All about Inhalation agent part FULL.pptx

About Inhalation agent .. history.. chemical properties,, factors,, side effects

1. Inhalation anesthetic agents by Dr. Alauddin ab alroub

2. Introduction: IV anesthesia : MAINLY to induce anesthesia Inhalation anesthesia : MAINLY to maintain anesthesia IV anesthesia : mg/KG or microgram/Kg Inhalation anesthesia : Percentage of the volume % EXAMPLE: 2 L/min. 02 + 4 L/min N20 Conc. Of N20 = 4/(2+4) = 66%

3. History of anesthesia

4. History of anesthesia Diethyl ether first used by William T.G. Morton in the USA in 1846 Chloroform was the next agent to receive attention, by James Simpson in 1847 it was discontinued due to:- severe cardiovascular depression (sudden death? VF) dose dependent hepatotoxicity Cyclopropane was discovered accidentally in 1929 and was very popular for almost 30 yrs increasing use of electronic equipment necessitated the discontinuation of this inflammable agent.

5. History of anesthesia Halothane , synthesized in 1951 by prominent British chemist, Charles Walter Suckling, while working at the Imperial Chemical Industries (ICI). Later in 1956, M. Johnstone used it clinically first time  Enflurane has been in use since 1970  Isoflurane -(1981), Desflurane -1996

6. a variety of other agents were investigated but discarded for various reasons A. Explosive mixtures with oxygen - diethyl ether ethyl chloride divinyl ether cyclopropane B. P ostoperative liver necrosis / sudden death: chloroform C.  P ostoperative renal failure: methoxyflurane History of anesthesia

7. The basic concepts

8. Mac definition Minimal alveolar concentration (MAC): Is defined as the conc. At 1 atmosphere of anesthetic in the alveoli that is required to produce immobility in 50% of adults patient subjected to a surgical incision. MAC is important to compare the potencies of various inhalational anesthetic agents. 1.2 -1.3 MAC prevent movement in 95% of patients

9. Mac value N20 = 105%  Halothane = 0.75%  Isoflurane = 1.16%  Euflurane = 1.68%  Sevoflurane = 2%  Desflurane = 6% N2O alone is unable to produce adequate anesthesia (require high conc)

10. Factors that alter anesthetic requirements (MAC): Hyperthermia Chronic drug abuse (ethanol) Acute use of amphetamines hyperthyroidism?? Increasing Age hypothermia Other anesthetic (opioids) Acute drug intoxication (ethanol) Pregnancy Other drugs ( clonidine ‚reserpine) Hypothyroidism ??

11. No effect on mac Gender Duration of anesthesia Carbon dioxide tension (21-95 mmHg) Metabolic Acid base status Hypertension Hyperkalemia Surgeons ??!!

12. Factors affecting mac

13. Vapour Pressure & Boiling point Pressure exerted by the molecules of the vapor phase at/ equilibrium of molecules moving in and out of liquid phase at given temprature. Vapor Pressure dependent on temperature and physical characteristics of liquid, independent of atmospheric pressure Increase Temperature —> increase Vapor Pressure . Vapor pressure is a measure of the agent's ability to evaporate (volatility) .The greater is the vapor pressure, the greater the concentration of inhalant deliverable to the patient (and environment). Boiling Point: Temperature at which vapor pressure equals atmospheric pressure

14. Vapour Pressure & BP

15. Pathway O2-brain

16. Pathway O2-brain

17. Pharmacokinetics of inhalational agents Divided into four phases: Uptake Metabolism (minimal) Distribution (to CNS = site of action) Elimination Goal : to produce partial pressure of gas in the alveolus that will equilibrate with CNS to render anesthesia

18. Uptake & distribution of inhalation agents 1. Transfer from Inspired Air to Alveoli: inspired gas concentration FI alveolar ventilation VA characteristics of the anesthetic circuit 2. Transfer from Alveoli to Arterial Blood: blood:gas partition coefficient T B:G cardiac output CO alveoli to venous pressure difference dPA-vGas 3. Transfer from Arterial Blood to Tissues: tissue:blood partition coefficient T T:B tissue blood flow Arterial to tissue pressure difference dPa-tGas

