2018-19 General Anesthetics PDF

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General Anesthetics Pharmacology Hiwa K. Saaed, PhD Department of Pharmacology & Toxicology College of Pharmacy, University of Sulaimani 2018-19 CLASSIFICATION General anesthetics Intravenous Inhalational Slower acting Gas Volatile liquids Dissociative anesthesia opioid Inducing agen...

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Gener General al Anesthetics Pharmacology

Hiwa K. Saaed, PhD Department of Pharmacology & Toxicology College of Pharmacy, University of Sulaimani 2018-19

CLASSIFICA CLASSIFICATION TION General anesthetics Intravenous

Inhalational Slower acting Gas

Volatile liquids

Dissociative anesthesia

opioid

Inducing agents Benzodiazepines

Nitrous oxide

diazepam

Zenon

Ether Halothane

ketamine

fentanyl

lorazepam midazolam

Enflurane

Thiopentone

Isoflurane

methohexitone propofol Etomidate droperidol

Desflurane Sevoflurane Methoxyflurane

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Gener General al Anes Anesthes thes thesia ia 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. 3

Pa Pattient fa facctors in selection of anesthesia: Drugs are chosen to provide safe and efficient anesthesia based on: 1. The type of the surgical or diagnostic procedure 2. 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. 4

St Status atus of o orrgan ssys ys ystem tem tems: s: 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. 1.Nitrous oxide can cause aplastic anemia in the unborn child. 2.Oral clefts have occurred in the fetuses of women who have received benzodiazepines. 3.Diazepam should not be used routinely during labor, because it results in temporary hypotonia and altered thermoregulation in the newborn. 5

St Status atus of o orrgan sy syst st ste ems: Nervous system:

• The existence of neurologic disorders (e.g., epilepsy or myasthenia gravis) • 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 (e.g, 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 6

Prea Prean nes esth th thet et etiic med ediica cati ti tio ons: 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 7

Prea Preane ne nesth sth sthet et etic ic m me edi dicati cati catio ons ns:: • 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. 8

St Stages ages 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 9

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. 10

Maint Maintenance enance 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

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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). 12

Dept Depth h of An Anes es esthesia thesia (GUEDEL (GUEDEL’S ’S Signs 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

Stage of Delirium

• 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 • 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 13

Depth of Anes Anesthesia thesia ((GUEDEL GUEDEL GUEDEL’S ’S Sig Signs) ns)

Surgical anaesthesia

Medullary paralysis

• 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. • 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

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Depth of Anesthesia (GUEDEL (GUEDEL’S ’S Signs)

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Inha Inhala la lation tion an anes es esthetics thetics 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. 16

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

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MAC (P (Potency) otency) The more lipid soluble, the lower the concentration needed to produce anesthesia and, thus, the higher the potency. 1. Factors that can increase MAC (make the patient less sensitive) include: • hyperthermia, • drugs that increase CNS catecholamines, • and chronic ethanol abuse.

2. 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). 18

upt uptaake and dis distribution tribution 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 (Palv) is the driving force moving the anesthetic into the alveolar space and, thence, into the blood (Pa), which delivers the drug to the brain (Pbr) 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 19

Stat at ate e: Factors Determine the time course for attaining Steady St

1. 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.

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Stat at ate e: Factors Determine the time course for attaining Steady St

2.

Anesthetic uptake (removal to peripheral tissues other than the brain): is the product of a) b) c)

gas solubility in the blood, cardiac output, 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>sevoflurane>desflurane>N2O Halothane Slow Induction & recovery N2O Fast Induction & recovery

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Stat at ate e: Factors Determine the time course for attaining Steady St 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. ühigher CO equals slower induction. üLow 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 (For all practical purposes, pulmonary endcapillary anesthetic partial pressure may be considered equal to alveolar anesthetic partial pressure). The greater the difference in anesthetic concentration between alveolar (arterial) and venous blood, the higher the uptake and the slower the induction. 22

Factors Determine the time course for attaining Stead Steadyy Sta State te: 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 (greater flow = a more rapidly achieved steady state). • directly proportional to the tissues volume and the tissue/blood solubility coefficient of the anesthetic molecules (tissue capacity).

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Factors Determine the time course for attaining Steady St Stat at ate e: Four major tissue compartments determine the time course of anesthetic uptake: a. Brain, heart, liver, kidney, and endocrine glands: these highly perfused tissues rapidly attain a steady-state with the PP of anesthetic in the blood. b. c. d.

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. Therefore, these tissues have minimal impact on the time course of anesthetic distribution in the body.

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. rate of induction: Blood solubility; Blood/ gas P. Coefficient; Alveolar (Arterial)/Venous gradient; CO Potency: Lipid Solubility; Partial Pressure

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MECH MECHANI ANI ANISSM OF A ACT CT CTIION OF ANA ANAEST EST ESTHES HES HESIIA 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). • glycine receptors in the spinal motor neurons: the activity is increased. • Nicotinic receptors: Blocks the excitatory postsynaptic current of the nicotinic receptors. 25

Hal Haloth oth othane ane (Pr (Pro ototyp totype) e) 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.

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Halothan Halothane: e: 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 Due to adverse effects and the availability of other anesthetics with fewer complications, halothane has been replaced in most countries. 27

Enflur Enflurane ane 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 28

Isoflur Isoflurane ane 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. 29

Desflurane: • 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. 30

Nitr Nitrous ous oxide (N2O) “la “laughing ughing...