General anaesthetics (GAs)

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General anaesthetics (GAs)

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GENERAL ANESTHESIA:

GENERAL ANESTHESIA Presented by: Sonu M.Pharma Ph.cology RBIP, Mohali , Punjab First year(2013-2015)

Contents:

Contents Introduction and History of General anesthesia Properties of ideal General anesthetic Classification of General anesthetic agents Mechanism of Anesthesia Stages of Anesthesia Complications of General anesthesia Pre- anesthetic medication Monitoring of patient Post anesthesia instructions   Latest Discoveries

INTRODUCTION:

INTRODUCTION General anaesthetics (GAs) are drugs which produce reversible loss of all sensations and consciousness. It usually involves a loss of memory and awareness with insensitivity to painful stimuli, during a surgical procedure

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Balanced anesthesia - it is a term used to describe the multidrug approach to managing the patient needs. Balanced anesthesia takes advantage of drug’s beneficial effects while minimizing each agent’s adverse qualities.   Combination Anesthesia - Since a single anesthetic agent will not meet the ideal, a combination of drugs is used to take advantage of their best properties and minimize the undesirable side effects.

HISTORY OF ANESTHESIA:

HISTORY OF ANESTHESIA Ether synthesized in 1540 by cordus Ether used as anesthetic in 1842 by dr. Crawford W.Long Ether publicized as anesthetic in 1846 by dr. William morton . Ether is no longer used in modern practice, yet considered to be the first ‘ideal’ anesthetic Chloroform used as anesthetic in 1853 by dr. John snow Endotracheal tube discovered in 1878 Thiopental first used in 1934 Curare first used in 1942 - opened the “Age of anesthesia”

PROPERTIES OF AN IDEAL ANAESTHETIC:

PROPERTIES OF AN IDEAL ANAESTHETIC For the patient - It should be pleasant, non irritating, should not cause nausea or vomiting. Induction and recovery should be fast with no after effects. For the surgeon - It should provide adequate analgesia, immobility and muscle relaxation. It should be noninflammable and nonexplosive so that cautery may be used. For the anaesthetist - Its administration should be easy, controllable and versatile.

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Margin of safety should be wide - no fall in BP. Heart, liver and other organs should not be affected. It should be potent so that low concentrations are needed and oxygenation of the patient does not suffer. Rapid adjustments in depth of anaesthesia should be possible. It should be cheap, stable and easily stored. It should not react with rubber tubing or soda lime.

CLASSIFICATION:

CLASSIFICATION

MECHANISM OF ACTION OF ANAESTHESIA:

MECHANISM OF ACTION OF ANAESTHESIA Anesthesia from physical interactions with lipophilic membrane components Anesthesia is produced by disturbance of the physical properties of cell membranes Anesthesia may be produced when anesthetics physically dissolved into the cell membrane’s lipid biophase MEYERS OVERTON RULE. This theory fails to explain how the proposed disturbance of the lipid bilayer would result in a dysfunctional membrane protein

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Anesthesia from selective interactions of anesthetics with cellular components GABA A Receptor (Ligand-gated ion channels) chloride channels gated by the inhibitory GABA A receptor GABA A receptor found throughout the CNS. Located in the post-synaptic membrane. GABA A Receptor mediates the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain 5 subunits arranged around a central pore:2 alpha, 2 beta, 1 gamma Each subunit has N-terminal extracellular chain which contains the Ligand-binding site 4 hydrophobic sections cross the membrane 4 times: one extracellular and two intracellular loops connecting these regions, plus an extracellular C-terminal chain

SIGNS & STAGES OF ANAESTHESIA (GUEDEL’S Signs)  :

SIGNS & STAGES OF ANAESTHESIA (GUEDEL’S Signs )   Guedel (1920) described four stages with ether anaesthesia, dividing the III stage into 4 planes.  

PHARMACOKINETIC CHARACTERISTICS:

PHARMACOKINETIC CHARACTERISTICS Distribution The rate of initial redistribution following the administration of a single iv bolus of drug is defined by the half life (t1/2a) and is generally about 8 min for most anesthetics Distribution of an anesthetic agent depends upon the blood supply of that part . Metabolism and Excretion of Intravenous Drugs Since drugs with long elimination half-lives (t1/2_) will have slow rates of clearance, their use by repeated IV bolus or continuous infusion to maintain anesthesia has been restricted. Long-term application with limited concern for the pharmacokinetics of the agents may lead to delayed awakening , As large quantities of these drugs may accumulate in Reservoir tissues, such as skeletal muscle and fat.

