Muscle Relaxants BPS 337 PDF

Muscle Relaxants BPS 337 12/04/2023 Richard T. Clements Muscle Relaxants Drugs that affect skeletal muscle function fall into two groups: (a) Neuromuscular blockers (NMJ)- used in intensive care units to cause paralysis and as an adjunctive to anes...

Muscle Relaxants BPS 337 12/04/2023 Richard T. Clements Muscle Relaxants Drugs that affect skeletal muscle function fall into two groups: (a) Neuromuscular blockers (NMJ)- used in intensive care units to cause paralysis and as an adjunctive to anesthesia (b) Spasmolytics- used to reduce spasticity in a variety of neurologic disorders Neuro- muscular Junction (NMJ) The nicotinic receptor in muscle tissue is different from the neuronal nicotinic receptor NMJ Nicotinic receptor  NMJ Nicotinic receptor The difference in subunit composition between the NMJ nicotinic receptor and the neuronal nicotinic receptor provides for differential specificity to agonists and antagonist when compared to the neuronal nicotinic receptor. NMJ nicotinic agonists include acetylcholine and succinylcholine. NMJ nicotinic antagonists include α-bungarotoxin and d-tubocurarine. Stimulation of the receptor causes an excitatory postsynaptic potential (EPSP) which involves opening the AchR receptor channel to Na+ and Ca+ + ions NMJ Blockers They are used for: relax skeletal muscles during surgery reduce the intensity of muscle spasms in electrically-induced convulsions manage patients who are fighting mechanical ventilation  NMJ Blockers Nondepolarizing agents- curare alkaloids such as tubocurarine, pancuronium bromide, pipecuronium, and vecuronium. Block neurotransmitter action of acetylcholine. Anesthesia is induced before neuromuscular blockade is started. Depolarizing agents (succinylcholine) cause excessive depolarization which desensitizes muscles and renders them unresponsive Neither cross the blood–brain barrier and have no action on the CNS. The first NMJ blocking agent was D- Tubocurarine Uses of Neuromuscular Blocking Agents  Facilitate intubation  Surgery  Enhanced ventilator synchrony  Reduce intracranial pressure (ICP)  Reduce oxygen consumption  Terminate status epilepticus and tetanus  Neuromuscular Blocking Agents (NMBA’s) Depolarizing Non-depolarizing Competitive antagonists of ACh at the Depolarizes the nicotinic postsynaptic nicotinic receptors on receptor of the skeletal the skeletal muscle fibers muscle fiber similar to Acetylcholine (2) groups: Succinylcholine Benzylisoquinoloniums: The only depolarizing Atracurium agent being used in clinical Cisatracurium practice Mivacurium Rapid onset, rapid elimination Aminosteroidals: Malignant hyperthermia Pancuronium trigger, hyperkalemia, Vecuronium increase in ICP Rocuronium Depolarizing NMJ blocker Succinylcholine consists of two molecules of joined Ach. Short half life-metabolized by plasma cholinesterase. Hyperkalemia is an issue.- K+ is lost from skeletal muscle into the blood. For this reason, succinylcholine is considered contraindicated in the routine management of children and adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with undiagnosed myopathies.  Phases of Depolarizing NMBA’s Phase I: Membrane is depolarized by opening the ACh channels causing a brief period of fasciculation (brief spontaneous muscle contraction) Phase II: End plate eventually repolarizes, however succinylcholine is not metabolized like ACh, it continues to occupy the ACh receptor to “desensitize” the end plate Non-depolarizing NMJ Blockers Competitive antagonists of AchR on skeletal muscle. These have longer half-lives than succinylcholine and take longer for their onset of action. Rocuronium (0.9-1.2 mg/kg) has an onset of action that approaches succinylcholine (60-90 s), making it a suitable alternative for rapid-sequence inductions Metabolism and excretion can be an issue with some compounds leading to longer half-life Effects can be reversed by administration of Ach cholinesterase inhibitors… Structures of various NMBA’s Types of Neuromuscular Blocking Agents Duration of Action  Non-depolarizing drugs PK Must be given parenterally Metabolized in the liver and excreted by the kidneys Mivacurium is metabolized by pseudo cholinesterase Atracurium is broken down spontaneously by a Hoffman elimination reaction  atracurium may be used in organ failure Drug that potentiate non- depolarizing neuromuscular blocking agents Corticosteroids Aminoglycoside antibiotics Tetracycline Calcium channel blockers Class IA antiarrhythmic drugs Furosemide Cholinesterases degrade Ach  Reversal of NMJ Blockade With succinylcholine just wait- rapidly metabolized Non-depolarizing NMBs may be partially reversed with cholinesterase inhibitors such as neostigmine, physostigmine, pyridostigmine, and edrophonium Sugammadex