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General anaesthetics for pg copy

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General anaesthetics for pg copy

  1. 1. General Anaesthetics For Post-Graduates
  2. 2. QUESTION • INHALATIONAL ANAESTHETICS (20MARKS)
  3. 3. • They are of mainly 2 types Volatile anesthetics (diethyl ether, halothane, enflurane, isoflurane, desflurane, sevoflurane) • They have low vapor pressures and high boiling points . • liquids at room temperature (20 deg C) Gaseous anesthetics (nitrous oxide, xenon) • They Have high vapor pressures and low boiling points
  4. 4. History • The use of nitrous oxide to relieve the pain of surgery was suggested by Humphrey Davy in 1800. • Crawford Long, a physician in rural Georgia, first used ether anesthesia in 1842. • In 1846 James Simpson, used chloroform to relieve the pain of childbirth.
  5. 5. Mechanism of action • Not properly understood. • Primary focus (of research) has been on the synapse. GABAA receptors • Almost all anaesthetics (with the exceptions of cyclopropane, ketamine and xenon) potentiate the action of GABA at the GABAA receptor. (GABAA receptors are ligand-gated Cl- channels made up of five subunits (generally comprising two α, two β and one γ or δ subunit).
  6. 6. • volatile anaesthetics (may) bind at the interface between α and β subunits. Two-pore domain K+ channels (These belong to a family of 'background' K+ channels that modulate neuronal excitability.) Channels made up of TREK1, TREK2, TASK1, TASK3 or TRESK subunits (can be) directly activated by low concentrations of volatile and gaseous anaesthetics. • Thus reducing membrane excitability.
  7. 7. NMDA receptors • (Glutamate the major excitatory neurotransmitter in the CNS, activates three main classes of ionotropic receptor-AMPA, kainate and NMDA receptors.) • Nitrous oxide, xenon apppear to reduce NMDA receptor-mediated responses. • Xenon appears to inhibit NMDA receptors by competing with glycine. • Other inhalation anaesthetics may also exert effects on the NMDA receptor in addition to their effects on other proteins such as the GABAA receptor
  8. 8. PHARMACOKINETICS • Inhaled anesthetics are taken up through gas exchange in the alveoli. Uptake & Distribution A. Inspired Concentration and Ventilation • The driving force for uptake is the alveolar concentration. • Two determinants : (controlled by the anesthesiologist) (1) inspired concentration or partial pressure (2) alveolar ventilation .
  9. 9. • Increases in the inspired partial pressure increase the rate of rise in the alveoli and thus accelerate induction. • The increase of partial pressure in the alveoli is expressed as a ratio of alveolar concentration (F A ) over inspired concentration (F 1 ); • The faster F A /F 1 approaches 1 (1 representing the equilibrium), the faster is the induction.
  10. 10. • The other parameter by which FA/F1 approaches to 1 is alveolar ventilation. • However The magnitude of the effect varies according to the blood:gas partition coefficient. Factors Controlling Uptake 1. Solubility 2. Cardiac output 3. Alveolar-venous partial pressure difference
  11. 11. Solubility : • The blood:gas partition coefficient is a useful index of solubility. • Defines the relative affinity of an anesthetic for the blood compared with that of inspired gas. • The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in blood, are extremely low.
  12. 12. • When an anesthetic with low blood solubility diffuses from the lung into the arterial blood, relatively few molecules are required to raise its partial pressure • Therefore, the arterial tension of gas rises rapidly.
  13. 13. • Conversely, for anesthetics with moderate to high solubility ( halothane, isoflurane), more molecules dissolve before partial pressure changes significantly, and arterial tension of the gas increases less rapidly. • A blood: gas partition coefficient of 0.47 for nitrous oxide means that - At equilibrium, the concentration in blood is 0.47 times the concentration in the alveolar space (gas).
  14. 14. Cardiac output— • An increase in pulmonary blood flow (ie, increased cardiac output) will increase the uptake of anesthetic. • But anesthetic taken up will be distributed in all tissues, not just the CNS. • Cerebral blood flow is well regulated and the increased cardiac output will therefore increase delivery of anesthetic to other tissues and not the brain.
  15. 15. Alveolar-venous partial pressure difference— • The anesthetic partial pressure difference between alveolar and mixed venous blood is dependent mainly on uptake of the anesthetic by the tissues, including non-neural tissues. • The greater this difference in anesthetic gas tensions, the more time it will take to achieve equilibrium with brain tissue.
  16. 16. Elimination • Recovery from inhalation anesthesia follows some of the same principles in reverse that are important during induction. • One of the most important factors governing rate of recovery is the • Blood : gas partition coefficient of the anesthetic agent. Lesser the value faster is the recovery. • nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate.
  17. 17. • Recovery also depends on 1. Alveolar Ventilation (controlled by Anaesthesiologist) 2. Metabolism of anaesthetic. • Modern inhaled anesthetics are eliminated mainly by ventilation and are only metabolized to a very small extent. • However , metabolism have important implications for their toxicity.
  18. 18. • In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is • halothane > enflurane > sevoflurane >isoflurane > desflurane > nitrous oxide
  19. 19. PHARMACODYNAMICS A. Cerebral Effects • Anesthetic potency is currently described by the minimal alveolar concentration (MAC) required to prevent a response to a surgical incision. • Inhaled anesthetics decreases the metabolic activity of the brain. • Decreased cerebral metabolic rate (CMR) generally reduces blood flow within the brain.
  20. 20. • However, volatile anesthetics also cause cerebral vasodilation, which can increase cerebral blood flow. • The net effect on cerebral blood flow (increase, decrease, or no change) depends on the concentration of anesthetic delivered. • Clinical importance : An increase in cerebral blood flow is undesirable in patients who have increased intracranial pressure because of brain tumor, intracranial hemorrhage, or head injury.