INHALATIONAL ANESTHETIC AGENTS :

INHALATIONAL ANESTHETIC AGENTS Inhalational anesthesia refers to the delivery of gases or vapours from the respiratory system to produce anesthesia.

NITROUS OXIDE:

NITROUS OXIDE It is prepared by priestly in 1776 and anesthetic properties described by davy in 1799. It is characterized by inert nature with minimal metabolism. It is colorless, odorless, tasteless, and does not burn. The mac value is 105%. It is a weak anesthetic, powerful analgesic. It has low blood solubility (quick recovery)

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Nitrous Oxide Systemic Effects Effects on heart rate and blood pressure May cause myocardial depression in sick patients Little effect on respiration Safe, efficacious agent Nitrous oxide concentration should be regulated during different stages of sedation as described   Induction Slow-0.5-1 lit/min Rapid-2-4 lit/min 40%nitrous oxide 60%oxygen Maintenance 20-30 % nitrous oxide Reversal 100%oxygen

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Nitrous Oxide Side Effects Manufacturing impurities toxic Beginning of case: second gas effect End of case: Diffusion hypoxia may be encountered. To avoid diffusion hypoxia, the anesthesiologist may employ 100% oxygen rather than room air after discontinuing administration of the anesthetic gas Mixture. Inhibits vitamin B-12 metabolism Dentists, OR personnel, abusers at risk  

HALOTHANE:

HALOTHANE It is synthesized in 1956 by suckling. It substituted ethane. It is a volatile liquid easily vaporized, stable, and nonflammable. It is the most potent inhalational anesthetic having a mac of 0.75%.It is efficacious in depressing consciousness It is very soluble in blood and adipose.

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Halothane systemic effects Inhibits sympathetic response to painful stimuli Inhibits sympathetic driven baroreflex response (hypovolemia) Sensitizes myocardium to effects of exogenous catecholamines-- ventricular arrhythmias Johnson found median effective dose 2.1 mg/kg Limit dose to 300 ug over one hour Other medications decreases respiratory drive-- central response to CO 2 and peripheral to O 2 Respirations shallow-- atelectasis Depresses protective airway reflexes Depresses myocardium-- lowers BP and slows conduction Mild peripheral vasodilation

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Halothane side effects Halothane hepatitis” -- 1/10,000 cases fever, jaundice, hepatic necrosis, death metabolic breakdown products are hapten-protein conjugates immunologically mediated assault Exposure dependent Malignant hyperthermia-- 1/60,000 with succinylcholine to 1/260,000 without halothane in 60%, succinylcholine in 77% Classic-- rapid rise in body temperature, muscle rigidity, tachycardia, rhabdomyolysis, acidosis, hyperkalemia, DIC most common masseter rigidity family history high association with muscle disorders autosomal dominant inheritance Diagnosis--previous symptoms, increase CO2,rise in CPK levels, myoglobinuria, muscle biopsy Physiology--hypermetabolic state by inhibition of calcium reuptake in sarcoplasmic reticulum

Enflurane:

Enflurane Developed in 1963 by Terrell, released for use in 1972.It is a stable, nonflammable liquid having a pungent odor and a MAC of 1.68%. Enflurane Systemic Effects Potent inotropic and chronotropic depressant and decreases systemic vascular resistance-- lowers blood pressure and conduction dramatically

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Inhibits sympathetic baroreflex response Sensitizes myocardium to effects of exogenous catecholamines—arrhythmias Respiratory drive is greatly depressed-- central and peripheral responses increases dead space widens A-a gradient produces hypercarbia in spontaneously breathing patient Enflurane Side Effects Metabolism one-tenth that of halothane– does not release quantity of hepatotoxic metabolites Metabolism releases fluoride ion-- renal toxicity Epileptiform EEG patterns  

Isoflurane:

Isoflurane Synthesized in 1965 by Terrell, introduced into practice in 1984 It is Nonflammable having a pungent odour It is less soluble than halothane or Enflurane having a MAC of 1.30 %

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Isoflurane Systemic Effects Depresses respiratory drive and ventilatory responses-- less than Enflurane Myocardial depressant-- less than Enflurane Inhibits sympathetic baroreflex response-- less than Enflurane Sensitizes myocardium to catecholamines -- less than halothane or Enflurane Produces most significant reduction in systemic vascular resistance-- coronary steal syndrome, increased ICP Excellent muscle relaxant-- potentiates effects of neuromuscular blockers Isoflurane Side Effects Little metabolism (0.2%) -- low potential of organotoxic metabolites No EEG activity like Enflurane Bronchoirritating, laryngospasm

Sevoflurane and Desflurane:

Sevoflurane and Desflurane Desflurane has low tissue and blood solubility compared with other halogenated hydrocarbons, and its anesthetic partial pressure is thus established more rapidly. Recovery is similarly prompt when the patient is switched to room air or oxygen. Desflurane’s popularity for outpatient procedures stems from its rapid onset and prompt elimination from the body by exhalation.

