CNS Pharmacology General Anesthetics 50 Hiwa K. Saaed, Bpharm, H.D, M.Sc, Ph.D Department of Pharmacology & Toxicology College of Pharmacy, University of Sulaimani 2017-18of Sulaimani

Dissociative anesthesia CLASSIFICATION General anesthetics Inhalational Gas Nitrous oxide Zenon Volatile liquids Ether halothane enflurane isoflurane desflurane Sevoflurane methoxyflurane Intravenous Slower acting Dissociative anesthesia ketamine opioid fentanyl Benzodiazepines diazepam lorazepam midazolam Inducing agents Thiopentone methohexitone propofol Etomidate droperidol

General Anesthesia General anesthesia is a reversible state of CNS depression, causing loss of response to and perception of stimuli. For patients undergoing surgical or medical procedures, anesthesia provides five important benefits: Sedation and reduced anxiety Lack of awareness and amnesia Skeletal muscle relaxation Suppression of undesirable reflexes Analgesia Because no single agent provides all desirable properties both rapidly and safely, several categories of drugs are combined (I.V and inhaled anesthesia and preanesthetic medications) to produce optimal anesthesia known as a Balanced anesthesia.

Patient factors in selection of anesthesia: Drugs are chosen to provide safe and efficient anesthesia based on: The type of the surgical or diagnostic procedure Patient characteristics such as organ function, medical conditions, and concurrent medications, e.g., IHD, HTN, hypovolemic shock, bronchial asthma. Status of organ systems: Cardiovascular system: whereas the hypotensive effect of most anesthetics is sometimes desirable, ischemic injury of tissues could follow reduced perfusion pressure. Respiratory system: All inhaled anesthetics depress the respiratory system. Interestingly, they are bronchodilators.

Status of organ systems: Liver and kidney: The release of fluoride, bromide, and other metabolic products of the halogenated hydrocarbons can affect these organs, especially with repeated anesthetic administration over a short period of time. Pregnancy: Effects on fetal organogenesis are a major concern in early pregnancy. Nitrous oxide can cause aplastic anemia in the unborn child. Oral clefts have occurred in the fetuses of women who have received benzodiazepines. Diazepam should not be used routinely during labor, because it results in temporary hypotonia and altered thermoregulation in the newborn.

Status of organ systems: Nervous system: The existence of neurologic disorders (e.g., epilepsy or myasthenia gravis) influences the selection of anesthetic. A patient history of a genetically determined sensitivity to halogenated hydrocarbon- induced malignant hyperthermia “an autosomal dominant genetic disorder of skeletal muscle” that occurs in susceptible individuals undergoing general anesthesia with volatile agents and muscle relaxants (eg, succinylcholine). The malignant hyperthermia syndrome consists of the rapid onset of tachycardia and hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base imbalance. Rx Dantroline

Preanesthetic medications: Preanesthetic medications serve to calm the patient, relieve pain, protect against undesirable effects of the subsequently administered anesthetics or the surgical procedure. facilitate smooth induction of anesthesia, lowered the required dose of anesthetic Preanesthetic Medicine: Benzodiazepines; midazolam or diazepam: anxiolytic & amnesia. barbiturates; pentobarbital: sedation Diphenhydramine: prevention of allergic reactions: antihistamines H2 receptor blocker- famotidine, ranitidine: reduce gastric acidity. Antiemetics- ondansetron: Prevents aspiration of stomach contents and post surgical vomiting: acetaminophen, celecoxib or opioids (fentanyl) for analgesia

Preanesthetic medications: Anticholinergics: (glycopyrrolate, scopolamine): Amnesia Reduce bronchial and salivary secretion: irritant inhaled anesthetic cause excessive salivation and secretion. Reduce any tendency to bronchospasm Prevent bradycardia and hypotension: manipulation of visceral organs stimulates vagus leading to bradycardia. Concomitant use of other drugs: Patients may take medications for underlying diseases or abuse drugs that alter response to anesthetics. For example, alcoholics have elevated levels of liver enzymes that metabolize anesthetics, and drug abusers may be tolerant to opioids.