19. Uptake & distribution of inhalation agents Alveolar ventilation Cl cardiac output MAC Blood gas partition co- efficient Concentration effect Second gas effect Diffusion hypoxia

20. PARTIAL PRESSURE : The partial pressure of a gas is a measure of thermodynamic activity of the gas's  molecules . Gases dissolve, diffuse, and react according to their partial pressures but not according to their  concentrations  in gas mixtures or liquids, so it all about Yields effect, not concentration At higher altitudes where P atm  < 760 mmHg, the same concentration of inhalation agent will exert a lower partial pressure within alveolus and therefore a REDUCED anesthetic effect At  equilibrium  the following applies P CNS =P arterial blood =P alveoli

21. FI (inspired concentration): Determined by fresh gas flows, volume of breathing system, and absorption by machine/circuit ↑ fresh gas flow, and ↓ circuit absorption allow actual Fi to be close to delivered Fi  FA (alveolar concentration): Determined by uptake, alveolar ventilation, and concentration/second gas effects PA (alveolar partial pressure) is determined by input (delivery) minus uptake (loss)

22. Uptake : Uptake is defined as gas taken up by the pulmonary circulation.  Affected by blood solubility, alveolar blood flow (i.e. cardiac output), alveolar-to-venous partial pressure difference ↓ blood solubility, ↓ CO, ↓ alveolar-venous partial pressure difference → ↓ uptake ↓ uptake → ↑ FA/FI → faster induction Highly soluble gases = more gas required to saturate blood before it is taken up by CNS High CO = equivalent to a larger tank; have to fill the tank before taken up by CNS Rate of rise in FA/FI ratio is a marker of anesthetic uptake by the blood. More uptake means slower rise of FA/FI Gases with the lowest solubilities in blood (eg. Desflurane) will have fastest rise in FA/FI

23. Alveolar Blood Flow: In the absence of any shunt, alveolar blood flow = cardiac output Poorly soluble gases are less affected by CO (so little is taken up into blood) Low cardiac output states predispose patients to overdose of inhalational agents as Fa/Fi will be faster (esp. for soluble gases)

24. Shunt States: Right to Left Shunt (intracardiac or transpulmonary, i.e. mainstem intubation) increases alveolar partial pressure, decreases arteriolar partial pressure; dilution from non-ventilated alveoli → slows onset of induction will have more significant delay in onset of poorly soluble agents IV anesthetics = faster onset (if bypassing lungs, quicker to CNS) Left to Right Shunt Little effect on speed of induction for IV or inhalation anesthetics

25. Concentration effect : ↑ FI not only ↑ FA , but also ↑ rate at which FA approaches FI Second Gas Effect : concentration effect of one gas augments another gas (questionably clinically relevant with nitrous both during induction and emergence) rapid intake of nitrous into blood → ↑ relative concentration of second gas

26. 1. Transfer from inspired air to alveoli A) Inspired Gas Concentration FI: according to Dalton's law of partial pressures, the tension of an individual gas in inspired air is equal to,  P Igas = F Igas X Atm the greater the inspired pressure the greater the approach of FA to FI = the concentration effect this is only significant where FI is very high, as is the case for N20 (or cyclopropane) when another gas is used in the presence of such an agent, there is increased uptake of the second gas, the second gas effect

27. B)Alveolar Ventilation each inspiration delivers some anesthetic to the lung and, if unopposed by uptake into the blood, normal ventilation would increase FA/FI to 95-98% in 2 minutes this rate of rise is dependent upon minute ventilation and Functional Residual Capacity (FRC). the greater the FRC, the slower the rise in FA hyperventilation will decrease Cerebral Blood Flow (CBF), and this tends to offset the increased rise of FA/FI

