General Anesthetics

1. General Anesthetics Assistant Professor Dr. Hayder B Sahib Ph.D., M.Sc., D.Sc. B.Sc. Pharm

2. General anesthesia is a state characterized by • 1- unconsciousness • 2- analgesia • 3- amnesia and skeletal muscle relaxation • 4- loss of reflexes. • Drugs used as general anesthetics are • 1- CNS depressants • 2- induced and terminated more rapidly than those of conventional sedative-hypnotics.

4. STAGES OF ANESTHESIA • Stage 1: Analgesia In stage 1, the patient has decreased awareness of pain, sometimes with amnesia. Consciousness may be impaired but is not lost. • Stage 2: Disinhibition In stage 2, the patient appears to be delirious and excited. Amnesia occurs, reflexes are enhanced, and respiration is typically irregular; retching and incontinence may occur. • Stage 3: Surgical Anesthesia In stage 3, the patient is unconscious and has no pain reflexes; respiration is very regular, and blood pressure is maintained.

5. Stage 4: Medullary Depression • In stage 4, the patient develops severe respiratory and cardiovascular depression that requires mechanical and pharmacologic support.

6. ANESTHESIA PROTOCOLS • Anesthesia protocols vary according to the proposed type of • 1- diagnostic • 2- therapeutic • 3- surgical intervention. • For minor procedures, conscious sedation techniques that combine intravenous agents with local anesthetics are often used. • These can provide profound • 1- analgesia • 2- retention of the patient’s ability to maintain a patent airway • 3- respond to verbal commands.

7. For more extensive surgical procedures, anesthesia protocols commonly include • 1- intravenous drugs to induce the anesthetic state • 2- inhaled anesthetics (with or without I.V agents) to maintain an anesthetic state • 3- neuromuscular blocking agents to effect muscle relaxation .

8. Vital sign monitoring remains the standard method of assessing “depth of anesthesia” during surgery. • Cerebral monitoring, automated techniques based on quantification of anesthetic effects on the electroencephalograph (EEG), is also useful.

9. MECHANISMS OF ACTION • Mechanisms of action include • 1- Effects on ion channels by interactions of anesthetic drugs with membrane lipids or proteins with subsequent effects on central neurotransmitter mechanisms. • 2- Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol facilitate γ-aminobutyric acid (GABA)-mediated inhibition at GABAA receptors.

10. These receptors are sensitive to clinically relevant concentrations of the anesthetic agents and exhibit the appropriate stereospecific effects in the case of enantiomeric drugs. • 3- Ketamine act possibly via its antagonism of the action of the excitatory neurotransmitter glutamic acid on the N-methyl-Daspartate(NMDA) receptor.

11. 4- Most inhaled anesthetics also inhibit nicotinic acetylcholine (ACh) receptor isoforms at moderate to high concentrations. • 5- The strychnine-sensitive glycine receptor is another ligand-gated ion channel that may function as a “target” for certain inhaled anesthetics. • CNS neurons in different regions of the brain have different sensitivities to general anesthetics • inhibition of neurons involved in pain pathways occurs before inhibition of neurons in the midbrain reticular formation.

12. INHALED ANESTHETICS • A. Classification and Pharmacokinetics • The agents currently used in inhalation anesthesia are nitrous oxide (a gas) and several easily vaporized liquid halogenated hydrocarbons, including halothane, desflurane, enflurane, isoflurane, sevoflurane, and methoxyflurane. • They are administered as gases; their partial pressure, or “tension,” in the inhaled air or in blood or other tissue is a measure of their concentration.

13. 50% nitrous oxide in the inhaled air would have a partial pressure of 380 mm Hg.

14. The speed of induction of anesthetic effect depends on several factors • 1. Solubility—The more rapidly a drug equilibrates with the blood, the more quickly the drug passes into the brain to produce anesthetic effects. • Drugs with a low blood: gas partition coefficient (eg, nitrous oxide) equilibrate more rapidly than those with a higher blood solubility (eg, halothane),

15. 2. Inspired gas partial pressure—A high partial pressure of the gas in the lungs results in more rapid achievement of anesthetic levels in the blood. This effect can be taken advantage of by the initial administration of gas concentrations higher than those required for maintenance of anesthesia.

