PHARMACOLOGY OF ANAESTHETICS Katarina Zadrazilova Kamil Hudacek Faculty of medicine, Masaryk University University Hospital Brno AIMS OF ANAESTHESIA Triad of anaesthesia •Analgesics IV/regional anaesthesia or analgesia • •Anaesthetic agents to produce unconsciousness • •Neuromuscular blocking agents for muscle relaxation • • • Why unconscious patient require analgesia ? Overview •Intravenous and inhalational anaesthetics •Analgesics – simple, opioids •Muscle relaxants •Decurarization • • • INTRAVENOUS ANAESTETICS Stages of anaesthetics •Induction – putting asleep •Maintenance – keeping the patient asleep •Reversal – waking up the patient • • Intravenous anaesthetics •Onset of anaesthesia within one arm – brain circulation time – 30 sec •Effect site brain ▫Propofol ▫Thiopentale ▫Etomidate ▫Ketamine ▫BZD General anaesthetic-how do they work •TASK – EXPLAIN 1.Loss of conscious awareness 2.Loss of response to noxious stimuli 3.Reversibility • •Anatomical site of action ▫Brain : thalamus, cortex ▫Spinal cord •Linear correlation between the lipid solubility and potency Molecular theories GA – how do they work \\credit: Cambridge University Press Meyer-Overton hypothesis •Critical volume hypothesis ▫Disruption of the function of ionic channels •Perturbation theory ▫Disruption of annular lipids assoc. with ionic channels •Receptors ▫Inhibitory – GABA A, glycin enhance ▫Excitatory - nAch, NMDA inhibit Molecular theories GA – how do they work GABAA receptor figure6-15.jpg GA – how do they work - ionotropic receptor Thiopentale •Barbiturate •Dose 3-7 mg/kg •Effects : hypnosis, atiepileptic, antanalgesic •Side effects ▫CVS: myocardiac depression, ¯CO ▫Reduction in MV, apnea • Intravenous anaesthetics Thiopentale •Problems with use ▫Extremely painfull and limbtreatening when given intra-arterially ▫Hypersensitivity reactions 1: 15 000 •Contraindications ▫Porphyria • Intravenous anaesthetics •Phenolic derivative •Dose 1- 2.5 mg/kg •Effects : hypnosis •Side effects ▫CVS: myocardiac depression, ¯SVR, ¯CO ▫Respiratory depression ▫Hypersensitivity 1 : 100 000 • • Propofol Propofol •Other effects ▫Pain on induction ▫Nausea and vomiting less likely ▫Better for LMA placement then thiopentale ▫ •Relative contraindications ▫Children under 3 Etomidate •Ester •Dose 0.3 mg/kg •Effects : hypnosis •Side effects ▫CVS: very little effect on HR, CO, SVR ▫Minimal respiratory depression • Etomidate •Problems with use ▫Pain on injection ▫Nausea and vomiting ▫Adrenocortical suppression ▫Hypersensitivity reaction 1: 75 000 ▫ •Relative Contraindications ▫Porphyria • Intravenous anaesthetics Ketamine •Phencyclidine derivative • •CV effects - HR, BP, CO, O2 consumption •RS - RR, preserved laryngeal reflexes •CNS – dissociative anaesthesia, analgesia, amnesia • •Use – analgesic in Emerg. Med Pharmakokinetics •Recovery from propofol single bolus 5-10 min Intravenous anaesthetics Choice of induction agent •1. Are any agents absolutely contraindicated ? ▫Hypersensitivity, porphyria •2. Are there any patient related factors ? ▫CVS status ▫Epilepsy •3. Are there any drug related factors ? ▫Egg allergy • Intravenous anaesthetics Induction + maintenance Intravenous anaesthetics - TIVA (=Total Intravenous Anesthesia) SUMMARY – IV anaesthetics • •Mechanism of action – via receptors •Used for anaesthesia and sedation •Used for induction ▫thiopentale, propofol, etomidate •Propofol used for maintenance as well • •Most of them cause CV and respiratory depression • • • INHALATIONAL ANAESTETICS = volatile anesthetics Anaesthetic gases •Isoflurane •Sevoflurane • •Halothane •Enflurane •Desflurane • •N2O – nitrous oxide Inhalational anaesthetics Anaesthetic gases •Any agent that exists as a liquid at room temperature is a vapour •Any agent that cannot be liquefied at room temperature is a gas ▫ ▫Anaesthetic ‘gases’ are ▫ administered via ▫ vaporizers Inhalational anaesthetics Potency •MAC – that concentration required to prevent 50 % of patients moving when subjected to standart midline incision • •Sevoflurane MAC 1.8 % •Isoflurane MAC 1.17 % Inhalational anaesthetics Respiratory and cardiovascular effects •All volatile anaesthetics cause ¯ MV and RR •Isoflurane is irritant vapour •¯ SVR, blood pressure falls, HR •Isoflurane - ? Coronary steel Inhalational anaesthetics