|Year : 2018 | Volume
| Issue : 3 | Page : 173-177
Inhalational anesthetics agents: The pharmacokinetic, pharmacodynamics, and their effects on human body
Negin Kassiri1, Seyed Hossein Ardehali2, Farzad Rashidi3, Seyed MohammadReza Hashemian1
1 Anesthesiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Anesthesiology and Critical Care, Shohadaye-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Monash Medical Centre, Melbourne, Australia
|Date of Web Publication||6-Sep-2018|
Dr. Seyed MohammadReza Hashemian
Anesthesiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
In this review article, inhalational anesthetics agents and their pharmacokinetic, pharmacodynamics and effects on the central nervous, cardiovascular, and respiratory systems are discussed. There is a wide spectrum of inhalational anesthetic agents with different characteristics. As some examples, in this study, recovery times of sevoflurane and halothane are reviewed. Overall, gas drugs have extensive usage in Intensive Care Unit. For example, a combination of oxygen and helium may be utilized in patients with obstructive airway disorders, endotracheal tubes, acute lung damage, diphtheria, respiratory distress syndrome, asthma, bronchiolitis, and chronic obstructive pulmonary disease. Xenon would be effective in reducing memories after traumatic events.
Keywords: Halothane, inhalational anesthetic, propofol, sevoflurane, xenon
|How to cite this article:|
Kassiri N, Ardehali SH, Rashidi F, Hashemian SM. Inhalational anesthetics agents: The pharmacokinetic, pharmacodynamics, and their effects on human body. Biomed Biotechnol Res J 2018;2:173-7
|How to cite this URL:|
Kassiri N, Ardehali SH, Rashidi F, Hashemian SM. Inhalational anesthetics agents: The pharmacokinetic, pharmacodynamics, and their effects on human body. Biomed Biotechnol Res J [serial online] 2018 [cited 2019 Sep 22];2:173-7. Available from: http://www.bmbtrj.org/text.asp?2018/2/3/173/240704
| Introduction|| |
Inhalational anesthetics agents have been used for surgical anesthesia and analgesia. In 1954, Charles Suckling presented the first modern halogenated inhalational anesthetics agent, halothane. Then, other halogenated inhalational anesthetic agents, including enflurane and isoflurane, were performed. Sevoflurane and desflurane are the most recent contributors of halogenated inhalational agents.,
| Pharmacokinetics|| |
By inhalation of anesthetics agents, they reach the alveoli and quickly pass through the alveolar membrane. Then, the bloodstream transfers the agents to all perfused organs. For an anesthetic agent, the blood gas partition coefficient and the relative solubility determine the rate of increase in alveolar concentration (end-tidal) toward inspired concentrations., Poorly soluble inhalational agents that have low blood–gas partition coefficients (e.g., sevoflurane) have more anesthetical effectiveness compared to high-soluble anesthetic agents with high blood–gas partition coefficients (e.g., halothane)., The chemical structures of sevoflurane and halothane are represented in [Figure 1]a and [Figure 1]b, respectively. Other elements that affect the level at which equilibrium is setup are as follow: (a) hyperventilation that reduce the required time for equilibrium setup, (b) high cardiac output that heighten the required time, and (c) high rates of uptake by various tissues that can heighten the time for setup the equilibrium between gas and blood.
