Adobe Systems General anesthetics Department of Pharmacology MU Adobe Systems General anesthesia (GA) General anesthesia is an induced short-term fully reversible deep unconsciousness combined with analgesia while perception of pain is eliminated and muscles are relaxed. Adobe Systems History •October 1846 in Massachusetts General Hospital in Boston, USA – the first public demonstration of ether GA • •dentist William Thomas Green Morton • •patient: Edward Gilbert Abbott, 22 years old, neck tumor Adobe Systems https://commons.wikimedia.org/wiki/File:Roots-criticall-care.jpeg Adobe Systems Stages of GA are historically characterized by Guedel’s scheme - following use of ether (today historical and didactical meaning only) No anesthesia runs according to this scheme presently. Adobe Systems General anesthetics ̶Inhalational liquid gaseous ̶Intravenous barbiturates non-barbiturates benzodiazepines Adobe Systems ̶gases ̶liquids (fluid under normal pressure - boiling point about 50°C, a special device is necessary for their use - vaporizer) ̶concentration of general anesthetic in the CNS depends on its concentration in blood and this correlates with its concentration in the inhaled air ̶ ̶ Inhalational anesthetics Physical and Chemical Properties Adobe Systems Inhalational anesthetics Mechanism of action: ̶dependent on liposolubility of the drugs (anesthetic effect of inhalational anesthetics grows with increasing liposolubility) – so called lipid (biophysical theory); Overton–Meyer’s correlation: anesthetic potency is closely associated with liposulubility, not with chemical structure ̶non-specific influence on ion channels in neuronal membranes ̶ ̶ MAC – minimal alveolar concentration = concentation which induces stadium of tolerance in 50 % of patients ̶ Adobe Systems isoflurane ̶low metabolisation ̶increases effect of muscle relaxants, causes hypotension ̶pungent smell – disadvantage in pediatrics ̶ desflurane ̶fast onset and recovery, pungent smell ̶used only for maintenance of anesthesia ̶suitable in obese patients (bariatric surgery) and in 1-day surgery sevoflurane ̶fast onset and recovery ̶pleasant fruit smell ̶most widely used in pediatrics Liquid (volatile) inhalational anesthetics Adobe Systems HISTORY diethylether (ether) used exceptionally nowadays (explosive, long excitatory stage, irritation of mucous membranes) advantage – low boiling point – can be used without anesthetic machine under field conditions Liquid (volatile) inhalational anesthetics Adobe Systems nitrous oxide N2O (laughing gas) ̶MA: inhibition of NMDA receptor ̶low anesthetic potency, effective analgesic drug ̶rapid onset and recovery, used in combined anesthesia (in obstetrics as monotherapy) and with muscle relaxants AE: ̶ supraventricular arrhythmia ̶ hallucinations, potentiates postoperative nausea risk of bone marrow suppression following exposition > 6 h. - (megaloblastic anemia, agranulocytosis following chronic use) ̶ not to be used in conditions with presence of gas in cavities (pneumothorax - risk of increase in intrathoracic pressure with shift of mediastinum) Gaseous inhalational anesthetics Adobe Systems Intravenous general anesthetics 1.BARBITURATES 2. 2.NON-BARBITURATES 3. 3.BENZODIAZEPINES Adobe Systems 1.BARBITURATES thiopental ̶MA: increases inhibitory effect of GABA receptor ̶for induction to anesthesia ̶fast onset (20s), duration 5-10 min ̶redistribution from the brain to muscles and fat – need of higher dose in obese patients, slow recovery in obese patients, „hang over“ during recovery ̶accidental injection into an artery causes pain and even necrosis or gangrene KI: in patients with liver damage, porphyria AE: cardiovascular and respiratory depression, vasodilation, negative inotropic effect; immunosuppression (following long-term use) Adobe Systems 2. NON-BARBITURATES ketamine ̶for induction or maintenance of short-term surgical procedures, it causes strong analgesia ̶MA: inhibition of NMDA receptor ̶patients experience dissociation from the environment and self → dissociative anesthesia ̶onset 1-2 min. following i.v. administration ̶suitable in pediatrics, in patients with hypovolemic shock after injury; to decrease pain during small surgical procedures, in burns, for anesthesia during natural disasters and wars AE: ↑ blood pressure and pulse (it can be used in shock) after recovery living hallucinations (prevention: combination with benzodiazepines) KI: hypertension, heart insufficiency, arteriosclerosis, intracranial hypertension, glaucoma Adobe Systems propofol ̶MA: increases activity of GABAA receptor ̶for induction and maintenance of GA, it has no analgesic effects, fast onset (30 s), short duration (t ½ 2-4 min) ̶administered as emulsion oil in water, which causes pain and increases risk of bacterial propagation in vial ̶prodrug fospropofol (soluble in water, Lusedra in USA) ̶AE: cardiovascular and respiratory depression, lactate acidosis Adobe Systems Long-term use (higher doses) can cause „propofol syndrome“ - green coloration of urine and hair http://www.doctoryg.com/2016/11/propofol-infusion-syndrome.html Adobe Systems etomidate ̶MA: allosterically increases affinity to GABA receptor ̶for induction to GA, it has no analgesic effects ̶ ̶fast onset, fast recovery, smaller risk of respiratory arrest ̶ ̶for short-term surgical procedures: cardioversion AE: myoclonus, tremor ↑ blood pressure, postoperative nausea and