Neuromascular Blocking Drug

Neuromuscular blocking agents

Divided into two types: - Acethylcholine competitive antagonists such as tubocurarine which inhibit nicotinic receptors

- Depolarizing antagonists such as Succinylcholine which acts as an acetylcholine excess.

Depolarizing NeuroMuscular Blocking Agent

Two molecule of acetylcholine. Use as anesthesia Produce excessive depolarisation which persist for longer duration at NMJ
Depolarizing the Muscle Resistant to degradation by acetylcholinesteras e

Depolarization 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 paralysis

Sodium Channel

Gate v is voltagedependent Gate t is time-dependent

Inside Sodium Channel

Resting stage v is closed while t is open

Active stage V open and ion will flow inside and gate T slowly close. Inactive stage Gate T close and gate V is open. Maintain because membrane is depolarized.

Succinylcholine
Also known as suxamethonium chloride (INN) and suxamethonium. Used to induce muscle relaxation and short-term paralysis. Succinylcholine acts as a depolarizing neuromuscular blocker Acts on nicotinic receptors at the motor end plate resulting in persistent depolarization. This depolarization may be observed as fasciculations. Degraded by butyrylcholinesterase, a plasma cholinesterase Succinylcholine has no direct action on the uterus or other smooth muscle structures.

Mechanism of action
The 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 steps During 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 1
Depolarizing 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 II Desensitization block Phase II block

Contd
Desensitization block Ach receptors insensitive to opening effect of agonist. Constant state of resting and desensitized state. Safe mechanism that prevents over-excitation of the neuromuscular junction.

Contd
Phase II block Occur 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.

 Explanation In 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, esophagoscopy For correction of dislocation and alignment offractures As a Muscle relaxant !

Contraindication / limitation
Hypersensitivity History of malignant hyperthermia History of skeletal muscle myopathy (rhabdomyolysis) Muscular dystrophies Penetrating eye injuries Genetic disorders of plasma pseudocholinesterase Recent burns or trauma Acute narrow-angle glaucoma or penetrating eye injuries Neuromascular diseases Alergy to succinylcholine

Adverse Effects
Hyperkalemia Malignant Hyperthermia Increased intraocular pressure Increased cranial pressure Changes in cardiac rhythm, including bradycardia, cardiac arrest and ventriculardysrhythmias.

Death

Decamethonium
Therapeutic use - For use as a skeletal muscle relaxant Absorption - Rapidly absorbed Toxicity - LD50=190 mg/kg (orally in mice) Affected organisms - Humans and other mammals

Pharmacodynamics
acts as a depolarizing muscle relaxant or neuromuscular blocking agent acts as an agonist of nicotinic acetycholine receptors - motor endplate and causes depolarization Class of drugs has its effect at the neuromuscular junction preventing the effects of acetylcholine Nerve stimulus acts to contract a muscle - releases acetylcholine Binding to receptors causes the muscle to contract

Mechanism of action
Binds to the nicotinic acetycholine receptors in the motor endplate and blocks access to the receptors the receptor is actually activated - causing a process known as depolarization not degraded in the neuromuscular junction -depolarized membrane remains depolarized and unresponsive to any other impulse - muscle paralysis

Contraindication / limitation
Does not produce unconsciousness or anesthesia Effects 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 arrest Hypersensitivity reactions including anaphylaxis may occur in rare instances. Malignant hyperthermia Arrhythmias Bradycardia Tachycardia Hypertension Hypotension Hyperkalemia Prolonged respiratory depression or apnea Increased intraocular pressure Muscle fasciculation Jaw rigidity Postoperative muscle pain Rhabdomyolysis with possible myoglobinuric acute renal failure Excessive salivation Rash

 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