Neuromuscular blocking agents Presentation.pptx

Neuromuscular blocking agents its reversal and neuromuscular monitoring.

1. PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS ITS REVERSAL AND NEUROMUSCULAR MONITORING Moderator : Dr. SHARAD GOEL (PROFSSOR & HOD) Presenter : Dr. MOHIT TANWAR (PG RESIDENT)

2. What is Neuromuscular Junction ( NMJ) The junction between terminal branch of the motor nerve fiber and muscle fiber. Structure of NMJ: - Presynaptic - Synaptic cleft - Post synaptic

3. PRE SYNAPTIC REGION: Synaptic vesicles are present in presynaptic nerve terminal that store acetylcholine. Acetylcholine is synthesized from acetyl and choline , reaction catalysed by enzyme choline acetyltransferase . Synaptic vesicles are synthesized in the neuronal cell body in the endoplasmic reticulum and transported to nerve terminal via micro tubular system. Two pools of vesicles are seen to release Ach , a releasable pool and a reserve pool. Vesicles in the releasable pool are smaller , limited and close to nerve membrane where they are bound to the active zone. The majority of the vesicles are sequestered in the reserve pool and tethered to the cytoskeleton via various proteins including synapsin , actin , synaptotagmin and spectrin . When there is an action potential and calcium ions enter, synapsin becomes phosphorylated , which frees the vesicle from its attachment to the cytoskeleton and release into synaptic cleft. The acetylcholine contained in a single vesicle is often referred to as a QUANTUM of transmitter.

4. Synaptic Cleft : Synaptic cleft contains basal lamina. It is a thin layer of spongy reticular matrix through which, the extracellular fluid diffuses. An enzyme called acetylcholinesterase ( AchE ) is attached to the matrix of basal lamina, in large quantities. Acetylcholine released into the synaptic cleft is destroyed very quickly, within one millisecond by the enzyme Acetylcholinesterase . Ach is hydrolysed into acetate and choline .

5. EVENTS AT NEUROMUSCULAR JUNCTION : NERVE ACTION POTENTIAL ↓ SODIUM INFLUX ,DEPOLARISATION ↓ OPENING OF CALCIUM CHANNEL ↓ CALCIUM ENTERS INTO NERVE ↓ ACH RELEASED ↓ ACH BINDS TO THE POST JUNCTIONAL NICOTINIC Ach RECEPTOR ( nAchR ) ↓ INCREASES SODIUM AND POTASSIUM CONDUCTANCE ↓ DEPOLARISATION OF END PLATE IS PRODUCED ↓ GENERATION OF ACTION POTENTIAL ↓ TRANSMISSION OF ACTION POTENTIAL ALONG SARCOLEMMA TO OPEN TUBULAR CALCIUM CHANNELS ↓ MUSCLE CONTRACTION

6. NEUROMUSCULAR BLOCKERS : Neuromuscular blockers are the drugs, which prevent transmission of impulses from nerve fiber to the muscle fiber through the neuromuscular junctions. These drugs are used widely during surgery and trauma care. Neuromuscular blockers used during anesthesia relax the skeletal muscles and induce paralysis so that surgery can be conducted with less complication. Following are important neuromuscular blockers, which are commonly used in clinics and research.

7. Decamethonium

8. NEUROMUSCUALR MONITORING: TOF PATTERN (TRAIN- OF -FOUR) It allows the anesthesiologist to administer these agents with appropriate dosing. To ensure that the patient recovers adequately from residual effects of the NMBD. The principle was to produce a pattern of stimulation that did not require the comparison of evoked responses to a control response obtained before administration of a neuromuscular blocking drug. The pattern involved stimulating the ulnar nerve with a TOF supramaximal twitch stimuli, with a frequency of 2 Hz, that is, four stimuli each separated by 0.5 s. The TOF was then repeated every 10 s (train frequency of 0.1 Hz).

