Neuromuscular blocking agents Flashcards
Motor neurons?
- Ventral horn of spinal cord - Cell body
- Axons encapsulated in myeline sheeth to speed up nerve conduction
- Nodes of Ranvier facilotate saltatory conduction. Increase in conduction speed
NMJ?
- Contains; pre-synaptic terminal(nerve), synaptic cleft (20nm) & post synaptic receptor (Muscle)
- Pre-synaptic Ach release + Binding to post-synaptic nicotinic Ach receptors.
- The AchR are neurotransmitters-gated channels opens for 1ms
- Influx of sodium and efflux of potassium
Pre-synaptic nerve terminals ?
- They contain schwann cells (Structural function, nerve homeostasis & reinnervation)
- Neuronal Ach receptors (Prejunctional nicotinic receptors, 5 subunits, positive feedback role)
- Actylcholine
Acetylcholine formation?
- Acetyl-CoA + Choline
2. About 2 pools - Reserve vesicles (20%) & readily released vesicles (80%).
Sequence at pre-synaptic terminal ?
- Nerve impulses activate sodium channels
- Activation of P-type voltage-dependent calcium channels
- Influx of calcium into the cell
- Acetylcholine vesicles released
Synaptic cleft?
- Its about 20-50nm
2. Contains acetylcholinesterase - Ionic site, esteratic site (serine), hydrolysis (10000 molecules)
Post-junctional cleft?
- Consists folds and crests
- Folds: Very high density of Ach receptors
- Crests: Voltage gated sodium channels
Acetylcholine receptors?
- Nicotinic
- About 50million AchR/crest
- Protein of 5 polypeptide subunits in ring structre forming ionic channel
Types of Acetylcholine receptors?
- Mature/adult junctional AchR
2. Immature/fetal extrajunctional AchR
Mature/adult junctional AchR?
- Consists - 2-alpha, 1-beta, 1-delta & 1-Epsilon
- High conductivity
- Very short opening (1ms)
Immature/fetal extrajunctional AchR
- Consists - 2-alpha, 1-beta, 1-delta & 1-gamma
- Longer opening of channels
- Low conductance channel
- Develops after - Burns, sepsis, upper & lower motor neuron injury
- Sensitive to Sux
Upregulation of Immature/fetal extrajunctional AchR?
- Upper & lower motor neuron defects
- Prolonged chemical denervation (NMB, MgSO, clostridial toxins)
- Direct muscle trauma, tumour or inflammation
- Thermal injury
- Disuse atrophy
- Severe infection
All the above could upregulate AchR
Types of NMB drugs according to mechanism of action?
- Preventing Ach release (MgSO, aminoglycosides)
- Preventing Ach synthesis (Hemicholinum)
- Depleting Ach stores (Tetanus toxin)
- Blocking Ach receptors (rocuronium, atracurium)
Ideal NMB agent?
See picture..
Suxamethonium?
- It is 2 acetylcholine molecules joined by ester linkage
- About 10% excreted in urine and minimally hepatically metabolised
- Hydrolysed by plasma cholinesterase
- Causes depolarization of receptors
- Onset 60s, duration 2-3mins
Side effect of suxamethonium?
- Myalgia
- Cardiac arrhythmia
- Hyperkalaemia
- Increase IOP
- Anaphylaxis & MH
Contraindications of Suxamethonium?
- Severe muscle trauma
- Burns > 24 hours - 18 months
- Muscle disease
Non-depolarizing agents?
Aminosteroids and Benzylquinolinums
- Do not alter structural conformity of the AchR
- Reversible binding to alpha subunit via quaternary ammonium group
- Highly ionised, water soluble drugs, distributed in plasma and ECF - Small Vd
Atracurium?
- About 0.5mg/kg, onset 2.5mins, lasting 20-35mins
- metabolised by ester hydrolysis (60%) & Hoffman degradation (40%)
- Hoffman - pH and temperature dependent.
- Laudanosine as an inactive metabolite - Epileptogenic properties.
