MUSCLE RELAXANTS pharmacokinetics and pharmacodynamics.pptx

BRIEF DESCRIPTION ON MUSCLE RELEXANTS THEIR TYPES ,USE , BENFITS WITH REVERSAL AGENTS

1. MUSCLE RELAXANTS MODERATOR - Dr Amit Kumar Singh PRESENTER - Dr Ankush Gautam

2. Contents Introduction Classification of muscle relaxants Depolarising drugs Nondepolarizing muscle relaxants Reversal agents

3. Introduction Muscle relaxants are neuromuscular blocking agents that act on the neuromuscular junction muscle fibre itself or centrally in cerebrospinal axis to reduce muscle tone and/or cause paralysis. Neuromuscular blocking drugs (NMBDs) have been integrated into most anaesthetic techniques for major surgery, while centrally acting muscle relaxants are used mainly for painful muscle spasms and spastic neurological conditions.

4. Classification On the basis of site of action Centrally acting muscle relaxants Peripherally acting muscle relaxants Peripheral acting NDMR further divided into Depolarising (succinylcholine) Non depolarising ( pancuronium , vecuronium, atracurium, cistracurium ) Non-depolarising muscle relaxants on the basis of chemical class Steroidal compounds Benzylisoquinolinium

5. Classification of Centrally acting muscle relaxants ( i ) Mephenesin Mephenesin , congeners Carisoprodol, Chlorzoxazone, Chlormezanone, Methocarbamol. (ii) Benzodiazepines Diazepam and others. (iii) GABA mimetic Baclofen, Thiocolchicoside (iv) Central α 2 agonist Tizanidine

6. Structure of Receptor Adult mature acetylcholine receptor: α 2 βδε Foetal immature receptor: α 2 βγδ Presynaptic: α 3 β 2

7. Depolarizing NMBA -Mechanism of action

8. Phase 1 block : Perijunctional sodium channel – cannot reopen until end plate repolarizes The endplate cannot repolarize if the depolarization muscle relaxant continues to bind to Ach receptors – phase 1 block Phase 2 block : Continous exposure of neuromuscular blocking agent After a period, prolonged end plate depolarization can cause poorly understood changes in the Ach receptor that result in the phase 2 block

9. Phase 1 block: Depolarising block No fadae during repetitive stimulation No post tetanic facilitation Block antagonized by butrylcholinesterase Phase 2 block : Non depolarizing block Fade during repetitive stimulation Post tetanic facilitation Block antagonized by administering a cholinesterase inhibitor

10. Succinylcholine Long thin flexible molecule 2 molecules of acetylcholine linked through the acetate methyl groups ONSET:1 minute(for complete suppression of N-M response) Elimination half life: 47 sec DURATION- 9 to 13 minutes DOSE: 1-1.5 mg/kg IV; 4mg/kg IM If given repetitive dose Behaves like NDMR = Phase II Blockade

11. Butyrylcholinesterase Normal – time to recovery to 90% muscle strength is 9 to 13 mins Synthesised in liver and found in plasma Metabolism of Mivacurium,Succinylcholine,Procaine and Chlorprocaine Sch – hydrolysis to succinylmonocholine and choline

12. Factors decreasing butrylcholinesterse Advanced liver disease Malnutrition Pregnancy Burns , OCPs Anticholinesterase drugs Echothiopate Cytotoxic drugs

13. Dibucaine number Dibucaine number only tells about the quality(percentage of enzyme that is normal), not the quantity. It can be normal, yet the total amount of enzyme may be reduced- for eg , due to liver disease/pregnancy/renal failure etc.

