Pharmacology of inhalational anesthetic agent

1. Pharmacology of inhalational anesthetic agent By Zemedu A.

2. Introduction • Is a group of drug administered via inhalation and acts on CNS • The first reports of the use of inhalation anesthetics such as ether (1846), chloroform (1847), and nitrous oxide (1844) began to emerge in the 1840s.

3. Unique Features of Inhaled Anesthetics • Speed: The inhaled anesthetics are among the most rapidly acting drugs in existence • Gas State: nitrous oxide and xenon are the only true gases; the other inhaled anesthetics are vapors of volatile liquids. • Route of Administration: delivered to blood stream via lung. • Inhaled anesthetics has the advantage of: -Controlling the depth of anesthesia. -Metabolism is very minimal. -Excreted by exhalation

4. Definition of terms • States of matter :exists in the solid, the liquid and gaseous state depending upon the temperature and pressure. • Vaporizer:-used to convert liquids into vapour • It should yield a constant concentration of anaesthetic agent • agent calibrated, flow compensated and temperature compensated

5. Definition of terms • Channeling:- is the preferential passage of exhaled gases via canister via pathways of low resistance such that bulk of the CO2 absorbent granules are bypassed. • Scavenging:- is the term applied to collection and removal of excess gases that normally exit via the overflow valve of the anaesthetic breathing.

6. Definition of terms…. • Solubility: a property of a solid, liquid or gaseous chemical substance to dissolve in a solid, liquid or gaseous solvent. • Solubility coefficient: a measure of distribution of an agent between two compartments (blood-gas, oil-gas, blood-tissue), the same as partition coefficient. • Boiling point: the temperature at which the vapor pressure of a liquid equals the pressure surrounding the liquid and the liquid changes into vapor.

7. Solubility coefficient

8. Definition of terms…. • Molecular weight (relative molecular mass) : is the sum of the atomic weights of each constituent element multiplied by the number of atoms of that element in the molecular formula.

9. Co2 absorbent • Sodalime canister: are constructed of metal or plastic and contain granules of soda-lime • Elimination of CO2 requires specified size granules, consistency and degree of hydration. Too large granules has less surface area and too small granules has resistant to gas flow. • About 14-19% of soda lime granules contain water molecule since neutralization of CO2 requires moisturization. • Soda lime and Barlime are common CO2 absorber in clinical use.

10. Chemistry of co2 absorbent • Soda lime:- A mixture of 80% Ca (OH)2, H2O 15% , 5 % NaOH, <0.1 % KOH with silicates to prevent powdering . • The hydroxides combine with CO2 in the presence of water to form carbonates. The reaction is….. CO2+ H2O → H2CO3 H2CO3+ NaOH → Na2CO3 (rapid) + 2H2O +heat H2CO3+ Ca (OH)2 CaCO3 (slow) 2H2O + Heat

11. Signs of exhaustion of Soda-lime • Change of colour of granules and coldness of the canister • Rise in measured ETCO2 on the capnography • Clinically-rise in B/P followed by a fall, ↑ HR • Increased oozing of blood from wound and perhaps sweating

12. Chemical structure

13. The main target of inhalation anesthetics is the________? ? OR

14. Pharmacokinetics of inhalational agent

15. Pharmacokinetics of inhalational agent………. • The goal of delivering inhaled anesthetics is to produce the anesthetic state by establishing a specific concentration (partial pressure) in the central nervous system (CNS). • This is achieved by establishing the desired partial pressure in the lungs that ultimately equilibrates with the brain and spinal cord. • At equilibrium, the CNS partial pressure equals the blood partial pressure, which equals alveolar partial pressure. • Uptake and removal of inhalation agents from the body depends on the alveolar concentration of the anesthetic agent (FA) and its uptake from the alveoli by the pulmonary circulation.

