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inhalational agents:brief review

brief review of inhalational agents

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inhalational agents:brief review

  2. 2. Flow of content History Ideal anesthetic agents  -property-physical  -pharmacokinatical  -pharmacodynamical. Classification of anesthetic agents. Stages of anesthesia. Individual drugs and properties.`
  3. 3. History  During the Middle Ages, attempts were made to use alcohol fumes as an analgesic during surgery.  Another inhaled technique, the soporific sponge, is mentioned in numerous manuscripts written in the Middle Ages.
  4. 4. History  The first public demonstration of inhalation anaesthetic was nitrous oxide used by Professor Gardner Q. Colton and dentist Horace Wells on 11 December 1844.  On Oct 16th 1846 William Morton successfully demonstrated Ether anaesthesia at Massachusetts general hospital.
  5. 5. John collin warren W.T.G.MORTON Gilbert Abott
  6. 6. Ideal inhalational anaesthetic  Physical properties  (1) Stable over a range of temperatures  (2) Not be degraded by light  (3) Does not require the presence of a preservative  (4) Non-explosive and does not support combustion  (5) Odourless or has a pleasant smell  (6) Environmentally safe  (7) Does not react with other compounds (e.g. Soda lime, plastic and metals etc.)  (8) Has a boiling point well above room temperature
  7. 7. Pharmacodynamic properties  (1) Predictable dose-related CNS depression  (2) Analgesic, anti-emetic and muscle relaxation properties  (3) Minimal respiratory depression, does not cause coughing or bronchospasm  (4) Minimal cardiovascular effects.  (5) No increase in cerebral blood flow (and therefore intracranial pressure).  (6) Not epileptogenic  (7) Does not impair renal or hepatic function  (8) No effect on uterine smooth muscle  (9) Does not trigger of malignant hyperthermia
  8. 8. Pharmacokinetic properties  (1) Low blood: gas solubility co-efficient  (2) Low oil: gas solubility co-efficient  (3) Not metabolised or no active metabolites  (4) Is excreted completely by the respiratory system
  9. 9. Classification of inhalational anesthetics Historical Gases Volatile agents  Ether  trilene Methoxyflurane Cyclopropane  chloroform  Nitrous oxide  Xenon  Halothane  Enflurane  Isoflurane  Sevoflurane  Desflurane
  10. 10. In administering an anesthesia Signpost Guides in determination of depth of anesthesia  Guedel describe depth of anaesthesia by dividing it into stages and planes. Stages of Anesthesia
  11. 11.  Guedel’s criteria based on :  Respiration  Eyeball movement  Presence or absence of various reflexes  Gillespie added other criteria  Secretion of tears  Response to skin incision  Evaluation of pharyngeal & laryngeal reflexes
  12. 12.  Stages were first described for ether anesthesia  Can be used with modification for all agents  Can be recognized during both induction & recovery
  13. 13.  Starts from beginning of anaesthetic inhalation and lasts up to the loss of consciousness.  Pain is progressively abolished.  Patient remains conscious, can hear and see, and feels a dream like state Stage I- Stage of Analgesia
  14. 14.  Reflexes and respiration remain normal.  Some minor operations can be carried out during this stage  But it is difficult to maintain  Therefore use is limited to short procedures
  15. 15.  Stage starts from loss of consciousness upto gain of rhythmical respiration  Respiration – Irregular and large in volume  Heart rate and BP raises  Pupils – Large and divergent  Muscle tone increased – jaw may be tight  Patient may shout or struggle  Involuntary micturation , or defecation Stage II – Stage of Excitement
  16. 16.  Extends from onset of regular respiration to cessation of spontaneous breathing.  This has been divided into 4 planes: o Plane 1- Roving eyeballs. o This plane ends when eyes become fixed. o Plane 2- Loss of corneal and laryngeal reflexes. o Plane 3- Pupil starts dilating and light reflex is lost. o Plane 4- Intercostal paralysis Shallow abdominal respiration Dilated pupil. Stage III- Surgical Anaesthesia
  17. 17.  As anaesthesia passes to deeper planes  Progressively-muscle tone decreases  BP falls  Heart Rate increases with weak pulse  Respiration decreases in depth and later in frequency
