Skeletal Muscle Relaxants Dr. Rene Anand Reference: Bertram Katzung et al, "Basic and Clinical Pharmacology", 12th edition, McGraw-Hill Lange, Chapter 27 Dr. Rene Anand Reference: Bertram Katzung et al, "Basic and Clinical Pharmacology", 12th edition, McGraw-Hill Lange, Chapter 27

Learning Objectives Describe the pharmacological properties of drugs classified as relaxants Describe the transmission process at the skeletal neuromuscular end plate and the points at which drugs modify this process Identify the major non-depolarizing neuromuscular blockers and one depolarizing neuromuscular blocker, compare their pharmacokinetics Describe the differences between depolarizing and non-depolarizing blockers from the standpoint of tetanic and post-tetanic twitch strength Describe the reversal of non-depolarizing blockade List drugs for treatment of skeletal muscle spasticity and identify their sites of action and adverse effects

Skeletal Muscle Relaxants Skeletal muscle relaxants interfere with the contraction of skeletal muscles: Neuromuscular blockers are used to completely paralyze skeletal muscle during surgical and orthopedic procedures in the controlled environment of a hospital. Spasmolytics are used to elicit a more modulatory effect on muscle contraction and do not completely block the activity of the skeletal musculature. These agents are used to reduce muscle spasms and are commonly used in ambulatory patients.

Classification of Skeletal Muscle Relaxants Peripherally acting drugs Neuromuscular blocking drugs. Direct acting spasmolytic. Centrally acting spasmolytics.

I Summary of Neuromuscular Transmission An action potential depolarizes the nerve terminal and Ca2+ enters. ACh-containing vesicles fuse with the prejunctional membrane releasing the ACh by exocytosis into the junctional space. The released ACh diffuses across the synaptic gap and binds to nicotinic (Nm) receptors leading to depolarization of the muscle end-plate region. The nicotinic receptor is a complex of 5 protein subunits. There are 2 a subunits, and one each of b, g and d subunits in embryonic muscle. In the adult d is replaced by an e subunit. When one molecule of ACh binds to each of the a subunits there is an increase of the fluxes of Na+ in, Ca2+ in, and K+ out. An action potential depolarizes the nerve terminal and Ca2+ enters. ACh-containing vesicles fuse with the prejunctional membrane releasing the ACh by exocytosis into the junctional space. The released ACh diffuses across the synaptic gap and binds to nicotinic (Nm) receptors leading to depolarization of the muscle end-plate region. The nicotinic receptor is a complex of 5 protein subunits. There are 2 a subunits, and one each of b, g and d subunits in embryonic muscle. In the adult d is replaced by an e subunit. When one molecule of ACh binds to each of the a subunits there is an increase of the fluxes of Na+ in, Ca2+ in, and K+ out.

II Summary of Neuromuscular Transmission There is propagation of a muscle action potential through the conducting system of the myofibrils, with release of Ca2+ from the sarcoplasmic reticulum. This triggers off the troponin-actin-myosin interaction and muscle contraction. Relaxation is associated with restorage of Ca2+ in the sarcoplasmic reticulum which is driven by energy supplied by an ATPase. There is a refractory period until repolarization of the muscle end-plate. ACh is inactivated by ACh esterase (AChE).

Quick Review: Model of Nicotinic Receptor

Quick Review Quick Review

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Peripherally acting drugs Neuromuscular Blocking Drugs Chemically most are bisquaternary ammonium compounds Interaction with the acetylcholine (ACh) receptor appears to be one to one but the exact nature is unknown. It is speculated that the charged compounds span and bind to the nicotinic (Nm) receptor and prevent ACh from reaching it. - - -N+______________N+- - - + Pancuronium

Characteristics of quaternary compounds considering their positive charge Poorly absorbed from the gut and generally rapidly excreted Will not cross the blood-brain barrier Will not cross the placenta Administered IV

Indications for Neuromuscular Blocking Drugs Adjunct for surgery to reduce muscle tone and fasciculation at the site of surgery (permit tracheal intubation). Electroshock therapy for psychiatric disorders (prevent bone breakage). Control convulsive disorders (status epilepticus, tetanus, eclampsia and toxic reactions to local anesthetics). Control respiration when the patient is unable to ventilate. Adjunct for surgery to reduce muscle tone and fasciculation at the site of surgery (permit tracheal intubation). Electroshock therapy for psychiatric disorders (prevent bone breakage). Control convulsive disorders (status epilepticus, tetanus, eclampsia and toxic reactions to local anesthetics). Control respiration when the patient is unable to ventilate.

