Generic Name: desflurane

Possible Mechanisms of Chemical Class: Action: haloether Desflurane is a noncompetitive PubChem 2D Structure: Trade Name: antagonist of NMDA receptor Suprane [Baxter] Manufacturers: channels (1). In addition, [FDA Search] desflurane increases the effect IUPAC Name: of GABA at GABA-A receptor 2-(difluoromethoxy)Prescribing channels (2). The drug may 1,1,1,2-tetrafluoroInformation: also activate the human ethane [Link] tandem pore domain potassium RxList: channel, TRESK (3). Desflurane Dosage [Link] may affect other types of Forms/Routes: potassium channels as well, but volatile liquid/inhalation Empirical more research is necessary to Formula: provide a more comprehensive C3H2F6O Major Metabolite: profile of the drug's effects on trifluoroacetic acid Molecular Mass: ion channels. Compared with 168.038 g/mol Database Search halothane, desflurane is a Links: relatively weak inducer [PubMed] of Ca2+ release from [Search PubMed for sarcoplasmic reticulum Randomized Controlled Ca2+ release channels in muscle Trials] cells (4). Nevertheless, the [PubChem] "3D" Structure (Requires Chime): drug should definitely be [PDSP Ki database] [Link] avoided in all patients susceptible to malignant hyperthermia (5) . Because the other fluorinated volatile anesthetics enhance the effect of glycine at glycine receptors, desflurane is likely to share this mechanism of action. However, further experimentation is needed in order to clarify the matter. In addition, desflurane is likely to share another key property with other fluorinated anesthetics: the ability to inhibit the exchange of GTPS for GDP bound to the nucleotide binding site of a subset of G proteins that may include Gq (6). Indications: Desflurane is indicated as an inhalation agent for induction and/or maintenance of anesthesia for inpatient and outpatient surgery in adults (see PRECAUTIONS in the prescribing information). Desflurane is not recommended for induction of anesthesia in pediatric patients because of a

Initial Approval: 09/18/1992

high incidence of moderate to severe upper airway adverse events (see WARNINGS in the prescribing information). After induction of anesthesia with agents other than desflurane, and tracheal intubation, desflurane is indicated for maintenance of anesthesia in infants and children. Generic Name: enflurane Possible Mechanisms of Chemical Class: Action: haloether Enflurane is a noncompetitive PubChem 2D Structure: Trade Name: inhibitor of NMDA and AMPA Ethrane [Baxter] Manufacturers: glutamate receptor channels [FDA Search] (7, 8). Enflurane enhances the IUPAC Name: effect of glutamate at GluR6 2-chloro-1Prescribing kainate receptor channels (difluoromethoxy)Information: (9, 10). In addition, the drug 1,1,2-trifluoro[Link] enhances the effect of glycine ethane Empirical at glycine receptor channels Formula: and the effect of GABA at Dosage C3H2ClF5O GABA-A receptor channels (11). Forms/Routes: volatile liquid/inhalation Molecular Mass: Furthermore, enflurane may inhibit voltage-gated 184.492 g/mol Na+ channels (12). Enflurane Major Metabolite: may also inhibit certain types of trifluoroacetic acid potassium channels, such as Database Search the human intermediate Links: conductance Ca2+ activated [PubMed] K+ channel hIK1 (13). The drug [Search PubMed for may also have a small Randomized Controlled inhibitory effect at Kv1.1 Trials] voltage-gated K+channels (14). "3D" Structure (Requires Chime): [PubChem] [Link] At sub-anesthetic doses, [PDSP Ki database] enflurane inhibits the exchange of GTPS for GDP bound to the nucleotide binding site of a subset of G (G alpha) proteins; these include Gi2 > Gi1 > Gi3 > Gs(15). Enflurane inhibits plasma membrane Ca2+-ATPase and sarcoplasmic reticulum Ca2+ATPase (16). The drug may also increase the release of Ca2+ from sarcoplasmic reticulum Ca2+ release channels in muscle cells (17). Depending on the cell type considered, enflurane might inhibit T-type and L-type voltage-gated Ca2+ channels (18). The drug may inhibit the effect of GABA at rho1 GABA-C receptors as Initial Approval: 08/28/1972

well (19). Finally, enflurane may enhance the effect of serotonin at 5-HT3 receptor channels (20). Indications: Enflurane may be used for induction and maintenance of general anesthesia. Enflurane may be used to provide analgesia for vaginal delivery. Low concentrations of enflurane (see DOSAGE AND ADMINISTRATION in the prescribing information) may also be used to supplement other general anesthetic agents during delivery by Cesarean section. Higher concentrations of enflurane may produce uterine relaxation and an increase in uterine bleeding. Generic Name: etomidate Trade Name: Amidate [Hospira] IUPAC Name: ethyl 3-(1phenylethyl)imidazole4-carboxylate Dosage Forms/Routes: injectable/injection Major Metabolite: R-(+)-1-(1phenylethyl)-1Himidazole5-carboxylic acid Database Search Links: [PubMed] [Search PubMed for Randomized Controlled Trials] [PubChem] [PDSP Ki database] Initial Approval: 09/07/1982 Possible Mechanisms of Chemical Class: Action: carboxylated imidazole Etomidate potentiates the PubChem 2D Structure: effect of GABA at GABA-A Manufacturers: receptor channels (21). At T[FDA Search] type voltage-gated calcium channels, etomidate may have Prescribing an inhibitory effect (22, 23). Information: Etomidate is also an inhibitor of [Link] (for adrenocortical 11 betageneric) hydroxylase (24). Empirical Indications: Formula: Etomidate injection is indicated C14H16N2O2 by intravenous injection for the Molecular Mass: induction of general anesthesia. 244.289 g/mol When considering use of etomidate, the usefulness of its hemodynamic properties (see CLINICAL PHARMACOLOGY in the prescribing information) should be weighed against the high frequency of transient skeletal muscle movements "3D" Structure (Requires Chime): (see ADVERSE REACTIONS in [Link] the prescribing information). Intravenous etomidate is also indicated for the supplementation of subpotent anesthetic agents, such as nitrous oxide in oxygen, during maintenance of anesthesia for short operative procedures such as dilation and curettage

or cervical conization. Generic Name: halothane Possible Mechanisms of Chemical Class: Action: haloalkane Halothane is a noncompetitive PubChem 2D Structure: IUPAC Name: antagonist of NMDA receptor 2-bromo-2-chloro-1,1,1Manufacturers: channels (25). In addition, trifluoro-ethane [FDA Search] halothane potentiates the effect of GABA at GABA-A receptor Dosage RxList: channels (26). The drug also Forms/Routes: [Link] potentiates the effect of glycine volatile liquid/inhalation Empirical at glycine receptor channels Formula: (27).Halothane may act as an Major Metabolite: C2HBrClF3 antagonist at glutamate AMPA trifluoroacetic acid Molecular Mass: receptors expressing subunits Database Search such as GluR1, GluR3, and 197.381 g/mol Links: GluR2+3, but the drug [PubMed] enhances the effect of [Search PubMed for glutamate at GluR6 kainate Randomized Controlled receptor channels (9). Trials] Halothane may also potentiate [PubChem] the effect of serotonin at 5-HT3 [PDSP Ki database] receptors (28, 29). In addition, the drug is an antagonist at some neuronal nicotinic acetylcholine receptor subtypes "3D" Structure (Requires Chime): [Link] such as the alpha7 (29) and alpha4beta2 (30) subtypes.Enflurane might also inhibit the effect of GABA at rho1 GABA-C receptors (19). Halothane activates human tandem pore domain potassium channels such as TRESK (3), TREK-1 (31), TREK-2 (32), TASK-1 (31, 33), and TASK-3 (33). In addition, halothane may inhibit voltage-gated Na+ channels (12). The drug may also inhibit L-type voltagegated calcium channels (34). Furthermore, halothane might weakly inhibit T-type voltagegated calcium channels (35). Halothanealso inhibits plasma membrane Ca2+-ATPase and sarcoplasmic reticulum Ca2+-ATPase (16). In skeletal muscle, the drug induces the release of Ca2+ from the sarcoplasmic reticulum Ca2+ release channel, also known as the ryanodine receptor (36). At sub-anesthetic doses, Initial Approval: 03/12/1958

