Muscle Relaxers
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Skeletal muscle relaxants are drugs that act peripherally at neuromuscular junction/muscle fibre itself or centrally in the cerebrospinal axis to reduce muscle tone and/or cause paralysis.
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.
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PERIPHERALLY ACTING MUSCLE RELAXANTS
I. Neuromuscular blocking agents
A. Nondepolarizing (Competitive) blockers
1. Long acting: d-Tubocurarine, Pancuronium,
Doxacurium, Pipecuronium
2. Intermediate acting: Vecuronium,
Atracurium, Cisatracurium, Rocuronium,
Rapacuronium
3. Short acting: Mivacurium
B. Depolarizing blockers
Succinylcholine (SCh., Suxamethonium),
Decamethonium (C-10)
II. Directly acting agents
Dantrolene sodium
Quinine
Note: 1. Decamethonium is not used clinically.
2. Aminoglycoside, tetracycline, polypeptide antibiotics
interfere with neuromuscular transmission at high
doses, but are not employed as muscle relaxants
MECHANISM OF ACTION of Muscle Relaxers
The site of action of both competitive and depolarizing blockers is the end plate of skeletal muscle fibres.
Competitive block (Nondepolarizing block)
This 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.
Depolarizing block 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 → Na+ channels get inactivated (because transmembrane potential drops to about –50 mV) → ACh released from motor nerve endings is unable to generate propagated MAP → flaccid paralysis in mammals. In other words a zone of inexcitability is created around the end plate preventing activation of the muscle fibre. In birds, the area of depolarization is more extensive and spastic paralysis occurs.
PHARMACOKINETICS of Muscle Relaxers
Doses of Muscle relaxers
All neuromuscular blockers are polar quaternary compounds—not absorbed orally, do not cross cell membranes, have low volumes of distribution and do not penetrate placental or bloodbrain barrier. They are practically always given i.v., though i.m. administration is possible.
Muscles with higher blood flow receive more drug and are affected earlier. Redistribution 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 t½.
The duration of action of competitive blockers is directly dependent on the elimination t½. Drugs that are primarily metabolized in the plasma/liver, e.g. vecuronium, atracurium, cisatracurium, rocuronium, and especially mivacurium have relatively shorter t½ and duration of action (20–40 min), while those largely excreted by the kidney, e.g. pancuronium, d-Tc, doxacurium and pipecuronium have longer t½ and duration of action (>60 min). With repeated administration redistribution sites are filled up and duration of action is prolonged.
INTERACTIONS of Muscle relaxers
1. Thiopentone sod and SCh solutions should not be mixed in the same syringe—react chemically.
2. General anaesthetics potentiate competitive blockers; ether in particular, followed by fluorinated hydrocarbons. Isofluorane, desflurane and sevoflurane potentiate to a greater extent than halothane. Nitrous oxide potentiates the least. Ketamine also intensifies nondepolarizing block. Fluorinated anaesthetics predispose to phase II blockade by SCh. Malignant hyperthermia produced by halothane and isoflurane in rare (genetically predisposed) individuals is more common in patients receiving SCh as well.
3. Anticholinesterases reverse the action of competitive blockers. Neostigmine 0.5–2 mg (30–50 μg/kg) i.v. is almost routinely used after pancuronium and other long/intermediate acting blockers to hasten recovery at the end of operation. Though neostigmine also reverses ganglionic blockade to some extent, hypotension and bronchospasm can occur due to muscarinic action of neostigmine; this can be prevented by prior atropinization (atropine or glycopyrrolate 5–10 μg/kg i.v.). Pretreatment with H1 antihistamines reduces hypotension due to d-TC and others which release histamine.
4. Antibiotics Aminoglycoside antibiotics reduce ACh release from prejunctional nerve endings by competing with Ca2+. They interfere with mobilization of ACh containing vesicles from a central location to near the terminal membrane, and have a weak stabilizing action on the postjunctional membrane. In clinically used doses, they do not by themselves produce muscle relaxation, but potentiate competitive blockers. The dose of competitive blocker should be reduced in patients receiving high doses of these antibiotics. Application of streptomycin powder locally at the end of bowel surgery has caused prolonged apnoea if a competitive blocker had been used during the operation. Tetracyclines (by chelating Ca2+), polypeptide antibiotics, clindamycin and lincomycin also synergise with competitive blockers.
5. Calcium channel blockers Verapamil and others potentiate both competitive and depolarizing neuromuscular blockers.
6. Diuretics may produce hypokalaemia which enhances competitive block.
TOXICITY of Muscle Relaxants
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1. Respiratory paralysis and prolonged apnoea is the most important problem.
