Skeletal muscle relaxants

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Skeletal muscle relaxants

  1. 1. Skeletal muscle relaxants
  2. 2. Types of skeletal muscle relaxants: 2 groups Neuromuscular blockers • • • • Relax normal muscles (surgery and assistance of ventilation) Interfere with transmission at the motor end plate No central nervous system activity. Used primarily as a part of general anesthesia Spasmolytics • • • Reduce spasticity Centrally acting (except dantrolene which act on the skeletal muscle) Used in a variety of neurologic conditions
  3. 3. Neuromuscular Blocking Drugs 1- Transmission at the neuromuscular junction 1) Motor neuron depolarization causes action potential to travel down the nerve fiber to the neuromuscular junction. 2) Depolarization of the axon terminal causes an influx of Ca 2+ 3) Calcium influx triggers fusion of the synaptic vesicles with the membrane of the neuron 4) Release of neurotransmitter (Acetylcholine; ACh) 5) ACh diffuses across the synaptic cleft and binds to post-synaptic nicotinic receptor (NM) located on the muscle fiber at the motor end-plate . Binding of 2 molecules of ACh to the receptor opens the membrane channels causing an influx of Na and outflux of K leading to depolarization of the end plate membrane. This change in voltage is termed the motor end plate potential. If the potential is small, the permeability and the end plate potential return to normal without an impulse being propagated from the end plate region to the rest of the muscle membrane.
  4. 4. 6) If the end plate potential is large, the adjacent muscle membrane is depolarized, and an action potential will be propagated along the entire muscle fiber and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum causing CONTRACTION. 7) Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE).
  5. 5. The depolarization-repolarization cycle of the motor end-plate and muscle membrane.
  6. 6. Neuromuscular blockers Definition: Drugs which relax skeletal muscles by acting at the neuromuscular junction. o All of the available neuromuscular blocking drugs are similar in structure to acetylcholine (e.g., succinylcholine is two acetylcholine molecules linked endto-end) o All have one or two quaternary nitrogens, which makes them poorly lipidsoluble (not absorbed orally, must be given parenterally and have limited entry into the CNS). Types: 1- Antagonist (nondepolarizing) neuromuscular blocking drugs prevent access of acetylcholine to its NM receptor and prevent depolarization of the motor end plate (d-tubocurarine) 2- Agonist (depolarizing) neuromuscular blocking drugs produce excessive depolarization of the motor end plate by causing excessive stimulation of the NM receptor (Succinylcholine)
  7. 7. Non-depolarizing neuromuscular blockers (prototype is tubocurarine) Duration Short acting (10-20 min) Drug Elimination 1. Mivacurium (moderate histamine release) Plasma Ch E -Duration prolonged in impaired renal function ( Ch –E) Spontaneous Intermediate acting (20-35 min) 1. Atracurium (slight histamine release) Rocuronium -Metabolite crosses blood-brain barrier and may cause seizures Mainly liver -onset of action after 60-120 seconds Long acting (> 35 min) 1. Pancuronium 2. Pipecuronium Mainly kidney
  8. 8. Depolarizing neuromuscular blockers Drug Succinylcholine Duration 5-10 min Elimination  Plasma Ch E (metabolizes succinylcholine more rapid than mivacurium).  Only a small amount reaches the neuro-muscular junction  Succinylcholine – induced blockade of the neuromuscular junction is terminated by diffusion (!)
  9. 9. Mechanism of action of non-depolarizing neuromuscular blockers Normal transmission Low doses: •competitive antagonist of Ach •Action reversed by Ach esterase inhibitors 1- resting 2- active ACh Non depolarizing neuromuscular blockade Na Ca ACh Large doses: •Ion channel is blocked •More weakness of neuromuscular transmission •Action could not be reversed by Ach esterase inhibitors K Other actions: Can block pre-junctional sodium channels and interfere with mobilization of Ach at nerve endings
  10. 10. Mechanism of action of depolarizing neuromuscular blockers Phase I block: Succinylcholine causes opening of the channels by : 1- reacting with the nicotinic receptors (NM) 2- Entering the channel and increasing ionic conductance This causes depolarization of the motor end plate which causes contraction. Because succinylcholine is not metabolized at the synapse, depolarization persists and the depolarized membranes remain unresponsive to subsequent impulses Phase II block (desensitization): With continued exposure to succinylcholine, the membrane becomes depolarized and cannot be repolarized again (desensitized)
