Anesthesia Lecture Notes PDF

Anesthesia 2 – 3rd stage LECTURE ONE (IV) LECTURE THREE ANESTHES IA (3) Intravenous Anaesthesia General anaesthesia may be produced by many drugs which depress the CNS, including se...

Anesthesia 2 – 3rd stage LECTURE ONE (IV) LECTURE THREE ANESTHES IA (3) Intravenous Anaesthesia General anaesthesia may be produced by many drugs which depress the CNS, including sedatives, tranquillizers and hypnotic agents. Only a few drugs are suitable for use routinely to produce anaesthesia after intravenous (i.v.) injection. Properties of Intravenous Anesthesia Developed later than inhalational anaesthesia. I used commonly to induce anaesthesia induction is usually smoother and more rapid than most of the inhalational agents. preferred now because it is faster with less risk of excitement or laryngospasm 2 may also be used for maintenance, either alone or in combination with nitrous oxide they may be administered as repeated bolus doses or by continuous i.v. infusion. Used for sedation during regional anaesthesia used for sedation in the intensive care unit (ICU) Useses used for treatment of status epilepticus. Used as the sole drug for short procedures (deep sedation) From induction to wake up-bolus of IV induction drug On entering the blood stream, a percentage of the drug binds to the plasma proteins, with the rest remaining unbound or ‘free’. The degree of protein binding will depend upon the physical characteristics of the drug. The drug is carried in the venous blood to the right side of the heart, through the pulmonary circulation, and via the left side of the heart into the systemic circulation. Page 20 of 104 Anesthesia 2 – 3rd stage The majority of the cardiac output (70%) passes to the brain, liver and kidney (often referred to as ‘vessel rich organs’); thus a high proportion of the initial bolus is delivered to the cerebral circulation. The drug then passes along a concentration gradient from the blood into the brain.  The rate of this transfer is dependent on a number of factors:  & Arterial concentration of the unbound free drug  2 Lipid solubility of the drug 3  Degree of ionization.  Unbound, lipid soluble, unionized molecules cross the blood brain barrier the quickest.  Once the drug has penetrated the CNS tissue, it exerts its effects. Like most anaesthetic drugs, the exact mode of action of the intravenous drugs is unknown. It is thought that each drug acts at a specific receptor – GABAA, NMDA and acetylcholine receptors.  Following the initial flooding of the CNS and other vessel rich tissues with non-ionized molecules, the drug starts to diffuse into other tissues that do not have such a rich blood supply. This secondary tissue uptake, predominantly by skeletal muscle, causes the plasma concentration to fall, allowing drug to diffuse out of the CNS down the resulting reverse concentration gradient. It is this initial redistribution of drug into other tissues that leads to the rapid wake up seen after a single dose of an induction drug.  Metabolism and plasma clearance have a much less important role following a single bolus, but are more important following infusions and repeat doses of a drug. Page 21 of 104 Anesthesia 2 – 3rd stage  The fat, with its poor blood supply (vessel poor tissues), makes little contribution to the early redistribution of free drug following a bolus. However, following repeat doses or infusions, equilibration with adipose tissue forms a drug reservoir, often leading to a delayed wake up. In state of reduced cardiac output In circumstances when cardiac output is reduced, for example after major blood loss, the body compensates by diverting an increased proportion of the cardiac output to the cerebral circulation. This preservation of cerebral blood flow in these situations is paramount. Thus a greater proportion of any given drug will enter the cerebral circulation. As a result, the dose of induction drug must always be reduced. Furthermore, as global cardiac output is reduced, the time taken for an induction drug to reach the brain and exert its effect is prolonged. The slow titration of a reduced dose of drug is the key to a safe induction in these patients. Properties of The Ideal Intravenous Anaesthetic Agent 1. Physical properties  Water