9. Subjective ( tectile ) evaluation of neuromuscular response at the adductor policis m/s in response to ulnar nerve stimulation. Black (negative) electrode is distal to the Proximal Red(positive) electrode. Subjective ( tectile ) evaluation of neuromuscular response at the orbicularis oculi m/s in response to facial nerve stimulation. Black (negative) electrode is distal to the Proximal Red(positive) electrode.

10. choice of Monitoring sites: 1)Away from surgical sites 2) For visual & tectile monitoring site should be accessible to anesthetist. 3)NIBP and SpO2 on different limb 4)For UMN disease avoid affected limb. Area over which electrode are placed: \ 1)clean skin with alcohol swab 2)should be dry 3)NO Hairs, No oils 4)Do not overlap electrodes 5)Fix electrode with tape

11. When a non-depolarizing agent is given, a typical pattern is observed. There is a reduction in the amplitude of the evoked responses, with T4 affected first, then T3, followed by T2, and finally T 1 . This decrement in twitch height is known as   fade . As the non-depolarizing block becomes more intense, T4 disappears followed by T3, T2, and finally T1. The reverse is true during recovery from non-depolarizing block: T1 reappears first followed by T2, T3, and finally, T 4  . The TOF pattern is less useful in monitoring depolarizing neuromuscular block. During onset of depolarizing block, each of the four twitches is decreased equally in size, that is, there is no fade. This is also observed during recovery. However, if larger doses of depolarizing agent are given, for example in techniques that require repeated bolus doses or infusions of succinylcholine, then a Phase 2 block may develop. This is a block produced by a depolarizing drug which develops some of the characteristics of a non-depolarizing block. With TOF monitoring, fade is observed.

12. ABOUT 0-75% OF Ach R become antagonized when 4 th twitch from TOF disappears. 80% when 3 rd twitch disappears. 90% when 2 nd twitch disappears. 95-100% when 1 st twitch disappears. Adequate relaxation for surgery is present when 1 to 2 twitches of the TOF are present. Recovery Return of 4 th response to TOF heralds recovery phase T 4 /T 1 ratio > 0.9 exclude clinically important residual NM Blockade Antagonism of NM Blockade should not be initiated before at least two TOF responses are observed

13. Depolarizing Muscle Relaxants SUCCINYLCHOLINE : The only depolarizing muscle relaxant in clinical use today is succinylcholine . Physical Structure Succinylcholine—also called suxamethonium —it is a long ,thin flexible molecule composed of two molecules of acetylcholine linked through the acetate methyl groups. Like acetylcholine stimulate cholinergic receptor at the NMJ and at Nicotinic(ganglionic) and muscarinic autonomic site(thus cause increase intraocular & intragastric pressure).

14. Mechanism of Action: They depolarize muscle end plates by opening Na+ channels (just as ACh does) and initially produce twitching and fasciculations. Continuous end-plate depolarization causes muscle relaxation because the opening of perijunctional sodium channels is time limited (sodium channels rapidly “inactivate” with continuing depolarization. After the initial excitation and opening these sodium channels inactivate and cannot reopen until the end-plate repolarizes.

15. Upper gate- Voltage dependent gate Lower gate- Time dependent/Inactivation gate Lower gate- Time dependent/Inactivation gate L ower gate-Time dependent 3 Schematic of the sodium channel. The sodium channel is a transmembrane protein that can be conceptualized as having two gates. Sodium ions pass only when both gates are open. Opening of the gates is time dependent and voltage dependent ; therefore, the channel possesses three functional states. At rest, the lower gate is open, but the upper gate is closed. When the muscle membrane reaches threshold voltage depolarization, the upper gate opens, and sodium can pass . Shortly after the upper gate opens, the time-dependent lower gate closes. When the membrane repolarizes to its resting voltage, the upper gate closes, and the lower gate opens.

16. Pharmacodynamics : Blockade develops faster in centrally located muscles (larynx, jaw, diaphragm) ; less profound & recovers more Quickly So the sequence of blockade is: ( Face-Jaw-Pharynx-Larynx -Respiratory- Trunck m/s- Limb m/s ) . Orbicularis oculi response to Facial nerve stimulation preferred as indicator of neuromuscular block at laryngeal muscle .

