Physiology at the<unk>  Junction<unk>  exert its effect by modulating the signal transmission in skeletal muscles. An action potential is, in other words, a depolarisation in neurone membrane due to a change in membrane potential greater than the threshold potential leads to an electrical impulse generation. The electrical impulse travels along the pre-synaptic neurone axon to synapse with the muscle at the<unk>  junction (NMJ) to cause muscle contraction. When the action potential reaches the axon terminal, it triggers the opening of the calcium ion gated channels, which causes the influx of Ca2+. Ca2+ will stimulate the release of neurotransmitter in the neurotransmitter containing vesicles by exocytosis (vesicle fuses with the pre-synpatic membrane). The neurotransmitter, acetylcholine(ACh) binds to the nicotinic receptors on the motor end plate, which is a specialised area of the muscle fibre's post-synaptic membrane. This binding causes the nicotinic receptor channels to open and allow the influx of Na+ into the muscle fibre. Fifty percent of the released ACh is hydrolysed by acetylcholinesterase (AChE) and the remaining bind to the nicotinic receptors on the motor end plate. When ACh is degraded by AChE, the receptors are no longer stimulated and the muscle can be repolarised. If enough Na+ enter the muscle fibre, it causes an increase in the membrane potential from its resting potential of -95mV to -50mV (above the threshold potential -55V) which causes an action potential to spread throughout the fibre. This potential travels along the surface of the sarcolemma. The sarcolemma is an excitable membrane that surrounds the contractile structures known as myofibrils that are located deep in the muscle fibre. For the action potential to reach the myofibrils, the action potential travels along the transverse tubules (T-tubules) that connects the sarcolemma and center of the fibre. Later, action potential reaches the sarcoplasmic reticulum which stores the Ca2+ needed for muscle contraction and causes Ca2+ to be released from the sarcoplasmic reticulum. Pharmacological of depolarising<unk> Pharmacology of Succinycholine (only depolarising<unk> available for clinical use) Succinycholine (aka diacetylcholine or suxamethonium chloride) has the fastest onset and shortest duration of all<unk> . It is indicated for rapid sequence intubation. It is administered intravenously. Within 30 seconds, the patient will experience fasciculation due to the depolarisation of muscle neurone fibres and seconds later, flaccid paralysis will occur. Dosing/onset of action IV dose 1-1.5mg/kg or 3 to 5 x ED95 Paralysis occurs in one to two minutes. Clinical duration of action (time from drug administration to recovery of single twich to 25% of baseline) is 7-12 minutes. If IV access is unavailable, intramuscular administration 3-4mg/kg. Paralysis occurs at 4 minutes. Use of succinylcholine infusion or repeated bolus administration increase the risk of Phase II block and prolonged paralysis. Phase II block occurs after large doses (>4mg/kg). This occurs when the post-synaptic membrane action potential returns to baseline in spite of the presence of succinylcholine and causes continued activation of nicotinic acetylcholine receptors. Pharmacokinetics Succinylcholine is metabolised by butyrylcholinesterase (aka pseudocholinesterase or plasma cholinesterase). Adverse effects of succinylcholine Contraindications: malignant hyperthermia, denervating conditions, major burns after 48 hours and severe hyperkalemia Hyperkalemia, malignant hyperthermia, myalgias, increased intragastric pressure, increased intraocular pressure, increased intracranial pressure, cardiac dysrhythmias and allergic reactions + Properties of depolarising<unk> (succinylcholine). Drug Elimination Site Clearance (mL/kg/min) Approximate Duration of Action (min) Succinylcholine Plasma ChE2 (100%) Data not found 95 of 0.3 mg/kg IV has a more rapid onset than Vecuronium with an ED95 of 0.05mg/kg. Steroidal compounds Steroidal compounds - Rocuronium and vecuronium are intermediate-acting drugs while Pancuronium and pipecuronium are long-acting drugs. +Comparison of Pharmacokinetics between nondepolarising<unk> <unk>  Dosing Onset time Duration Pharmacokinetics, Precautions and Side Effects Rocuronium 0.6mg/kg (2 x ED95) maintenance dose: 0.1mg/kg or infusion at a dose of 5-12mcg/kg/minute 1.5-3 minutes 30-70 minutes Fastest onset time, alternative to succinylcholine for rapid sequence intubation Volume of distribution of 0.3-0.7L/kg, excreted mainly through biliary route Vecuronium 0.1mg/kg or 2 x ED95 for 3-4 minutes maintenance dose: 0.01mg/kg or an infusion at 1-2mcg/kg/min 3-4 minutes 25-50 minutes Volume of distribution of 0.4 L/kg,<unk>  monitoring is required for patients with renal or hepatic disease that may have prolonged response to vecuroniu Pancuronium 0.1mg/kg (1.5 x ED95) for 3-5 minutes maintenance dose: 0.02mg/kg 3-5 minutes 60-120 minutes Rarely used due to high incidence of postoperative residual<unk>  weakness and cause tachycardia due to direct sympathomimetic stimulation and blockage of cardiac muscarinic receptors. Volume of distribution of 0.2 to 0.3 L/kg, eliminated mostly through the renal route, with 20 percent biliary excretion, avoided in patients with renal and hepatic impairment Atracurium 0.5 mg/kg, or 2 x ED95 for 3-5 minutes maintenance dose: 0.1mg/kg or an infusion rate at 10-20 mcg/kg/min 3-5 minutes 30-45 minutes side effects: skin flushing, hypotension and tachycardia due to the increase in plasma histamine level Volume of distribution is 0.15L/kg, metabolism of Atracurium is independent of hepatic and renal function Metabolised by non-specific plasma esterase-mediated hydrolysis and a nonenzymatic, pH- and temperature-dependent degradation called Hofmann elimination Cisastracurium 0.15-0.2 mg/kg or 3 x ED95 for 4-7 minutes maintenance dose: 0.01 mg/kg or an infusion at 1-3 mcg/kg/min guided by<unk>  monitoring 4-7 minutes 35-50 minutes Volume of distribution is 0.16 L/kg, metabolised through Hofmann elimination Mivacurium 0.2 mg/kg, or 3 x ED95 for 3-4 minutes maintenance dose: 0.1mg/kg or an infusion at 5 to 8 mcg/kg/min guided by<unk>  monitoring 3-4 minutes 15-20 minutes Volume of distribution of 0.2 L/kg, metabolized by butyrylcholinesterase and should not be used in patients with butyrylcholinesterase deficiency It can be reversed by neostigmine or edrophonium. + Comparison of properties of nondepolarising<unk> . Drug Elimination Site Clearance (mL/kg/min) Approximate Potency Relative to Tubocurarine Isoquinoline derivatives Tubocurarine Kidney (40%) 2.3-2.4 1 Atracurium Spontaneous 5-6 1.5 Cisatracurium Mostly Spontaneous 2.7 1.5 Doxacurium Kidney 2.7 6 Metocurine Kidney (40%) 1.2 4 Mivacurium Plasma ChE2 70-95 4 Steroid derivatives Pancuronium Kidney (80%) 1.7-1.8 6 Pipecuronium Kidney (60%) and liver 2.5-3.0 6 Rapacuronium Liver 6-11 0.4 Rocuronium Liver (75-90%) and kidney 2.9 0.8 Vecuronium Liver (75-90%) and kidney 3-5.3 6
Neuromuscular blocking agents
Neuromuscular-blocking drug
Cholinergic blocking drugs
Muscle relaxant
Antiarrhythmic agent
Antihypotensive agent
Steroid
Neuroleptanalgesic