Metabolism and toxicity •Isoflurane (0.2 %)and Sevoflurane(3.5%) are metabolized by liver •F- ions are produced - ? Renal impairment •Iso and Sevo trigger malignant hyperthermia •N2O ▫Megaloblastic anaemia ▫Teratogenic ▫PONV – Inhalational anaesthetics SUMMARY – inhalational anaesthetics •Mechanism of action – via receptors •Used for induction (sevoflurane) •And maintenance of anaesthesia •Commonly used : Sevoflurane, Isoflurane •Dose dependent CV and respiratory depression •All, but N2O trigger malignant hyperthermia • • • NEUROMUSCULAR BLOCKING AGENTS = NMBAs Neuromuscular blocking agents •Exclusively used in anaesthesia and intensive care • •Two classes ▫Depolarizing –succinylcholine – ▫Non depolarizing –Vecuronium, rocuronium - aminosteroid –Atracurium, cisatracurium - benzylisoquinolinium – Use of NMBAs • •Tracheal intubation • •Surgery where muscle relaxation • is essential • •Mechanical ventilation Neuromuscular blocking agents Neuromuscular junction Neuromuscular blocking agents Mechanism of action •Depolarizing ▫structurally related to Ach (=acetylcholine) ▫first activating muscle fibres, then preventing further response ▫short acting drugs ▫ •Non depolarizing •compete with Ach at nicotinic receptor at the neuromuscular junction •middle and long acting drugs Neuromuscular blocking agents Choice for tracheal intubation Elective surgery Emergency surgery Standart induction Rapid sequence induction Non depolarizing agent Succinylcholine or rocuronium Neuromuscular blocking agents Succinylcholine 1 – 2 mg/kg AcBW Rocuronium 0.6 - 1 mg/kg IBW Atracurium 0.5 mg/kg IBW Intubating doses To maintain paralysis • •Non depolarizing muscle relaxants Neuromuscular blocking agents Succinylcholine No Rocuronium maintenance dose: 0.1 – 0.2 mg/kg Atracurium maintenance dose: 0.1 – 0.2 mg/kg Succinylcholine pharmacokinetics •Duration of action : 3 – 6 min (full recovery over 10 min) • •Metabolism – plasma cholinesterase ▫Cave: suxamethonium apnea • • • ▫ Neuromuscular blocking agents Succinylcholine - adverse effects •Bradycardia •Muscle pain – ‘sux’ pain •Transient raised pressure in eye, stomach and cranium •Raise in potassium !! ▫ Neuromuscular blocking agents Succinylcholine - contraindications •Patient related contraindications ▫Malignant hyperpyrexia ▫Anaphylaxis to SCh ▫Succinycholine apnea / Pseudocholinesterase deficiency ▫ •Clinical contraindications ▫Denervation injury / long term immobilized patient ▫Patient with burns ▫Penetrating eye injury ▫ Neuromuscular blocking agents Non depolarizing muscle relaxants •Choice of NMBs ▫Personal preference ▫Atracurium or cisatracurium better in renal or hepatic failure ▫Avoid atracurium in asthmatic patients – cisatracurium is drug of choice ▫Rocuronium (or vecuronium) could be reversed (by antidotum sugammadex) ▫ ▫ ▫ Neuromuscular blocking agents Obsah obrázku text Popis byl vytvořen automaticky Brull, Sorin; Naguib, Mohamed. "Clinical use of neuromuscular blocking agents in anesthesia". UpToDate. Retrieved 20 April 2020. Reversal • •Acetylcholine esterase inhibitor – neostigmine ▫Increases concentration of Ach at NMJ •Neostigmine acts at all sites where acetylcholine esterase is present including heart ▫ Neuromuscular blocking agents What effect this might have and how this can be overcome? Neostigmine • •Dose of neostigmine – 0.05 mg/kg •In > 50 kg man 2.5 mg •Given with atropine 0.5 mg Neuromuscular blocking agents Sugammadex (Bridion) •medication for the reversal of neuromuscular blockade induced by rocuronium and vecuronium • •the first selective relaxant binding agent (SRBA) • •dose depends on time of use •(16 - 4 - 2 mg kg−1) • •expensive Obsah obrázku text Popis byl vytvořen automaticky Peripheral nerve stimulator •Check the depth of neuromuscular blockade ▫TOF, PTC .. ▫ •Determine that neuromuscular blockade is reversible • •Check that blockade has been reversed fully (TOFr ≤ 0.9) Neuromuscular blocking agents Obsah obrázku text, osoba Popis byl vytvořen automaticky SUMMARY – muscle relaxants •Mechanism of action – via acetylcholine receptor •Used to facilitate tracheal intubation, mechanical ventilation and surgery •Depolarizing – Succinylcholine ▫Lots of side effects •Non depolarizing – Rocuronium, Atracurium, .. ▫Minimal CV and respiratory effects • • • ANALGESICS