Anesthetics & Muscle Relaxants PDF

“In the name of GOD” Dr.SE. Mousavi Department of Pharmacology, TUMS 1  ‫تاریخچه‬ ‫‪-‬‬ ‫هدف یا منظور از بیهوش کردن‬ ‫‪-‬‬ ‫مقدمات پیش از بیهوشی‬ ‫‪-‬‬ ‫داروها ( استنشاقی یا وریدی یا ‪)....

“In the name of GOD” Dr.SE. Mousavi Department of Pharmacology, TUMS 1  ‫تاریخچه‬ ‫‪-‬‬ ‫هدف یا منظور از بیهوش کردن‬ ‫‪-‬‬ ‫مقدمات پیش از بیهوشی‬ ‫‪-‬‬ ‫داروها ( استنشاقی یا وریدی یا ‪)...‬‬ ‫‪-‬‬ ‫کار ها و مراقبت های در جریان بیهوشی‬ ‫‪-‬‬ ‫کار ها و مراقبت های بعد از بیهوشی‬ ‫‪-‬‬ ‫بیهوشی مدرن یا نوین‬ ‫‪-‬‬ ‫‪2‬‬ 3  A drug that brings about a reversible loss of consciousness  Generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery. 4 ❖ REVERSIBLE ▪ Sleep induction ▪ Amnesia ▪ Loss of Pain (Analgesia) ▪ Inhibition of Sensory and Autonomic Reflexes ▪ Skeletal Muscle Relaxation 5  Rapid in : INDUCTION Rapid out : RECOVERY ✓ Onset of Action; Smooth ✓ Safe ✓ No Adverse Reaction 6 STAGE I: ANALGESIA (Disorientation, altered consciousness) STAGE II: DELERIUM (Excitatory stage, delirium, uncontrolled movement, irregular breathing, Enhance reflexes. Goal is to move through this stage as rapidly as possible.) 7  STAGE III: SURGICAL ANESTHESIA (return of regular respiration) Plane 1: “light” anesthesia Plane 2: Loss of blink reflex, regular respiration. Surgical procedures can be performed at this stage. Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed. Level of anesthesia for painful surgeries Plane 4: Diaphragmatic respiration only, assisted ventilation is required. Cardiovascular impairment. 8 STAGE IV: MEDULLARY DEPRESSION Too deep; essentially an overdose and represents anesthetic crisis. This is the stage between respiratory arrest and death due to circulatory collapse. ‫اما در عمل این مراحل قابل تفکیک نیست و دیده نمیشود‬ 9 o HR, BP o Respiration : Rate, Depth o Pupillary Size o Pupillary Reflexes o EEG, EKG o etc,... !!!‫خداحافظ‬ 10  Types of Anesthetics I. Inhalation anesthetics (‫) استنشاقی‬ II. Intravenous anesthetics (‫) وریدی‬ 11  Inhaled Anesthetic Agents (‫) استنشاقی ها‬ ‫بصورت گاز یا بصورت مایعی که گاز میشود‬ 1.Gaseous Nitrous oxide (N2O) 2.Volatile liquids Desflurane, Sevoflurane, Isoflurane Enflurane, Halothane, Methoxyflurane 12  Inhaled Anesthetic Agents Mechanisms of Action: Receptors??? Activate GABA-A, GlyR and K+ channels Block Na+ channels and NMDAR Disrupt membrane lipids In general, all general anesthetics increase the cellular threshold for firing, thus decreasing neuronal activity. 13 ▪ Interaction with protein receptors ▪ Volatile A – increase GABA and Glycine (inhibitory neurotransmitters) 14 ‫‪‘Minimum‬‬ ‫‪Alveolar‬‬ ‫’‪Concentration‬‬ ‫غلطتی از داروی بیهوشی در آلوئل ها که جلوی درد را در ‪ %50‬بیماران میگیرد‬ ‫‪ MAC‬توان اثر دارو (‪ )POTENCY‬میباشد‬ ‫‪15‬‬ Nitrous Oxide 100 Desflurane 6 Sevoflurane 2 Enflurane 1.7 Halothane 0.75 Methoxyflurane 0.16  Lipid solubility =  Potency =  MAC 16  Speed of induction is influenced by: 1. Amount that reaches the brain Indicated by oil:gas ratio (lipid solubility) 2. Solubility of gas into blood The lower the blood:gas ratio, the