  21. 21. • Anesthetic effects on the brain produce four stages or levels of increasing depth of CNS depression (Guedel’s signs, derived from observations of the effects of inhaled diethyl ether): • Stage I—analgesia: The patient initially experiences analgesia without amnesia. Later in stage I, both analgesia and amnesia are produced. • Stage II—excitement: During this stage, the patient appears delirious, may vocalize but is completely amnesic. Respiration is rapid, and heart rate and blood pressure increase.
  22. 22. Stage III—surgical anesthesia: • This stage begins with slowing of respiration and heart rate and extends to complete cessation of spontaneous respiration (apnea). • Four planes of stage III are described based on changes in ocular movements, eye reflexes, and pupil size, indicating increasing depth of anesthesia.
  23. 23. Stage IV—medullary depression: • Severe depression of the CNS, including the vasomotor center and respiratory center in the brainstem. • Without circulatory and respiratory support, death would rapidly ensue.
  24. 24. B. Cardiovascular Effects • All depress normal cardiac contractility (halothane and enflurane more so than isoflurane, desflurane, and sevoflurane). • So they tend to decrease mean arterial pressure in direct proportion to their alveolar concentration.
  25. 25. • In halothane and enflurane, the reduced arterial pressure is caused primarily by myocardial depression (reduced cardiac output) and there is little change in systemic vascular resistance.
  26. 26. • In contrast, isoflurane, desflurane, and sevoflurane produce greater vasodilation with minimal effect on cardiac output. • Clinical importance : These differences may have important implications for patients with heart failure.
  27. 27. C. Respiratory Effects • All volatile anesthetics possess varying degrees of bronchodilating properties. • The control of breathing is significantly affected by inhaled anesthetics. • With the exception of nitrous oxide, all inhaled anesthetics cause a dose-dependent decrease in tidal volume increase in respiratory rate (rapid shallow breathing pattern).
  28. 28. • All volatile anesthetics are respiratory depressants (reduced ventilatory response to increased levels of carbon dioxide in the blood) D. Renal Effects • Inhaled anesthetics tend to decrease glomerular filtration rate (GFR) and urine flow.
  29. 29. Effects on Uterine Smooth Muscle • Nitrous oxide appears to have little effect on uterine musculature. • However, the halogenated anesthetics are potent uterine muscle relaxants (concentration-dependent)
  30. 30. • Toxicity of inhaled Anesthetics A. Acute Toxicity 1. Nephrotoxicity— • Metabolism of enflurane and sevoflurane may generate compounds that are potentially nephrotoxic. (liberate fluoride ions) 2. Hematotoxicity— • Prolonged exposure to nitrous oxide decreases methionine synthase activity, which could cause megaloblastic anemia
  31. 31. • All inhaled anesthetics can produce some carbon monoxide (CO) from their interaction with strong bases in dry carbon dioxide absorbers. (desflurane) 3. Malignant hyperthermia— is a heritable genetic disorder of skeletal muscle that occurs in susceptible individuals exposed to volatile anesthetics while undergoing general anesthesia. ( Halothane)
  32. 32. 4. Hepatotoxicity (halothane hepatitis)— Hepatic dysfunction • a small subset of individuals previously exposed to halothane has developed fulminant hepatic failure. • Cases of hepatitis of others have rarely been reported.
  33. 33. B. Chronic Toxicity Mutagenicity, teratogenicity. • Under normal conditions, inhaled anesthetics including nitrous oxide are neither mutagens nor carcinogens in patients. • Nitrous oxide can be directly teratogenic in animals under conditions of extremely high exposure. • Halogenated agents may be teratogenic in rodents.
  34. 34. Nitrous oxide Important features. • Nitrous oxide is completely eliminated by the lungs. • Non toxic to liver , kidney and brain. No much adverse effects on CVS , RS. • Probably the safest with 30% oxygen
  35. 35. • N2O is a weak, low potency anesthetic agent. • Action is quick and smooth . • Recovery is rapid. Rarely exceeds 4 min. • It is a poor muscle Relaxant. • It has significant analgesic effects. • Nitrous oxide is used primarily as an adjunct to other inhalational or intravenous anesthetics mainly during maitenance phase. • 70% N2O +25-30% oxy + 0.2-2% potent anaesthetic
  36. 36. Adverse effects  Pneumothorax. Megaloblastic anemia peripheral neuropathy (because of methionine synthetase inactivation
  37. 37. Halothane • Induction is relatively slow. • Halothane is soluble in fat and other body tissues, it will accumulate during prolonged administration. • Halothane can sensitize the myocardium to the arrhythmogenic effects of Adrenaline. Uses : Induction and maintenance anaesthesia in pediatric age group. Maintenance anaesthesia in adults
  38. 38. • Adverse Effects : Shivering during recovery Malignant hyperthermia Fulminant hepatic necrosis
  39. 39. Enflurane • Induction of anesthesia and recovery from enflurane are relatively slow. • It is primarily utilized for maintenance rather than induction of anesthesia. • Enflurane provokes seizure attacks in susceptible patients. • Enflurane produces significant skeletal muscle relaxation
  40. 40. Isoflurane • Induction with isoflurane and recovery from isoflurane are faster than with halothane. • It is typically used for maintenance of anesthesia after induction with other agents because of its pungent odor. Another e.g, Desflurane.
  41. 41. Sevoflurane • Eventhough non-explosive in mixtures of air or oxygen. sevoflurane can undergo an exothermic reaction with desiccated CO2 to produce airway burns. So it should be used in open system airway ventilation. • Effects on CVS and RS is modest. • It is well-suited for inhalation induction of anesthesia (particularly in children)

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