is an alternative: a cyclodextrin that chelates the aminosteroidals Sugamaddex mechanism continued  Summary / Things to know Understand the difference in action of depolarizing and non-depolarizing agents: Non-depolarizing are competitive blockers of nAchR Depolarizing (succinylcholine) is a potent activator of Ach Understand how this blocks Ach signals at the NMJ NMJ structure and mechanism of signal transmission How Sugammadex reverses NMJ blockade by specific non-depolarizing NMBA How nAchR differs from other nAchR Presence of gamma and delta subunits  Spasticity  Increase in tonic stretch reflexes  Increased flexor muscle spasm  Muscle weakness  Reflex arc involvement  Higher center involvement ("upper motor neuron disease") affects descending pathways leading to alpha motor neurons hyper-excitability  Spasmolytics- these are skeletal muscle relaxing agents that relieve acute musculoskeletal pain, spasm or spasticity Centrally active “Spasmolytic” agents These include carisoprodol, diazepam and baclofen Diazepam (a benzodiazepine)- is effective for both acute spasms and chronic spasticity. Anti-spasmolytic effect in part due to action in the spinal cord {effective in patients with cord transection} Also causes sedation Diazepam Diazepam (a benzodiazepine)- is effective for both acute spasms and chronic spasticity. Anti-spasmolytic effect in part due to action in the spinal cord {effective in patients with cord transection} Also causes sedation  Mechanism of action of diazepam Diazepam /benzodiazepines 1.GABA activates Cl- channels on post- synaptic neurons 2.This inhibits depolarization and nerve transmission 3.Benzodiazepines increase the Cl- conductance through these channels 4.Limits nerve transmission to muscle Benzodiazepines’ indications Benzodiazepines possess psycholeptic, sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions, which are useful in a variety of indications including: Anxiety disorders Seizures Muscle spasms Sedation Carisoprodol  Carisoprodol (Soma)- alters interneuron activity in the spinal cord and of the descending reticular formation, located in the brain.  It is a GABAergic drug which is rapidly converted to meprobamate which is a sedative-hypnotic.  This stimulates GABA receptors on neurons  GABA receptors are inhibitory and blocks neurotransmission  Schedule IV controlled substance and can have abuse/dependence  Exact mechanism of GABA receptor stimulation unclear  Baclofen Orally active GABA mimetic which acts as a GABA agonist at GABA-B receptors GABA-B receptors are G-protein coupled receptors which hyperpolarize neurons by decreasing calcium conductance (inhibitory) Baclofen works at the spinal level to reduce reflexes Activation of GABA-B receptors in the brain by Baclofen results in hyperpolarization of neurons in the brain and cord to decrease the release of excitatory neurotransmitters Decreases the frequency and degree of muscle spasms and reduces muscle tone Baclofen It is the drug of choice because it produces less sedation than diazepam and less peripheral muscle weakness than dantrolene. Used for paraplegic or quadraplegic patients with spinal cord lesions caused by either multiple sclerosis or trauma. Intrathecal Baclofen use for management of severe spasticity/pain when nonresponsive to medication by other routes of administration Spasmolytics (Peripheral) Dantrolene- has similar effects to other central drugs but it works directly on the muscle by inhibiting calcium release. Lessens excitation-contraction coupling in muscle cells. Most effective for spasticity with cerebral origin (multiple sclerosis, cerebral palsy). Also used in malignant hyperthermia and NMS (neuroleptic malignant syndrome). Excitation- Contraction coupling in Skeletal Muscle Calcium-induced calcium release (CICR) is a biological process where calcium is able to activate calcium release from intracellular Ca2+ stores (sarcoplasmic reticulum) Depolarization initiates calcium influx by voltage dependent calcium channels (VDCC) also known as dihydropyridine receptors in SkM This initiates CICR via the ryanodine receptors(RyR1, heart is RyR2) which are voltage gated calcium channels on the sarcoplasmic reticulum membrane. Dantrolene- A ryanodine receptor antagonist used in malignant hyperthermia and spastic disorders Malignant hyperthermia  Summary: Things to know. Mechanism of action of Diazapam: Blocks muscle stimulation by increasing Cl- influx of GABA receptors. (not an agonist) Clarisoprodol: promotes GABA activity in neurons. Baclofen: is a GABA agonist. Dantrolene: inhibits Ca++ release of RyR1 (skeletal muscle) to inhibit contraction Mechanism of skeletal muscle Ca++ release: Very similar to heart – but RyR1 and different Ca++ channels with very similar mechanism