halothane inhibits the exchange of GTPS for GDP bound to the nucleotide binding site of a subset of G (G alpha) proteins; these include Gi2 > Gi1 > Gi3 > Gs(15). Indications: Halothane is indicated for the induction and maintenance of general anesthesia. Generic Name: isoflurane Possible Mechanisms of Chemical Class: Action: haloether Isoflurane is a noncompetitive PubChem 2D Structure: Trade Name: antagonist of NMDA receptor Forane [Baxter] Manufacturers: channels (1). In addition, [FDA Search] isoflurane potentiates the effect IUPAC Name: of GABA at GABA-A receptor 2-chloro-2Prescribing channels (26). Glycine's effect (difluoromethoxy)Information: at glycine receptor channels is 1,1,1-trifluoro[Link] also potentiated by isoflurane ethane RxList: (37). Isoflurane may weakly [Link] inhibit glutamate AMPA Dosage receptors expressing subunits Empirical Forms/Routes: such as GluR1, GluR3, and Formula: volatile liquid/inhalation GluR2+3, but the drug C3H2ClF5O enhances the effect of Major Metabolite: Molecular Mass: glutamate at GluR6 kainate trifluoroacetic acid 184.492 g/mol receptor channels (9). Database Search Isoflurane may also potentiate Links: the effect of serotonin at 5-HT3 [PubMed] receptors (28, 29). In addition, [Search PubMed for the drug is an antagonist at Randomized Controlled some neuronal nicotinic Trials] acetylcholine receptor subtypes "3D" Structure (Requires Chime): [PubChem] [Link] such as the alpha7 (29) and [PDSP Ki database] alpha4beta2 (30) subtypes. Isoflurane might also inhibit the effect of GABA at rho1 GABA-C receptors (19). Isoflurane may inhibit voltagegated Na+ channels (12). The drug may also inhibit L-type voltage-gated calcium channels (34). Isoflurane might also weakly inhibit T-type voltagegated calcium channels (22, 38). Isoflurane is likely to activate human tandem pore domain potassium channels such as TRESK (3), TREK-1 (31), TREK-2 (32), TASK-1 (31), and TASK-3 (39). Isoflurane also inhibits plasma membrane Ca2+-ATPase Initial Approval: 12/18/1979

and sarcoplasmic reticulum Ca2+-ATPase (16). The drug may also increase the release of Ca2+ from sarcoplasmic reticulum Ca2+ release channels in muscle cells (17). At sub-anesthetic doses, isoflurane inhibits the exchange of GTPS for GDP bound to the nucleotide binding site of a subset of G (G alpha) proteins; these include Gi2 > Gi1 > Gi3 > Gs(15). Indications: Isoflurane may be used for the induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia. Generic Name: Initial ketamine hydrochloride Approval: 02/19/1970 Trade Name: Ketalar [Parkedale] Manufacturers: [FDA Search] IUPAC Name: 2-(2-chlorophenyl)-2methylaminocyclohexan-1-one hydrochloride Dosage Forms/Routes: injectable/injection Major Metabolites: norketamine; hydroxynorketamine Database Search Links: [PubMed] [Search PubMed for Randomized Controlled Trials] [PubChem] [PDSP Ki database] Prescribing Information: [Link] RxList: [Link] Empirical Formula: C13H17Cl2NO Possible Mechanisms of Chemical Class: Action: arylcyclohexylamine Ketamine is a noncompetitive PubChem 2D Structure: antagonist of NMDA receptor channels (1). The drug also inhibits some subtypes of neuronal nicotinic acetylcholine receptors in a noncompetitive and voltage-dependent manner (40). In addition, ketamine may be an antagonist at muscarinic M1 receptors (41). Further research is needed to clarify whether ketamine affects additional receptors at clinical concentrations.

Molecular Mass: Indications: 274.186 g/mol Ketamine hydrochloride injection is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketamine "3D" Structure (Requires Chime): hydrochloride injection is best [Link] suited for short procedures but it can be used, with additional doses, for longer procedures. Ketamine hydrochloride injection is indicated for the induction of anesthesia prior to the administration of other general anesthetic agents. Ketamine hydrochloride

injection is indicated to supplement low-potency agents, such as nitrous oxide. Specific areas of application are described in the CLINICAL PHARMACOLOGY section of the prescribing information. Generic Name: methohexital Possible Mechanisms of Chemical Class: Action: barbiturate Methohexital potentiates the PubChem 2D Structure: Trade Name: effect of GABA at GABA-A Brevital Sodium [King] Manufacturers: receptor channels and directly [FDA Search] causes the channels to open at IUPAC Name: higher concentrations (42). 1-methyl-5-(1Prescribing Methohexital may also act as methylpent-2-ynyl)-5- Information: an antagonist at kainate prop[Link] glutamate receptors (43, 44). 2-enylRxList: Methohexital is likely to bind to hexahydropyrimidine[Link] glycine receptors without 2,4,6-trione activating them or blocking Empirical glycine's effects; however, the Formula: Dosage drug may block the effects of C14H17N2NaO3 Forms/Routes: thiopental and pentobarbital at injectable/injection Molecular Mass: glycine receptors (45). 284.286 g/mol Major Metabolite: Indications: 4'-hydroxymethohexital Brevital Sodium can be used in adults as follows: Database Search Links: [PubMed] [Search PubMed for Randomized Controlled Trials] [PubChem] [PDSP Ki database] 1. For intravenous induction of anesthesia prior to the use of other "3D" Structure (Requires Chime): general anesthetic [Link] agents. 2. For intravenous induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for short surgical procedures; Brevital Sodium may be given by infusion or intermittent injection. 3. For use along with other parenteral agents, usually narcotic analgesics, to supplement subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for longer surgical procedures. Initial Approval: 06/27/1960

4. As intravenous anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli (see WARNINGS in the prescribing information). 5. As an agent for inducing a hypnotic state. Brevital Sodium can be used in pediatric patients older than 1 month as follows: 1. For rectal or intramuscular induction of anesthesia prior to the use of other general anesthetic agents. 2. For rectal or intramuscular induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures.

3. As rectal or

intramuscular anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Chemical Class: 1,4-imidazole benzodiazepine PubChem 2D Structure:

Generic Name: midazolam hydrochloride IUPAC Name: 8-chloro-6-(2fluorophenyl)-1-methyl4HImidazo(1,5-a) (1,4)benzodiazepine Dosage Forms/Routes: injectable/injection; syrup/oral Major Metabolites: 1-hydroxymidazolam; 4-hydroxymidazolam Database Search Links:

Initial Approval: 12/20/1985

Manufacturers: Indications: [FDA Search] Midazolam hydrochloride is Prescribing indicated: Information: intramuscularly or [Link] intravenously for (injectable) preoperative sedation/ [Link] (syrup) anxiolysis/amnesia; RxList: [Link] Empirical Formula: C18H14Cl2FN3 Molecular Mass: 362.228 g/mol intravenously as an agent for sedation/anxiolysis/amn esia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy,

Possible Mechanism of Action: Midazolam is a water soluble benzodiazepine agonist (46).

cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and "3D" Structure (Requires Chime): oxygen (balanced [Link] anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.

[PubMed] [Search PubMed for Randomized Controlled Trials] [PubChem] [PDSP Ki database]

Generic Name: nitrous oxide

Possible Mechanisms of Chemical Class: Action: inorganic nitrogen compound The key effect of nitrous oxide PubChem 2D Structure: IUPAC Name: dinitrogen oxide Molecular Mass: is its noncompetitive antagonism of NMDA receptor 44.0129 g/mol complexes (47). Nitrous oxide Dosage also slightly inhibits glutamate Forms/Routes: AMPA and kainate receptors gas/inhalation (47). The drug is a noncompetitive antagonist at Metabolism: some subtypes of neuronal Nitrous oxide is not nicotinic acetylcholine receptors metabolized in the body. such as the alpha4beta2 Database Search subtype (47). Nitrous oxide Links: weakly potentiates the effect of [PubMed] GABA at GABA-A receptor [Search PubMed for channels, but this effect may

