Muscle relaxant
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2008-07-16T15:27:20Z
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:''This article refers to skeletal muscle relaxants. For information on [[smooth muscle]] relaxants, see [[Antispasmodic]].''
A '''muscle relaxant''' is a drug which affects [[skeletal muscle]] function and decreases the [[muscle tone]]. It may be used to alleviate symptoms such as muscle [[spasm]] and pain, and [[hyperreflexia]]. The term "muscle relaxant" is used to refer to two major therapeutic groups: [[Neuromuscular-blocking drugs|neuromuscular blockers]] and [[Antispasmodic|spasmolytics]]. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no [[Central nervous system|CNS]] activity. They are often used during surgical procedures and in [[intensive care]] and [[emergency medicine]] to cause [[paralysis]]. Spasmolytics, also known as "centrally-acting" muscle relaxants, are used to alleviate musculoskeletal pain and spasms and to reduce [[spasticity]] in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxants,<ref name="medicinenet">"[http://www.medterms.com/script/main/art.asp?articlekey=77812 Definition of Muscle relaxant]." ''[http://www.medterms.com/ MedicineNet.com].'' (c) 1996-2007. Retrieved on [[September 19]], [[2007]].</ref><ref name="medilexicon">"[http://www.medilexicon.com/medicaldictionary.php?t=77351 muscle relaxant]." ''[http://www.medilexicon.com/ mediLexicon].'' (c) 2007. Retrieved on [[September 19]], [[2007]].</ref> the term is commonly used to refer to spasmolytics only.<ref name="webmd">"[http://www.webmd.com/back-pain/Muscle-relaxants-for-low-back-pain Muscle relaxants]." ''[[WebMD]].'' Last Updated: [[February 15]], [[2006]]. Retrieved on [[September 19]], [[2007]].</ref><ref name="mayoclinic">"[http://www.mayoclinic.com/health/drug-information/DR602309 Skeletal Muscle Relaxant (Oral Route, Parenteral Route)]." ''[[Mayo Clinic]].'' Last Updated: [[April 1]], [[2007]]. Retrieved on [[September 19]], [[2007]].</ref>
==History==
<!--focuses solely on neuromuscular blockers-->
The earliest known use of muscle relaxant drugs dates back to the [[16th century]], when European explorers encountered natives of the [[Amazon Basin]] in [[South America]] using [[poison]]-tipped [[arrow]]s that produced death by skeletal muscle paralysis. This poison, known today as [[curare]], led to some of the earliest scientific studies in [[pharmacology]]. Its active ingredient, [[tubocurarine]], as well as many synthetic derivatives, played a significant role in scientific experiments to determine the function of [[acetylcholine]] in [[neuromuscular transmission]].<ref name="MillerRD">Miller, R.D. "Skeletal Muscle Relaxants," in, "Basic & Clinical Pharmacology: Seventh Edition," by Bertram G. Katzung. Published by Appleton & Lange, 1998, p.434-449. ISBN 0838505651</ref> By 1943, neuromuscular blocking drugs became established as muscle relaxants in the practice of [[anesthesia]] and [[surgery]].<ref name="BowmanWC">Bowman, W.C. "Neuromuscular block." ''Br. J. Pharmacol.'' January 2006. Vol. 147, Suppl. S277-86. PMID: 16402115</ref>
==Neuromuscular-blocking drugs==
[[Image:Synapse diag4.png|thumb|200px|Detailed view of a neuromuscular junction:<Br />1. [[Presynaptic]] terminal<Br />2. [[Sarcolemma]]<Br />3. [[Synaptic vesicle]]<Br />4. [[Nicotinic acetylcholine receptor]]<Br />5. [[Mitochondrion]]]]
{{main|Neuromuscular-blocking drugs}}
Muscle relaxation and paralysis can theoretically occur by interrupting function at several sites, including the [[central nervous system]], [[myelin]]ated somatic nerves, unmyelinated motor nerve terminals, [[nicotinic acetylcholine receptor]]s, the motor end plate, and the muscle membrane or contractile apparatus. Most neuromuscular blockers function by blocking transmission at the end plate of the [[neuromuscular junction]]. Normally, a nerve impulse arrives at the motor nerve terminal, initiating an influx of [[calcium]] ions which causes the [[exocytosis]] of [[vesicle (biology)|synaptic vesicles]] containing [[acetylcholine]]. Acetylcholine then diffuses across the synaptic cleft. It may be hydrolysed by [[Acetylcholine esterase]] (AchE) or bind to to the nicotinic receptors located on the motor end plate. The binding of two acetylcholine molecules results in a [[Protein conformation|conformational change]] in the receptor that opens the sodium-potassium channel of the nicotinic receptor. This allows Na<sup>+</sup> and Ca<sup>2+</sup> ions to enter the cell and K<sup>+</sup> ions to leave the cell causing a depolarization of the end plate, resulting in muscle contraction.<ref>C.R. Craig
, R. E. Stitzel (2003) Modern Pharmacology with clinical applications Lippincott Williams
& Wilkins ISBN 0781737621 p339</ref> Following depolarization, the acetylcholine molecules are then removed from the end plate region and enzymatically hydrolysed by acetylcholinesterase.<ref name="MillerRD"/>
Normal [[end plate]] function can be blocked by two mechanisms. Nondepolarizing agents like [[tubocurarine]] block the [[agonist]], acetylcholine, from binding nicotinic receptors and activating them, thereby preventing depolarization. Alternatively, depolarizing agents such as [[succinylcholine]] are nicotinic receptor [[agonist]]s which mimic Ach, block muscle contraction by depolarizing to such an extent that it [[Nicotinic acetylcholine receptor#Receptor regulatation|desensitizes]] the receptor and it can no longer initiate an [[action potential]] and cause muscle contraction.<ref name="MillerRD"/>These neuromuscular blocking drugs are structurally similar to acetylcholine, the endogenous ligand, in many cases containing two acetylcholine molecules linked end-to-end by a rigid carbon ring system, as in [[pancuronium]].<ref name="MillerRD"/>.
