depolarizers muscle_relaxants_-_scoline1
TRANSCRIPT
DEPOLARIZING NEUROMUSCULAR-BLOCKING DRUGS
Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA,
Dip. Software statistics- PhD ( physiology), IDRA
but In 1942 was DTC • Succinylcholine, introduced by Thesleff and Foldes and
colleagues in 1952,
• changed anesthetic practice drastically.
• Its rapid onset of effect and ultra short duration of action
permitted rapid endotracheal intubation
• quaternary ammonium compound
• comparable to two molecules of acetylcholine linked
together Decamethonium went out of use
Water soluble
Six methyl groups – suxa methonium
Basic chemistry
• Positive charges at these sites in the molecules
mimic the quaternary nitrogen atom of the
transmitter acetylcholine and are the principal
reason for the attraction of these drugs to muscle-
and neuronal-type nAChRs at the neuromuscular
junction.
Ach receptors
• These receptors are also located at other physiologic
sites of acetylcholine in the body, such as the
neuronal-type nicotinic receptors in autonomic
ganglia and as many as five different muscarinic
receptors on both the parasympathetic and
sympathetic sides of the autonomic nervous system
Mechanism
• The depolarising muscle relaxants act in the same
way as ACh.
• They act by attaching on the same binding site of ACh
on the α-subunit of nicotinic receptor to open the
receptor channel and initiates depolarisation.
Acetyl choline and scoline
• Sodium channel has two gates • Voltage gated and time gated • Time gate – open • Depolarization – voltage gated opens and na flows
depolarization occurs • Time gate closes after 1 -2 millisecond • It can open only if voltage gate closes • Acetyl choline destroyed - VG closes - Time gate
opens but in scoline – continuos depolarization VG opens continuosly –s o time gate never opens
Ach
Scoline
Scoline – again !!
• Depolarization opens Na channel
• Voltage gated (VG) opens • Na flows. • Time gated(TG) – closes • It does not open until VG
closes • Depolarization –
relaxation TG
VG
Pictures taken and modified from internet for closed academic purpose only
Accommodation
• a further burst of acetylcholine from the nerve
terminal cannot produce depolarisation of end plate
due to the still presence of succinylcholine at the end
plate and can not overcome the inactivated state of
Na+ channel in perijunctional area due to continuous
depolarisation of end plate.
• So, neuromuscular transmission is blocked
Fasciculation
• Succinylcholine also has presynaptic action.
• Binding of succinylcholine to this presynaptic nicotine
receptors depolarises the nerve terminals
• action potential may be generated which travel
backwards retrogradely along the nerve terminals to
invade the neighbouring branches and thus produce
contraction of a whole motor unit.
Extra ocular and IOP rise
• Multiple receptors
• Special receptor which does not cause to paralyse with scoline
• Hence sustained contraction may occur
DPs and NDPs
• Stimulate Ach receptors like Ach , persistent – time gate – paralysis
• Scoline
• Competitively antagonize Ach receptors vecuronium
Pharmacokinetics • Dose is 1 mg / kg – intravenous --but IM 4 mg• Ideal body weight • Fasciculation in 30 seconds • Usually complete relaxation in 60 seconds • Duration 5 – 10 minutes • Lot of studies prove 0.6 mg /kg is enough• Higher the dose , may not increase duration• 2.5 mg/min IV infusion• Rapid and profound relaxation for a short
duration
So low dose NDPs decrease fasciculation
• Binding of succinylcholine to this presynaptic nicotine
receptors depolarises the nerve terminals and action
potential may be generated which travel backwards
retrogradely along the nerve terminals to invade the
neighbouring branches and thus produce contraction
of a whole motor unit• Fasciculation !!
Not like nondepolarizers
• Succinylcholine produces a characteristic
depolarizing block that is associated with the
absence of fade in response to train-of-four
and tetanic stimulations, the absence of post-
tetanic facilitation, and increased block in the
presence of anticholinesterase drugs
• The transition from a depolarizing to a phase II block
is gradual and usually occurs after administration of
7-10mg/ kg of succinyl choline.
• The recovery from a phase II block is much slower.
Phase I block
• Muscle fasciculation preceding the onset of
neuromuscular blockade
• Absence of post tetanic potentiation
• Lack of fade to frequent stimulation (eg, tetanus, train of
four, or double burst)
• Block antagonized by nondepolarizing drugs
• Block potentiated by acetylcholinesterase inhibitors
Phase II block ( Dual block ) • Absence of muscle fasciculation
• Presence of post tetanic potentiation
• Fade with frequent stimulation
• Possible synergism between various groups of non
depolarizing relaxants
• Phase II block and non depolarizing block potentiate each
other
• Block may be reversed by acetylcholinesterase inhibitors
Phase II block
• Duration - more than ten minutes
• Dosage more than 10 mg/kg
• Agents
prolonged exposure of the neuromuscular junction to SCh, there is a conformational change at the
receptors
Phase II block
drug itself enter into the channel to obstruct it, and pass through the
channel into the cytoplasm like open and close channel blockade.
Dual block • Phase A – depolarizing – 30 minutes • Phase B – non depolarizing block – develops • Phase C – persistence – 30 minutes • Phase D – wearing off – 2 hours
• Can we reverse ?? • Controversial – can be done
It gets metabolized as such
Repeat dose – bradycardia
Presynaptic , NMJ and extrajunctional
Muscle pains • Middle age , females – more
• First day but may be in fourth day also
• Fasciculations , Muscle lactic acid and increased
muscle potassium –reasons
• Less frequent in muscular persons and slow injection
• But can we give slow ? Already only a fraction of the
given dose reaches the NM junction – slow means ??