Stages and depth of anesthesia General anesthesia has three stages: induction, maintenance, and recovery. Use preanesthetic medication ↓ Induce by I.V thiopental or propofol Use muscle relaxant → Intubate Use, usually a mixture of N2O and a halogenated hydrocarbon→ maintain and monitor. Withdraw the drugs → recover

Stages and depth of anesthesia/ Induction Induction: the period of time from the onset of administration of the anesthetic to the development of effective surgical anesthesia in the patient. It depends on how fast effective concentrations of the anesthetic drug reach the brain. Thus GA is normally induced with an I.V thiopental, which produces unconsciousness within 25 seconds or propofol producing unconsciousness in 30 to 40 seconds after injection. At that time, additional inhalation or IV drugs may be given to produce the desired depth of surgical stage III anesthesia. This often includes an IV neuromuscular blocker such as rocuronium, vecuronium, or succinylcholine to facilitate tracheal intubation and muscle relaxation. Inhalation induction: For children without IV access, non pungent agents, such as halothane or sevoflurane, are used to induce GA.

Stages and depth of anesthesia/ Maintenance Maintenance: After administering the anesthetic, vital signs and response to stimuli are monitored continuously to balance the amount of drug inhaled and/or infused with the depth of anesthesia. Maintenance is commonly provided with volatile anesthetics, which offer good control over the depth of anesthesia. Opioids such as fentanyl are used for analgesia along with inhalation agents, because the latter are not good analgesics. IV infusions of various drugs may be used during the maintenance phase. -Usually: N2O + volatile agent (halothane, isoflurane) -Less often N2O + I.V Opioid analgesic (fentanyl, morphine, pethidine + N.M blocking agents

Stages and depth of anesthesia/ Recovery Recovery: the time from discontinuation of administration of the anesthesia until consciousness and protective physiologic reflexes are regained. It depends on how fast the anesthetic drug diffuses from the brain. For most anesthetic agents, recovery is the reverse of induction. Redistribution from the site of action (rather than metabolism of the drug) underlies recovery. If neuromuscular blockers have not been fully metabolized, reversal agents may be used. The patient is monitored to assure full recovery, with normal physiologic functions (spontaneous respiration, acceptable blood pressure and heart rate, intact reflexes, and no delayed reactions such as respiratory depression).

Depth of Anesthesia (GUEDEL’S Signs) Guedel (1920) described four sequential stages with ether anaesthesia, dividing the stage 3 into 4 planes. The order of depression in the CNS is: Cortical centers→basal ganglia→spinal cord→medulla   Stage of Analgesia analgesia and amnesia, the patient is conscious and conversational. Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness Pain is progressively abolished Reflexes and respiration remain normal Use is limited to short procedures Stage of Delirium From loss of consciousness to beginning of regular respiration Patient may shout, struggle and hold his breath; muscle tone increases, jaws are tightly closed, breathing is jerky; vomiting, involuntary micturition or defecation may occur Heart rate and BP may rise and pupils dilate due to sympathetic stimulation No operative procedure carried out Can be cut short by rapid induction, premedication

Depth of Anesthesia (GUEDEL’S Signs) Surgical anaesthesia Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes which may be distinguished as: Plane 1 roving eye balls. This plane ends when eyes become fixed. Plane 2 loss of corneal and laryngeal reflexes. Plane 3 pupil starts dilating and light reflex is lost. Plane 4 Intercostal paralysis, shallow abdominal respiration, dilated pupil. Medullary paralysis Cessation of breathing to failure of circulation and death. Pupil is widely dilated, muscles are totally flabby, pulse is thready or imperceptible and BP is very low

Depth of Anesthesia (GUEDEL’S Signs)

Inhalation anesthetics Inhaled gases are used primarily for maintenance of anesthesia. Depth of anesthesia can be rapidly altered by changing the inhaled concentration, very narrow therapeutic index, No antagonists exist. Common features of inhaled anesthetics Modern inhalation anesthetics are nonflammable, nonexplosive agents. Decrease cerebrovascular resistance, resulting in increased perfusion of the brain Cause bronchodilation, and decrease both spontaneous ventilation and hypoxic pulmonary vasoconstriction (increased pulmonary vascular resistance in poorly aerated regions of the lungs, redirecting blood flow to more oxygenated regions). Movement of these agents from the lungs to various body compartments depends upon their solubility in blood and tissues, as well as on blood flow. These factors play a role in induction and recovery.

