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Pharmacology – II [PHL 322] General Anesthetics Dr. Mohd Nazam Ansari What are General Anesthetics? A drug that brings about a reversible loss of consciousness. Anesthetics are not to be confused with sleep medicine. These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery. Background General anesthesia was absent until the mid-1800’s William Morton administered ether to a patient having a neck tumor removed at the Massachusetts General Hospital, Boston, in October 1846. The discovery of the diethyl ether as general anesthesia was the result of a search for means of eliminating a patient’s pain perception and responses to painful stimuli. COMPONENTS OF ANAESTHESIA The famous components of general anaesthesia are TRIAD 1. UNCOSCOUSNESS. 2. ANALGESIA 3. MUSCLE RELAXATION. But those triad are under modifications: Unconsciousness replaced by amnesia or loss of awareness Analgesia replaced by no stress autonomic response Muscle relaxation replaced by no movement in response to surgical stimuli Anesthetics divide into 2 classes: Inhalation Anesthetics Gasses or Vapors Usually Halogenated (hydrogen is replaced with a halogen atom like Fluorine, Chlorine, Iodine, Bromide). Intravenous Anesthetics Injections Subcutaneous Intramuscular intravenous Inhaled Anesthetics Volatile Liquids Ether Halothane Enflurane Isoflurane Sevoflurane Desflurane Gases Nitrous oxide Cyclopropane Ethylene Physical and Chemical Properties of Inhaled Anesthetics Although halogenations of hydrocarbons and ethers increase anesthetic potency, it also increase the potential for inducing cardiac arrhythmia in the following order F<Cl<Br Ethers that have an asymmetric halogenated carbon tend to be good anesthetics (such as Enflurane). Halogenated methyl ethyl ethers (Enflurane and Isoflurane) are more stable, are more potent, and have better clinical profile than halogenated diethyl ethers. The presence of double bonds tends to increase chemical reactivity and toxicity. Intravenous Anesthetics Used in combination with Inhaled anesthetics to: Supplement general anesthesia Maintain general anesthesia Control blood pressure Protect the brain Inducing Agent (~11 sec) Thiopentone sodium Propofol Etomidate Slower Acting Drugs Benzodiazepines Diazepam (5-10 min) Lorazepam Dissociative anesthesia Ketamine Neurolept analgesia Fentanyl + Droperidol Anesthetic Suppression of Physiological Response to Surgery Hypotheses of General Anesthesia 1. Lipid Theory: based on the fact that anesthetic action is correlated with the oil/gas coefficients. (solubility of anesthetics is in oil) 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 GABAA receptor is a potential target of anesthetics action. Mechanism of Action UNKNOWN!! Most Recent Studies: General Anesthetics acts on the CNS by modifying the electrical activity of neurons at a molecular level by modifying functions of ION CHANNELS. This may occur by anesthetic molecules binding directly to ion channels or by their disrupting the functions of molecules that maintain ion channels. Molecular mechanism of the GA : GABA –A : Potentiation by Halothane, Propofol, Etomidate NMDA receptors : inhibited by Ketamine Molecular Actions: GABAA Receptor Ligand-gated ion channels Chloride channels gated by the inhibitory GABAA receptor GABAA receptor mediates the effects of gammaamino butyric acid (GABA), the major inhibitory neurotransmitter in the brain GABAA receptor found throughout the CNS Most abundant, fast inhibitory, ligand-gated ion channel in the mammalian brain Located in the post-synaptic membrane Molecular Action: GABAA Receptor Molecular Action: GABAA Receptor Receptor sits in the membrane of its neuron at the synapse GABA, endogenous compound, causes GABA to open Receptor capable of binding 2 GABA molecules, between an alpha and beta subunit Binding of GABA causes a conformational change in receptor Opens central pore Chloride ions pass down electrochemical gradient Net inhibitory effect, reducing activity of the neuron Injectable anesthetics - Mechanisms Ketamine (Ketalar) – Causes dissociative anesthesia. Patients feel dissociated from the environment. Similar to neuroleptic anesthesia, but caused by a single agent. Phencyclidine (PCP) has similar effects. Ketamine is injectable. Mechanism – Blocks NMDA glutamate receptors Etimodate (Amidate) – is a ultrashort acting hypnotic without analgesic properties. Used only for induction because of the very short, 5 minute, duration. Mechanism – GABA receptor. Similar to barbiturates Propofol (Diprivan) – Another IV anesthetic. Similar to thiopental in anesthetic effects and