General Anesthesia and General Anesthetic Drugs General anesthesia is a state of drug-in- duced reversible inhibition of central nervous function, during which surgical procedures can be carried out in the ab- sence of consciousness, responsiveness to pain, defensive or involuntary move- ments, and significant autonomic reflex responses (A). The required level of anesthesia de- pends on the intensity of the pain-pro- ducing stimuli, i.e., the degree of noci- ceptive stimulation. The skilful anesthe- tist, therefore, dynamically adapts the plane of anesthesia to the demands of the surgical situation. Originally, anes- thetization was achieved with a single anesthetic agent (e.g., diethylether— first successfully demonstrated in 1846 by W. T. G. Morton, Boston). To suppress defensive reflexes, such a “mono-anes- thesia” necessitates a dosage in excess of that needed to cause unconscious- ness, thereby increasing the risk of par- alyzing vital functions, such as cardio- vascular homeostasis (B). Modern anes- thesia employs a combination of differ- ent drugs to achieve the goals of surgical anesthesia (balanced anesthesia). This approach reduces the hazards of anes- thesia. In C are listed examples of drugs that are used concurrently or sequen- tially as anesthesia adjuncts. In the case of the inhalational anesthetics, the choice of adjuncts relates to the specific property to be exploited (see below). Muscle relaxants, opioid analgesics such as fentanyl, and the parasympatholytic atropine are discussed elsewhere in more detail. Neuroleptanalgesia can be consid- ered a special form of combination an- esthesia, in which the short-acting opi- oid analgesics fentanyl, alfentanil, remi- fentanil is combined with the strongly sedating and affect-blunting neurolep- tic droperidol. This procedure is used in high-risk patients (e.g., advanced age, liver damage). Neuroleptanesthesia refers to the combined use of a short-acting analge- sic, an injectable anesthetic, a short-act- ing muscle relaxant, and a low dose of a neuroleptic. In regional anesthesia (spinal an- esthesia) with a local anesthetic (p. 204), nociception is eliminated, while consciousness is preserved. This proce- dure, therefore, does not fall under the definition of general anesthesia. According to their mode of applica- tion, general anesthetics in the restrict- ed sense are divided into inhalational (gaseous, volatile) and injectable agents. Inhalational anesthetics are admin- istered in and, for the most part, elimi- nated via respired air. They serve to maintain anesthesia. Pertinent sub- stances are considered on p. 218. Injectable anesthetics (p. 220) are frequently employed for induction. Intravenous injection and rapid onset of action are clearly more agreeable to the patient than is breathing a stupefying gas. The effect of most injectable anes- thetics is limited to a few minutes. This allows brief procedures to be carried out or to prepare the patient for inhalation- al anesthesia (intubation). Administra- tion of the volatile anesthetic must then be titrated in such a manner as to coun- terbalance the waning effect of the in- jectable agent. Increasing use is now being made of injectable, instead of inhalational, an- esthetics during prolonged combined anesthesia (total intravenous anesthe- sia—TIVA). “TIVA” has become feasible thanks to the introduction of agents with a suit- ably short duration of action, including the injectable anesthetics propofol and etomidate, the analgesics alfentanil und remifentanil, and the muscle relaxant mivacurium. These drugs are eliminated within minutes after being adminster- ed, irrespective of the duration of anesthesia. 216 General Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs 217 Pain stimulus C. Regimen for balanced anesthesia A. Goals of surgical anesthesia B. Traditional monoanesthesia vs. modern balanced anesthesia Muscle relaxation Loss of consciousness Autonomic stabilization Analgesia Motor reflexes Pain and suffering Autonomic reflexes Nociception Paralysis of vital centers Mono-anesthesia e.g., diethylether Reduced pain sensitivity Muscle relaxation Loss of consciousness Pancur onium N 2 O Halothane autonom ic stabilization Atr opine Pentazocine analgesia Neostigm ine r eversal of neurom uscular block M idazolam unconsciousness Pentazocine analgesia Diazepam anxiolysis Muscle relaxation Analgesia Unconsciousness m uscle r elaxation; intubation Succinycholine Pre- medication Induction