Nondepolarizing muscle relaxants

Nondepolarizing muscle relaxants

1. Nondepolarizing Muscle Relaxants Presenter- Dr. Suresh Pradhan Moderator- Prof. UC Sharma

2. History: From Fun Hunting in Jungle to Operation Theatre modern use of NMB’s drugs-1932 1st agent to undergo clinical investigation- INTOCOSTRIN or dTC purified product obtained from plant Chondodendrom tomentosum CURARE – term coined for extracts from these plants " curare " comes from the South American Indian name for the arrow poison, ourare

3. Used to control skeletal muscle spasms in patient with tetanus 1940s dTC administered as an adjuvant to drug-induced electroshock therapy 1942( Griffith and Johnson) used dTC to produce surgical skeletal muscle relaxation during GA

4. 1949, succinylcholine prepared by Dr. Daniel Bovet 1956, distinction between depolarizing and NDM’s blocked made by William D.M. Paton 1964, pancuronium was introduced 1979, vecuronium was introduced 1993, mivacurium released for clinical use 1994, rocuronium introduced to clinical practice

5. Classification Muscle Relaxants are classified as: I)Peripherally acting A. Neuromuscular blocking agents : Depolarizing muscle relaxants Non-depolarizing muscle relaxants B. Directly acting: Dantrolene , Quinine II)Centrally acting Benzodiazipines - Diazepam GABA -B Agonist - Baclofen Central α 2 Agonist - Tizanidine Mephenesin Group - Methenesin , Methocarbamol, Chlorzoxazone

6. Non-depolarizing Muscle relaxants Short acting (15- 20 min) : Mivacurium Intermediate acting (20-50min) : Atracurium Cisatracurium Vecuronium Rocuronium Long acting ( >50min) : Doxacurium Pancuronium Pipecuronium

7. STRUCTURAL CLASSIFICATION broadly divided into steroidal compounds and benzylisoquinoline compunds Steroidal compounds Pancuronium Vecuronium Pipecuronium Rocuronium Rapacuronium Benzylisoquinoline compounds D- tubocurare metocurine doxacurium atracurium mivacurium Cisatracurium Others gallamine alcuronium

8. Clinical Uses NMB’s are co-administrated with anesthetic in the induction phase to induce muscle paralysis facilitate the surgery, especially intra-abdominal and intra-thoracic surgeries facilitate endotracheal intubation in ICU settings- in patients requiring prolonged ventilation especially where it is mandatory to reduce the work of breathing

9. Use of NDMR in Anesthesia maintenance of anaesthesia for intubation where succinylcholine is contraindicated ( rocuronium is of choice) for precurarization to prevent postoperative myalgias by succinylcholine ( dTC and rocuronium )

10. Mechanism of Action competitive antagonism at the post- synaptic ACh Receptors in small clinical doses they act predominantly at the nicotinic receptor site to block Ach at higher does they can block prejunctional Na + channels thereby decreasing ACh release

11. Characteristics of NDMR Blockade Skeletal muscle response in presence of NDMR as evoked by PNS include: Decreased twitch response to a single stimulus Fade during continuous stimulation Post-tetanic potentiation TOF ratio <0.7 Antagonism by anticholinesterase

12. Pharmacokinetics highly ionised and water soluble at physiological pH all NDMR are quarternary ammonium compounds & highly water soluble i.e. hydrophilic hence, they do not cross blood brain barrier & placenta (except Gallamine ) Most of the drugs undergo Renal and Hepatic elimination

13. ED 95 the effective dose of a drug in 95% of individuals for neuromuscular blockers, one often specifies the dose that produces 95% twitch depression in 50% of individuals denotes potency of a NDMR

14. D- Tubocurarine 1 st agent to undergo clinical investigation purified curare – Chondodendrom tomentosum ED 95 = 0.5mg/kg undergoes minimal metabolism- is excreted 10% in urine 45% in bile not extensively protein bound excretion impaired in Renal Failure

15. CVS Effects hypotension frequently even at doses < ED 95 histamine released (skin flushing frequently) autonomic ganglionic blockade- manifests as hypotension Clinical Use long duration of action(60 to 120 mins) and CVS effects restricted its use used as “ precurarization ”