[[Image:Pancuronium acetylcholine-highlighted.png|center|thumb|300px|Chemical diagram of [[pancuronium]], with red lines indicating the two acetylcholine "molecules" in the structure.]]
==Spasmolytics==
[[Image:Spasticity2.svg|thumb|right|250px|A view of the spinal cord and skeletal muscle showing the action of various muscle relaxants. Black lines ending in arrow heads represent chemicals or actions that enhance the target of the lines. Blue lines ending in squares represent chemicals or actions that inhibition the target of the line. Click image to enlarge diagram.]]
The generation of the [[action potential|neuronal signals]] in motor neurons that cause muscle contractions are dependent on the balance of synaptic excitation and inhibition that the motor neuron receives. Spasmolytic agents generally work by either enhancing the level of inhibition, or reducing the level of excitation. Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, such as [[GABA]].
===Terminology===
Because they may act at the level of the cortex, brain stem or spinal cord, or all three areas, they have traditionally been referred to as "centrally-acting" muscle relaxants. However, it is now known that not every agent in this class has CNS activity (e.g. [[dantrolene]]), so this name is inaccurate.<ref name="MillerRD"/>
Most sources still use the term "centrally acting muscle relaxant". According to [[MeSH]], dantroline is usually classified as a centrally acting muscle relaxant.<ref>{{MeshName|Dantrolene}}</ref> The [[World Health Organization]], in its [[Anatomical Therapeutic Chemical Classification System|ATC]], uses the term "centrally acting agents",<ref name="urlATC/DDD Index1">{{cite web |url=http://www.whocc.no/atcddd/indexdatabase/index.php?query=M03B |title=ATC/DDD Index |format= |work= |accessdate=}}</ref> but adds a distinct category of "directly acting agents", for dantrolene.<ref name="urlATC/DDD Index2">{{cite web |url=http://www.whocc.no/atcddd/indexdatabase/index.php?query=M03CA01 |title=ATC/DDD Index |format= |work= |accessdate=}}</ref> Use of this terminology dates back to at least 1973.<ref name="pmid4712630">{{cite journal |author=Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP |title=Dantrolene, a direct acting skeletal muscle relaxant |journal=J Pharm Sci |volume=62 |issue=6 |pages=948–51 |year=1973 |month=June |pmid=4712630 |doi= |url=}}</ref>
The term "spasmolytic" is also considered a synonym for [[antispasmodic]].<ref name="urlDorlands Medical Dictionary:antispasmodic">{{cite web |url=http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/one/000006336.htm#000006336 |title=Dorlands Medical Dictionary:antispasmodic |format= |work= |accessdate=}}</ref>
===Mechanism===
Because of the enhancement of inhibition in the CNS, most spasmolytic agents have the side-effects of sedation, drowsiness and may cause dependence with long term use. Several of these agents also have abuse potential, and their prescription is strictly controlled.<ref name="RangDale">Rang, H.P. & Dale, M. M "Drugs Used in Treating Motor Disorders" in, "Pharmacology 2nd Edition" Published by Churchill Livingston London, 1991, p.684-705.</ref><ref name="GnGStandaert">Standaert, D.G. & Young, A. B "Treatment Of Central Nervous System Degerative Disorders" in, "Goodman & Gilman's The Pharmacological Basis of Therapeutics 10th Edition" by Hardman, J.G. & Limbird, L.E. Published by McGraw Hill, 2001, p.550-568.</ref><ref name="GnGCharney">Charney, D.S., Mihic, J. & Harris, R.A. "Hypnotics and Sedatives" in, "Goodman & Gilman's The Pharmacological Basis of Therapeutics 10th Edition" by Hardman, J.G. & Limbird, L.E. Published by McGraw Hill, 2001, p.399-427.</ref>
The [[benzodiazepine]]s, such as [[diazepam]], interact with the [[GABAA receptor|GABA<sub>A</sub> receptor]] in the central nervous system. While it can be used in patients with muscle spasm of almost any origin, it produces sedation in most individuals at the doses required to reduce muscle tone.<ref name="MillerRD"/>
