Skeletal muscle relaxants

Skeletal muscle relaxants

Physiology of SKM Contraction

1. Motor nerve impulse à 2. Release of ACh à 3. Binds with N_M receptors at NMJ à 4. Depolarization & development of EPP at motor end plate (Mainly due to influx of Na⁺) à 5. Muscle action potential (MAP) – contraction of SKM à 6. ACh is rapidly inactivated by ChE leading to repolarization à 7. Muscle is ready for a fresh nerve impulse.

MECHANISM OF ACTION OF MUSCLE RELAXANTS

Centrally acting muscle relaxants

-          Reduce SKM tone by a selective action in the cerebrospinal axis, without altering consciousness.

-          They selectively depress spinal and supraspinal polysynaptic reflexes involved in the regulation of muscle tone without significantly affecting monosynaptically mediated stretch reflex.

-          Polysynaptic pathways in ascending reticular formation also depressed, though to a lesser extent.

-          All centrally acting muscle relaxants have some sedative property.

-          They have no effect on NM transmission and on muscle fibres, but reduce decerebrate rigidity, upper motor neurone spaticity and hyperreflexia.

Centrally acting SKM relaxants

-          Mephenesin and congeners Mefenesin       Carisoprodal   Chlorzoxazone                                                                         Chlormezanone           Methocarbamol

-          BZDs                                       Diazepam and others

-          GABA mimetic                        Baclofen                      Gabapentin     Thiocolchicoside        

-          Central α₂ agonist                  Tizanidine

-                      Classification based on chemical nature:

-          Carbamate derivatives          Methocarbamol          Carisoprodal  Meprobamate

-          Glyceryl ethers                       Guaifenesin     Mefenesin

-          GABA analogues                    Baclofen                     Gabapentin

-          BZDS

-          Miscellaneous                        Cyclobenzaprine         Tizanidine                    Orphenadrine                                                 Metaxalone     Chlorzoxazone Chlormezanone

MECHANISM OF ACTION OF MUSCLE RELAXANTS

Peripherally acting muscle relaxants

-          NMBs are agents which intrefere with transmission of nerve impulses from the somatic motor nerve endings to the SKM fibres.

-          Although nerve transmission to SKM can be inhibited by a variety of mechanisms at different sites viz., inhibition of axonal conduction (local anaesthetics), inhibition of ACh synthesis (hemicholinium) or release (botulinum toxin) and interference with conc. of Ca⁺⁺ at contractile apparatus (dantrolene), the term NMB is specifically used for those which block N_M nicotinic receptors at the EP of NMJ.

Competitive / Non-depolarizing NMBs:

-          They combine with N_M nicotinic receptors in the NMJ and inhibit or interfere with the binding of ACh to the receptor. These do not allow conformational changes in the nicotinic receptors needed for opening of the channel and subsequent depolarization of cell memb. and muscular contraction. At very high conc., competitive blockers directly block Na⁺ channels to produce non-competitive NM blockade.

-          These cause flaccid paralysis of the SKM (Curariform effect).

-          The order of paralysis is eyes, neck, limbs and diaphragm.

-          The muscle paralysis lasts for 30 – 60 minutes.

-          Curariform drugs cause hypotension through histamine release, but do not cross the BBB / placenta.

-          These drugs are not absorbed from GIT or metabolized in liver and excreted unaltered through urine and bile.

-          The curariform effect is potentiated by quinidine, anaesthetics (barbiturates, halothane, methoxyflurane and ether) and many antibiotics (aminoglycosides, tetracyclines, polymixins and lincosamides).

-          The effect can be overcome by AntiChE agents like neostigmine, pyridostigmine and edrophonium.

-          AntiChEs must be given with concurrent atropine injection to counter excessive muscarinic effects of antiChEs.

Depolarizing NMBs:

-          These have affinity as well as submaximal intrinsic activity at the nicotinic receptors on SKM.