|Figure 1: Chemical structures of (a) sevofluran, (b) halothane and (c) propofol|
Click here to view
For different agents including therapeutic or toxic agents, several factors can determine the rate of the uptake to a particular tissue.,,,,,, The factors include partial pressure difference between artery and tissues, the tissue–blood solubility coefficient, volume of tissues, and blood perfusion. In brain, heart, and kidney tissues that have high blood flow, concentrations of the agents equilibrate with their blood concentrations within hours. Some tissues such as fat have a low blood flow. Therefore, in such tissues, concentrations of the agents require several days to equilibrated with the blood concentrations.,,,,,,
Inhalational anesthetics agents are essentially eradicated through the respiratory system. Nevertheless, all inhalational anesthetics may be metabolized in different rates. About 15%–20%, 5%, and 0.2% of inhaled halothane, sevoflurane, and isoflurane  are metabolized, respectively. Modern inhalational anesthetic agents are mainly metabolized by cytochrome P450 in the liver and produce several metabolites, such as inorganic fluoride, that are eliminated through the urinary system.,
| Pharmacodynamics|| |
Mean alveolar concentration (MAC) has been utilized as routine criteria to determine the efficiency of inhalational anesthetics agents. In definition, MAC is a concentration of an inhalational anesthetics agent that prevents muscular movements in reaction to the surgical stimulation in 50% of individuals. Values of MAC change for various agents and are dependent to the patients' ages. For example, in neonates, MAC of sevoflurane is almost 3.3%, and in adults aged 40–50 years, it is near 2%.,
Impact in central nervous system
The functional mechanisms of inhalational anesthetics agents are known in some aspects., Functional mechanisms of the agents were affected by the Meyer–Overton rule for more than a century. Meyer–Overton rule indicates a relationship between the lipid solubility of inhalational anesthetics agents and their anesthetic effectiveness.,
Inhalational anesthetic modifies the electrical action of the central nervous system that can be assessed using electroencephalogram. Enflurane can enhance epileptic waves, while desflurane and isoflurane do not induce epileptic activity. Information about sevoflurane in this aspect is arguable. Using isoflurane and sevoflurane, one can suppress convulsions in patients with intractable epilepsy.
Inhalational anesthetics partly influence on the cerebrovascular CO2 sensitivity. In clinical concentrations, desflurane and isoflurane lead to decrease in cerebral blood flow but preserve responsiveness of cerebral circulation to CO2.
Inhalational anesthetics decrease cardiac output and mean arterial pressure (MAP) in a dose-relative mode. Sevoflurane, isoflurane, and desflurane decrease the MAP through decreasing the systemic vascular resistance., In 1985, it was  suggested that enflurane may increase postischemic myocardial recovery in isolated rat hearts. Afterward, it was shown that exhibition to anesthetics agents simulate the cardioprotective influences of repetitive ischemia. This event has been named pharmacological preconditioning. To protect myocardium and minimize ischemia-reperfusion myocardium injury, preconditioning and postconditioning treatments are performed before and after ischemic events, respectively.
In several researches, the possible advantages of myocardial protection by anesthetics agents, the mechanisms of protection and preconditioning and postconditioning through inhalational anesthetics have been widely investigatedin vivo and in vitro. The agents protect myocardium through opening of K ATP channels ,, and increasing of reactive oxygen species (ROS) in mitochondria., Besides, they can stimulate or translocate the tyrosine kinase, protein kinase C, and p38 mitogen-activated protein kinase. Such mechanisms can reduce content of cytosolic and mitochondrial calcium.
In two meta-analyses, cardioprotective effects of inhalational anesthetics were discussed. The results showed that morbidity and mortality in patients experiencing cardiac surgery were decreased., In a recent study, to promote late pharmacological conditioning, inhalational sevoflurane was used. Results showed that even a low dose, late and short applied of the agent can induce cardiac protection.
