Skeletal Muscle Relaxants reduce muscle tone and/or cause paralysis. To achieve this, Skeletal Muscle Relaxants may act peripherally at the neuromuscular junction/muscle fiber itself or centrally in the cerebrospinal axis. Drugs, that block transmission of impulses at the skeletal neuromuscular junction, are called neuromuscular blocking agents. These blockers act mainly at the post-junctional level. On the basis of their mechanism of action, they are classified as:
1. Non-depolarising or competitive blockers: D-tubocurarine, Pancuronium, Gallamine, Alcuronium, Atracurium, Mivacurium, Doxacurium, Rocuronium and Vecuronium.
2. Depolarizing blockers: Succinylcholine and Decamethonium
3. Dual action blocker: Benzoquinonium
4. Directly acting neuromuscular blocking agents: Dantrolene sodium and Quinine
Neuromuscular Blocking Agents
Non-depolarizing agents: These agents competitively block acetylcholine receptors on the motor end plate. The blockage can be overcome or reversed by increasing the concentration of acetylcholine at the receptor site. The salient features of pharmacokinetics of these agents are:
Being quaternary compounds, these are not absorbed on oral administration; usually given i.v.
Except gallamine, none of these drugs cross blood—brain barrier. These drugs do not cross placental barrier (can be given during cesarean).
Route of administration plays an important role to determine their duration of action such as:
a. Longer duration of action with drugs excreted by kidney
b. Intermediate to short duration of action with drugs eliminated by liver
c. Shorter duration of action with drugs which are inactivated by plasma cholinesterase
d. Intermediate action with some isoquinoline derivatives (atracurium and cisatracurium) which are inactivated spontaneously by Hofmann elimination (rupture of the ester containing bridge joining the two isoquinoline moieties)
• Steroidal neuromuscular blocking drugs, primarily metabolized in liver (e.g. vecuranium, rocuranium, and rapacuranium), may accumulate on prolonged administration.
• Duration of action of atracurium is reduced during respiratory alkalosis caused by hyperventilation because it is chemically unstable at alkaline pH.
• Skeletal Muscle Relaxants do not show pharmacogenetic variation in metabolism/response.
Curare: It is the generic name for various South American arrow poisons. It is obtained from strychnos toxifera, chondrodendron tomentosum and related plants. The active principles of curare are d-tubocurarine, toxiferins, etc. Since absorption is irregular and poor from the gastrointestinal tract, dtubocurarine is given by parenteral route. Neuromuscular blockage occurs in 3—4 minutes and lasts up to 30 minutes. The Skeletal Muscle Relaxants is of progressive flaccid paralysis type.
Hypothermia decreases its effect while neuromuscular blocking drugs such as ether and aminoglycoside antibiotics potentiate it. Neostigmine antagonizes its effect on neuromuscular junction. Hypotension is its major side effect which is due to histamine release and ganglionic blockage. It is a dose related phenomenon. Histamine release is also responsible for an erythematous rash on the chest and neck as well as for bronchospasm. Its dose depends on the type of anaesthesia used. Usually adult dose is 0.2 to 0.7 mg/kg intravenously.
Dimethyl tubocurarine iodide is three times as potent as d-tubocurarine. However, it may be avoided in patients sensitive to iodides.
Pancuronium: It has a steroid nucleus. Its onset of action is quick (40—50 seconds). It is more potent than d-tubocurarine and causes full (100%) Skeletal Muscle Relaxants. Histamine release is not significant. It does not cause significant change in blood pressure and is devoid of ganglionic blocking property. Increase in heart rate and cardiac output are its modest side effects which can be abolished by prior administration of atropine. It is given intravenously in a dose of 60—100 pig/kg for initial intubation and then 30—40 tag/kg for muscle relaxation.
Gallamine: Its onset of action is rapid but duration of action is short than d-tubocurarine. Histamine release is insignificant and acetylcholine esterase inhibitors reverse its effect less readily. It causes tachycardia by depressing the vagus nerve. Since it crosses placental barrier, it should be used with great care during cesarean sections. It is employed intravenously in doses of 80—120 mg.
Alcuronium: It has no advantage on tubocurarine or pancuronium. It is given intravenously in a dose of 10—15 mg. Other short acting neuromuscular blocking agents are vecuronium and atracurium.
Atracurium and its congeners: Atracurium is a bis-quarternary compound. It is unstable at physiological pH but indefinitely stable at an acidic pH. Its duration of action is short. Its ester moiety is hydrolysed by plasma pseudocholinesterases. It is also degraded by spontaneous or Hofmann degradation. It can be safely given to patients with renal and hepatic impairments because its metabolism is not affected in these two conditions.
