SKELETAL MUSCLE RELAXANTS These drugs help patients with

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SKELETAL MUSCLE RELAXANTS

SKELETAL MUSCLE RELAXANTS

These drugs help patients with : A. Skeletal muscle spasm : due to local

These drugs help patients with : A. Skeletal muscle spasm : due to local trauma or nerve root irritation e. g. prolapsed intervertebral disk B. Spasticity : Spasticity is due to excessive afferent stimulation of spinal alpha-motor neurons cells (located in anterior horn) whose axons innervate skeletal muscles leading to hypertonicity. It is usually more evident in anti-gravity muscles. It occurs in upper motor neuron lesion ( UMNL) such as strokes , cerebral palsy , multiple sclerosis and spinal cord lesions.

Spasticity , when severe , may be accompanied by painful spasm , esp. of

Spasticity , when severe , may be accompanied by painful spasm , esp. of flexor muscles of lower limbs. Drugs relieve spasticity by decreasing excess afferent stimulation of spinal motoneurons

Skeletal muscle relaxants that are used clinically : I. Centrally-acting skeletal muscle relaxants :

Skeletal muscle relaxants that are used clinically : I. Centrally-acting skeletal muscle relaxants : These drugs do not interfere with voluntary power A. Drugs acting mainly on spinal cord : 1. Baclofen : It acts as agonist on presynaptic GABA -B receptors in spinal cord causing decrease calcium ion conductance in axon terminals of primary afferent neurons , so decreases release of excitatory neurotransmitters like glutamate, thus leading to presynaptic inhibition of spinal motoneurons.

It is effective orally for spasticity. It is also effective in reducing the flexor

It is effective orally for spasticity. It is also effective in reducing the flexor spasms that accompanies spasticity due to multiple sclerosis and spinal cord lesions. It also decreases pain transmission in spinal cord by decrease release of substance P from nerve ending of primary afferent sensory neurons. Due to this action, it is sometimes used for trigeminal neuralgia. S. E. s. are : Drowsiness , hypotension (occurs with overdose), and seizures.

2. Diazepam : reduce skeletal muscle spasm and spasticity by its sedative action and

2. Diazepam : reduce skeletal muscle spasm and spasticity by its sedative action and by enhancing polysynaptic and presynaptic inhibition on the spinal motoneurons. It is useful for : A. Spasticity : diazepam is less effective than baclofen in relieving flexor spasms that can accompany spasticity. B. Skeletal muscle spasm due to local trauma or disc prolapse: more commonly used than baclofen S. Es : dose-dependent sedation 3. Tizanidine : central alpha 2 - agonist; it also relieves spasticity and decreases pain transmission in spina cord. S. E. : include hypotension, sedation.

B. Drugs acting on brain stem : These include : Carisoprodol, Cyclobenzaprine, Orphenadrine These

B. Drugs acting on brain stem : These include : Carisoprodol, Cyclobenzaprine, Orphenadrine These reduce skeletal muscle spasm due to local trauma or strain. They are not effective for spasticity. All are effective orally ; orphenadrine is also useful by injection IM or IV. S. Es : antimuscarinic for cyclobenzaprine and orphenadrine causing sedation, dry mouth.

II. Peripheral-acting skeletal muscle relaxants 1. Botulinum toxin ( type A) : It is

II. Peripheral-acting skeletal muscle relaxants 1. Botulinum toxin ( type A) : It is taken actively and selectively by cholinergic nerve endings of motor nerve fibers leading to inhibition of release of acetylcholine from their nerve endings at NMJ , thus causing relaxation of skeletal muscle or flaccid paralysis This toxin is injected locally for relief of spasmodic torticollis and blepharospasm; it is also useful to decrease spasticity following strokes. Its effect is reversible , persisting for few months

2. Dantrolene : acts on skeletal muscle fibers directly to decrease Ca++ ion release

2. Dantrolene : acts on skeletal muscle fibers directly to decrease Ca++ ion release from sarcoplasmic reticulum, so decreases muscle tension, spasm, and muscle power. It is also first choice drug IV to relax skeletal muscles in malignant hyperthemia. It may also be used for spasticity due to stroke e. g. hemiplegia ; here it is given orally It is eliminated by liver. S. E. : skeletal muscle weakness, hepatotoxicity