MAC (Potency) MAC (potency): the minimum alveolar concentration, the end-tidal concentration of inhaled anesthetic needed to eliminate movement in 50% of patients stimulated by a standardized incision. MAC is the ED50 of the anesthetic. the inverse of MAC is an index of potency of the anesthetic. MAC expressed as the (%) percentage of gas in a mixture required to achieve that effect. Numerically, MAC is small for potent anesthetics such as sevoflurane and large for less potent agents such as nitrous oxide.

MAC (Potency) The more lipid soluble, the lower the concentration needed to produce anesthesia and, thus, the higher the potency. Factors that can increase MAC (make the patient less sensitive) include: hyperthermia, drugs that increase CNS catecholamines, and chronic ethanol abuse. Factors that can decrease MAC (make the patient more sensitive) include: increased age, hypothermia, pregnancy, sepsis, acute intoxication, concurrent IV anesthetics, and α2-adrenergic receptor agonists (for example, clonidine, dexmedetomidine).

uptake and distribution of inhalation anesthetics The principal objective of inhalation anesthesia is a constant and optimal brain partial pressure (Pbr) of inhaled anesthetic (Palv=Pbr). Thus, the alveoli are the “windows to the brain” for inhaled anesthetics. The partial pressure of an anesthetic gas at the origin of the respiratory pathway is the driving force moving the anesthetic into the alveolar space and, thence, into the blood (Pa), which delivers the drug to the brain and other body compartments. Because gases move from one compartment to another within the body according to partial pressure gradients, a steady state (SS) is achieved when the partial pressure in each of these compartments is equivalent to that in the inspired mixture. Palv = Pa = Pbr

Factors Determine the time course for attaining Steady State: Alveolar wash-in: This refers to replacement of the normal lung gases with the inspired anesthetic mixture. The time required for this process is directly proportional to the functional residual capacity of the lung, and inversely proportional to the ventilatory rate; it is independent of the physical properties of the gas. As the partial pressure builds within the lung, anesthetic transfer from the lung begins.

Factors Determine the time course for attaining Steady State: Anesthetic uptake (removal to peripheral tissues other than the brain): is the product of gas solubility in the blood, cardiac output, and the alveolar to venous partial pressure gradient of the anesthetic. a. Solubility in the blood: called the blood/gas partition coefficient. The solubility in blood is ranked in the following order: halothane>enflurane>isoflurane>sevofluran e>desflurane>N2O Halothane Slow Induction & recovery N2O Fast Induction & recovery

Factors Determine the time course for attaining Steady State: b. Cardiac output: CO affects removal of anesthetic to peripheral tissues, which are not the site of action. higher CO removes anesthetic from the alveoli faster and thus slows the rate of rise in alveolar concentration of gas. It therefore takes longer for the gas to reach equilibrium between the alveoli and the site of action in the brain. higher CO equals slower induction. Low CO (shock) speeds the rate of rise of the alveolar concentration of gas, since there is less removal to peripheral tissues. c. Alveolar to venous partial pressure gradient of the anesthetic: this is driving force of delivery. The greater the difference in anesthetic concentration between alveolar (arterial) and venous blood, the higher the uptake and the slower the induction.

Factors Determine the time course for attaining Steady State: 3. Effect of different tissue types on anesthetic uptake: It is also directly proportional to the capacity of that tissue to store anesthetic (a larger capacity results in a longer time required to achieve steady state). Capacity, in turn, is directly proportional to the tissue’s volume and the tissue/ blood solubility coefficient of the anesthetic. The time required for a particular tissue to achieve a steady-state with PP of an anesthetic gas in the inspired mixture is inversely proportional to the blood flow to that tissue. directly proportional to the tissues volume and the tissue/blood solubility coefficient of the anesthetic molecules (tissue capacity).

