1. Anesthetics and Anesthetic Adjuncts Analgesics [Opiates, fentanyl (Sublimaze)] General depressants a.Benzodiazepines [benzodiazepines midazolam (Versed)] b. Barbiturates [secobarbital] Neuroleptics [droperidol (Inapsine)] Muscarinic blockers (atropine, scopolomine, glycopyrate) Neuromuscular blockers (paralytics) Miscellaneous Agents ( antagonists: naloxone, flumazanil, neostigmine)

2. Analgesics Used with anesthesia to provide analgesia. Important ADRs: respiratory depression, cardiovascular depression. Potent Analgesics (opiates): morphine, fentanyl, nalbuphine, alfentanil, sufentanil.

3. Pre-Anesthetic Depressants Benzodiazepines : diazepam, lorazepam, midazolam Barbiturates : secobarbital, pentobarbital Mechanism - enhancement of GABA action.

4. Neuroleptics Antipsychotic agents: droperidol Produces a trance-like state, for neuroleptic anesthesia. Effective antiemetics

5. Antagonists of Adjuncts to Anesthesia ChEI - competitive NMBs Naloxone - opiates Flumazenil - BZD

6. Miscellaneous Drugs anticholinergic agents: atropine, scopolamine, glycopyrrolate. Use to reduce secretions.

7. GABA A Receptors The GABA A receptor is a heteromeric-pentamer. Binding of GABA to its site on the GABA A receptor opens the chloride channel generally resulting in an IPSC (hyperpolarizing the postsynaptic neuron reducing excitation). At least 21 different subunits have been identified. Specific GABA A subunit combinations define the nature of the BDZ response. Different subtype combinations appear to mediate the different actions of BDZs, including amnesia, anxiolysis, sedation, antispasticity. Midazolam has twice the affinity for BDZ receptors than does diazepam. The antianxiety action of BDZs may be a result of their ability to selectively block subunit constructs found in cortical and limbic arousal following stimulation of the reticular pathways.

8. Midazolam Midazolam is a short-acting benzodiazepine. Midazolam is used for conscious sedation, anxiolysis, and amnesia during minor surgical or diagnostic procedures. Midazolam is used as an inducing agent, and as an adjunct to regional anesthesia. Midazolam, as other benzodiazepines (BDZs) act at limbic, thalamic, and hypothalamic structures producing a dose dependant CNS depression including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. BDZs act by potentiating the action of GABA at GABA A receptors. Benzodiazepines cause allosteric modulation of GABA A receptor complex, but do not activate the channel. –Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels remain open, BDZs enhance GABA efficacy by increasing the affinity of GABA to its binding site on the GABA A receptor.

9. Propofol Propofol (2,6-diisopropylphenol) is an intravenous anesthetic. Propofol induces anesthesia that can be maintained by continuous infusion. Propofol induces anesthesia as quickly as thiopental, but emergence from anesthesia is 10 times more rapid than with thiopental and is associated with minimal postoperative confusion. Only desflurane has a more rapid recovery time than propofol, but desflurane is associated with more nausea/vomiting. Unlike many other general anesthetics, propofol possesses an antiemetic action. Propofol acts by binding to unique  3 /  5 containing GABA A receptor subunit constructs. Propofol anesthesia is immediate and short-lived. Cardiorespiratory depression, apnea and significant hypotension are possible and are dose-related.

10. Fentanyl Fentanyl is a potent synthetic opiate agonist. Fentanyl is a phenylpiperidine derivative, structurally similar to meperidine, Fentanyl is highly lipid soluble. Fentanyl is used to aid induction and maintenance of general anesthesia and to supplement regional and spinal analgesia. Fentanyl is preferred to morphine in anesthesia due to its ability to attenuate hemodynamic responses and maintain cardiac stability. Fentnayl may be administered alone or in combination with inhaled anesthetics, local anesthetics such as bupivacaine, or benzodiazepines.

11. Fentanyl Mechanism of Action Fentanyl is a strong agonist at µ- and kappa- opiate receptors. Opioids close N-type voltage-operated calcium channels (kappa- receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (µ and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Analgesia is mediated through changes in the perception of pain at spinal cord (µ2-, delta-, kappa-receptors) and brain (µ1- and kappa3 receptors). Opiate receptors are G-protein coupled receptors. Opioid-G-protein systems include cAMP and PLC-intositol triphosphate. The emotional response to pain is altered. Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli. Opioids can modulate the endocrine and immune systems inhibiting release of vasopressin, somatostatin, insulin and glucagons. Stimulatory effects of opioids are the result of "disinhibition" as the release of inhibitory neurotransmitters such as GABA is blocked.

12. Opiate Actions Clinically, stimulation of µ-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Miosis is produced by excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Opiate-induced respiratory depression is caused by direct action on brain stem. respiratory centers while bradycardia is due to depression of the medullary vasomotor center and vagal nucleus stimulation. Opiate agonists action on the GI tract results in constipation and delayed digestion, while urinary smooth muscle tone is increased by opiate agonists, sometimes causes urinary retention.