![SEVOFLURANE & COMPOUND A
• Halogenated anaesthetics can undergo chemical breakdown while interacting
with CO2 absorbents.
• Strong bases extract a proton from the isopropyl group of sevoflurane
resulting in haloalkene (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl
ether), known as compound A.
• Compound A is volatile.
• Inhaled concentration is dependent on the FGF rate and the type of CO2
absorbent present.
• Higher FGF rates result in a smaller accumulation of compound A .
• However, compound A exposure is not associated with clinically significant
nephrotoxicity in humans](https://image.slidesharecdn.com/inhalationalagents-240219162006-1959c6d2/85/INHALATIONAL-AGENTS-power-point-presentation-81-320.jpg)
INHALATIONAL AGENTS power point presentation
- 1. SPEAKER - DR. SRINIVAS INHALATIONAL AGENTS
- 2. WHAT ARE INHALATIONALAGENTS ?? • Inhalational anaesthetics are volatile agents administered in vapour form through a vaporizer to the patient via pulmonary route.
- 3. HISTORY • Experimentation with inhalation of gases and vapors for the purpose of obtunding the distress associated with surgery began in the 19th century. • Discovery of anesthetic properties of N2O, diethyl ether & chloroform took place in 1840’s. • William.T.G.Morton – October 16 1846. • 1951 – Fluroxene • 1956 – Halothane • 1960 – Methoxyflurane • 1973 – Enflurane • 1981 – Isoflurane • 1992 – Desflurane • 1994 - Sevoflurane
- 4. PROPERTIES OF INHALATIONAL AGENTS • Inhaled anaesthetics are both taken up and eliminated through alveolar blood–gas exchange. • Tissue-dependent metabolism is unnecessary for drug clearance.
- 5. PARTIAL PRESSURE !! • Partial pressure is the portion of total pressure contributed by one component of a gas mixture. • Usually expressed as a % of the delivered gas mixture. • Gas moves from regions of high partial pressures to low partial pressures until a state of Equilibrium is achieved. • Maximum partial pressure of a volatile agent is called its VAPOR PRESSURE.
- 7. PARTITION COEFFICIENT : • Ratio of concentrations of drug in one compartment versus other intercommunicating compartment at equilibrium.
- 8. BLOOD GAS PARTITITON COEFFICIENT : ( OSTWALD ) • Ratio of con. of an agent in the blood phase to that in the gas phase. • Tells about solubility of the agent. • The lower the solubility coefficient, the less soluble the vapour, and the faster its onset of action or change in depth of anaesthesia. • The anaesthetic effect is only achieved when the concentration in the blood is the same as that in the gas in the alveoli.
- 9. • For eg: blood/gas coefficient of isoflurane is 1.4 at 37ºc. It implies that after attaining equilibrium blood contains more isoflurane than alveolar gas. affinity of agent for blood (λb ) Blood gas coefficient = ____________________ affinity of agent for gas ( λg )
- 11. OIL GAS PARTITION COEFFICIENT : • Concentration of the agent in the olive oil divided by its concentration in gas at equilibrium. • Tells about the POTENCY of the agent.
- 13. • The lower the oil : gas solubility coefficient, the less lipid soluble the drug and the faster it’s offset.
- 14. PHARMACODYNAMICS
- 15. MECHANISM OF ACTION: • By the 1870s, a wide range of structurally unrelated compounds were known to have anaesthetic properties leading Claude Bernard to postulate a common mechanism of action, the ‘unitary theory of narcosis’. • Meyer and Overton observed a strong correlation between anaesthetic potency and solubility in olive oil, theorizing that anaesthetic agents act non-specifically on the hydrophobic, lipid components of cells.
- 16. MEYER OVERTON RULE : • First experimental evidence on the mechanism of action. (1899) • Linear relationship. • The greater the lipid solubility of the agent greater is its potency.
- 18. SHORTCOMING’S !! • Stereo-isomers of a drug have different anesthetic potency but their oil – gas partition coefficients are same. • Certain lipid soluble agents are convulsants rather than anesthetics. • Increased temperature. • Non-immobilizers : Halogenated alkanes
- 19. CRITICAL VOLUME HYPOTHESIS • Mullins. • States that the absorption of anesthetic molecules could expand the bilayer beyond a critical volume, altering membrane function. • Distort channels necessary for sodium ion flux and the development of action potentials necessary for synaptic transmission.