28. 2 . Transfer from alveoli to arterial blood A) Blood: Gas Partition Coefficient: the solubility of a gas in liquid is given by its Ostwald solubility coefficient, T this represents the ratio of the concentration in blood to the concentration in the gas phase  lower B:G coefficients are seen with , haemodilution ,obesity , hypoalbuminaemia and starvation  higher coefficients are seen in , adults versus children, hypothermia & postprandially

29. Solubility of inhaled drug

30. Solubility of inhaled drug

31. Solubility of inhaled drug

32. B)Cardiac Output CO:- Effective pulmonary blood flow determines the rate at which agents pass from gas to blood an increase in flow will slow the initial portion of the arterial tension/time curve by delaying the approach of FA to FI A low CO state, conversely, will speed the rise of FA/FI these effects are greater for highly soluble agents

33. C) Alveoli to Venous Pressure Difference:- this represents tissue uptake of the inhaled agent blood cannot approach equilibrium with alveolar air until the distribution of anesthetic from the blood to the tissues is nearly complete with equilibration, the alveolar/mixed venous tension difference progressively falls as tissue tensions rises since diffusion is directly proportional to the tension difference, the rate of diffusion into the blood progressively slows

34. 3. Transfer from arterial blood to brain & tissues A) Tissue: Blood Partition Coefficient:- the rate of rise of tension in these regions is proportional to the arterial-tissue tension difference conversely, their solubility in lipid tissues is far greater than that for blood at equilibrium the concentration in lipid tissues will be far greater than that in blood the tissue concentration will rise above that of blood well before pressure equilibrium, even though the tissue tension is lower

35. Fat:Blood coefficient at 37°C Methoxyflurane- 61 Halothane- 62 Enflurane -36 Isoflurane- 52 Sevoflurane -55 Desflurane - 30 Nitrous Oxide- 2.3

36. B) Tissue Blood Flow: the higher the blood flow to a region, the faster the delivery of anesthetic and the more rapid will be equilibration. The body tissues have been divided into groups according to their level of perfusion and tissue blood flow.

37. Vessel rich group VRG - brain, heart, kidney & liver The muscle group MG – muscle & skin The fat group FG – large capacity/minimal flow. Vessel poor group VPG - bone, cartilage, СТ

38. C) Arterial-Tissue Pressure Difference: with equilibration tissue tension rises and the rate of diffusion slows, as does uptake in the lung. The rate is determined by the tissue time constant, which in turn depends upon both the tissue capacity ( T T :B) and the tissue blood flow.

39. Other Factors Affecting Uptake & Distribution:- Concentration and Second Gas Effects increasing the inspired concentration not only increases the alveolar conc but also increases the rate of rise of volatile anesthetic agents in the alveoli eg., during the inhalation of 75% N20/02, initially as much as 1 I/min may diffuse into the bloodstream across the lungs, this effectively draws more gas into the lungs from the anesthetic circuit, thereby increasing the effective minute ventilation

40. this effect is also important where there is a second gas, such as 1% halothane, in the inspired mixture the removal of a large volume of N20 from the alveolar air increases the delivery of the second gas, effectively increasing its delivery to the alveoli and increasing its diffusion into arterial blood K/A Second Gas Effect

41. Example : Blood:gas partition coefficient of nitrous = 0.47 = at steady state 1ml of blood contains 0.47 as much nitrous oxide as does 1 ml of alveolar gas. In other words, at steady state if your fraction inspired gas is 50% N2O then 1ml of blood will contain 0.47x0.5 ml’s of N2O or 0.235 ml. Fat:blood partition coefficient is >1. Therefore, things that increase fat in the blood (e.g. postprandial lipidemia will increase the overall blood:gas partition coefficient → slows induction

42. Important tips Factors that increase the rate of rise of FA/FI Relatively  low  blood:gas partition coefficient (solubility) for the anesthetic Low  cardiac output (affects soluble gasses more) High  minute ventilation Low  (Parterial – Pvenous), meaning less blood uptake Increase in cardiac output would decrease rate of rise in FA/FI for relatively soluble inhaled anesthetics, (*but would NOT produce much effect for insoluble agents.) Shunts on the other hand, typically affect insoluble agents more than soluble agents Which of the following is true about Fa/Fi when cardiac output is doubled? A. increasing cardiac output has no significant effect on anesthetic uptake. B. Fa/Fi ratio rises faster for soluble agents than insoluble agents. C. Fa/Fi ratio rises slower for soluble agents than insoluble agents. D. the rate of rise is the same for insoluble and soluble agents.