Inhalational anesthetic agents reduce tidal volume and depress spontaneous breathing. They increase the threshold of CO2 to activate respiratory centers and decrease in ventilation that leads to CO2 accumulation., Sevoflurane can decrease airway resistance. A number of case reports have revealed prosperous healing of status asthmaticus with sevoflurane.,,
Relation between oxidative stress in one-lung ventilation and inhalational anesthesia
In thoracic surgery, one-lung ventilation (OLV) is commonly carried out to prepare expanded surgical space. At the time of the OLV, in the nonventilated lung, a hypoxic pulmonary vasoconstriction occurs and the oxygenation and perfusion diminishes, while the blood flow of the other lobe heightens. Consequently, the nonventilated site undergoes a tissue ischemia. After resuming two-lung ventilation (2 LV), the production of ROS increase quickly and meaningfully as a result of the reperfusion of the blood and reentry of oxygen to the ischemic tissue. Increasing of ROS leads to peroxidation of unsaturated lipids in plasma lipoproteins as well as cell membranes. This phenomenon is named ischemia-reperfusion injury (IRI) that may generate a number of cardiac complications. Ability of human cells to act against oxidative stress depends on the their total antioxidant status (TAS). After the treatment of pneumothorax and initiating the 2 LV, hydrostatic pressure increases and leads to increase in alveolocapillary membrane permeability., It can lead to a lung edema. It was revealed that in acute pulmonary damages, TAS is reduced by pulmonary edema fluid. Serious oxidative damages that is appeared after 2 LV, can be remarkable in subjects without suitable TAS. Aim to prevent IRI, several studies have been conducted.,,,,,,, Fatty acid peroxidation and reperfusion damage can be prevented by using antioxidants. For example, propofol, an analogous to phenolic-free radical scavengers [Figure 1]c, can be employed.,,,, Besides, the halogenated inhalation agents such as sevoflurane have been showed to reduce the rate of IRI.,, When reperfusion of ischemic tissue, levels of ischemia-modified albumin (IMA) and malondialdehyde (MDA) heighten in bloodstream. MDA is a toxic compound that is produced through lipid peroxidation. IMA and MDA have been utilized as markers in studies on IRI.,,,,,,, In a study, patients subjected to the thoracic surgery performing the OLV, were surveyed, and the influences of sevoflurane and propofol on IRI were compared. Some important criteria including MDA, IMA, blood–gas levels, and hemodynamics were assessed. Results showed that sevoflurane may protect against IRI induced after OLV in the thoracic surgery.
Recovery after using sevoflurane versus halothane
Sevoflurane has been considered a valuable candidate for stimulation of anesthesia because of some useful properties as follow: the low-solubility in blood, nonirritant for the respiratory tract, fast-inducer of the anesthesia, and inducing the patients' hemodynamic in a constant route. Fast recovery is worthwhile to confirm early efficient coughing and reduce the percentage of postoperative airway problems. In a comparative research, patients who had received either halothane or sevoflurane to keep anesthesia during operation, were compared for the features of their postoperative recovery. Results showed that sevoflurane induced less recovery time and minimum time to obtain discharge criteria.
Wake-up times after using sevoflurane or propofol in cardiac surgery
In Intensive Care Unit (ICU) patients, to induce tolerance to the tracheal tubes and mechanical ventilation, sedative infusions have been used. However, wake-up times after using these agents is unpredictable. Moreover, they may not be suitable to use for prolonged mechanical ventilation. Benzodiazepines and propofol may be partly responsible for the promoting of delirium and delusional memories. Compared to midazolam, the inhaled isoflurane induces delusional memories in a lower rate while using for sedation in ICU. In a randomized control trial, the cardiac effects of performing sedation by sevoflurane were compared with propofol following coronary artery bypass surgery. Compared to propofol, sedation by sevoflurane resulted in lower wake-up times and faster cooperation after cardiac surgery. No changes were observed in the stay time in the ICU, damaged memories, and recovery events in short-range sedation.
Xenon is capable to reduce memories of traumatic events
Xenon (Xe) is a noble gas used for inhalational anesthesia and diagnostic imaging. The gas has some properties to use as a perfect anesthetics agent; however, the practical complication of the Xe apparatus and the high price of the gas have limited its extensive using. As an anesthetic, Xe has some advantages including fast induction, low solubility in blood and tissues, and inducing stable hemodynamics in patients with damaged cardiac activity. Xe prevents glutamate receptors associated with memory and learning. It can also influence synaptic flexibility in the brain areas including amygdala and hippocampus. These areas involve in fear conditioning models of posttraumatic stress disorder (PTSD). The glutamate receptors are effective in fear memory reconsolidation, a condition in which recalled memories become sensitive to alternation. In a study, Xe (25%, 1h) was administered in rats after fear memory reactivation and its potency to influence fear memory reconsolidation and next expression of fear-like behavior assessed. Results showed that Xe could considerably inhibit memory reconsolidation in a time-dependent mode. It was suggested that Xe could be employed as a novel factor to study representation of reconsolidation and other memory procedures. It may be utilized to treat patients with diseases associated with emotional and fear memories (e.g., PTSD).