Mivacurium and doxacurium are new congeners of atracurium. Mivacurium has short duration of action (onset 2-4 minutes; duration of action: 12—18 minutes) because it is rapidly catalyzed by cholinesterases. On the other hand, doxacurium has longer duration of action (onset 4—6 minutes; duration of action 90—120 minutes) because it is not significantly affected by cholinesterases.
Rocuronium is a new agent. Its onset of action is very quick like succinylcholine, but duration of action is long (30—40 minutes). So it can be used as an alternative to succinylcholine to facilitate tracheal intubation (relaxes laryngeal and jaw muscles).
Depolarizing agents: These agents mimic acetylcholine like action at neuromuscular junction but cause blockage by producing prolonged depolarization, i.e. dissociation of the drug from the receptor site and subsequent breakdown is slower than acetylcholine. There occurs rapid, complete and predictable paralysis and the recovery is spontaneous. Muscle fasciculations occur prior to the development of paralysis. There may occur prolonged paralysis leading to apnea in patients with atypical plasma pseudocholinesterase enzyme. Succinylcholine belongs to this group.
Succinylcholinet: It is ultra short acting Skeletal Muscle Relaxants. Its action occurs with in 15 seconds and is reversed on cessation of its administration because it is rapidly metabolized by plasma pseudocholinesterase enzyme. It causes initial fasciculations followed by flaccid paralysis. Hypothermia and neostigmine potentiate its relaxant effect. It causes negligible histamine release. It produces bradycardia in children which can be overcome by prior use of atropine. Postoperative muscle pain is common in patients who show muscle fasciculations. It stimulates cardiac muscarinic receptors and causes bradycardia in low doses. However, in large doses, it causes tachycardia. Other side effects are nausea, vomiting, hyperkalaemia and raised intraocular pressure. In presence of abnormal pseudocholinesterase enzyme, there occurs prolongation of its effect leading to apnea. Another pharmacogenetic toxicity is occurrence of malignant hyperthermia. It should not be used in severe liver disease and in burn patients. According to the patient’s need, it is given intravenously in a dose of 30— 100 mg. Blocking action of succinyicholine can be prolonged by hexafluorenium which is a selective inhibitor of plasma pseudocholinesterase.
Toxicity and treatment of Skeletal Muscle Relaxants: There occurs paralysis of the diaphragm muscle and respiratory paralysis leading to death when an excessive dose of tubocurarine and related drugs are administered. Certain general anesthetics (ether in particular) and aminoglycoside antibiotics potentiate the action of these agents. The treatment consists of insertion of endotracheal tube and artificial respiration with oxygen. Neostigmine or edrophonium may be given intravenously to overcome muscle paralysis. However, they may worsen the hypotension and bronchospasm produced by d-tubocurarine. To counter muscarinic stimulation, atropine or glycopyrrolate is administered.
Uses of neuromuscular blocking agents:
1. Used as adjunct to general anesthesia to have adequate Skeletal Muscle Relaxants.
2. Succinyicholine is used for brief procedures, e.g. endotracheal intubation, laryngoscopy, bronchoscopy, oesophagoscopy, reduction of fractures and dislocations.
3. Succinylcholine is also used to avoid convulsions and trauma from electroconvulsive therapy.
4. If diazepam and other drugs do not control severe cases of tetanus and status epilepticus, a neuromuscular blocker (repeated doses of competitive blocker) may be used to induce paralysis and maintain on intermittent positive pressure respiration.
Directly Acting Skeletal Muscle Relaxants
Dantrolene: It acts directly on the contractile machinery of skeletal muscle. It causes uncoupling of excitation from contraction in the muscle and reduces the depolarization- induced Ca release into sarcoplasm caused by conducted muscle action potential. It has little effect on smooth and cardiac muscles. It is given in doses of 25 mg orally daily. Important side effects are gastrointestinal disturbances, drowsiness, weakness, fatigue and mental disturbances. It is used in the treatment of spasticity due to stroke, spinal, cerebral and multiple sclerosis.
Quinine: It decreases the muscle tone by increasing the refractory period and decreasing the excitability of motor end-plates. It is used in myotonia congenita and nocturnal leg cramps (200—300 mg).
Centrally Acting Skeletal Muscle Relaxants
Skeletal Muscle Relaxants drugs do not alter consciousness. They decrease muscle tone by selectively depressing spinal and supraspinal polysynaptic reflexes. Skeletal Muscle Relaxants do not affect monosynaptically mediated stretch reflex significantly and do not block transmission of impulses at the neuromuscular junction. They are classified as:
i. Mephenesin group: Mephenesin, Meprobamate, Carisoprodol, Chlorzoxazone, Chlormezanone and Methocarbamol
ii. Benzodiazepines: Diazepam and others and CABA derivatives (baclofen).