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Advantage -it may be used to maintain anesthesia after induction with an alternative IV or inhalational agent, preserving the advantage of rapid recovery.   Disadvantage - is that Desflurane irritates the respiratory tract; thus, it is not preferred for induction of anesthesia using an inhalational technique.   Sevoflurane ( Ultane ) it is the most recently introduced inhalation anesthetic. It has low tissue and blood solubility,which allows for rapid induction and emergence and makes it useful for outpatient and ambulatory procedures.

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Advantage - non pungent, a characteristic that permits a smooth inhalation induction, and is particularly useful in pediatric anesthesia. Disadvantage -it undergoes hepatic biotransformation (about 3% of the inhaled dose), and it is somewhat degraded by conventional CO2 absorbents. The degradation product from the absorbent has been reported to be nephrotoxic, although the report is controversial and not substantiated by more recent studies.

Intravenous Anesthetic Agents:

Intravenous Anesthetic Agents The First attempt at intravenous anesthesia was by Wren in 1656-- opium into his dog. Use in anesthesia in 1934 with thiopental. They have Appealing, pleasant experience  

Thiopental:

Thiopental It is an ultrashort acting thiobarbiturate, highly soluble in water yielding a very alkaline solution, which must be prepared freshly before injection. Dose-3-5 mg/kg

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Thiopental Systemic Effects Varied effects on cardiovascular system in people-- mild direct cardiac depression-- lowers blood pressure-- compensatory tachycardia (baroreflex) Dose-dependent depression of respiration through medullary and pontine respiratory centers Thiopental Side Effects Noncompatibility Tissue necrosis—gangrene Tissue stores Post-anesthetic course

Etomidate:

Etomidate Its Structure similar to ketoconozole .it is a Direct CNS depressant (thiopental) and GABA agonist Etomidate Systemic Effects Little change in cardiac function in healthy and cardiac patients

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Mild dose-related respiratory depression Decreased cerebral metabolism Etomidate Side Effects Pain on injection (propylene glycol) Myoclonic activity Nausea and vomiting (50%) Cortisol suppression

Ketamine:

Ketamine Structurally it is similar to PCP.it Interrupts cerebral association pathways resulting in dissociative anesthesia”. It stimulates central sympathetic pathways. Dose 0.5-2mg/kg

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Advantage - its potential for administration by the IM route. This is particularly useful in anesthetizing children, since anesthesia can be induced relatively Quickly in a child who resists an inhalation induction or the insertion of an IV line. Ketamine has a limited but useful role as an IM induction agent and in pediatrics. Disadvantage - ketamine and its propensity evoke excitatory and hallucinatory Phenomena as the patient emerge from anesthesia. Patients in the recovery period may be agitated, scream and cry, hallucinate, or experience vivid dreams. These episodes may be controlled to some extent by maintaining A quiet reassuring atmosphere in which the patient can awaken or if necessary by administering tranquilizing doses of diazepam.

Propofol:

Propofol Rapid onset and have a short duration of action. Myocardial depression and peripheral vasodilation may occur. Insoluble in water, causing pain in 50% of patients. Side effects are Minimal (nausea and vomiting) Propofol can be used to supplement inhalational anesthesia in longer procedures. Both continuous infusion of Propofol for conscious sedation and with opioids for the maintenance of anesthesia for cardiac surgery are acceptable techniques. Dose-2-2.5mg/kg  

Benzodiazepines:

Benzodiazepines They Produce sedation and amnesia, Potentiate GABA receptors and have a Slower onset and emergence.  

