Neuromuscular Blockers PDF

Neuromuscular Blockers Adegoke Adeniji RPh, PhD Assoc. Professor, Pharm. Sci. 1  Objectives Compare and contrast the mechanism of action of a depolarizing neuromuscular blocker (NMB) versus a non-depolarizing neuromuscular blocker...

Neuromuscular Blockers Adegoke Adeniji RPh, PhD Assoc. Professor, Pharm. Sci. 1  Objectives Compare and contrast the mechanism of action of a depolarizing neuromuscular blocker (NMB) versus a non-depolarizing neuromuscular blocker Describe the role of NM receptors and calcium in the contraction of muscle Explain why there is a reversal drug for non- depolarizing NMBs action but not for  Neuromuscular Blockers Used during surgical procedures to induce muscle paralysis – Adjuncts to general anesthesia – Facilitation of intubation Control of muscle contraction in status epilepticus – Continuous seizure lasting longer than 30mins – Two or more seizure episodes without recovery of consciousness Peripherally acting agents – Do not cross the blood-brain barrier  History of NMB 16th century – Curare : an alkaloid obtained from plants used as an arrow poison – Killed animals by skeletal muscle paralysis How??  Mechanism of Action of NMB Neuromuscular blockers bind and modulate the activation of nicotinic receptors located in the neuromuscular junction (NM) Types of NMBs 1. Non-depolarizing blockers 2. Depolarizing blockers  Nicotinic Receptor Subtypes Nicotinic cholinergic receptors (N) – Autonomic ganglia (NN / NG) – Neuromuscular junction (NM) Five subunits that are slightly different in NN and NM NM NN  N N N N N M  Drug Selectivity for Nicotinic Receptors 1. Diversity in nicotinic receptor composition allows for pharmacological discrimination between NM and NN 2. Site of action is determined by the drug’s ability to reach the receptor site  The Neuromuscular Junction Under resting conditions, spontaneous low level ACh release at the motor end plate (neuromuscular jxn) results in: – Miniature end-plate potential (MEPP) Low change in membrane voltage – Inadequate to generate an AP in skeletal muscle Membrane potential does not reach the threshold potential Arrival of action potential at the axon terminal causes the release of large quantities of Ach and results in large depolarization at the motor end plate termed: – End-plate potential (EPP)  The Neuromuscular Junction The EPP is sufficient to generate an action potential in the muscle cell which ultimately results in muscle contraction EPP MEPP The MEPP can not generate an action potential Neuromuscular Junction Activation and Muscle Contraction http://inhome-personaltrainer.com/smooth-muscle-contraction-cascade  Neuromuscular Blockers Mechanism of neuromuscular blockade 1. Depolarizing neuromuscular blockers Act as nicotinic receptor agonists Activation of the Nm receptor – Opening of ion channel causing Na+ influx Longer duration compared to Ach – Initial muscle contraction followed by widespread fasciculation (muscle twitching or involuntary contraction) and then flaccid paralysis 2. Non-depolarizing neuromuscular blockers Act as nicotinic receptor antagonists Inhibits muscle contraction  Depolarizing Neuromuscular Blocker Succinylcholine (Anectine) – Only depolarizing neuromuscular blocker used in clinical setting (FDA approved 1952) – Rapid onset of muscle paralysis coupled with an extremely short duration of action (5-10 minutes) Resistant to acetylcholinesterase Hydrolysis by plasma cholinesterases (butyrylcholinesterase) – Small amount of drug reaches neuromuscular junction Effect prolonged in genetic deficiency of butyrylcholinesterase or patients with a less active Dibucaine geneticnumber is a variant measure of a patient’s ability to metabolize (rare) succinylcholine. Used to identify at risk patients  Mechanism of Action Binds to nicotinic receptor and opens the ion channel – Prolonged receptor occupancy keeps membrane depolarized and unresponsive