Empirical Formula: N2O

not be relevant at clinical concentrations (47). In addition, the drug might inhibit the effect of GABA at rho1 GABA-C receptors (47). Glycine's effects at glycine receptor channels may be slightly potentiated by nitrous oxide (47). Nitrous oxide may slightly inhibit serotonin 5-HT3 receptors in a competitive manner (28, 47). The drug might also inhibit T-type voltage-gated calcium channels as well (48). Finally, nitrous oxide activates TREK-1, a two pore-domain potassium channel (49). Nitrous oxide increases the production of nitric oxide (NO) via the neuronal isoform of nitric oxide synthase (nNOS) (50). Nitrous oxide- induced NO production may lead to the neuronal release of endogenous opioid peptides (50). Indications: Nitrous oxide is indicated for the induction and maintenance of sedation. In addition, it is approved for the induction and maintenance of general anesthesia. However, nitrous oxide is rarely used alone; other medications are "3D" Structure (Requires Chime): frequently administered to [Link] induce or supplement anesthesia. Because of its weak anesthetic potency and muscle relaxant properties, nitrous oxide must be supplemented with another anesthetic or anesthesia adjunct (such as a barbiturate, benzodiazepine, opioid analgesic, or another inhalation anesthetic) and/or a neuromuscular blocking agent. Also, nitrous oxide is often administered concurrently with one of the other inhalation anesthetics to decrease the requirement for the more potent anesthetic. Initial Approval: Possible Mechanisms of Action: Chemical Class:

Randomized Controlled Trials] [PubChem] [PDSP Ki database]

Generic Name: propofol

Propofol potentiates the effects phenol derivative Trade Name: of GABA at GABA-A receptors PubChem 2D Structure: Diprivan [Abraxis] Manufacturers: and glycine at glycine receptors [FDA Search] (51). At higher concentrations, IUPAC Name: propofol directly causes both 2,6-dipropan-2-ylphenol Prescribing GABA-A and glycine receptor Information: channels to open (51). Propofol Dosage [Link] may also inhibit and slow the Forms/Routes: RxList: activation of hyperpolarizationinjectable/injection [Link] activated, cyclic nucleotidegated channels such as HCN1, Empirical Major Metabolites: HCN2, and HCN4 (52). Formula: propofol-glucuronide; 4-(2,6-diisopropyl-1,4- C12H18O In addition, propofol may have quinol)-sulphate; Molecular Mass: a small but significant inhibitory 1-(2,6-diisopropyl-1,4- 178.271 g/mol effect on voltage-dependent quinol)-glucuronide; Na+ channels (12). Propofol 4-(2,6-diisopropyl-1,4may also inhibit T-type voltagequinol)-glucuronide gated calcium channels (22, 23). Finally, propofol is an Database Search inhibitor of fatty acid amide Links: hydrolase (53). [PubMed] [Search PubMed for Randomized Controlled Trials] [PubChem] [PDSP Ki database]

10/02/1989

"3D" Structure (Requires Chime): Indications: [Link] Propofol is an IV sedativehypnotic agent that can be used for both induction and/or maintenance of anesthesia as proof of a balanced anesthetic technique for inpatient and outpatient surgery in adults and in children 3 years of age or older. Propofol, when administered intravenously as directed, can be used to initiate and maintain monitored anesthesia care (MAC) sedation during diagnostic procedures in adults. Propofol may also be used for MAC sedation in conjunction with local/regional anesthesia in patients undergoing surgical procedures. (See PRECAUTIONS in the prescribing information). Propofol should only be administered to intubated, mechanically ventilated adult patients in the Intensive Care Unit (ICU) to provide continuous sedation and control of stress responses. In this setting, propofol should be administered only by persons skilled in the medical

management of critically ill patients and trained in cardiovascular resuscitation and airway management. Generic Name: sevoflurane Possible Mechanisms of Chemical Class: Action: haloether Sevoflurane is a noncompetitive PubChem 2D Structure: Trade Name: antagonist of NMDA receptor Ultane [Abbott] Manufacturers: channels (1). In addition, [FDA Search] sevoflurane enhances the effect IUPAC Name: of GABA at GABA-A receptor 1,1,1,3,3,3-hexafluoro- Prescribing channels (2). Glycine's effect at 2Information: glycine receptor channels is (fluoromethoxy)propane [Link] also potentiated by sevoflurane RxList: (37). Sevoflurane may weakly Dosage [Link] inhibit glutamate AMPA Forms/Routes: receptors, and more research is volatile liquid/inhalation Empirical necessary to better Formula: characterize its effects at these C4H3F7O Major Metabolite: receptors (54). Sevoflurane is hexafluoroisopropanol Molecular Mass: also a noncompetitive 200.055 g/mol Database Search antagonist at serotonin 5-HT3 Links: receptors (28). In addition, the [PubMed] drug is likely to be an [Search PubMed for antagonist at some neuronal Randomized Controlled nicotinic acetylcholine receptor Trials] subtypes such as the [PubChem] "3D" Structure (Requires Chime): alpha4beta2 (30) subtype. [PDSP Ki database] [Link] Sevoflurane may inhibit voltage-gated Na+channels (55). The drug may also inhibit L-type voltage-gated calcium channels (56). Sevoflurane might inhibit T-type voltagegated calcium channels as well (57). In skeletal muscle, sevoflurane induces the release of Ca2+ from the sarcoplasmic reticulum Ca2+ release channel, also known as the ryanodine receptor (36). Furthermore, sevoflurane is a potent activator of the human tandem pore domain potassium channel, TRESK (3). The drug is also likely to activate the human tandem pore domain potassium channel TASK-1 (58). At sub-anesthetic doses, sevoflurane inhibits the exchange of GTPS for GDP bound to the nucleotide binding site of a subset of G (G alpha) proteins; these include Gi2 > Initial Approval: 06/07/1995

Gi1 > Gi3 > Gs(15). Indications: Sevoflurane is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery. Sevoflurane should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane should be used. Generic Name: thiopental sodium Possible Mechanisms of Chemical Class: Action: thiobarbiturate Thiopental potentiates the PubChem 2D Structure: Trade Name: effect of GABA at GABA-A Pentothal [Hospira] Manufacturers: receptor channels (59). The [FDA Search] drug also potentiates the effect IUPAC Name: of glycine at glycine receptor sodium 5-ethyl-6-oxo-5- Prescribing channels (27). Furthermore, pentan-2Information: thiopental may potently inhibit yl-2-sulfanylidene[Link] voltage-gated calcium channels pyrimidin-4-olate RxList: and weakly inhibit NMDA [Link] glutamate receptor channels Dosage (60). Thiopental may also Empirical Forms/Routes: inhibit neuronal nicotinic injectable/injection [the Formula: acetylcholine receptors (61). C11H17N2NaO2S drug is prepared as a sterile powder and after Molecular Mass: Indications: reconstitution with an Pentothal (Thiopental Sodium 264.321 g/mol appropriate diluent is for Injection, USP) is indicated administered by the (1) as the sole anesthetic agent intravenous route] for brief (15 minute) procedures, (2) for induction of Major Metabolite: anesthesia prior to pentobarbital administration of other "3D" Structure (Requires Chime): anesthetic agents, (3) to Database Search [Link] supplement regional Links: anesthesia, (4) to provide [PubMed] hypnosis during balanced [Search PubMed for anesthesia with other agents Randomized Controlled for analgesia or muscle Trials] relaxation, (5) for the control of [PubChem] convulsive states during or [PDSP Ki database] following inhalation anesthesia, local anesthesia, or other Initial Approval: 1959

causes, (6) in neurosurgical patients with increased intracranial pressure, if adequate ventilation is provided, and (7) for narcoanalysis and narcosynthesis in psychiatric disorders.

Table of Contents
1. Module Objectives
The objectives of this module are: to introduce the student to the administration of anesthetics to laboratory animals; to discuss anesthesia under the following broad headings: preanesthesia; effects of anesthetic agents; anesthetic administration; anesthetic emergencies; recovery from anesthesia;

to provide information on the effects of drugs used during anesthesia; to consider the consequences of anesthesia and the surgical procedures on recovery; and to discuss anesthetic emergencies and their treatment.

2. Introduction 3. 4. "Animals must not be subjected to unnecessary pain or distress. The experimental design must offer them every
practical safeguard whether in research, in teaching or in testing procedures"(CCAC policy statement on: ethics of animal investigation (1989)). In this module we will discuss the alleviation of pain during painful procedures such as surgery, through the use of anesthetic drugs. Anesthesia is also used for producing muscle relaxation, suppressing reflexes, and producing loss of consciousness for purposes other than prevention of pain perception. For example, anesthesia is required for MRI, CT scans and in some cases for radiology. Because of the wide variability of laboratory animal species and strains, as well as anesthetic agents, an appropriate anesthetic regimen should be developed in consultation with a veterinarian prior to the commencement of any study. Related Information Covered in Other Modules The relief of pain after a surgical procedure, or at other times, is covered in the module "Analgesia". The signs of pain and distress in animals are covered in the module "Pain and Distress and Endpoints". Readers can refer to these modules for further information. The need to use an anesthetic to perform a procedure implies that the procedure would be painful for an awake animal. In addition there may be some residual pain after the animal recovers from the anesthetic and analgesics should be used. Some drugs described here appear in both the anesthesia and analgesia modules.

