INHALATION anaesthetic agents and their indication

Inhalation anaesthetic agents and their pharmacokinetics and pharmacodynamic

1. INHALATIONAL ANESTHETIC AGENTS MODERATOR- DR HIMANSHU PRINCE PRESENTER- MAMTA KUSHWAHA

2. INDEX HALOTHANE ISOFLURANE SEVOFLURANE DESFLURANE NITROUS OXIDE

3. HALOTHANE It is halogenated alkane. Least expensive 2 bromo-2-chloro 1,1,1-trifluoroethane Non-flammable and non explosive Non irritant vapors Absorbed by rubber Corrodes metals 25% metabolized in the liver Decomposed by light (0.01% thymol,amber bottles) C C F F F H Br Cl Partial pressure Solubility MAC 243mmHg 2.4 0.75

4. EFFECTS ON ORGAN SYSTEM A. CARDIOVASCULAR : Dose dependent reduction of arterial blood pressure by direct myocardial depression. It is a coronary artery vasodilator. It causes slowing of SA node conduction resulting in bradycardia. No effect on systemic vascular resistance Sensitizes heart to catecholamine and induces arrhythmias B . RESPIRATORY SYSTEM: Causes rapid ,shallow breathing. Decrease in alveolar ventilation and Paco2 elevated. Potent bronchodilator.

5. C . CEREBRAL : Increased cerebral blood flow Increased temperature- malignant hyperthermia - Dantrolene is used for treatment D . NEUROMUSCULAR : Relaxes skeletal muscle and potentiates non depolarizing neuromuscular blocking agents. E . RENAL : Reduces renal blood flow, glomerular filtration rate and urinary output. F . HEPATIC : Decreases hepatic blood flow.

6. Metabolism Extent of tissue metabolism-25% Oxidizing enzyme- CYP2E1, CYP2A6 Oxidative metabolites- F3C-COOH, HBr, HCL Reducing enzyme- CYP2A6, CYP3A4 Reductive metabolites- fluoride, bromide,etc Trifluoroacetylated hepatocellular proteins formation Tissue toxicity- hepatic

7. Pathophysiology of Halothane Hepatitis Decrease in hepatic blood flow that impair hepatic oxygenation Immune mediated hepatotoxicity Most compelling evidence for an immune mediated mechanism is the presence of circulatory Ig G antibodies in 70% of patient with diagnosis of halothane hepatitis.

8. Halothane induced hepatic injury Types of Hepatotoxicity Associated with Halothane Type 1: Subclinical Hepatotoxicity Nature : Typically self-limiting and resolves without intervention. Prevalence : Occurs in approximately 20% of patients exposed to halothane. Symptoms : mild elevation of liver enzymes, nausea, lethargy, and fever.

9. Type 2: Halothane Hepatitis Nature : Irreversible and can lead to severe outcomes, including massive hepatic necrosis and potential death. Incidence : 1 in 30,000 to 40,000 patients. Predisposing Factors: Gender : Females Obesity Age : Middle-aged individuals. Preexisting Liver Disease Recent Halothane Use : Reuse of halothane within three months of prior exposure. Halothane induced hepatic injury

10. Elimination 75% by lungs 25 % metabolized by liver and excreted in the urine. Indication of Halothane Induction and maintenance Bronchial asthma Bronchospasm or laryngospasm Relaxes both skeletal and uterine muscles and can be used in obstetrics when uterine relaxation is indicated

11. CONTRAINDICATION Unexplained liver dysfunction. Hypovolemic patient with severe cardiac diseases. History of halothane induced hepatic injury. History of multiple episode of halothane exposure. Positive family history of post exposure hepatitis. Malignant hyperthermia

12. DRUG INTERACTION B-blockers and CCB TCA and MAO inhibitors Aminophylline

13. Main advantages of halothane: ‣ Rapid smooth induction . ‣ Minimal stimulation of salivary & bronchial secretion. ‣ Bronchodilation ‣ Muscle relaxant . ‣ Relatively rapid recovery

14. ISOFLURANE Physical Properties Non Flammable volatile anesthetic A pungent ethereal odor . Partial pressure Solubility MAC 240 mmHg 1.4 1.2% ‹#›

15. A. Cardiovascular M inimal left ventricular depression, Cardiac output is maintained by a rise in heart rate due to partial preservation of carotid baroreflexes. Decreases systemic vascular resistance ,lowers arterial blood pressure Dilation of normal coronary arteries, coronary “steal” phenomenon. ‹#› Effects on Organ Systems