soluble & stable in solution  Stable on exposure to light  Long shelf life  No pain on intravenous injection  Painful when injected into an artery  Non-irritant when injected subcutaneously  Low incidence of thrombophlebitis  Cheap Page 22 of 104 Anesthesia 2 – 3rd stage 2. Pharmacokinetic properties o Rapid onset in one arm-brain circulation time o Rapid redistribution to vessel rich tissue o Rapid clearance and metabolism o No active metabolites. Pharmacodynamics properties o High therapeutic ratio (ratio of toxic dose : minimally effective dose ) o Minimal cardiovascular and respiratory effects o No histamine release/hypersensitivity reactions o No emetic effects o No involuntary movements o No emergence nightmares o No hang over effect o No adrenocortical suppression o Safe to use in porphyria. BENZODIAZEPINES: The mechanism of action was on the GABAA receptor. Flumazenil is a specific benzodiazepine–receptor antagonist that effectively reverses most of the central nervous system effects of benzodiazepines Pharmacokinetics Absorption: Benzodiazepines are commonly administered orally, IM, and IV to provide sedation or, less commonly, to induce general anesthesia. Page 23 of 104 Anesthesia 2 – 3rd stage Diazepam (Valium) was well absorbed from the gastrointestinal tract. IM and IV injections of diazepam are painful while midazolam has no pain. Distribution: valium (diazepam) is lipid soluble and readily penetrates into the blood, Redistribution is fairly rapid for the benzodiazepines while midazolam is water soluble. Biotransformation: diazepam depends on the liver for biotransformation (metabolism) into water-soluble end products. The metabolites of diazepam are pharmacologically active. It has long elimination half-life for diazepam (30 h). Excretion The metabolites of benzodiazepine are excreted chiefly in the urine. Intestinal - hepatic circulation produces a secondary peak in diazepam. Effects on Organ Systems (pharmacodynamics) A. Cardiovascular The diazepam had minimal cardiovascular depressant effects, it decreases blood pressure and sometimes increase heart rate. B. Respiratory: diazepam depresses the respiratory system. apnea may occur after induction; even small intravenous doses of diazepam have resulted in respiratory arrest. C. Cerebral: diazepam reduces cerebral oxygen consumption, cerebral blood flow, and intracranial pressure. It prevents and controls seizures, produce amnesia, mild muscle-relaxation, anti-anxiety, and sedation BARBITURATES: Sodium thiopental (thiopentone) Barbiturates depress the reticular activating system (RAS) in the brainstem, which controls multiple vital functions. Their primary mechanism of action is believed to be through binding to (GABA) receptor. Barbiturates potentiate the action of GABA Thiopental’s great lipid solubility and high nonionized fraction (60%) account for rapid brain uptake (within 30 s) Page 24 of 104 Anesthesia 2 – 3rd stage Pharmacokinetics Absorption: thiopental was frequently administered intravenously for induction of general anesthesia in adults and children (prior to the introduction of propofol). Rectal thiopental has been used for induction in children Distribution The duration of sleep doses of the thiopental is determined by redistribution, not by metabolism or elimination. Redistribution to the peripheral compartment specifically, the muscle group lowers plasma and brain concentration within 20–30 min. Patients typically lose consciousness within 30 s and awaken within 20 min. Induction dose of thiopental will depend on body weight and age. Reduced induction doses are required for elderly patients primarily due to slower redistribution. Sodium thiopental (thiopentone) Presentation: Supplied as a pale yellow powder. Vials commonly contain sodium thiopental with 6% sodium carbonate. Reconstituted with water to yields a 2.5% solution (25mg.ml-1) with a pH of 10.8. The alkaline solution is bacteriostatic and safe to keep for 48 hours, but make it incompatible with many basic drugs. Main action: important  Hypnotic and anticonvulsant Pharmaceutical: A dose (3–6 mg kg-1) of thiopentone produces a smooth onset of hypnosis within 30 seconds of intravenous injection. Page 25 of 104 Anesthesia 2 – 3rd stage Recovery after a single dose is