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GENERAL ANESTHESIA PHL421-1440-1441 Edited By: Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology +201003256675
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General Anesthesia Introduction Mechanism of Action of GA Pharmacokinetic of GA Pharmacological Effect of GA Inhaled Anesthetics Intravenous Anesthetics Clinical Indication
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The physiologic state of general anesthesia is a reversible condition of comfort, quiescence and physiological stability in a patient before, during and after performance of a procedure, and typically includes: 1. Analgesia (Loss of pain) 2. Amnesia (transient loss of memory) 3. Loss of consciousness (Hypnosis) 4. Inhibition of sensory and autonomic reflexes (Decreased spinal reflexes) Skeletal muscle relaxation (Adequate muscle relaxation) The extent to which any individual anesthetic agent can produce these effects depends on the specific drug, the dosage, and the clinical situation. General Anesthesia
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Ideal General Anesthetics All of the followings are the characteristics of ideal anesthetic agents: Induction a smooth and rapid loss of consciousness. Allowing for a prompt recovery after its administration is discontinued. Wide margin of safety and be devoid of adverse effects. Use of combinations of intravenous and inhaled drugs (so-called Balanced Anesthesia techniques). Anesthesia Protocols (Balanced Anesthesia): No single anesthetic agent is capable of achieving all of these effects Anesthesia Protocol involves the use of combinations of intravenous and inhaled drugs. Intravenous drags to induce anesthetic state, and inhaled anesthetics to maintain anesthesia
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Stages of General Anesthetics √
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Anesthetic potency in humans is usually expressed as the minimal alveolar concentration (MAC) MAC is defined as the median concentration that results in immobility in 50% of patients when exposed to a noxious stimulus (eg, surgical incision). The MAC value greater than 100% for nitrous oxide demonstrates that it is the least potent inhaled anesthetic. Lower MAC values = Higher potency The Minimum Alveolar Anesthetic Concentration (MAC )
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Types of General Anesthetics
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General Mechanism of GA Lipid matrix of the nerve membrane: Older concepts of the mechanism of GA Nonspecific interactions of GA with the lipid matrix of the nerve membrane (the so-called Meyer-Overton principle). These interactions that were thought to lead to secondary changes in ion flux. 2. GABAA receptor-Cl- channel Now primary target of GA and has 3 subunits (α, β and γ) GABAA has inhibitory synaptic transmission These drugs facilitate the action of GABA to increase Cl-ion flux Volatile anesthetics bind at the interface between α and β subunit IV anesthetics may bind only on the β subunit Example : Inhaled anesthetics, benzodiazepines, etomidate, and propofol. General anesthetic agent ↑ Cl- Inhibitory effect
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General Mechanism of GA General anesthetic agent ↑ Cl- Inhibitory effect 3. Glycine receptors Glycine receptors are the major inhibitory receptors in the CNS. Facilitates fast inhibitory neurotransmission, open Cl-channels Inhalational anesthetics: play role in the maintenance state 4. N -methyl-D -apartate (NMDA) channel receptor Glutamate receptors are the major excitatory receptors in the CNS. GA blocks the action of the excitatory neurotransmitter glutamic acid on the NMDA channel receptor. Example: Nitrous oxide, xenon and ketamine General anesthetic agent ↓ Na+ Inhibitory effect
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General Mechanism of GA 5. Two-pore domain K+ channels (TREK) They are K+ channels that modulate neuronal excitability. Low doses reducing membrane excitability by activating TREK. This causes analgesic, hypnotic and immobilizing effects. Example: Volatile and gaseous anaesthetics
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↑ Neuronal inhibition by ↑ the actions of GABA and ↓ CNS excitation by opening K+ channels. The anaesthetized state has 3 components: unconsciousness, loss of reflexes (muscle relaxation) and analgesia. Inhibition of midbrain reticular formation, thalamic sensory relay nuclei results in unconsciousness and analgesia. Inhibition at the spinal level, results in loss of reflex responses to painful stimuli (volatile anesthetics). Effects On The Brain/CNS Pharmacological effects of GA