  18. 18.  There is cessation of breathing leading to failure of circulation and death.  Pupil is widely dilated  Muscles are totally flabby  Pulse is thready or imperceptible  BP is very low. Stage IV- Stage of Medullary Paralysis
  19. 19. Ether  MAC 1.92  ,B:G partition coefficient 12  Guedel’s 4 stages of anaesthesia based on ether  Good Analgesic  Good Muscle Relaxant
  20. 20.  Pungent smell  Inflammable and explosive  Irritant  Slow Induction and Recovery  High incidence of Nausea and Vomitting
  21. 21. ether  High CVS stability ; no myocardial depression.  sympathetic stimulation and preservation of baroreceptor reflex.  No respiratory depression and no blunting of Hypoxic drive.  Bronchodilatation and Preserves cilliary activity
  22. 22. Nitrous oxide Physical Property • Not flammable but support combustion. • Odorless • Colorless • Tasteless • Prepared by heating NH4NO3 at 245-270°C
  23. 23. NH4NO3 --> N2O + 2H2O Small amounts of NH3 and HNO3 produced recombine to NH4NO3 on cooling. Small amounts of NO and NO2 are also produced- - Can cause methaemoglobinaemia, pulmonary edema if inspired. - N2O must be purified to remove these contaminants
  24. 24. Nitrous oxide Colour of cylinder = blue. MAC - 104% Blood gas partition coefficient -0.46. Pin index - 3;5
  25. 25. Nitrous oxide  Unlike the potent volatile agents, nitrous oxide is a gas at room temperature and ambient pressure.  It can be kept as a liquid under pressure because its critical temperature lies above room temperature  With a MAC value of 104%, nitrous oxide, by itself is not suitable as a sole anaesthetic agent.  Nitrous oxide is an effective analgesic but poor muscle relaxant  It undergoes minimal metabolism.
  26. 26. Nitrous Oxide C.V.S EFFECTS-  The circulatory effects of nitrous oxide are explained by its tendency to stimulate the sympathetic nervous system.  Even though nitrous oxide directly depresses myocardial contractility in vitro, arterial blood pressure, cardiac output, and heart rate are essentially unchanged or slightly elevated in vivo because of its stimulation of catecholamine
  27. 27. Nitrous oxide CEREBRAL  By increasing CBF and cerebral blood volume, nitrous oxide produces a mild elevation of intracranial pressure.  Nitrous oxide also increases cerebral oxygen consumption (CMRO2).
  28. 28. The second gas effect  The second gas effect usually refers to nitrous oxide combined with an inhalational agent. Because nitrous oxide is not soluble in blood, its' rapid absorption from alveoli causes an abrupt rise in the alveolar concentration of the other inhalational anaesthetic agent.
  29. 29. Diffusion Hypoxia •At the end of anesthesia after discontinuation of N2O, N2O diffuses from blood into the alveoli much faster than N2 diffuses from alveoli into the blood. • Total volume of gas in the alveolus → fractional concentration of gases in the alveoli is diluted by N2O → ↓ PaO2 & PaCO2 → hypoxia. •This occurs in the first 5-10 mins of recovery. Therefore it is advised to use 100% O2 after discontinuation of N2O.
  30. 30. Toxicities – Nitrous Oxide  Hematologic:  N2O antagonizes B12 metabolism  inhibition of methionine-synthetase  Decreased DNA production  RBC production depressed (megaloblastic anaemia)  Neurologic  Long term exposure to N2O is hypothesized to result in neurologic disease similar to B12 deficiency
  31. 31. 35 times more soluble in blood than nitrogen, N2 so fills and expands any air-containing cavities: air embolism pneumothorax intracranial air lung cysts intraocular air bubbles tympanoplasty may exacerbate pulmonary hypertension
  32. 32. Entonox 50% N2O + 50% O2 Colour coding = blue body with blue &white quarters. Pin index = 7 Poyinting effect: normally N2O is liquid at 2400 psig. But If N2O is mixed with O2 it remains in gaseous state called poyinting efect.  Use: 1)labour analgesia. 2)field analgesia(wars)
  33. 33. Halothane 2-chloro,bromo 1-trifluro ethane. Halogenated alkane compound chemically Amber colored bottled – red colour coding • Thymol preservative-to prevent spontaneous oxidative decomposition. • MAC- 0.75% So potent anesthetic. • low blood/gas solubility coeffient - 2.5 thus induction - relatively rapid.
