18. Muscle Relaxants (1).pptx

SKELETAL MUSCLE RELAXANTS By Dr E Kezia  Introduction  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 block...

SKELETAL MUSCLE RELAXANTS By Dr E Kezia  Introduction  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. 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 PERIPHERALLY ACTING MUSCLE RELAXANTS  I. Neuromuscular blocking agents  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 PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  Curare is the generic name for certain plant extracts 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. 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 latest additions are doxacurium, pipecuronium, rocuronium, mivacurium, rapacuronium and cisatracurium. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  MECHANISM OF ACTION  The site of action of both competitive and depolarizing blockers is the end plate of skeletal muscle fibres.  Competitive blockers (Nondepolarizing blockers) have affinity for the nicotinic (NM) cholinergic receptors at the muscle end plate. ACh released from motor nerve endings is not able to combine with its receptors to generate end plate potential (EPP) and this reduces the frequency of channel opening.  When the magnitude of EPP falls below a critical level, it is unable to trigger propagated muscle action potential (MAP) and muscle fails to contract in response to nerve impulse. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  MECHANISM OF ACTION  Depolarizing blockers depolarize muscle end plates by opening Na+ channels. 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. In other words a zone of inexcitability is created around the end plate preventing activation of the muscle fibre.  Depolarizing agents injected in high doses or infused continuously produce dual mechanism neuromuscular blockade which can be divided into two phases PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  MECHANISM OF ACTION  Phase I block It is rapid in onset, results from persistent depolarization of muscle end plate and has features of classical depolarization blockade. This depolarization declines shortly afterwards and repolarization occurs gradually despite continued presence of the drug at the receptor, but neuromuscular transmission is not restored and phase II block supervenes.  Phase II block It is slow in onset and results from desensitization of the receptor to Ach. The block is partially reversed by anticholinesterases. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  ACTIONS  1. Skeletal muscles  I.V 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: respiration stops.  2. Autonomic ganglia  Competitive neuromuscular blockers produce some degree of ganglionic blockade. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  ACTIONS  3. Histamine release  d-TC releases histamine from mast cells. This is due to the bulky cationic nature of the molecule. Flushing, bronchospasm and increased respiratory secretions are other effects. Heparin may also be simultaneously released from mast cells.  4. C.V.S.  d-Tubocurarine produces significant fall in BP due to ganglionic blockade, histamine release and reduced venous return PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  ACTIONS  5. G.I.T.  The ganglion blocking activity of competitive blockers may enhance postoperative paralytic ileus after abdominal operations.  6. C.N.S.  All neuromuscular blockers are quaternary compounds hence do not cross blood-brain barrier. Thus, on i.v. administration no central effects follow. However, d-TC applied to brain cortex or injected in the cerebral ventricles produces strychnine like effects. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  PHARMACOKINETICS  All neuromuscular blockers are polar quaternary compounds hence are not absorbed orally, do not cross cell membranes, have low volumes of distribution and do not penetrate placental or blood- brain barrier.  They are given i.v., though i.m. administration is possible.  Muscles with higher blood flow receive more drug and are affected earlier  Metabolism is in the liver and plasma  Excretion via urine PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  Uses  1. As adjuvants to general anesthesia by providing adequate muscle relaxation  2. Assisted ventilation for critically ill patients in intensive care units who need ventilatory support. Vecuronium is the drug of choice  3. Convulsions and trauma from electroconvulsive therapy can be avoided by the use of muscle relaxants without decreasing the therapeutic benefit. Succinyl Choline is most commonly used with Mivacurium is an alternative.  4. Severe cases of tetanus and status epilepticus, who are not controlled by diazepam or other drugs, may be paralysed by a neuromuscular blocker. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  Adverse Effects (Toxicity)  1. Respiratory paralysis and prolonged apnoea is the most important problem.  