SKELETAL MUSCLE RELAXANTS.

•Skeletal muscle relaxants are drugs which act peripherally at the neuro muscular junction(NMJ) and centrally in the cerebrospinal axis to relax muscles.•The drugs which act at the NMJ or neuro muscular blocking drugs are used in conjunction with general anaesthetics to provide muscle relaxation during surgery.•The centrally acting muscle relaxants are used mainly for painful muscle spasms and spastic neurological conditions.

NEURO MUSCULAR BLOCKING AGENTS.

CLASSIFICATION.• A) Non depolarizing (competitive) blockers.• Long acting: d-Tubocurarine, Pancuronium,

Doxacurium, Pipecuronium.• Intermediate acting: Vecuronium, atracurium,

cisatracurium, Rocuronium, Rapacuronium• Short acting: Mivacurium.• B) Depolarizing blockers.• Succinyl choline (suxamethonium).• Decamethonium.

CLASSIFICATION CONT..

• C) Directly acting agents

• Dantrolene sodium.

• Quinine.

Other agents that interfere with neuro muscular transmission.

• Aminoglycosides, tetracycline, polypeptide antibiotics: these are not used as muscle relaxants.

MECHANISM OF ACTION OF NON-DEPOLARIZING NEURO MUSCULAR

BLOCKERS.

• These are competitive inhibitors of acetyl choline at the motor end plate.

• The motor end plate is found at the junction of the motor nerve and the skeletal muscle and it contains nicotinic Nm or N2 receptors of acetylcholine.

• ACH Combines with these post synaptic receptors leading to influx of sodium ions and the development of end plate potential causing muscle contraction.

MECHANISM OF ACTION OF NON-DEPOLARIZING NEURO MUSCULAR BLOCKERS.

CONT..• The competitive neuro muscular blockers are

generally bulky in nature and therefore block access of the nicotinic receptors to ACH with no generation of end plate potentials and causing flaccid paralysis.

• ACH also acts presynaptically on cholinergic neurons and augments its own release(positive feedback).

• Tubocurarine can reversibly block both presynaptic and post synaptic receptors while α-bungarotoxin blocks only post synaptic receptors but not presynaptic receptors.

MECHANISM OF ACTION OF NON-DEPOLARIZING NEURO MUSCULAR

BLOCKERS. CONT..

• Gallamine also inhibits neuronal release of ACH by acting on presynaptic cholinergic M2 receptors.

• 80-90% of nicotinic receptors must be blocked before neurotransmission fails.

• Anticholinesterases agents like neostigmine are able to reverse the effects of neuromuscular blockers by building up the concentration of the agonist (ACH).

PHARMACOKINETICS OF COMPETITIVE NEURO MUSCULAR BLOCKERS.

• All competitive neuro muscular blockers are quaternary ammonium compounds: They are:

• Poorly absorbed after oral administration• Low volume of distribution because they don’t

cross membranes.• Do not penetrate placenta or blood brain barrier.

They are safe in obstetrical surgery except gallamine)

• They are always administered by IV route although the IM route is also possible.

PHARMACOKINETICS OF COMPETITIVE NEURO MUSCULAR BLOCKERS. CONT..

• The drugs are first distributed to muscles with higher blood flow and these muscles are affected first. Redistribution to non-muscular tissues plays a role in terminating the activity of the NMJ blocker.

• Duration of muscle relaxation following IV administration : tubocurarine 30 min, gallamine 15 mins, pancuronium 60 min, atracuronium 10 min, alcuronium 30 mins.

PHARMACOLOGICAL ACTIONS OF D- TUBOCURARINE

• When injected I.V there is immediate onset of action, peak effect within 5-7 mins. and duration of action of between 30- 60 mins.

• Effects of d-tubocurarine on skeletal muscles.

• There is flaccid paralysis of the muscles. • Muscles of fine movements are more sensitive

than larger and stronger muscles of coarse movements.

• Small rapidly moving muscles of the face,neck, eyes and pharynx are affected first, leading to difficulty in speaking, accumulation of secretions in throat, and diplopia.

PHARMACOLOGICAL ACTIONS OF D- TUBOCURARINE CONT..

• Other small muscles of fingers, toes, hands and intercostal muscles are affected next leading to difficulty in performing delicate motor tasks.

• Muscles of limb, trunk, abdomen, chest and finally diaphragm are paralyzed with cessation of respiration.

