Skeletal muscle relaxants are drugs that act peripherally at neuromuscular junction/muscle fibre itself or centrally in the cerebrospinal axis to cause paralysis or reduce muscle tone. The neuromuscular blocking agents are used primarily in conjunction with general anaesthetics to provide muscle relaxation for surgery, while centrally acting muscle relaxants are used mainly for painful muscle spasms and spastic neurological conditions.
Muscle relaxers (also called muscle relaxants) are prescription medications that affect muscle function. Healthcare providers prescribe them to treat several symptoms, such as muscle spasms, spasticity and musculoskeletal pain. The term "muscle relaxant" refers to two major drug classes: antispastics and antispasmodics. These two classes differ in their uses, ways of working and side effects.
Curare It is the generic name for certain plant extracts which were used by south American tribals as arrow poison for game hunting. The animals got paralysed even if not killed by the arrow. Natural sources of curare are Strychnos toxifera, Chondrodendron tomentosum and related plants. The muscle paralysing active principles of these are tubocurarine, toxiferins, etc. Tubocurarine was first clinically used in 1930s; many synthetic compounds including Succinylcholine were introduced subsequently. Search has continued for neuromuscular blockers to provide greater cardiovascular stability during surgery, and for drugs with differing onset and duration of action to suit specific requirements.
The site of action of both competitive and depolarizing blockers is the end plate of skeletal muscle fibres. Non-depolarizing block is produced by curare and related drugs. Claude Bernard (1856) precisely localized the site of action of curare to be the neuromuscular junction. He stimulated the sciatic nerve of pithed frog and recorded the contractions of gastrocnemius muscle. Injection of curare in the ventral lymph sac caused inhibition of muscle twitches but there was no effect if the blood supply of the hind limb was occluded. This showed that curare acted peripherally and not centrally. Soaking a portion of the sciatic nerve in curare solution did not affect the twitches and a curarized muscle still responded to direct stimulation thus, nervous conduction and muscle contraction were intact. The only possible site of action could be the neuromuscular junction. This has now been confirmed by close iontophoretic application of d-TC to the muscle end plate and by other modern techniques.
The competitive blockers also block prejunetional nicotinic receptors located on motor nerve endings. Since activation of these receptors by ACh normally facilitates mobilization of additional quanta of ACh from the axon to the motor nerve endings, their blockade contributes to depression of neuromuscular transmission. Accordingly, the competitive blockers exhibit the "fade" phenomenon, i.e. twitch. responses during partial block are progressively depressed on repetitive stimulation.
Tetanic stimulation during partial non-depolarizing block increases the response to a subsequent single stimulation (twitch). This is called post-tetanic potentiation', and is probably due to a transient increase in prejunctional ACH mobilization following tetanic stimulation.
Decamethonium and SCh have affinity as well as submaximal intrinsic activity at the Nm cholinoceptors. They depolarize muscle end plates by opening Na' channels (just as ACh does) and initially produce twitching and fasciculations. Because in the focally innervated mammalian muscle, stimulation is transient; longer lasting depolarization of muscle end plate produces repetitive excitation of the fibre. In the multiplely innervated contracture muscle (rectus abdominis of frog) stimulation is prolonged resulting in sustained contraction. These drugs do not dissociate rapidly from the receptor and are not hydrolysed by AChE. They induce prolonged partial depolarization of the region around muscle end plate resulting in inactivation of sodium channels. In this state ACh released from motor nerve endings is unable to generate a propagated MAP causing flaccid paralysis in mammals. In other words, a zone of inexcitability, is created around the end plate preventing activation of the p muscle fibre. In birds, the area of depolarization is more extensive and spastic paralysis occurs.
All neuromuscular blockers are polar quaternary compounds; therefore not absorbed orally, do not cross cell membranes, have low volumes of distribution and do not penetrate placental or blood brain barrier. They are practically always given intravenous, though intramuscular administration is possible. Muscles with higher blood flow receive more drug and are affected earlier. Re-distribution to non-muscular tissues plays a significant role in the termination of surgical grade muscle relaxation, but residual block may persist for a longer time depending on the elimination half life. The duration of action of competitive blockers is directly dependent on the elimination half life. Drugs that are primarily metabolized in the plasma and liver, e.g. vecuronium, atracurium, cisatracurium, rocuronium, and especially mivacurium have relatively shorter half life and duration of action (20-40 min), while those largely excreted by the kidney, e.g. pancuronium, d-Tc, doxacurium and pipecuronium have longer half life and duration of action (>60 min). With repeated administration, redistribution sites are filled up and duration of action is prolonged. The unchanged drug is excreted in urine as well as in bile.
Intravenous injection of nondepolarizing blockers rapidly produces muscle weakness followed by flaccid paralysis. Small fast response muscles (fingers, extraocular) are affected first; paralysis spreads to hands, feet-arm, leg, neck, face-trunk-intercostal muscles finally diaphragm. The rate of attainment of peak effect and the duration for which it is maintained depends on the drug, its dose, anaesthetic used, haemodynamic, renal and hepatic status of the patient and several other factors. Recovery occurs in the reverse sequence; diaphragmatic contractions resume first. In general, the more potent non-depolarizing blockers have a longer onset of action. Depolarizing blockers typically produce fasciculations lasting a few seconds before inducing flaccid paralysis, but fasciculations are not prominent in well-anaesthetized patients.