General anesthetics Introduction & History Principles of General anesthesia General anesthetics Inhalational anesthetics Intravenous anesthetics

Anesthesiology Anesthesia – is a reversible condition of comfort, quiescence and physiological stability in a patient before, during and after performance of a procedure. Anesthesia – for surgical procedure to render the patient unaware / unresponsive to the painful stimuli. Quiescence - KWI- essence.

Anesthesiology Original in the Royal College of Surgeons of England, London.

Ether Massachusetts General Hospital, 16th October, 1846.

History of Anesthesia 2000 B.C. - "Here, take this hammer.“ 1000 B.C. - "That hammer is heathen, say this prayer.“ 1850 A.D. - "That prayer is superstition, drink this potion.“ 1940 A.D. - "That potion is snake oil, swallow this pill.“ 1985 A.D. - "That pill is ineffective, take this inhalation“ 2000 A.D. - "That inhalation is artificial. Show me your back". 2025 A.D. - "Here, take this hammer". Four stages of illness ill pill bill will

Anesthesiology Surgical stress evokes HPA axis and sympathetic system. Tissue damage during surgery induces coagulation factors and activates platelets leading to hypercoagulability of blood. Most anesthetics are associated with decrease in systemic blood pressure – myocardial depression and direct vasodilatation. reduce ventilatory drive and eliminate reflexes that maintain airway patency.

General anesthesia - principles Goals of Balanced Anesthesia Amnesia Analgesia Attenuation of autonomic reflexes Immobility Unconsciousness Blunting of baroreceptor control and decreased central sympathetic tone. General anesthetics have therapeutic indices of about 2 - 4.

General anesthesia - principles Preanesthetic medications: It is the use of drugs prior to anesthesia to make it more safe and pleasant. To relieve anxiety – benzodiazepines. To prevent vomiting – antiemetics. To supplement analgesia – opioids. To prevent vagal stimulation and secretion – atropine. The aim is to relieve apprehension and facilitate smooth induction. To supplement analgesic, amnesic action of anesthetics. To prevent bradycardia and secretion.

General anesthesia - principles Stages of anesthesia: Stage I : Analgesia Stage II : Excitement, combative behavior – dangerous state Stage III : Surgical anesthesia Stage IV : Medullary paralysis - respiratory and vasomotor control ceases.

General anesthetics - mechanism Molecular mechanism of the GA : GABA –A : Potentiation by Halothane, Propofol, Etomidate NMDA receptors : inhibited by Ketamine

General anesthetics There are two types of anesthetics : Inhalational --- for maintenance Intravenous --- for induction and short procedures Inhalation anesthetics: Advantage of controlling the depth of anesthesia. Metabolism is very minimal. Excreted by exhalation.

General anesthetics Inhalational anesthetics : Nitrous oxide Halothane Enflurane – rarely used Isoflurane – most commonly used Desflurane Sevoflurane Methoxyflurane – not available in US because of concerns of nephrotoxicity.

General anesthetics Blood / Gas coefficient Blood/gas coefficient is the ratio of the amount of anaesthetic in blood and gas when the two phases are of equal volume and pressure and in equilibrium at 37oC. In other words it is a reflection of the gas' solubility - a high b/g ratio = highly soluble. You might think that the more of a substance in the blood - the greater it's effect. Oddly, that is not the case. The greater the partial pressure of a gas in the blood - the greater the effect. Partial pressure = Total pressure x % by volume. So a gas with a high solubility will exert a low partial pressure and will be slow to take effect and to offset. A gas with a low solubility (like Sevoflurane) exerts a high partial pressure and therefore has a rapid onset and offset.

General anesthetics The important characteristics of Inhalational anesthetics which govern the anesthesia are : Solubility in the blood (blood : gas partition co-efficient) Solubility in the fat (oil : gas partition co-efficient) Inhalational agent : Solubility in blood is the single most important factor in determining the speed of induction and recovery The more soluble an agent is in the blood the more must be dissolved to raise its partial pressure (tension).

