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General Anesthetics.ppt
- 4. 4 General anesthetics (GA) •Depress CNS to the extent that permit performance of surgery & other noxious/unpleasant procedures •Physiologic state induced by GA – analgesia – amnesia – loss of consciousness – inhibition of sensory & autonomic reflexes – skeletal muscle relaxation
- 5. 5 Property of an Ideal anesthetic 1.For patient • Pleasant, non-irritant, not cause nausea, vomiting & with wide margin of safty •Fast induction & recovery without after effect 2.For the surgeon •Adequate analgesia, immobility and muscle relaxation 3.For the anesthetist •Easy administration, controllable and versatile General anesthetics
- 6. 6 No single anesthetic has all these Balanced anesthesia, pre and post oprative medications are required General anesthetics
- 7. STAGES OF GENERAL ANESTHESIA 1. Stage of analgesia: The patient initially experiences analgesia without amnesia. Later, both analgesia and amnesia are produced. 2. Stage of excitement: During this stage, the patient often appears to be delirious and may vocalize but is definitely amnesic. 3. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends to complete cessation of respiration (apnea). 4. Stage of medullary depression: Includes severe depression of the vasomotor center in the medulla, as well as the respiratory center. Without circulatory and respiratory support, the patient dies. 7
- 8. 8 • Most anaesthetics enhance activity of inhibitory GABAA receptors, and inhibit activation of excitatory receptors such as glutamate and nAch receptors • However individual anaesthetics differ in their actions and affect cellular function in several different ways Mechanism of action GA
- 9. 9 1. Inhaled anesthetics (gases or volatile liquids) Types of GA •Enflurane •Halothane •Ethoxyflurane •Nitrous oxide •Diethyl ether •Xenon • Desflurane • Sevoflurane • Isoflurane (Most commonly used)
- 10. 10
- 11. 11 Main factors that determine the speed of induction and recovery of inhalational anesthetic • Properties of the anaesthetic –solubility in blood (blood:gas partition coefficient) –Partial pressure of anesthetics –lipid solubility (oil:gas partition coefficient) • Physiological factors –alveolar ventilation rate –cardiac output (CO) greater induction time Increased CO
- 12. 12 • Rapid induction and recovery allowing flexible control over the depth of anaesthesia • low solubility in blood produce rapid induction and recovery (e.g. nitrous oxide, desflurane) • High solubility in blood - slow induction and recovery (e.g.halothane) • High lipid solubility (e.g. halothane) accumulate gradually in body
- 13. 13 •Potency expressed as Minimal Alveolar Conc (MAC) •1MAC = the lowest concentration of anaesthetics in alveoli needed to produce immobility in response to a painful stimulus (surgical incision) in 50% individuals Steady-state alveolar concentration provide relative potencies of GA –MAC inversely proportional to potency –The MAC value for nitrous oxide is greater than 100% (least potent) Measurement of anesthetic potency
- 14. 14 Anes theti c Blood:Gas Partition Coefficient1 Brain:Blood Partition Coefficient1 Minimal Alveolar Conc (MAC) (%)2 Meta bolis m Comments Nitrous oxide 0.47 1.1 > 100 None Incomplete anesthetic; rapid onset and recovery Desflur ane 0.42 1.3 6–7 < 0.05% Low volatility; poor induction agent; rapid recovery Sevoflu rane 0.69 1.7 2.0 2–5% (fluoride ) Rapid onset and recovery; unstable in soda-lime Isoflura ne 1.40 2.6 1.40 < 2% Medium rate of onset and recovery Enflura ne 1.80 1.4 1.7 8% Medium rate of onset and recovery Halotha ne 2.30 2.9 0.75 > 40% Medium rate of onset and recovery Methox yfluran e 12 2.0 0.16 > 70% (fluoride ) Very slow onset and recovery anesthetic potency
- 15. 15 • Respiration – Depressed respiration and response to CO2 • Kidney – Depression of renal blood flow and urine output • Muscle – High concentrations will relax skeletal muscle General actions of inhaled anesthetics
- 16. 16 •CVS – Generalized reduction in arterial pressure and peripheral vascular resistance •CNS – Increased cerebral blood flow and decreased cerebral metabolism •Liver – Conc-dependent decrease in hepatic blood flow – permanent changes in liver enzyme function are rare General actions of inhaled anesthetics
- 17. 17 • Hepatotoxicity (halothane) • Nephrotoxicity • Malignant hyperthermia • Mutagenicity • Carcinogenicity • Hematotoxicity Toxicity
- 18. 18 Individual inhalation anaesthetics • Halothane (widely used) – potent, non-explosive and non-irritant, hypotensive – 'hangover' likely, due to high lipid solubility – risk of liver damage if used repeatedly
- 19. 19 • Nitrous oxide – low potency, therefore must be combined with other agents – rapid induction and recovery – good analgesic properties – risk of bone marrow depression with prolonged administration
- 20. 20 • Enflurane – less metabolism than halothane , therefore less risk of toxicity – faster induction and recovery than halothane (less accumulation in fat) – some risk of epilepsy-like seizures Individual inhalation anaesthetics