16. Coronary steal syndrome ‣ is a phenomenon where an alteration of circulation patterns lead to a reduction in the blood directed to the coronary circulation ‣ It is caused when there is narrowing of the coronary arteries and a coronary vasodilator is used - "stealing' blood away from those parts of the heart ‣ This happens as a result of the narrowed coronary arteries being always maximally dilated to compensate for the decreased upstream blood supply. Thus, dilating the resistance vessels in the coronary circulation causes blood to be shunted away from the coronary vessels supplying the ischemic zones, creating more ischemia

17. B. Respiratory Irritates upper airway reflexes. More pronounced fall in minute ventilation. Even low levels of isoflurane (0.1 MAC) blunts the normal ventilatory response to hypoxia and hypercapnia Less bronchodilator than Halothane ‹#› Effects on Organ Systems

18. C. Cerebral Increases CBF and intracranial pressure Decrease cerebral metabolic rate of O2(CMRO2) D. Neuromuscular Isoflurane relaxes skeletal muscle. E. Renal Isoflurane decreases renal blood flow glomerular filtration rate, and urinary output ‹#› Effects on Organ Systems

19. F. Hepatic Total hepatic blood flow (hepatic artery and portal vein flow) may be reduced during isoflurane anesthesia. Hepatic oxygen supply is better maintained with isoflurane than with halothane, however because hepatic artery perfusion is preserved. Liver function tests are usually not affected. ‹#› Effects on Organ Systems

20. Biotransformation & Toxicity Isoflurane is metabolized to trifluoroacetic acid . Its limited oxidative metabolism also minimizes any possible risk of significant hepatic dysfunction. ‹#›

21. Contraindications Severe hypovolemia Malignant hyperthermia Drug Interactions Epinephrine can be safely administered in doses up to 4.5 mcg/kg. Nondepolarizing NMBAs are potentiated by isoflurane. ‹#›

22. Isoflurane Advantages and Disadvantages Advantages Rapid induction and recovery Little risk of hepatic or renal toxicity Cardiovascular stability. Muscle relaxation. Disadvantages - Pungent odor Coronary vasodilatation

23. VARIABLE BYPASS VAPORI Z ER

24. Variable bypass vaporizer (A) Basic components. Vaporizer in the off or "o" position Fresh gas from the flowmeter assembly enters the vaporizer and then flows through the bypass chamber, around the temperature compensator and out the vaporizer without passing through the vaporizing chamber. (B) Selecting a vaporizer output (turning the vaporizer "on") diverts an agent-specific ratio of gas through the pressure- compensating labyrinth, into the vaporizing chamber where it becomes saturated with anesthetic vapor, and then past the concentration cone where it reunites with the fresh gas stream.

25. The temperature compensation device further adjusts the ratio of bypass to vaporizing chamber flow, to compensate for changes in anesthetic vapor pressure resulting from temperature changes. As the liquid anesthetic cools by evaporation, more gas is diverted to the vaporizing chamber to compensate for the decrease in vapor pressure. The labyrinth compensates for pressure fluctuations within the vaporizer from the gas supply side and the breathing circuit side to stabilize vaporizer output; it is not present to compensate for changes in atmospheric pressure.

26. SEVOFLURANE Physical Properties Sevoflurane solubility in blood is slightly greater than desflurane. Non Pungency and rapid increase in alveolar anesthetic concentration make sevoflurane an excellent choice for smooth and rapid inhalation inductions. Inhalation induction with 4% to 8% sevoflurane in a 50% mixture of nitrous oxide and oxygen can be achieved within 1 min. Partial pressure Solubility MAC 160 mmHg 0.6 2% ‹#›

27. High vapor pressure: need a precision vaporizer Low Blood:gas partition coefficient (0.65) = rapid induction and recovery Good for induction with a mask or chamber. Easier to mask a patient, more pleasant smelling High controllability of depth of anesthesia Cost about 10x more than Isoflurane Eliminated by the lungs, minimal hepatic metabolism- 2-5% Can react with potassium hydroxide (KOH) or sodium hydroxide (NaOH) in desiccated CO2 absorbent to produce a chemical (Compound A) that causes renal damage SEVOFLURANE

28. Effects on Organ Systems y. A. Cardiovascular Mildly depresses myocardial contractility Systemic vascular resistance and arterial blood pressure decline slightly less than with isoflurane or desflurane Sevoflurane causes slight rise in heart rate. ‹#›

