Muscle relaxants and factors affecting their action

Muscle relaxants and factors affecting their action

1. Muscle Relaxants and Factors Affecting their Actions Dr. Suresh Pradhan

2. Physiology and Pharmacology cell bodies of motor neurons supplying skeletal muscle lie in the spinal cord information is carried by an elongated axon that ends in a specialized structure that is designed for the production and release of ACh main site of action of the muscle relaxants is on the nicotinic cholinergic receptors at the end plate of the muscle

3. Schematic representation of the NMJ

4. Neuromuscular Blocking Agents i nteract with the ACh receptors either by: depolarizing the end plate- depolarizing agents c ompeting with Ach for binding sites- nondepolarizing agents

5. Pharmacologic Characteristics of NMB Drugs t he effect of NMBDs is measured as the depression of adductor muscle contraction/twitch after electrical stimulation of the ulnar nerve pharmacologic characteristics of NMBDs are explained by various descriptors of the clinical effects

6. Descriptors of the clinical effects of Neuromuscular blocking drugs

7. Descriptors of the clinical effects Potency : i s determined by the constricting the dose response curves which describe the relationship between twitch depression and dose the effective dose 95 is a clinically relevant value that corresponds to 95% block of single twitch in 50% of the patients

8. Onset time: a lso known as the time to maximum blockade i s the time from injection of the drug to onset of maximal single twitch depression

9. Duration of action: i s the time from injection of the NMBD to return of 25% twitch height c ategories of NMBDs may be based on their durations of action

10. Recovery index: is the time interval between 25% and 75% twitch height r eflects the speed of recovery after return of twitch a dductor pollicis is the most commonly monitored muscle for determining the onset and duration of action of NMBDs

11. Classification Muscle Relaxants are classified as: Peripherally acting Centrally acting

12. Classification contd … Peripherally acting: A. Neuromuscular blocking agents : Depolarizing muscle relaxants: Succinylcholine Non-depolarizing muscle relaxants B. Directly acting: Dantrolene , Quinine

13. Centrally acting: Benzodiazipines - Diazepam GABA -B Agonist - Baclofen Central α 2 Agonist - Tizanidine Mephenesin Group - Methenesin , Methocarbamol , Chlorzoxazone

14. Depolarising muscle relaxants physically resemble ACh quaternary ammonium compound with + vely charged nitrogen that imparts affinity to – vely charged nicotinic Ach receptor act as agonist (similar to acetylcholine) at postsynaptic nAChR attaches to one or both of alpha sub units of nACh receptor and mimics action of Ach thus they depolarise the post junctional membrane

15. p rolonged depolarization of the endplate region that results in desensitization of nAchR ; inactivation of voltage gated Na channels at NMJ-increases K permeability in surrounding membrane e nd result---failure of action potential generation due to membrane hyperpolarisation and block ensues

16. Characteristics of Depolarizing Blockade Succinylcholine initially produces features characterized as phase I block decreased twitch amplitude a bsence of fade with tetanic stimulation s imilar decrease in the amplitude of all twitches in the train-of-four ratio (>0.7) a bsence of post-tetanic potentiation a ntagonism by non-depolarizing muscle relaxants a ugmentation by anticholinesterase drugs

17. Phase II block develops after prolongs exposure to SCh or high doses of SCh and has characteristics of a non-depolarizing neuromuscular blockade the onset of phase II block coincides with the appearance of tachyphylaxis to the effects of SCh

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

19. 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

20. 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

21. Characteristics of Non-Depolarizing Blockade decreased twitch amplitude fade with tetanic stimulation train-of-four ratio <0.7 post-tetanic potentiation absence of fasciculations antagonism by anticholinesterase drugs augmentation by other non-depolarizing muscle relaxants

22. Factors Affecting Action of NMBDs Inhalational Agents i nhalation agents potentiate blockade (dose related) at similar MAC enflurane > isoflurane> halothane a nesthetic induced depression of CNS d ecreases the sensitivity of post junctional membrane to depolarization