2. Flushing is common with d-Tubocurarine (due to histamine release).  3. Fall in BP and cardiovascular collapse can occur, especially in hypovolemic patients.  4. Cardiac arrhythmias and even arrest have occurred, especially with Succinyl Choline  5. Precipitation of asthma by histamine releasing neuromuscular blockers. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  Adverse Effects (Toxicity)  6. Postoperative muscle soreness and myalgia may be complained after Succinyl Choline.  7. Malignant hyperthermia can be triggered by Succinyl Choline in patients anaesthetized with fluorinated anaesthetics. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  Interactions  1. Thiopentone and Succinyl Choline react chemically hence their solutions should not be mixed in the same syringe.  2. General anaesthetics potentiate competitive blockers.  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 surgery. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  Interactions  4. Aminoglycoside antibiotics reduce ACh release from prejunctional nerve endings by competing with Ca2+.  5. Calcium channel blockers e.g. Verapamil potentiate both competitive and depolarizing neuromuscular blockers.  6. Diuretics may produce hypokalemia which enhances competitive block.  7. Diazepam, propranolol and quinidine intensify competitive block, while high dose of corticosteroids reduces it. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  1. d-Tubocurarine  Because of its prominent histamine releasing, ganglion blocking and cardiovascular actions as well as long duration of paralysis needing pharmacological reversal, d- TC is not used now.  2. Doxacurium  A bisquaternary muscle relaxant having the least rapid onset and the longest action.  It is suitable for long duration surgeries.  It is primarily eliminated by kidney, though hepatic metabolism also occurs.  Cardiovascular changes are less marked. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  3. Succinylcholine  Despite its propensity to cause muscle fasciculations and soreness, changes in BP and HR, arrhythmias, histamine release and K+ efflux from muscles causing hyperkalaemia and its complications, SCh is the most commonly used muscle relaxant for passing tracheal tube.  It induces rapid, complete and predictable paralysis with spontaneous recovery in ~5 min.  Occasionally SCh is used by continuous i.v. infusion for producing controlled muscle relaxation of longer duration.  It should be avoided in younger children unless absolutely necessary, because risk of hyperkalaemia and cardiac arrhythmia is higher.  Risk of regurgitation and aspiration of gastric contents is increased by SCh in GERD patients and in the obese, especially if stomach is full. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  4. Pancuronium  A synthetic steroidal compound, ~5 times more potent and longer acting than d-TC.  It provides good cardiovascular stability, seldom induces flushing, bronchospasm or cardiac arrhythmias because of lower histamine releasing potential.  Rapid i.v. injection may cause rise in BP and tachycardia due to vagal blockade and NA release.  It is primarily eliminated by renal excretion.  Because of longer duration of action, needing reversal, its use is now restricted to prolonged operations, especially neurosurgery. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  5. Pipecuronium  It has a slow onset and long duration of action  It is steroidal in nature  It is recommended for prolonged surgeries.  It exerts little cardiovascular action, though transient hypotension and bradycardia can occur.  Elimination occurs through both kidney and liver. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  6. Vecuronium  A close congener of pancuronium with a shorter duration of action due to rapid distribution and metabolism.  It is excreted mainly in bile,  Reecovery is generally spontaneous, but may need neostigmine reversal.  Cardiovascular stability is still better due to lack of histamine releasing and ganglionic action, although tachycardia sometimes occurs.  Currently, it is the most commonly used muscle relaxant for routine surgery and in intensive care units. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  7. Atracurium  It is 4 times less potent than pancuronium and shorter acting hence reversal is mostly not required.  The unique feature of atracurium is inactivation in plasma by spontaneous nonenzymatic degradation (Hofmann elimination) in addition to that by cholinesterases.  Consequently its duration of action is not altered in patientswith hepatic/renal insufficiency or hypodynamic circulation.  It is the preferred muscle relaxant for liver/kidney disease patients as well as for neonates and the elderly.  Hypotension may occur due to dose dependent histamine release PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  8. Cisatracurium  This R-Cis enantiomer of atracurium is nearly 4 times more potent, slower in onset, but similar in duration of action.  