Neuromascular Blocking Drug

Neuromascular Blocking DrugNeuromuscular blocking agents Divided into two types: Acethylcholine competitive antagonists such as tubocurarine which inhibit nicotinic receptorsDepolarizing antagonists such as Succinylcholine which acts as an acetylcholine excess.Depolarizing NeuroMuscular Blocking AgentTwo molecule of acetylcholine.Use as anesthesiaProduce excessive depolarisation which persist for longer duration at NMJDepolarizing the Muscle Resistant to degradation by acetylcholinesteraseDepolarization Process Drug bind to nicotine receptor in skeletal muscle and cause depolarization of motor end plate

Fast circulation (Transient muscle contraction )

Followed by a sustained muscle paralysisSodium Channel

Gate v is voltage- dependentGate t is time-dependentInside Sodium Channel

Resting stagev is closed while t is open

Active stageV open and ion will flow inside and gate T slowly close.Inactive stageGate T close and gate V is open. Maintain because membrane is depolarized.SuccinylcholineAlso known as suxamethonium chloride (INN) and suxamethonium.Used to induce muscle relaxation and short-term paralysis.Succinylcholine acts as a depolarizing neuromuscular blockerActs on nicotinic receptors at the motor end plate resulting in persistent depolarization.This depolarization may be observed as fasciculations. Degraded by butyrylcholinesterase, a plasma cholinesteraseSuccinylcholine has no direct action on the uterus or other smooth muscle structures.

Mechanism of actionThe mechanism of action of Succinylcholine involves what appears to be a "persistent" depolarization of the neuromuscular junction.This depolarization is caused by Succinylcholine mimicking the effect of acetylcholine but without being rapidly hydrolysed by acetylcholinesterase. This depolarization leads to desensitization.Succinylcholine acts on the nicotinic receptors of the muscles, stimulates them and then ultimately cause their relaxation.This process occurs in 2 stepsDuring phase I (depolarizing phase), They cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers.Phase II- After sufficient depolarization has accured, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the nerve endings.

Phase 1Depolarizing drugs are agonists at ACh receptors. Succinylcholine is the only depolarizing NMBD in clinical use. It is effectively two ACh molecules joined through the acetate methyl groups. The two quaternary ammonium radicals bind to the two -subunits of one nicotinic receptor, and depolarization occurs. When voltage-sensitive sodium channels sense membrane depolarization - they first open and thereafter close and become inactivated. The membrane potential must be reset before the sodium channels can be reactivated. This is a very rapid process with ACh (1 ms), as it is hydrolysed by acetylcholinesterase (AChE) within the synaptic cleft. However, succinylcholine is not metabolized by AChE, so a prolonged activation of the ACh receptors is produced. The sodium receptors at the end-plate and the perijunctional zone remain inactivated and junctional transmission is blocked. The muscle becomes flaccid.

Mechanism of action (Contd)Phase IIDesensitization blockPhase II blockContdDesensitization blockAch receptors insensitive to opening effect of agonist.Constant state of resting and desensitized state.Safe mechanism that prevents over-excitation of the neuromuscular junction.ContdPhase II blockOccur from repeated boluses or prolonged use of depolarizing NMBD.After initial depolarization, membrane potential return to resting state.However, NMJ still exposed to drug. Thus, no neurotransmission occur.

ExplanationIn normal skeletal muscle, acetylcholine dissociates from the receptor following depolarization and is rapidly hydrolyzed by acetylcholinesterase.Suxamethonium has a longer duration of effect than acetylcholine, and is not hydrolyzed by acetylcholinesterase. By maintaining the membrane potential above threshold, it does not allow the muscle cell to repolarize. When acetylcholine binds to an already depolarized receptor, it cannot cause further depolarization.

>This later leads to Paralysis of the affected muscles!!!!

Uses of depolarizing neuromuscular blockers(succinylcholine)

For Endotracheal intubation.During electro convulsive therapy.For laryngoscopy, bronchoscopy, esophagoscopyFor correction of dislocation and alignment offracturesAs a Muscle relaxant !

Contraindication / limitationHypersensitivity History of malignant hyperthermia History of skeletal muscle myopathy (rhabdomyolysis) Muscular dystrophiesPenetrating eye injuriesGenetic disorders of plasma pseudocholinesteraseRecent burns or traumaAcute narrow-angle glaucoma or penetrating eye injuriesNeuromascular diseasesAlergy to succinylcholineAdverse EffectsHyperkalemiaMalignant HyperthermiaIncreased intraocular pressureIncreased cranial pressureChanges in cardiac rhythm, including bradycardia, cardiac arrest and ventriculardysrhythmias.Death

DecamethoniumTherapeutic use - For use as a skeletal muscle relaxantAbsorption - Rapidly absorbedToxicity - LD50=190 mg/kg (orally in mice)Affected organisms - Humans and other mammals

Pharmacodynamicsacts as a depolarizing muscle relaxant or neuromuscular blocking agentacts as an agonist of nicotinic acetycholine receptors - motor end-plate and causes depolarization Class of drugs has its effect at the neuromuscular junction - preventing the effects of acetylcholineNerve stimulus acts to contract a muscle - releases acetylcholineBinding to receptors causes the muscle to contract

Mechanism of actionBinds to the nicotinic acetycholine receptors in the motor endplate and blocks access to the receptorsthe receptor is actually activated - causing a process known as depolarizationnot degraded in the neuromuscular junction -depolarized membrane remains depolarized and unresponsive to any other impulse - muscle paralysis Contraindication / limitationDoes not produce unconsciousness or anesthesiaEffects may cause considerable psychological distress Simultaneously making it impossible for a patient to communicate except in necessary emergency situations

Adverse effect Prolonged apnoea, Neuromuscular paralysis Cardiac arrestHypersensitivity reactions including anaphylaxis may occur in rare instances. Malignant hyperthermiaArrhythmiasBradycardia Tachycardia

Hypertension HypotensionHyperkalemia Prolonged respiratory depression or apnea Increased intraocular pressureMuscle fasciculationJaw rigidityPostoperative muscle painRhabdomyolysis with possible myoglobinuric acute renal failure Excessive salivationRash

Post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) - use of neuromuscular blocking agents - ANECTINE (succinylcholine chloride)Life-threatening and fatal - reactions were reported voluntarily from a population of uncertain size