43. CHARACTERISTICS OF AN IDEAL ANESTHETIC Rapid and pleasant induction Rapid changes in the depth of anesthesia Adequate muscle relaxation Wide margin of safety Absence of toxic/adverse effects No single agent yet identified is an ideal anesthetic

44. See you tomorrow in part 2

45. INHALATIONAL ANAESTHETIC AGENTS classification: 1- Gas: Nitrous oxide 2. Volatile Liquids : Ether Halothane Enflurane Isoflurane Desflurane Sevoflurane

46. Nitrous oxide N2O

47. Nitrous oxide N2O  Physical property : laughing Not flammable Odorless Colorless Tasteless

48. Nitrous oxide N2O  PHARMACOLOGY: Good Analgesic Weak anesthetic Excreted via lungs MAC = 105% Lower water solubility Not Metabolized in the body Blood:Gas partition coefficient 0.47

49. Nitrous oxide (N2O) SIDE EFFECTS: Diffusion Hypoxia. Effects on closed gas spaces. (nitrous oxide can diffuse 20 times faster into closed spaces than it can be removed, resulting in expansion of pneumothorax, bowel gas, or air embolism or in an increase in pressure within noncompliant cavities such as the cranium or middle ear. CVS depression Toxicity Teratogenic

50. Nitrous oxide (n2o) diffusion hypoxia What is diffusion hypoxia? Diffusion hypoxia is a decrease in PO2, usually observed as the patient is emerging from an inhalational anesthetic where nitrous oxide (NO2) was a component. The rapid outpouring of insoluble NO2 can displace alveolar oxygen, resulting in hypoxia . All patients should receive supplemental O2, at the end of an anesthetic & during the immediate recovery period.

51. Second gas effect : The ability of the large volume uptake of one gas (first gas) to accelerate the rate of rise of the alveolar partial pressure of a concurrently administered companion gas (second gas) is known as the second gas effect. Nitrous oxide (n2o) second gas effect

52. Ether

53. Ether  Properties: Colorless, highly volatile, pungent odor , flammable, explosive, stored in cool area. Solubility 12; MAC 2-3% Blood:Gas partition coefficient 12

54.  Pharmacodynamics: Lungs : Stimulates respiration, increases secretion, not good in respiratory diseases  Kidney : decreases urine output  Liver : Minimum effect, decreases liver glycogen  Heart : Initially increases cardiac output, then decreases card. output, suppresses vasomotor center.

55. Advantage : CNS depression, excellent muscle relaxant , causes surgical anesthesia  Disadvantage : Flammable, irritates mucus membrane , breath holding, induces nausea & vomiting  Contraindications : Respiratory, kidney and liver diseases  Better agents are available now, so not used now.

56. Halothane

57. Halothane: (2-bromo-2-chloro-1,1,1-trifloroethane) Synthesized in 1951. Most potent inhalational anesthetic MAC of 0.75% Blood:Gas partition coefficient 2.3

58. Chemical and Physical Properties: Halogenated compound chemically: 2-bromo-2-chloro-1, 1,1-tri fluoro ethane Volatile, so kept in sealed bottles Colorless, Pleasant odor , Non-irritant Non-explosive, Non-inflammable Light-sensitive Corrosive, Interaction - rubber and plastic tubing

59. Pharmacokinetics : Solubility in blood This is determined by a physical property of the anesthetic called the : blood/gas partition coefficient: when the anesthetic is in equilibrium between the two phases.