more anesthetics will arrive at the brain 17  Alveoli Blood Brain Nitrous oxide (low solubility) Halothane (high solubility)  Blood solubility = b:g PC = Speed of action 18  Speed of induction is influenced by: Pulmonary blood flow (Inverse relationship ) Inspired concentration Ventilation rate 19  Clearance by the lungs into the expired air is the major route of elimination 20  Respiration ▪ Depressed respiration and response to CO2 ▪ Bronchodilators ▪ Respiratory depression (‫هایپوکسی‬/‫)آپنه‬  Kidney ▪ Depression of renal blood flow and urine output ‫کاهش جریان خون کلیوی وجلوگیری از برون ده ادراری‬ ✓ 21  Muscle ▪ High enough concentrations will relax skeletal muscle ▪ Uterus effects )‫(شل کننده عضالت رحم‬ (Intrauterine manipulation during delivery)  Central Nervous System ▪ Increased cerebral blood flow and ICP ▪ Decreased cerebral metabolism rate(CMR) 22  Cardiovascular System ▪ Generalized reduction in arterial pressure and peripheral vascular resistance. ▪ Isoflurane maintains CO and coronary function better than other agents 23 Inhaled Anesthetics Widely used Potent analgesic Produce a light anesthesia (Low potency) Do not depress the respiration/vasomotor center Used adjunct to supplement other inhalationals 24  Inhaled Anesthetic Agents O Nitrous Oxide/ laughing gas N N  Rapid onset - Extremely fast absorption & elimination ⇒ Rapid induction & recovery  Not metabolized  Hematotoxic; inhibits methionine synthetase(precursor to DNA synthesis) activity in long term use; Megaloblastic Anemia  Dentists, or personnel abusers at risk 25  Halogenated Anesthetic Agents F Br Halothane F C CH F Cl  Potent anesthetic effect  Narrow margin of safety  Sensitize the myocardium to the arrhythmogenic effects of catecholamines ‫آریتمی‬ 26  Halothane Side Effect MALIGNANT HYPERTHERMIA Malignant hyperthermia (MH) is a rare pharmacogenetic hypermetabolic state of skeletal muscle induced in susceptible individuals by inhalational anesthetics and/or succinylcholine (and maybe by stress or exercise). 27  Halothane Side Effect MALIGNANT HYPERTHERMIA  Genetic susceptibility-Ca+ channel defect (CACNA1S) or RYR1 (ryanodine receptor)  Excess calcium ion leads to excessive ATP breakdown/depletion 28  Halothane Side Effect MALIGNANT HYPERTHERMIA  Signs:Includes a dangerously high body temperature/fever(102 to 104 degrees F), muscle rigidity or spasm, tachycardia, tachypnea, irregular pulse, arrhythmia, hyperkalemia, metabolic acidosis.  May be fatal *** Treated with Dantrolene and supportive management 29  ADR Hepathotoxicity 30  Halogenated Anesthetic Agents F F F H C C O CH Enflurane Cl F F Rapid, smooth induction and maintenance 2-10% metabolized in liver Metabolism releases fluoride ion--renal toxicity Alter EEG pattern– seizure Introduced as replacement for halothane 31  Halogenated Anesthetic Agents Isoflurane Smooth and rapid induction and recovery Good muscle relaxation Good coronary vasodilatation More expensive & Less potent No reports of hepatotoxicity or nephrotoxicity Most widely employed 32  Halogenated Anesthetic Agents