Like atracurium it undergoes Hofmann elimination, but in contrast it is not hydrolysed by plasma cholinesterase.  Most importantly, it does not provoke histamine release.  Side effects are fewer. PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  9. Rocuronium  A newer nondepolarizing blocker with a rapid onset and intermediate duration of action which can be used as alternative to SCh for tracheal intubation without the disadvantages of depolarizing block and cardiovascular changes.  It also serves as maintenance muscle relaxant, seldom needing reversal.  The onset and duration of action is dose-dependent;  It is also being used to facilitate mechanical ventilation in intensive care units.  Though little metabolized, it is eliminated mainly in bile PERIPHERALLY ACTING MUSCLE RELAXANTS  NEUROMUSCULAR BLOCKING AGENTS  10. Mivacurium  It is the shortest acting competitive blocker hence does not need reversal.  Dose and speed of injection related transient cutaneous flushing can occur due to histamine release.  Fall in BP is possible, but change in HR is minimal.  It is metabolized rapidly by plasma cholinesterases.  Prolonged paralysis can occur in pseudocholinesterase deficiency, but this can be reversed by neostigmine. PERIPHERALLY ACTING MUSCLE RELAXANTS  DIRECTLY ACTING MUSCLE RELAXANTS  Dantrolene  This muscle relaxant is chemically and pharmacologically entirely different from neuromuscular blockers.  Its effect superficially resembles that of centrally acting muscle relaxants.  Dantrolene acts on the RyR1 (Ryanodine Receptor) calcium channels in the sarcoplasmic reticulum of skeletal muscles and prevents Ca2+ induced Ca2+ release through these channels.  Intracellular release of Ca2+ needed for excitation- contraction coupling is interfered with. PERIPHERALLY ACTING MUSCLE RELAXANTS  DIRECTLY ACTING MUSCLE RELAXANTS  Dantrolene  This muscle relaxant is chemically and pharmacologically entirely different from neuromuscular blockers.  Its effect superficially resembles that of centrally acting muscle relaxants.  Dantrolene acts on the RyR1 (Ryanodine Receptor) calcium channels in the sarcoplasmic reticulum of skeletal muscles and prevents Ca2+ induced Ca2+ release through these channels.  Intracellular release of Ca2+ needed for excitation- contraction coupling is interfered with. PERIPHERALLY ACTING MUSCLE RELAXANTS  DIRECTLY ACTING MUSCLE RELAXANTS  Dantrolene  Pharmacokinetics  Dantrolene is slowly but adequately absorbed from the g.i.t.  It penetrates brain and produces some sedation, but has no selective effect on polysynaptic reflexes responsible for spasticity.  It is metabolized in liver and excreted by kidney with a t½ of 8–12 hours. PERIPHERALLY ACTING MUSCLE RELAXANTS  DIRECTLY ACTING MUSCLE RELAXANTS  Dantrolene  Uses  Dantrolene is used orally (25–100 mg QID) to reduce spasticity in upper motor neurone disorders, hemiplegia, paraplegia, cerebral palsy and multiple sclerosis.  It is used i.v. (1 mg/kg repeated as required) as the drug of choice for malignant hyperthermia which is due to persistent release of Ca2+ from sarcoplasmic reticulum (induced by fluorinated anaesthetics and Succinyl Choline in genetically susceptible individuals with abnormal RyR1) PERIPHERALLY ACTING MUSCLE RELAXANTS  DIRECTLY ACTING MUSCLE RELAXANTS  Dantrolene  Adverse Effects  Muscular weakness is the dose limiting side effect.  Sedation, malaise, light headedness and other central effects occur, but are less pronounced.  Troublesome diarrhea is another problem.  Long term use causes dose dependent serious liver toxicity in 0.1–0.5% patients. This has restricted its use in chronic disorders. PERIPHERALLY ACTING MUSCLE RELAXANTS  DIRECTLY ACTING MUSCLE RELAXANTS  Quinine  It increases refractory period and decreases excitability of motor end plates. Thus, responses to repetitive nerve stimulation are reduced.  It decreases muscle tone in myotonia congenita.  Taken at bed time (200–300 mg) it may abolish nocturnal leg cramps in some patients. CENTRALLY ACTING MUSCLE RELAXANTS By Dr E Kezia  Introduction  These are drugs which reduce skeletal muscle tone by a selective action in the cerebrospinal axis, without altering consciousness  They mitigate tension and spasm of skeletal muscles.  They are structurally heterogeneous and act at a variety of receptors in the CNS.  These are also called skeletal muscle spasmolytics.  They are given either orally or parenterally.  Introduction  They selectively inhibit polysynaptic reflexes in the CNS  They decrease muscle tone without reducing voluntary power  They are used in chronic spastic conditions  They cause some CNS depression  Classification  Mephenesin Congeners  Mephenesin, Carisoprodol, Chlorzoxazone, Chlormezanone, Methocarbamol,  Benzodiazepines  Diazepam and chlordiazepoxide  Gamma-aminobutyric acid (GABA) derivatives  Baclofen, Thiocolchicoside  Central α2 agonist  Tizanidine  Mephenesin Congeners  1. Mephenesin  It was the first drug found to cause muscle relaxation in animals without producing unconsciousness and was called internuncial neurone blocking agent because its primary site of action is the spinal internuncial neurone which modulates reflexes maintaining muscle tone.  