  34. 34. HALOTHANE  Volatile- kept in sealed bottles  Colorless,  Pleasant odor-suitable in pediatrics for inhalation induction (although sevoflurane is now the agent of choice )  Non-irritant  Non-explosive, Non-inflammable  Light-sensitive  Corrosive-Interaction – rubber and plastic tubing
  35. 35. metabolism  20% metabolized in liver by oxidative pathways.  Major metabolites : bromin, chlorine, Trifloroacetic acid, Trifloroacetylethanl amide
  36. 36. Systemic effects of Halothane  CNS:  Generalized CNS depression  cerebrovascular dilation causes increased ICP  Autoregulation is blunted  Cardiovascular: • A dose-dependent reduction of arterial blood pressure is due to direct myocardial depression • blunts baroreceptor reflex
  37. 37. •Although halothane is a coronary artery vasodilator, coronary blood flow decreases, due to the drop in systemic arterial pressure. • Adequate myocardial perfusion is usually maintained, as oxygen demand also drops- maybe advantages In pts with CAD •Halothane sensitizes the heart to the arrhythmogenic effects of catecholamine ◦To minimize effects : Avoid hypoxemia and hypercapnia Avoid conc. Of adrenaline higher than 1 in 10000
  38. 38. Pulmonary:  best bronchodilator among the currently available volatile anesthetics.  attenuates airway reflexes and relaxes bronchial smooth muscle by inhibiting intracellular calcium mobilization.  depresses clearance of mucus from the respiratory tract (mucociliary function), promoting postoperative hypoxia and atelectasis.
  39. 39.  Renal: -Both GFR and renal blood flow is decreased-because of decrease cardiac output. - associated with reversible reduction in GFR. Gastro intestinal tract:- Inhibition of gastrointestinal motility. Cause sever post. Operative nausea & vomiting. Uterus:  Halothane relaxes uterine muscle, may cause postpartum hemorrhage .  Concentration of less than 0.5 % associated with increase blood loss during therapeutic abortion.
  40. 40. Skeletal muscle:  Its cause skeletal muscle relaxation .  Postoperatively, shivering is common , this increase oxygen requirement>>> which cause hypoxemia. Post operative shivering (halothane shakes) and hypothermia is maximum with halothane among inhalational agents.
  41. 41. Halothane - Hepatic Toxicity  All inhaled AA can cause hepatic injury in animal studies  All inhaled AA have immunohistochemical evidence of binding to hepatocytes  Thought that Trifluoroacetic acid metabolites are root cause  Another theory is due to Hypoxia as halothane causes Hepatic arterial constriction
  42. 42. Halothane Hepatitis  The incidence of fulminant hepatic necrosis terminating in death associated with halothane was found to be 1 per 35,000.  Demographic factors ; It’s a idiosyncratic reaction, susceptible population include Mexican Americans,Obese women, , Age >50 yrs, , Familial predisposition, Severe hepatic dysfunction while Children are resistant. Prior exposure to halothane is a important risk factor & multiple exposure increases the chance of hepatitis.
  43. 43. Mechanism of Toxicity  There are various proposed mechanisms: • Metabolite-mediated direct toxicity • Immunologically-mediated damage to liver cells  a proportion is biotransformed by hepatic microsomal enzyme CYP 2E1 to a trifluoroacetic acid which can be detected in the urine, but which also can trifluoroacetylate hepatic proteins, some of which may be immunogenic and induce cytotoxic reactions. • Hypoxia alone
  44. 44. Hepatic dysfunction:  Two type of dysfunction:  1- Type I hepatotoxicity:-mild, associated with derangement in liver function test , this result from metabolic of Halothane in liver. results from reductive (anaerobic) biotransformation of halothane rather than the normal oxidative pathway.  2- Type II hepatotoxicity: fulminate (uncommon); sever jaundice ,fever, progressing to fulminating hepatic necrosis, Its increased by repeated exposure of the drugs. high mortality 30-70%
  45. 45.  1- A careful anesthetic history .  2- repeated exposure of halothane within 3 months should be avoided.  3- History of unexplained jaundice or pyrexia after previous exposure of halothane. Recommendation for Halothane anesthesia:
  46. 46. Drug Interactions  1. Beta blockers and calcium channel blockers can produce severe depression of cardiac function with halothane  2. Aminophylline can produce serious ventricular arrhythmias with halothane.  3 .Halothane sensitizes the heart to the arrhythmogenic effects of epinephrine, so that doses of epinephrine above 1.5 g/kg should be avoided.