5.

6.

7. 8.

9.

Preanesthetic Treatments There are several reasons why the use of preanesthetic agents should be considered: to reduce apprehension in the animal to allow a reduction in the dose of anesthetic required to reduce some of the side effects of the anesthetic agent to provide some analgesia after the anesthetic has worn off

The preanesthetic agent should allow a reduction in the dose of anesthetic required. This applies particularly to injectable anesthetics where control of the depth and duration of anesthesia is often more challenging than with inhaled anesthetics. The combination of preanesthetic and anesthetic drugs must provide sufficient pain blocking so that the animal does not feel pain during the surgical procedure. Most anesthetic agents do more than produce unconsciousness and pain relief. They are potent drugs that may affect every system in the body. The effects on the respiratory and cardiovascular systems may be particularly significant during the anesthetic period, however effects on other organ systems may be more significant depending on the goals of the research. While some preanesthetic agents may reduce anesthetic side effects, more often it is the reduction in anesthetic dose that provides the greatest relief from the side effects. An ideal preanesthetic agent should provide some analgesia after the surgery. Some analgesics are quite short acting in animals and depending on the length of the surgery may not last into the recovery period. It is important to ensure that analgesia continues through the surgical period, into and beyond recovery. The effects of the ideal preanesthetic as described above are not to be found in a single agent. Sometimes more than one drug is used but with care the undesirable side effects do not outweigh the potential beneficial effects. Summary The ideal preanesthetic agent should: Reduce apprehension Allow a reduction in anesthetic doses Reduce or eliminate some of the undesirable side effects of anesthetics Provide some analgesia after the anesthetic has worn off

Types of Preanesthetic Drugs The major groups of preanesthetic drugs are analgesics (particularly the opioids), tranquilizers and anticholinergic drugs. Paralytic or neuromuscular blocking drugs are also used as adjuncts to anesthesia, particularly in human surgery. Analgesics Some analgesics, as well as providing pain relief, also have a desirable sedative effect. They calm the animals and allow a reduction in the amount of anesthetic required along with a smoother recovery from anesthesia. Moreover, a pre-emptive strike against pain is thought to result in a reduced need for analgesics after the surgery. For these reasons, some analgesics may be given as preanesthetic agents. Of the analgesics, the opioids are commonly used as preanesthetic agents. Opioids Among the effects of opioids that make them useful as preanesthetic agents are analgesia (they make pain more tolerable without abolishing it completely) and CNS depression (there is usually depression although some opioids may produce excitation and convulsions in some species). As a general rule, the suitability of any drug for a given species should be checked before using it. The combination of analgesia and CNS depression are both desirable for anesthesia. This allows for a reduction in the dose of anesthetic agent and provides pre-emptive analgesia.

Tranquilizers The principal drugs in this group are the phenothiazine derivatives (e.g., acepromazine, chlorpromazine), the benzodiazepines (e.g., diazepam, midazolam), and the butyrophenones (e.g., droperidol, fluanisone). The alpha 2 adrenergic receptor agonists (e.g., xylazine, medetomidine) could be considered as tranquilizers as well as analgesics but they are seldom used for their tranquilizing effect alone because of their profound cardiovascular effects. The principal effect of tranquilizer drugs administered prior to anesthesia is the reduction of anxiety in animals. This effect may be achieved with low doses and may not be accompanied by CNS depression. At higher doses, CNS depression may be profound, depending on the drug, and the species. Most of the tranquilizers do not have any analgesic effects and so a lack of response or a diminished response to painful stimuli should not be interpreted as a sign of analgesia. The alpha 2 adrenergic receptor agonists provide some analgesia as well as tranquilization. Tranquilizers generally cause minimal cardiovascular and respiratory depression and some have an effect in reducing the occurrence of cardiac arrhythmias during anesthesia. There are some exceptions. The alpha 2 adrenergic receptor agonists have profound effects on both cardiovascular and respiratory systems. Some tranquilizers (e.g., chlorpromazine) can cause moderate to severe hypotension, and some phenothiazine derivatives decrease the seizure threshold in certain species. Summary of effects of tranquilizers Minimal or no analgesia Minimal CNS depression Anxiolytic (calming) Minimal cardiovascular and respiratory depression

Anticholinergic Drugs Anticholinergic drugs block the muscarinic actions of the neurotransmitter, acetylcholine. Acetylcholine is a neurotransmitter at many sites throughout the body and so the effects of anticholenergic drugs are widespread. Anticholinergic drugs are used to block two effects in particular during anesthesia, secretions in the respiratory tract in response to the irritating nature of some inhalant anesthetics, and bradycardia (slowing of the heart) which accompanies most anesthetics. Respiratory secretions are a complicating factor especially in animals with small airways where even a low level of secretion may compromise respiration. With the advent of less irritating volatile anesthetics, concerns about respiratory secretions have been reduced, and the primary use is to minimize the bradycardia that follows stimulation of the vagus nerve. Salivation is reduced in many animals although not in ruminants. The muscarinic receptors in the eye are also affected resulting in dilated pupils (mydriasis). There may be a decrease in gastro-intestinal motility. The most commonly used anticholinergics are atropine and glycopyrrolate. Some rabbits possess atropinase, an enzyme which rapidly breaks down atropine and reduces its effectiveness in this species. Glycopyrrolate may be used in place of atropine in cases where the anticholinergic effect is required for a longer period of time. The effects are similar to atropine although the increase in heart rate may be less. Minimize this section Types of Anesthetic Agents Anesthetic agents should produce a loss of sensation with a minimum of side effects and they should have a calming effect on the animal during the recovery phase. While there is not a requirement for a loss of consciousness during anesthesia, that is the case with general anesthetics. Local anesthetics for example will produce quite localized or even regionalized anesthesia without any loss of consciousness. As well, it is advantageous for an anesthetic agent to provide some level of analgesia during the recovery phase. There are three broad groups of anesthetic agents namely volatile anesthetics like isoflurane and halothane, injectable anesthetics like ketamine, propofol and barbiturates, and local anesthetics like lidocaine, procaine and bupivacaine. For general anesthesia inhalant anesthetics are highly preferred as the anesthesia is much easier to control and the agent quickly cleared from the body. Volatile Anesthetic Agents

The common effects of anesthetic agents described above apply to the volatile anesthetics. These drugs are usually supplied as liquids and require a vaporizer and a carrier gas such as oxygen to deliver them to the patient. Altering the concentration of the anesthetic agent in the inspired gases easily controls the depth of anesthesia. In the event that the animal becomes too deeply anesthetised, the anesthetic agent is quickly removed from the animal through the lungs. It is important to scavenge waste anesthetic gases to minimize exposure of people to these agents. Isoflurane Highly volatile and must be administered using a calibrated vaporizer to prevent exposure to high concentrations of gas Must be scavenged to avoid occupational exposure Respiratory depression greater than with halothane and may necessitate external ventilation Little hepatic metabolism and a lessened risk of hepatitis Rapid recovery (1-3 minutes)

Halothane Highly volatile and must be administered using a calibrated vaporizer to prevent exposure to high concentrations of gas Must be scavenged to avoid occupational exposure May cause cardiac arrhythmias May cause hepatitis in humans but rare in other species Will cause malignant hyperthermia in genetically susceptible pigs Rapid recovery (1-3 minutes) except from very long and deep anesthesia

Nitrous Oxide Comes as a gas in cylinders Low anesthetic potency and cannot produce anesthesia in animals by itself Causes minimal cardiovascular and respiratory depression May be used to reduce the concentration of other anesthetic gases although this effect is less than that seen in humans Use with caution in ruminants

Injectable Anesthetics The general effects of anesthetics apply to the injectable anesthetics, with some exceptions. Ketamine, for example, does not cause significant cardiovascular depression at the usual anesthetic doses. Injectable anesthetics are easily administered requiring little more than a needle and syringe, but once they have been injected it is very difficult to control their effects. There are no specific antidotes for many of these drugs and recovery from anesthesia depends on redistribution of the drug from the blood to the tissues or its metabolism or a combination of both processes. There are many injectable anesthetic drugs in use, ketamine, propofol, pentobarbital, methohexital, thiopental. The following notes on a few injectable anesthetics highlight some important features or exceptions from expected effects. Full details on the activities of the drugs in particular species should be obtained from the veterinarian. Ketamine Poor analgesia in most laboratory species and should not be used alone Increased muscle tone Many reflexes remain although animal is unresponsive to pain (e.g., swallowing and blink reflexes) Usually used in combination with another drug (e.g., xylazine, diazepam)

Duration of anesthesia depends on dose.