Mephenesin: It is the first centrally acting Skeletal Muscle Relaxants. At present it is not used for this purpose systemically because it causes thrombophlebitis, haemolysis, marked fall in blood pressure, strong gastric irritation and has short duration of action. However, it has been included in counter irritant ointments.
Meprobamate:It is a mephenesin congener. It is seldom used now because of having low Skeletal Muscle Relaxants: sedative ratio and drug dependence liability like barbiturates.
Carisoprodol: It is a useful centrally acting Skeletal Muscle Relaxants with weak analgesic, antipyretic and anticholinergic actions.
Chlorzoxazone:Its pharmacological actions are similar to mephenesin. However, it has longer duration of action and better tolerated orally.
Chlormezanone: It is an anti-anxiety and hypnotic drug which is used for tension associated with muscle spasm.
Methocarbamol: It is a better Skeletal Muscle Relaxants than mephenesin because it is less sedative, longer acting, available by oral route and does not produce thrombophlebitis and haemolysis on intravenous administration.
Note: Clinical usefulness of none of the above drugs as centrally acting Skeletal Muscle Relaxants is well established.
Diazepam: It is a benzodiazepine derivative which enhances CABAergic transmission in the brain on specific receptors. It is a popular anxiolytic-sedative and is used for reducing tone.
Baclofen: It is a GABA (gamma-aminobutyric acid—an inhibitory transmitter) derivative. It is potent neuronal depressant. It mainly acts in the spinal cord on presynaptic mechanism rather than postsynaptic GABAB receptors. It reduces the release of excitatory transmitters. It is lipophilic and crosses the blood—brain barrier with much ease. On oral administration, it is rapidly absorbed and is excreted unchanged in urine. The recommended daily dose is 5 mg 3 times a day to be increased every 3—4 days up to a maximum of 80 mg per day. Drowsiness, lassitude, and mental disturbances may appear as side effects.
Uses of Centrally Acting Skeletal Muscle Relaxants
1. Mephenesin like and benzodiazepine muscle relaxants are often combined with analgesics and are used in the treatment of acute muscle spasms, torticollis, lumbago, backache, and neuralgias. However, efficacy of these drugs is not impressive.
2. Diazepam group of drugs and chlormezanone are used to treat diseases of central nervous system.
3. Baclofen, diazepam and dantrolene have beneficial effect in the treatment of hemiplegia, paraplegia, spinal injuries, multiple sclerosis, and cerebral palsy. However, therapy of these disorders is far from satisfactory.
4. Diazepam or methocarbamol is used to treat tetanus, to reduce intensity of convulsions during electro-convulsive therapy and at the time of orthopedic manipulations. For this purpose, they are given intravenously.
5. Centrally acting Skeletal Muscle Relaxants are used in myofacial pain of temporomandibular disorder in dental practice.
Points for Dental Students
1. Skeletal Muscle Relaxants are used as adjuncts to general anesthetic for adequate muscle relaxation. Initially succinyl choline is used for endotracheal intubation. This is followed by an administration of non-depolarizing drug such as pancuranium or vecuronium. Such a procedure will prolong the action of non- depolarizing drug; so lower doses of drug can be used.
2. Centrally acting Skeletal Muscle Relaxants such as chlorzoxazone plus an antianxiolytic drug alprazolam are used in myofacial pain of temporomandibular disorder in dental practice.
3. For setting mandibular fractures, neuromuscular blockers can be used in dental practice. For this purpose short acting non- depolarizing agents (mivacurium or rapocurium) are preferred. Although short acting succinyl choline can also be used but not preferred because it causes muscle fasciculations which may aggravate the fracture associated injury.
4. Succinyl choline is used to prevent laryngospasm in certain dental procedures.
1. Peripherally acting Skeletal Muscle Relaxants cause paralysis of skeletal muscles with loss of voluntary movements. They are practically always given i.v. for short- term purposes (as adjunct to surgical anaesthesia). Skeletal Muscle Relaxants act by blocking the neuromuscular transmission and has no effect on central nervous system.
2. Centrally acting Skeletal Muscle Relaxants act by selectively inhibiting polysynaptic reflexes in central nervous system. Skeletal Muscle Relaxants decrease muscle tone without reducing voluntary power. However, Skeletal Muscle Relaxants cause some central nervous system depression. Skeletal Muscle Relaxants can be given orally as well as some times parenterally. Although they have been used in chronic spastic conditions, acute muscle spasms, tetanus, etc. efficacy of these drugs is not impressive.