29. Effects on Organ Systems se B. Respiratory Decrease in tidal volume and an increase in respiratory rate. Decrease in alveolar ventilation that causes a rise in Paco2 Non Pungency and not airway irritation so that used as good induction agents in pediatrics ‹#›

30. Effects on Organ Systems C. Cerebral Similar to isoflurane and desflurane, sevoflurane causes slight increases in CBF and intracranial Pressure D Neuromuscular Sevoflurane produces adequate muscle relaxation for intubation of children following an inhalation induction. ‹#›

31. Effects on Organ Systems E. Renal Sevoflurane slightly decreases renal blood flow. Its metabolism to substances associated with impaired renal tubule function (eg, decreased concentrating ability) high urine output renal failure ‹#› F. Hepatic Sevoflurane decreases portal vein blood flow, but increases hepatic artery blood flow, thereby maintaining total hepatic blood flow and oxygen delivery.

32. Biotransformation & Toxicity S evoflurane metabolizes at a rate one fourth that of halothane (5% versus 20%) to inorganic fluoride but clinically significant renal dysfunction has not been associated with sevoflurane anesthesia. Barium hydroxide lime or soda lime (but not calcium hydroxide) can degrade sevoflurane, producing nephrotoxic end product ( compound A , fluoromethyl-2,2-difluoro-1-trifluoromethyl vinyl ether ). Most studies have not associated sevoflurane with any detectable postoperative impairment of renal function Accumulation of compound A increases with Increased respiratory gas temperature Low flow anesthesia Dry barium hydroxide absorbent (Baralyme) High sevoflurane concentrations Anesthetics of long duration. ‹#›

33. Contraindications Severe hypovolemia Susceptibility to malignant hyperthermia Increase of intracranial pressure Drug Interactions Like other volatile anesthetics, sevoflurane potentiates NMBAs. It does not sensitize the heart to catecholamine- induced arrhythmias. ‹#›

34. Sevoflurane Advantages Advantages 1. Well tolerated (non-irritant, sweet odor), even at high concentrations, making this the agent of choice for inhalational induction. 2. Rapid induction and recovery (low blood:gas coefficient) 3. Does not sensitize the myocardium to catecholamines as much as halothane. 4. Does not result in carbon monoxide production with dry soda lime.

35. Sevoflurane Disadvantages Disadvantages 1. Less potent than similar halogenated agents 2. Interacts with CO2absorbers. In the presence of soda lime (and more with barium lime) compound A (a vinyl ether) is produced which is toxic to the brain, liver, and kidneys 3. About 5% is metabolized and elevation of serum fluoride levels has led to concerns about the risk of renal toxicity 4. Postoperative agitation may be more common in children than seen with halothane.

36. SEVOFLURANE VAPORIZERS Sevoflurane vaporizer set to deliver 2% sevoflurane. A splitting ratio of 12:1 is required for 2% sevoflurane in a variable bypass vaporizer at 1 atm (760 mm Hg). Starting with 2000 mL/min of fresh gas flow, 1850 mL/min bypasses the vaporizing chamber, and 150 mL/min enters the vaporizing chamber, a ratio of 12:1. The 150 mL/min vaporizing chamber flow picks up 40 mL/min of sevoflurane. Total flow out of the vaporizer is now 2040 mL/min, of which 40 mL/min is sevoflurane, meaning 40/2040 or approximately 2% sevoflurane.

37. DESFLURANE Physical Properties Non flammable volatile anesthetic with pungent ether odor Boils at room temperature Vapor pressure of desflurane at 20°C is 660 mm Hg Low solubility of desflurane in blood and body tissues causes a very rapid induction and emergence of anesthesia. Partial pressure Solubility MAC 52 681 mmHg 0.42 6%

38. Effects on Organ System A. Cardiovascular Decrease vascular resistance Hypotension Increase heart rate Rapid increases in desflurane concentration lead to increase catecholamine levels cause tachycardia and hypertension ‹#›

39. B. Respiratory Decrease in tidal volume and an increase in respiratory rate. Decrease in alveolar ventilation that causes a rise in resting Paco2 Pungency and airway irritation during so that not use in induction. ‹#› Effects on Organ System

40. C. Cerebral Increases CBF and intracranial pressure Decreases cerebral metabolic rate of O2(CMRO2) D. Neuromuscular Desflurane relaxes skeletal muscle E. Renal Desflurane decreases renal blood flow, glomerular filtration rate, and urinary output ‹#› Effects on Organ System