Factors Determine the time course for attaining Steady State: Four major tissue compartments determine the time course of anesthetic uptake: Brain, heart, liver, kidney, and endocrine glands: these highly perfused tissues rapidly attain a steady- state with the PP of anesthetic in the blood. Skeletal muscles: poorly perfused, and have a large volume, prolong the time required to achieve steady- state. Fat: poorly perfused. However, potent GA are very lipid soluble. Therefore, fat has a large capacity to store anesthetic. This combination of slow delivery to a high capacity compartment prolongs the time required to achieve steady-state. Bone, ligaments, and cartilage: these are poorly perfused and have a relatively low capacity to store anesthetic. 4. Wash out: when the administration of anesthetics discontinued, the body now becomes the “source” that derives the anesthetic into the alveolar space. The same factors that influence attainment of steady-state with an inspired anesthetic determine the time course of clearance of the drug from the body. Thus N2O exits the body faster than halothane.

MECHANISM OF ACTION OF ANAESTHESIA No specific receptor has been identified. The fact that chemically unrelated compounds produce anesthesia argues against the existence of a single receptor. The focus is NOW on proteins comprising ion channels: GABAA receptors, Glycine receptors, NMDA glutamate receptors (nitrous oxide and ketamine): Nicotinic receptors: Blocks the excitatory postsynaptic current of the nicotinic receptors.

Halothane (Prototype) Advantages: Potent anesthetic, rapid induction & recovery Neither flammable nor explosive, sweet smell, non irritant Does not augment bronchial and salivary secretions. Low incidence of postoperative nausea and vomiting. Relaxes both skeletal and uterine muscle, and can be used in obstetrics when uterine relaxation is indicated. Not hepatotoxic in pediatric patient, and combined with its pleasant odor, this makes it suitable in children for inhalation induction.

Halothane : Disadvantages: Weak analgesic (thus is usually coadministerd with N2O, opioids) Is a strong respiratory depressant Is a strong cardiovascular depressant; halothane is vagomimetic and cause atropine-sensitive bradycardia. Cardiac arrhythmias: serious if hypercapnia develops due to hypoventilation and an increase in the plasma concentration of catecholamines) Hypotensive effect (phenylephrine recommended) Hepatotoxic: is oxidatively metabolized in the liver to tissue-toxic hydrocarbons (e.g., trifluroethanol and bromide ion). Malignant hyperthermia

Enflurane Advantages: Less potent than halothane, but produces rapid induction and recovery ~2% metabolized to fluoride ion, which is excreted by the kidney Has some analgesic activity Differences from halothane: Fewer arrhythmias, less sensitization of the heart to catecholamines, and greater potentiation of muscle relaxant due to more potent “curare-like” effect. Disadvantages: CNS excitation at twice the MAC, Can induce seizure

Isoflurane Advantages: A very stable molecule that undergoes little metabolism Not tissue toxic Does not induce cardiac arrhythmias Does not sensitize the heart to the action of catecholamines Produces concentration-dependent hypotension due to peripheral vasodilation It also dilates the coronary vasculature, increasing coronary blood flow and oxygen consumption by the myocardium, this property may make it beneficial in patients with IHD.

Desflurane: Sevoflurane: Methoxyflurane Rapidity of induction and recovery: outpatient surgery Less volatility (must be delivered using a special vaporizer) Like isoflurane, it decreases vascular resistance and perfuse all major tissues very well. Irritating cause apnea, laryngospasm, coughing, and excessive secretions Sevoflurane: Has low pungency, not irritating the airway during induction; making it suitable for induction in children Rapid onset and recovery: Metabolized by liver, releasing fluoride ions; thus, like enflurane, it may prove to be nephrotoxic. Methoxyflurane The most potent and the best analgesic anesthetic available for clinical use. Nephrotoxic and thus seldom used.

Nitrous oxide (N2O) “laughing gas” It is a potent analgesic but a weak general anesthetic. Rapid onset and recovery: Does not depress respiration, and no muscle relaxation. No effect on CVS or on increasing cerebral blood flow Clinical use: dental surgery, obstetrics, postoperative physiotherapy, refractory pain in terminal illness, and maintenance of anesthesia. The least hepatotoxic, Teratogenic, bone marrow depression. Second gas effect: N2O can concentrate the halogenated anesthetics in the alveoli when they are concomitantly administered because of its fast uptake from the alveolar gas. Diffusion hypoxia: speed of N2O movement allows it to retard oxygen uptake during recovery.

