Muscle relaxants neuromuscular blocking drugs 2

1. 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.

2. 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

3. 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

4. THE NEUROMUSCULAR JUNCTION

5. PHYSIOLOGY OF NEUROMUSCULAR TRANSMISSION

6. FACTORS AFFECTING NMT Muscle 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. CLASSIFICATION OF NON-DEPOLARIZERS LONG ACTING D-TUBOCURARINE METOCURINE DOXACURIUM PANCURONIUM GALLAMINE PIPECURONIUM INTERMEDIATE ACTING ATRACURIUM CIS-ATRACURIUM VECURONIUM ROCURONIUM SHORT ACTING MIVACURIUM RAPACURONIUM

13. 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

14. 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

15. 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

16. CAUSES OF PROLONGATION OF ACTION IN PLASMACHOLINESTERASE DEFFICIENCY PHYSIOLOGICAL PREGNANCY CONTRACEPTIVE PILLS MALNUTRITION LIVER DX CIRRHOSIS HEMODIALYSIS ECHOTHIOPATE (AN EYE DROP)

17. 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

18. 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

19. GALLAMINE SOLELY EXCRETED BY THE KIDNEY HENCE ABSOLATELYCONTRAINDICATED IN RENAL DISEASE CROSSES THE PLACENTA HENCE CONTRAINDICATED IN OBST Vagolytic , causing early, severe tachycardias

20. 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 Laudanosine Laudanosine is a convulsant in high doses, but clinically has not been a problem It is safe in hepatic & renal failure Non-cumulative, even after prolonged infusions Similar duration of action to Vecuronium Expensive

21. CIS-ATRACURIUM Dose 0,15 mg kg -1 or 10 mg Amps 5 ml = 10 mg Features Similar to Atracurium without the histamine release.

22. 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 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

23. 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

24. 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 1 ly eliminated by d liver & slightly by d kidney Expensive.

25. 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.

26. DOXACURIUM B enzylisoquinoline compound closely related to mivacurium and atracurium MOST POTENT CURRENTLY ONSET-10MIN DURATION 3HOURS ELIMINATED UNCHANGED BY THE KIDNEY SLIGHTLY METABOLISED BY PLASMA CHOLINESTERASE

27. METOCURINE BIS-QUARTERNARY AMINE DERVATIVE OF DTC PHARMACOLOGY SIMILAR TO DTC

28. 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

29. 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 mg or Neostigmine 2,5 mg plus Glycopyrrolate 0,4 - 0,6 mg mixed in the same syringe.