2. Flushing is common with d-TC (due to histamine release), can occasionally occur
with atracurium and mivacurium, rare with others.
3. Fall in BP and cardiovascular collapse can occur, especially in hypovolemic patients. This is less likely with the newer drugs. Muscle relaxants should be used with great caution in patients with severe hepatic and renal disease.
4. Cardiac arrhythmias and even arrest have occurred, especially with SCh, particularly in digitalized patients. SCh releases K+ from muscles. Intubating dose generally raises serum K+ by 0.5 mEq/L, but dangerous hyperkalemia can occur, especially in patients with extensive burns and soft tissue injuries.
5. Precipitation of asthma by histamine releasing neuromuscular blockers.
6. Postoperative muscle soreness and myalgia may be complained after SCh.
7. Malignant hyperthermia can be triggered by SCh in patients anaesthetized with fluorinated anaesthetics.
USES of Muscle Relaxers
1. The most important use of neuromuscular blockers is as adjuvants to general anaesthesia; adequate muscle relaxation can be achieved at lighter planes. Many surgical procedures are performed more safely and rapidly by employing muscle relaxants. Muscle relaxants also reduce reflex muscle contraction in the region undergoing surgery, and assist maintenance of controlled ventilation during anaesthesia. They are particularly helpful in abdominal and thoracic surgery, intubation and endoscopies, orthopedic manipulations, etc.
Choice of the neuromuscular blocker depends on the nature and duration of the procedure, pharmacokinetics of the blocker and cardiovascular stability that it provides.
Vecuronium and rocuronium are the most frequently selected nondepolarizing blockers. SCh is employed for brief procedures, e.g. endotracheal intubation, laryngoscopy, bronchoscopy, esophagoscopy, reduction of fractures, dislocations, and to treat laryngospasm. For ocular surgery competitive blockers are preferred, because they paralyse extraocular muscles at doses which have little effect on larger muscles. Other factors which should be considered in selecting the relaxant are—onset of action, duration of blockade required, cardiovascular effects of the drug as well as patient’s hepatic, renal and haemodynamic status.
CENTRALLY ACTING MUSCLE RELAXERS
These are drugs which reduce skeletal muscle
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 the ascending reticular formation
which are involved in the maintenance of wakefullness
are also depressed, though to a lesser
extent. All centrally acting muscle relaxants do
have some sedative property. They have no effect
on neuromuscular transmission and on muscle
fibres, but reduce decerebrate rigidity, upper
motor neuron spasticity and hyperreflexia.
CLASSIFICATION of Centrally acting Muscle Relaxers
(i) Mephenesin Mephenesin, congeners Carisoprodol, Chlorzoxazone,
Chlormezanone, Methocarbamol.
(ii) Benzodiazepines Diazepam and others.
(iii) GABA mimetic Baclofen, Thiocolchicoside
(iv) Central α2 agonist Tizanidine
Uses of centrally acting muscle relaxants
1. Acute muscle spasms Overstretching of a muscle, sprain, tearing of ligaments and tendons, dislocation, fibrositis, bursitis, rheumatic disorders, etc. cause painful spasm of muscles. The mephenesin-like and BZD muscle relaxants, combined with analgesics, are commonly used, but efficacy is not impressive.
2. Torticollis, lumbago, backache, neuralgias These are other conditions in which painful spasm of certain muscles is a prominent feature; respond in the same way as acute muscle spasms.
3. Anxiety and tension Increased tone of muscles often attends these states
4. Spastic neurological diseases Impairment of descending pathways in the cerebrospinal axis and withdrawal of inhibitory influence over the stretch reflex causes chronic increase in muscle tone or spasticity. Hemiplegia, paraplegia, spinal injuries, multiple sclerosis, ALS and cerebral palsy fall in this category. These conditions are benefited by baclofen, diazepam, tizanidine and dantrolene but not by mephenesin group of drugs. However, therapy of these disorders is far from satisfactory.
5. Tetanus Most commonly diazepam is infused i.v. and the dose is titrated by the response. Methocarbamol is an alternative.
6. Electroconvulsive therapy Diazepam decreases the intensity of convulsions resulting from ECT, without diminishing its therapeutic effect. Often SCh is used in addition for total suppression of the muscular component of ECT.
7. Orthopedic manipulations These procedures may be performed under the influence of diazepam or methocarbamol given i.v.
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