16. Atracurium Bisquaternary ammonium Benzylisoquinoline ED 95 = 0.2 to 0.25mg/kg Intubating dose- 0.5mg/kg. Maintenance- 0.05 to 0.1mg/kg Drug of choice in patient with renal and hepatic dysfunction onset of action= 3-5min (0.5mg/kg) duration of action= 20-35min about 82% is bound to albumin triggers dose-dependent histamine release that becomes significant at doses above 0.5 mg/kg

17. may also cause a transient drop in systemic vascular resistance and an increase in cardiac index can cause bronchospasm in susceptible individuals duration of action can be markedly prolonged by hypothermia and to a lesser extent by acidosis will precipitate as a free acid if it is introduced into an intravenous line containing an alkaline solution such as thiopental two separate processes for metabolism Ester Hydrolysis (2/3)- catalyzed by nonspecific esterases Hofmann Elimination (1/3) -spontaneous nonenzymatic chemical breakdown occurs at physiological pH and temperature

18. Laudanosine Toxicity a tertiary amine breakdown product of atracurium’s Hofmann elimination has been associated with CNS excitation, resulting in elevation of the minimum alveolar concentration and even precipitation of seizures Laudanosine is metabolized by the liver and excreted in urine and bile

19. Cisatracurium potent isomer of Atracurium ED 95 = 0.05mg/kg Intubating dose= 0.2mg/kg Maintainence dose= 0.02mg/kg Duration of action = 30-45 min (0.1 mg/kg) Metabolism similar to Atracurium Hofmann & Ester hydrolysis Side Effects Devoid of histamine- releasing properties even at high doses

20. CLINICAL USES Facilitate tracheal intubation at the dose 3 -4 times ED 95 (0.15 to 0.2mg/kg) Blockade maintained at stable level by continuous intravenous infusion (1-2 µg/kg/min) Elimination independent on end- organ function,so Ideal for ICU @5 µg/kg/min

21. Mivacurium Benzylisoquinoline derivative short duration of action presented as mixture of three isomers (cis-trans, trans-trans, and cis-cis) pharmacology governed by trans-trans and cis-trans ED 95 = 0.08 to 0.15mg/kg Intubating dose= 0.2 or 0.25mg/kg Onset: 2-3 mins Duration of action: 12-20 mins

22. Side Effects Histamine release Hypotension, tachycardia, flushing if dose >0.2mg/kg Bronchospasm rare Clearance Like succinylcholine–metabolized by pseudocholinesterases

23. CLINICAL USES surgical procedure require brief relaxation not recommended for RSI small dose (0.04 to 0.08mg/kg) for LMA maintenance of relaxation by constant infusion(5 to 7µg/kg/min) for intubation and maintenance for short procedures mainly in children

24. Pancuronium Bisquaternary aminosteroid compounds ED 95 = 0.07mg/kg Intubating dose= 0.12mg/kg Longer duration of action = 1.5 to 2 hrs Clearance: 80% of single dose eliminated unchanged in urine 10-40%undergoes hepatic deacetylation to 3-desacetylpancuronium (50% as potent as Pancuronium ) 17-desacetylpancuronium 3,17-desacetylpancuronium

25. CVS EFFECTS- Increased HR, BP, and CO after large doses(2 X ED 95 ) Cause is uncertain but vagolytic effects on postganglionic nerve terminal no histamine release

26. CLINICAL USE slow onset of action limits its usefulness in facilitating tracheal intubation administration in divided doses-small dose given 3 min before induction( priming principle), produce small but measurable acceleration popular in Cardiac anesthesia (counters bradycardia effect of high dose of opioids) Difficult to reverse than other intermediate agents

27. Pipecuronium Bisquaternary Aminosteroid compound ED 95 : 50 – 60 µg/kg Onset: 3 – 5 minutes Duration: 60 – 90 minutes Like Pancuronium , excretion is mainly from kidneys Major advantage is hepatic cirrhosis doesn’t affect the pharmacokinetics/ dynamics of Pipecuronium 10 times less vagolytic than Pancuronium no histamine release. More expensive than Pancuronium