• Recovery of paralysis occurs in reverse order.

Effects of d- tubocurarine on other systems.

• Blocks transmission at autonomic ganglia and decreases secretion of adrenaline from the adrenal glands leading to fall in blood pressure.

• Releases histamine from mast cells leads to fall in blood pressure and bronchospasm. Contraindicated in patients of bronchial asthma and other allergic states.

Important Pharmacological Effects of Other Agents.

• All are quaternary ammonium compounds with same pharmacokinetic profile as d-tubocurarine.

Gallamine.

• Does not release histamine or block autonomic ganglia.

• Blocks M2 muscarinic receptors of the heart and releases NA, inducing tachycardia.

Pancuronium

• Does not release histamine or block autonomic ganglia.

• Blocks M2 muscarinic receptors of the heart and releases NA leading to tachycardia.

• Duration-60-120 mins.

• Inhibits plasma cholinesterase.

Atracurium

• 4 times less potent than pancuronium and shorter acting (20-35mins.)

• Neostigmine reversal not required because of short duration of action.

• It is inactivated by plasma cholinesterase and spontaneous non enzymatic degradation in the plasma (Hofmann elimination) therefore duration of action is not altered by liver diseases.

• Preferred muscle relaxant for patients of hepatic diseases, neonates and the elderly.

• Releases histamine and may cause hypotension.

Pipecuronium.

• Slow onset and long duration of action (onset2-4min Duration-50-100mins)

• Recommended for prolonged surgeries.

• Has little cardiovascular action, though there may be transient hypotension and bradycardia.

Vecuronium.

• A close congener of pancuronium with a shorter duration (30-60mins) due to rapid distribution and metabolism.

• Recovery is generally spontaneous not requiring neostigmine reversal unless repeated dose has been given.

• Cardiovascular stability is better due to lack of histamine release and ganglion blockage, tachycardia occasionally occurs.

• Currently the most commonly used muscle relaxant for routine surgery.

Doxacurium

• Has the least rapid onset (4-8 mins) and the longest duration of action (60-120 mins).

• Suitable for long surgeries.• Minimal cardiovascular effects.• Mivacurium• Shortest acting (onset 2-4 and duration 12-20

mins).• Does not need neostigmine reversal.• Cause slight histamine release leading to fall in

BP but minimal effect on heart rate.• Hydrolyzed by plasma cholinesterase and

prolonged paralysis can occur in pseudo cholinesterase deficiency.

Rocuronium.

• New compound with rapid onset (1-2 mins) and intermediate duration of action (25-40 mins). Onset is dose dependent.

• Can be used as an alternative to succinyl choline for tracheal intubation without the disadvantages of depolarizing block and cardiovascular changes.

• May serve as maintenance muscle relaxant.• Seldom needs neostigmine reversal.

ADVERSE REACTIONS OF COMPETITIVE NEUROMUSCULAR BLOCKERS

• Hypoxia and prolonged respiratory paralysis. Managed by artificial respiration, maintenance of patient’s airway and injection of neostigmine (1-3mg i.v) and atropine sulfate (0.6 mg i.v). Atropine is used to block the peripheral muscarinic actions of ACH e.g. bronchospasm and hypotension.

ADVERSE REACTIONS OF COMPETITIVE NEUROMUSCULAR BLOCKERS CONT..

• Bronchospasm due to histamine release as with tubocurarine.

• Hypotension due to autonomic ganglion blockage and histamine release. Less likely with the new compounds.

• Neuro muscular paralysis especially in children, myasthenia gravis and patients with hepatic and renal failure.

DRUG INTERACTIONS INVOLVING COMPETITIVE NEUROMUSCULAR BLOCKERS.

• Neuro muscular block and paralysis are potentiated by:

• Inhalation anaesthetics (ether, halothane, cyclopropane, enflurane.

• Lignocaine, quinidine, beta blockers, calcium channel blockers and lithium which inhibit ACH release or action.

DRUG INTERACTIONS INVOLVING COMPETITIVE NEUROMUSCULAR BLOCKERS. CONT..

• Antibiotics (aminoglycosides, clindamycin) which inhibit ACH release.

• Anticholinesterases reverse the action of competitive blockers. Neostigmine (0.5-2mg i.v) is routinely used after pancuronium and other long acting blockers to hasten recovery at end of operation.

SUMMARY OF ADVANTAGES OF NEW COMPETITIVE NEURO MUSCULAR BLOCKERS.