Inhalational anesthetics Blood : gas partition co-efficient: It is a measure of solubility in the blood. It determines the rate of induction and recovery of Inhalational anesthetics. Lower the blood : gas co-efficient – faster the induction and recovery – Nitrous oxide. Higher the blood : gas co-efficient – slower induction and recovery – Halothane. The blood:gas partition coefficient is the ratio of the concentrations of anesthetic gas in the blood and gas phases at equilibrium. In general, the blood:gas partition coefficient represents the capacity of the blood or a specific tissue to absorb the anesthetic. A higher blood:gas partition coefficient (e.g., 2.0 equals a 2% blood concentration and a 1% lung concentration at equilibrium) shows greater affinity for the blood. An anesthetic that has a blood concentration of 3% and a lung concentration of 6% at equilibrium would have a partition coefficient of 0.5, showing a greater affinity for the gas phase. The blood/gas partition coefficient describes how the gas will partition itself between the two phases after equilibrium has been reached. Isoflurane for example has a blood/gas partition coefficient of 1.4. This means that if the gas is in equilibrium the concentration in blood will be 1.4 times higher than the concentration in the alveoli. A higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction time. It takes longer until the equilibrium with the brain partial pressure of the gas is reached

Uptake of inhalational general anesthetics Uptake of inhalational general anesthetics. The rise in end-tidal alveolar (FA) anesthetic concentration toward the inspired (FI) concentration is most rapid with the least soluble anesthetics, nitrous oxide and desflurane, and slowest with the most soluble anesthetic, halothane. All data are from human studies. The more soluble the anesthetic agent is in blood the faster the drug goes into the body The more soluble the anesthetic agent is in blood the slower the patient becomes anesthetized (goes to sleep) To some degree this can be compensated for by increasing the inhaled concentration but there are limits Lower anesthetic solubility  in blood results in the "blood" compartment becoming saturated with the drug following fewer gas molecules transferred from the lungs into the blood.   Once the "blood" compartment is saturated with anesthetic, additional anesthetic molecules are readily transferred to other compartments, the most important one of which is the brain. When a gas is dissolved in the blood, its partial pressure is directly proportional to its concentration but inversely proportional to its solubility ( brody’s human pharmacology, 4th edition, page # 345) At equilibrium, partial pressures are equal in alveoli and inspired gas mixtures. A higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction time. It takes longer until the equilibrium with the brain partial pressure of the gas is reached.

BLOOD GAS PARTITION COEFFICIENT Agents with low solubility in blood quickly saturate the blood. The additional anesthetic molecules are then readily transferred to the brain BLOOD GAS PARTITION COEFFICIENT Imagine two cups of warm water: into one you put a spoon of sugar and into the other a spoon of sand. Which will be in higher concentration in the bottom of the cup? The sand is insoluble, the sugar dissolves, so very little reaches the bottom. For bottom of cup read brain. The blood:gas partition coefficient is the ratio of the concentrations of anesthetic gas in the blood and gas phases at equilibrium. In general, the blood:gas partition coefficient represents the capacity of the blood or a specific tissue to absorb the anesthetic. A higher blood:gas partition coefficient (e.g., 2.0 equals a 2% blood concentration and a 1% lung concentration at equilibrium) shows greater affinity for the blood. An anesthetic that has a blood concentration of 3% and a lung concentration of 6% at equilibrium would have a partition coefficient of 0.5, showing a greater affinity for the gas phase. The blood/gas partition coefficient describes how the gas will partition itself between the two phases after equilibrium has been reached. Isoflurane for example has a blood/gas partition coefficient of 1.4. This means that if the gas is in equilibrium the concentration in blood will be 1.4 times higher than the concentration in the alveoli. A higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction time. It takes longer until the equilibrium with the brain partial pressure of the gas is reached Agents with low blood solubility require few molecules to dissolve into the blood to raise the partial pressure to equilibrium.