3. Stabilizers of skeletal muscle membrane : e. g. quinine, procainamide These are clinically

3. Stabilizers of skeletal muscle membrane : e. g. quinine, procainamide These are clinically useful orally for myotonia , enhancing skeletal muscle relaxation Myotonia congenita : is a hereditary disorder where delayed relaxation occurs following a muscle contraction. The skeletal muscle membrane is hyperexcitable and becomes stimulated by prolonged after-potential due to excess K+ ion extracellularly and decreased Cl- ion conductance

BLOCKERS OF THE NEUROMUSCULAR JUNCTION

BLOCKERS OF THE NEUROMUSCULAR JUNCTION

BLOCKERS OF NEUROMUSCULAR JUNCTION These drugs act by blocking the nicotinic receptors Nm located

BLOCKERS OF NEUROMUSCULAR JUNCTION These drugs act by blocking the nicotinic receptors Nm located on the motor end-plate at the neuro-muscular junction (NMJ). They are of 2 types : A. Competitive non-depolarizing or hyperpolarizing NMJ blockers : These compete with Acetylcholine for the Nm receptors on the motor end-plate, thus prevent released Ach. from binding to these receptor. This leads quickly to flaccid muscle paralysis after their IV use. They are quaternary ammonium compounds which makes them not effective orally and also poorly pass blood-brain-barrier to enter brain.

The first one used was d-tubocurarine (Curare) : an alkaloid from plant Chenodendum venenosum

The first one used was d-tubocurarine (Curare) : an alkaloid from plant Chenodendum venenosum ; it was used as arrow poison by African natives and Red Indians to produce death by paralysis. Paralysis begins in small muscles (e. g. eyelids , face) then proceeds to neck muscles , then to larger muscles of trunk and limbs, and finally the diaphragm. Recovery begins in reverse order : diaphragm recovers first, followed by limbs , trunk, neck , and finally small muscles. The drug is equally eliminated by liver and kidney; its duration of action is long , from 40 -60 min

Uses of d-tubocurarine (Curare) : 1. With general anaesthesia for major surgery in order

Uses of d-tubocurarine (Curare) : 1. With general anaesthesia for major surgery in order to produce skeletal muscle relaxation of long duration during surgery. When used for this purpose , measures for endotracheal intubation and assisted ventilation are employed to maintain ventilation of lung during surgery. 2. Severe tetanus : when persistant respiratory muscle spasm threatens life 3. Assisted ventilation in ICUs : to relax the respiratory muscle , and thus we get less resistance to flow of air pumped by ventilation machine

Its adverse effects include : 1. Hypotension : due to some block of autonomic

Its adverse effects include : 1. Hypotension : due to some block of autonomic ganglia and release of histamine from mast cells 2. Bronchospasm : due to effect of released histamine on bronchial smooth muscle 3. In overdose : persistent apnoea results due to prolonged respiratory muscle paralysis :

This apnea is managed by : assisted ventilation, oxygen administration, and Neostigmine IV which

This apnea is managed by : assisted ventilation, oxygen administration, and Neostigmine IV which is specific antidote. Neostigmine acts by inhibiting Ch. E leading to accumulation of Ach which competes with and displaces d-tubocurarine from Nm receptors , thus it restores skeletal muscle tone and contraction

Because of these side effects, safer curare-like drugs were developed, and are used much

Because of these side effects, safer curare-like drugs were developed, and are used much more frequently at present than d-tubocurarine. The main curare-like drugs include : 1. Metocurine : this is about 6 times more potent than d-tubocurarine 2. Pancuronium : This is long acting similar to d-tubocurarine , but it is more potent , and does not block autonomic ganglia or releases histamine from mast cells. But it can cause tachycardia due to selective cardiac anti-muscarinic action. It is mainly eliminated by kidney (about 80%)

3. Vecuronium : This is shorter acting for about 20 -30 min. No significant

3. Vecuronium : This is shorter acting for about 20 -30 min. No significant side effects occur with its use. It is mainly eliminated by liver (about 80%) 4. Mivacurium : This is short acting for about 10 -15 min due to its inactivation by plasma Ch. E 5. Atracurium : This undergoes spontaneous hydrolysis in plasma. One of its metabolites can enter brain to increase epileptic activity. Atracurium can release histamine from mast cells