41. F. Hepatic Total hepatic blood flow (hepatic arterial and portal vein flow) may be reduced during desflurane anesthesia. Hepatic oxygen supply is better maintained with desflurane than with halothane, however, because hepatic artery perfusion is preserved. Liver function tests are usually not affected. ‹#› Effects on Organ System

42. Biotransformation & Toxicity Desflurane undergoes minimal metabolism. Desflurane more than other volatile anesthetics is degraded by desiccated (dry) CO2 absorbent particularly barium hydroxide lime into potentially clinically significant levels of carbon monoxide. ‹#› Effects on Organ System

43. Contraindications Severe hypovolemia Malignant hyperthermia Drug Interactions Epinephrine can be safely administered in doses up to 4.5 mcg/kg as desflurane does not sensitize the myocardium to the arrhythmogenic effects of epinephrine. ‹#›

44. Problems of Desflurane

45. Desflurane’s high rate of evaporation would require excessive diluting gas (bypass chamber) flow D esflurane’s high rate of evaporation would cause substantial anesthetic cooling. D esflurane is more likely to boil. TEC 6 DESFLURANE VAPORIZER

46. TEC 6 DESFLURANE VAPORIZER

47. NITROUS OXIDE Colorless and odorless. Nonexplosive and nonflammable Nitrous oxide is a gas at room temperature It can be kept as a liquid under pressure because its critical temperature lies above room temperature Partial pressure Solubility MAC 1590 mmHg 0.65 105%

48. ‹#› EFFECT ON ORGAN SYSTEM A. Cardiovascular Stimulates the sympathetic nervous system Directly depresses myocardial contractility arterial blood pressure, cardiac output, and heart rate are essentially unchanged or slightly elevated Constriction of pulmonary vascular smooth muscle increases pulmonary vascular resistance B. Respiratory Tachypnea and decrease in tidal volume Minimal change in minute ventilation and resting arterial CO2 levels

49. ‹#› EFFECT ON ORGAN SYSTEM C. Cerebral Mild elevation of intracranial Pressure Increase cerebral blood flow increases cerebral oxygen consumption (CMRO 2 ) D. Neuromuscular Nitrous oxide does not provide significant muscle relaxation Not a triggering agent of malignant hyperthermia.

50. ‹#› E. Renal Decreases renal blood flow by increasing renal vascular resistance. This leads to drop in glomerular filtration rate and urinary output. F. Hepatic Hepatic blood flow probably falls during nitrous oxide anesthesia, but to a lesser extent than with the other volatile agents. G. Gastrointestinal Nitrous oxide in adults increases the risk of postoperative nausea and vomiting EFFECT ON ORGAN SYSTEM

51. ‹#› Side effect Prolonged exposure to anesthetic concentrations of nitrous oxide can result in bone marrow depression (megaloblastic anemia) and even neurological deficiencies (peripheral neuropathies)

52. ‹#› Contraindications 35 times more soluble than nitrogen in blood which diffuses into the cavity more rapidly than the air Arterial air embolism P neumothorax A cute intestinal obstruction with bowel distention P neumocephalus P ulmonary air cysts I ntraocular air bubbles T ympanic membrane grafting

53. ‹#› Drug Interactions Because of the high MAC of nitrous oxide, prevents its use as a complete general anesthetic, it is frequently used in combination with the more potent volatile agents ( Additive effect) Potentiates neuromuscular blockade, but than the volatile agents.

54. PROPERTIES

55. Metabolism

56. . Best inhalational agent for CARDIAC disease……… Isoflurane > Sevoflurane > Desflurane Nitrous Oxide > Halothane Best inhalational agent for NEUROsurgery ……… Sevoflurane > Isoflurane > Desflurane > Nitrous Oxide > Halothane Best inhalational agent for patients with HEPATIC disease Sevoflurane > Isoflurane > Desflurane > Nitrous Oxide > Halothane Best inhalational agent for patients with RENAL disease Desflurane> Isoflurane > > Nitrous Oxide > Sevoflurane > Halothane Best inhalational agent for DAY CARE surgery…… Desflurane > Sevoflurane > Nitrous Oxide > Isoflurane > Halothane Best inhalational agent as Induction agent …… Sevoflurane > Halothane > Isoflurane > Nitrous Oxide > Desflurane

57. MILLER’S ANAESTHESIA STOELTING’S PHARMACOLOGY AND PHYSIOLOGY IN ANAESTHETIC PRACTICE MORGAN & MIKHAIL’S CLINICAL ANAESTHESIOLOGY REFERENCES

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