Sodium Pentobarbital Narrow safety margin Poor analgesia until animal is completely unconscious Excitation during the recovery phase Gives up to 60 minutes of anesthesia Controlled drug status

Urethane Provides long periods of surgical anesthesia with little respiratory depression Urethane is carcinogenic Animals should not be allowed to recover from urethane anesthesia

Local Anesthetic Agents Local anesthetics are dealt with in more detail in the Analgesia module. They are used particularly for pain relief following surgical procedures in small animals. They are also employed for regional anesthesia in larger animals (e.g., sheep and cattle for procedures such as dehorning, castrations and caesarean sections). Frequently they are supplemented with tranquilizing drugs to help provide restraint. Animal Factors in Anesthesia There are a number of factors related to the animal that impact on the quality of anesthesia. These factors should be considered when the type of anesthetic agent is being chosen. Species. Different species require different doses of anesthetic agents. This applies particularly to the injectable anesthetics. In general, the smaller animals require a higher dose in mg/kg of a given anesthetic than larger animals. Familiarity with the effects of an anesthetic agent in one species should not be assumed in another species. The volatile anesthetics are more consistent in their application between species. The mean alveolar concentration of the anesthetic agent required for anesthesia is similar among species and this is controlled by the concentration of the agent in the inspired gases. Differences in the respiratory tract in birds (fixed lungs, air sacs) and other nonmammalian species must be considered when administering inhalation anesthetics. Strain. Strain differences have been noted even within the same species. Some strains of pigs are more susceptible to malignant hyperthermia during halothane anesthesia than others (a genetic trait). Age. Young animals and old animals may have an increased risk for anesthetic complications. In older animals, pathological changes if present in the respiratory system, may result in complications. Young animals may not have developed all the processes required to metabolize the drugs and so may have longer than expected recovery from anesthesia. Volatile anesthetics allow more refined control of the anesthesia in both groups. Weight. Very fat animals may not breathe as effectively during anesthesia as thinner animals, leading to the problems associated with hypoventilation. In addition, if an agent is given on a mg/kg basis, there may be a relative overdose because the fat does not participate to a great degree in the circulation and distribution of the drug. If part of the recovery from an anesthetic depends on its removal from the blood into tissues including fat (e.g., the short acting barbiturates) then animals with very little fat (e.g., greyhounds, calves) may experience longer than usual recovery from anesthesia. Sex. There is some evidence for a difference between the sexes for some anesthetics. Health of an Animal. Pre-existing disease or pathology may complicate an otherwise smooth anesthesia. Any disease in the lungs will further compromise respiration during anesthesia. Liver disease may interfere with the metabolism of anesthetic agents and kidney disease may limit their excretion. Surgically altered animals (e.g., hypophysectomy, adrenalectomy, thyroidectomy) may be at increased risk at subsequent anesthesias. Demeanor. An exited animal with high levels of circulating adrenalin, elevated heart rate and blood pressure is at an increased risk when undergoing anesthesia.

Previous Anesthesia. Some of the injectable anesthetics are not completely cleared from the body for several days (e.g., pentobarbital), even if the animal has recovered consciousness and is behaving normally. Care must be taken if a second anesthetic quickly follows the first. For those anesthetics that are extensively metabolized as part of the excretory process, a second anesthetic may result in more rapid metabolism of the drug than the first, with a shorter period of anesthesia. Other Factors. Some non-anesthetic drugs have effects on anesthetic agents. Chloramphenicol may lengthen the duration of pentobarbital anesthesia and some antibiotics potentiate the actions of muscle relaxants. Side Effects of Anesthetic Drugs Like many drugs, anesthetics also have other effects that may not be desirable. It may be necessary to take account of these side effects whether the animal is anesthetized for a surgical procedure or for a physiological study of an organ system. The side effects described below occur to a greater or lesser degree with all general anesthetics. Central Nervous System (CNS) Depression. The commonly used anesthetics provide CNS depression to the point of loss of consciousness. This does not mean that all neuronal activity has been abolished. Many of the reflexes that are used to assess anesthetic depth are retained after unconsciousness. However if anesthetic depth increases, these are gradually lost and even automatic functions like respiration may be lost. Cardiovascular Depression. Anesthetics usually cause a decrease in cardiac output and a fall in blood pressure. These effects are a combination of a direct influence of the anesthetic on the heart, reducing its contractility and an effect on the heart and blood vessels by way of the nerve supply to these tissues. Respiratory Depression. One of the effects of anesthetic agents is to cause a loss of muscle tone and a decrease in contractility. In the respiratory system, this results in smaller breaths i.e., the tidal volume is decreased. At the same time the respiratory rate is decreased. There is also a decreased sensitivity in the receptors that detect the level of oxygen and carbon dioxide in the blood. The overall effect is to reduce the respiratory capability of the animal. Loss of Temperature Control. Anesthetic agents inhibit the mechanisms responsible for maintaining a steady body temperature. These include the temperature regulating centres in the brain and processes like shivering. The result is a tendency for the animal's temperature to drift downwards towards the environmental temperature. Hypothermia is a major consideration in anesthesia especially for small animals such as rodents, and controlled supplemental heat must be provided to maintain body temperature. Hormone Release Depressed. Generally, the release of hormones is depressed. Prolactin release may be increased by some general anesthetics. Depression of Other Functions. Gastro-intestinal motility is depressed by general anesthetics as is liver function. Urinary excretion is decreased. Anesthetic Techniques Inhalation Anesthesia This type of anesthesia requires the animals to breathe in the anesthetic. Initially the anesthetic concentration is highest in the alveoli and as the gas passes into the bloodstream, the animal becomes anesthetised. At the end of the surgery, the concentration in the inspired gas is reduced to zero and the agent passes from the blood to the alveoli and the animal recovers. The balance between blood and alveolar levels controls the depth of anesthesia. There are several techniques for anesthetizing animals with volatile anesthetics. The animal may be placed in a chamber and the chamber flooded with the anesthetic gas in the carrier gas at the required concentration. Once anesthetized, the chamber should be opened in a fume hood and the animal may be removed and placed on a nose cone or some other apparatus for delivering the anesthetic to prolong the anesthesia, if that is necessary. This technique is most suitable for small animals. Assisted ventilation may be required in some species (e.g., sheep).

Courtesy of Dr Paul Flecknell, University of Newcastle

Courtesy of Dr Paul Flecknell,

University of Newcastle

Animals may be masked down by placing a mask over the nose and mouth and allowing them to breathe the anesthetic gases. Even fairly large animals may be anesthetized in this manner but it usually results in some accidental exposure to the gases. Some species hold their breath when the mask is placed on their face. Animals may be anesthetised initially with a short acting anesthetic, injected intravenously, an endotracheal tube placed in the trachea and the tube connected to an anesthetic circuit delivering the volatile anesthetic. This system has several advantages. It makes it possible to ventilate the animal using a respirator and so maintain normal breathing and respiratory values. It makes it easier to deal with anesthetic emergencies should they occur and it allows for better control of stray anesthetic gases in the room. However, endotracheal intubation is difficult in some small animals (e.g., rodents) and the reduction in diameter of the airway in the trachea may significantly affect respiration. Care must also be taken not to significantly increase the dead space i.e., the part of the respiratory

system where exchange of gases with the blood does not occur. The ventilation rate and the tidal volume should be set to maintain normal blood gases and this should be discussed with a veterinarian.