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↓ the metabolic rate of the brain. ↑ cerebral blood flow because they decrease cerebral vascular resistance → clinically undesirable in patients who have increased intracranial pressure (ICP). The margin between surgical anesthesia and potentially fatal respiratory and circulatory depression is quite narrow, requiring careful monitoring by the anesthetist and adjustment of the level of anesthesia. High doses without artificial respiration, may lead to death from respiratory failure. Effects On The Brain/CNS Pharmacological effects of GA
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Dose-dependent decrease in respiratory volume and an increase in respiratory rate. All volatile anesthetics are respiratory depressants isoflurane and enflurane being the most depressant. The respiratory depressant effects are overcome by assisting (or controlling) ventilation mechanically. Inhaled anesthetics also depress mucociliary function in the airway → prolonged anesthesia may lead to pooling of mucus and then result in atelectasis and postoperative respiratory infections. Effects On The Respiratory System Pharmacological effects of GA
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Inhalational agents Some have Bronchodilation properties (halothane and sevoflurane) → useful in asthma, bronchitis, and COBD. Airway irritation, which may provoke coughing or breath-holding such as halothane and sevoflurane Desflurane is liable to cause coughing, laryngospasm and bronchospasm Effects On The Respiratory System Pharmacological effects of GA
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Volatile anesthetics cause a concentration-dependent decrease in hepatic blood flow ranging from 15% to 45%. Following repeated exposures to Halothane, permanent changes in liver enzyme function. Nitrous oxide appears to have little effect on uterine system. Halogenated anesthetics cause a concentration-dependent relaxation in uterine muscle used when profound uterine relaxation is required for an intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. However, it can also lead to increased uterine bleeding. Effects On Liver And Uterine Smooth Muscle Pharmacological effects of GA
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All inhaled anesthetics depress the myocardial function (cardiac contractility) Desflurane: → ↑transient sympathetic activation with ↑ in catecholamine levels (increases in heart rate and blood pressure). Halothane: → bradycardia through direct vagal stimulation and ventricular extrasystoles due to sensitization to adrenaline. Isoflurane: → ↓ sympathetic outflow; decrease arterial pressure and venous pressure. Effects On Cardiovascular System Pharmacological effects of GA
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Inhaled Anesthetics Factors influencing the pharmacodynamics effects and the rate of recovery: Solubility The blood:gas partition coefficient is a useful index of solubility. Partition coefficients, defined as the ratio of the concentration of the agent in two phases at equilibrium. Concentration of GA in the inspired air, Pulmonary blood flow, Partial pressure. Pharmacokinetics
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Pharmacokinetics of Inhaled Anesthetics The Blood: Gas Partition Coefficient is the ratio of the concentrations of a compound in blood to the concentration in gas at equilibrium. For example: 1- Enflurane has a blood/gas partition coefficient of 1.7. Therefore, if the gas is in equilibrium the concentration in blood will be 1.7 times higher than the concentration in the alveoli. 2- Nitrous oxide has a blood/gas partition coefficient of 0.47. It reaches high arterial tensions rapidly, which in turn results in rapid equilibration with the brain and fast onset of action Solubility and Partial pressure If the partition coefficient is low :↓solubility in blood – ↑arterial tension/pressure. Ex. Desflurane, Nitrous Oxide- Rapid onset and Recovery If the partition coefficient is high :↑solubility in blood – ↓arterial tension/pressure. Ex. Halothane, Enflurane, Isoflurane – Slow onset and Recovery
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Low Solubility: N2O, Desflurane High Solubility: Halothane, isoflurane larger compartment Partial pressure/tensions Solubility
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Speed of induction and recovery: determined by two factors: solubility in blood (blood:gas partition coefficient) solubility in fat (lipid solubility). Agents with low blood:gas partition coefficients: produce rapid induction and recovery (e.g. N2O, Desflurane); Agents with high blood:gas partition coefficients: show slow induction and recovery. (e.g. Halothane, Enflurane, Isoflurane) Agents with high lipid solubility: accumulate gradually in body fat may produce a prolonged ‘hangover’ if used for a long operation. Pharmacokinetics of Inhaled Anesthetics