-          They attach to the receptors and act like ACh to depolarize the post-junctional memb. by opening Na⁺ channels associate with receptors.

-          However, unlike ACh, they remain attached to the receptor for a relatively longer period and provide a constant stimulation of receptor resulting in persistent depolarization.

-          There are 2 phases to the depolarizing block – Phase I & II.

-          During Phase I (depolarizing phase), the NMB bind to receptors and cause dp of MEPs by opening of monovalent cation channels (Na⁺). In response to this, Ca²⁺ is released from the sarcoplasmic reticulum leading to repetitive excitation and muscular fasciculation. At this stage the membrane is fully depolarized and the muscle fibre is therefore inexitable. This is the phase of sustained or persistent dp, where the continued binding of dp-ing agents has rendered the receptors incapable of transmitting further impulses (Phase I block). With time, the continuous dp gives way to general rp despite continued presence of drug at receptor sites as the Na-channels close. This causes onset of Phase II (desensitizing phase) when the muscle fibres no longer responsive to further dp either by drug or by ACh released by motoneurons. Here the receptors undergo desensitization and eventual closure and Ca²⁺ is removed from the muscle cell cytoplasm and is taken up the sarcoplasmic reticulum. At this point, full NM block is achieved and a flaccid paralysis is produced (Phase II block).

PERIPHERALLY ACTING MUSCLE RELAXANTS (NEUROMUSCULAR BLOCKERS)

a. Non-depolarizing (Competitive) blockers

      Ultra-short acting      : Gantacurium

      Short acting               : Mivacurium

      Intermediate acting  : Vecuronium  Atracurium

                                            Cisatracurium           Rocuronium

                                            Rapacuronium          Alcuronium

      Long acting                : d-Tubocurarine        Pancuronium

                                            Doxacurium  Pipecuronium  Gallamine

     

b. Depolarizing blockers : Succinylcholine (SCh, Suxamethonium)

                                            Decamethonium (C-10)

c. Others                           : Botulinum toxin A

d. Directly acting on SKM                       : Dantrolene    Quinine

Chemical classification of Competitive NMBs

Aminosteroids     Pancuronium   Vecuronium    Rocuronium    Dacuronium

Benzylisoquinolinium      Atracurium      Doxacurium    Mivacurium    Gantacurium  

d-Tubocurarine

Trisquarternary ether     Gallamine

Others                               Alcuronium     Fazadinium

Comparative features of centrally and peripherally acting muscle relaxants

Centrally acting	Peripherally acting
Decrease muscle tone without reducing voluntary power	Cause muscle paralysis, voluntary movements lost
Selectively inhibit polysynaptic reflexes in CNS	Block NM transmission
Cause some CNS depression	No effect on CNS
Given orally, some times parenterally	Practically always given i.v.
Used in chronic spasm conditions, acute muscle spasms, tetanus	Used for short term procedures (surgical operations)

Differences between Competitive NMBs and Depolarizing NMBs

	Competitive NMBs	Depolarizing NMBs
Action at motor end plate	No depolarization	Persistent Depolarization
Initial effect on muscles	No effect	Transient fasciculations
Type of muscle paralysis	Flaccid	Tonic
Effect of AntiChE agents	Antagonism	Synergistic effect
Species sensitivity	Rat>Rabbit>Cat	Cat>Rabbit>Rat

Directly acting muscle relaxants

Dantrolene

This is chemically and pharmacologically entirely different from NMB; effect superficially resembles that of centrally acting muscle relaxants.

NM transmission or MAP are not affected, but muscle contraction is uncoupled from dp of the membrane.

Dantrolene acts on the RyR1 (Ryanodine receptor) calcium channels in the sarcoplasmic reticulum of the SKM and prevents Ca⁺⁺ induced Ca⁺⁺ release through these channels.

Intracellular Ca²⁺ needed foe excitation-contraction coupling is interfered with.

Fast contracting ‘twitch’ muscles are affected more than slow contracting ‘antigravity’ muscles.