application, but has little renal or hepatic interaction and/or toxicity. Low incidence of side effects, little postoperative confusion. Mechanism – Probably similar to the volatile anesthetics and ethanol. GABA, nACh 15 Pathway for General Anesthetics Induction /Recovery Induction and Recovery Induction rate and recovery are important considerations. The more lipophilic compounds have slower induction and recovery. N2O is not lipophilic, has low solubility, and therefore has fast induction and recovery. The low solubility of N2O means that the equilibration with blood from gas is quite rapid. Induction of anesthesia involves a series of equilibration events. The anesthetic first equilibrates with the alveoli and may be slow, equilibration into the blood is rapid. The blood must become saturated for transfer to the tissues to occur, this can be slow. Inhaled and exhaled gases Aveoli Blood Tissues, including Brain Elimination Recovery processes are similar (reversed) to those of induction Major route of elimination is via the lungs and the agents follow a gradient back to the alveoli Agents with low blood solubility are eliminated quickly Minimal metabolism, primarily in the liver MAC (Minimum Alveolar Concentration) MAC is the concentration necessary to prevent responding in 50% of population. Values of MAC are additive: Avoid cardiovascular depressive concentration of potent agents. Provides a means to compare the potency of the various inhalational agents Serves as a guide to determining dose 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 Cardiovascular System General reduction in arterial pressure and peripheral vascular resistance. Central Nervous System Increased metabolism cerebral blood flow and decreased cerebral Toxicity and Side Effects Depression of respiratory drive Decreased CO2 drive (medullary chemoreceptors), Takes MORE CO2 to stimulate respiration Depressed cardiovascular drive Example: Halothane may depress the myocardium and cause ventricular arrhythmias Fluoride-ion toxicity from methoxyflurane Metabolized in liver = release of Fluoride ions Decreased renal function allows fluoride to accumulate = nephrotoxicity Malignant hyperthermia Some anesthetic agents can trigger malignant hyperthermia which is a hypermetabolic state of skeletal muscles (rare, inherited, and potentially lethal syndrome). Excess calcium ion leads to excessive ATP breakdown/depletion, lactate production, increased CO2 production. Signs: tachycardia + metabolic acidosis; also hyperthermia, muscle rigidity, sweating, arrhythmia. May be lethal if not treated with Dantrolene: to block release of Calcium from sarcoplasmic reticulum and increases reuptake of Ca++ STAGES OF ANESTHESIA Irregular descending depression of CNS STAGE 1 (ANALGESIA/ONSET/INDUCTION): Extends from the administration of anesthesia to the time of loss of consciousness. Pain is progressively abolished during this stage. Patient remains conscious, can hear and see, and feels a dream like state. Reflexes and respiration remain normal. Some minor and major operation can be carried out. STAGE 2 (EXCITEMENT/DELIRIUM): Extends from the time of loss of consciousness to beginning of regular respiration Characterized by struggling, delirium, irregular respiration, and breatholding are commonly seen. Muscle tone increases, jaws are tightly closed, vomiting, involuntary micturation or defecation may occur. Heart rate and BP may rise. Pupils are dilated. No operation. STAGE 3 (Surgical Anesthesia): Extends from the regular respiration to the loss of most of the reflexes. Muscle tone decreases, BP falls, HR increases, constricted pupils, and regular respirations. Surgical procedure is started. STAGE 4 (Impending Death/ Stage of Danger): Cessation of breathing, to failure of circulation and death. Pupil is widely dilated. It is due to anesthesia overdose. Stage of Maintenance During the maintenance phase, anesthetic doses are adjusted based upon signs of the depth of anesthesia Stage of Emergence- resumption of normal CNS function resumption of normal respiration Selection of anesthetic technique Safest for the patient Appropriate duration i.v. induction agents for short procedures Facilitates surgical procedure Most acceptable to the patient General vs. regional techniques Associated costs Anesthesiology: Pre-anesthetic medication It is the use of drugs prior to anesthesia to make it more safe and pleasant. To relieve anxiety – benzodiazepines. To prevent allergic reactions – antihistaminics. To prevent nausea and vomiting – antiemetics. To provide analgesia – opioids. To prevent bradycardia and secretion – atropine. Thank you