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Inhaled Anesthetics Nitrous oxide Odourless gas and has rapid onset of action (why? low blood: gas partition coefficient). is an effective analgesic. Has low anesthetic potency and good analgesic action. It is used as a 50:50 mixture with O2 to reduce pain during childbirth. (never be given as 100% gas). used as 70% nitrous oxide in oxygen as an adjunct to volatile anesthetics to speed up induction
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Inhaled Anesthetics Isoflurane It is now the most widely used volatile anesthetic It can cause hypotension and is a powerful coronary vasodilator. This can exacerbate cardiac ischaemia in patients with coronary disease. Desflurane It is used as an anaesthetic in obese patients undergoing bariatric surgery and for day-case surgery It causes some respiratory tract irritation, which can lead to coughing and bronchospasm. It increases sympathetic activity, which is undesirable in patients with ischemic heart disease
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Inhaled Anesthetics Enflurane It can cause seizures, either during induction or following recovery from anesthesia, especially in patients suffering from epilepsy Halothane Potent anesthetic and potent bronchodilator but a relatively weak analgesic. Co-administered with nitrous oxide, opioids, or local anesthetics. Suitable in pediatrics for inhalation induction. Halothane has a marked relaxant effect on the uterus which can cause postpartum bleeding and limits its usefulness for obstetric purposes.
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Inhaled Anesthetics Rarely used as the sole agents for both induction and maintenance of anesthesia (Except children) They are usually combined with intravenous agents as part of a balanced anesthesia technique. Used for ambulatory ("short-stay") basis. Clinical uses
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Inhaled Anesthetics Nephrotoxicity Metabolism of Methoxyflurane, Enflurane, and Sevoflurane leads to the formation of fluoride ions. Sevoflurane degradation in anesthesia machines leads to formation of a haloalkene which is metabolized by renal β -lyase and causes a proximal tubular necrosis. Acute Toxicity Hepatotoxicity Halothane develops potentially life-threatening hepatitis. The formation of reactive metabolites that either cause: - Direct hepatocellular damage or Initiate immune-mediated response autoantibodies against hepatic proteins.
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Inhaled Anesthetics Malignant Hyperthermia Idiosyncratic reaction. Symptoms consists of the rapid onset of tachycardia and hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base imbalance with acidosis. It is due to an increase in free calcium level in skeletal muscle. Treatment: Administration of Dantrolene (to reduce calcium release from the sarcoplasmic reticulum). Hematotoxicity Nitric oxide produce transient hypoxia (known as diffusional hypoxia). This is important for patients with respiratory disease. Prolonged exposure (>6 h) causes inactivation of methionine synthase, an enzyme required for DNA and protein synthesis, Resulting in bone marrow depression that may cause megaloblastic anemia and leucopenia. So its use should be avoided in patients with anemia related to vitamin B12 deficiency. Acute Toxicity
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Inhaled Anesthetics Mutagenicity, Teratogenicity, and Carcinogenicity Inhaled anesthetics are neither mutagens nor carcinogens in patients. Epidemiologic studies has shown increase in the cancer rate in operating room personnel who were exposed to trace concentrations of anesthetic agents. However, no study has demonstrated the existence of a causal relationship between anesthetics and cancer. Most operating rooms now use scavenging systems to remove trace concentrations of anesthetics released from anesthetic machines. Chronic Toxicity
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Intravenous Anesthetics They act more rapidly, producing unconsciousness in about 20 s, as soon as the drug reaches the brain from its site of injection They are normally used for induction of anaesthesia. They are not suitable for maintaining anesthesia because have slow elimination from the body Examples: . Propofol, Thiopental and Etomidate Introduction
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Intravenous Anesthetics Propofol Properties: Less postoperative nausea and vomiting (Propofol has antiemetic effect). Used for both induction and maintenance; Short acting and potent anesthesia Low water solubility, pain at injection site. Fospropofol -new water-soluble derivative; less painful on injection. Administered as an oil-in-water emulsion because its poorly water soluble. Uses: Useful for day-case surgery –ambulatory (less nausea and vomiting). Toxicity: Cardiovascular depressant effect which leads to hypotension and bradycardia. Decrease blood pressure causes vasodilation; greater direct negative inotropic effects.