Inhalational anesthetics Blood gas partition co-efficient affecting rate of induction and recovery Fa = anesthetic concentration in alveoli; Fi = inspired anesthetic concentration. Fe = end tidal anesthetic concentration. FA: alveolar concentration of anesthetic FI: inspired concentration of anesthetic FA /FI shows the increasing rate of anesthetic in alveolar The blood:gas partition coefficient is the ratio of the concentrations of anesthetic gas in the blood and gas phases at equilibrium. In general, the blood:gas partition coefficient represents the capacity of the blood or a specific tissue to absorb the anesthetic. A higher blood:gas partition coefficient (e.g., 2.0 equals a 2% blood concentration and a 1% lung concentration at equilibrium) shows greater affinity for the blood. An anesthetic that has a blood concentration of 3% and a lung concentration of 6% at equilibrium would have a partition coefficient of 0.5, showing a greater affinity for the gas phase. The blood/gas partition coefficient describes how the gas will partition itself between the two phases after equilibrium has been reached. Isoflurane for example has a blood/gas partition coefficient of 1.4. This means that if the gas is in equilibrium the concentration in blood will be 1.4 times higher than the concentration in the alveoli. A higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction time. It takes longer until the equilibrium with the brain partial pressure of the gas is reached

Inhalational anesthetics Oil: gas partition co-efficient: It is a measure of lipid solubility. Lipid solubility - correlates strongly with the potency of the anesthetic. Higher the lipid solubility – potent anesthetic. e.g., halothane

Inhalational anesthetics MAC value is a measure of inhalational anesthetic potency. It is defined as the minimum alveolar anesthetic concentration ( % of the inspired air) at which 50% of patients do not respond to a surgical stimulus. MAC values are additive and lower in the presence of opioids. Doses of anesthetics in MAC's are additive. MAC of anesthetic that prevents movement in response to tracheal intubation in 50% of subjects (MACTI). For sevoflurane, MACTI is 2.7-3.2% in children. Whether nitrous oxide and sevoflurane are additive is determined by MACTI of sevoflurane with and without nitrous oxide in children. The addition of 33% and 66% nitrous oxide decreased the MACTI of sevoflurane by 18% and 40%, respectively. Nitrous oxide and sevoflurane suppress the responses to tracheal intubation in a linear and additive fashion.

OIL GAS PARTITION CO-EFFICIENT Higher the Oil: Gas Partition Co-efficient lower the MAC . E.g., Halothane 0.8 1.4 220

Inhalation Anesthetic MAC value % Oil: Gas partition Nitrous oxide >100 1.4 Desflurane 7.2 23 Sevoflurane 2.5 53 Isoflurane 1.3 91 Halothane 0.8 220

Clinical case KJ is a 7-year-old, 20-kg boy who has been undergoing multidrug chemotherapy for aggressive osteosarcoma of his right femur. The time has now come for a surgical resection. 8:00 PM (night before the operation): Dr. S, the anesthesiologist, provides reassurance and revisits the importance of fasting after midnight to prevent aspiration of gastric contents while under general anesthesia. 6:30 AM: KJ clings to his mother and appears anxious, cachectic, and in some pain. His vital signs are stable with an elevated pulse of 120 and a blood pressure of 110/75.

Clinical case An oral dose of midazolam is given to relieve anxiety and to allow KJ to separate from his parents. 7:00 AM: Dr. S injects a small amount of lidocaine subcutaneously before inserting an intravenous catheter (which he carefully conceals from KJ until the last possible moment). Through the catheter, Dr. S delivers an infusion of morphine sulfate for analgesia.

Clinical case 7:30 AM: Dr. S rapidly induces anesthesia with an intravenous bolus of 60 mg (3 mg/kg) of thiopental (a barbiturate; Within 45 seconds, KJ is in a deep anesthetic state. The doctor adds a dose of intravenous succinylcholine (a depolarizing muscle relaxant) to facilitate endotracheal intubation, and KJ is placed on artificial respiration. 7:32 AM: A mixture of inhaled general anesthetics consisting of 2% isoflurane, 50% nitrous oxide, and 48% oxygen is provided through the ventilator to maintain the anesthetic state. 7:50 AM: KJ shows no response, either through movement or increased sympathetic tone (e.g., increased heart rate, increased blood pressure), to the first surgical incision.

Clinical case 12:35 PM: After a long surgery, Dr. S stops the isoflurane and nitrous oxide and turns on pure oxygen for a few minutes. 12:45 PM: In less than 10 minutes, KJ is breathing spontaneously and is able to respond to questions, although he is still somewhat groggy. KJ's parents are relieved to find him awake and alert after more than 5 hours of anesthesia.