• No or minimal ganglionic, cardiac or vascular effects.

• No or minimal histamine release.

• Many are short acting and easy reversal

• Some are rapid acting: provide alternative to Succinyl choline without the attendant complications.

DEPOLARIZING BLOCKING AGENTS.

• The group is also referred to as persistent depolarizing agents and includes succinyl choline and decamethonium.

• Mechanism of action: the drugs cause persistent depolarization at the motor end plate and prevent any response due to acetyl choline combining with the nicotinic receptors at the motor end plate.

• Persistent depolarization means there is no resting phase of the action potential and hence no response to ACH.

• It is caused by sustained opening of sodium channels by the depolarizing neuro muscular blocker.

PHARMACOKINETICS OF DEPOLARIZING NEURO MUSCULAR BLOCKERS.

• Onset of action of succinyl choline is 1-1.5 minutes after IV injection ad duration of action is 3-6 minutes.

• It is rapidly hydrolyzed by plasma and tissue pseudo- CHE.

• Duration of action of succinyl choline is prolonged in patients withpseudo CHE deficiency or with atypical pseudo –CHE which may lead to respiratory paralysis or succinyl apnea.

• Decamethonium is not easily metabolized having longest duration of action, hence not used clinically.

PHARMACOLOGICAL EFFECTS OF SUCCINYL CHOLINE

• It causes transient fasciculation of groups of muscle fibres for 10-15 seconds followed by flaccid paralysis. This is called phase one block.

• In this depolarized state(phase), the block cannot be reversed by anticholinesterases like neostigmine or edrophonium.

• Paralysis of neck and limb muscles occurs before those of face and pharynx.

PHARMACOLOGICAL EFFECTS OF SUCCINYL CHOLINE CONT..

• With continued exposure to Succinyl choline, the initial depolarization decreases, the membrane is repolarized but now cannot be depolarized again as long as the succinyl choline is present in the receptor sites. This is called phase II or desensitization block, which can be antagonized by anti cholinesterases.

• Succinyl choline has muscarinic and ganglion stimulating actions but does not release histamine.

• It may cause bradycardia in therapeutic doses and tachycardia in larger doses. It may also cause cardiac arrhythmia (extra systole).

• Muscle power recovery occurs within minutes.

ADVERSE EFFECTS OF SUCCINYL CHOLINE.

• Muscle fasciculation and post-operative muscle pain are common and are due to depolarizing effect of the drug.

• Muscarinic effects are manifested as bradycardia, hypotension, salivation and increases gut motility.

• Raised intra ocular tension due to prolonged contraction of extra- ocular muscles and transient dilation of choroidal blood vessels. It may be dangerous in acute glaucoma.

ADVERSE EFFECTS OF SUCCINYL CHOLINE. CONT..

• Hyperkalemia may be due to persistent depolarization, especially in patients of deep burns and muscle damage. Cardiac arrhythmias and arrest can also be caused.

• Succinyl apneas in patients with atypical pseudo –CHE (genetic variant) which does not hydrolyze succinyl choline.

• Malignant hyperthermia, a rare congenital abnormality characterized by intense muscle spasm and sudden rise in body temperature. Treated with dantrolene.

DRUG INTERACTIONS INVOLVING SUCCINYL CHOLINE

• The action of Succinyl choline is potentiated by:

• Drugs which inhibit neuro muscular transmission-aminoglycosides, quinidine, calcium channel blockers, local anaesthetics and magnesium ions.

• Drugs which inhibit pseudo cholinesterase-anticholinesterases, MAOI and cytotoxic agents.

FACTORS TO BE CONSIDERED WHEN CHOOSING AN NMB.

• Neuromuscular blockers are used whenever relaxation of skeletal muscles is desirable.

• The following factors must be considered when selecting appropriate NMBs

• The duration of the surgical procedure: Succinyl choline (duration of action 3-6 mins) is employed for brief procedures e.g. endotracheal intubation, laryngoscopy, bronchoscopy, esaphogoscopy, reduction of fractures, dislocations and to treat laryngospasms.

• Onset of action of the NMB.• Cardiovascular effects of the drug.• Patient’s hepatic, renal and hemodynamic status.

THERAPEUTIC USES OF NMBs

• As an adjunct to general anaesthetics: For skeletal muscle relaxation, both non-depolarizing and depolarizing neuro muscular blockers are used clinically.