Sevoflurane Is degraded by contact with the CO2 absorbent in anesthesia machines, yielding a vinyl ether; Nephrotoxic 33 ▪ Commonly used IV induction agents ▪ Procedures of short duration ▪ Supplementation of weak inhalation agents such as N2O 34  CH(CH3)2 PROPOFOL OH ‫فعال و عمال مهمترین و پرمصرف ترین است‬ CH(CH3)2  Sedative-Hypnotic agent  No analgesic effects  Rapid onset (30-60 sec) and recovery  Antiemetic actions  Used in induction and for maintenance (‫)انفوزیون مداوم‬ 35  PROPOFOL ▪ It is highly protein bound in vivo and is metabolised by conjugation in the liver ▪ Side-effect ▪ Pain on injection ▪ Hypotension ▪ Transient apnoea following induction 36  ‫▪ درد در هنگام تزریق پروپوفول یک شکایت شایع است‬ alkaline phosphatase Fospropofol Propofol ▪ Onset and recovery are both slower than with propofol ▪ Less pain at injection sites 37  Short-acting Barbiturates Thiopental (Pentothal)  Fast, Pleasant induction(20 s)  Use for short surgical procedures  Rapid onset and rapid recovery  Respiratory and circulatory depressants  Decrease cerebral blood flow and ICP 38  Benzodiazepines Midazolam (‫)پرمصرف‬  Sedative- Anxiolytic effects  Muscle Relaxant  Amnesia  Long duration of action(10-12 min)  The onset of its CNS effects is slower than that of thiopental  Antagonist: Flumazenil 39  Cl - Bz GABA Receptor Receptor Profoundly Exterior Hyperpolarized! Interior 40  Ketamine  Highly lipophilic (Rapid onset )  Analgesic  NMDA Receptor Antagonist 41  Ketamine Dissociative anesthesia; Cataleptic state ✓ A state characterized by immobility, amnesia and analgesia with light sleep and feeling of dissociation from ones own body and mind, but may have their eyes open, move their limbs involuntarily, and breathe spontaneously. 42  Ketamine Psychomimetic – “emergence reactions” ▪ Post-op Emergence Delirium: ✓ Characterized by excitation, hallucinations, vivid dreams, and delusions ✓ Less frequently in children ✓ Benzodiazepines reduce the incidence of emergence delirium 43  Ketamine ▪ Stimulates sympathetic nervous system ▪ Cardiovascular stimulant  Heart rate, arterial BP & Abnormal Heart Rhythms 44  Etomidate ▪ ↑GABA receptor activity ▪ Rapid onset ▪ Short duration of action ▪ Minimal change in cardiac function or respiratory rate 45 ▪ Adrenocortical Suppression (‫)کاهش سطح سرمی آلدسترون و کورتیزول‬ ✓ Dose dependent inhibits adrenal biosynthetic enzymes(11β- hydroxylase) required for the production of cortisol and some other steroids. Can be used to treat hypercortisolemia. High incidence of nausea & vomiting 46  Morphine, Fentanyl Alfentanil, Sufentanil, Remifentanil  Used in: ✓ In combination with diazepam used in diagnostic, endoscopic and angiographic procedures ✓ Naloxone reversal available 47  Before Anesthesia During Anesthesia After Anesthesia BALANCED ANESTHESIA 48  ‫کاهش ترشحات بزاق و برونش‪/‬‬ ‫جلوگیری از ایجاد برادی کاردی‬ ‫ متوکلوپرامید‪ :‬آنتاگونیست گیرنده دوپامین‪ ،‬ضد استفراغ و محرک دستگاه گوارش‬ ‫‪49‬‬   Fentanyl  Morphine  Propofol  Thiopental sodium  N2O  N2O  Sevoflurane  Halothane  Relaxant of choice  Relaxant