Courtesy of Dr Paul Flecknell, University of Newcastle

Occupational Health and Safety Concerns Human exposure to the inhalation anesthetic gases should be avoided. Hepatic toxicity may occur with exposure to some volatile anesthetics. Others are known to be carcinogenic (e.g., urethane). Procedures should be in place to collect or remove all waste anesthetic gases that leak out or are expired by the anesthetized animal. Injectable Anesthesias Anesthetics may be injected by a number of routes, intravenously, intraperitoneally, intramuscularly and subcutaneously. Injectable anesthetic drugs may be used to produce general, regional or local anesthesia. For regional anesthesia, anesthetics may be injected into the subarachnoid or epidural spaces to block both the sensory and motor nerves entering or emerging from the spinal cord at that level. Anesthetics such as the thiobarbiturates should be given intravenously because their high pH (alkalinity) causes tissue damage if injected subcutaneously or intramuscularly. Anesthesia through Drugs Placed in the Animal's Environment This refers particularly to anesthetics administered in the water of fish and amphibians. There are several anesthetics that can be added to the water and the animals allowed to swim until they become anesthetised. Tricaine methanesulfonate (TMS; MS-222) is commonly used to anesthetise frogs and fish. In water, it is very acidic and must be buffered with sodium bicarbonate. Cold-induced "anesthesia" - Hypothermia Induction of hypothermia has been used for immobilizing neonatal rodents since they do not yet have well-developed thermoregulatory mechanisms, and for immobilising amphibians and reptiles, for surgical procedures with an apparent wide safety margin. It is known that a neural tissue temperature less than about 9C (5C is sometimes cited as the desired core body temperature) results in blockage of transmission in the brain and central nervous system to produce unconsciousness. The lack of response to surgery trauma during such levels of hypothermia has been accepted as an indication of insensitivity to pain. However, there are important welfare concerns about the chilling down and warming up periods, the methods of doing so, and the absence of post-operative analgesia with this technique. Definitive studies on the anesthetic and analgesic effects of hypothermia as the sole agent have not been reported, and since safe and effective alternatives are available, these should be used. Assessment of Anesthesia Anesthesia has been described as a series of four Stages. Stage 1: the period between administration of an anesthetic and loss of consciousness.

Stage 2: the period after loss of consciousness, which may include actions such as uncontrolled movement, delirium, vocalization. Stage 3: the level at which surgery can be performed. Stage 3 anesthesia is divided into four planes. Plane 1: "light" anesthesia - the animal still has blink and swallowing reflexes, and regular respiration. Plane 2: "surgical" anesthesia - the animal has lost blink reflexes, pupils become fixed and respiration is regular. Plane 3: "deep" anesthesia - the animal starts losing the ability to use the respiratory muscles and breathing becomes shallow; may require assisted ventilation. Plane 4: the animal loses all respiratory effort, and breathing may stop entirely.

Stage 4: anesthetic crisis! Respiratory arrest and death from circulatory collapse imminent.

Reflexes are used to estimate the depth of anesthesia and while there is some variation in the activity of these reflexes with different anesthetics, they are consistent enough to be useful as a group. A single reflex should not be used as the sole determinant of anesthetic depth. Pupillary Reflex. Shine a light in the eye and the pupil constricts. This reflex is present at the start of Stage 3 and starts to decrease and will be absent by about the middle of Stage 3. Palpebral Reflex. Touch the corner of the eye and the animal blinks. This disappears early in Stage 3. Corneal Reflex. Touch the cornea and the animal blinks. This disappears early in Stage 3. Be careful not to damage the cornea if this reflex is tested. Withdrawal Reflex. Pull a limb gently, pinch the toe and the animal will pull back the limb. This reflex indicates whether the animal feels pain or not and should be absent before surgery starts. This will occur early in Stage 3. Laryngeal (Swallowing) Reflex. Stimulation of the larynx will cause the animal to swallow. The stimulation may be from outside, for example, an attempt to pass an endotracheal tube or may be internal for example the presence of secretions at the larynx. This is a mechanism to prevent accidental aspiration of fluids into the lungs. This reflex will disappear early in Stage 3. There are some other signs that will help judge the depth of anesthesia. Respiratory efforts change as anesthesia deepens. In Stage 1, the animal is awake and respiration may be quite rapid due to the excitation of being handled. It is evenly apportioned between the chest and abdomen and is quite regular. In Stage 2, breathing is still evenly apportioned between chest and abdomen but is less regular and breath holding may occur. Early in Stage 3, breathing is regular with equal contributions from chest and abdomen. As anesthesia deepens, breathing becomes shallower and more predominantly abdominal. Late in Stage 3 it becomes irregular and in Stage 4 will stop. Muscle tone decreases from a maximum during Stage 2 all the way through Stage 3. Jaw tone is a good indication of muscle tone. Response to Surgical Stimuli. Care should be taken to note any responses to surgical stimuli. Once it has been determined by the reflexes that an appropriate depth of anesthesia has been reached, surgery will commence. The first incision should be observed to determine if the animal makes any response. A response could include a movement, a pause in respiration or a deeper breath if the animal is breathing spontaneously or an increase in heart rate or blood pressure. If there is surgery in the abdomen, traction on the abdominal viscera is known to be painful and this may provide another indication of whether the anesthesia is adequate or not.

DEPTH OF AnestheSIA Stages Stage 1: the period between Reflexes/Signs Respiratory efforts change as anesthesia deepens. In Stage 1, the animal

administration of an anesthetic and loss of consciousness.

awake and respiration may be quite rapid due to the excitation of being handled. It is evenly apportioned between the chest and abdomen and is quite regular. Muscle tone decreases from a maximum during Stage 2 all the way through Stage 3. Jaw tone is a good indication of muscle tone. Respiratory efforts. In Stage 2, breathing is still evenly apportioned between chest and abdomen but is less regular and breath holding may occur.

Stage 2: the period after loss of consciousness, which may include actions such as uncontrolled movement, delirium, vocalization.

Stage 3: the level at which surgery can be performed. Stage 3 anesthesia is divided into four planes. 1. Plane 1: "light" anesthesia - the animal still has blink and swallowing reflexes, and regular respiration. 2. Plane 2: "surgical" anesthesia - the animal has lost blink reflexes, pupils become fixed and respiration is regular. 3. Plane 3: "deep" anesthesia - the animal starts losing the ability to use the respiratory muscles and breathing becomes shallow; may require assisted ventilation. 4. Plane 4: the animal loses all respiratory effort, and breathing may stop entirely.

Pupillary Reflex. Shine a light in the eye and the pupil constricts. This reflex is present at the start of Stage 3 and starts to decrease and will be absent by about the middle of Stage 3. Palpebral Reflex. Touch the corner of the eye and the animal blinks. This disappears early in Stage 3. Corneal Reflex. Touch the cornea and the animal blinks. This disappears early in Stage 3. Be careful not to damage the cornea if this reflex is tested Withdrawal Reflex. Pull a limb gently, pinch the toe and the animal will pull back the limb. This reflex indicates whether the animal feels pain or not and should be absent before surgery starts. This will occur early in Stage 3. Laryngeal (Swallowing) Reflex. Simulation of the larynx will cause the animal to swallow. The stimulation may be from outside, for example, an attempt to pass an endotracheal tube or may be internal for example the presence of secretions at the larynx. This is a mechanism to prevent accidental aspiration of fluids into the lungs. This reflex will disappear early in Stage 3. Respiratory efforts. Early in Stage 3, breathing is regular with equal contributions from chest and abdomen. As anesthesia deepens, breathing becomes shallower and more predominantly abdominal. Late in Stage 3 it becomes irregular and in Stage 4 will stop.

Stage 4: anesthetic crisis! Respiratory arrest and death from circulatory collapse imminent.
Body temperature should be measured and steps taken to prevent the fall in body temperature that usually accompanies anesthesia, particularly in small animals. Capillary refill time may give an indication of the adequacy of cardiovascular function. If a pink paw is squeezed, it will go white but the pink will return within about two seconds. If the time is significantly longer than this, then blood flow through the capillaries is compromised, usually because anesthesia is too deep and the blood pressure is too low. If a pulse can be felt and if the anesthetist is experienced with respect to the feel of the normal pulse, it is possible to get an indication of the cardiac output. In addition, the pulse rate can be counted and compared with the heart rate as heard through a stethoscope or counted from an electrocardiogram. There should not be a difference between the two. Blood pressure gives a good indication of the effectiveness of the heart's contractions and the resistance to flow in the peripheral vessels. It may be measured either indirectly (e.g., a Doppler system or directly with a catheter in an