14. Uses of Sch Rapid onset of action, profound depth of blockade and short duration of action Used for rapid sequence induction of anaesthesia and tracheal intubation Used in cases of anticipated difficult intubation For laryngospasm

15. Side effects of SCH Bradycardia, especially in children after 2 nd dose due to muscarinic receptor activation at SA node (succinylmonocholine and choline may sensitize heart to subsequent dose of SCH) Tachycardia, ventricular arrythmia and nodal arrythmia- Autonomic stimuli Increase: ICP, IOP, BP, Gastric pressure, LE sphincter tone Hyperkalemia - Depolarization by SCH causes egress of k+ ions from muscle cells- normally increases serum K+ by upto 0.5 mEq Severe hyperkalemia – metabolic acidosis and hypovolemia Burn: can use SCH within 24 hours of burn, or 2 years after burned skin has healed Massive trauma: use SCH within 1 week, or after 60 days/healing of muscle

16. Fasciculations -disorganized muscle contractions precrurization -pretreatment with small dose of nondepolarizing NMBA (vecuronium – 0.1mg/ kg;Atracurium -0.03mg/kg) Myalgias – neck,back and abdomen Masseter muscle spasm – early indication of malignant hyperthermia Malignant hyperthermia Myoglobinuria – pediatric patients

17. NDMR

18. Nondepolarising muscle relaxants bind to Ach receptors but are incapable of inducing the conformational change necessary for an ion channel opening Neuromuscular blockade occurs even if only one alpha subunit is blocked Decrease in twitch tension Fade during repetitive stimulation Posttetanic potentiation

19. ACTION OF NDMR AND ACETYLCHOLINE

20. Tubocurarine Monoquaternary long acting No active metabolite Excreted unchanged in urine and liver is secondary route for elimination. Slow onset and prolonged action Intubating dose 0.5 to 0.6 mg/kg Maintenance dose 0.1 to 0.2 mg/kg

21. ATRACURIUM Benzylisoquinoline structure ,Intermediate acting Mixture of ten isomers Metabolism : 1/3 rd by Hoffman Degradation 2/3 rd by non specific Alkaline ester hydrolysis Produces metabolite LAUDANOSINE and monoquaternary acrylate Can cause convulsions (seizure threshold is not known in humans) Depends on liver for clearance; hepatic Cirrhosis doesn’t alter clearance but excretion is impaired in bileduct obstruction Dosage: intubating - 0.5mg per kg maintenance - 0.1mg per kg infusion- 5-10 mcg/kg/min

22. Side effects Hypotension and tachycardia Bronchospasm Laudanosine Toxicity Allergic Reactions

23. Cis-atracurium Cisatracurium is a stereoisomer of atracurium that is four times more potent. Like atracurium, cisatracurium undergoes degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate and laudanosine ) have no neuromuscular blocking effects. Dosage - Cisatracurium produces good intubating conditions following a dose of 0.1 to 0.15 mg/kg within 2 min

24. DOC in : renal failure : hepatic failure : Atypical pseudocholinesterase : Myasthenia gravis Cisatracurium is preferred over Atracurium – Does not cause histamine release Cisatracurium is 4-5 times more potent than atracurium

25. Mivacurium Mivacurium is a short-acting, benzylisoquinoline , M etabolized by pseudocholinesterase. Edrophonium more effectively reverses mivacurium blockade than neostigmine because neostigmine inhibits plasma cholinesterase activity. Dosage The usual intubating dose of mivacurium is 0.15 to 0.2 mg/kg. Onset time 2-3 min Relatively short duration than atracurium (20-30 min)

26. Pancuronium : Long acting steroidal NDMR Pancuronium is metabolized (deacetylated) by the liver to a limited degree Dosage Intubation dose- 0.08 to 0.12 mg/kg Maintenance dose-0.04 mg/kg Vagolytic property and butrylcholinesterase -inhibiting properties Available as sol. of 1 or 2 mg per ml Excreted unchanged in urine Side effects Hypertension and tachycardia due to vagal blocked Arrhytmias Allergic reactions