Questions What determines the rate of induction and recovery from anesthesia? What are the advantages of using a mixture of two anesthetics (in this example, nitrous oxide and isoflurane) instead of just one or the other? Why did Dr. S give pure oxygen for a few minutes following the cessation of anesthetic administration?

Inhalational anesthetics Nitrous oxide: Safest inhalational anesthetic. Very weak anesthetic but a good analgesic. No toxic effect on the heart, liver and kidney. Administered with more potent anesthetics to hasten the uptake of the other agent(s) Unlike most general anesthetics, N2O appears to affect the GABA receptor. In many behavioral tests of anxiety, a low dose of N2O is a successful anxiolytic. This anti-anxiety effect is partially reversed by benzodiazepine receptor antagonists. Nitrous oxide can be habit-forming because of its short-lived effect (generally from 0.1 - 1 minutes in recreational doses). Long-term use in excessive quantities has been associated with vitamin B12 deficiency anemia due to reduced hemopoiesis, neuropathy, tinnitus, and numbness in extremities. Pregnant women should not use nitrous oxide as chronic use is teratogenic and foetotoxic. No respiratory depression also. Metabolism does not occur and quickly removed from the body by lungs. Weak anesthetic – surgical anesthesia cannot be produced on its own. Second gas effect of nitrous oxide may be utilized to help speed anesthesia by halothane. irreversibly oxidizes cobalt atom of vitamin B12, inhibiting B12-dependent enzymes: methionine synthetase (myelin formation)

Inhalational anesthetics Nitrous oxide Commonly used for dental procedures Quick induction and recovery. Caution about diffusional hypoxia megaloblastic anemia. In dentistry, it is commonly used as a single agent (with oxygen) for partial sedation, most commonly in pediatric dental populations. Dentistry In dentistry, nitrous oxide is indicated to decrease the pain and anxiety associated with procedures. It is commonly delivered by a nasal mask in combination with oxygen.[1] The specially designed nasal mask fully covers the nose, allowing the mixture of nitrous oxide with oxygen to flow while the dentist works on the patient’s mouth. Nitrous oxide is commonly offered by pediatric dentists to assist in inducing amnesia, as well as increasing analgesia, relaxation, and cooperation in younger patients.[1] Indications in adult dental patients include anxiety, low pain tolerance, underlying psychiatric disorders, and mental retardation.[1, 4] Nitrous oxide may also be useful for prolonged or more involved dental procedures as well as in patients with hyperresponsive gag reflexes.[5] Other indications Although not standard practice, additional described uses may include colonoscopy, sigmoidoscopy, laser procedures, obstetrical labor pain, ophthalmic procedures, emergency medical care of patients in accidents and during ambulance transport, and minor invasive medical procedures, including joint injections.[6] Less commonly, self-administered nitrous oxide is reported for chronic pain from terminal illness and pain associated with cancer treatment.[6] Nitrous oxide use in children undergoing basic procedures including lumbar puncture, venous cannulation, or dressing changes has demonstrated a significant reduction in pain levels, allowing for a shorter recovery.[7, 8] The children who were administered nitrous oxide displayed less anxiety and distress during medical procedures.[7] A 2009 prospective, randomized study showed that a 70:30 mix of nitrous oxide in oxygen, administered for 3 minutes, was effective in reducing pain in children undergoing venipuncture.[8] Nitrous oxide has been proven beneficial in young children receiving injections for juvenile arthritis.[9] Additionally, nitrous oxide has been used successfully as an anesthetic for children undergoing minor surgeries such as cyst surgery and abscess drainage.[5]

Inhalational anesthetics Halothane: It is a potent and pleasant anesthetic. It sensitizes the heart to catecholamines. It dilates bronchus – last resort in status asthmaticus. It inhibits uterine contractions which can lead to severe bleeding – not used in labor. Halothane hepatitis and malignant hyperthermia can occur. It produce dose dependent hypotension. It is the only inhalational anesthetics in which is metabolized significantly (30%) to bromide, trifluro-acetic acid which is responsible for hepatotoxicity, abortion and congenital abnormalities. Certain anesthetics such as halothane (Fluothane) produce marked uterine relaxation with the potential of subsequent postpartal hemorrhage and possibly maternal liver damage. In addition, fetal depression is a significant problem. Probably, such agents should be restricted to clinical situations requiring rapid uterine relaxation.