Since Ca²⁺ channels in the sarcoplasmic reticulum of cardiac and smooth muscles are of a different sub type (RyR2), these muscles are affected little by dantrolene.

Quinine

It increases refractory period and decreases excitability of MEPs. Thus responses to repetitive nerve stimulation are reduced.

Botulinum toxin

It inhibits the NT ACh release.

•      Succinylcholine (suxamethonium) is the only commonly used, peripherally acting muscle relaxant that is a depolarizing agent.

•      Decamethonium, the other member of the group, is rarely used clinically.

•      Depolarizing blocking drugs occupy the postjunctional cholinergic receptors and, by mechanisms that remain obscure, elicit prolonged depolarization of the endplate region.

•      This prevents the synaptic membrane from completely repolarizing, thus rendering the motor endplate unresponsive to the normal action of acetylcholine.

•      Characteristically, succinylcholine elicits transient muscle fasciculations before causing neuromuscular paralysis.

•      The onset of action of succinylcholine is rapid after IV injection (20–50 sec), and the duration of the effect is usually 5–10 min in most species. 

•      Succinylcholine is rapidly hydrolyzed by pseudocholinesterases in the plasma and liver in most species, but substantial genetic differences exist.

•      Other pharmacologic effects are associated with the depolarizing muscle relaxants.

•      After IV administration of succinylcholine, transient muscle fasciculations are usually evident, although general anesthesia tends to attenuate them. 

•      Succinylcholine-induced cardiac arrhythmias are many and varied. 

•      Succinylcholine stimulates all autonomic cholinergic receptors—both nicotinic and muscarinic.

•      Sudden hyperkalemia may be precipitated by succinylcholine, and muscle pain is seen with the use of succinylcholine in the absence of anesthesia.

•      After recovery from succinylcholine-induced muscle paralysis, muscle damage and even myoglobinuria can develop.

•      Malignant hyperthermia or clinical signs related to this syndrome may also follow the use of succinylcholine in susceptible animals.

•      Factors that can alter the activity of competitive blocking agents can also affect the action of succinylcholine.

•      In addition, previous (within 1 mo) or concurrent use of organophosphate anthelmintics or external parasiticides can have a significant impact on the recovery time from succinylcholine immobilization because of prolonged inhibition of the pseudocholinesterase enzyme systems.

•      A genetically mediated deficiency of pseudocholinesterases also has been identified in certain strains of sheep.

•      Cattle are much more susceptible to the effects of succinylcholine than other species.

•      The indications for the clinical use of succinylcholine are similar to those for the nondepolarizing agents. However, it must be emphasized that succinylcholine should never be used as an agent for euthanasia or for immobilization for castration without local or general analgesia.

•      The use of succinylcholine for game-cropping procedures is also highly undesirable.

•      No antagonists are available to reverse the action of the depolarizing muscle relaxants.

•      Continued positive-pressure ventilation until recovery occurs is the only therapy in cases of overdosage.

•      The IV dose rates for succinylcholine by species are as follows:

•                  horses: 0.125–0.20 mg/kg (~8 min recumbency);

•                  cattle: 0.012–0.02 mg/kg (~15 min recumbency);

•                  dogs: 0.22–1.1 mg/kg (~15–20 min paralysis); and

•                  cats: 0.22–1.1 mg/kg (~3–5 min paralysis).

CONTRAINDICATIONS

•      Hyperkalemia: Serum K > 5.5 is an absolute contraindication for use of Sch.

•      Head Injury: It increase ICP

•      Newborns and infants: These have extrajunctional receptors which are sensitive to depolarizing agents & Sch can produce severe hyperkalemia by interacting with these receptors.

•      Glaucoma & eye injuries.

•      Up to 2-3 months after trauma, Up to 6 months after hemiplegia/paraplegia

•      Renal Failure : If associated with hyperkalemia.

•      Prolonged intra abdominal infection can be associated with hyperkalemia.

•      Diagnosed case of atypical pseudocholinesterase & low pseudocholinesterase.