Gas drugs in Intensive Care Unit
Overall, gas drugs have extensive usage in ICU. For example, a combination of oxygen and helium may be utilized in patients with obstructive airway disorders, endotracheal tubes, acute lung damage, diphtheria, respiratory distress syndrome, asthma, bronchiolitis, and chronic obstructive pulmonary disease.
| Conclusion|| |
It can be concluded that inhalational anesthetic agents can be used in anesthesia and ICU. The agents have beneficial effects on a wide range of patients including the patients with status epileptics, exacerbations of obstructive lung disease, or ischemic heart disease. Yet, utilizing the inhalational anesthetics in an ICU is impeded if usual anesthetic circuits should be employed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Miller RD, editor. Miller's Anesthesia. Ch. 21. Philadelphia, PA 19103-2899: Elsevier Churchill Livingston; 2010.
Miller RD, editor. Miller's Anesthesia. Ch. 24. Philadelphia, PA 19103-2899: Elsevier Churchill Livingston; 2010.
Suer H, Bayram H. Liposomes as potential nanocarriers for theranostic applications in chronic inflammatory lung diseases. Biomed Biotechnol Res J 2017;1:1-8. [Full text]
Jena L, Harinath BC. Anti-tuberculosis therapy: Urgency for new drugs and integrative approach. Biomed Biotechnol Res J 2018;2:16-9. [Full text]
Farhadi T. Advances in protein tertiary structure prediction: A review. Biomed Biotechnol Res J 2018;2:20-5. [Full text]
Farhadi T, Fakharian A, Hashemian SM. Affinity improvement of a humanized antiviral antibody by structure-based computational design. Int J Pept Res Ther 2017. [doi: 10.1007/s10989-017-9660-y].
Farhadi T, Ovchinnikov RS, Ranjbar MM. In silico
designing of some agonists of toll-like receptor 5 as a novel vaccine adjuvant candidates. Netw Model Anal Health Inform Bioinform 2016;5: [doi: 10.1007/s13721-016-0138-1].
Rehder K, Forbes J, Alter H, Hessler O, Stier A. Halothane biotransformation in man: A quantitative study. Anesthesiology 1967;28:711-5.
Kharasch ED, Karol MD, Lanni C, Sawchuk R. Clinical sevoflurane metabolism and disposition. I. Sevoflurane and metabolite pharmacokinetics. Anesthesiology 1995;82:1369-78.
Holaday DA, Fiserova-Bergerova V, Latto IP, Zumbiel MA. Resistance of isoflurane to biotransformation in man. Anesthesiology 1975;43:325-32.
Reichle FM, Conzen PF. Halogenated inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 2003;17:29-46.
Eger EI 2nd
, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: A standard of anesthetic potency. Anesthesiology 1965;26:756-63.
Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N
Engl J Med 2003;348:2110-24.
Miller RD, editor. Miller's Anesthesia. Ch. 20. Philadelphia, PA 19103-2899: Elsevier Churchill Livingston; 2010.
Meyer H. To the theory of anesthesia. Arch Exp Pathol Pharmakol 1899;42:109-18.
Overton E, editor. Studies on anesthesia with the contribution of general pharmacology. Jena, Germany: Verlag von Gustav Fischer; 1901.
Neigh JL, Garman JK, Harp JR. The electroencephalographic pattern during anesthesia with ethrane: Effects of depth of anesthesia, PaCo2, and nitrous oxide. Anesthesiology 1971;35:482-7.
Endo T, Sato K, Shamoto H, Yoshimoto T. Effects of sevoflurane on electrocorticography in patients with intractable temporal lobe epilepsy. J Neurosurg Anesthesiol 2002;14:59-62.