- 21. 21 • Isoflurane – similar to enflurane but lacks epileptogenic property – may precipitate myocardial ischemia in patients with coronary disease – irritant to respiratory tract
- 22. 22 • Desflurane – similar to isoflurane but with faster onset and recovery – respiratory irritant, so liable to cause coughing and laryngospasm • Sevoflurane – similar to deslurane with lack of respiratory irritation Individual inhalation anaesthetics
- 23. 23 • Ether – obsolete except where modern facilities are not available – easy to administer and control – slow onset and recovery, with postoperative nausea and vomiting – analgesic and muscle relaxant properties – highly explosive – irritant to respiratory tract Individual inhalation anaesthetics
- 24. 24 2. Intravenous anesthetics •Barbiturates (eg, thiopental, methohexital) •Propofol • Ketamine • Etomidate •Dexmedetomidine Types of GA
- 25. 25 • I.V. anaesthetics have faster onset of action than the most rapid inhaled agents (eg. desflurane and sevoflurane) • Used for induction of general anesthesia • Rapid recovery and used for short ambulatory (outpatient) surgical procedures Intravenous anesthetics
- 26. 26 Thiopental (barbiturate) • high lipid solubility • Rapid action due to rapid transfer across BBB • Short duration due to redistribution • Slowly metabolised and liable to accumulate in body fat • No analgesic effect Adverse effects – narrow margin between anaesthetic dose and dose causing cardiovascular depression – risk of severe vasospasm if accidentally injected into artery
- 27. 27 Etomidate • Similar to thiopental but more quickly metabolised • Causes minimal cardiovascular and respiratory depression(compared to other i.v.anesthetics) • Used for induction of anesthesia in patients with limited cardiovascular reserve • Minimal hypotension even in elderly patients with poor cardiovascular reserve
- 28. 28 Etomidate Adverse effects •Pain on injection •Postoperative nausea and vomiting •Prolonged use may cause suppresses of adrenal steroids production (not to be used for patients with adrenal insufficiency) •Prolonged infusion to critically ill patients may result in – hypotension and electrolyte imbalance – oliguria b/c of its adrenal suppressive effects
- 29. 29 Propofol • Rapidly metabolized / rapid recovery with out hangover • Patients are able to ambulate earlier after general anesthesia • less postoperative nausea and vomiting • For induction and maintenance of anesthesia as part of total intravenous or balanced anesthesia • Effective to induce prolonged sedation for patients in critical care settings (prolonged infusion )
- 30. 30 ketamine • MoA: may involve blockage of glutamate on NMDA receptor subtype • The only i.v anesthetic with analgesic & dose- related cardiovascular stimulation effects • cardiovascular effects via – stimulating central sympathetic nervous system – to some extent by inhibiting the reuptake of NE • Slow onset of action (2-5 minutes)
- 31. 31 • Increases cerebral blood flow, oxygen consumption, & intracranial pressure • Causes dissociative anesthesia (patient may remain conscious) ketamine
- 32. 32 3. Balanced anesthesia •Combination of i.v and inhaled anesthetics – i.v.( induction of anesthesia) – inhaled (maintenance of anesthesia) •Muscle relaxants used to facilitate tracheal intubation and optimize surgical conditions •Local anesthetics provide perioperative analgesia •Potent opioid analgesics and cardiovascular drugs (eg, β-blockers, α2 agonists, Ca 2+ channel blockers) Types of GA
- 33. 33 Characteristics of Intravenous Anesthetics. Drug Induction and Recovery Comments Etomidate Rapid onset and moderately fast recovery Cardiovascular stability; decreased steroidogenesis; involuntary muscle movements Ketamine Moderately rapid onset and recovery Cardiovascular stimulation; increased cerebral blood flow; emergence reactions impair recovery Midazolam Slow onset and recovery Used in balanced anesthesia and conscious sedation; cardiovascular stability; marked amnesia Propofol Rapid onset and rapid recovery Used in induction and for maintenance; hypotension; useful antiemetic action Thiopental Rapid onset and rapid recovery (bolus dose)— slow recovery following infusion Standard induction agent; cardiovascular depression; avoid in porphyrias Fentanyl Slow onset and recovery Used in balanced anesthesia and conscious sedation; marked analgesia
- 34. 34 • Preanesthetic medications –Anticholinergics –Anxiolytics –Antiemetics –Antacids • Post anesthetic medications –Analgesics
- 36. 36 Comparing features of general & local anesthesia GA LA Site of action CNS PNS Area of body involved Whole body Restricted area Consciousness lost Maintained Care for vital functions Essential Not needed For poor health patient Risky Safer Surgery For major surgery For minor surgery Use in non cooperative patients Possible Difficult MoA Enhance inhibitory & inhibit excitatory NTs actions ↓Na+ entry Local anaesthetics
- 37. 37 •Coca leaves used to be chewed for numbing effect they produced on mouth and tongue •The leaves contains cocaine •Cocaine was the 1st local anaesthetic proposed for surgical procedures •Sigmund Freud studied cocaine's physiological actions •Carl Koller introduced cocaine as ophthalmic anesthetic Local anaesthetics