Inhalational anesthesia Malignant Hyperthermia Side effect of halogenated anesthetics Fever of 110°F or more Life threatening Treatment: dantrolene (Dantrium) Dantrolene is a muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor. Sweet and ethereal odor. Generally do not sensitizes the heart to catecholamines. Seizures occurs at deeper levels –contraindicated in epileptics. Caution in renal failure due to fluoride. Enflurane is a halogenated ether that was commonly used for inhalational anesthesia during the 1970s and 1980s. Enflurane is a structural isomer of isoflurane. Clinically, enflurane produces a dose-related depression of myocardial contractility. Between 2% and 5% of the inhaled dose is oxidised in the liver, producing fluoride ions and difluoromethoxy-difluoroacetic acid. This is significantly higher than the metabolism of its structural isomer isoflurane. Enflurane also lowers the threshold for seizures and should especially not be used on people with epilepsy. It is also known to cause malignant hyperthermia. Relaxes the uterus (can cause spontaneous birth) in pregnant woman. Higher concentrations of enflurane may produce uterine relaxation and an increase in uterine bleeding. Enflurane and Methoxyflurane have a nephrotoxic effect and cause acute renal failure usually by its nephrotoxic metabolite. Enflurane is used as an inhalational agent for adults; but is not widely used for pediatric cases.

Inhalational anesthetics Isoflurane: It is commonly used with oxygen or nitrous oxide. Its pungency can irritate the respiratory system. No reports of hepatotoxicity. Isoflurane is always administered in conjunction with air and/or pure oxygen. Often nitrous oxide is also used. Although its physical properties means that anaesthesia can be induced more rapidly than with halothane, its pungency can irritate the respiratory system, negating this theoretical advantage conferred by its physical properties. It is usually used to maintain a state of general anesthesia that has been induced with another drug, such as thiopentone or propofol. It vaporizes readily, but is a liquid at room temperature. It is completely non-flammable. A major advantage of isoflurane is that the patent covering its use has expired, therefore it is very economical to use.

Inhalational anesthetics Desflurane: It is delivered through special vaporizer. It is a popular anesthetic for day care surgery. Induction can be troublesome and it can irritates the air passages producing cough and laryngospasm. Recovery is fast as cognitive and motor impairment are short lived. Malignant hyperthermia may occur with desflurane.

Inhalational anesthetics Sevoflurane: Induction and recovery is fast. It is an effective bronchodilator due to lack of pungency. It is a good anesthetic in patients with myocardial ischemia. Some concerns about nephrotoxicity. The successful use of remifentanil and sevoflurane in a woman with mitral stenosis, pulmonary hypertension and aortic stenosis undergoing cesarean section.

Anesthetic B:G PC O:G PC Features Notes Halothane 2.3 220 PLEASANT Arrhythmia Hepatitis Hyperthermia Enflurane 1.9 98 PUNGENT Seizures Hyperthermia Isoflurane 1.4 91 Widely used Sevoflurane 0.62 53 Ideal Desflurane 0.42 23 IRRITANT Cough Nitrous 0.47 Anemia

Respiratory effects of inhalational anesthetics. Spontaneous ventilation with all of the halogenated inhalational anesthetics reduces minute volume of ventilation in a dose-dependent manner (lower panel). This results in an increased arterial carbon dioxide tension (top panel). Differences among agents are modest. Respiratory effects of inhalational anesthetics. Spontaneous ventilation with all of the halogenated inhalational anesthetics reduces minute volume of ventilation in a dose-dependent manner (lower panel). This results in an increased arterial carbon dioxide tension (top panel). Differences among agents are modest.