16. Alveolar concentration of the inhalation agent • The alveolar concentration of anesthetic agent depends on three factors -Inspired concentration of agent -Alveolar ventilation -Functional residual capacity

17. Inspired concentration of agent • The concentration of inhaled anesthetic affects the rate of increase of the alveolar concentration (FA) towards the inspired concentration (Fi). • The greater the inspired concentration, the more rapid the increase in the FA/Fi ratio, and the faster the induction of anesthesia. • Inspired concentration is affected by Fresh gas flow rate (mainly), Volume of breathing circuit and Absorption by machine / circuit • Higher fresh gas flow(mainly), lower breathing system volume, and lower circuit absorption leads to higher inspired gas concentration and faster induction and emergence from anesthesia.

18. Alveolar ventilation • Increased alveolar ventilation results in faster increase in alveolar partial pressure by constantly replacing the inhalation agent taken up by the pulmonary blood flow. • The alveolar partial pressure is important because it determines the partial pressure of anesthetic in the blood and, ultimately, in the brain. • Similarly, the partial pressure of the anesthetic in the brain is directly proportional to its brain tissue concentration, which determines clinical effect.

19. Functional residual capacity (FRC) • A larger FRC dilutes theinspired concentration of gas resulting initially in a lower alveolarpartial pressure and therefore slower onset of anesthesia. • Alveolar concentration of inhaled agent is determined mainly by: • Uptake • Ventilation • Concentration

21. Factors affecting alveolar concentration (FA) Tissue Uptake • " Vessel-rich groups" • brain / heart / liver / kidney / endocrine organs" • 1st to take up & 1st to fill (limited capacity)! • " Muscle group" • slower uptake (less well perfused)" • greater capacity (larger vol) - so uptake lasts hrs! • " Fat group" • perfusion similar to muscle group" • much higher gas sol in fat, so huge total capacity! • " Vessel-poor group" • insignificant uptake" • bone / ligaments / teeth / hair / cartilage!

22. Factor affecting transfer of anesthetic from blood to tissues • The transfer of anesthetic from blood to tissues is determined by three factors analogous to systemic uptake: • Tissue solubility of the agent (tissue/blood partition coefficient) • Tissue blood flow • The difference in partial pressure between arterial blood and the tissue.

24. Factors affecting alveolar concentration (FA) : Ventilation • The lowering of alveolar partial pressure can be countered by increase alveolar ventilation. • The effect of increase ventilation will be most obvious for soluble anesthetics, since they are more subject to uptake.

25. Factors that increase or decrease the rate of increase of FA/FI determine the speed of induction of anesthesia • Metabolism plays little role in opposing induction but may have some significance in determining the rate of recovery.

26. Factors That Increase or Decrease the Rate of Increase of Alveolar Anesthetic Concentration (FA)/Inspired Anesthetic Concentration (FI)

27. Over-pressurization and Concentration Effect • Over-pressurization (delivering a higher FI than the FA actually desired for the patient) can speeds the induction of anesthesia. • Concentration effect (the greater the FI of an inhaled anesthetic, the more rapid the rate of increase of the FA/FI) is a method used to speed the induction of anesthesia.

28. Second gas effect • Second gas effect: A special case of the concentration effect is administration of two gases simultaneously (nitrous oxide and a potent volatile anesthetic) in which the high volume uptake of nitrous oxide increases the FA (concentrates) of the volatile anesthetic.

30. Perfusion Effects (effects of perfusion on rate of induction and rise in FA/FI) • As with ventilation, cardiac output does not greatly affect the rate of increase of the FA/FI for poorly soluble anesthetics. • Cardiovascular depression caused by a high FI results in depression of anesthetic uptake from the lungs and increases the rate of increase of FA/FI (positive feedback that may result in profound cardiovascular depression).

31. Exhalation /Recovery and diffusion hypoxia • Recovery from anesthesia, similar to induction of anesthesia, depends on the drug's solubility (primary determinant of the rate of decrease in FA), ventilation, and cardiac output. • The “reservoir” of anesthetic in the body at the conclusion of anesthesia is determined by the solubility of the inhaled anesthetic and the dose and duration of the drug's administration (can slow the rate of decrease in the FA).

32. Diffusion hypoxia: an abrupt transient decrease in alveolar oxygen tension when room air is inhaled at the conclusion of nitrous oxide anesthesia, because nitrous oxide is diffusing out of the blood and dilutes alveolar oxygen.