- 38. 38 Chemistry of LAs • Most local anesthetic agents consist of • hydrophobic /lipophilic group • Amine substituents /ionizable group – separated by an intermediate ester or amide linkage Benzocaine does not have basic / ionizable group
- 42. 42 •Ester links prone to hydrolysis in plasma or tissue by non-specific esterases & have short duration of action •Amide links are more stable & have longer plasma half lives •LAs are weak bases with pKa values mainly in the range 8-9 Chemistry of LAs
- 43. 43 Pharmacokinetics (ADME) Absorption of LA determined by –dosage –site of injection –drug-tissue binding –local blood flow –presence of vasoconstrictors –physicochemical property of the drug
- 44. 44 • Distribution – Amides well distributed – Initial distribution to highly perfused organs (Brain , heart, kidney, liver) Pharmacokinetics
- 45. 45 •Amide type (in liver) or ester type(in plasma) converted to more water-soluble metabolites •Ester-type LAs hydrolyzed very rapidly in the blood to inactive metabolites – Enzyme: plasma butyrylcholinesterase (pseudocholinesterase) •Amides metabolised in liver – Enzyme: microsomal cytochrome P450 Metabolism Pharmacokinetics
- 46. 46 •Amide metabolism depends on • liver disease & hepatic blood flow • competition for the same enzyme •Toxicity from amide type LAs is more likely to occur in patients with hepatic disease • Reduced hepatic blood flow decreased hepatic elimination of LAs – volatile anesthetics reduce liver blood flow Pharmacokinetics
- 47. 47 Excretion •Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form •more readily excreted •Unionized form diffuse readily through lipid membranes, little/no urinary excretion of the neutral form occurs Pharmacokinetics
- 48. 48 •LAs block voltage-gated Na+ channel •Bind the intracellular component of the channel •LAs block the initiation & propagation of action potentials by preventing the voltage-dependent increase in Na+ conductance •Use dependent effect – Cationic form of LA is able to interact with the receptor only when the channel is open – No significant affinity for resting channels Mechanism of action Pharmacodynamics
- 49. 49 • LAs prolong inactive state of the channel & it will take longer time for recovery • Higher Ca2+ concentration reduce inactivation of Na+ channel & lowers LA effects • K+ increases the activity of LA Mechanism of action
- 50. 50 Use and techniques of LAs 1. Topical /surface anaesthesia – Applied to mucus membrane & abraded skin – Only superficial layer is anaesthetized – Onset & duration of action depends on the site, the drug, conc.,& form – Typically are used LAs; tetracaine (2%), lidocaine (2% to 10%) & cocaine (1% to 4%) – Dosage form could be Drops, ointment, cream, spray, suspension, suppository
- 51. 51 2. Infiltration anesthesia •Dilute solution of LA is infiltrated under the skin in the area of operation - block sensory nerve endings •Duration of action can be approximately doubled by adding epinephrine to the injection solution •Epinephrine-containing solutions should not be injected into tissues supplied by end arteries (Eg. ears, nose, penis, fingers & toes) – vasoconstriction may cause gangrene •Commonly used; lidocaine (0.5% to 1%), procaine (0.5% to 1%) & bupivacaine (0.125% to 0.25
- 52. 52 3. Conduction block 3.1.Field block anaesthesia • Injecting LA subcutaneously so that all nerves coming to a particular field are blocked • Used in case of appendicectomy,dental procedure, scalp stitching, operation of forearms & legs, etc
- 53. 53 3. Conduction block 3.2.Nerve block anaesthesia • Injecting LA into or about individual peripheral nerves or nerve plexuses • Blockade of mixed peripheral nerves & nerve plexuses anesthetizes somatic motor nerves – producing skeletal muscle relaxation & is essential for some surgical procedures • Produces greater areas of anesthesia than the topical & infltiration anaesthesia do
- 54. 54 4. Spinal Anesthesia • Injection of LA into the cerebrospinal fluid (CSF) in the lumbar space • Safe & effective technique, especially during surgery involving the lower abdomen, the lower extremities & the perineum 5. Epidural anesthesia • Injecting into the epidural space
- 55. 55 CNS effects • All LAs produce sequence of stimulation followed by depression • Initial stimulation is due to inhibition of inhibitory NTs & at high dose all neurons are inhibited • Cociane is powerful CNS stimulant causing the following effects in sequence – Euphoria/excitement--mental confusion-- convulsion--unconsciousness--respiratory depression--death – Effect is concentration dependent
- 56. 56 • Procaine & other synthetic LAs – Produce little CNS effects at safe clinical dose – Higher dose produce CNS stimulation followed by depression • Lidocaine – Initially causes drowsiness & lethargy – At higher dose it produces excitation followed by depression
- 57. 57 Toxicity Two major forms of LAs toxicity 1. Systemic effects •CNS •CVS •Hematological • Allergic reactions from p-aminobenzoic acid derivatives (ester link LAs metabolite) 2. Direct neurotoxicity from the local effects •At high concentration