17. Pharmacokinetics: Intubating dose 1-1.5mg/kg (I/V) Infants and small children- 2 mg/kg (I/V) (greater volume of distribution) Onset of action: 60 sec(1mg/kg of SCh results in complete suppression of response to neuromuscular stimulation ) Duration of action: 9-13 minutes Elimination: t ½ :47 sec. It also appears that there are no advantage to using SCh doses larger than 1.5mg/kg in a rapid sequence induction of anesthesia. The drug is hydrolysis by plasmacholinesterase (Butyrylcholinesterase) into succinic acid and choline. Eighty percent of the administered dose is hydrolysed before it reaches the NMJ.

18. PHASE I BLOCK: The end plate depolarization initially stimulates muscles contraction bcoz SCh is not degraded by Ach, it remain in the neuromuscular junction to cause continuous end plate depolarization and subsequent m/s relaxation. This is termed as phase I block. This gives characteristic non Fade equal depression of stimuli in TOF. PHASE II BLOCK: Phase II block occurs due to continuous exposure to depolarizing muscle relaxants. associated with a fade phenomenon. Phase II block may be seen clinically with doses of SCh >4mg/kg. Also referred as desensitization block . Fade is due to the interaction of depolarizing action of SCh on prejunctional ACHRS. Factors affecting phase 2 block are Duration of exposure( given as an infusion) Drug and concentration Type of muscle(fast/slow)

19. Short duration of action is due to its rapid hydrolysis by Butyrylcholinestrase (tetrameric glycoprotein synthesis in liver) succinylmonocholine and choline-succinic acid and choline. Neuromuscular block induced by succinylcholine or Mivacurium can be significantly prolonged if the patient has an abnormal genetic variant of Butyrylcholinesterase. ACTION TERMINATES AS SCH DIFFUSE AWAY FRM NMJ. ONSET & DOA depend– RATE OF HYDROLYSIS Butyrylcholinesterase Synthesized in liver and found in plasma. Level<75%,important for prolongation of Sch effect. Factors decreasing butyrylcholinesterase activity are : Advanced liver disease Malnutrition, burns Advanced age Pregnancy Chemotherapy drugs like cyclophosphamide Cytotoxic drugs, anticholinestrases , OCPs, MAO inhibitors, metochlopromide .

20. Analysis of butyrylcholinesterase activity involves: 1)determination of 2)biochemical phenotype enzyme activity. use of specific enzyme inhibitors (dibucaine and fluoride) or by molecular genetics. Dibucaine number Dibucaine is a amide group local anesthetic. Dibucaine Number is the percent of pseudocholinesterase enzyme activity that is inhibited by dibucaine. It is important to recognize that the Dibucaine number reflects quality of cholinesterase enzyme(ability to hydrolyze succinylcholine) If dibucaine number =80 :normal variant

21. Type of Butyrylche Genotype Incidence Dibucaine number Response of Sch Homozygous Typical E 1 u E 1 u Normal 70-80 Normal Heterozygous atypical E 1 u E 1 a 1/480 50-60 Lenthened by 50-100% Homozygous atypical E 1 a E 1 a 1/3200 20-30 Prolonged by 4-8hrs

22. Indications: Medical procedures requiring short term muscle paralysis Endotracheal intubation Neuromuscular surgeries Electroconvulsive therapy Orthopedic surgery Fractures alignment & correction of dislocation Procedures like Laryngoscopy Bronchoscopy Esophagoscopy .