- 20. • Change in Membrane Physical State: Fluidization Theory: Anesthetics increase the general fluidity of plasma membranes Lateral Phase Separation Theory: Anesthetics inhibit the formation of an ordered, low volume gel phase around ion channels, normally required for channel opening.
- 21. A change in the membrane lateral pressure shifts conformational equilibrium of certain membrane proteins
- 22. • Protein Interaction Theory: Anaesthetics bind to specific proteins that affect ion flux, resulting in either potentiation of inhibitory neurotransmitters (e.g., GABA, glycine) or inhibition of excitatory neurotransmitters (e.g. glutamate NMDA receptors)
- 23. • The mechanisms of action of inhalation anaesthetics may be subclassified as Macroscopic (brain and spinal cord), Microscopic (synapses and axons), and Molecular (pre- and post-synaptic membranes)
- 24. MACROSCOPIC • At the spinal cord level: decrease transmission of noxious afferent information ascending from the spinal cord to the cerebral cortex. There is also inhibition of spinal efferent neuronal activity reducing movement response to pain. • Hypnosis and amnesia, on the other hand, are mediated at the supraspinal level. • Inhalation agents globally depress cerebral blood flow and glucose metabolism.
- 25. MICROSCOPIC(SYNAPSES AND AXONS) • Inhaled anaesthetics are believed to inhibit excitatory presynaptic channel activity mediated by neuronal nicotinic, serotonergic and glutaminergic receptors, while also augmenting the inhibitory post- synaptic channel activity mediated by GABAA and glycine receptors. The combined effect is to reduce neuronal and synaptic transmission
- 26. MOLECULAR(PRE AND POST SYNAPTIC MEMBRANES) • Inhalation anaesthetics prolong the GABA receptor- mediated inhibitory Cl¯ current, thereby inhibiting post- synaptic neuronal excitability. • Two-pore domain potassium channels Voltage independence coupled with absent activation and inactivation kinetics are characteristics of these channels. Most recently their role has been described.
- 27. MINIMUM ALVEOLAR CONCENTRATION : • The alveolar concentration of an anaesthetic at 1 atmosphere that prevents movement in 50% of patients in response to a noxious stimulus. • It is a population average not an individual’s response. • MAC values are additive. • Analgesia begins at about 0.3 MAC; Amnesia at about 0.5 MAC. • It’s an indicator of POTENCY
- 32. MAC VARIANTS : • MAC AWAKE : defined as the anaesthetic concentration needed to suppress a voluntary response to verbal command. ( emergence concept ) • MAC UNAWAKE : concentration at which patient remain responsive to verbal commands when anaesthetic concentration is increased ( induction concept )
- 33. • MAC BAR : defined as concentration that blocks autonomic responses to surgical incision • MAC CLASSIC/ MAC SKIN INCISION : MAC that allows for surgical procedure. • MAC INTUBAION : MAC allows for intubation without movement or coughing. • MAC BAR>MAC intubation>MAC incision>MAC awake
- 34. • Blood gas partition coefficient – solubility • Oil gas partition coefficient – potency • MAC – potency
- 35. PHARMACOKINETICS
- 36. FACTORS AFFECTING UPTAKE & REDISTRIBUTION : • Transfer from inspired air to alveoli . • Transfer from alveoli to arterial blood . • Transfer from arterial blood to tissues . PA Pa Pbrain
- 37. • INSPIRED CONCENTRATION ( Fi ) : Pi = Fi x Atm Greater the inspired concentration greater is the partial pressure. 1. Breathing circuit volumes 2. Fresh gas flow rate 3. Absorption of the agent in the rubber or plastic components of the breathing system.
- 38. • Wash in of the circuit - PRIMING • Breathing circuit components, such as CO2 adsorbents and the plastic or rubber of the circuit tubing and connectors, influence the rate of equilibration. • Because such materials can absorb volatile anaesthetics, increasing the effective circuit volume.
- 39. FACTORS THAT SPEED INDUCTION • High fresh gas flows • Low circuit volume • Low circuit absorption
- 40. • ALVEOLAR VENTILATION : Rate of rise in FA is dependent upon minute ventilation and FRC. A larger FRC dilutes the inspired concentration of gas resulting initially in a lower alveolar partial pressure and therefore slower onset of anaesthesia If minute ventilation is increased, the tension in alveolar air and arterial blood will rise more quickly - Lung washin.