23. Intravenous Anesthetics : light potentiation of neuromuscular blockade has been demonstrated with high doses of most intravenous induction agents in animals studies however, clinical doses of drugs such as midazolam, thiopental, propofol, fentanyl, and ketamine have little or no neuromuscular effect in humans

24. Local Anesthetics enhance effects of all neuromuscular blockers interfere with pre-junctional release of Ach, hence produce neuromuscular blockade in their own stabilize post junctional membranes directly depress skeletal muscle fibers

25. Interactions Between Non-depolarizing Blocking Drugs: c ombinations of two non-depolarizing neuromuscular blocking drugs are either additive or synergistic, depending on which two drugs are involved a ddition occurs when the total effect equals that of equipotent doses of each drug atracurium and cisatracurium have an additive interaction cisatracurium and rocuronium have synergestic effect

26. Nondepolarizing –Depolarizing Interactions : d epolarizing and nondepolarizing relaxants are mutually antagonistic w hen d - tubocurarine or other nondepolarizing agents are given before succinylcholine to prevent fasciculations and muscle pain , the succinylcholine is less potent and has a shorter duration of action

27. Gender women are more sensitive to vecuronium than men (duration of blockade longer in women than men) m ay be related to difference in body composition, volume of distribution and plasma protein concentration g reater muscle mass in men than women

28. Renal Function aging associated with decreasing renal function; hence decreased clearance of the drug from the body

29. Hepatic Clearance Pancuronium and vecuroniun metabolized significant degree by liver hence prolonged duration of Neuromuscular Blockade (exception atracurium , cisatracurium , and mivacurium )

30. Hypothermia and Hyperthermia slowing of hepatic enzyme activity or metabolism decreased clearance of the drug and hence prolonged duration of the blockade h yperthermia potentiates the effects of non-depolarizing neuromuscular blockers hypothermia potentiates the effects of depolarizing neuromuscular blockers

31. Magnesium i nterfere with the Calcium channels in the Pre- Synaptic membrane and cause decreased release of Acetylcholine i n eclamptic patient always suspect longer duration of blockade

32. Antibiotics - Aminoglycosides and Polymyxins enhance blockade Neomycin and Streptomycin most potent mechanism for potentiation of Blockade is similar to that of Magnesium

33. Cardiovascular Drugs : Beta ­ blockers and calcium channel antagonists have been found to have neuromuscular effects in vitro, but in practice, the duration of action of neuromuscular blocking agents is not altered in patients taking these drugs chronically ephedrine given at induction of anesthesia has been found to accelerate onset of action of rocuronium while esmolol prolongs onset time

34. the mechanism for this effect is probably by alteration of drug delivery to the site of action by changes in cardiac output it is possible to improve intubating conditions provided by rocuronium by giving ephedrine at induction of anesthesia

35. Other Drugs p atients treated chronically with anticonvulsants (phenytoin, carbamazepine) relatively resistant to Pancuronium , Vecuronium , Rocuronium , Cisatracurium , Doxacurium But NOT to Mivacurium , Atracurium a cute administration of phenytoin has been associated with augmentation of blockade by Rocuronium Metoclopramide: inhbits plasma cholinesterase and prolongs action of SCh and Mivacurium

36. Burn Injury m ay cause resistance to effects of non-depolarizing blockade manifest 10 days after injury peaks at about 40 days – declines after about 60 days a pproximately >30% of body must be burnt to produce resistance a ltered affinity of nicotinic receptors for non-depolarizing muscle relaxants may be the basis for resistance

37. Serum K + acute hypokalemia- increases transmembrane potential, causing hyperpolarization of cell membrane increase sensitivity to non-depolarizing blockers resistance to depolarizing neuromuscular blockers

38. THANK YOU !!!

39. Physiological factors Age- infants- greater dose Old age Electrolyte disturbances Pathological Conditions Drugs