60. Potency Potency is defined (determined) quantitatively as the minimum alveolar concentration (MAC). Numerically, MAC is small for potent anesthetics such as Halothane and large for less potent agents such as nitrous oxide.

61. Therapeutic uses:  Halothane is a potent anesthetic but a relatively weak analgesic. Thus, it is usually coadministered with nitrous oxide, opioids, or local anesthetics. It is a potent bronchodilator . Halothane relaxes both skeletal and uterine muscles and can be used in obstetrics when uterine relaxation is indicated. Halothane is not hepatotoxic in children (unlike its potential effect on adults). Combined with its pleasant odor , it is suitable in pediatrics for inhalation induction, although sevoflurane is now the agent of choice.

62. Mechanism of Action: No specific receptor has been identified as the locus of general anesthetic action -generally-. It appears that a variety of molecular mechanisms may contribute to the activity of general anesthetics.  Halothane activates GABA, , glycine receptors, 5-HT and twin-pore K+channels . It antagonizes NMDA receptor . It inhibits nACh (block excitatory postsynaptic currents of nicotinic receptors) and voltage-gated sodium channels. At clinically effective concentrations, general anesthetics increase the sensitivity of the v-aminobutyric acid (GABA-A) receptors to the inhibitory neurotransmitter GABA. This increases chloride ion influx and cause Hyperpolarization —> Decrease Excitability —> CNS Depression

63. Metabolism 20% metabolized in liver by oxidative pathways. Major metabolites: bromine, chlorine, Tri-floro-acetic acid, Tri-floro-acetyl-ethanl amide

64. Dosage, Administration and supply: The induction dose varies from patient to patient. The maintenance dose varies from 0.5 to 1.5%. Halothane may be administered with either oxygen or a mixture of oxygen and nitrous oxide.

65. Indications: Halothane is indicated for the induction and maintenance of general anesthesia.  Contraindications : Halothane is not recommended for obstetrical anesthesia except when uterine relaxation is required.

66. Effect on systems Respiratory system: Halothane anesthesia progressively depresses respiration. Its cause inhibition of salivary & bronchial secretion. Its may cause tachypnea & reduce in tidal volume and alveolar ventilation. Its cause decrease in mucocillary function which lead to sputum retention. It causes bronchodilation, Hypoxia, acidosis, or apnea may develop during deep anesthesia.

67. Cardiovascular system: Halothane anesthesia reduces the blood pressure, and cause bradycardia. (atropin may reverse bradycardia.). It cause myocardial relaxation & Hypotension. Its also causes dilation of the vessels of the skin and skeletal muscles Halothane maybe advantages In pts with CAD , because of decrease of oxygen demand. Arrhythmias are very common (especially with epinephrine). To minimize effects :  * Avoid hypoxemia and hypercapnia  * Avoid conc. Of adrenaline higher than 1 in 10000 Effect on systems

68. GI tract: Inhibition of gastrointestinal motility. Cause sever post. Operative nausea & vomiting Uterus: Halothane relaxes uterine muscle , may cause postpartum hemorrhage. Concentration of less than 0.5 % associated with increase blood loss during therapeutic abortion. Skeletal muscle: Its cause skeletal muscle relaxation . Postoperatively, shivering is common, this increase oxygen requirement>>> which cause hypoxemia Effect on systems

69. Hepatic dysfunction: Two type of dysfunction: 1- Type I hepatotoxicity : mild, associated with derangement in liver function test, this result from metabolic of Halothane in liver. Results from reductive (anaerobic) biotransformation of halothane rather than the normal oxidative pathway. 2- Type II hepatotoxicity : fulminate (uncommon); sever jaundice fever, progressing to fulminating hepatic necrosis, Its increased by repeated exposure of the drugs. high mortality 30-70% Effect on systems

70. Recommendation for halothane anesthesia 1- A careful anesthetic history. 2- repeated exposure of halothane within 3 months should be avoided. 3- History of unexplained jaundice or pyrexia after previous exposure of halothane.

