General anaesthetics for pg copy

General anaesthetics for pg copy

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  General Anaesthetics For Post-Graduates
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  QUESTION • INHALATIONAL ANAESTHETICS(20MARKS)
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  • They areof 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
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  History • The useof 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.
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  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).
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  • 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.
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  NMDA receptors • (Glutamatethe 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
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  PHARMACOKINETICS • Inhaled anestheticsare 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 .
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  • Increases inthe 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.
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  • The otherparameter 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
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  Solubility : • Theblood: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.
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  • When ananesthetic 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.
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  • Conversely, foranesthetics 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).
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  Cardiac output— • Anincrease 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.
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  Alveolar-venous partial pressuredifference— • 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.
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  Elimination • Recovery frominhalation 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.
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  • Recovery alsodepends 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.
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  • In termsof the extent of hepatic metabolism, the rank order for the inhaled anesthetics is • halothane > enflurane > sevoflurane >isoflurane > desflurane > nitrous oxide
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  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.
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  • However, volatileanesthetics 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.
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  • Anesthetic effectson 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.
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  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.
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  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.
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  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.
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  • In halothaneand enflurane, the reduced arterial pressure is caused primarily by myocardial depression (reduced cardiac output) and there is little change in systemic vascular resistance.
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  • 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.
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  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).
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  • All volatileanesthetics 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.
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  Effects on UterineSmooth Muscle • Nitrous oxide appears to have little effect on uterine musculature. • However, the halogenated anesthetics are potent uterine muscle relaxants (concentration-dependent)
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  • Toxicity ofinhaled 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
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  • All inhaledanesthetics 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)
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  4. Hepatotoxicity (halothanehepatitis)— 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.
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  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.
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  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
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  • N2O isa 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
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  Adverse effects  Pneumothorax. Megaloblasticanemia peripheral neuropathy (because of methionine synthetase inactivation
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  Halothane • Induction isrelatively 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
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  • Adverse Effects: Shivering during recovery Malignant hyperthermia Fulminant hepatic necrosis
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  Enflurane • Induction ofanesthesia 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
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  Isoflurane • Induction withisoflurane 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.
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  Sevoflurane • Eventhough non-explosivein 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)