[[Baclofen]] is considered to be at least as effective as diazepam in reducing spasticity, and causes much less sedation. It acts as a GABA [[agonist]] at [[GABAB_receptor|GABA<sub>B</sub> receptors]] in the brain and spinal cord, resulting in hyperpolarization of neurons expressing this receptor, most likely due to increased potassium ion conductance. Baclofen also inhibits neural function presynaptically, by reducing calcium ion influx, and thereby reducing the release of excitatory neurotransmitters in both the brain and spinal cord. It may also reduce pain in patients by inhibiting the release of [[substance P]] in the spinal cord as well.<ref name="pmid9928310">{{cite journal |author=Cazalets JR, Bertrand S, Sqalli-Houssaini Y, Clarac F |title=GABAergic control of spinal locomotor networks in the neonatal rat |journal=Ann. N. Y. Acad. Sci. |volume=860 |issue= |pages=168–80 |year=1998 |pmid=9928310|doi=10.1111/j.1749-6632.1998.tb09047.x}}</ref><ref name="MillerRD"/>
[[Clonidine]] and other imidazoline compounds have also been shown to reduce muscle spasms by their central nervous system activity. [[Tizanidine]] is perhaps the most thoroughly studied clonidine analog, and is an agonist at [[Adrenergic receptor|α<sub>2</sub>-adrenergic receptors]], but reduces spasticity at doses that result in significantly less [[hypotension]] than clonidine.<ref name="YoungRR">Young, R.R. (editor). "Symposium: Role of tizanidine in the treatment of spasticity." ''Neurology.'' 1994, Vol. 44 (Suppl. 9), p. 1.</ref> Neurophysiologic studies show that it depresses excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity.<ref name="pmid12106064">{{cite journal |author=Bras H, Jankowska E, Noga B, Skoog B |title=Comparison of Effects of Various Types of NA and 5-HT Agonists on Transmission from Group II Muscle Afferents in the Cat |journal= |volume=2 |issue=12 |pages=1029–1039 |year=1990 |pmid=12106064 |doi=}}</ref><ref name="pmid10712650">{{cite journal |author=Jankowska E, Hammar I, Chojnicka B, Hedén CH |title=Effects of monoamines on interneurons in four spinal reflex pathways from group I and/or group II muscle afferents |journal=Eur. J. Neurosci. |volume=12 |issue=2 |pages=701–14 |year=2000 |pmid=10712650|doi=10.1046/j.1460-9568.2000.00955.x}}</ref> Furthermore, several clinical trials indicate that tizanidine has a similar efficacy to other spasmolytic agents, such as diazepam and baclofen, with a different spectrum of adverse effects.<ref name="YoungRR2">Young, R.R; Weigner, A.W. "Spasticity." ''Clin. Orthop.'' 1987, Vol. 219, p. 50.</ref>
The [[hydantoin]]-derivative [[dantrolene]] is a spasmolytic agent with a unique mechanism of action outside of the CNS. Dantrolene reduces skeletal muscle strength by inhibiting the excitation-contraction coupling in the [[muscle fiber]]. In normal muscle contraction, calcium is released from the [[sarcoplasmic reticulum]] through the [[ryanodine receptor]] channel, which causes the tension-generating interaction of [[actin]] and [[myosin]]. Dantrolene interferes with the release of calcium by binding to the ryanodine receptor and blocking the endogenous ligand ryanodine by [[competitive inhibition]]. Muscle that contracts more rapidly is more sensitive to dantrolene than muscle that contracts slowly, although [[cardiac muscle]] and [[smooth muscle]] are depressed only slightly, most likely because the release of calcium by their sarcoplasmic reticulum involves a slightly different process. Major adverse effects of dantrolene include general muscle weakness, sedation, and occasionally [[hepatitis]].<ref name="MillerRD"/>
Other common spasmolytic agents include: [[methocarbamol]], [[carisoprodol]], [[chlorzoxazone]], [[cyclobenzaprine]], [[gabapentin]], [[metaxalone]], and [[orphenadrine]].
== See also ==
* [[Paralysis]]
* [[quaternary ammonium muscle relaxants]]
==References==
{{reflist|2}}
==External links==
* [http://www.ohsu.edu/drugeffectiveness/reports/documents/SMR%20Final%20Report%20Update%2021.pdf Review of skeletal muscle relaxants] (PDF)
* {{MeshName|Skeletal+Muscle+Relaxants}}
{{Muscle relaxants}}
{{Major Drug Groups}}
[[Category:Muscle relaxants| ]]
[[de:Muskelrelaxans]]
[[es:Relajante esqueletomuscular]]
[[fr:Myorelaxant]]
[[nl:Spierverslapper]]
[[ja:筋弛緩剤]]
[[pl:Środki zwiotczające]]
[[zh:肌肉鬆弛劑]]