Mielck F, Stephan H, Buhre W, Weyland A, Sonntag H. Effects of 1 MAC desflurane on cerebral metabolism, blood flow and carbon dioxide reactivity in humans. Br J Anaesth 1998;81:155-60.
Malan TP Jr., DiNardo JA, Isner RJ, Frink EJ Jr., Goldberg M, Fenster PE, et al.
Cardiovascular effects of sevoflurane compared with those of isoflurane in volunteers. Anesthesiology 1995;83:918-28.
Torri G. Inhalation anesthetics: A review. Minerva Anestesiol 2010;76:215-28.
Freedman BM, Hamm DP, Everson CT, Wechsler AS, Christian CM 2nd
. Enflurane enhances postischemic functional recovery in the isolated rat heart. Anesthesiology 1985;62:29-33.
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways. Anesthesiology 2002;97:4-14.
Nakae Y, Kohro S, Hogan QH, Bosnjak ZJ. Intracellular mechanism of mitochondrial adenosine triphosphate-sensitive potassium channel activation with isoflurane. Anesth Analg 2003;97:1025-32.
de Ruijter W, Musters RJ, Boer C, Stienen GJ, Simonides WS, de Lange JJ, et al.
The cardioprotective effect of sevoflurane depends on protein kinase C activation, opening of mitochondrial K(+)(ATP) channels, and the production of reactive oxygen species. Anesth Analg 2003;97:1370-6.
Fujimoto K, Bosnjak ZJ, Kwok WM. Isoflurane-induced facilitation of the cardiac sarcolemmal K(ATP) channel. Anesthesiology 2002;97:57-65.
Varadarajan SG, An J, Novalija E, Stowe DF. Sevoflurane before or after ischemia improves contractile and metabolic function while reducing myoplasmic Ca(2+) loading in intact hearts. Anesthesiology 2002;96:125-33.
Symons JA, Myles PS. Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: A meta-analysis. Br J Anaesth 2006;97:127-36.
Landoni G, Biondi-Zoccai GG, Zangrillo A, Bignami E, D'Avolio S, Marchetti C, et al.
Desflurane and sevoflurane in cardiac surgery: A meta-analysis of randomized clinical trials. J Cardiothorac Vasc Anesth 2007;21:502-11.
Steurer MP, Steurer MA, Baulig W, Piegeler T, Schläpfer M, Spahn DR, et al.
Late pharmacologic conditioning with volatile anesthetics after cardiac surgery. Crit Care 2012;16:R191.
Miller RD, editor. Miller's Anesthesia. Ch. 22. Philadelphia, PA 19103-2899: Elsevier Churchill Livingston; 2010.
Doi M, Ikeda K. Respiratory effects of sevoflurane. Anesth Analg 1987;66:241-4.
Lockhart SH, Rampil IJ, Yasuda N, Eger EI 2nd
, Weiskopf RB. Depression of ventilation by desflurane in humans. Anesthesiology 1991;74:484-8.
Goff MJ, Arain SR, Ficke DJ, Uhrich TD, Ebert TJ. Absence of bronchodilation during desflurane anesthesia: A comparison to sevoflurane and thiopental. Anesthesiology 2000;93:404-8.
Schultz TE. Sevoflurane administration in status asthmaticus: A case report. AANA J 2005;73:35-6.
Watanabe K, Mizutani T, Yamashita S, Tatekawa Y, Jinbo T, Tanaka M, et al.
Prolonged sevoflurane inhalation therapy for status asthmaticus in an infant. Paediatr Anaesth 2008;18:543-5.
Tobias JD. Inhalational anesthesia: Basic pharmacology, end organ effects, and applications in the treatment of status asthmaticus. J Intensive Care Med 2009;24:361-71.
Cheng YJ, Chan KC, Chien CT, Sun WZ, Lin CJ. Oxidative stress during 1-lung ventilation. J Thorac Cardiovasc Surg 2006;132:513-8.
Akyol A, Ulusoy H, Imamoğlu M, Cay A, Yuluğ E, Alver A, et al.