27. VECURONIUM Intermediate acting STEROIDAL COMPOUND Mainly hepatic metabolism Approx. 25% renal excretion Most cardiac stable agent Metabolite of vecuronium: 3 – OH vecuronium has 80% of the NM blocking potency of vecuronium. Therefore, during prolonged administration this metabolite may contribute to prolonged NM blockade. Dosage :intubating -0.08 to 0.12 mg per kg maintenance dose 0.04 mg per kg infusion 1-2 mcg per kg per min Lyophilised powder Side effects :

28. Rocuronium S teroid analogue of vecuronium was designed to provide a rapid onset of action. U ndergoes no metabolism and is eliminated primarily by the liver and slightly by the kidneys Dosage : Intubation- 0.45 to 0.9 mg/kg intravenously ( 1 -2 mg per kg for im inj.) maintenance dose 0.15 mg/kg

29. GANTACURIUM Onset-90 seconds Duration of action- 10 – 15min Half life – 10 minutes Metabolism –metabolized by cysteine adduction in plasma results in replacement of chlorine with cysteine, resulting in formation of heterocyclic ring which cannot interact with post junctional acetylcholine receptor and excreted by kidneys in urine Advantages - Gantacurium is safe in renal and hepatic failure with rapid onset of action CW002 Benzylisoquinolinium fumarate Intermediate acting No histamine release

30. POTENCY OF NMBA Potency of NM agents expressed as dose of drug required to produce an effect ED 50 -50% depression of twitch height ED 95 -95% depression of twitch height Onset of action of NMBA is inversely proportional to potency A low potency drug will have higher number of molecules than a high potency drug , resulting in greater diffusion gradient of low potency drug from capillary to NMJ - resulting in faster onset Eg : Low molar potency drug rocuronium has faster onset as more molecules are administered and they diffuse into the NMJ at faster rate Intubating dose is 2 x ED95 Maintenance dose is ¼ of ED95 for intermediate acting; and 1/10 of ED95 for long acting NDMR

31. REVERSAL OF NEUROMUSCULAR BLOCKADE Acetylcholinesterase inhibitors- MOA- block acetylcholinesterase enzyme, increasing the concentration of ACH at NM junction acetylcholine that accumulates at NMJ competes with residual molecules of NMB drug for available unoccupied nicotinic acetylcholine receptors at NMJ Antagonism by NDMR by Acetylcholinesterase inhibitors depend on- Depth of blockade Anticholinesterase chosen Dose administered Rate of spontaneous clear NM blocker from plasma Choice and depth of anaesthetic agent

32. Neostigmine Increase Ach by blocking AchE enzyme DOSE- 40-70µg/kg PEAK ANTAGONISM- 7 to 11 minutes Advantage: it is quaternary ammonium compound therefore doesn’t penetrate BBB so no central effects seen. S/E: bradycardia : bronchospasm : increase bladder tone : increase secretion : increase peristalsis : meiosis Always to be combined with glycopyrrolate or Atropine Better than edrophonium for deeper block reversal

33. SUGAMMADEX Modified gamma-cyclodextrin molecule composed of 8 glucose molecules forming a ring. Designed to encapsulate aminosteroid NDMR- after which it is excreted in urine Sugammadex has action in the plasma, not at NMJ Exerts its effect by forming tight complexes at 1:1 ratio with steroidal NMBA (Rocuronium>vecuronium>> pancuronium ) Dosing (2 – 16 mg/kg) For Moderate Block: A typical dose is 2 mg/kg for moderate blockade (train-of-four count 2–3). For Deep Block: A typical dose is 4 mg/kg for deep blockade (train-of-four count 0–1). Advantages of Sugammadex Rapid Reversal Faster Recovery Less Dependence on Acetylcholinesterase Activity SIDE EFFECTS – hypersensitivity, should be avoided in patients with creatine clearance < 30 ml per min as it mainly excreted via renal route and increase in APTT and PT

34. Refrences Miller ’ s anaesthesia 9 th edition Stoeltings textbook of physiology and pharmacology 8 th edition K.D Tripathi Essentials of Medical Pharmacology

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