71. Main advantages of halothane: Rapid smooth induction. Minimal stimulation of salivary & bronchial secretion. Bronchodilatation. Muscle relaxant. Relatively rapid recovery. Main disadvantages are: Poor analgesia. Arrhythmias. Post operatively shivering. Possibility of liver toxicity.

72. Enflurane MAC =1.68% Blood:Gas partition coefficient 1.9  Potent cardiovascular depressant 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 .

73. Isoflurane Properties isomer of enflurane. Carcinogenic (not approved) colorless, volatile, liquid, pungent odor . stable. No preservative Non-flammable. MAC = 1.2% Blood:Gas partition coefficient 1.4

74. Least soluble of the modern inhalational agent - equilibrate more rapidly Induction rapid theoretically (pungency??) pungency -> cough, breath holding.

75. effects on systems Respiratory: dose dependent depression of ventilation. CVS: Myocardial depressant (vitro Vs Clinical), Coronary vasodilatation (coronary steal-syndrome). Uterus: Relaxation of uterine muscles (same.) CNS: low concentration Vs High concentration. "Low : no change on the flow. "High: increase blood flow by vasodilatation of the cerebral arteries. Muscles: Relaxation (dose-dependent).

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

77. Sevoflurane Properties: New drug. Non flammable. Pleasant smell.  MAC 2%. Stable.  Blood:Gas partition coefficient 0.63 which is low —> faster equilibrium.  non irritant —> so the fastest for induction.

78. effects on systems Respiratory: non-irritant, depression.  CVS: Myocardial depressant (vitro Vs Clinical), Coronary vasodilatation (coronary steal-syndrome). same as isoflurane (slightly lower effect) CNS: low concentration Vs High concentration. "Low : no change on the flow. "High: increase blood flow by vasodilatation of the cerebral arteries. same as halothane and isoflurane.  Muscle relaxation: Relaxation (dose-dependent). same as isoflurane.

79. Advantages and Disadvantages Advantages : Well tolerated (non-irritant, sweet odor), even at high concentrations, making this the agent of choice for. inhalational induction) Rapid induction and recovery (low blood: gas coefficient. Does not sensitize the myocardium to catecholamines as much as halothane Does not result in carbon monoxide production with dry soda lime Disadvantages : Less potent than similar halogenated agents. Interacts with CO2 absorbers. 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 About 5% is metabolized and elevation of serum fluoride levels has led to concerns about the risk of renal toxicity Postoperative agitation may be more common in children than seen with halothane

80. Desflurane  MAC = 6.6% Blood:Gas partition coefficient 0.45 desflurane would boil at normal operating room temperatures A new vaporizer technology addressed this property. Solubility characteristics (blood: gas partition coefficient 0.45) and potency (MAC 6.6%) permit rapid achievement of an alveolar partial pressure necessary for anesthesia followed by prompt awakening when desflurane is discontinued. Pungent odor --desflurane less likely to be used for inhalation induction compared to halothane or sevoflurane. Airway irritation, breath-holding, coughing, laryngospasm,significant salivation, when >6% desflurane administered to an awake patient. Produces the highest carbon monoxide concentrations, followed by enflurane and isoflurane

81. effects on systems  CNS: Generalized depression Extremely rapid emergence Increased ICP  Cardiovascular: Vascular resistance decreased Heart rate (deep anesthesia); tachycardia with rapid concentration change  Pulmonary : decrease tidal volume increase respiratory rate irritant

82. Dual-circuit gas-vapour blender It was created specifically for the agent desflurane. Desflurane boils at 23.5 °C, which is very close to room temperature. This means that at normal operating temperatures, the saturated vapour pressure of desflurane changes greatly with only small fluctuations in temperature. A desflurane vaporizer (e.g. the TEC 6 produced by Datex-Ohmeda) is heated to 39C and pressurized to 200kPa

83. Agent of choice for day care (fastest induction) Agent of choice for geriatric (old) patients. Agent of choice for hepatic failure Agent of choice for renal failure

84. Summary

85. Referencies

86. Thank you