Diazepam:

Diazepam Often used as premedication or seizure activity, rarely for induction Minimal systemic effects- respirations decreased with narcotic usage Not water soluble- venous irritation Metabolized by liver- not redistributed Dosage-oral/rectal0.2-0.5mg/kg -IV 0.25 mg/kg

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Lorazepam Slower onset of action (10-20 minutes)-- not used for induction Used as adjunct for anxiolytic and sedative properties Not water soluble-- venous irritation Midazolam More potent than diazepam or lorazepam,Induction slow, recovery prolonged May depress respirations when used with narcotics Minimal cardiac effects Dosage – pediatrics dose: 0.05-0.1mg/kg(iv/im)

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Narcotic agonists (opioids)   Used for years for analgesic action-- civil war for wounded soldiers Predominant effects are analgesia, depression of sensorium and respirations Mechanism of action is receptor mediated Bradycardia in large doses Some peripheral vasodilation and histamine release -hypotension Side effects nausea, chest wall rigidity, seizures, constipation, urinary retention  

COMPLICATIONS OF GENERAL ANAESTHESIA:

COMPLICATIONS OF GENERAL ANAESTHESIA During anaesthesia Respiratory depression and hypercarbia. Salivation, respiratory secretions -less now as non-irritant anaesthetics are mostly used. Cardiac arrhythmias, asystole. Fall in BP Aspiration of gastric contents: acid pneumonitis. Laryngospasm and asphyxia.

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Delirium, convulsions. Excitatory effects are generally seen with i.v. anaesthetics especially if phenothiazines or hyoscine have been given in premedication. These are suppressed by opioids. Fire and explosion - rare now due to use of noninflammable agents. After anaesthesia Nausea and vomiting. Persisting sedation: impaired psychomotor function. Pneumonia, atelectasis. Organ toxicities: liver, kidney damage. Nerve palsies - due to faulty positioning. Emergence delirium.

Contraindication:

Contraindication Patients for whom general anesthesia is usually contraindicated include those with a medical contraindication to general anesthesia and healthy and cooperative patients with minimal dental needs. 

Technique of general anesthesia:

Technique of general anesthesia

Preanaesthetic medication:

Preanaesthetic medication Preanaesthetic medication refers to the use of drugs before anaesthesia to make it more pleasant and safe.

Monitoring of patient:

Monitoring of patient There should be quiet environment the operatory should be equipped with suction, monitoring equipments, emergency drugs, and equipments like defibrillators and a system capable of delivering oxygen under positive pressure

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gas delivery machines should have an oxygen fail-safe system, and should be checked and calibrated periodically on a scheduled basis. an anesthesia chart should be maintained for monitoring the patient Monitoring should be done according to the following criteria : 1) Level of consciousness The response of patient to the commands during procedures performed under sedation as a guide to their level of consciousness     Defibrillator

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2 ) Respiration pulmonary ventilation capnometer The rate and depth of respiration should be monitored. Respiratory rate in children is 10-18/min whereas depths can b judge by movements of chest and abdomen     3) Oxygenation Clinical colour of tongue and nails help to have an idea of oxygenation of blood.pulseoximetry has revolutionized modern monitoring procedures under normal circumstances, a child’s oxygen saturation is 97-100%

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4) Haemodynamics cardio scope Pulse rate, blood pressure and continuous ECG monitoring reduces the likelihood of adverse outcomes during the procedure.ecg monitoring should be used in all patient undergoing sedation   5) Recording of monitored parameters Vital signs and respiratory variable should be recorded before initiating sedation, after administration of medication, at a regular interval during procedure, upon initiation if recovery, and immediately before discharge.

Post anesthesia instructions :

Post anesthesia instructions   After the treatment the first drink should be sips of plain water, sweet drinks can be given next For elevate body temperature, patient can be given antipyretic and fluids Patient should seek advice if there is; persistent vomiting beyond 4 hours increased temp above 101 f any breathing difficulty excessive drowsiness 4. A 24 hr contact no. of the dental surgeon or pedodontics should be given to the parents 5. Emphasize check up on the following day and essential follow up

Latest Discoveries :

Latest Discoveries Explosion of new information on the structure and function of GABAa receptors. Cloning and sequencing multiple subunits-large number of different subunits allows for a great variety of different types of GABAa receptors that will likely differ in drug sensitivity. Profol delivery technology: mechanically driven pumps computer-controlled infusion systems target control infusion

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Findings collectively enhance the understanding on the mechanism of action of profol Allows the medicinal chemist to rationally design analogues with the better pharmacological profiles The Wall Streat Journal: FDA wants more research on anesthesia risk to kids anesthesia can be harmful to developing brain prolonged changes in behavior, memory and learning impairments

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REFERENCES The Pharmacological basis of therapeutics- Goodman & Gilman Clinical Pharmacology- Bennett & Brown Essentials of medical pharmacology- Tripathi KD Basic & Clinical Pharmacology- Katzung G Peterson‘s Principles of oral and maxillofacial surgery

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