of choice 50 Do not generalize Please: CASES Payan 51 SKELETAL MUSCLE RELAXANTS 52  What are they used for? ▪ Facilitate intubation of the trachea ▪ Facilitate mechanical ventilation ▪ Optimized surgical working conditions (Surgery where muscle relaxation is essential) ‫ عضله‬-‫ کاربرد بلوکه کننده های عصب‬o ‫ شل کردن عضالت حین جراحی‬ ‫ لوله گذاری نای‬ ‫ کنترل تهویه ریوی‬ ‫ درمان تشنج‬ 53  Types of skeletal muscle relaxants: 2 groups Neuromuscular blockers Spasmolytics Relax normal muscles Reduce spasticity (surgery and assistance of Centrally acting (except ventilation) dantrolene which act on No central nervous system the skeletal muscle) activity. Used in a variety of Used primarily as a part of neurologic conditions general anesthesia 54  Skeletal Muscle Relaxants Neuromuscular blockers Spasmolytics Non-depolarizing (Competitive) D tubocurarine Centrally Directly Pancuronium acting acting Vecuronium Diazepam Dantrolene Atracurium Chlorzoxazone Mivacurium Tizanidine Depolarizing Baclofen (Non-Competitive) Succinylcholine & Decamethonium 55  NMreceptor Motor neuron ACHEsterase Skeletal Muscle 56 57  Normal d-Tubocurarine Succinylcholine Ach A Ch Ach Ach SCh Ach SCh Depolarization No Depolarization Persistent Depolarization Contraction Repolarization (Fasciculation) Contraction No contraction Relaxation Relaxation Flaccid Paralysis 58  (Non-competitive) Succinylcholine One Drug, Two blocks, quick effect, Genetic variability in metabolism, Malignant hyperthermia 59 Quaternary Depolarising muscle relaxants Quaternary ammonium ammonium (Two molecules of Acetylcholine) Acetylcholine 60  ‫?‪How do they work‬‬ ‫مکانیسم عمل داروهای بالک کننده ی عصبی‪-‬عضالنی‪:‬‬ ‫ ‬ ‫‪Depolarizing Agent:‬‬ ‫✓ مرحله ‪ : )depolarizing( 1‬تحریک بیش از اندازه ی گیرنده نیکوتینی توسط‬ ‫دارو (اثر توسط مهارکننده کولین استراز تقویت می شود)‪ -‬پرش و‬ ‫فاسیکوالسیون اولیه عضالت‬ ‫✓ مرحله ‪ :(desensitizing) 2‬غیرحساس شدن گیرنده و مهار انقباض‬ ‫‪61‬‬ Succinylcholine  Small rapidly moving muscles (eye, jaw, larynx) relax before those of limbs and trunks  Ultimately intercostals and finally diaphragm paralysis occur → respiratory paralysis  Recovery in the reverse order  Muscle relaxation: Onset: within 1 min; peak: 2 min, duration: 5 min; longer duration relaxation requires continued IV infusion 62 Succinylcholine  Blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally (IV).  Duration of action of succinylcholine (10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma 63 Succinylcholine Does it has side effects? ▪ Transient Intraocular Tension ‫✓ بدلیل انقباض میوفیبریل ها‬ ▪ Hyperkalemia : Fasciculations release potassium in blood ▪ Respiratory paralysis (Succinylcholine apnea) ‫در صورت عدم درمان (تهویه مکانیکی) منجر به مرگ می شود‬:‫فلج تنفسی‬ ✓ ▪ Malignant hyperthermia: when used along with halothane in general anaesthesia ▪ Treatment is by rapid cooling of patient & dantrolene i.v 64 Succinylcholine ▪ Does it has side effects? ▪ Cardiovascular (Bradycardia); activates cardiac muscarinic R )‫تحریک گیرنده موسکارینی قلب (برادی کاردی‬ ✓ ▪ Muscle