rapid due to redistribution and there is a low incidence of restlessness and nausea and vomiting. Thiopentone is 65-85% protein bound in plasma. Metabolism is slow and occurs in the liver. Excretion of metabolites occurs mainly in the urine. Repeated doses or infusions of thiopental leading to an accumulation of the active drug and delayed recovery. Biotransformation: thiopental is principally metabolized by the liver via hepatic oxidation to inactive water-soluble metabolites. Excretion: the metabolites are excreted by urine Effects on Organ Systems A. Cardiovascular: Intravenous bolus induction doses of barbiturates cause a decrease in blood pressure and an increase in heart rate. Patients with poorly controlled hypertension are particularly prone to wide swings in blood pressure during anesthesia induction. The cardiovascular effects of barbiturates depend on rate of administration, dose, volume status, baseline autonomic tone, and preexisting cardiovascular disease. B. Respiratory: thiopental causes: Depress respiratory center. Apnea may occur after induction dose. Tidal volume and respiratory rate are decreased Thiopental incompletely depress airway reflex responses to laryngoscopy and - intubation (much less than propofol) and airway instrumentation may lead to bronchospasm (in asthmatic patients) or laryngospasm in lightly anesthetized patients. Bronchospasm may occur Page 26 of 104 Anesthesia 2 – 3rd stage Clinical use:  induction of anaesthesia  Treatment of status epilepticus  Brain protection from the effects of hypoxia after stroke and head injury. Effects on Organ Systems C. Cerebral: Thiopental decrease cerebral blood flow, cerebral blood volume, and intracranial pressure. It also decrease cerebral oxygen consumption Some patients relate a taste sensation of garlic, onions, or pizza Thiopental do not impair the perception of pain. In fact, they sometimes appear to lower the pain threshold (increase the pain sensation) It controls seizures. Other Thiopental may precipitate acute intermittent porphyria in susceptible individuals. Anaphylactic allergic reactions are rare.  In particular, the usual recommended dose may need to be considerably reduced in elderly, debilitated and hypovolemic patients. Chemical:  Ketamine is a derivative of phencyclidine Presentation:  Ketamine is prepared in a slightly acidic colourless solution (pH 3.5–5.5) containing 10,50 or 100mg.ml 1. Page 27 of 104 Anesthesia 2 – 3rd stage Main action: Dissociative anaesthesia. Pharmaceutical:  Ketamine is unique amongst induction drugs in that it can be administered IV, IM, orally, nasally, rectally, subcutaneously and the preservative free solution epidurally.  For induction of anaesthesia a dose of 1–2 mg.kg-1 can be given IV, or 3–5 mg.kg-1 IM. plasma levels are usually achieved within 10–15 min after intramuscular injection.  The onset of action is slower than other induction drugs  Ketamine is metabolized in the liver, and excreted in the urine. Ketamine has multiple effects throughout the central nervous system, Inhibition of reflexes in the spinal cord Excitation in selected areas of the brain. ketamine functionally “dissociates” the brain from the awareness sensation. Clinically, this state of dissociative anesthesia may cause the patient to appear conscious (eg, eye opening, swallowing, muscle contracture) but unable to process or respond to sensory input. Ketamine has been demonstrated to be an N -methyl- d-aspartate (NMDA) receptor antagonist. Pharmacokinetics A. Absorption Ketamine has been administered orally, nasally, rectally, subcutaneously, and epidurally, but in usual clinical practice it is given intravenously or intramuscularly plasma levels are usually achieved within 10–15 min after intramuscular injection. Page 28 of 104 Anesthesia 2 – 3rd stage B. Distribution Ketamine is more lipid soluble and less protein bound than thiopental. So rapid brain uptake and subsequent redistribution was found in ketamine (the distribution half-life is 10–15 min). Awakening is due to redistribution from brain to peripheral compartments. C. Biotransformation Ketamine is metabolized in the liver to several metabolites, one of which (nor ketamine) retains anesthetic activity. D. Excretion: End products of ketamine are excreted