23. Side Effects of Succinylcholine: Hyperkalemia ( Normally leads to 0.5meq/ lt increase in K+ which is insignificant ) (d/t upregulation of immature Ach R in Burns, severe abdominal infection, severe metabolic acidosis, closed head injury patients) Increased intraocular pressure(d/t contraction of tonic myofibrils,transient dilation of choroidal blood vessels) Increased intragastric pressure(d/t the intensity of fasciculation of the abdominal SK m/s, or by direct increase in vagal tone) Increased intracranial pressure(d/t increase CO2 and histamine level leads to vasodilation and increase resistance to venous outflow) Myalgias(d/t muscle damage by SCh induced Fasciculations, secreations of prostaglandin and cyclooxygenase) Malignant Hyperthermia( Hypermetabolic disease of skeletal muscles) Sinus Bradycardia

24. Contraindications: Muscular disorders Muscular dystrophy Myasthenia gravis Crush injury Burns Glaucoma Head injury Neurological disorders : Gullain Barre syndrome Stroke paralysis Paraplegia Hemiplegia

25. NON DEPOLARISING/ COMPETITIVE NMBDs History In 1942 Griffith & Johnson suggested that d- tubocuranine is a safe drug to use during surgery In 1967 Baird & Reid first administered pancuronium Vecuronium , a amino steroid & atracurium , a benzylisoquinolium introduced in 1980 Mivacurium introduced in 1990 All modern agents are entirely synthetic

26. CLASSIFICATION OF NON-DEPOLARISING MUSCLE RELAXANT :

27. 1.BENZYLISOQUINOLINIUM COMPOUNDS 1 (a)TUBOCURARINE : Onset of action is slow and recovery is slow Long duration of action Not indicated for use in patients with hepatitis or renal failure Intubation dose-0.5-0.6 mg/kg Maintainence dose-0.1-0.2mg/kg Not used now because of its highest propensity for ganglion blockade causing severe hypotension, also cause histamine release .

28. 1(b) ATRACURIUM: Racemic mixture of 10 sterioisomers , seperated into 3 groups designated, cis-cis, cis-trans and trans-trans based on their configuration about Tetrahydroisoquinoline . Should be stored at 4 degree celsius Intubation dose : 0.5-0.6mg/kg Maintainence dose-0.1 mg/kg Infusion dose : 4-10 mcg/kg onset : 2-3 mins Duration of action : 20-30 mins Elimination half life -21 mins Metabolised through 2 pathways-HOFMANN(a spontaneous nonenzymatic chemical breakdown occurs at physiological pH and temp) elimination & NON SPECIFIC ESTER hydrolysis. Atracurium is relatively stable at pH 3.0 and 4 degree celcius temperature and becomes unstable when it is injected into the blood stream and it undergoes spontaneous degradation yielding LAUDONOSINE and mono quaternary acrylate as metabolites. Laudanosine is about 70% excreted in the bile and rest in urine Laudanosine easily crosses BBB and has CNS stimulating properties. However adverse effects are unlikely to occur with atracurium use in operating room or the ICU. Can cause dose dependent HISTAMINE release. As atracurium metabolism is not dependant on hepatic and renal functions ,it is RELAXANT OF CHOICE for –HEPATIC FAILURE, RENAL FAILURE,NEW BORN (immature hepatic/renal functions ), OLD AGE , Neuromuscular disease like myasthenia gravis. It cause Histamine release ( flushing,bronchospasm,itching,hypotenion,tachycardia )

29. 1(c) cis -ATRACURIUM: It is the 1R cis -1’R cis isomer of Atracurium. Intubation dose -0.15-0.2 mg/kg Maintenance dose 0.02mg/kg It represents 15% by weight of the marketed atracurium and more than 50% of the potency. Like Atracurium it is metabolized by HOFMANN elimination to laudanosine and mono quaternary acrylate metabolite. Cis atracurium iss about 4 to 5 times as apotent as Atracurium.There is over 5 times less production of laudanosine . There is no ester hydrolysis Does not cause histamine release 1(d) MIVACURIUM : Consist of mixture of three stereoisomers. Intubation dose :0.15-0.25mg/kg Maintenance dose :0.05mg/kg Time to maximum block:2-3 mins Duration of action :5-10 mins It is metabolised by butyrlcholinestrase at about 70% to 88 % the rate of succinylcholine . Prolonged block is expected in conditions causing low byutyrylcholinestrase levels ( eg . Liver disease , hypoproteinemia, drugs like metoclopramide,neostigmine , betablockers) May Causes histamine release,especially if administered rapidly. It cause Histamine release ( flushing,bronchospasm,itching,hypotenion,tachycardia )