  47. 47. Contraindication  Malignant hyperthermia.  susceptibility unexplained liver dysfunction after previous halothane exposure  intracranial mass lesion  hypovolemia  aortic stenosis  pheochromocytoma  with aminophylline has been associated with severe ventricular dysrhythmias
  48. 48. Isoflurane 2-chloro 1-trifluro methyl- ethyl ether. MAC is 1.17 % B:G p co-ef is 1.17. Isoflurane is characterized by extreme physical stability, undergoing no detectable deterioration during 5 years of storage or on exposure to carbondioxide absorbents or sunlight. The stability of isoflurane obviates the need to add preservatives such as thymol to the commercial preparation.
  49. 49.  RESPIRATORY SYSTEM  Initially, until deeper levels of anesthesia are reached, isoflurane stimulates airway reflexes with:  increases in secretions  coughing  laryngospasm.
  50. 50. Isoflurane  CNS:  low concentration Vs High concentration.  Low : no change on the flow.  High : increase blood flow by vasodilatation of the cerebral arteries. Generalized CNS depression; Rapid emergence  Increased ICP reversed by Hyperventilation  Agent of choice for neuro-anaesthesia.
  51. 51.  Cardiovascular:  myocardial depression, decreased vascular assistance & decreased MAP  Preserves baroreceptor reflex . So that reflex tachycardia occurs in response to decrease B.P maintaining cardiac output.  Agent of choice for cardiac anaesthesia.
  52. 52. Coronary steal phenomenon  Isoflurane induced coronary artery vasodilatation can lead to redistribution of coronary blood flow away from diseased areas where arterioles are maximally dilated to areas with normal responsive coronary arteries. This phenomenon is called the coronary steal syndrome
  53. 53. Sevoflurane Florinated Methyl – isopropyl ether. MAC -1.80. Low blood:gas partition coefficient -0.69 (Rapid induction and recovery. Compared with isoflurane, recovery from sevoflurane anesthesia is 3 to 4 minutes faster and the difference is magnified in longer duration surgical procedures (>3 hours)
  54. 54.  Pleasant smell , non irritant,bronchodilatation and least airway irritation among current volatile agents makes it acceptable for inhalation induction of anesthesia. • agent of choice for paediatric anesthesia. • 2nd agent of choice for • Neuro anesthesia. • Cardiac anesthesia . • Asthmatics Does not sensitize the myocardium to catecholamines as much as halothane. Does not result in carbon monoxide production with dry soda lime. Sevoflurane
  55. 55.  Sevoflurane may be 100-fold more vulnerable to metabolism than desflurane -estimated 3% to 5% of the dose undergoing biodegradation.  metabolites - inorganic fluoride  hexafluoroisopropanol.  cannot undergo metabolism to an acyl halide.  does not result in the formation of trifluoroacetylated liver proteins.  Therefore cannot stimulate the formation of antitrifluoroacetylated protein antibodies.  So devoid of the potential to produce hepatotoxicity as well as cross-sensitivity between drugs.
  56. 56. Sevoflurane and Compound A  Sevoflurane forms a degradation product, compound A [fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether] on contact with the soda lime in a rebreathing apparatus.  Compound A is a dose-dependent nephrotoxin in rats.  A proposed mechanism for nephrotoxicity is the metabolism of compound A to a reactive thiol via the β-lyase pathway.  Because humans have less than one-tenth of the enzymatic activity for this pathway compared to rats, it is possible that humans should be less vulnerable to injury by this mechanism.
  57. 57.  Sevoflurane can also be degraded into hydrogen fluoride by metal and environmental impurities present in manufacturing equipment, glass bottle packaging, and anesthesia equipment.  Hydrogen fluoride can produce an acid burn on contact with respiratory mucosa.  The risk of patient injury has been substantially reduced by inhibition of the degradation process by adding water to sevoflurane during the manufacturing process and packaging it in a special plastic container.  Postoperative agitation may be more common in children then seen with halothane.
  58. 58. Desflurane 2-fluro,1-trifluro methyl ethyl ether.  MAC =6.6 % differs from isoflurane only by substitution of a fluorine atom for the chlorine atom found on the alpha-ethyl component of isoflurane. Fluorination rather than chlorination increases vapor pressure (decreases intermolecular attraction), enhances molecular stability, and decreases potency.