- May cause histamine release / anaphylaxis
- Associated with critical illness myopathy
- No direct CVS effect
Cisatracurium? (1 of 10 isomers of atracurium)
- Dose 0.15-0.2mg/kg, onset 2-3mins, duration 20-35mins
- Isomer of atracurium
- Reduced side effect
- About 3-4 times more potent than atracurium
- Hoffman degradation - Less laudanosine produced
- Does not release histamine
- Greater CVS stability
- useful for critical illness infusion
Vecuronium?
- Dose 0.1mg/kg, onset 3-4mins, duration 30-45 mins
- Monoquaternary amine
- About 30% eliminated in urine
- Active metabolites (hepatic deacetylation)
- Avoid repeated doses in renal or hepatic failure
- No histamine release
- No CVS effect
- Partial affinity for sugammadex
Rocuronium? Rapid onset curonium
- Dose 0.6mg/kg, onset 1-1.5mins, duration 30-45 mins
- About 6-8 times less potent than vecuronium
- Excreted unchanged in urine (30%) and bile (50%)
- Dependent on hepatic function
- No active metabolites
- Minimal histamine release
- Mild vagolytic properties - Increases HR
- Painful on injection and useful for critical illness infusion
Factors affecting duration of non-DNMB agents ?
- Concomitant use of volatile agents
- pH (Acidosis)
- Temperature (Hypothermia)
- Age
- Hypokalaemia
- Hypocalcaemia
- Myasthenia gravis
- Hepatic & renal diseases
Anticholinesterases ?
- Include; Neostigmine, Edrophonium, Pyridostigmine, Organophosphorous
- Inhibits acetylcholinesterases
- Prolongs half-life of Ach
- Muscarinic effects
Cyclodextrans ? Sugammadex
- About 8 oligosccharides in a cylindrical structure.
- Lipophilic core and hydrophilic tail
- Encapsulates rocuronium
- Sug+Roc complex excreted in urine
- No muscarinic effects
- Prolonged QT interval and bradycardia reported
Qualitative NMB monitoring ?
- Nerve stimulator
Quantitative NMB monitoring ?
- Mechanomyography - Ulnar nerve stimulation - Gold standard
- Electromyography - Measures muscle AP following nerve stimulation - influenced by local temperature & diathermy
- Acceleromyography - Piezoelectric sensor - Acceleration of stimulated muscle
Newton’s second law of motion - F=ma
Site for nerve stimulation?
- Adductor pollicis - Adduction of thumb
- Black -ve close to wrist and red +ve proximally
- Facial nerve - Less accurate than ulnar nerve. (Orbicularis oculi & corrugator supercilli)
Differential muscle sensitivity?
- Fast in central muscles - Larynx & diaphragm
2. Slower in peripheral muscles - Adductor pollicis
Times to receovery (fastest to slowest)?
Diaphragm > Laryngeal muscles > Corrugator supercilli > Abdominal muscles > Orbicularis oculi > Geniohyoid muscles > Adductor pollicis muscle.
TOF?
- Supremaximal twitch at 2Hz (4 twitches in 2 secs)
- Twitches are 500ms apart
- No fade in depolarising agent
Phase II block?
- After > 4mg/kg of Sux
- Repeat doses or infusion of Sux
- Fade is noted
- Post-tetanic potentiation
TET? Tetanus
- Repetitive stimulation at high frequency 50-200Hz for 5 secs
- Fade with NDNMB increases
- Affects presynaptic AchR
Post-tetanic count ?
- Tetanic stimulus 50Hz for 5 secs
- Followed 3secs later by ST stimuli at 1Hz for 20 secs
- Tetanus mobilises presynaptic Ach release
- Potentiates response to subsequent stimulation - Postetanic facilitation
- Assess deep NMB
DBS ?
- Two mini tetanic bursts @ 50Hz within 0.75 sec apart
- Easy to subjectively assess fade
- No advantage over TOF
Physiological conditions potentiating NMB?
See pictures