16. 3. Ventilation rate—The greater the ventilation, the more rapid is the rise in alveolar and blood partial pressure of the agent and the onset of anesthesia • 4. Pulmonary blood flow—At high pulmonary blood flows, the gas partial pressure rises at a slower rate; thus, the speed of onset of anesthesia is reduced.At low flow rates, onset is faster. • In circulatory shock, this effect may accelerate the rate of onset of anesthesia with agents of high blood solubility.

17. 5. Arteriovenous concentration gradient—Uptake of soluble anesthetics into highly perfused tissues may decrease gas tension in mixed venous blood. • This can influence the rate of onset of anesthesia because achievement of equilibrium is dependent on the difference in anesthetic tension between arterial and venous blood

18. B. Elimination • Anesthesia is terminated by redistribution of the drug from the brain to the blood and elimination of the drug through the lungs. • The rate of recovery from anesthesia using agents with low blood:gas partition coefficients is faster than that of anesthetics with high blood solubility.

19. This important property has led to the introduction of several newer inhaled anesthetics(eg, desflurane, sevoflurane), which, because of their low blood solubility, are characterized by recovery times that are considerably shorter than is the case with older agents. • Halothane and methoxyflurane are metabolized by liver enzymes to a significant extent • Metabolism of halothane and methoxyflurane has only a minor influence on the speed of recovery from their anesthetic effect but does play a role in potential toxicity of these anesthetics

20. C. Minimum Alveolar Anesthetic Concentration • The potency of inhaled anesthetics is best measured by the minimum alveolar anesthetic concentration (MAC), defined as the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients. • Each anesthetic has a defined MAC but this value may vary among patients depending on • 1- Age • 2- Cardiovascular status • 3- Use of adjuvant drugs.

21. Estimations of MAC value suggest a relatively “steep” dose-response relationship for inhaled anesthetics. • MACs for infants and elderly patients are lower than those for adolescents and young adults. • When several anesthetic agents are used simultaneously, their MAC values are additive.

22. D. Effects of Inhaled Anesthetics • 1. CNS effects—Inhaled anesthetics • 1- decrease brain metabolic rate. • 2- reduce vascular resistance and thus increase cerebral blood flow. This may lead to an increase in intracranial pressure. • 3- High concentrations of enflurane may cause spike-and-wave activity and muscle twitching, but this effect is unique to this drug. • 4- Although nitrous oxide has low anesthetic potency (ie, a high MAC), it exerts marked analgesic and amnestic actions.

23. 2. Cardiovascular effects—Most inhaled anesthetics • 1- decrease arterial blood pressure moderately. 2- Enflurane and halothane are myocardial depressants that decrease cardiac output 3- isoflurane, desflurane, and sevoflurane cause peripheral vasodilation. • Nitrous oxide is less likely to lower blood pressure than are other inhaled anesthetics.

24. Blood flow to the liver and kidney is decreased by most inhaled agents. • Inhaled anesthetics depress myocardial function—nitrous oxide least. • Halothane, and to a lesser degree isoflurane, may sensitize the myocardium to the arrhythmogenic effects of catecholamines.

25. 3. Respiratory effects—Although the rate of respiration may be increased, all inhaled anesthetics cause a dose-dependent decrease in tidal volume and minute ventilation, leading to an increase in arterial CO2 tension. • Inhaled anesthetics decrease ventilatory response to hypoxia even at sub-anesthetic concentrations (eg, during recovery). • Nitrous oxide has the smallest effect on respiration.

26. Most inhaled anesthetics are bronchodilators, but desflurane is a pulmonary irritant and may cause bronchospasm. • enflurane causing breath-holding this effect lead to limits its use in anesthesia induction.

27. 4. Toxicity— • Postoperative hepatitis has occurred (rarely) after halothane anesthesia in patients experiencing hypovolemic shock or other severe stress. • The mechanism of hepatotoxicity is unclear but may involve formation of reactive metabolites that cause direct toxicity or initiate immune-mediated responses.

28. Fluoride released by metabolism of methoxyflurane (and possibly both enflurane and sevoflurane) may cause renal insufficiency after prolonged anesthesia. • Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anemia. • Susceptible patients may develop malignant hyperthermia when anesthetics are used together with neuromuscular blockers (especially succinylcholine). This rare condition is thought in some cases to be due to mutations in the gene loci corresponding to the ryanodine receptor (RyR1)

29. Other chromosomal loci for malignant hyperthermia include mutant alleles of the gene-encoding skeletal muscle L-type calcium channels. Theuncontrolled release of calcium by the sarcoplasmic reticulum of skeletal muscle leads to 1- muscle spasm 2- hyperthermia 3- autonomic lability. Dantrolene is indicated for the treatment of this life-threatening condition, with supportive management.