28. Rocuronium Monoquaternary aminosteroid ED 95 : 0.3mg/kg Onset: 1-2 min Duration: 20-35 min Clearance: Largely excreted unchanged in bile (up to 50% in 2 hours) Renal excretion >30% in 24 hrs CVS Effects: No histamine release even at 4XED 95 (1.2mg/kg) May produce slight vagolytic effect Useful in surgery with vagal stimulation ( laparascopic,opthalmologic ) Anaphylactic reaction has been described

29. Clinical Implications Replacement for succinylcholine for rapid sequence intubation (>1mg/kg) Rocuronium and thiopental do not mix- form a precipitation Replacing vecuronium Infusion rates range 5 -10 µg/kg/min

30. Vecuronium Monoquaternary aminosteroid ED 95 = 0.04 to 0.05mg/kg Intubating Dose= 0.12mg/kg Onset: 3-5 mins Duration of blockade: 20-35 mins Clearance Undergo both hepatic metabolism and renal excretion Undergo deacetylation to 3- desacetylvecuronium (50% potent as vecuronium ) 17-desacetylvecuronium 3,17- desacetylvecuronium

31. CVS Effects No CVS effects at clinical doses No histamine release Hepatic dysfunction Elimination half time at dose 0.1mg/kg IV not increased in alcoholic liver disease Dose at 0.2mg/kg IV is associated with prolong elimination half time and corresponding prolong duration of action in hepatic cirrhosis Renal dysfunction Elimination half life of vecuronium and 3- desacetyl vecuronium prolonged with renal failure

32. Clinical Uses CVS neutrality and intermediate duration suitable agents for patient with IHD Like rocuronium , care should taken with thiopental At large dose 0.1-0.2mg/kg facilitate tracheal intubation For maintenance intermittent bolus- 0.01mg to 0.02mg/kg , continuous infusion – 1 to 2µ g/kg/min

33. Gallamine Introduced in 1948 Low potency NDMR (ED 95 = 2mg/kg) Longer duration of action Produced significant tachycardia Used to prevent succinylcholine- induced fasciculation

34. Summary of Pharmacology of NDMR

35. Clinical characteristics of nondepolarizing muscle relaxants

36. Considerations in special population

37. Factors causing altered responses Inhalational Agents Inhalation agents potentiate blockade (dose related) At similar MAC enflurane > isoflurane> halothane Anesthetic induced depression of CNS Decreases the sensitivity of post junctional membrane to depolarization Local Anesthetics Enhance neuromuscular blockade Interfere with pre-junctional release of acetylcholine Stabilize post junctional membranes Directly depress skeletal muscle fibers

38. Gender women are more sensitive to vecuronium than men (duration of blockade longer in women than men) May be related to difference in body composition, volume of distribution and plasma protein concentration Greater muscle mass in men than women Renal Function Aging associated with decreasing renal function; hence decreased clearance of the drug from the body Hepatic Clearance Pancuronium and vecuroniun metabolized significant degree by liver hence prolonged duration of Neuromuscular Blockade (exception atracurium , cisatracurium , and mivacurium )

39. Magnesium Interfere with the Calcium channels in the Pre- Synaptic membrane and cause decreased release of Acetylcholine In pre- eclamptic patient always suspect longer duration of blockade Antibiotics - Aminoglycosides Enhance blockade Neomycin and Streptomycin most potent Mechanism for potentiation of Blockade is similar to that of Magnesium

40. Other Drugs Patients treated chronically with Anticonvulsants (phenytoin, carbamazepine) relatively resistant to Pancuronium , Vecuronium , Rocuronium , Cisatracurium , Doxacurium But NOT to Mivacurium , Atracurium Acute administration of phenytoin has been associated with augmentation of blockade by Rocuronium Hypothermia Slowing of hepatic enzyme activity or metabolism Decreased clearance of the drug and hence prolonged duration of the blockade

41. Burn Injury May cause resistance to effects of non-depolarizing blockade manifest 10 days after injury peaks at about 40 days – declines after about 60 days Approximately >30% of body must be burnt to produce resistance Altered affinity of nicotinic receptors for non-depolarizing muscle relaxants may be the basis for resistance Serum K + Acute hypokalemia- increases transmembrane potential, causing hyperpolarization of cell membrane Increase sensitivity to non-depolarizing blockers Resistance to depolarizing neuromuscular blockers

42. THANK YOU !!!