to further impulses (Phase I depolarizing blockade) – Succinylcholine is not degraded in synapse Prolonged depolarization – Muscle contraction followed by widespread fasciculation and then flaccid paralysis Membrane repolarized but not easily depolarized (Phase II desensitizing block) – Usually at higher doses – Receptor becomes unresponsive to Ach – Drug may also bind in pore to block channel – Prolonged muscle paralysis  Depolarizing Neuromuscular Blocker Paralysis occurs for two reasons: 1. Activated receptor maintains the cell membrane in a depolarized condition – Effective inactivation of the sodium channel – New action potential cannot be achieved 2. Agonist-bound nicotinic receptor desensitizes – No receptor response to additional Harvey. Lippincott’s Illustrated Review: Pharmacology 5 th edition  Succinylcholine Adverse Side Effects Muscle pain(myalgia)/ muscle weakness – Secondary to unsynchronized contractions of adjacent muscle fibers prior to muscle paralysis Cardiovascular effects – Transient bradycardia – Cardiac arrhythmias – Possible cardiac arrest Due to non-specific stimulation of NN and M receptors Treatment option - anticholinergics  Succinylcholine Adverse Side Effects Acute hyperkalemia – Patients with burns, nerve damage, neuromuscular disease, closed head injury, and other trauma may respond to succinylcholine by releasing excessive amounts of potassium into the blood. Upregulation of the Nm receptor Raised intraocular pressure Histamine release Hypotension and bronchospasm Pre-treat with antihistamine  Succinylcholine Adverse Side Effects Malignant hyperthermia (MH) – Dysregulation of body heat Heat generation far exceeds heat dissipation – Autosomal dominant genetic disorder triggered in patients receiving inhalation anesthetics and succinylcholine – Characterized by increased body temperature, tachycardia, hypertension, and muscle rigidity  Succinylcholine Adverse Side Effects Malignant hyperthermia (MH) – Drugs induce massive Ca2+ discharge from the sarcoplasmic reticulum through a defective muscle cell ryanodine receptor-type 1 (RyR1) Hypermetabolism and sustained muscle contraction – In the majority of cases, no clinical signs of the RyR1 mutation are visible in the  Ryanodine Receptor (DHP) Figure 20-40, Lodish 4th edition. Guyton 12th ed., Figure 7-6  Reversal of Malignant Hyperthermia Non pharmacological treatment – Ice packs Dantrolene (Dantrium) – Mechanism of action Inhibits Ca2+ release from the SR of skeletal muscle Blocks the interaction of myosin and actin to limit muscle contraction  Dantrolene Adverse Side Effects: – Diarrhea, sedation and asthenia – Black Box Warning: Hepatotoxicity – Liver function monitoring – Cardiac and smooth muscle cells have RyR2 therefore minimal effect by dantrolene  Non-depolarizing Neuromuscular Blockers Several non-depolarizing NMB are on the market – Isoquinoline derivatives Tubocurarine Atracurium (Tracrium) Cisatracurium (Nimbex) – Steroid derivatives Rocuronium (Zemuron), Vecuronium (Norcuron) Pancuronium (Pavulon)  Nicotinic Receptor Antagonist Mechanism of action – Competitive antagonist at NM – Muscle-cell non-depolarization – Flaccid paralysis Duration of action – Major point of differentiation among Neuromuscular blockers – Short-, intermediate-, and long-acting  Adverse Effects Adverse effects are mostly due to non-selective actions at NN and M receptors and the tendency to induce histamine release – Tubocurarine blockade of NN receptors – Complex autonomic effects Effect at NN receptors eliminated with newer agents  Agent Duratio Effects Effects Histami Relativ n of at NN ? at M? ne e Action Release Potenc (minute ? y s) Tubocurarine > 50 weak none modera 1 block te Cisatracuriu 25 - 44 none none none 1.5 m Pancuronium > 35 none moderate none 6 block Atracurium 20 - 35 none None slight 1.5 Rocuronium 20 - 35 none slight none 0.8 block Vecuronium 20 - 35 none none none 6 Succinylcholi