Drug interactions of competitive NMJ blockers : The effect of these drugs is increased

Drug interactions of competitive NMJ blockers : The effect of these drugs is increased by : 1. General anaesthetic vapours 2. Local anaesthetics 3. Class I Anti-arrhythmic drugs : e. g. quinidine 4. Antimicrobials like Aminoglycoside (e. g. streptomycin, gentamicin) Note : The effect of d-tubocurarine and curare-like drugs eliminated by kidney is also enhanced in renal failure, and in myasthenia gravis

B. Non-competitive or depolarizing NMJ blocker : This is represented by the synthetic drug

B. Non-competitive or depolarizing NMJ blocker : This is represented by the synthetic drug succinylcholine (suxamethonium) It is quaternary , and is given IV producing quick muscle fasciculation followed by flaccid paralysis of short duration (5 -7 min). About 95% of succinylcholine in plasma is destroyed by plasma Ch. E ; the remaining 5 % of drug reaches the NMJ to produce paralysis Succinylcholine , like Ach , combines with Nm receptors at motor end-plate but produce disorganized persistent depolarization of end plates of skeletal muscle fiber membranes leading to irregular fasciculation of muscle.

Persistant depolarization of end-plates leads to failure of resumption of normal contraction, thus muscle

Persistant depolarization of end-plates leads to failure of resumption of normal contraction, thus muscle tone disappears and flaccid paralysis quickly occurs (phase I block) This block is made worse by Neostigmine. Note : Curare-like drugs are pharmacological antagonists to succinylcholine but are not clinically useful for this purpose since they also result in paralysis. Patient with myasthenia gravis show resistance to paralysis by succinylcholine

Rarely , repeated IV use of succinylcholine results in repolarization of end-plate leading to

Rarely , repeated IV use of succinylcholine results in repolarization of end-plate leading to dual block (sometimes called phase II block) which is reversed by neostigmine Uses of succinylcholine : To produce skeletal muscle paralysis of short duration for the following : a. Endotracheal intubation before surgery b. Electro-convulsive therapy c. Status epilepticus

Adverse effects : 1. Post-operative skeletal muscle pain : This occur in 2 -20%

Adverse effects : 1. Post-operative skeletal muscle pain : This occur in 2 -20% of cases. It is due to injury of skeletal muscle fibers by the disorganized muscle fasciculation 2. Hyperkalemia : may occur , and is due to release of K+ ions from injured muscle fibers. Hyperkalemia may be severe enough to cause cardiac arrest esp. in children or in burn cases

3. Rare genetic side effects include : A. Malignant hyperthermia : Following use of

3. Rare genetic side effects include : A. Malignant hyperthermia : Following use of succinylcholine, patient develops rigidity of muscles, hyperthermia, metabolic acidosis, with high risk of death. It is due to genetic defect interfering with sequestration of Ca++ ions back into sarcoplasmic reticulum after its release by fasciculation. It is treated in ICU by assisted ventilation and : a. Dantrolene IV b. Cold sponging for hyperthermia c. Sodium bicarbonate IV for the acidosis

B. Apnoea of long duration : This occurs rarely in patients with genetic defect

B. Apnoea of long duration : This occurs rarely in patients with genetic defect in plasma Ch. E which becomes either deficient in amount or is not effective in destroying succinylcholine. In either case, the effect of succinycholine becomes excessive and prolonged leading to prolonged apnoea. This case is treated in ICU by : a. Assisted ventilation and giving oxygen b. Transfusion of fresh normal blood or plasma which contains adequate levels of effective normal Ch. E enzyme

D-tubocurarine & similar drugs Succinylcholine Phase I Hyperpolarized Persistent depolarization Fasciculation Absent Initially present

D-tubocurarine & similar drugs Succinylcholine Phase I Hyperpolarized Persistent depolarization Fasciculation Absent Initially present Paralysis Flaccid Effect of Neostigmine Antagonistic Augmented (made worse) Effect of tetanic stimulation Fade (not sustained) Sustained but depressed Post-tetanic potentiation Present Absent Longer, depending on drug used Short 5 -7 min End-plate Duration