General anesthetics Parenteral anesthetics (IV): These are used for induction of anesthesia. Rapid onset of action. Also reduce the amount of inhalation anesthetic for maintenance. E.g., Thiopental, Midazolam Propofol, Etomidate, Ketamine. Used for short procedures. Also includes methohexital.

Intravenous anesthetics Thiopental (Pentothal): It is an ultra short acting barbiturates. A typical induction dose produces duration of anesthesia of 5-8 minutes. The principal mechanism limiting anesthetic duration after single dose is redistribution from brain to other tissues like skeletal muscle. A single dose can produce psychomotor impairment for about 8 hrs. It produces unconsciousness ~ 20 seconds. Cerebral blood flow is not increased and thus no increase in ICT. Not an analgesic and a weak muscle relaxant. Initially, thiopental often causes coughing, laryngospasm and bronchospasm. Histamine release. Methohexital: Three times more potent than the thiopental Quicker and shorter action than thiopental. There is faster recovery with methohexital.

Inhalational anesthetics Thiopental It can be used for rapid control of seizures. Thiopental (barbiturates) can induce fatal attacks of porphyria in patients with acute intermittent or variegate porphyria Methohexital is another barbiturate which is preferred anesthetic in patients undergoing ECT because of its short duration of action.

Intravenous anesthetics Propofol (Diprivan): Most commonly used IV anesthetic for both induction and maintenance. Recovery is rapid and clearer than thiopenthal makes it best for day care surgery - residual impairment is less marked. Anti-emetic in action. It is used for sedation in intensive care units. Dose dependent decrease in BP

Intravenous anesthetics Propofol One of the most frequent side effects is pain on injection. Rare and potentially fatal complication, propofol infusion syndrome (PRIS), after prolonged and high dose, which is characterized by acidosis and rhabdomyolosis. Propofol is not having an analgesic action, so opioids are used with propofol to alleviate pain.

Intravenous anesthetics Etomidate: It is primarily used for anesthetic induction of patients at risk of hypotension. It suppress the production of steroids from the adrenal gland and not for long term infusions. It can cause seizures and nausea/vomiting. CVS stability is the main advantage over anesthetics. Etomidate is a short acting intravenous anaesthetic agent used for the induction of general anaesthesia and for sedation for short procedures such as reduction of dislocated joints and cardioversion. Minimal respiratory depression. Its duration of action ~ 5-10 mins.

Intravenous anesthetics Ketamine : Dissociative anesthesia Produce - profound analgesia, involuntary movements, amnesia and breathe spontaneously. Acts by blocking NMDA receptors Heart rate and BP are elevated due to sympathetic stimulation. Best suited for children and in patients with asthma as respiration is not depressed.

Intravenous anesthetics Ketamine: Emergence delirium, hallucinations and vivid dreams occurs in 50% cases during recovery. It is useful for burn dressing and trauma surgery. Dangerous for hypertensive and myocardial ischemia patients.

Intravenous anesthetics Analgesics: Opioids Opioids are the primarily used analgesics during perioperative period. The order of potency relative to morphine is: Sufentanil (1000 X ) Remifentanil (300 X) Fentanyl (100 X), Meperidine ( 0.1 X) Respiratory depression is a major adverse effect. Antagonist naloxone (Narcan) reverse opioids overdose and actions.

Benzodiazepines Used for short procedures and useful in controlling seizures. Midazolam (Versed) Fast action, potent and short half lifes are its salient features. Flumazenil (Romazicon) can reverse overdose / actions of benzodiazepines.

Newer anesthetics i.v α-2 adrenergic agonists: Dexmedetomidine It is FDA approved for short term sedation in non-intubated patients. Activation of α-2 receptors produces sedation and analgesia. It is a sedative-hypnotic that produce analgesia with little respiratory depression and mild drop in blood pressure. Short term sedation is usually < 24 hrs

--- Anesthetic I.V Duration mins Analgesia Muscle relaxation Others Thiopental 5 - 10 --- Respiratory depression Propofol 5-10 Ketamine +++ Hallucinations Midazolam 5-20 Amnesia Fentanyl Neuroleptanalgesia : It is characterized by general quiescence, psychic indifference and intense analgesia without total loss of consciousness. Combination of Fentanyl and Droperidol as Innovar