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- Each motor nerve sends processes to each muscle fiber in the motor unit.
- Forming a highly organized and specialized structure called the neuromuscular junction, or motor endplate.
- The invagination of the muscle fiber sarcolemma forms the synaptic trough.
- The space between the axon terminal and the invaginated sarcolemma is called the synaptic cleft.
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- Muscle relaxants are potentiated by various factors:
- Drugs:
- Most of the inhalational anesthetic agents
- Aminoglycoside antibiotics, especially Gentamycin and Kanamycin
- β-Blockers
- Ca-channel blockers
- Electrolytes:
- Depressed Ca++
- Raised Mg++
- Raised K+
- Acidosis
- Temperature:
- If temperature is depressed, then Suxamethonium is potentiated.
- If temperature is raised, then Non-depolarizers are potentiated.
- Myasthenia gravis and other inherited muscle abnormalities (e.g., dystrophies, dystonias)
- Muscle contraction is controlled by motor neurons that release the neurotransmitter acetylcholine at neuromuscular junctions.
- Acetylcholine then diffuses across the narrow synaptic cleft and binds to acetylcholine receptors on the membrane of the muscle cell.
- Opening of ion channels within the receptor molecules, in such a way that a depolarizing, synaptic ion current can flow. This current triggers an all-or-nothing response in the form of an action potential across the plasma membrane of the muscle cells.
- The action potential moves out in all directions from the neuromuscular junctions, resulting in stimulation of the entire muscle fiber within a few milliseconds, and the contractile mechanism responds, causing the fiber to contract.
Depolarizing Neuromuscular Blockade
- Acetylcholine Analogues Interact With Postjxnal Cholinergic-Nicotinic Receptor
- Depolarization Of Endplate And Muscle Fibre Then Muscle Contracts
- Contraction Is Not Sustained
- Persistent Occupation Of Receptors, Depolarization, Interruption Of Neuromuscular Transmission
- End Result Is Muscle Paralysis
Non-Depolarizing Neuromuscular Blockade
- Combine Reversibly with Pjxnal Cholinergic-Nicotinic Receptors Without Opening Sodium Channels
- Competing with Acetylcholine Reducing the Receptors Available for ACh
- 70% Occupancy Blocks Response of End-Plate Potential in Response to a Single Nv Impulse - Msc Remain Inert
- 90-95% Occupancy Results in Complete Failure of NMT Hence Msc Become Flaccid
- Non-depolarizing
- Fast onset
- Free of cardiovascular side effects
- Easily antagonized
- Stable pharmacokinetic and pharmacodynamic properties in the presence of hepatic and renal diseases
- No such drug yet
- Depolarizing:
- Succinylcholine
- Decamethonium (short-acting)
- Non-depolarizing:
- Aminosteroids (vagolysis):
- Pancuronium
- Vecuronium
- Pipecuronium
- Rocuronium
- Rapacuronium
- Benzylisoquinolinium:
- D-tubocurarine
- Atracurium
- Doxacurium
- Mivacurium
- Cis-atracurium
- Metocurine
- Gallamine
Classification of Non-Depolarizers
- Long Acting:
- d-tubocurarine
- metocurine
- doxacurium
- pancuronium
- gallamine
- pipecuronium
- Intermediate Acting:
- atracurium
- cis-atracurium
- vecuronium
- rocuronium
- Short Acting:
- mivacurium
- rapacuronium
Differences Btw Depolarisers And Non Depolarizers
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- CLINICAL: Requires a conscious and cooperative patient
- Sustained head lift for 5 seconds
- Firm hand grip for 5 seconds
- Vital capacity breath of >10ml/kg
- Inability to perform this with see-sawing respiration indicates residual neuromuscular blockade
- PERIPHERAL NERVE STIMULATION: Used in anesthetized patients
SUXAMETHONIUM
- Chemical Structure: 2 molecules of Acetyl Choline linked together with 2 quaternary amine groups.
- Physical Properties: It is available in 2 forms:
- Succinylcholine chloride - Aqueous - Temperate
- Succinylcholine bromide - Powder - Tropic
- Rapid onset, short duration: 3-5 minutes
- Indications: To facilitate endotracheal tube (ETT) placement
- Dose:
- Intubating dose in adults is 1mg/kg
- X-ray examinations, especially in infants, is 1.5-2.0mg/kg
- Rapidly hydrolyzed by plasma cholinesterase
SIDE-EFFECTS
- Cardiac arrhythmias:
- Sinus bradycardia
- Ventricular premature beats
- Hyperkalemia, especially in:
- Patients with massive burns
- Muscle trauma
- Upper motor neuron lesions (UMNL) and lower motor neuron lesions (LMNL)
- Renal disease
- Severe abdominal infections
- Raised Intraocular Pressure (IOP)
- Raised Intracranial Pressure (ICP)
- Raised Intragastric Pressure (IGP)
- Scoline pain, particularly in ambulant and muscular patients
- Anaphylactoid reaction
- Masseter spasm, which could herald Malignant Hyperthermia (MH)
CAUSES OF PROLONGATION OF ACTION IN PLASMACHOLINESTERASE DEFICIENCY
- Physiological
- Pregnancy
- Contraceptive pills
- Malnutrition
- Liver disease (cirrhosis)
- Hemodialysis
- Echothiopate (an eye drop)
D-TUBOCURARINE
- First NMB Agent Used in Anesthesia
- It Causes Muscle Paralysis Within 3 Minutes
- Duration = 30-40 Minutes (Long Acting)
- Causes Hypotension by Two Mechanisms:
- Sympathetic Ganglionic Blockage
- Histamine Release
- Metabolized in the Liver and Excreted by Kidney
PANCURONIUM
- Is an Aminosteroid Muscle Relaxant Acting Within 2 Minutes
- Recommended Loading Dose Within 0.06-0.08 mg/kg
- Increment of 0.01-0.02 mg/kg
- Large Amount Bound to Plasma Protein
- Dependent on Renal Excretion (80%)
- Metabolized and Excreted by the Liver
- Does Not Release Histamine
- Cardiovascular System Effects:
- Increases Blood Pressure Due to Norepinephrine Release
- Sinus Tachycardia Due to Its Vagolysis Effect
GALLAMINE
- Solely Excreted by the Kidney, Hence Absolutely Contraindicated in Renal Disease
- Crosses the Placenta, Hence Contraindicated in Obstetrics
- Vagolytic, Causing Early, Severe Tachycardias
ATRACURIUM
- Dose:
- 0.3-0.4 mg/kg or 30 mg increment 0.08-0.1 mg/kg
- Amps: 2.5 ml = 25 mg
- Cardiovascularly stable, but larger doses release histamine with mild hypotension
- Breakdown occurs spontaneously and is dependent on pH and Temperature (Hoffman degradation).