renally. Effects on Organ Systems A. Cardiovascular ketamine increases arterial blood pressure, heart rate, and cardiac output. These cardiovascular effects are due to central stimulation of the sympathetic nervous system and inhibition of the reuptake of norepinephrine. Increases in pulmonary artery pressure and myocardial work. ketamine’s indirect stimulatory effects on the heart may be beneficial to patients with acute shock. B. Respiratory Ventilatory drive is minimally affected by induction doses of ketamine It may produce apnea. Potent bronchodilator, making it a good induction agent for asthmatic patients Upper airway reflexes remain largely intact C. Cerebral Ketamine increases cerebral oxygen consumption cerebral blood flow, and intracranial pressure. Undesirable psychotomimetic side effects (eg, disturbing dreams and delirium)during Page 29 of 104 Anesthesia 2 – 3rd stage recovery It had analgesic effect Ketamine comes closest to being a “complete” anesthetic as it induces analgesia, amnesia, and unconsciousness. D. Gastrointestinal: Postoperative nausea and vomiting are common. Increase in salivation (can be reduced by premedication with anti-muscarinic drug such as Glycopyrrolate or atropine) PROPOFOL  Propofol action is on GABA receptor.  Propofol actions are not reversed flumazenil  it is not water soluble but it is available for intravenous administration as an oil- in-water emulsion containing soybean oil, glycerol, and egg lecithin.  A history of egg allergy does not necessarily contraindicate the use of propofol because most egg allergies involve a reaction to egg white (egg albumin), whereas egg lecithin is extracted from egg yolk.  Intravenous bolus dose (1–2.5 mg kg-1) for induction of anesthesia.  It causes pain during injection that can be decreased by prior injection of lidocaine.  Propofol formulations can support the growth of bacteria, so sterile technique must be observed in preparation and handling and it should be administered within 6 h of opening of ampule  Postoperative nausea and vomiting appear to be extremely uncommon Page 30 of 104 Anesthesia 2 – 3rd stage Pharmacokinetics A. Absorption Propofol is available only for intravenous administration for the induction of general anesthesia and for moderate to deep sedation. B. Distribution Propofol has a rapid onset of action(approximately 30 seconds). Awakening from a single bolus dose is also rapid due to a very short rapid distribution half-life (2–8 min). Recovery from propofol is more rapid than recovery from thiopental and ketamine  Propofol should be titrated against the response of the patient until the clinical signs show the onset of anaesthesia. The best endpoint is loss of verbal contact with the patient C. Biotransformation It has extrahepatic metabolism. Conjugation in the liver results in inactive metabolites The pharmacokinetics of propofol do not appear to be affected by obesity, cirrhosis, or kidney failure. Use of propofol infusion for long-term sedation of children who are critically ill or young adult neurosurgical patients has been associated with sporadic cases of lipemia, metabolic acidosis, and death, the so-termed propofol infusion syndrome. D. Excretion: Propofol is excreted in the urine by the kidney Effects on Organ Systems A. Cardiovascular: the major cardiovascular effect of propofol is  decrease in arterial blood pressure (Propofol causes the most marked decrease in blood pressure of all the induction drugs.)  Decrease in cardiac contractility. Page 31 of 104 Anesthesia 2 – 3rd stage  Factors associated with propofol- induced hypotension include large doses, rapid injection, & old age.  Myocardial oxygen consumption and coronary blood flow usually decrease comparably B. Respiratory  Propofol is a profound respiratory depressant that usually causes apnea following an induction dose. it depresses the normal response to hypercarbia. It induced depression of upper airway reflexes exceeds that of thiopental, allowing intubation, endoscopy, or laryngeal mask placement in the absence of neuromuscular blockade.  