General Anesthetics Amber Johnson

What are General Anesthetics? A drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery. Can be viewed as a pharmacological intervention used to prevent psychological and somatic adverse effects of surgical trauma and also to create convenient conditions for 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. Yet, the most famous contribution by the United States to medical progress at this period was undoubtedly the introduction of general anesthesia. Drugs of various kinds have been used for many centuries to reduce the distress of surgical operations. It was a procedure that not only liberated the patient form the fearful pain of surgery, but also enabled the surgeon to perform more extensive operations. Now, known as one of the most important discoveries in medical science, Morton’s technique quickly reached Europe, and establishing the practice of anesthesiology. Safely has improved greatly, less than one death per 200,000 procedures occurs currently. (CH3CH2)2O

Anesthetics divide into 2 classes: Inhalation Anesthetics Gasses or Vapors Usually Halogenated Intravenous Anesthetics Injections Anesthetics or induction agents Drugs given to induce or maintain general anesthesia are either given as: inhalation or intravenous!  Basically extremely diverse group of chemicals which produce a similar endpoint!!!! The most commonly used methods of administering general anesthetics are inhalation, in which the patient breathes a gas or vapor into the lungs, from which the anesthetic can enter the bloodstream; and injection with a hypodermic needle, usually into a vein.  Most commonly there two forms are combined, although its is possible to deliver anesthesia solely by inhalation or injection.

Inhaled Anesthetics Halothane Enflurane Isoflurane Desflurane Inhalational anesthetics refers to the delivery of gases or vapors form the respiratory system to produce anesthesia.  Special set of physical principles govern absorption, distribution, and elimination. Halogenated compounds: Contain Fluorine and/or bromide Simple, small molecules

Physical and Chemical Properties of Inhaled Anesthetics Although halogenations of hydrocarbons and ethers increase anesthetic potency, it also increase the potential for inducing cardiac arrhythmias in the following order F<Cl<Br.1 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. fluorination decrease flammibity and increase stability of adjacent halogenated carbons. Complete halogenations of alkane and ethers or full halogenations of end methyl groups decrease potency and enhances convulsant activity. Flurorthyl (CF3CH2OCH2CF3) is a potent convulsant, with a median effective dose (ED50) for convulsions in mice of 0.00122 atm. The presence of double bonds tends to increase chemical reactivity and toxicity.

Overview

Intravenous Anesthetics Used in combination with Inhaled anesthetics to: Supplement general anesthesia Maintain general anesthesia Provide sedation Control blood pressure Protect the brain

Essential Components of Anesthesia Analgesia- perception of pain eliminated Hypnosis- unconsciousness Depression of spinal motor reflexes Muscle relation * These terms together emphasize the role of immobility and of insensibility! According to the American Society of Anesthesiologists, in general anesthesia the patient is unconscious and has no awareness or other sensations while, in addition the patient is carefully monitored, controlled and treated by the anesthesiologist.  By identifying these signs anesthesia can be measured. The relationship between the amount of general anesthetic administered and the depression of the brain's sensory responsiveness is arbitrarily, but usefully divided into stages to describe the depth of anesthesia.1,3,5 Furthermore, the following four stages can recognize both during induction of and recovery from general anesthesia.

Hypotheses of General Anesthesia Lipid Theory: based on the fact that anesthetic action is correlated with the oil/gas coefficients. The higher the solubility of anesthetics is in oil, the greater is the anesthetic potency. Meyer and Overton Correlations Irrelevant 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 acton. Importantly, Morton’s technique proved that a chemical substance can achieve all of the actions of general anesthesia that have been considered clinically essential. Nevertheless, many attempts have been made to produce a single explanation of action that would embrace all anesthetics. Although these compounds have a common chemical structure, consequently no structure-activity relationships have been recognized. Throughout decades of debates, most of the theories have made attempts to correlate anesthesia potency with some physical property of the anesthetic agents. PROTEIN-BASED: theory that anesthetics bind to hydrophobic/lipophilic sites of proteins. It is thought that anesthetics act on the membrane protein to cause it to be change by:  inducie/prevent conformation change, alter kinetics of conformational changes, and compete with ligands (competitive antagonsim) !!!!!!!!!!

