8 General Anesthetic Agents - posting.pptx

General Anesthetic Agents Anupam Bishayee, M.Pharm., Ph.D. Professor of Pharmacology Lake Erie College of Osteopathic Medicine 941-782-5950 [email protected] MMS1070: October 17, 2023 1 Reference Basic and Clinical Pharmacology 15th Edition Chapter 25 MMS1070: October 17, 2023 2 Learning O...

General Anesthetic Agents Anupam Bishayee, M.Pharm., Ph.D. Professor of Pharmacology Lake Erie College of Osteopathic Medicine 941-782-5950 [email protected] MMS1070: October 17, 2023 1 Reference Basic and Clinical Pharmacology 15th Edition Chapter 25 MMS1070: October 17, 2023 2 Learning Objectives      Explain the concept of general anesthesia. Identify the main inhalational anesthetic agents & describe their mechanism of action. Describe the major clinical characteristics of nitrous oxide, halothane, desflurane, sevoflurane, isoflurane & enflurane. Describe the major toxicities associated with nitrous oxide & the halogenated anesthetics including halothane & methoxyflurane. Describe the major indications for use of the i.v. anesthetics: barbiturates, benzodiazepines, opioids, propofol & etomidate. MMS1070: October 17, 2023 3 General Anesthesia It can be defined as a reversible modification / alteration in the activity of CNS, which is drug induced, resulting in a state of unconsciousness, amnesia & non-responsiveness to a painful stimuli. To bring about these effects these drugs are to be administered systemically. Two routes are usually followed for administration, i.e., inhalation or intravenous. The criteria desirable for a good general anesthetic are: • Wide margin of safety • Induction should be rapid & pleasant • Recovery should be complete, fast & smooth • Should provide adequate skeletal muscle relaxation MMS1070: October 17, 2023 4 General Anesthesia MMS1070: October 17, 2023 5 General Anesthesia MMS1070: October 17, 2023 6 General Anesthetics Inhalational Anesthetics Nitrous oxide Cyclopropane Halothane (FLUOTHANE) Desflurane (SUPRANE) Isoflurane (FORANE) Sevoflurane (ULTANE) Enflurane (ETHRANE) Methoxyflurane (Penthrane) Parenteral Anesthetics Thiopental (PENTOTHAL) Methohexital (BREVITAL) Midazolam (VERSED) Ketamine (KETALAR) Propofol (DIPRIVAN) Etomidate (AMIDATE) Fentanyl (SUBLIMAZE) Sufentanil (SUFENTA), Alfentanil (ALFENTA) Remifentanil (ULTIVA) MMS1070: October 17, 2023 7 Mechanism of Anesthesia      These drugs usually increase the threshold for firing of CNS neurons. The most important sites at which the anesthetics act are the reticular formation & hippocampus. The potency of most inhaled anesthetics is proportionate to their lipid solubility. A primary molecular target of many general anesthetics is the GABAA receptor-chloride channel. Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol facilitate GABA-mediated inhibition at GABAA receptor sites. MMS1070: October 17, 2023 8 Inhalational Anesthetics MMS1070: October 17, 2023 9 Gases     Nitrous Oxide It is an odorless, nonflammable & non-explosive gas. Advantages are: • Induction & recovery prompt as it has a low blood gas partition. • Nonflammable & non-explosive. • Does not affect respiration, liver & kidneys. Minimal effect on CVS. • Good analgesic without loss of consciousness and it is often used for minor surgery and dental procedures. Disadvantages are: • Very low potency, i.e., weak anesthetic. • Inadequate muscular relaxation. • Diffusion hypoxia / increase pressure in closed cavities. • Spontaneous abortion. MMS1070: October 17, 2023 10 Volatile Liquids     Diethyl ether (historical) It is a colorless, flammable & highly volatile liquid. Advantages are: • Safe has a wide therapeutic index. • Potent (10-15% in inspired air). • Good & effective analgesic. • Profound skeletal muscle relaxation. • Non-toxic to liver & kidney. • Does not sensitize myocardium to catecholamines. Disadvantages are: • Slow induction & prolonged recovery as it has high blood gas coefficient. • As it is flammable & explosive in nature, precaution should be taken while using it. • Highly irritating to respiratory tract, leads to increased bronchial & salivary secretions, which increases the risk of postoperative infection. MMS1070: October 17, 2023 11 Halothane It is a non-irritant & non-explosive volatile liquid. Nearly 30% of the drug is metabolized. It is no longer used in the USA.  Advantages are: • High potency (2-3% in inspired air). • Medium rate of induction & recovery. • Skeletal muscle relaxation is good (but inadequate). • Non-irritant to respiratory tract. • Non-flammable.  Disadvantages are: • Poor analgesic. • Inadequate skeletal muscle relaxation. • Sensitizes the myocardium to catecholamines, so it places patients at a great risk for cardiac arrhythmias. • Repeated administration can lead to liver damage (cumulative) & nephrotoxicity. • Can produce respiratory & cardiovascular failure. • Relaxes the uterus making it useless in obstetrical cases. • Patients should not be re-exposed to it for 6 to12 months. MMS1070: October 17, 12 Enflurane    It is halogenated ether. Advantages are:  Fast induction & rapid recovery.  