1. Dr. Laila M. Matalqah Ph.D. Pharmacology PHARMACOLOGY OF CNS 3 Anesthetics General Pharmacology M212

2. Introduction General Anesthetics :A drug that produce a reversible loss of sensation and consciousness Anesthesia must provide these five important benefits: 1. Sedation and reduction of anxiety 2. Unconsciousness and amnesia 3. Skeletal muscle relaxation 4. Suppression of motor reflexes 5. Analgesia: loss of pain

3. Anesthetics divide into 2 classes: Inhalation Anesthetics Gasses or Volatile liquids Usually Halogenated Intravenous Anesthetics Injections Anesthetics or induction agents Most commonly the two forms are combined, although its is possible to deliver anesthesia solely by inhalation or injection

4. Hypotheses of General Anesthesia Mechanism of action 1. Lipid Theory: MAC based on the fact that anesthetic action is correlated with the oil/gas coefficients. The higher the solubility of anesthetics is in lipid, the greater is the anesthetic potency. 2. Protein (Receptor) Theory: based on the fact that anesthetic potency is correlated with the ability of anesthetics to inhibit enzymes activity of a pure, soluble protein. Also, attempts to explain the GABA A receptor is a potential target of anesthetics action. NMDA receptor???

6. Pre-anesthetic medications 1. Antacid: H2 blockers, such as famotidine or ranitidine to Reduce gastric acidity; 2. Benzodiazepines, such as midazolam or diazepam to relieve anxiety and facilitate amnesia; 3. Opioids such as Fentanyl for analgesia; (if inhalation) 4. Antihistamines such as Diphenhydramine for prevention of allergic reactions; 5. Antiemetics such as Ondansetron to prevent nausea and the possible aspiration of stomach contents; 6. Anticholinergics to prevent bradycardia and secretion of fluids into the respiratory tract

7. Stages and depth of anesthesia A. Induction: produces unconsciousness within 30–40 seconds 1. Propofol (I.V) 2. Halothane (Inhalation) for children Muscle relaxant is given at this stage to facilitate: intubation such as Succinylcholine B. Maintenance of anesthesia: I.V or inhalation C. Recovery: the anesthetic admixture is withdrawn

8. Stages and depth of anesthesia D. Depth of anesthesia 1. Stage I—Analgesia: Loss of pain sensation and amnesia 2. Stage II—Excitement: uncontrolled movement, irregular breathing. Goal is to move through this stage as rapidly as possible. 3. Stage III—Surgical anesthesia: gradual loss of muscle tone and reflexes, return of regular respiration 4. Stage IV—Medullary paralysis: Too deep, Severe depression of the respiratory and vasomotor centers. Death can be happen.

9. Induction intravenous Faster onset avoiding the excitatory phas e of anaesthesia inhalational where IV access is difficult Anticipated difficult intubation patient preference (children)

10. Maintenance In order to prolong anaesthesia for the required duration breathe to a carefully controlled mixture of oxygen, nitrous oxide, and a volatile anaesthetic agent transferred to the patient's brain via the lungs and the bloodstream, and the patient remains unconscious

11. I. Inhalation Anesthetics Nonflammable, nonexplosive agents Include 1. Nitrous oxide 2. Halogenated hydrocarbons : Halothane, Isoflurane, Sevoflurane, Enflurane MOA: 1. Interaction with protein receptors 2. Volatile A – increase the activity of GABA and Glycine receptor ( inhibitory neurotransmitters)

12. Halothane Enflurane Isoflurane Desflurane Halogenated compounds contain Fluorine and/or bromide Simple, small molecules I. Inhalation Anesthetics

13. Potency MAC (minimum alveolar concentration) A measure of potency of inhaled anesthetics MAC is the concentration necessary to prevent responding in 50% of population. The more lipid soluble an anesthetic, the lower the concentration of anesthetic needed to produce anesthesia and, thus, the higher the potency of the anesthetic. Numerically, MAC is small for potent anesthetics, such as sevoflurane, and large for less potent agents, such as nitrous oxide (N2O).

14. Pathway for General Anesthetics Move into and out of the blood based on the partial pressure gradient. Alveoli -----Blood ____ Brain PA = Pa = Pbr DEPTH of anesthesia, the rate of induction and recovery: depends primarily on the PARTIAL PRESSURE Of the anesthetics in the brain

15. Partition coefficient = Cons (anesthetic ) in Blood Conc (Anesthetics) in Gas

16. Uptake and distribution of inhalation anesthetics Depends on: 1. Solubility of gas into blood The lower the blood/gas partition coefficient (ratio), the more anesthetics will arrive at the brain ------lower solubility in blood -----reach brain faster ---highly potent induction The solubility in blood : halothane > isoflurane > sevoflurane> nitrous oxide = desflurane. The potency of induction : desflurane= nitrous oxide > sevoflurane> isoflurane = halothane