•      Duchene muscular dystrophy

•      Dystrophia myotonica: Permanent contractures may develop if SCh is given in these patients.

•      Tetanus.

•      Gullian Barre Syndrome

•      Metabolic Acidosis: Acidosis is associated with hyperkalemia.

•      Shock: It is associated with acidosis which in turn is associated with hyperkalemia.

•      Spinal cord injury.

•      In general, nondepolarizing muscle relaxants are not absorbed from the GI tract and must be administered parenterally, usually IV.

•      Plasma-protein binding is insignificant, and there is rapid equilibration but only within the extracellular fluid.

•      The blood-brain and blood-placental barriers are rarely crossed.

•      Tubocurarine, metocurine, and gallamine are not biotransformed to any extent and are excreted unchanged, principally in the urine but sometimes in bile.

•      The other members of the group undergo metabolic transformation to some degree, and the metabolites are excreted by both renal and biliary routes in most instances.

•      The elimination half-lives at standard dosages are 60–100 min, and the duration of paralysis is 30–60 min, except in the case of atracurium and vecuronium, which have shorter actions of ~20–30 min.

•      After IV administration of these agents, the skeletal muscles become totally flaccid and nonresponsive to neuronal stimulation.

•      Muscles capable of rapid movement, such as those of the eye, are paralyzed before the larger muscles of the head and neck, which are followed by those of the limbs and body. Lastly, the diaphragm becomes paralyzed, and respiration ceases. If ventilation is controlled (tracheal intubation and positive-pressure ventilation), there are no adverse effects, and full recovery ensues in reverse order, with the diaphragm regaining function first.

•      All of the currently used nondepolarizing muscle relaxants have cardiovascular effects, many of which are mediated by autonomic and histamine receptors.

•      Tubocurarine and, to a much lesser extent, metocurine result in hypotension, which probably results from the liberation of histamine and, in larger doses, from ganglionic blockade.

•      Premedication with an antihistamine reduces tubocurarine-induced hypotension. 

•      Pancuronium causes a moderate increase in heart rate and, to a lesser degree, cardiac output.

•      Gallamine increases heart rate by both a vagolytic action and sympathetic stimulation.

•      A number of agents can potentiate the activity of neuromuscular blockers. These include other peripherally acting skeletal muscle relaxants, inhalant anesthetics (halothane, methoxyflurane), antibiotics (aminoglycosides, polymyxins, tetracyclines, and lincosamides), and various other drugs (quinidine, procaine, lidocaine, diazepam, and barbiturates).

•      Several states, such as hyper- and hypomagnesemia, hypokalemia, acidosis, and hypothermia, also prolong the action of this group of drugs.

•      Animals with myasthenia gravis are much more susceptible to the action of muscle relaxants.

Indications for the use of nondepolarizing neuromuscular blocking agents include

•                  muscle relaxation of the operative field,

•                  hypoxemic animals resisting mechanical ventilation,

•                  tracheal intubation,

•                  animals with unstable cardiovascular function that require anesthesia but cannot tolerate cardiac depression,

•                  cesarean section in toxic or high-risk animals,

•                  epileptiform convulsions not controllable with usual anticonvulsant agents,

•                  tetanus,

•                  strychnine poisoning,

•                  shivering animals in which the metabolic demand for oxygen should be reduced, and

•                  capture of certain exotic species (eg, gallamine used for immobilization of crocodiles).

•      Animals should always be carefully monitored when under the influence of neuromuscular blocking drugs, and support of ventilation is essential.

•      The action of the competitive relaxants can be reversed by anticholinesterase drugs, especially neostigmine, after the administration of atropine, which eliminates excessive muscarinic responses. This attribute is a great advantage for this group of peripherally acting muscle relaxants.

BENZYLISOQUINOLINE COMPOUNDS

•      D-Tubocurarine

•      It is named so because it was carried in bamboo tubes & used as arrow poison for hunting by Amazon people. D-T is so called because the plant samples containing the curare were earlier stored and shipped to Europe in bamboo tubes.