It is not used clinically because orally it causes marked gastric irritation, and injected i.v., it causes thrombophlebitis, haemolysis and fall in BP.  It has been included in counterirritant ointments where its irritant rather than muscle relaxant property could be affording relief.  Mephenesin Congeners  2. Carisoprodol  It has a favourable muscle relaxant: sedative activity ratio with weak analgesic, antipyretic and anticholinergic properties.  It is used in musculoskeletal disorders associated with muscle spasm  3. Chlorzoxazone  It is pharmacologically similar to mephenesin, but has a longer duration of action and is better tolerated orally  Mephenesin Congeners  4. Chlormezanone  It has antianxiety and hypnotic actions as well, and has been used for tension states associated with increased muscle tone.  5. Methocarbamol  It is less sedative and longer acting than mephenesin.  Orally it has been used in reflex muscle spasms and chronic neurological diseases.  It can be injected i.v. without producing thrombophlebitis and haemolysis  It is used for orthopedic procedures and tetanus.  Benzodiazepines  Diazepam  It is the prototype of benzodiazepines (BZDs) which act in the brain on specific receptors enhancing GABAergic transmission.  Muscle tone is reduced by supraspinal rather than spinal action;  Muscle relaxant: sedative activity ratio is low.  No gastric irritation occurs and it is very well tolerated, though sedation limits the dose which can be used for reducing muscle tone.  It is particularly valuable in spinal injuries and tetanus.  Combined with analgesics, it is popular for rheumatic disorders associated with muscle spasm.  Gama Amino Butyric Acid (GABA) Derivatives  Baclofen  This analogue of the inhibitory transmitter GABA acts as a selective GABAB receptor agonist.  The primary site of action of baclofen is considered to be in the spinal cord where it depresses both polysynaptic and monosynaptic reflexes.  Baclofen is the preferred drug for symptomatic relief of spasticity manifested in many neurological disorders like multiple sclerosis, amyotropic lateral sclerosis (ALS), spinal injuries and flexor spasms  Gama Amino Butyric Acid (GABA) Derivatives  Baclofen  Baclofen is well absorbed orally and is primarily excreted unchanged in urine with a t½ of 3–4 hours.  Side effects are drowsiness, mental confusion, weakness and ataxia; serum transaminases may rise.  Sudden withdrawal after chronic use may cause hallucinations, tachycardia and seizures  Gama Amino Butyric Acid (GABA) Derivatives  Thiocolchicoside  Chemically related to colchicine, this muscle relaxant is believed to act as a GABA mimetic and glycinergic drug.  Combined with NSAIDs, it is being used for painful muscle spasms, such as torticolis, sprains, backache, etc.  Side effects are gastric upset and photosensitivity reactions  Central α2 Agonist  Tizanidine  This clonidine congener is a central α2 adrenergic agonist.  It inhibits release of excitatory amino acids in the spinal interneurones.  Polysynaptic reflexes are inhibited resulting in decreased muscle tone and frequency of muscle spasms without reducing muscle strength.  Efficacy similar to baclofen or diazepam has been noted in multiple sclerosis, spinal injury and stroke, with fewer side effects  Central α2 Agonist  Tizanidine  Tizanidine is absorbed orally, undergoes first pass metabolism and is excreted by the kidney; t½ 2–3 hours.  It is indicated in spasticity due to neurological disorders and in painful muscle spasms of spinal origin.  Side effects are dry mouth, drowsiness, night-time insomnia and hallucinations.  Dose-dependent elevation of liver enzymes occurs.  Though no consistent effect on BP has been observed, it should be avoided in patients receiving antihypertensives, especially clonidine. 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.  2. Torticollis, lumbago, backache, neuralgias  These are other conditions in which painful spasm of certain muscles is a prominent feature;They respond in the same way as acute muscle spasms. Uses of Centrally Acting Muscle Relaxants  3. Anxiety and tension  Increased tone of muscles often attends these states. Diazepam group of drugs and chlormezanone benefit by their antianxiety as well as muscle relaxant actions.  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. Uses of Centrally Acting Muscle Relaxants  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.  7. Orthopedic manipulations  These procedures may be performed under the influence of diazepam or methocarbamol given i.v.