18. Uptake and distribution of inhalation anesthetics Depends on: 1. Solubility of gas into blood lower blood solubility, such as nitrous oxide- the equilibrium between the inhaled anesthetic and arterial blood occurs rapidly- raise arterial anesthetic partial pressure –rapidly achieving a steady state (rapid induction and recovery) High blood solubility, such as halothane, dissolves more completely in the blood, and greater amounts of the anesthetic and longer periods of time are required to raise blood partial pressure (slow induction and recovery)

19. Uptake and distribution of inhalation anesthetics Depends on: 2. Cardiac output: Cardiac output (CO) affects removal of anesthetic to peripheral tissues, Higher CO = slower induction

21. Rate of Entry into the Brain: Influence of Blood and Lipid Solubility LOW solubility in blood= fast induction and recovery HIGH solubility in blood= slower induction and recovery.

22. General Actions of Inhaled Anesthetics Respiration Depressed respiration and response to CO2 Kidney Depression of renal blood flow and urine output Muscle High enough concentrations will relax skeletal muscle

23. Cont’ Cardiovascular System Generalized reduction in arterial pressure and peripheral vascular resistance. Isoflurane maintains CO and coronary function better than other agents Central Nervous System Increased cerebral blood flow and decreased cerebral metabolism

24. 1.Nitrous Oxide Colourless, odourless, noninfalamable GAS widely used / cheap Potent analgesic Weak general anesthesia Do not depress the respiration/vasomotor center It is poorly soluble in blood and other tissues, allowing it to move very rapidly in and out of the body by lung Rapid induction and rapid recovery Used as adjuvant to other inhalational gases and dental procedure Non-toxic to liver Inhaled Anesthetics

25. 2.Halothane Volatile liquid Potent anesthetics Weak analgesic / not muscle relaxants Non-flammable Induce the anesthetic state rapidly and allow quick recovery a potent bronchodilator 20% metabolism by CYP450 Inhaled Anesthetics

26. 2.Halothane Adverse effect: Cardiac effects: Myocardial depressant (SA node): bradycardia and hypotension Respiratory depreccion Transient hepatic damage (Hepatitis ??) Liver necrosis if repeated exposure Malignant hyperthermia (MH): life-threatening condition. Inhaled Anesthetics

27. Malignant Hyperthermia It is a increase in skeletal muscle oxidative metabolism, caused by stimulation of calcium channel at the sacroplasmic reticulum lead to release massive amount of Ca+2 in the muscle—continuous muscle contraction and heat. Signs: tachycardia, tachypnea, metabolic acidosis, hyperthermia, muscle rigidity, sweating, arrhythmia May be fatal Treated with cooling and dantrolene (muscle relaxant)

28. 3.Isoflurane Smooth and rapid induction and recovery compared to halothane Very little metabolism (0.2%) No reports of hepatotoxicity or renotoxicity Does not induce cardiac arrhythmias s/e: hypotension Advantages: Most widely employed because of cost factor, less toxicity Desflurane is 5-times less potent than isoflurane Inhaled Anesthetics

29. Intravenous Induction Agents Most exert their actions by potentiating GABA A receptor GABAergic actions may be similar to those of volatile anesthetics, but act at different sites on receptor Commonly used IV induction agents Propofol Thiopental sodium Ketamine

30. Fast acting Propofol Thiopental Slow acting Ketamine Fentanyl Diazepam /lorazepam

31. 1.Propofol Short-acting agent used for the induction maintenance of GA and sedation Fast onset within 30-40 sec of injection Duration last for 5-10 min Supplementation with narcotics for analgesia (Fenantyl) is required?? S/E: hypotension pain on injection (Lidocaine?? Added) transient apnoea following induction Fospropofol: Pro-drug, is metabolized to propofol in the body Sustained action Less painful

32. 2.Ketamine NMDA (N-methyl-D-aspartate receptor) Antagonist It cause dissociative anesthesia: provides analgesia, sedation, amnesia, and immobility usually stimulate rather than depress the circulatory system: increased blood pressure and CO. Used mainly in children and elderly adults for short procedures. Injection not painful Respiration is not depressed Use: in head and neck surgery Asthmatic patient

33. Local anesthetics (LA) Local anesthetics abolish sensation and, in higher concentrations, motor activity in a limited area of the body MOA: Local anesthetics work by blocking sodium ion channels LA cause vasodilation - short duration of action So- vasoconstrictor is added like., epinephrine. This both minimizes systemic toxicity and increases the duration of action S/e: Cardiovascular arrhythmias, bradycardia and hypotension Convulsions Injection is painful Allergic reaction Lidocaine and bupivacaine are used for epidural anesthetics??

34. local anesthetic compounds are 1. Injectable: Low potency/short duration: Procaine Intermediate potency and duration: Lidocaine High potency /long duration : Bupivacaine, Ropivacaine, Mepivacaine 2. Surface: Lidocaine, cocaine, Tetracaine, benzocaine