•      It is a prototype non-depolarizing NMB and an important constituent of curare.

•      Curare is a generic term applied to extract of some plants (Strychnos toxifera and Chondodendron tomentosum) used by South American tribal as arrow poison for hunting animals.

•      Presently, tubocurarine is rarely used as an adjunct for clinical anaesthesia because safer alternatives available.

•      It has highest propensity to release histamine

•      It causes maximum ganglion blockade. Because of ganglion blocking & histamine releasing property it can produce severe hypotension.

STEROIDAL COMPOUNDS

Pancuronium (PAVULON)

•      Very commonly used as it is inexpensive.

•      It releases noradrenaline & can cause tachycardia & hypertension. Because of this there are increased chances of arrhythmia with halothane

Pipercuronium

•      It is a pancuronium derivative with no vagolytic activity, so cardiovascular stable, slightly more potent

Vercuronium (Norcuron)

•      It is very commonly used now a days. It is cardiovascular stable. Shorter duration of action.

•      It is the muscle relaxant of choice in cardiac patient.

Rocuronium

•      8 times more potent than vecuronium and it also has earlier onset of action

•      Because of onset comparable to succinylcholine it is suitable for rapid sequence intubation as an alternative to succinylcholine.

Competitive Nondepolarizing Agents and Antagonists

Drug	Dosage
Nondepolarizing agents
Tubocurarine chloride	Horses: ≤0.22–0.25 mg/kg , IV
	Dogs, cats: ≤0.4 mg/kg, IV
Gallamine triethiodide	All species (except pigs): 0.8–1 mg/kg, IV
Pancuronium bromide	Dogs, cats: 0.6 mg/kg, IV
Alcuronium chloride	Dogs, cats: 0.1 mg/kg, IV
Atracurium besylate	Dogs, cats: 0.5 mg/kg, IV
Antagonists
Neostigmine	0.04 mg/kg, with atropine at 0.04 mg/kg, IV
Pyridostigmine	0.2–0.25 mg/kg, with atropine at 0.04 mg/kg, IV
Edrophonium	0.125 mg/kg, IV

Methocarbamol is a centrally acting muscle relaxant chemically related to guaifenesin.

•      Its exact mechanism of action is unknown, and it has no direct relaxant effect on striated muscle, nerve fibers, or the motor endplate. It also has a sedative effect.

•      In dogs, cats, and horses, methocarbamol is indicated as adjunct therapy of acute inflammatory and traumatic conditions of skeletal muscle and to reduce muscle spasms.

•      Because methocarbamol is a CNS depressant, it should not be given with other drugs that depress the CNS.

•      Overdosage is generally characterized by CNS depression, but emesis (small animals), salivation, weakness, and ataxia may be seen.

Guaifenesin (glyceryl guaiacolate) is a centrally acting muscle relaxant believed to depress or block nerve impulse transmission at the internuncial neuron level of the subcortical areas of the brain, brain stem, and spinal cord.

•      It also has mild analgesic and sedative actions.

•      Guaifenesin is given IV to induce muscle relaxation as an adjunct to anesthesia for short procedures.

•      It relaxes both laryngeal and pharyngeal muscles, allowing easier intubation, but has little effect on diaphragm and respiratory function.

•      It may cause transient increases in cardiac rate and decreases in blood pressure.

•      It is also used in treatment of horses with exertional rhabdomyolysis and in dogs with strychnine intoxication.

•      Overdose results in apneustic breathing, nystagmus, hypotension, and contradictory muscle rigidity.

•      Treatment of overdose is supportive until the drug is cleared to nontoxic levels.

Benzodiazepines, such as diazepam, affect polysynaptic reflexes at the supraspinal level, act as a spinal cord depressant at the interneuronal level, and inhibit presynaptic acetylcholine release.