30. 2.STERIODAL COMPOUNDS 2(a) PANCURONIUM : Potent long acting NMBD with both vagolytic(block reuptake norepinephrine) and butyrylcholinestrase inhibiting properties. Intubation dose :0.08-0.12mg/kg Maintenance dose :0.02mg/kg Duration of action : 70-90mins Elimination half life -132 mins Metabolism:40-60% of pancuronium is cleared by kidney, 11% excreted in the bile,15-20 % metabolised by deacetylation in the liver. Accumulation of the 3-OH metabolite is responsible for prolongation of the dusration of block induced by Pancuronium . At room temperature Pancuronium is stable for 6 months.

31. . 2(b) VECURONIUM : Is simply Pancuronium without the quaternized methyl group, this minor structural difference means vecuronium has, slightly decreased potency, Loss of vagolytic properties of pancuronium . Molecular instability leading to shorter duration of action Increased lipid solubility, leading to greataer biliary elimination Intubation dose :0.08-0.12 mg/kg Infusion dose: 0.01-0.02 mg/kg Duration of action :40-50 min Principal organ of elimination is liver 30-40% of vecuronium is cleared in the bile as parent compound, 30% renally excreted. Metabolised in liver by acetylation, the 3-OH metabolite has 80% neuromuscular blocking potency of vecuronium. Available as lyophilised powder because it is less stable in solution.

32. 2(c) ROCURONIUM: Fast onset of action Intubation dose: 0.6 -1.0mg/kg Maintenance dose:0.1 mg/kg Duration of action : 20-30mins Six time less potent than vecuronium Rocuronium (0.1mg/kg) has been shown to be a rapid (90 sec) and effective agent to decrease fasciculations and post tetanic post operative myalgias . It is Primarily eliminated by liver and excreted in bile. At room temperature rocuronium is stable for 60 days. Rocuronium and Sch both are used in RSI(rapid sequence induction).

33. 3.CHLOROFUMARATES. 3(a) GANTACURIUM: Ultra short acting drug similar to SCh. Pattern of blockade similar to SCh. Dose: 0.2mg/kg Time of onset is :1-2 mins Duration of action :5-10 mins Causes histamine release. Recovery can be accelerate by Edrophonium, and administer by Exogenous Cysteine. 3(b) CW 002: Is benzylisoquinolinium fumarate ester based compounds Investigational drug Intermediate duration of action :60-70min Metabolism and Elimination similar to Gantacurium .

34. FACTORS THAT INCREASES THE POTENCY OF NON DEPOLARISING NMBDs: > Inhalational anaesthetics potentiates the neuromuscular blocking effect of non depolarising NMBDs. > Rank of order of potentiation : Desflurane > Sevoflurane, Isoflurane > Halothane > Nitrous oxide – Barbiturates – Opoids – or Propofol anasthesia . > Some antibiotics: Aminoglycosides, Lincomycin , Clindamycin, Polymixin . > Hypothermia and Magnesium sulfate > Combining two non depolarising NMBDs of chemically related drugs have ADDITIVE effect [ eg atracurium and mivacurium] > Combining two structurally disimilar drugs have SYNERGISTIC effect [ eg rocuroniun and mivacurium]

35. FACTORS THAT DECREASES THE POTENCY OF NON DEPOLARISING NMBDs : Resistance has been seen in patients receiving chronic anticonvulsant therapy. Patients with bipolar disorder taking LITHIUM , prolongs the block. In hyperparathyroidism, hypercalcemia is associated with decreased sensitivity to atracurium

