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