Analgesics •paracetamol (=acetaminophen), metamizole •Nonsteroidal anti-inflammatory drugs = NSAIDs ▫(aspirin, ibuprofen, naproxen, indomethacin, diclofenac, meloxicam,..) •Opioids • •Local anaesthetics •Antidepressants •Anti-epileptics •Ketamine •Clonidine • Paracetamol = acetaminophen •classified as a mild analgesic •does not have significant anti-inflammatory activity •for severe pain, such as cancer pain and pain after surgery, in combination with opioid pain medication •is generally safe at recommended doses •max daily dose for an adult is 4 grams - overdose results in a lengthy, painful illness, acute liver failure and death •safe during pregnancy and when breastfeeding • • 1877 NSAIDs - effects • •reduces pain •decreases fever •prevents blood clots •decreases inflammation ▫in higher doses • Simple analgesics •Antipyretic agents found in willow tree and led to development of acetylsalicylic acid 1853 Charles Frédéric Gerhardt Bayer company had named it "Aspirin" Acetylsalicylic acid (ASA) = Aspirin • •Anti-inflamatory agent in joint disease •Cardiovascular - unstable angina •Antiplatelet drug - prevention of stroke / aMI •Radiation induced diarrhoea •Alzheimer’s disease • • Simple analgesics NSAIDs – mechanism of action •Inhibition of cyclo-oxygenase enzymes (COX-1, COX-2) • Simple analgesics NSAIDs – side effects Aspirin Paracetamol Chemistry Acetic acid Paraaminophenol Mechanism of action Inhibition of COX 1 ? COX 3 inhib Metabolism Estrases in gut wall, liver Liver Toxicity Hepatic/renal inpairment GI upset GI upset Trombocytopenia Rayes syndrome in kids Liver necrosis Dose 300 – 900 mg every 6 h 1 g every 6 h Route of administration orally PO/PR/IV Simple analgesics Other NSAIDs •Ibuprofen – the lowest risk of GI upset •Indomethacin, Diclofenac – mainly antiinflamatory effect • • •Aspirin and NSAIDs are not contraindicated for regional anesthesia SUMMARY – simple analgesics • •Paracetamol •NSAIDs •MOA – inhibition of COX •Renal, gastric, hepatic side effects •Can trigger NSAID sensitive asthma • Opiods •MORPHEUS Morphine •- GREAK GOD OF DREAMS Definitions •Opiate - naturally occuring substance with morphine-like properties; mean a substance derived from opium • •Opioid - all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonists) • •Narcotic - from greek word ‘numb’ Opiods Opium is dried latex obtained from the seed capsules of the opium poppy Papaver somniferum. Opioids – mechanism of action •Via opioid receptors - in the central and peripheral nervous system and the gastrointestinal tract ▫ ▫m - receptor ▫k - receptor ▫d - receptor Uses and routes of administration •Analgesics •Anti-tussive •Anti-diarrhoea • •Intravenously •Intramuscularly •Oral, Buccal, Rectal •Transdermal - Patches •Epidural / Intrathecal • Opiods Opioids - effects •Brain: ▫Analgesia, sedation ▫Respiratory depression / arrest ▫Euphoria and dysphoria ▫Addiction, tolerance ▫Nausea and vomiting •Eyes ▫Miosis •Cardiovascular system ▫Hypotension, bradycardia •Respiratory system ▫Anti-tussive effect •GI tract ▫Spastic immobility •Skin ▫Pruritus – histamine release •Bladder ▫Urinary retention Opioids - effects Commonly used opioids Dose Elimination ½ life Metabolism Comment Sufentanyl 0.1 mg/kg 50 min liver Faster onset then fentanyl Fentanyl 1-2 mg/kg 190 min liver Neurosurgery, patches Alfentanyl 5 – 25 mg/kg 100 min liver Faster onset then sufentanyl Remifentanyl 0.05 – 2 mg/kg 10 min Plasma and tissue esterases Infusion only, very short context sensit. ½ life Opiods Naloxone •Pure opioid anatagonist at m, d and k - receptors •Used in opioid overdose as an antidote •Dose : 1- 4 mg/kg •Duration of action 30 – 40 min •! Often shorter then duration of action of opioid, need for repeated doses Opiods Multimodal analgesia SUMMARY – opioids • •Morphine, Fentanyl, Sufentanyl, Alfentanyl •MOA – via opioid receptors •Used for analgesia, anti–tussive, anti–diarrhoea •Side effects : respir. depression, tolerance, constipation, nausea + vomiting •Opioid overdose reversal – Naloxone •Multimodal analgesia – simple analgesics + opioids • SUMMARY •Triad of anaesthesia ▫Analgesia ▫Anaesthesia ▫Muscle relaxation ▫ •Choice depends on ▫Patient factors ▫Type of surgery ▫Whether the surgery is elective or emergency Questions ? ana_1_075_anaphylaxis_13_01_med