36. GENERAL PHARMACOLOGY OF NON- DEPOLARISING NMBDs TEMPERATURE: Hypothermia prolongs blockade by decreasing metabolism ACID BASE BALANCE : Respiratory acidosis potentiates blockade and antagonises its reversal. ELECTROLYTE ABNORMALITY: Hypokalemia , Hypocalcemia , Hypermagnesemia augments a non depolarising blockade AGE : ● Neonate have increased sensitivity because of their immature NMJ. This sensitivity does not necessarily decrease dosage requirements as neonate’s greater extracellular space provides largest volume of distribution . ● In ELDERLY AND OBESE , there is prolonged duration of non depolarising NMBDs except cis atracurium . ‘ CONCURRENT DISEASE: Cirrhotic liver disease and kidney failure results in increase volume of distribution and lower plasma conc. Thus greater initial loading dose but smaller maintanence dose might be required in these diseases

37. ADVERSE EFFECTS OF NEUROMUSCULAR BLOCKERS A) AUTONOMIC EFFECTS: Tachycardia Hypotension Dysrythmias – pancuronium + halothane Bradycardia – when combined with opiods , can even lead to asystole – Tubocurarine administration is associated with marked ganglion blockade resulting in hypotension - Pancuronium has a direct vagolytic effect leading to tachycardia B) HISTAMINE RELEASE: Erythma of face, neck, and upper part of torso may develop, as well as hypotenion and Reflex Tachycardia. Can cause bronchospasm in patients with hyperactive airway disease.[ Rapacurium has highest incidence – withdrawn] Seen with d-Tubocurarine, atracurium and mivacurium Histamine release are decreased by slowing the injection rate. TREATEMENT: Anti histaminics

38. C) ALLERGIC REACTION: IgE mediated Life threatening reactions 1 in 1000 to 1 in 25,000 TREATEMENT: 100% oxygen inhalation i.v epinephrine-10 to 20 µg/kg Early tracheal intubation in case of developing angioedema. Fluids (crystalloids/crystals) Dysrythmias should be treated , if they occur. Norepinephrine or a sympathomimetic drug(phenylephrine) may also be necessary to maintain perfusion pressure.

39. Reversal (Antagonism) of NM blockade : WHO NEED REVERSAL? Who received nondepolarizing NMBDs. . Given once patient shows some signs of spontaneous Recovery ( spont respiration) & TOF shows Atleast two twitches, otherwise they might potentiate the effect of non depolarizing NMBDs Theoretically possible by three principal mechanisms : 1· A decrease in enzymatic metabolism of acetylcholine by cholinesterase, thereby increasing receptor binding competition. 2. An increase in presynaptic release of acetylcholine 3. A decrease in the concentration of the NMBD, hence, freeing the postsynaptic receptors

40. ANTAGONISM NEEDED AT: NICOTINIC END ANTICHOLINESTERASES: MUSCARINIC END ANTICHOLINERGICS: NEOSTIGMINE PYRIDOSTIGMINE EDROPHONIUM GLYCOPYRROLATE ATROPINE SCOPOLAMINE

41. NEOSTIGMINE: • Carbamate with Quaternary Ammonium Group • lipid Insoluble ; doesn’t cross BBB • recommended dosage- 0.04 – 0.08 mg/kg (maximum of 5mg in adults) • repeating the dose has no benefit as AChE are already maximally inhibited Onset : 5 to 10 minutes ( peak at 10 min) duration : lasts for more than 1 hour paediatric and geriatric patients: onset is more rapid requires smaller dosing duration of action is prolonged in GERIATRIC PATIENTS.