  59. 59.  desflurane would boil at normal operating room temperatures  A new vaporizer technology addressed this property, producing a regulated concentration by converting desflurane to a gas (heated and pressurized vaporizer that requires electrical power),which is then blended with diluent fresh gas flow  Solubility characteristics (blood:gas partition coefficient 0.45) and potency (MAC 6.6%) permit rapid achievement of an alveolar partial pressure necessary for anesthesia followed by prompt awakening when desflurane is discontinued.
  60. 60. Desflurane  Pungent odor --desflurane less likely to be used for inhalation induction compared to halothane or sevoflurane.  Airway irritation, breath-holding, coughing, laryngospasm,significant salivation, when >6% desflurane administered to an awake patient.  Produces the highest carbon monoxide concentrations, followed by enflurane and isoflurane
  61. 61. Desflurane  CNS:  Generalized depression  Extremely rapid emergence  Increased ICP  Cardiovascular:  Vascular resistance decreased  Heart rate (deep anesthesia); tachycardia with rapid concentration change  Pulmonary:  decrease tidal volume  increase respiratory rate  irritant
  62. 62. Dual-circuit gas–vapour blender  It was created specifically for the agent desflurane.  Desflurane boils at 23.5 ºC, which is very close to room temperature.  This means that at normal operating temperatures, the saturated vapour pressure of desflurane changes greatly with only small fluctuations in temperature.  A desflurane vaporiser (e.g. the TEC 6 produced by Datex- Ohmeda) is heated to 39C and pressurised to 200kPa .
  63. 63.  Agent of choice for day care (fastest induction)  Agent of choice for geriatric (old) patients.  Agent of choice for hepatic failure  Agent of choice for renal failure
  64. 64. Anesthetic B:G PC MAC Features Notes Halothane 2.3 0.74% PLEASANT Arrhythmia Hepatitis Hyperthermia Enflurane 1.9 1.69% PUNGENT Seizures Hyperthermia Isoflurane 1.4 1.17% PUNGENT Widely used Sevoflurane 0.62 1.92% PLEASANT Ideal Desflurane 0.42 6.1% IRRITANT Cough Nitrous 0.47 104% PLEASANT Anemia
  65. 65. XENON  Most ideal inhalational agent.  Blood gas partition co-efficient is 0.14. least of all .least soluble. so fastest induction and fastest recovery.  MAC is 70% so can be given with 30%O2.  Most cardiostable.  No metabolism in body –least side effects non terratogenic.  Non inflamble,does not deplete ozone layer.  Disadvantages = costly, needs special equipment for delivary, bronchospasm.  Acts on NMDA receptor
  66. 66. Enflurane 1-chloro ,fluro 2-difluro methyl-ethyl ether. •Halogenated, methyl ethyl ether •Pungent odour •MAC 1.68% •B:G- 1.8 •Inflammable at> 5 %concentration
  67. 67.  : CNS- • increased ICP secondary to increased cerebral blood flow (CBF) • produce fast frequency and high voltage on the EEG. • Decrease the threshold for seizure-Epileptogenic inhalational agent. • It is primarily used for procedure in which a low threshold for seizure generation is required like ECT.  Cardiovascular: • myocardial depressant • decreased vascular resistance; decreased mean arterial pressure (MAP), tachycardia
  68. 68. ENFLURANE  Contraindications/Precautions  malignant hyperthermia susceptibility  preexisting kidney disease  seizure disorder  intracranial hypertension  isoniazide enhances enflurane defluorination
  69. 69. Trichloroethylene (trilene)  Most potent analgesic agent - trielene  Reaction with sodalime :- dichloroacetylene – neurotoxic- V, VII. phosgene - pulmonary toxicity(ARDS) CHLOROFORM  1st agent used for labour analgesia.  Cardiotoxic- death due to ventricular fibrillation.  Hepatotoxic.  Profound hyperglycemia.
  70. 70. Methoxy-flurane  Most potent inhalational agent (mac-0.16%).  Slowest induction and recovery(b:g – 15).  Most nephro-toxic agent –high output renal failure  Reacts with rubber tubing of closed circuit
  71. 71. Cyclopropane Most inflamable & explosive agent Liquid gas-Orange cylinder. Increases sympathetic tone and B.P. Agent Of Choice in Shock Cyclopropane shock.
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brief review of inhalational agents


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