Other Theories included Binding theory: Anesthetics bind to hydrophobic portion of the ion channel Studies of individual cells in the brain during anesthesia have begun to pin down at least what anesthetics do, if not how they do it. All anesthetics appear to shut off the brain from external stimuli. One way they can do this is by altering the chemistry of the synapes. Which are the gaps between nerve cells. Chemicals called neurotransmitters normally act as MESSAGERS, crossing the synapse to relay a nerve signal. Other brain chemicals, in particular once called GABA, tend to shut off the signal. Many anesthetics appear to block the excitatory neurotransmitters or enhance the natural effect of GABA. Yet, precisely how they do this remains unclear!!!

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. Although despite decades of research, the efforts to characterize the mechanism of action by which general anesthetics produce loss of consciousness remain mysterious Clearly, a general anesthetic is a drug that has the ability to bring about a reversible loss of consciousness, by act on the central nervous system (CNS) via shutting off the brain from external stimuli.5,7.

Cont on Mechanism Scientists have cloned forms of receptors in the past decades, adding greatly to knowledge of the proteins involved in neuronal excitability. These include: Voltage-gated ion channels, such as sodium, potassium, and calcium channels Ligand-gated ion channel superfamily and G protein-coupled receptors superfamily.

Anesthetic Suppression of Physiological Response to Surgery Basically this picture helps to show what is thought to be the mode of action! In the nervous system a general anesthetic changes the nerve cells so that normal communication among many of them is closed off for a time. Anesthetics can achieve this is by altering the chemistry of the synapses, the gaps between the nerve cells. 5,7 Therefore, sensations of all kinds are temporarily blocked from reaching the brain. At the same time, the person under anesthesia cannot move parts of the body. The muscles are completely relaxed, making surgery easier. At any point along this branching nerve system, the pain message can be blocked.5 Ultimately, what all anesthetics do is block the signal for pain.

Pharmacokinetics of Inhaled Anesthetics Amount that reaches the brain Indicated by oil:gas ratio (lipid solubility) Partial Pressure of anesthetics 5% anesthetics = 38 mmHg Solubility of gas into blood The lower the blood:gas ratio, the more anesthetics will arrive at the brain Cardiac Output Increased CO= greater Induction time Factors influencing the effects of inhaled anesthetics included:

Pathway for General Anesthetics Partial Pressure in brain quickly equilibrates with partial pressure in arterial blood which has equilibrated with partial pressure perfused alveoli. Furthermore, the DEPTH of anesthesia induced by an inhaled anesthetic depends primarily on the PARTIAL PRESSURE!!! Of the anesthetics in the brain, and the rate of induction and recovery from anesthesia depends on the rate of change of partial pressure in the brain.  These drugs are small lipid-soluble molecules that cross the alveolar membrane easily. Move into and out of the blood based on the partial pressure gradient.

Variables that Control Partial Pressure in Brain Direct Physician's Control Solubility of agent Concentration of agent in inspired by air Magnitude of alveolar ventilation Indirect Physician’s Control Pulmonary blood flow-function of CO Arteriovenous concentration gradient

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.

MAC A measure of potency 1MAC is the concentration necessary to prevent responding in 50% of population. Values of MAC are additive: Avoid cardiovascular depressive concentration of potent agents. MAC is the “gold standard” for measuring anesthesia!!!!!!!!!!!!!!!!!!!! MINIMUM ___ ALVEOLAR_____ CONCENTRATION

Increase in Anesthetic Partial Pressure in Blood is Related to its Solubility Significance of solubility Agents of low solubility in blood included -nitrous oxide -desflurane -Sevoflurane With low solubility the partial pressure in blood rises quickly Agents of medium solubility in blood included:’ -halothane Isofulane With medium solubility in blood partial pressure in blood raises slowly

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 General anesthetics work by altering the flow of sodium molecules in to nerve cells or neurons through the cell membrane. Exactly how they do this is not understand since the drug apparently does not bind

Cont’ Cardiovascular System Central Nervous 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

Toxicity and Side Effects Depression of respiratory drive Decreased CO2 drive (medullary chemoreceptors), Takes MORE CO2 to stimulate respiration Depressed cardiovascular drive Gaseous space enlargement by NO Fluoride-ion toxicity from methoxyflurane Metabolized in liver = release of Fluoride ions Decreased renal function allows fluoride to accumulate = nephrotoxicity

Toxicity and Side Effects Malignant hyperthermia Rapidly cool the individual and administer Dantrolene to block S.R. release of Calcium