• For operations lasting more than 30 minutes e.g. intra-abdominal operations or orthopedic manouvres, d –tubocurarine is used for these reasons:

• It relaxes muscle tone• It reduces the dose of anaesthetic agents and the

post anaesthetic complications and keeps the blood pressure on the lower side.

• D- Tubocurarine has been largely replaced by synthetic derivatives which have fewer side effects (atracurium-duration 20-35 mins, pipecuronium 50-100 mins, vecuronium, 30-60 mins).

THERAPEUTIC USES OF NMBs CONT..

• b. In obstetric conditions- any of the non-depolarizing drugs (except gallamine) can be used.

• c. In selected cases of arterial surgery, pancuronium is used.

• d. For producing transient muscle relaxation as required in endotracheal intubation, bronchoscopy, direct laryngoscopy, esophagoscopy and electroconvulsive therapy (ECT).

• Succinyl choline is the drug of choice as the onset of action is immediate and recovery is within 5 minutes.

THERAPEUTIC USES OF NMBs CONT..

• The intravenous muscle relaxant doses in mg are: tubocurarine 10-15, gallamine1-2, pancuronium, 1-2, pancuronium1-2 and altracurium 0.5-1.

• 2. In the treatment of painful muscle spasm- as in tetanus, muscle relaxation is the key to therapy and mild sedation is also desirable.

• Diazepam i.v as a running drip is given in adults (60-240 mg /24 hours, in children (30-40 mg/24 hours) and in neonates (20-40mg/24 hours). Maintenance on intermittent positive pressure respiration is necessary.

THERAPEUTIC USES OF NMBs CONT..

• 3. In very small doses (1/10) atracurium may be used for diagnosis of myasthenia gravis.

• 4. Severe cases of status epilepticus which are not controlled by diazepam or other drugs may be paralyzed by an NMB (repeated doses of competitive blocker) and maintained on intermittent positive pressure respiration till the disease subsides.

INDIRECTLY ACTING MUSCLE RELAXANTS.• DANTROLENE.• It exerts a direct action on the skeletal

muscle by interfering with the release of calcium from the sarcoplasmic reticulum.

• It interfers with the excitation- contraction coupling

• Cardiac and smooth muscles are not affected by dantrolene as the mechanism of calcium entry is different in these tissues.

• It has no effect on CNS and neuro muscular junction.

PHARMACOKINETICS OF DANTROLENE

• It is absorbed after oral administration, but the absorption is slow and incomplete.

• It penetrates the brain and produces some sedation, but has no selective action on polysynaptic reflexes responsible for spasticity.

• It is metabolized in the liver and excreted by the kidneys with a half- life of 8-12 hours.

THERAPEUTIC USES OF DANTROLENE.

• 1. Neurological spastic disorders e.g. multiple sclerosis, cerebral palsy, spinal injury, hemiplegia and paraplegia.

• The initial oral dose is 25mg once a day which is gradually increased to 100mg QDS daily. The dose limiting toxicity is generalized muscle weakness.

• 2. Malignant hyperthermia following use of succinyl choline or halothane in genetically predisposed people.

• Dantrolene is given initially 1 mg /kg IV and repeated up to 100 mg/kg IV which is followed by 50-100mg QDS for 2-3 days.

ADVERSE EFFECTS OF DANTROLENE.

• Muscle weakness is the dose limiting toxicity.• Sedation, malaise lightheadedness and other

central effects occur, but are less pronounced than centrally acting muscle relaxants.

• Troublesome diarrhea.• Long term use cause dose dependent liver

toxicity in 0.1-0.5 % of patients. This has restrictedits use in chronic disorders.

QUININE.

• It increases refractory period and decreases excitability of motor end plates, thus reducing response to repetitive nerve stimulation.

• It reduces muscle tone in myotonia congenita.

• When taken at bedtime (200-300mg) it may abolish nocturnal leg cramps in some patients.

CENTRALLY ACTING MUSCLE RELAXANTS.

• These are drugs which reduce skeletal muscle tone by a selective action in the cerebrospinal axis, without altering consciousness.

• They selectively depress spinal and supra spinal poly synaptic reflexes involved in the regulation of muscle tone.

• Polysynaptic pathways in the ascending reticular formation which are involved in wakefulness are also depressed, though to a smaller extent.

CENTRALLY ACTING MUSCLE RELAXANTS. CONT..

• All centrally acting muscle relaxants cause sedation.