30. INTRAVENOUS ANESTHETICS • A. Barbiturates • Thiopental and methohexital have high lipid solubility, which promotes rapid entry into the brain and results in surgical anesthesia in one circulation time (<1 min). • These drugs are used for induction of anesthesia and for short surgical procedures. • The anesthetic effects of thiopental are terminated by redistribution from the brain to other highly perfused tissues

31. But hepatic metabolism is required for elimination from the body. • Barbiturates are respiratory and circulatory depressants; because they depress cerebral blood flow, they can also decrease intracranial pressure. • B. Benzodiazepines • Midazolam is widely used adjunctively with inhaled anesthetics and intravenous opioids. The onset of its CNS effects is slower than that of thiopental, and it has a longer duration of action. • severe postoperative respiratory depression have occurred. • The benzodiazepine receptor antagonist, flumazenil, accelerates recovery from midazolam and other benzodiazepines.

32. C. Ketamine • This drug produces a state of “dissociative anesthesia” in which the patient remains conscious but has marked catatonia (Catatonia is a severe motor syndrome with an estimated prevalence among psychiatric inpatients of about 10%. At times, it is life-threatening especially in its malignant form when complicated by fever and autonomic disturbances.), analgesia, and amnesia. • Ketamine is a chemical congener of the psychotomimetic agent, phencyclidine (PCP). • The drug is a cardiovascular stimulant, and this action may lead to an increase in intracranial pressure..

33. Emergence reactions, including • 1- disorientation • 2- excitation • 3- hallucinations, which occur during recovery from ketamine anesthesia • can be reduced by the preoperative use of benzodiazepines

34. D. Opioids • Morphine and fentanyl are used with other CNS depressants (nitrous oxide, benzodiazepines) in anesthesia regimens and are especially valuable in high-risk patients who might not survive a full general anesthetic. • Intravenous opioids may cause chest wall rigidity, which can impair ventilation. • Respiratory depression with these drugs may be reversed postoperatively with naloxone.

35. Neurolept anesthesia is a state of analgesia and amnesia is produced when fentanyl is used with droperidol and nitrous oxide. • Newer opioids related to fentanyl have been introduced for intravenous anesthesia. • Alfentanil and remifentanil have been used for induction of anesthesia. Recovery from the actions of remifentanil is faster than recovery from other opioids used in anesthesia because of its rapid metabolism by blood and tissue esterases.

36. E. Propofol • Propofol produces anesthesia as rapidly as the intravenous barbiturates, and recovery is more rapid. • Propofol has antiemetic actions, and recovery is not delayed after prolonged infusion. • The drug is commonly used as a component of balanced anesthesia and as an anesthetic in outpatient surgery.

37. Propofol is also effective in producing prolonged sedation in patients in critical care settings. • Propofol may cause marked hypotension during induction of anesthesia, primarily through decreased peripheral resistance. • Total body clearance of propofol is greater than hepatic blood flow, suggesting that its elimination includes other mechanisms in addition to metabolism by liver enzymes.

38. Fospropofol, a water-soluble prodrug form, is broken down in the body by alkaline phosphatase to form propofol. • However, onset and recovery are both slower than with propofol. • While fospropofol appears to cause less pain at injection sites than the standard form of the drug, many patients experience paresthesia.

39. F. Etomidate • This imidazole derivative affords rapid induction with minimal change in cardiac function or respiratory rate and has a short duration of action. • The drug is not analgesic, and its primary advantage is in anesthesia for patients with limited cardiac or respiratory reserve. • Etomidate may cause pain and myoclonus on injection and nausea postoperatively. • Prolonged administration may cause adrenal suppression.

40. G. Dexmedetomidine • This centrally acting α2-adrenergic agonist has analgesic and hypnotic actions when used intravenously. • Its characteristics include rapid clearance resulting in a short elimination half-life. • Dexmedetomidine is used mainly for short-term sedation in an ICU setting.

41. When used in general anesthesia, the drug decreases dose requirements for both inhaled and intravenous anasthesia