Does propofol or caffeic acid phenethyl ester prevent lung injury after hindlimb ischaemia-reperfusion in ventilated rats? Injury 2006;37:380-7.
Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol 1997;273:H1707-12.
Fitzpatrick S, Acheson J, Curran P. Re-expansion pulmonary oedema and circulatory shock in a 20-year-old man. Eur J Emerg Med 2003;10:146-8.
Misthos P, Katsaragakis S, Milingos N, Kakaris S, Sepsas E, Athanassiadi K, et al.
Postresectional pulmonary oxidative stress in lung cancer patients. The role of one-lung ventilation. Eur J Cardiothorac Surg 2005;27:379-82.
Bowler RP, Velsor LW, Duda B, Chan ED, Abraham E, Ware LB, et al.
Pulmonary edema fluid antioxidants are depressed in acute lung injury. Crit Care Med 2003;31:2309-15.
Turan R, Yagmurdur H, Kavutcu M, Dikmen B. Propofol and tourniquet induced ischaemia reperfusion injury in lower extremity operations. Eur J Anaesthesiol 2007;24:185-9.
Huang CH, Wang YP, Wu PY, Chien CT, Cheng YJ. Propofol infusion shortens and attenuates oxidative stress during one lung ventilation. Acta Anaesthesiol Taiwan 2008;46:160-5.
Erturk E, Cekic B, Geze S, Kosucu M, Coskun I, Eroglu A, et al.
Comparison of the effect of propofol and N-acetyl cysteine in preventing ischaemia-reperfusion injury. Eur J Anaesthesiol 2009;26:279-84.
Kahraman S, Kilinç K, Dal D, Erdem K. Propofol attenuates formation of lipid peroxides in tourniquet-induced ischaemia-reperfusion injury. Br J Anaesth 1997;78:279-81.
Cheng YJ, Wang YP, Chien CT, Chen CF. Small-dose propofol sedation attenuates the formation of reactive oxygen species in tourniquet-induced ischemia-reperfusion injury under spinal anesthesia. Anesth Analg 2002;94:1617-20.
Annecke T, Kubitz JC, Kahr S, Hilberath JM, Langer K, Kemming GI, et al.
Effects of sevoflurane and propofol on ischaemia-reperfusion injury after thoracic-aortic occlusion in pigs. Br J Anaesth 2007;98:581-90.
Carles M, Dellamonica J, Roux J, Lena D, Levraut J, Pittet JF, et al.
Sevoflurane but not propofol increases interstitial glycolysis metabolites availability during tourniquet-induced ischaemia-reperfusion. Br J Anaesth 2008;100:29-35.
Conzen PF, Fischer S, Detter C, Peter K. Sevoflurane provides greater protection of the myocardium than propofol in patients undergoing off-pump coronary artery bypass surgery. Anesthesiology 2003;99:826-33.
Erturk E, Topaloglu S, Dohman D, Kutanis D, Beşir A, Demirci Y, et al.
The comparison of the effects of sevoflurane inhalation anesthesia and intravenous propofol anesthesia on oxidative stress in one lung ventilation. Biomed Res Int 2014;2014:360936.
Ravi PR, Nanda HS, Anant S. Comparative study of recovery after sevoflurane versus halothane anaesthesia in adult patients. Med J Armed Forces India 2008;64:325-8.
Hellström J, Öwall A, Sackey PV. Wake-up times following sedation with sevoflurane versus propofol after cardiac surgery. Scand Cardiovasc J 2012;46:262-8.
Baumert JH. Xenon-based anesthesia: Theory and practice. Open Access Surg 2009;2:5-13.
Meloni EG, Gillis TE, Manoukian J, Kaufman MJ. Xenon impairs reconsolidation of fear memories in a rat model of post-traumatic stress disorder (PTSD). PLoS One 2014;9:e106189.
Hashemian SM, Fallahian F. The use of heliox in critical care. Int J Crit Illn Inj Sci 2014;4:138-42.
] [Full text]