• They have no effect on neuro muscular transmission and on muscle fibres but reduce decelebrate rigidity, upper motor neuron spasticity and hyperreflexia.

• Note the differences between peripherally and centrally acting muscle relaxants in table 25.3.

CLASSIFICATION OF CENTRALLY ACTING MUSCLE RELAXANTS.

• Mephenesin congeners: Mephenesin, Carisoprodol, Chlozoxazone, Chlormezanone, Methocarbamol.

• Benzodiazepines: Diazepam. Trizolam and others.

• Gabba derivative: Baclofen

• Central α2agonist: Tizanidine

PROPERTIES OF CENTRALLY ACTING

• MUSCLE RELAXANTS.• MEPHENESIN• First drug to be discovered as a muscle

relaxant.• Modulates reflexes maintaining muscle

tone.• It is not used clinically because it causes

gastric irritation, and when administered IV it causes thrombophlebitis, hemolysis and marked fall in BP.

• CARIS0PRODOL.• Has favorable muscle relaxant, sedative,

analgesic antipyretic, and anticholinergic properties.

• It is used in musculo skeletal disorders associated with muscle spasm.

• CHLOZOXAZONE.• Pharmacologically similar to mephenesin, has a

longer duration of action and is better tolerated orally.

• CHLORMEZANONE.• Has anti- anxiety and hypnotic actions and is

used for tension states associated with increased muscle tone.

• METHOCARBAMOL.

• Less sedative and longer acting than mephenesin.

• Orally used in reflex muscle spasm and chronic neurological diseases.

• It can be given IV without producing thrombophlebitis and hemolysis-used for orthopedic procedures and tetanus.

DIAZEPAM.• A benzodiazepine (BDZ) which acts in the brain on

specific receptors, enhancing transmission by the inhibitory amino acid neurotransmitter GABA.

• Muscle tone is reduced by supraspinal rather than spinal action.

• It has more sedative activity than muscle relaxation and sedation limits the dose that can be used for muscle relaxation.

• Diazepam is particularly valuable in tetanus and spinal injuries.

• When combined with analgesics, it is useful for rheumatic disorders associated with muscle spasm.

• BACLOFEN.• Is a GABA B receptor agonist which depresses

both polysynaptic and monosynaptic reflexes in the spinal cord.

• It does not produce muscle weakness like diazepam because it does not affect chloride conductance.

• ( BDZs facilitates the effect of GABA on GABA A receptors increasing chloride conductance while baclofen acts on GABAB receptors, hyperpolarizing neurons by increasing K+ conductance and altering Ca2+ flux.).

BACLOFEN. CONT..

• It reduces spasticity in many neurological disorders like multiple sclerosis, spinal injuries and flexor spasms.

• It is relatively in effective in stroke, cerebral palsy, rheumatic and traumatic muscle spasms and Parkinsonism.

• TIZANIDINE.

• It is a new skeletal muscle relaxant which is a congener of clonidine.

• It is a central α2-adrenergic agonist which inhibits the release of excitatory amino acids e.g. aspartate in the spinal interneurons while facilitating the inhibitory amino acid neurotransmitter glycine.

TIZANIDINE. CONT..

• It inhibits polysynaptic reflexes; reduce muscle tone and frequency of muscle spasms without reducing muscle strength.

• Efficacy similar to baclofen and diazepam has been noted in multiple sclerosis, spinal injury and stroke with fewer side effects.

• It is well absorbed and is administered as tablets of 2 and 4 mg.

ADVERSE EFFECTS OF CENTRALLY ACTING MUSCLE RELAXANTS (CAMs)

• Gastric irritation except for diazepam. Baclofen and tizanidine.

• All CAMs cause drowsiness and sedation.

• Baclofen can cause tachycardia, hypotension and rarely visual and auditory hallucinations. It can also cause ataxia and elevation of serum transaminase.

ADVERSE EFFECTS OF CENTRALLY ACTING MUSCLE RELAXANTS (CAMs) CONT..

• Tizanidine may cause dry mouth, drowsiness, night time insomnia and hallucinations. Dose dependent elevation of liver enzymes has been noted.

• No consistent effect on BP has been noticed but should still be avoided in patients receiving anti hypertensives, especially clonidine.

END.DR. OCHOLA.F.O, DEPT OF PHARMACOLOGY AND

TOXICOLOGY- MOI UNIVERSITY, SCHOOL OF MEDICINE.