- 41. ALVEOLI BLOOD • Anaesthetic uptake into blood depends on - Pulmonary blood flow (which is typically close to cardiac output, Q ) Blood’s capacity to solvate anaesthetic from the gas state (the blood/gas partition coefficient, λb/g) Alveolar–venous partial pressure gradient and tissue uptake Uptake= Q × λb/g × (PA −PMV)
- 42. - THESE EFFECTS ARE GREATER FOR HIGHLY SOLUBLE AGENTS Increased cardiac output Increased pulmonary blood flow Increased anaesthetic uptake Rapid delivery to the tissues including the CNS Accelerates the equilibration of tissue anaesthetic partial pressures with that of arterial blood However, this does not hasten induction, as the alveolar concentration is lowered by the high uptake of anaesthetic Decrease in alveolar concentration Delayed induction
- 44. • key factor determining the speed of onset and recovery alveolar partial pressure of the agent, • A higher blood–gas partition coefficient (higher solubility) Greater uptake by the pulmonary circulation, but slower increase in alveolar partial pressure of the agent (FA/Fi ratio) and therefore more prolonged induction and recovery from anaesthesia.
- 46. Alveolar–venous partial pressure gradient and tissue uptake: • The difference between alveolar and venous partial pressures is due to tissue uptake of inhalation agents. • Tissue uptake is dependent on - tissue blood flow, -the blood to tissue partial pressure difference, and -the blood tissue solubility coefficient.
- 47. • Brain tissue equilibrates quickly because it is highly perfused with blood. • Lean tissue (muscle) has roughly the same affinity for anaesthetic agents as blood (blood tissue coefficient 1:1), but perfusion is much lower than brain tissue; therefore, equilibration is slower. • Fat–blood coefficients are significantly >1. Such high affinity of fat tissue for anaesthetic and its low perfusion levels result in a very long equilibration time
- 49. OTHER FACTORS • Dead space . • Shunts : right – left & left – right .
- 51. CONCENTRATION EFFECT & SECOND GAS EFFECT : • The higher the inspired concentration the more rapid is the rise in alveolar concentration • Includes two factors Concentrating effect Augmentation inflow effect. Concentrating effect is more significant with nitrous oxide than volatile agents.
- 52. • As alveolar gas volume diminishes, the concentration of N2O is maintained (the concentration effect), and the concentrations of other gases increase (the second gas effect).
- 53. • AUGUMENTATION INFLOW EFFECT : When appreciable volumes of anaesthetic is taken rapidly the lungs do not collapse, instead sub atmospheric pressure created by anaesthetic uptake which causes passive drive in of additional volume of gas to replace that lost by uptake.
- 55. Nitrous oxide Augments its own alveolar conc. augments alveolar conc of volatile agent simultaneously used Concentrating effect second gas effect
- 56. • DIFFUSION HYPOXIA : Described by Fink . ( FINK EFFECT ) Opposite of above effects . The elimination of a poorly soluble gas, such as N2O, from the alveoli may proceed at as greater rate as its uptake, thereby adding as much as 1 l/min to alveolar air. This gas effectively dilutes alveolar air, and available oxygen, so that when room air is inspired hypoxia may result this is usually only mild and rarely clinically significant.
- 57. BLOOD TISSUES : • Depends on : Tissue:blood partition coefficient Tissue blood flow Arterial to tissue pressure difference
- 58. • The time required for anaesthetic partial pressure equilibration between arterial blood (Part = PA) and a specified tissue is shorter if its blood flow is high, and longer if that tissue has a large effective volume. • The rate of rise of tension in different regions is proportional to the arterial-tissue tension difference. • At equilibrium the concentration in lipid tissues will be far greater than that in blood.
- 62. ELIMINATION OF INHALATIONAL AGENTS : • The factors affecting the elimination of an anaesthetic agent are identical to those for uptake and distribution. • Removal of anaesthetic agent from the body is via 1. Exhalation 2. Biotransformation& 3. Transcutaneous loss Biotransformation is more important for halothane and methoxyflurane. Both undergo extensive metabolism in liver via 450(cyp). Fat and muscle act as reservoirs for anaesthetic agent and more time will be required for elimination.