Classification of Neuromuscular Blocking Drugs Nondepolarizing Blocking Drugs (competitive, stabilizing, or antidepolarizing drugs). Depolarizing Blocking Drugs.

1. Nondepolarizing Blocking Drugs Block neuromuscular junction nicotinic receptors competitively. They compete for the receptor with ACh.

I Classification of some neuromuscular blocking agents based on duration of action Drug Effect on Autonomic Ganglia Effect on Histamine Release Effect on Cardiac Muscarinic Receptors Nondepolarizing Drugs Long-acting (>35 min) Pancuronium Intermediate-Acting (20-35 Min) Vecuronium Atracurium Rocuronium Cisatracuium None Slight Moderate Blockade (-ium)

Nondepolarizing Blocking Drugs Because they are competitive blockers their action can be reversed by increasing the concentration of endogenous ACh at the NMJ. Use ChE inhibitors such as neostigmine, physostigmine, edrophonium together with atropine to protect muscarinic receptors against excessive stimulation by increased levels of ACh.

II Classification of some neuromuscular blocking agents based on duration of action Drug Effect on Autonomic Ganglia Effect on Histamine Release Effect on Cardiac Muscarinic Receptors Depolarizing Drugs Short-Acting (5-15 min) Succinylcholine Stimulation Slight Succinylcholine (Anectine®) structurally looks like two molecules of ACh end-to-end. It is a relatively short duration (5-15 min) ACh-like agonist at nicotinic receptors.

Progression of pharmacological response to succinylcholine Initial depolarization of the end-plate region. Transient muscle fasciculation followed by relaxation. Phase 1 Block. Desensitization of the receptor to ACh. End-plate repolarization possibly do to conformational change of the receptor molecule. Phase 2 Block. Note. Cholinesterase inhibitors will intensify the response to succinylcholine during Phase 1 block. They may reinitiate muscle contraction if administered during late Phase 2 block.

Metabolism of succinylcholine ACh (CH3)3-N-CH2-CH2-O-OC-CH3 Succinylcholine (CH3)3-N-CH2-CH2-O-OC-CH2-CH2-CO-O-CH2-CH2-N-(CH3)3 plasma ChE  succinylmonocholine 1/2 activity succinic acid + choline Note. ACh metabolism takes place primarily in the NMJ, while succinylcholine metabolism takes place in the plasma + + +

Plasma ChE Plasma ChE is synthesized in the liver and therefore patients with liver dysfunction, decreased hepatic blood flow or genetic abnormalities would show prolonged responses to succinylcholine. Neonates have low plasma ChE. A clinical dose of 1-2 mg/kg usually lasts <15 min while an atypical patient may respond for >2 hr. About 1:3000 patients have a genetic related decrease of plasma ChE. Treatment- mechanical respiration

I Adverse Effects of neuromuscular blocking drugs Do not enter brain - CNS fully functional, pain is not dulled. Depolarizing Drug (Succinylcholine) Fasciculation can result in: Post operative muscle stiffness and pain. Increase of intraocular pressure-contraction of the extraocular muscles. Increased intragastric pressure – occasionally leading to emesis. Hyperkalemia – in some patients especially with burns, nerve damage, closed head injury, renal failure.

II Adverse Effects of neuromuscular blocking drugs Nondepolarizing Drugs Atracurium (occasionally succinylcholine) Release of endogenous histamine into the circulation- bronchospasm, increased excretions, vasodilation resulting in decreased blood pressure. Treatment - antihistamines Pharmacological response Potentiated by: Some general anesthetics (methoxyflurane) and local anesthetics. Antibiotics (aminoglycosides; neomycin and streptomycin have a tendency to inhibit Ca2+ fluxes). Fluid and electrolyte imbalance.