Intravenous anesthetics Barbiturates (thiopental, methohexital) Potent anesthetic but a weak analgesic High lipid solubility; quickly enter the CNS and depress function, often in less than one minute, and redistribution occur very rapidly as well to other body tissues, including skeletal muscle and ultimately adipose tissue (serve as a reservoir). Thiopental has minor effects on the CVS but it may cause sever hypotension in hypovolemic or shock patient All barbiturates can cause apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm

Intravenous anesthetics/ Propofol Propofol, Phenol derivative, It is an IV sedative-hypnotic used in the induction and or maintenance of anesthesia. Onset is smooth and rapid (40 seconds) It is occasionally accompanied by excitatory phenomena, such as muscle twitching, spontaneous movement, or hiccups. Decrease BP without depressing the myocardium, it also reduce intracranial pressure. It is widely used and has replaced thiopental as the first choice for anesthesia induction and sedation, because it produces a euphoric feeling in the patient and does not cause post anesthetic nausea and vomiting. Poor analgesia.

Intravenous anesthetics/ Etomidate Is used to induce anesthesia, it is a hypnotic agent but lacks analgesic activity. Induction is rapid, short acting No effect on heart and circulation. Thus it is only used for patients with coronary artery disease or cardiovascular dysfunction, Adverse effects: a decrease in plasma cortisol and aldosterone levels which can persist for up to eight hours. This is due to inhibition of 11- B-hydroxylase

Intravenous anesthetics/ ketamine Ketamine (phencyclidine derivative) a short- acting, anesthetic, induces a dissociated state in which the patient is unconscious (but may appear to be awake) and does not feel pain. This dissociative anesthesia provides sedation, amnesia, and immobility. Ketamine stimulates central sympathetic outflow, causing stimulation of the heart with increased blood pressure and CO. It is also a potent bronchodilator. Therefore, it is beneficial in patients with hypovolemic or cardiogenic shock and in asthmatics. Conversely, it is contraindicated in hypertensive or stroke patients. Ketamine is used mainly in children and elderly adults for short procedures. It is not widely used, because it increases cerebral blood flow and may induce hallucinations, particularly in young adults.

Dexmedetomidine Is a sedative used in intensive care settings and surgery. It is relatively unique in its ability to provide sedation without respiratory depression. Like clonidine, it is an α2 receptor agonist in certain parts of the brain. Dexmedetomidine has sedative, analgesic, sympatholytic, and anxiolytic effects that blunt many cardiovascular responses. It reduces volatile anesthetic, sedative, and analgesic requirements without causing significant respiratory depression.

Adjuvants/ BDZs & Opioids (fentanyl, sufentanil) Benzodiazepine (midazolam, lorazepam and diazepam) Are used in conjunction with anesthetics to sedate the patient. Opioids: Analgesic, not good amnesic, used together with anesthetics. They are administered either I.V, epidurally, or intrathecally All cause hypotension, respiratory depression and muscle rigidity as well as post anesthetic nausea and vomiting, antagonized by naloxone. Neuroleptanesthesia: Is a state of analgesia and amnesia produced when fentanyl is used with droperidol and N2O, Is suitable for burn dressing, endoscopic examination

Properties of Intravenous Anesthetic Agents Drug Induction and Recovery Main Unwanted Effects Notes thiopental Fast onset (accumulation occurs, giving slow recovery) Hangover Cardiovascular and respiratory depression Used as induction agent declining. ↓ CBF and O2 consumption Injection pain etomidate Fast onset, fairly fast recovery Excitatory effects during induction Adrenocortical suppression Less cvs and resp depression than with thiopental, Injection site pain propofol Fast onset, very fast recovery cvs and resp depression Pain at injection site. Most common induction agent. Rapidly metabolized; possible to use as continuous infusion. Injection pain. Antiemetic ketamine Slow onset, after-effects common during recovery Psychotomimetic effects following recovery, Postop nausea, vomiting， salivation Produces good analgesia and amnesia. No injection site pain midazolam Slower onset than other agents Minimal CV and resp effects. Little resp or cvs depression. No pain. Good amnesia.