- 64. IDEAL ANAESTHETIC AGENT : • PHYSICAL PROPERTIES o Stable over a range of temperatures o Not be degraded by light o Does not require the presence of a preservative o Non-explosive and does not support combustion o Odourless or has a pleasant smell o Environmentally safe o Does not react with other compounds (e.g. Soda lime) o Has a boiling point well above room temperature
- 65. Pharmacodynamic properties 1. Predictable dose-related CNS depression 2. Analgesic, anti-emetic and muscle relaxation properties 3. Minimal respiratory depression, does not cause coughing or bronchospasm 4. Minimal cardiovascular effects. 5. No increase in cerebral blood flow (and therefore intracranial pressure). 6. Not epileptogenic 7. Does not impair renal or hepatic function 8. No effect on uterine smooth muscle 9. Does not trigger malignant hyperpyrexia
- 66. Pharmacokinetic properties 1. Low blood: gas solubility co-efficient. 2. Low oil: gas solubility co-efficient 3. Not metabolised or no active metabolites 4.Is excreted completely by the respiratory system
- 67. • AN IDEAL ANAESTHETIC AGENT IS YET TO BE DISCOVERED!!
- 73. HALOTHANE : • Amber colored bottle. • Color code – red. • Thymol preservative. • Pleasant smell- pediatrics group. • Agent of choice for asthmatics. • Most arrhythmogenic agent . • Atony of uterus. • Halothane shakes – postop shivering. • Malignant hyperthermia.
- 74. HALOTHANE HEPATOTOXICITY : • Associated with two distinct types of hepatic injury. • Subclinical hepatotoxicity : - halothane reduction to a 2-chloro-1,1,1-trifluoroethyl radical - seen in 20% of cases - elevation of hepatic enzymes postoperatively - reversible • Fulminant hepatitis : - elevated AST, ALT, ALP, bilirubin - massive hepatitis - very rare
- 75. ENFLURANE : • Orange color coded. • Epileptogenic. • Potent cardiovascular depressant.
- 76. ISOFLURANE : • Isomer of enflurane. • Volatile & pungent. • Only agent that preserves baro-receptor reflex best. • Agent that causes coronary steal . • Agent of choice for neuro-anaesthesia. • Agent of choice for controlled hypotension.
- 77. DESFLURANE : • Agent that boils at room temp. • Agent of choice for geriatric patients. • Agent of choice for hepatic failure pt’s. • Agent of choice for renal failure pt’s.
- 78. SEVOFLURANE : • Pleasant smell. • Agent of choice for pediatric populations. • 2nd agent of choice for - neuro anesthesia - cardiac anesthesia - asthmatics
- 79. FLUORIDE ASSOCIATED NEPHROTOXICITY : • Methoxyflurane causes polyuric renal insufficiency. • Attributed to inorganic fluoride (F) released during its metabolism. • The nephrotoxic threshold for plasma F− is approximately 50 μM. • Typical peak fluoride concentrations after 2 to 3 MAC-hours of sevoflurane anaesthesia are 20 to 30 μM, and less than 5 μM after isoflurane and desflurane.
- 80. • Absence of renal toxicity with current volatile anaesthetics likely derives from a combination of factors: their lower tissue solubility's, particularly in kidney resulting in lower intrarenal fluoride production lower rates of biotransformation more rapid respiratory clearance from the body
- 81. SEVOFLURANE & COMPOUND A • Halogenated anaesthetics can undergo chemical breakdown while interacting with CO2 absorbents. • Strong bases extract a proton from the isopropyl group of sevoflurane resulting in haloalkene (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether), known as compound A. • Compound A is volatile. • Inhaled concentration is dependent on the FGF rate and the type of CO2 absorbent present. • Higher FGF rates result in a smaller accumulation of compound A . • However, compound A exposure is not associated with clinically significant nephrotoxicity in humans
- 82. • PTN in rats . • Compound A exposure can be limited by careful selection of fresh gas flows, vaporizer output, and CO2 absorbent materials. • The use of 2 L/min fresh gas flows ensures that for the vast majority of patients, exposure to compound A will be below the most conservative threshold for nephrotoxicity.
- 83. N2O & VITAMIN B12 : • N2O is unique among anaesthetics in irreversibly inhibiting cobalamins (vitamin B12) by oxidizing the Co ligand. • Long-term N2O exposure, can cause megaloblastic anemia, myelopathy, neuropathy, and encephalopathy, sometimes presenting as psychosis.
- 84. ENVIRONMENTAL EFFECTS : • GLOBAL WARMING : Inhaled anaesthetics are recognized greenhouse gases The global warming potential of volatile anaesthetics ranges from 1230-fold (isoflurane) to 3714-fold (desflurane) that of an equal mass of CO2. The global warming potential of N2O is approximately 300-fold greater than that of an equal mass of CO2 . • OZONE DEPLETION : Halogenated volatile anesthetics are similar to chlorofluorocarbons (CFCs), which are major ozone depleting pollutants.