vomiting, pain during administration not to be used in patients with suprarenal insufficiency, immunosuppression Adobe Systems dexmedetomidine ̶has analgesic and anesthetic/analgesic sparing effects ̶ ̶for premedication and vegetative stabilization during surgery ̶ ̶MA: specific agonist of α2-adrenergic receptor ̶ ̶highly soluble in fat (fast penetration to the CNS and fast onset of sedative and hemodynamic effects) ̶ Adobe Systems dexmedetomidine (cont.) ̶effect on presynaptic α2-adrenergic receptors inhibits particularly release of noradrenaline, and furthermore acetylcholine, serotonin, dopamine and substance P ̶ ̶use: in intensive care and for sedation ̶ ̶AE: hypotension, bradycardia Adobe Systems 3. BENZODIAZEPINES ̶their effect is caused by sensibilisation of binding site for GABA on chloride channel midazolam ̶for premedication, induction to GA ̶depressive effect on respiration - see topic Hypnosedatives Adobe Systems Course of general anesthesia 1.Premedication 2. 2. Induction 3. Maintenance 4. Recovery Adobe Systems Premedication •used to sedate and tranquillize the patient • •prevention of adverse effects (both of anestetic drugs and organism) •decrease in consumption of anesthetics • •analgesia before the surgery • •ensuring amnesia • •decrease in gastric volume and acidity, prevention of aspiration pneumonia • •attenuation of vagal reflexes during intubation Class of drug Drug Expected effect benzodiazepines diazepam bromazepam midazolam anxiolytic antisecretoric agents, antacids H2 antihistamines (ranitidine, famotidine) decrease in acidity of stomach content opioids fentanyl, sufentanil analgesic neuroleptic drugs thioridazine, droperidol central sedation + antiemetic effect Adobe Systems Induction to GA ̶shortly acting injection administration i.v. or i.m., rarely in children per rectum thiopental ketamine propofol (etomidate) ̶for intubation muscle relaxation is necessary (depolarizing muscle relaxants) suxamethonium (onset of effects within 30 s, duration up to 3 min.) Adobe Systems Maintenance of GA ̶Inhalational (balanced) §combination of inhalational anesthetic drug, opioids and relaxants §mixture N2O + O2 (2:1) + sevoflurane or isoflurane + analgesic drugs + muscle relaxants ̶TIVA §total i.v. anesthesia Adobe Systems TIVA •Bristol regime ("manual" infusion) • •premedication: benzodiazepine (temazepam) • •induction: fentanyl 2 µg/kg, bolus of propofol 1 mg/kg • •propofol infusion in scheme 10-8-6: 10 mg/kg/hour for 10 minutes, 8 mg/kg/hour for 10 minutes, 6 mg/kg/hour as needed • •patient on artificial ventilation • •advantage: decrease in propofol consumption, higher hemodynamic stability, faster recovery Adobe Systems Recovery anesthesia should subside spontaneously When problems with recovery occur: ̶neostigmine – blocks effects of non-depolarizing muscle relaxants (after surgery to terminate muscle relaxation) ̶ ̶naloxone – restores vigility supports respiratory center (opioid antagonist) ̶flumazenil – restores vigility (benzodiazepine antagonist) ̶itopride, metoclopramide- prevention of postoperative nausea Adobe Systems Recovery ̶furosemide - in case of anuria ̶noradrenaline - in case of hypotension ̶beta-blockers (metoprolol) - in case of tachycardia ̶ ̶sugammadex •coats molecules of peripheral (non-depolarizing) muscle relaxants and complexes are then eliminated by kidney •for fast decurarization •sugammadex has the largest effect on rocuronium, smaller on vecuronium and the smallest on pancuronium • ̶postoperative analgesia: morphine, piritramid, paracetamol, metamizole Adobe Systems Neuroleptanalgesia ̶neuroleptic drug + opioid analgesic drug = state of psychomotor sedation, neurovegetative stability and analgesia ̶amnesia after recovery, patient is not unconsciousness – important during neurosurgical procedures ALTERNATIVES OF GA Adobe Systems Analgosedation ̶opioid analgesic drug + benzodiazepine midazolam (diazepam) + fentanyl Tranquanalgesia ̶i.v. anesthetic drug + benzodiazepine ketamine + midazolam (diazepam) ALTERNATIVES OF GA Adobe Systems Malignant hyperthermia •disorder that can be considered a gene-environment interaction, it causes an increased release of calcium or limited re-uptake of calcium to sarcoplasmic reticulum in muscle cells • •the most common triggering agents are volatile anesthetics, (most frequently halothane) or the muscle relaxant suxamethonium • •symptoms: very high temperature, increased heart rate and abnormally rapid breathing, increased carbon dioxide production, increased oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis • Adobe Systems Malignant hyperthermia •When suspect: discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction • •treatment is the intravenous administration of dantrolene, the only known antidote • •testing: a muscle (small part of musculus femoralis) biopsy is carried out • •National center for malignant hyperthermia was founded in Brno in 2001 Adobe Systems Most frequent complication of GA Induction hypotension, dysrhythmia, laryngospasms, aspiration Maintenance hypo- and hypertension, dysrhythmia, hypoxia, hypothermia Recovery hypotension, tremor, delayed recovery, persisting muscle relaxation Adobe Systems New substances xenon (inhalational anesthetic drug – gas) •the fastest introduction and recovery •MA: inhibition of NMDA receptors •non-toxic, no metabolisation, analgesic effect •anti-apoptotic and neuroprotective effects •