42. • Disadvantages – High incidence of nausea and vomiting, pruritis. Muscarinic side effects are minimized by prior or concomitant administration of an Anticholinergic. Glycopyrolate dose with neostigmine : 1/5 th to 1/6 th . ( Eg if we have given 50 micro grams/kg of neostigmine , we will give 8 micrograms/ kg glycopyrolate )

43. PHYSOSTIGMINE: Natural alkaloid derived from Calabar bean ( Physostigma venenosum ) Tertiary amine Lacks quaternary ammonium : lipid soluble Doses: 0.01-0.03mg/kg Penetrates CNS: limits use as reversal agent effective in reversing: central anticholinergic actions due to Atropine or Scopolamine over dosages; Benzodiazepine and volatile anaesthetic induced CNS depression and delirium; effective in preventing post-operative shivering (0.04mg/kg) Almost completely metabolized by plasma esterases . Physostigmine may also be used to reverse the ventilatory depression cause by Morphine without decreasing its analgesic effects Physostigmine (40ugm/kg/IV) decreases the incidence of postoperative shivering

44. PYRIDOSTIGMINE : Carbamate with Quaternary Ammonium Group only as 20% as potent as Neostigmine dose : 0.1 to 0.35 mg/kg (Max of 20 mg in adults) onset : Slower – 10 to 15 minutes duration : Longer - > 2 hours preferred Anticholinergic : Glycopyrrolate 0.05 mg per mg of Pyridostigmine If Atropine used; 0.1 mg per mg of Pyridostigmine

45. EDROPHONIUM: Quaternary Ammonium Group lacks carbamate group unlike other agents, it forms reversible electrostatic attachment to the enzyme less than 10% as potent as Neostigmine dose : 0.5 – 1 mg/kg most rapid Onset : 1-2 min shortest duration / but higher doses prolong the duration to >1 hour

46. SUGAMMADEX: Physical Structure-It is a novel selective relaxant binding agent. Three-dimensional structure resembles a hollow truncated cone or doughnut with a hydrophobic cavity and a hydrophilic exterior. It is modified Y-cyclodextrin. MECHANISM: Hydrophobic interactions trap the drug ( eg , rocuronium ) in the cyclodextrin cavity (doughnut hole), resulting in tight formation of a water-soluble guest–host complex in a 1:1 ratio. Terminates the neuromuscular blocking action and restrains the drug in extracellular fluid where it cannot interact with Nicotinic Acetylcholine receptors. Eliminated unchanged via the kidneys. Clinical Considerations Doses of 4–8 mg/kg. Injection of 8 mg/kg, given 3 min after administration of 0.6 mg/kg of rocuronium, recovery of TOF ratio to 0.9 was observed within 2 min. Produces rapid and effective reversal of both shallow and profound Rocuronium-induced neuromuscular blockade.

47. Whereas Anticholinesterase drugs, such as neostigmine, are unable to reverse deeper levels of neuromuscular blockade (e.g., posttetanic count of 1-2) because of a ceiling effect, sugammadex is effective in reversing profound neuromuscular blockade. Optimal doses of sugammadex of 4.0 mg/kg produced prompt recovery of the TOF ratio to 0.90 within minutes. Therefore reversal of moderate and profound rocuronium and vecuronium neuromuscular blockades can be reliably achieved by administration of sugammadex , provided a dose of 2.0 and 4.0 mg/kg, respectively, is used. Because neostigmine has neuromuscular effects when given alone, some spontaneous recovery of the TOF should be evident before it is given. In contrast, sugammadex has no neuromuscular effects when given alone. Accordingly, sugammadex can be given even if there is no response to TOF stimulation. Sugammadex allows a profound neuromuscular blockade to continue until the end of surgery.

48. Advantages over Anticholineesterases : No Cardiovascular side effects No bronchospasm , so safe in pulmonary disease. Not recommended for use in Renal failure or Renal transplant patients because sufficient research is not yet been done to ensure safety. Should be used with caution in patients with hepatobiliary disease. Reduces effectiveness of OCPs. So a non hormonal contraceptive method should be used for 7 days after its use in female patients. Should use Total body weight instead of lean body weight to calculate Dose of sugammadex in obese patients with bmi above 30. LBW = Ideal BMI * Height (in meter square) . Safe for use in pregnant and breast feeding mothers.

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