pain---common ‫✓ احساس درد در قفسه ی سینه و پهلوها پس از عمل جراحی بدلیل انقباض‬ ‫همزمان عضالت‬ ▪ Increase intragastric pressure (Regurgitation with possible aspiration of gastric contents) )‫ تهوع‬/‫✓ افزایش فشار معده در اثر فاسیکوالسیون (بازگشت محتویات معده‬ 65  No antidote is available  Fresh frozen plasma should be infused  Patient should be ventilated artificially until full recovery 66 (Non-depolarizing Blockers) 67 Anti-cholinestrases (neostigmine, edrophonium) which preserve acetylcholine Agonist are used to reverse the effect of d-tubocurarine Ach Ach Antagonist d-Tubocurarine NM receptor Motor End Plate 68  ‫?‪How do they work‬‬ ‫مکانیسم عمل داروهای بالک کننده ی عصبی‪-‬عضالنی‪:‬‬ ‫ ‬ ‫‪Non Depolarizing Agent:‬‬ ‫آنتاگونیست گیرنده های نیکوتینی استیل کولین‬ ‫✓‬ ‫رقابت با استیل کولین در اتصال به گیرنده نیکوتینی‬ ‫✓‬ ‫جلوگیری از دسترسی‪ Ach‬به گیرنده های نیکوتینی نوع ‪M‬‬ ‫✓‬ ‫مهار دپالریزاسیون‬ ‫✓‬ ‫برگشت اثر با مهار کننده های استیل کولین استراز (نئوستیگمین)‬ ‫✓‬ ‫‪69‬‬  Long-acting: d-tubocurarine, pancuronium  Intermediate: Atracurium, vecuronium, rocuronium  Short-acting: Mivacurium o Metabolized by plasma cholinesterase; Mivacurium(10-20 min) 70  Muscle weakness → Flaccid paralysis  Order of muscle affected: ▪ Extrinsic eye muscles, muscles of finger ▪ Neck muscles (muscles of phonation and swallowing) ▪ Face ▪ Hands, ▪ Feet ▪ Trunk ▪ Respiratory muscles (intercostal and diaphragm)  Recovery in the reverse order  Consciousness, appreciation of pain not affected 71  Autonomic ganglion blocking property  Histamine release (by d-tubocurarine)  CVS: ▪ Significant fall in BP ▪ Increase in Heart rate ▪ Vagal gangionic blockade  Newer competitive blockers: ▪ Negligible effect on BP and HR 72  Hypotension  Tachycardia  Respiratory paralysis  Bronchospasm  Aspiration of gastric contents 73  Less histamine release  Do not block autonomic ganglia  Spontaneous recovery with most of drugs  Rapacuronium & rocuronium have rapid onset  Atracuronium (intermediate)  Mivacurium short acting 74  Blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally (IV)  Hepatic metabolism, Atracurium clearance involves rapid spontaneous breakdown (Hofmann elimination) to form Laudanosine and other products.  At high blood levels, laudanosine may cause seizures.  Eliminated in the bile ;Vecuronium(20-35 min) 75 ▪ Does it has side effects? ▪ Respiratory paralysis ▪ Tubocurarine and mivacurium are the most likely of these agents to cause histamine release ▪ but it may also occur to a slight extent with atracurium and succinylcholine. )‫✓ مهار گيرنده هاي موسكاريني قلب (تاكيكاردي‬ )‫✓ آزادسازي هيستامين و ايجاد عوارض آلرژيک(خصوصا با توبوكورارين‬ 76 Sr.no Competitive Succinyl choline 1 Competitive blockade Persistant depolarization 2 Non depolarizing Depolarizing 3 Single block Dual block 4 Anticholinesterases Do not reverse reverse blockade 5 Initial fasciculations not Present present 6 Slow onset long duration Rapid onset short duration 7 Release histamine Doesn’t release 77 Thank you Desensitization, tachyphylaxis Down-regulation Up-regulation 78