Direct-Acting (myotropic) Spasmolytics Dantroline Interferes with release of Ca2+ from the sarcoplasmic reticulum which is required for muscle contraction. Indications Chronic disorders characterized by muscle spasms. Spinal cord injury Stroke Cerebral palsy Multiple sclerosis ( Potential toxicity: Hepatotoxicity) Malignant Hyperthermia: Genetic disorder, autosomal dominant. Triggered by halogenated anesthetic and/or succinylcholine. Sudden rise of Ca2+ in muscle fiber with increase of body temperature, rigidity.- 50% mortality. Dantroline: Interferes with release of Ca2+ from the sarcoplasmic reticulum which is required for muscle contraction. Indications Chronic disorders characterized by muscle spasms. Spinal cord injury Stroke Cerebral palsy Multiple sclerosis ( Potential toxicity: Hepatotoxicity) Malignant Hyperthermia: Genetic disorder, autosomal dominant. Triggered by halogenated anesthetic and/or succinylcholine. Sudden rise of Ca2+ in muscle fiber with increase of body temperature, rigidity.- 50% mortality.

I Centrally Acting Spasmolytics Antispastic action Exerted mainly on the spinal cord by inhibiting mono- and poly-synaptic activation of motor neurons. Baclofen. GABAB receptor agonist. Activates GABAB receptors on nerve endings that release excitatory neurotransmitters and prevents the release of the excitatory neurotransmitters (glutamate) onto motor neurons. Diazepam. Belongs to the benzodiazepine class of drugs. Enhances the actions of the inhibitor neurotransmitter GABA in the spinal cord. Indications: Chronic disorders characterized by muscle spasticity. spinal cord injury stroke cerebral palsy multiple sclerosis Side effects: Sedation and drowsiness

II Centrally Acting Spasmolytics Tizanidine. Mechanism of action is unclear. Derivative of clonidine and has significant α2- adrenoceptive agonist activity. Appears to reinforce pre- and postsynaptic inhibition in the cord. Also inhibits nociceptive transmission in the cord. Indications: Chronic disorders characterized by muscle spasticity. Side effects: Sedation, drowsiness, hypotension, dry mouth, and asthenia.

I Drugs used for acute local muscle spasm There are a large number of sedative drugs that are promoted for the relief of acute temporary muscle spasm caused by local trauma or strain. The drugs include: Carisoprodol Chlorzoxazone Cyclobenzaprine Metaxalone Orphenadrine Side effects: Most are sedative hypnotics and some have antimuscarininc activity. There are a large number of sedative drugs that are promoted for the relief of acute temporary muscle spasm caused by local trauma or strain. The drugs include: Carisoprodol Chlorzoxazone Cyclobenzaprine Metaxalone Orphenadrine Side effects: Most are sedative hypnotics and some have antimuscarininc activity.

II Drugs used for acute local muscle spasm Botulinum Toxin Inhibits the release of ACh from cholinergic nerve terminals. Local injection is finding increasing use in the treatment of spastic disorders due to neurologic injury. Benefits may persist for weeks after a single injection. Potential toxicity May spread beyond injection site and lead to difficulty swallowing and breathing. Botulinum Toxin. Inhibits the release of ACh from cholinergic nerve terminals. Local injection is finding increasing use in the treatment of spastic disorders due to neurologic injury. Benefits may persist for weeks after a single injection. Potential toxicity: May spread beyond injection site and lead to difficulty swallowing and breathing.

Botulinum Toxin (Types A-G). The heavy chain is similar for all types, the light chains differ.

Botox approved to treat: Strabismus (Cross-eyes) Uncontrollable blinking Cervical dystonia (a neurological disorder that causes severe neck and shoulder contractions) Moderate to severe frown lines between eyebrows Unintended consequence: Appears to be effective for the treatment of some forms of headache

Muscle Relaxants Quiz

Summary of Key Points to Remember Two therapeutic groups of muscle relaxants: Neuromuscular blockers (nondepolarizing and depolarizing) - Act on nicotinic acetylcholine receptors at neuromuscular junction - Used in surgical relaxation, endotracheal intubation, control of ventilation and treatment of convulsions B. Spasmolytics (typically act on targets in the spinal chord) - Used to treat spasticity associated cerebral palsy, multiple sclerosis, and stroke

Thank you for completing this module Email: Anand.20@osu.edu Reference: Bertram Katzung et al, "Basic and Clinical Pharmacology", 12th edition, McGraw-Hill Lange, Chapter 27

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