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Intravenous Anesthetics Etomidate Properties Larger margin between the anesthetic dose and the cardiovascular depression dose. Rapidly metabolized than thiopental, and thus less likely to cause a prolonged hangover. It causes minimal cardiovascular (unchanged heart rate) and respiratory depression. Induction is rapid, and the drug is short-acting. It is not analgesic Uses: usually only used for patients with coronary artery disease or cardiovascular dysfunction. Toxicity: Prolonged use causes adrenal suppression. A high incidence of pain on injection, myoclonic activity, and postoperative nausea and vomiting.
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Intravenous Anesthetics Ketamine (Dissociative’ anesthesia) Properties It inhibits of NMDA-type glutamate channel receptors (excitatory receptor). Powerful analgesic. Cardio-stimulatory stimulant (stimulate epinephrine and norepinephrine levels as early as 2 minutes after an intravenous bolus of ketamine). Uses: Used mainly for minor procedures in children. It is also used in low doses for outpatient anesthesia in combination with Propofol (e.g., as part of a monitored anesthesia care technique) and in children undergoing painful procedures (e.g., dressing changes for burns). Ketamine is compounded for topical use for some types of arthritic pain.
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Intravenous Anesthetics Ketamine (Dissociative’ anaesthesia) Toxicity: Produces ‘dissociative’ anaesthesia, in which the patient may remain conscious although amnesic and insensitive to pain. Symptoms of dissociative’ anaesthesia: catatonia, amnesia, and analgesia, with or without loss of consciousness (hypnosis). High incidence of dysphoria, hallucinations, etc. during recovery; Postoperative disorientation, sensory and perceptual illusions, and vivid dreams (so-called emergence psychic phenomena). Diazepam/Midazolam/Propofol given before the administration of ketamine reduce the incidence of these psychic adverse effects.
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Intravenous Anesthetics Thiopental and Methohexital Properties They have very high lipid solubility. They are potent anesthetics but weak analgesics. Rapid action due to rapid transfer across BBB. They are not used to maintain surgical anesthesia but only as an induction agent. Fast onset and short duration (about 5 min) due to redistribution, mainly to muscle. Uses: It is used for patients with cerebral swelling (e.g., head trauma, brain tumors). Useful for neurosurgical procedures involving ablation of seizure foci. Useful for providing anesthesia in patients undergoing electroconvulsive therapy (ECT).
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Intravenous Anesthetics Thiopental and Methohexital Toxicity: Thiopental produces a long-lasting hangover. Narrow margin between anesthetic dose and dose causing cardiovascular depression. At large dose: they cause a potent respiratory depressant, transient apnea and lowering the sensitivity of the medullary respiratory center to CO2. Apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm (of particular concern for asthmatics).
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Intravenous Anesthetics Opioids (Analgesia) Examples: Morphine (IV), Sufentanil, Remifentanil, and Fentanyl. Uses: High doses of opioids and benzodiazepines used in combination to achieve a general anesthesia during cardiac or other major surgery when the patient's circulatory reserve is limited. Low dose opioids given by the epidural and subarachnoid (spinal) routes to produce postoperative analgesia Fentanyl and Droperidol administered together to produce analgesia and amnesia and combined with N2O to provide a state referred to as Neuroleptic Anesthesia. Remifentanil – Extremely short acting and rapid recovery from the effects; used to minimize residual ventilatory depression Toxicity: Hypotension, respiratory depression, and muscle rigidity, as well as postanesthetic nausea and vomiting
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Intravenous Anesthetics Benzodiazepines (Pre-anesthetics) Examples: Diazepam, Lorazepam, and Midazolam. Uses: Due to their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these drugs used as premedication. Toxicity: They produce a high incidence of Anterograde amnesia. Antidote: The antagonist is Flumazenil.
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THANK YOU FOR YOUR ATTENTION
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