- Hepatic degradation also occurs resulting in the formation of Laudanosine.
- Laudanosine is a convulsant in high doses but clinically has not been a problem.
- It is safe in hepatic and renal failure.
- Non-cumulative, even after prolonged infusions.
- Similar duration of action to Vecuronium.
- Expensive
CIS-ATRACURIUM
- Dose:
- 0.15 mg/kg or 10 mg
- Amps: 5 ml = 10 mg
- Features:
- Similar to Atracurium without the histamine release.
MIVACURIUM
- Dose:
- 0.15 mg/kg or 10 mg
- Amps: 5 ml = 10 mg and 10 ml = 20 mg
- New on the market
- Much shorter acting than the previous 2 agents (approximately 10 minutes), with rapid recovery. It will not replace Suxamethonium.
- Degraded by plasma cholinesterase (competing with Suxamethonium) and thus contraindicated in patients with "Scoline Apnoea."
- May be used as an infusion
- Expensive
VECURONIUM
- Dose:
- 0.1 mg/kg or 6 mg
- Amps: 2 ml = 4 mg and 10 ml = 20 mg as a dry powder needing reconstituting with sterile water
- Cardiovascularly very stable, with occasional bradycardia
- No histamine release
- Shorter acting (approximately half the duration of the preceding drugs)
- Hepato-biliary excretion and can thus be used in renal failure
- Expensive
ROCURONIUM
- Dose:
- 0.3 - 0.9 mg/kg or 20 - 50 mg
- Amps: 5 ml = 50 mg and 10 ml = 100 mg
- New on the market
- Low dose provides slow intubation and short duration (approximately 15 minutes). High dose provides very fast intubation (approximately 60 - 90 seconds) and long duration.
- Cardiovascularly stable with a mild increase in heart rate and blood pressure
- Very rapid onset (similar to, but not as predictable as Suxamethonium) but has an intermediate to long duration of action.
- Undergoes no metabolism and is primarily eliminated by the liver and slightly by the kidney
- Expensive
ALCURONIUM
- Dose:
- 0.25 mg/kg or 15 mg
- Amps: 2 ml = 10 mg
- Cardiovascularly more stable, with occasional tachycardia
- Histamine release with possible mild hypotension
DOXACURIUM
- Benzylisoquinoline compound closely related to mivacurium and atracurium
- Most potent currently
- Onset: 10 minutes
- Duration: 3 hours
- Eliminated unchanged by the kidney
- Slightly metabolized by plasma cholinesterase
METOCURINE
- Bis-quaternary amine derivative of DTC
- Pharmacology similar to DTC
PIPECURONIUM
- Elimination depends on renal (70%) and secondarily biliary (20%).
- Principal advantage over pancuronium is its lack of cardiovascular side effects due to a decreased binding to cardiac muscarinic receptors.
- Acetyl Choline is normally degraded in milliseconds by Cholinesterases. The degradation of Acetyl Choline may be inhibited by the use of an Acetyl Cholinesterase inhibitors, e.g.,
- Edrophonium
- Pyridostigmine
- Neostigmine
- Physostigmine
- Acetyl Choline is the neuro-transmitter at numerous receptors, and the use of an Acetyl Cholinesterase inhibitor will result in an increase in Acetyl Choline at all cholinergic receptors (pre- and post-ganglionic Parasympathetic nerves, as well as pre-ganglionic Sympathetic nerves).
- The effects of relative overactivity of Acetyl Choline that would result if a Muscarinic blocker were not given at the same time includes the following:
- Severe bradycardia
- Bronchospasm
- Copious secretions
- Other parasympathetic effects, e.g., increased gut motility, pupil constriction, etc.
- The standard reversal "cocktail" for an adult is, therefore, a mixture of:
- Neostigmine 2.5 mg plus Atropine 1.0 - 1.2 mg
- Or Neostigmine 2.5 mg plus Glycopyrrolate 0.4 - 0.6 mg, mixed in the same syringe.
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