PHARMACEUTICALS AFFECTING THE GABA SYSTEM WILL SPEND SEVERAL WEEKS ON THIS TOPIC, COVERING: ANESTHETICS SEDATIVES AND HYPNOTICS USED FOR INSOMNIA ANTIEPTILEPTICS ANXIOLYTICS DESIRABLE PROPERTIES OF ANESTHETICS: ANALGESIA ANXIOLYTIC MUSCLE RELAXANT INDUCTION OF UNCONSCIOUSNESS?? AMNESIA CONTROL OF SIDE-EFFECTS: Respiratory depression Vomiting Salivation Coughing LARGE THERAPEUTIC INDEX OF COURSE NO ONE AGENT DOES ALL THE ABOVE! HISTORY OF ANESTHESIA: BY 1845, ETHER AND NITROUS OXIDE WERE RECREATIONAL DRUGS, EXHIBITED AT FAIRS THE DISCOVERY OF ETHER ANESTHESIA: 1846: Massachusetts General Hospital, Boston William T. Morton, Boston dentist and second yr med student, begins experimenting with ether anesthesia in animals Asks surgeon Dr. Warren to try on a patient Before a large audience, the ether works! At end of history's first painless surgery, Warren turns to the audience and exclaims: "Gentlemen, this is no humbug" CHLOROFORM FIRST USED IN SCOTLAND IN 1847 NITROUS OXIDE FOR DENTAL WORK IN 1860S HALOTHANE, THE FIRST MODERN INHALATION ANESTHETIC, DEVELOPED IN 1956 Neither as toxic as chloroform nor explosive as ether MODE OF ACTION OF GASEOUS ANESTHETICS: Potency correlates perfectly with lipid solubility Now thought to be misleading, mechanism is stimulation of the GABA-A complex, perhaps at a lipophilic binding site ANESTHETICS CURRENTLY IN USE: ANESTHETICS ALWAYS COMBINED To enhance anesthetic properties To control side-effects ANESTHETIC POTENCY: THE MAC MAC: Minimum Alveolar Concentration of anesthetic required to produce loss of response to noxious stimulation in 50% of patients THE HALOTHANE FAMILY Non-explosive Rapid induction and recovery Relatively low postoperative nausea, vomiting Problems include: + Hypotension + Low TI, due to respiratory depression + Hepatotoxicity - very rare, potentially fatal + Little analgesia, muscle relaxation other halothane-like anesthetics Include: + Enflurane: less vomiting, better muscle relaxation than halothane + Isoflurane: Most widely used anesthetic, due to lower cardiovascular side effects, lower hepatotoxicity, better muscle relaxant than halothane NITROUS OXIDE: Dental use as mild anagesic/anxiolytic Use in anesthesia allows low levels of halothane or other true anesthetics BARBITURATES: Fast, short-acting injectable barbiturates such as Thiopental sodium are universally used to INDUCE anesthesia Pleasant, rapid induction of anesthesia Little postoperative problem But like all barbiturates, have a low TI, hence not used to sustain anesthesia BENZODIAZEPINES: Excellent muscle-relaxant, anxiolytic and amnesic properties Also has sedative properties at high doses OPIOIDS: All have the added benefit of almost-instantaneous reversibility with naltrexone! Often used to supplement anesthetics, for their potent analgesic properties High doses of synthetic opioids such as fentanyl are often used in cardiac surgery, typically with nitrous oxide and muscle relaxants, due to lack of effect on the cardiovascular system Problems are chiefly respiratory depression, vomiting upon recovery of consciousness Neuroleptics are often given with opioids to produce NEUROLEPT ANALGESIA, accompanied by sedation, lack of affect; useful for dressing wounds, burns, etc The combination of neuroleptics, fentanyl and nitrous oxide may be used for NEUROLEPT ANESTHESIA; but respiratory depression is so severe that artificial respiration is necessary OTHER DRUGS GIVEN WITH ANESTHETICS: ANTIEMETICS: Usually some form of neuroleptic ANTICHOLINERGICS: These are given for two reasons: Drying, especially of the respiratory tract: atropine is common Block vagal reflexes, especially in visceral surgery: again atropine is common PROTECTION AGAINST PULMONARY ASPIRATION: Antacids Histamine H2 antagonists: decrease gastric acid secretion TREATMENT OF INSOMNIA INSOMNIA AND SLEEP DEPRIVATION THESE ARE AMONG THE MOST PREVALENT COMPLAINTS IN USA: Most common cause of first adult visit to a physician 1995 Gallup poll: 40% of adult population complained of chronic or intermittent insomnia Problems increase steadily with advancing age More common in women The disappearing 40-hr work week has caused persistent sleep loss in the US population in the 80s and 90s, compared to the 1930s (MMPI) CONSEQUENCES OF SLEEP PROBLEMS Accidents + 17 hrs sleep deprivation is behaviorally comparable to being legally drunk! Chronic insomnia often predicts later depression TYPES OF INSOMNIA: A variety of schemes exists for categorizing insomnia: TIME OF OCCURRENCE: Problems in getting to sleep (sleep onset insomnia) Problems staying asleep (sleep maintenance insomnia) Early morning awakening (Terminal insomnia) CHRONICITY: Transient Insomnia: + Recurring stressful situations + Jet lag, shift work Short-term insomnia: + Usually triggered by major environmental stressors such as deaths, divorces, etc + Thus often accompanied by depression Chronic Insomnias: + Last from months to years + Can reflect an underlying hyperarousal CONDITIONS PREDISPOSING TO CHRONIC INSOMNIA: "PRIMARY" INSOMNIA: + ALL insomnias are characterized by a curious over-estimation of the time spent awake! + The primary disorder often involves anxiety- induced arousal, and the anxiety is often about insomnia, creating a negative feedback loop IATROGENIC INSOMNIA: Many drugs, including drugs of abuse, interfere with sleep: + Stimulants: bronchodilators, some decongestants, L-DOPA, Ritalin, coffee + -blockers, calcium blockers + MAOIs + Hormones, including steroids, ACTH, thyroid hormones PSYCHIATRIC DISORDERS, including depressive and anxiety disorders CIRCADIAN DISORDERS: Sleep is regulated in part by retinoid projections to sympathetic nervous system, hypothalamus, then pineal gland release of the serotonin metabolite melatonin + SADs: Seasonal Affective Disorder + Delayed Sleep Phase Syndrome: Patients can't sleep until 3/4 PM, then sleep until noon + These disorders often respond to properly-timed bright light + melatonin