MUSCLE RELAXANTS - NEUROMUSCULAR BLOCKING DRUGS

BY

Dr Oyedepo O. O. (B.Sc.; MBBS; FMCA)Dept. of Anaesthesia,

College of Health Sciences,University of Ilorin. Ilorin.

Nigeria.

OUTLINE

ANATOMY OF NEUROMUSCULAR JUNCTION PHYSIOLOGY OF NEUROMUSCULAR

TRANSMISSION FACTORS THAT MAY AFFECT NMT&NMB CHARACTERISTICS OF IDEAL MUSCLE

RELAXANT CLASSIFICATION OF NMB & DISTINCTION

BTW DMR&NDMR INDIVIDUAL AGENT REVERSAL OF NMB

ANATOMY OF NMJ Each motor nerve sends processes to

each muscle fiber in the motor unit Forming a highly organized and

specialized structure neuromuscular junction, or motor endplate

The invagination of the muscle fiber sarcolemma forms the synaptic trough

The space between the axon terminal and invaginated sarcolemma is called the

synaptic cleft

THE NEUROMUSCULAR JUNCTION

PHYSIOLOGY OF NEUROMUSCULAR TRANSMISSION

FACTORS AFFECTING NMTMuscle relaxants are potentiated by various factors:- Drugs Most of the inhalational anaesthetic agents.

Aminoglycoside antibiotics esp. Gentamycin, Kanamycin. β-Blockers Ca-channel blockers Electrolytes Depressed Ca++

Raised Mg++ Raised K+ Acidosis Temperature -If T° depressed then Suxamethonium is

potentiated. -If T° raised then Non-depolarisers 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, the contractile mechanism responds and the fiber contracts

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, INTERUPTION 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 BLOCK 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

CHARACTERISTICS OF IDEAL MUSCLE RELAXANT

NON DEPOLARZING FAST ONSET FREE OF CVS SIDE EFFECT EASILY ANTAGONISED STABLE PHARMACOKINETIC &

PHARCODYNAMIC IN PRESENCE HEPATIC AND RENAL DISEASES

NO SUCH DRUG YET

CLASIFICATIONS 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

 

EVOKE STIMULUS DEPOLARIZING NON-DEPOLARIZING

TRAIN OF FOUR CONSTANT BUT DIMINISHED

FADE

TETANY CONSTANT BUT DIMINISHED

FADE

DOUBLE BURST STIMULATION

CONSTANT BUT DIMINISHED

FADE

POSTTETANIC POTENTIATION

ABSENT PRESENT

NEED NO REVERSAL OF BLOCK

NEED REVERSAL OF BLOCK

FASCULATION PRESENT FASCULATION ABSENT

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-Aqeous-Temperate

Succinylcholine bromide-Powder-Tropic

Rapid onset, short duration(3-5mins) Indications-To facilitate ETT placement Dose-Intubating dose in adult is 1mg/kg -Xren esp infants is 1.5-2.0mg/kg Rapidly hydrolysed by plasma

cholinesterase

SIDE-EFFECTS Cardiac arrhythmias-sinus bradycardia,

ventricular premature beats Hyperkalaemia esp-massive burns, muscle

trauma, UMNL&LMNL, renal dx and severe abd infx

Raised IOP Raised ICP Raised IGP Scoline pain-ambulant and muscular pts Anaphylactoid rxn Masseter spasm-could erald MH

CAUSES OF PROLONGATION OF ACTION IN PLASMACHOLINESTERASE DEFFICIENCY

PHYSIOLOGICAL

PREGNANCY

CONTRACEPTIVE PILLS

MALNUTRITION

LIVER DX CIRRHOSIS

HEMODIALYSIS

ECHOTHIOPATE (AN EYE DROP)

D- TUBOCURARINE FIRST NMB AGENT USEDD IN ANESTHESIA IT CAUSES MS PARALYSIS WITHIN 3 MINS DURATION= 30-40 MINS (LONG ACTING) CAUSES HYPOTENSION BY 2 MECH 1.SYMPATHETIC GANGLIONIC BLOKAGE 2.HISTAMINE RELEASE METABOLISED IN LIVER & EXCRETED BY

KIDNEY

PANCURONIUM IS AN AMINOSTEROID MS RELAXATION WITHIN 2

MIN RECOMMENDED LOADING DOSE WITHING 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% METABOLISED AND EXCRETED BY THE LIVER DOES NOT RELEASE HISTAMINE CVS- INCR BP DUE TO NOR ADRENALINE

RELEASE - SINUS TACHYCARDA DUE TO ITS

VAGOLYSIS EFFECT

GALLAMINE

SOLELY EXCRETED BY THE KIDNEY HENCE

ABSOLATELYCONTRAINDICATED IN RENAL

DISEASE

CROSSES THE PLACENTA HENCE

CONTRAINDICATED IN OBST

Vagolytic, causing early, severe tachycardias

ATRACURIUM Dose 0.3-0.4 mg kg-1 or 30 mg increment 0.08-

0.1mg kg-1 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 T° (Hoffman degradation).

Hepatic degradation also occurs resulting in the formation of LaudanosineLaudanosine is a convulsant in high doses, but clinically has not been a problem

It is safe in hepatic & renal failureNon-cumulative, even after prolonged infusionsSimilar duration of action to Vecuronium

Expensive

CIS-ATRACURIUM

Dose 0,15 mg kg-1 or 10 mg

Amps 5 ml = 10 mg

Features Similar to Atracurium without

the histamine release.

MIVACURIUM Dose 0.15 mg kg-1 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 (± 10 minutes), with rapid recoveryIt 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-1 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 (± ½ 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-1 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

(± 15 min)High dose provides very fast intubation (± 60 - 90 sec) and long duration

Cardiovascularly stable with a mild increases 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 10ly eliminated by d liver & slightly by d kidney

Expensive.

ALCURONIUM

Dose 0,25 mg kg-1 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-10MIN

DURATION 3HOURS

ELIMINATED UNCHANGED BY THE KIDNEY

SLIGHTLY METABOLISED BY PLASMA CHOLINESTERASE

METOCURINE

BIS-QUARTERNARY AMINE DERVATIVE 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

REVERSAL OF NMB 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 Physiostigmine 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 mgor Neostigmine 2,5 mg plus Glycopyrrolate 0,4 - 0,6 mgmixed in the same syringe.