artery). A falling mean arterial pressure is a sure indicator of deepening anesthesia, if there are no other possible causes like severe haemorrhage. Additional Monitoring. If an arterial blood sample and the capability to measure blood gases are available, then this information provides a very accurate picture of the effectiveness of the ventilation. This information can be used to fine tune ventilation to maintain normal physiological parameters. End tidal CO2 and pulse oximetry are noninvasive methods of obtaining information on the blood gas status. Anesthetic Management Whenever possible, and particularly for more complex surgeries, there should be an "anesthetist" involved. Anesthetic management accounts for all the processes and events during a period of anesthesia that will result in freedom from pain during the surgical procedure and a return to a normal physiological state as soon as possible after recovery. The assessment of the depth of anesthesia is only one part of anesthetic management. An important component is ensuring that all equipment is functioning properly. During the course of the surgical procedure, there will have been changes in the fluid balance of the animal that should be corrected. Some of these are normal: continued production of urine, and losses from the respiratory tract. Continuous saliva production, especially in ruminants, will deplete body water and electrolytes. An anesthetized sheep may produce 800 ml/hr of saliva high in bicarbonate, which is lost to the animal because it cannot swallow while under anesthesia. This secretion is not reduced by anticholinergic drugs like atropine and will soon lead to fluid depletion and an acid/base imbalance. Blood loss may account for a serious loss of fluids and this is particularly important in small animals that have a very small blood volume. (It is convenient to estimate the blood volume of an animal at 70 ml/kg. This is only an estimate for the purpose of rapid simple calculation of blood loss or the volume of blood that might be taken from an animal. A 20g mouse has about 1.4 ml of blood and a loss of 0.2 ml represents 14% of its blood volume.) The loss of fluids through evaporation may be significant if deep body cavities are open during the surgery. It has been estimated that the fluid loss through evaporation from an open human abdomen is about 500 ml/hr. Fluid losses should be replenished throughout the surgery, rather than waiting to the end. Unexpectedly large losses should be replaced as soon as possible. It is not always possible or desirable to replace blood with blood but the consequences of a reduced circulating blood volume on cardiovascular performance must be considered. If vascular access has been established, it is important to ensure that this access is patent. This is usually accomplished by slowly running fluids through the needle or catheter. Occasionally, the needle becomes displaced or there is a kink in the tubing and the vascular access is lost through clotting of the needle. Minimize this section

Paralytic Agents (Neuromuscular Blocking Drugs) Neuromuscular blocking drugs are used as an adjunct to anesthetics to provide greater muscle relaxation during a surgical procedure or when control of respiration is necessary. These compounds paralyze skeletal muscle so that voluntary control of the muscles is lost. Most significantly, there is loss of activity in the muscles of respiration and in muscles that are responsible for some reflexes used to judge the depth of anesthesia (see above). Loss of the muscles responsible for respiration means that an artificial method of respiration must be used. Loss of reflexes means that it is difficult to ensure how deeply the animal is anesthetized. The major concerns about the use of paralyzing agents are that they produce paralysis, but not loss of consciousness or pain relief, and that their effects may last beyond the anesthesia. Thus an animal may appear to be anesthetized (i.e., unresponsive to any painful stimuli) while in reality, it is unable to respond because of the muscle paralysis. Emergencies The three major emergencies while an animal is anesthetized result from anesthetic overdose, blood loss and equipment failure. Any of these could result in the death of the animal.

Anesthetic overdoses with injectable anesthetics are the most difficult to deal with because there are no specific reversal agents. Respiratory depression is the most easily observed effect of the overdose and takes the form of a decreasing ventilatory effort. If this occurs artificial ventilation should be initiated to try to maintain normal blood gases until the animal metabolizes the anesthetic or otherwise reduces the concentration in blood. It is advisable to have respiratory support equipment always available when animals are anesthetized.

Courtesy of Dr Paul Flecknell, University of Newcastle

Blood loss will be recognized if a large vessel is accidentally cut. However, the continual loss of small amounts of blood may add up to a serious problem. This may occur if the animal has been given anti-coagulating drugs like heparin and there is no spontaneous clotting. If the level of anesthesia has been deep at the start of the surgery, there may have been little bleeding due to the low blood pressure. The surgeon may not have had to deal with the many small bleeding points that would have been obvious if the blood pressure had been higher. Many of these will start to bleed as the animal recovers or if the anesthesia is lighter. If blood loss is anticipated then appropriate replacement fluids should be available as well as a venous catheter placed at the start of anesthesia so that fluids, drugs, etc., may be administered if necessary. The anesthetist should be aware of the functioning of the equipment at all times and have backup plans to protect the animal if there should be a failure. Such failures could include a massive electrical shutdown that halts all electrically driven devices. Recovery from Anesthesia Recovery from anesthesia more or less mirrors the induction pathway although the timing differs. Thus while rapid induction pushed the animal through Stage 2 and avoided the excitement stage, recovery is slower and some excitation may be seen particularly following barbiturate anesthesia. Very close monitoring of the animal must continue into the recovery phase, and particular care must be taken to ensure that the airways are patent and that breathing is unimpeded. Any anesthesia-induced abnormalities present at the end of the anesthesia, such as hypothermia or dehydration, should be corrected. One dangerous effect of hypothermia is that the anesthetic drugs will not be metabolized as quickly and the duration of the anesthesia unnecessarily prolonged. There are a number of factors that will influence the rate and quality of the recovery. If a preanesthetic agent was used, this may increase the time to full recovery because of the tranquillizing effects of some of these drugs. On the other hand they will make recovery calmer with less of the excitement phase. The anesthetic agent will determine the rate of recovery. Volatile anesthetics are quickly blown off and the animal regains consciousness. Injectable anesthetics are slower since they depend on metabolism and excretion for their inactivation. The duration of anesthesia may govern the rate of recovery, especially for those agents where rapid recovery is due to clearing into tissues from the blood with metabolism later (e.g., thiobarbiturates). Long anesthesia with one of

these drugs will result in saturation of the tissues and prolonged rather than rapid recovery. The longer the period of anesthesia, the more difficult it is to keep everything normal, even with very extensive monitoring. It is likely then that recovery will be different compared to a short anesthesia. The quality of the anesthesia may be important in the recovery. If anesthesia was turbulent with periods of very deep anesthesia, the likelihood of abnormal physiology and biochemistry is greater, with delayed recovery. The surgical procedure, especially if it was accompanied by blood loss may affect recovery. The duration of the surgery and the insult on the organs may be important. For example, a thoracic procedure may result in incomplete expansion of the lungs and the compromised ventilation may need longer to return the respiratory parameters to normal. Some of the animal factors described as influencing anesthesia may also affect recovery. Older and younger animals, for example, may not metabolize the drugs as quickly.

Anesthesia, general

Definition
General anesthesia is the induction of a balanced state of unconsciousness, accompanied by the absence of pain sensation and the paralysis of skeletal muscle over the entire body. It is induced through the administration of anesthetic drugs and is used during major surgery and other invasive surgical procedures.

Purpose
General anesthesia is intended to bring about five distinct states during surgery:
analgesia, or pain relief amnesia, or loss of memory of the procedure loss of consciousness motionlessness weakening of autonomic responses

Precautions

A complete medical history, including a history of allergies in family members, is an important precaution. Patients may have a potentially fatal allergic response to anesthesia known as malignant hyperthermia, even if there is no previous personal history of reaction. General anesthetics should be administered only by board-certified medical professionals. Anesthesia providers consider many factors, including a patient's age, weight, allergies to medications, medical history, and general health when deciding which anesthetic or combination of anesthetics to use. The American Society of Anesthesiologists has compiled guidelines for classifying patients according to risk levels as follows:
I: healthy patient II: patient with mild systemic disease without functional limitations III: patient with severe systemic disease with definite functional limitations IV: patient with severe systemic disease that is life-threatening V: dying patient not expected to survive for 24 hours without an operation

Equipment for general anesthesia should be thoroughly checked before the operation; all items that might be needed, such as extra tubes or laryngoscope blades, should be available. Staff members should be knowledgeable about the problems that might arise with the specific anesthetic being used, and be able to recognize them and respond appropriately. General anesthetics cause a lowering of the blood pressure (hypotension), a response that requires close monitoring and special drugs to reverse it in emergency situations.

Description
General anesthetics may be gases or volatile liquids that evaporate as they are inhaled through a mask along with oxygen. Other general anesthetics are given intravenously. The amount of anesthesia produced by inhaling a general anesthetic can be adjusted rapidly, if necessary, by adjusting the anesthetic-to-oxygen ratio that is inhaled by the patient. The degree of anesthesia produced by an intravenously injected anesthetic cannot be changed as rapidly and must be reversed by administration of another drug. The precise mechanism of general anesthesia is not yet fully understood. There are, however, several hypotheses that have been advanced to explain why general anesthesia occurs. The first, the so-called Meyer-Overton theory, suggests that anesthesia occurs when a sufficient number of molecules of an inhalation anesthetic dissolve in the lipid cell membrane. The second theory maintains that protein receptors in the central nervous system are involved, in that inhalation anesthetics inhibit the enzyme activity of proteins. A third hypothesis, proposed by Linus Pauling in 1961, suggests that anesthetic molecules interact with water molecules to form clathrates (hydrated microcrystals), which in turn inhibit receptor function.