•      Clinically, diazepam is used as an adjunct to anesthesia, in management of clinical signs of tetanus, and in treatment of functional urethral obstruction and urethral sphincter hypertonus in cats.

Dantrolene, a hydantoin derivative, is structurally and pharmacologically different from other skeletal muscle relaxants.

•      Dantrolene has a direct action on muscle, probably by interfering with the release of calcium from the sarcoplasmic reticulum.

•      It has no discernible effects on respiratory and cardiac function but can cause dizziness and sedation.

•      In veterinary medicine, dantrolene is used to treat malignant hyperthermia in various species, porcine stress syndrome, equine postanesthetic myositis, and equine exertional rhabdomyolysis.

Phenytoin is a hydantoin derivative, primarily used as an anticonvulsant in people. 

•      Phenytoin has shown efficacy in some horses susceptible to exertional rhabdomyolysis. 

•      Phenytoin may alter the function of neurotransmitters at the neuromuscular junction, the release of calcium from the sarcoplasmic reticulum, and sodium flux at the sarcolemma.

•      Dosages are adjusted in horses to maintain serum concentrations of 5–10 mcg/mL.

Baclofen is a centrally acting skeletal muscle relaxant used to control spasticity and pain in people with multiple sclerosis and spinal disorders. 

•      Baclofen is structurally similar to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It acts as a GABA receptor B agonist to reduce calcium influx into presynaptic nerve terminals, thereby decreasing the amount of excitatory neurotransmitters released by primary afferent neurons in the spinal cord and brain. This results in reduced muscle tone as well as pain associated with spasticity.

•      Because of a very narrow safety margin, baclofen has limited use in veterinary medicine. It has been used to treat dogs with tetanus and to reduce urethral resistance in treatment of urinary retention. 

•      Baclofen transiently inhibits lower esophageal sphincter relaxation in dogs and theoretically is of benefit in the treatment of gastroesophageal reflux disease. 

•      Baclofen is not recommended for use in cats.

•      Even at therapeutic doses, dogs may show clinical signs of vomiting, depression, and vocalization. With overdose, the severity of CNS signs can be substantial and may include dysphoria, lateral recumbency, or coma.

•      Treatment of baclofen toxicity should include rapid and aggressive decontamination, along with intensive supportive treatment.

•      Management of affected dogs may require positive-pressure ventilation as a result of severe obtundation, respiratory depression, and respiratory arrest or hypoventilation. 

•      Cyproheptadine, a serotonin antagonist, may be given orally or rectally as needed to reduce vocalization or disorientation.

•      IV lipid emulsion has been useful to treat some dogs with baclofen toxicity.

Drug	Dosage
Methocarbamol	Dogs, cats: 44 mg/kg, IV, up to 330 mg/kg/day for tetanus or strychnine poisoning; 132 mg/kg/day, PO, divided bid-tid
	Horses: 4.4–5.5 mg/kg, IV
Guaifenesin	Dogs: 44–88 mg/kg, IV
	Horses, ruminants: 66–132 mg/kg, IV
Diazepam	Cats: 2–5 mg, PO, tid, for urethral obstruction
Dantrolene	Horses: 15–25 mg/kg, slow IV, qid; 2 mg/kg/day, PO, for prevention of exertional rhabdomyolysis
	Swine: 3.5 mg/kg, IV
Phenytoin	Horses: 6–8 mg/kg/day, PO, increase by 1 mg/kg every 3 days until rhabdomyolysis is prevented or the horse appears sedated
Baclofen	Dogs: 12 mg/kg, PO, tid

Therapeutic uses of NMBs / SM spasmolytics

•      As preanaesthetic (adjuncts to GA)

•      For control / restraint and capture of ferocious wild animals (Curariform drugs: Capture / dart guns)

•      As anticonvulsants

•      For orthopaedic surgical manipulation

•      Adjunct therapy in attending acute muscle injuries

•      Prevention and treatment of malignant hyperthermia or rhabdomyolysis in horses or other species and porcine stress syndrome