone (for example bradycardia and other cardiac arrhythmias and bronchoconstriction ), are disadvantageous. Attempts are made to reduce this by giving atropine .
After intravenous administration of sugammadex , which has been approved since 2008, the muscle relaxant is tightly bound (“encapsulated”) and the effect ceases. Sugammadex can only bind rocuronium and, to a lesser extent, vecuronium . In contrast to the acetylcholinesterase inhibitors, the effect does not take place on the neuromuscular endplate, but in the serum ; parasympathetic side effects do not occur.
Myotropic muscle relaxants
Myotropic muscle relaxants do not work on the motor endplate, but directly on the striated muscle. The most important representative is dantrolene , which by a direct blockade of the intracellular ryanodine calcium release from the receptor sarcoplasm (intracellular calcium stores) into the cytoplasm of the muscle cell electromechanical coupling prevents interrupts and so a contraction. The indication for administration is malignant hyperthermia . Dantrolene has hardly any effect on the heart muscles and smooth muscles , as other receptors predominate in these muscles.
Central muscle relaxants (myotonolytics)
Central muscle relaxants (Engl. Central muscle relaxants ) are drugs that have an effect on the central nervous system have such. B. tetrazepam , flupirtine , tizanidine , baclofen , pridinol , tolperisone , eperisone or methocarbamol . They are used when there is a pathological increase ( spasticity ) in the muscle tone. The “dampening” effect of the medication reduces the muscle tone.
See also
literature
- WC Bowman: Neuromuscular block. In: Br. J. Pharmacol. 147 Suppl 1, 2006, pp. S277-S286, PMID 16402115 PMC 1760749 (free full text).
- T. Raghavendra: Neuromuscular blocking drugs: discovery and development. In: JR Soc Med. 95, 2002, pp. 363-367, PMID 12091515 PMC 1279945 (free full text).
- Erich Kirchner, Wolfgang Seitz (ed.): Clinic of muscle relaxation. 50 years after Griffith and Johnson. Steinkopff, Darmstadt 1994; Reprint ibid 2012, ISBN 978-3-642-95978-3 .
Individual evidence
- ↑ Duden: Relaxants
- ↑ Reinhard Larsen: Anesthesia and intensive medicine in cardiac, thoracic and vascular surgery. (1st edition 1986) 5th edition. Springer, Berlin / Heidelberg / New York et al. 1999, ISBN 3-540-65024-5 , p. 36 f.
- ↑ Withdrawal from the market of Rapacuronium
- ↑ Michael Heck, Michael Fresenius: Repetitorium Anaesthesiologie. Preparation for the anesthesiological specialist examination and the European diploma in anesthesiology. 3rd, completely revised edition. Springer, Berlin / Heidelberg / New York et al. 2001, ISBN 3-540-67331-8 , p. 803.
- ↑ Erich Kirchner: Preliminary remark. In: Wolfgang Seitz (Ed.): Clinic of muscle relaxation. 50 years after Griffith and Johnson. 1994, p. 1.
- ↑ http://clinicaltrials.gov/ct2/show/record/NCT00895778
- ↑ Thomas Mencke, Mathias Echternach, Stefan Kleinschmidt, Philip Lux, Volker Barth, Peter K. Plinkert, Thomas Fuchs-Buder: Laryngeal Morbidity and Quality of Tracheal Intubation. In: Anesthesiology. 98, 2003, pp. 1049-1056, doi : 10.1097 / 00000542-200305000-00005 .
- ↑ Reinhard Larsen (1999), p. 39.