A nurse anesthetist injecting medication into the intravenous tube of a patient during surgery. ( Photo Researchers Inc. Reproduced by permission. )

Stages of anesthesia
There are four stages of general anesthesia that help providers to better predict the course of events, from anesthesia induction to emergence.
Stage I begins with the induction of anesthesia and ends with the patient's loss of consciousness. The patient still feels pain in Stage I. Stage II, or REM stage, includes uninhibited and sometimes dangerous responses to stimuli, including vomiting and uncontrolled movement. This stage is typically shortened by administering a barbiturate, such as sodium pentothal, before the anesthetic agent. Stage III, or surgical anesthesia, is the stage in which the patient's pupillary gaze is central and the pupils are constricted. This is the target depth of surgical anesthesia. During this stage, the skeletal muscles relax, the patient's breathing becomes regular, and eye movements stop.

Stage IV, or overdose, is marked by hypotension or circulatory failure. Death may result if the patient cannot be revived quickly.

Types of anesthetic agents

There are two major types of anesthetics used for general anesthesia, inhalation and intravenous anesthetics. Inhalation anesthetics, which are sometimes called volatile anesthetics, are compounds that enter the body through the lungs and are carried by the blood to body tissues. Inhalation anesthetics are less often used alone in recent clinical practice; they are usually used together with intravenous anesthetics. A combination of inhalation and intravenous anesthetics, often with opioids added for pain relief and neuromuscular blockers for muscle paralysis, is called balanced anesthesia.
INHALATION ANESTHETICS. The following

are the most commonly used inhalation anesthetics:

Halothane causes unconsciousness but provides little pain relief; often administered with analgesics . It may be toxic to the liver in adults. Halothane, however, has a pleasant smell and is therefore often the anesthetic of choice when mask induction is used with children.

Enflurane is less potent, but produces a rapid onset of anesthesia and possibly a faster recovery. Enflurane is not used in patients with kidney failure.

Isoflurane is not toxic to the liver but can induce irregular heart rhythms. Nitrous oxide (laughing gas) is used with other such drugs as thiopental to produce surgical anesthesia. It has the fastest induction and recovery time. It is regarded as the safest inhalation anesthetic because it does not slow respiration or blood flow to the brain. However, because nitrous oxide is a relatively weak anesthetic, it is not suited for use in major surgery. Although it may be used alone for dental anesthesia, it should not be used as a primary agent in more extensive procedures.

Sevoflurane works quickly and can be administered through a mask since it does not irritate the airway. On the other hand, one of the breakdown products of sevoflurane can cause renal damage.

Desflurane, a second-generation version of isoflurane, is irritating to the airway and therefore cannot be used for mask (inhalation) inductions, especially not in children. Desflurane causes an increase in heart rate, and so should be avoided for patients with heart problems. Its advantage is that it provides a rapid awakening with few adverse effects.

INTRAVENOUS ANESTHETICS. Commonly administered

intravenous general anesthetics include ketamine,

thiopental (a barbiturate), methohexital (Brevital), etomidate, and propofol (Diprivan). Ketamine produces a different set of reactions from other intravenous anesthetics. It resembles phencyclidine, which is a street drug that may cause hallucinations. Because patients who have been anesthetized with ketamine often have sensory illusions and vivid dreams during post-operative recovery, ketamine is not often given to adult patients. It is,

however, useful in anesthetizing children, patients in shock, and trauma casualties in war zones where anesthesia equipment may be difficult to obtain.

General anesthesia in dental procedures

The use of general anesthesia in dental and oral surgery patients differs from its use in major surgery because the patient's level of fear is usually a more important factor than the nature of the procedure. In 1985, an NIH Consensus Statement reported that high levels of preoperative anxiety, lengthy and complex procedures, and the need for a pain-free operative period may be indications for general anesthesia in healthy adults and very young children. The NIH statement specified that at least three professionals are required when general anesthesia is used during dental procedures: one is the operating dentist; the second is a professional responsible for observing and monitoring the patient; the third person assists the operating dentist. Although the United States allows general anesthesia for dental procedures to be administered outside hospitals (provided that the facility has the appropriate equipment and emergency drugs), Scotland banned the use of general anesthesia outside hospitals in 2000, after a ten-year-old boy died during a procedure to have a tooth removed.

Preparation
Preparation for general anesthesia includes the taking of a complete medical history and the evaluation of all factorsespecially a family history of allergic responses to anestheticsthat might influence the patient's response to specific anesthetic agents. Patients should not eat or drink before general anesthesia because of the risk of regurgitating food and liquid or aspirating vomitus into the lungs.

Informed consent
Patients should be informed of the risks associated with general anesthesia as part of their informed consent . These risks include possible dental injuries from intubation as well as such serious complications as stroke, liver damage, or massive hemorrhage. If local anesthesia is an option for some procedures, the patient should be informed of this alternative. In all cases, patients should be given the opportunity to ask questions about the risks and benefits of the procedure requiring anesthesia as well as questions about the anesthesia itself.

Premedication
Depending on the patient's level of anxiety and the procedure to be performed, the patient may be premedicated. Most medications given before general anesthesia are either anxiolytics, usually benzodiazepines; or analgesics. Patients in severe pain prior to surgery may be given morphine or fentanyl. Anticholinergics (drugs that block impulses from the parasympathetic nervous system) may be given to patients with a known history of bronchospasm or heavy airway secretions.

Aftercare
The anesthetist and medical personnel provide supplemental oxygen and monitor patients for vital signs and monitor their airways. Vital signs include an EKG (unless the patient is hooked up to a monitor), blood pressure, pulse rate, oxygen saturation, respiratory rate, and temperature. The staff also monitors the patient's level of consciousness as well as signs of excess bleeding from the incision.

Risks
Although the risk of serious complications from general anesthesia are low, they can include heart attack, stroke, brain damage, and death. The risk of complications depends in part on the patient's age, sex, weight, allergies, general health, and history of smoking, alcohol or drug use. The overall risk of mortality from general anesthesia is difficult to evaluate, because so many different factors are involved, ranging from the patient's overall health and the circumstances preceding surgery to the type of procedure and the skill of the physicians involved. The risk appears to be somewhere between 1:1,000 and 1:100,000, with infants younger than age one and patients older than 70 being at greater risk.

Awareness during surgery

One possible complication is the patient's "waking up" during the operation. It is estimated that about 30,000 patients per year in the United States "come to" during surgery. This development is in part the result of the widespread use of short-acting general anesthetics combined with blanket use of neuromuscular blockade. The patients are paralyzed with regard to motion, but otherwise "awake and aware." At present, special devices that measure brain wave activity are used to monitor the patient's state of consciousness. The bispectral index monitor was approved by the FDA in 1996 and the patient state analyzer in 1999.

Nausea and vomiting

Post-operative nausea and vomiting is a common problem during recovery from general anesthesia. In addition, patients may feel drowsy, weak, or tired for several days after the operation, a combination of symptoms sometimes called the hangover effect. Fuzzy thinking, blurred vision, and coordination problems are also possible. For these reasons, anyone who has had general anesthesia should not drive, operate machinery, or perform other activities that could endanger themselves or others for at least 24 hours, or longer if necessary.

Anesthetic toxicity
Inhalation anesthetics are sometimes toxic to the liver, the kidney, or to blood cells. Halothane may cause hepatic necrosis or hepatitis. Sevoflurane may react with the carbon dioxide absorbents in anesthesia machines to form compound A, a haloalkene that is toxic to the kidneys. The danger to red blood cells comes from carbon monoxide formed by the breakdown products of inhalation anesthetics in the circuits of anesthesia machines.

Malignant hyperthermia
Malignant hyperthermia is a rare condition caused by an allergic response to a general anesthetic. The signs of malignant hyperthermia include rapid, irregular heartbeat; breathing problems; very high fever; and muscle tightness or spasms. These symptoms can occur following the administration of general anesthetics, especially halothane.

Normal results
General anesthesia is much safer today than it was in the past, thanks to faster-acting anesthetics; improved safety standards in the equipment used to deliver the drugs; and better devices to monitor breathing, heart rate, blood pressure, and brain activity during surgery. Unpleasant side effects are also less common, in part because of recent developments in equipment that reduces the problems of anesthetizing patients who are difficult to intubate. These developments include the laryngeal mask airway and the McCoy laryngoscope, which has a hinged tip on its blade that allows a better view of the patient's larynx.

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General anesthetics
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