Although propofol can cause histamine release, induction with propofol is accompanied by a lesser incidence of wheezing in both asthmatic and non-asthmatic patients compared with barbiturates or Etomidate. Effects on Organ Systems C. Cerebral Propofol decreases cerebral blood flow, cerebral blood volume and intracranial and intraocular pressure. propofol and thiopental probably provide a similar degree of cerebral protection. Unique to propofol are its antipruritic properties. Its antiemetic effects provide yet another reason for it to be a preferred drug for outpatient anesthesia. Propofol has anticonvulsant properties, has been used successfully to terminate status epilepticus, and may safely be administered to epileptic patients. Induction is occasionally accompanied by excitatory phenomena such as muscle twitching, spontaneous movement, opisthotonus, or hiccupping. Page 32 of 104 Anesthesia 2 – 3rd stage Tolerance does not develop after long-term propofol infusions. Propofol is often combined with remifentanil, or ketamine for TIVA. Etomidate Chemical:  Etomidate is an imidazole ester. Presentation:  It is usually presented as a lipid emulsion or as a clear solution containing propylene glycol at a concentration of 2mg.ml-1.the pH of aqueous solution is 8.1 Main action:  Hypnotic Pharmaceutical:  The standard induction dose is 0.3mg.kg-1  The recovery is rapid due to redistribution to muscle and fat.  It is rapidly metabolized by hepatic and plasma esterases  Excretion is predominantly urinary Clinical use:  induction of anaesthesia is an ultrashort-acting, non-barbiturate hypnotic intravenous anesthetic agent. Etomidate does not have any analgesic properties. It is administered only by intravenous route. Etomidate has a favorable hemodynamic profile on induction, with minimal blood pressure depression, making it ideal for shock trauma, hypovolemic patients, or patients with significant cardiovascular disease. Etomidate has been approved for use during induction. Pharmacokinetics: The onset of action: 30 to 60 seconds, Peak effect: 1 minute Page 33 of 104 Anesthesia 2 – 3rd stage Metabolism: Metabolism is primarily hepatic by ester hydrolysis to inactive metabolites. Excretion: 75% of the administered dose is excreted in the urine on the first day after injection. Another route of excretion is bile. Like most intravenous anesthetics, etomidate is highly protein-bound (77%). Thus, it can achieve a higher concentration in the brain in low albumin states since it will be less bound to albumin, and more free-drug would be available in the brain. Adverse Effects Transient inhibition of adrenal steroid synthesis is considered etomidate's most significant adverse effect. Etomidate is no longer administered by continuous infusion because of the risks of sustained suppression of endogenous cortisol and aldosterone production. The most common adverse reaction associated with etomidate use is transient intravenous pain on injection. The pain appears less frequent when larger, more proximal arm veins are used, or IV lidocaine is given before an etomidate bolus. Transient skeletal muscle movements or myoclonus were observed in about 32% of the patients. Postoperative nausea and vomiting with etomidate are comparable to the general frequency of PONV. The incidence of PONV was higher when etomidate was used for both induction and maintenance of anesthesia in short procedures such as dilation and curettage or when analgesia was insufficient Cardiovascular Effects  Etomidate has minimal effects on the cardiovascular system and is the major reason for choosing this drug as an induction agent.  Etomidate does not release histamine. However, etomidate by itself, even in large doses, produces relatively light anesthesia for laryngoscopy, and marked increases in Page 34 of 104 Anesthesia 2 – 3rd stage heart rate and blood pressure may be recorded when etomidate is solely used for induction. Respiratory Effects  Ventilation is not significantly affected. Induction doses do not result in apnea unless opioids have also been administered.  The most distinctive effect on the respiratory system is a slight rise in arterial carbon dioxide tension (PaCO2). Central Nervous System Effects  Etomidate decreases cerebral metabolic rate, cerebral blood flow, and intracranial pressure.  Because of minimal cardiovascular effects, cerebral perfusion pressure is well maintained.  Etomidate lacks analgesic properties Page 35 of 104