• occurs in unusual sites, such as the diaphragm, intercostal muscles and between the scapulae
• Children elderly and pregnant – less incidence
• Interval between thio and scoline – more the incidence
• Sore throat – is it muscle pain or tube ?
Prevent myalgias • Low dose non depolarizers pretreatment • ? Atracurium • Preop stretching, magnesium , phenytoin,
vitamin C , dantrolene, NSAIDs • Iv lignocaine 2 mg / kg
• Give scoline 10 mg – wait and then give rest • Self pretreatment
Side effects of SCh
• Hyperkalemia In normal patients, the depolarization
induced by SCh administration causes an increase in serum
potassium level of 0.5 to 1.0 mEq/L.
• burns, massive tissue trauma, disuse atrophy,
hemiparesis, spinal cord trauma, and neuromuscular
disorders (eg, Guillain-Barré disease, amyotrophic lateral
sclerosis, Friedreich ataxia
OK
Three days to three months • (1) loss of motor nerve control over motor endplates that
results in a proliferation of extrajunctional receptors,
• (2) damaged muscle membranes,
• (3) defective muscle membranes in certain muscle
diseases.
• In the acutely injured state, the critically dangerous
period begins after a grace period of 48 to 72 hours.
Kids ?
• Marked hyperkalemia may also give rise to cardiovascular effects
• Pretreatments given to attenuate the muscle pains also attenuate the increase in plasma potassium to a certain extent.
• Avoid
• Hyperkalaemia after succinylcholine has also been
reported, albeit rarely, in patients with widespread
intra-abdominal infection, severe trauma and closed
head injury.
• Mind it – not sickle cell
Sick cell syndrome
• SCh can increase the intraocular pressure (IOP)
• Increased IOP reaches a maximum approximately 2
minutes after SCh is administered and disappears in
approximately 6 minutes
• Acute eye injuries – really want scoline – precurarize
and go deep before intubation
Clinical relevance ??
• Increased intragastric pressure of
approximately 40 cm H2O occurs after
scoline
• blunted by pretreatment using a NDP
drug and a larger dose of SCh (1.5 mg/kg) to
achieve good intubating conditions
• GE sphincter also contracts – no problem
• In hiatus hernia ?
ICT
• Increased intracranial pressure can occur via muscle fasciculations, creating a venous pressure elevation in epidural and jugular veins, and through increased cerebral blood flow
• Pretreatment with NDPs • Don’t allow insufficient anesthesia and
hypercapnia
• The direct vagal effect (muscarinic) produces sinus
bradycardia, especially in patients with high vagal
tone, such as children and the physically fit.
• Repeat doses – dangerous
• Glyco or atropine Pretreatment
• Nodal rythms
Masseter
• Administration of succinylcholine has been observed
to give rise to masseter muscle spasm. This may be
severe in some patients, making laryngoscopy and
intubation difficult
• Harbinger of malignant hyperthermia !!
scoline apnea
• Stop breathing
• Operation over ! Wake up ??!
• little effort to cough or breathe
• The pulse rate and blood pressure rise.
• Patients may sweat and the pupils may dilate. This
occurs because the patient becoming aware but is
still paralysed.
• Inherited reductions in butyrylcholinesterase activity occur because
of mutations at a single autosomal location on the long arm of
chromosome 3.
• Physiologic reductions may occur with extremes of age and during
pregnancy.
• reduced availability of the enzyme in the presence of other
substrates (e.g. etomidate, ester local anaesthetics, methotrexate
and esmolol).
•
Some more causes
• Causes of reduced plasma cholinesterase activity include
reduced enzyme synthesis (e.g. liver disease, carcinomatosis,
starvation and renal disease); enzyme inhibition by other drugs
(e.g. neostigmine, organophosphorus compounds and
metoclopramide);
• plasma cholinesterase activity as low as 150 u litre (normal
range 677--1,560) did not cause the clinical duration of
succinylcholine to exceed 22min.
Dibucaine
• Plasma cholinesterase also named- butyryl cholinesterase
• Butyryl choline intravenously, the enzyme converts it to
the products butyric acid and choline.
• it hydrolyses succinylcholine, in two stages to succinyl
monocholine and choline, then to succinic acid and a
second molecule of choline.
• Dibucaine inhibits normal butyrylcholinesterase activity,
reducing the ability to convert butyrylcholine to its
byproducts
Dibucaine number
• Plasma + benzoyl choline – light emitted • Percentage of plasma cholinesterase inhibited by 10
-5 molar solution dibucaine • Normal is 75 – 85 • E u E u
• E a E u
• E a E a
• E f
• E s
Taken from the internet and books for closed academic purpose only
Scoline apnea
• IPPV and sedation • Send blood for cholinesterase level • Fresh blood • FFP
• And wait Vaisiya chettiyar- community prone
for apnea
• post-operative care of patient and families
• Suxamethonium apnea in a 72 year old Case report –
• Any non depolarizer with metabolism by plasma cholinesterase
• Innumerable problems with scoline but the ideal drug for RSI and laryngospasm
• But with the onslaught of rocuronium and suggamadex -- ?
• Is it not the time to stop the use of Scoline® (suxamethonium chloride) for rapid sequence intubation?
Summary
• Structure, chemistry • Dose- pharmacokinetics • Pharmacodynamics and mechanism • Dual block • Advantage • Side effects • Scoline apnea