  11. 11. Neuromuscular block Non-depolarizing Depolarizing Action motor weakness, followed by skeletal muscle flaccidity and inexcitability to electrical stimulation fasciculations especially over the chest and abdomen followed by complete paralysis Order of muscle involvement 1- smaller muscles (eg, facial, foot, hand) 2- larger muscles (eg, abdominal, trunk) 3- diaphragm 1- arm, neck, and leg muscles 2- facial and pharyngeal muscles. 3- respiratory muscle weakness follows rapidly, usually within 60 seconds Recovery in reverse order, with the diaphragm regaining function firs in reverse order
  12. 12. Adverse effects Non-depolarizing Depolarizing (succinylcholine) Histamine release (hypotension and bronchospasm) Slight: atracurium Moderate: mivacurium Slight Other cholinergic receptors Pancuronium: moderate increase in heart rate (inhibit vagus) Small doses: negative inotropic and chronotropic actions (prevented by atropine) due to: 1- Stimulation of NN receptors at sympathetic and parasympathetic ganglia 2- Stimulates M2 receptors in heart Large doses cause positive inotropic and chronotropic actions
  13. 13. Other adverse effects of succinylcholine Effect Cause Cardiac arrest Hyperkalemia due to release of K to blood in cases of burns and trauma increased intraocular pressure contraction of myofibrils or dilation of choroidal blood vessel Increased Intragastric Muscle fasciculations Pressure (causing emesis) Muscle Pain Malignant hyperthermia unsynchronized contractions of adjacent muscle fibers just before the onset of paralysis.
  14. 14. Reversal of neuromuscular blockade Nondepolarising cholinesterase inhibitors as neostigmine and pyridostigmine by: 1- increasing the availability of acetylcholine at the motor end plate 2- to a lesser extent, neostigmine and pyridostigmine increase release of transmitter from the motor nerve terminal. Depolarizing (succinylcholine) Plasma
  15. 15. Interactions with other drugs • Inhaled anesthetics: augment the neuromuscular blockade produced by nondepolarizing muscle relaxants because 1) CNS depression 2) peripheral vasodilatation which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction 3) decreased sensitivity of the postjunctional membrane to depolarization.
  16. 16. • Aminoglycosides: augment the neuromuscular blockade produced by nondepolarizing muscle relaxants by decreasing release of Ach • Local Anesthetics enhance the neuromuscular block produced by both nondepolarizing and depolarizing
  17. 17. Indications 1. 2. 3. Muscle relaxation during surgery Control of ventilation in critically ill patients with ventilatory failure Treatment of Convulsions
  18. 18. Spasmolytic drugs Definition of muscle spasm (spasticity): 1. Increased muscle tone 2. together with muscle weakness It is often associated with cerebral palsy, multiple sclerosis, and stroke.
  19. 19. Centrally acting spasmolytic drugs Drug Mechanism 1- Diazepam GABA receptor 2- Baclophen GABA receptors causing hyperpolarization by increasing potassium conductance Averse effects: drowsiness and increased seizure activity 3- Tizanidine α2 adrenoreceptor agonist 4- Gabapentin
  20. 20. Peripheraly acting spasmolytic drugs Dantrolene: MOA: Dantrolene reduces skeletal muscle strength by interfering with excitationcontraction coupling in the muscle fibers Normal contraction involves release of calcium from its stores in the sarcoplasmic reticulum through a calcium channel • Dantrolene interferes with the release of calcium through this sarcoplasmic reticulum calcium channel. • Cardiac muscle and smooth muscle are depressed only slightly, perhaps because the release of calcium from their sarcoplasmic reticulum involves a different process.
  21. 21. Indications: 1- Muscle spasticity 2- Malignant hyperthermia: o Patients at risk for this condition have a hereditary impairment in the ability of the sarcoplasmic reticulum to sequester calcium. o Following administration of one of the triggering agents (general anesthetics or succinylcholine) there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid production, and increased body temperature. Treatment of malignant hyperthermia: 1. control acidosis and body temperature 2. Reduce calcium release with intravenous dantrolene

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