Good analgesic & skeletal muscle relaxant  Non-irritant to respiratory tract.  Non-flammable & non-explosive.  Does not cause hepatic damage & frequency of renal damage is much less. Disadvantages are:  Respiratory depression.  Causes epilepsy like seizures during induction or following recovery. MMS1070: October 17, 2023 13 Isoflurane  Advantages are: • Highly potent. • Fast induction & rapid recovery. • Non-flammable & non-explosive. • No renal or hepatic toxicity. • No epilepsy like seizures.  Disadvantages are: • Expensive. • Respiratory depression is prominent. • Increases heart rate. • Sensitize myocardium to catecholamines to a lesser extent in comparison to halothane. MMS1070: October 17, 2023 14 Intravenous Anesthetics MMS1070: October 17, 2023 15 Thiopentone Sodium  It is a highly lipid-soluble barbiturate and rapidly crosses the blood brain barrier.  On intravenous administration it causes unconsciousness within 20 sec, which lasts for 5-10 minutes.  “Redistribution to muscle fat leads to a fall in its effect”. Slowly metabolized.  As it is highly lipid-soluble, repeated administration leads to accumulation in body fats.  As it has a high oil gas partition coefficient, recovery is slow & leads to a hangover.  It is a poor analgesic. MMS1070: October 17, 2023 16 Thiopentone sodium  It causes respiratory & cardiovascular depression.  It is vasospastic in nature & can even cause gangrene if accidentally injected in an artery.  It is used exclusively as an inducing agent prior to an inhalational agent.  Usually given in a dose of 100-150 mg injected slowly over 10-15 seconds, can be repeated after 30 seconds depending upon response up to a maximum of 4 mg/kg. MMS1070: October 17, 2023 17 Methohexital/Methohexitone  It is an oxybarbiturate.  It is similar in properties to thiopentone, but it causes less hang over due to rapid hepatic metabolism.  Its administration is associated with high incidence of muscle twitching.  In epilepsy patient it brings about changes in EEG & thus its use should be restricted in such patients. MMS1070: October 17, 2023 18 Benzodiazepines  Midazolam, diazepam, and lorazepam are benzodiazepines derivatives used in anesthesia.  The most popular of these for induction of anesthesia is midazolam because of its aqueous solubility and shorter duration of action.  Diazepam and lorazepam are dissolved in propylene glycol, which is irritant to the vasculature on parenteral administration.  IV administration causes unconsciousness, without analgesia; skeletal muscle relaxation is inadequate for intubation or short surgical procedures.  Intraoperative use of midazolam with inhalation anesthetics may prolong the postanesthesia recovery period. MMS1070: October 17, 2023 19 Etomidate  The pharmacological properties are similar to barbiturates, but it has an advantage as it preserves the cardiovascular and respiratory stability.  It also produces a mild coronary vasodilatation, thus is helpful in patients with compromised myocardial oxygen and blood supply.  It may cause pain on injection and also may produce myoclonic muscle movement in 40% of patients during induction. MMS1070: October 17, 2023 20 Propofol  Rapidly acting, has a short recovery time, and possesses antiemetic properties.  A rapid onset of anesthesia (50 seconds) is achieved, and recovery will take place in 4 to 8 minutes.  Rapid recovery and its antiemetic properties make propofol anesthesia very popular as an induction agent for outpatient anesthesia.  Both continuous infusion of propofol for conscious sedation (procedural sedation and analgesia) and with opioids for the maintenance of anesthesia for cardiac surgery are acceptable techniques. MMS1070: October 17, 2023 21 Opioid Agonists  Fentanyl is a strong opioid agonist used to treat moderate to severe pain.  Administered intravenously or epidurally in combination with other drugs for surgical or obstetric analgesia and anesthesia.  Fentanyl does not produce amnesia or complete loss of consciousness (patient recall), so it is often combined with a benzodiazepine (e.g., diazepam) to produce amnesia and increased sedation.  Fentanyl is more likely to cause skeletal muscle rigidity than relaxation.  Another disadvantage is the occurrence of hypertensive responses to surgical stimulation. MMS1070: October 17, 2023 22 Ketamine  Ketamine is chemically and pharmacologically related to phencyclidine (PCP), a street drug that is abused because of its pronounced effects on sensory perception.  Ketamine produces less sensory distortion and euphoria than does PCP and, therefore, is more suitable for use as an anesthetic.  Both ketamine and PCP act by blocking the action of excitatory amino acids, primarily glutamate, at N-methyl-Daspartate (NMDA) receptors. MMS1070: October 17, 2023 23