33. Factors affecting elimination. • Biotransformation – minimal • (2-5%-sevoflurane, 0.02% -desflurane, 0.2-isoflurane, 2.4% -enflurane and 20% halothane) • Transcutaneous loss - insignificant • Exhalation – factors that speed induction also speed recovery

34. Pharmacodynamics Theories of Action • The mechanisms of action of inhalation anesthetics may be sub classified as macroscopic (brain and spinal cord), microscopic (synapses and axons), and molecular (pre- and post-synaptic membranes) • Unitary hypothesis theory

35. Macroscopic • At the spinal cord level, inhalation anaestheticsdecrease transmission of noxious afferent information ascending from the spinal cord to the cerebral cortex via the thalamus, thereby decreasing supraspinalarousal. • 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.

36. Synaptic (microscopic) • The actions of inhalation agents on ion channels of neuronal tissue can influence either the presynaptic release of neurotransmitters, alter the post-synaptic response threshold to neurotransmitters, or both. • Inhaled anesthetics 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.

37. Molecular • Recent evidence suggests that the interaction of general anaestheticsis dependent on precise molecular interactions with certain anaesthetictargets within the central nervous system (CNS). • Effects of inhalation agents on a-subunits of the GABA-a transmembranereceptor complex are likely to be important.

38. GABA binding to its receptor leads to opening of a chloride channel leading to increased Cl-2ion conductance and hyperpolarization of the cell membranethereby increasing the depolarization threshold. • Inhalation anesthetics prolong the GABAA receptor-mediated inhibitory Cl2 current, thereby inhibiting post-synaptic neuronal excitability.

39. Unitary hypothesis (unitary theory of narcosis) = all inhalational agents share a common mechanism action at molecular level – supported by Meyer-Overton rule. • Meyer-Overton rule = anesthetic potency of inhalational anesthetics correlates directly with lipid solubility.

40. MOA… • However, during the past few decades it has been confirmed that actions on protein receptors (e.g. ligand gated ion channels) are responsible for many of the effects of inhaled anaestheticagents. • Potentiation at GABA receptors by volatile anaesthetics and inhibition at N-methyl-D-aspartate (NMDA) receptors by the anesthetic gases N2O and xenon are likely to be important mechanisms of action. • Increasing experimental evidence on the role of two-pore domain potassium channels mediating the effects of inhalation anaesthetics has recently been reported.

41. The effect of IAA on CNS depends on • Solubility of the agent • The potency of the agent • The time for which the agents acts on the cell

42. 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) • Alveolar concentration represents brain concentration after a short period of equilibration

43. MAC value is a measure of inhalational anesthetic potency. • The minimum alveolar concentration of inhalational anesthetic agent is the concentration that prevents movement in response to skin incision in 50% of (unpremedicated animals) subjects studied at sea level (1 atmosphere), in 100% oxygen. Hence, it is inversely related to potency. • MAC values are additive and lower in the presence of opioids. • ≈1.3 MAC prevents movement in 95%. • 0.3-0.4 MAC associated with wakening • Other MAC? • MAC awake (0.1*MAC) • MAC recall (0.3-0.5*MAC) • MAC bar (1.8-2*MAC)

45. Factor affecting MAC Increased MAC Decreased MAC

46. No change on MAC

48. Summary of IAA physical properties

49. Properties of ideal anesthetic agent Physical properties 1. Non-flammable, non-explosive at room temperature2. Stable in light.3. Liquid and vaporizable at room temperature i.e. low latent heat of vaporisation.4. Stable at room temperature, with a long shelf life 5. Stable with soda lime, as well as plastics and metals6. Environmentally friendly - no ozone depletion 7. Cheap and easy to manufacture 

50. Biological properties 1. Pleasant to inhale, non-irritant, induces bronchodilatation2. Low blood:gas solubility - i.e. fast onset3. High oil:water solubility - i.e. high potency4. Minimal effects on other systems - e.g. cardiovascular, respiratory, hepatic, renal or endocrine5. No biotransformation - should be excreted ideally via the lungs, unchanged6. Non-toxic to operating theatre personnel