Maintenance Recovery For unconsciousness: e.g., halothane or propofol For muscle relaxation e.g., pan- curonium For autonomic stabilization e.g., atropine For analgesia e.g., N 2 O or fentanyl Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhalational Anesthetics The mechanism of action of inhala- tional anesthetics is unknown. The di- versity of chemical structures (inert gas xenon; hydrocarbons; halogenated hy- drocarbons) possessing anesthetic ac- tivity appears to rule out involvement of specific receptors. According to one hy- pothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excit- ability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal al- veolar concentration (MAC) at which 50% of patients remain immobile fol- lowing a defined painful stimulus (skin incision). Whereas the poorly lipophilic N 2 O must be inhaled in high concentra- tions (>70% of inspired air has to be re- placed), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. The rates of onset and cessation of action vary widely between different in- halational anesthetics and also depend on the degree of lipophilicity. In the case of N 2 O, there is rapid elimination from the body when the patient is ventilated with normal air. Due to the high partial pressure in blood, the driving force for transfer of the drug into expired air is large and, since tissue uptake is minor, the body can be quickly cleared of N 2 O. In contrast, with halothane, partial pres- sure in blood is low and tissue uptake is high, resulting in a much slower elimi- nation. Given alone, N 2 O (nitrous oxide, “laughing gas”) is incapable of produc- ing anesthesia of sufficient depth for surgery. It has good analgesic efficacy that can be exploited when it is used in conjunction with other anesthetics. As a gas, N 2 O can be administered directly. Although it irreversibly oxidizes vita- min B 12 , N 2 O is not metabolized appre- ciably and is cleared entirely by exhala- tion (B). Halothane (boiling point [BP] 50 °C), enflurane (BP 56 °C), isoflurane (BP 48 °C), and the obsolete methoxyflu- rane (BP 104 °C) have to be vaporized by special devices. Part of the administered halothane is converted into hepatotoxic metabolites (B). Liver damage may re- sult from halothane anesthesia. With a single exposure, the risk involved is un- predictable; however, there is a correla- tion with the frequency of exposure and the shortness of the interval between successive exposures. Up to 70% of inhaled methoxyflu- rane is converted to metabolites that may cause nephrotoxicity, a problem that has led to the withdrawal of the drug. Degradation products of enflurane or isoflurane (fraction biotransformed <2%) are of no concern. Halothane exerts a pronounced hy- potensive effect, to which a negative in- otropic effect contributes. Enflurane and isoflurane cause less circulatory de- pression. Halothane sensitizes the myo- cardium to catecholamines (caution: se- rious tachyarrhythmias or ventricular fibrillation may accompany use of cate- cholamines as antihypotensives or toco- lytics). This effect is much less pro- nounced with enflurane and isoflurane. Unlike halothane, enflurane and isoflu- rane have a muscle-relaxant effect that is additive with that of nondepolarizing neuromuscular blockers. Desflurane is a close structural rela- tive of isoflurane, but has low lipophilic- ity that permits rapid induction and re- covery as well as good control of anes- thetic depth. 218 General Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs 219 Low potency high partial pressure needed relatively little binding to tissue B. Elimination routes of different volatile anesthetics A. Lipophilicity, potency and elimination of N 2 O and halothane Anesthetic potency Lipophilicity Nitrous oxide N 2 O Xenon Cyclopropane Diethylether Enflurane Chloroform Halothane Partial pressure in tissue Time Termination of intake Partial pressure of anesthetic Binding Tissue Blood Alveolar air High potency low partial pressure sufficient relatively high binding in tissue Halothane N 2 O MetabolitesMetabolites Halothane Methoxy- fluraneEther Nitrous oxide N 2 O H 5 C 2 OC 2 H 5 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Injectable Anesthetics Substances from different chemical classes suspend consciousness when given intravenously and can be used as injectable anesthetics (B). Unlike inha- lational agents, most of these drugs af- fect consciousness only and are devoid of analgesic activity (exception: keta- mine). The effect cannot be ascribed to nonselective binding to neuronal cell membranes, although this may hold for propofol. Most injectable anesthetics are characterized by a short duration of ac- tion. The rapid cessation of action is largely due to redistribution: after intravenous injection, brain concentra- tion climbs rapidly to anesthetic levels because of the high cerebral blood flow; the drug then distributes evenly in the body, i.e., concentration rises in the pe- riphery, but falls in the brain—redistri- bution and cessation of anesthesia (A). Thus, the effect subsides before the drug has left the body. A second injection of the same dose, given immediately after recovery from the preceding dose, can therefore produce a more intense and longer effect. Usually, a single injection is administered. However, etomidate and propofol may be given by infusion over a longer time period to maintain unconsciousness. Thiopental and methohexital belong to the barbiturates which, depending on dose, produce sedation, sleepiness, or anesthesia. Barbiturates lower the pain threshold and thereby facilitate defen- sive reflex movements; they also de- press the respiratory center. Barbitu- rates are frequently used for induction of anesthesia. Ketamine has analgesic activity that persists beyond the period of uncon- sciousness up to 1 h after injection. On regaining consciousness, the patient may experience a disconnection between outside reality and inner men- tal state (dissociative anesthesia). Fre- quently there is memory loss for the du- ration of the recovery period; however, adults in particular complain about dis- tressing dream-like experiences. These can be counteracted by administration of a benzodiazepine (e.g., midazolam). The CNS effects of ketamine arise, in part, from an interference with excita- tory glutamatergic transmission via li- gand-gated cation channels of the NMDA subtype, at which ketamine acts as a channel blocker. The non-natural excitatory amino acid N-methyl-D- aspartate is a selective agonist at this re- ceptor. Release of catecholamines with a resultant increase in heart rate and blood pressure is another unrelated ac- tion of ketamine. Propofol has a remarkably simple structure. Its effect has a rapid onset and decays quickly, being experienced by the patient as fairly pleasant. The inten- sity of the effect can be well controlled during prolonged administration. Etomidate hardly affects the auto- nomic nervous system. Since it inhibits cortisol synthesis, it can be used in the treatment of adrenocortical overactivity (Cushing’s disease). Midazolam is a rapidly metabolized benzodiazepine (p. 228) that is used for induction of anesthesia. The longer-act- ing lorazepam is preferred as adjunct anesthetic in prolonged cardiac surgery with cardiopulmonary bypass; its am- nesiogenic effect is pronounced. 220 General Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs 221 B. Intravenous anesthetics A. Termination of drug effect by redistribution CNS: relatively high blood flow Periphery: relatively low blood flow ml blood min x g tissue Initial situation i.v. injection High concentration in tissue Relatively large amount of drug Relatively small amount of drug mg drug min x g tissue Low concentration in tissue Preferential accumulation of drug in brain Decrease in tissue concentration Further increase in tissue concentration Redistribution Steady-state of distribution Sodium thiopental Ketamine Etomidate Sodium methohexital Propofol Midazolam Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Soporifics, Hypnotics During sleep, the brain generates a pat- terned rhythmic activity that can be monitored by means of the electroen- cephalogram (EEG). Internal sleep cy- cles recur 4 to 5 times per night, each cycle being interrupted by a Rapid Eye Movement (REM) sleep phase (A). The REM stage is characterized by EEG activ- ity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of indi- vidual muscle groups against a back- ground of generalized atonia of skeletal musculature. Normally, the REM stage is entered only after a preceding non-REM cycle. Frequent interruption of sleep will, therefore, decrease the REM por- tion. Shortening of REM sleep (normally approx. 25% of total sleep duration) re- sults in increased irritability and rest- lessness during the daytime. With un- disturbed night rest, REM deficits are compensated by increased REM sleep on subsequent nights (B). Hypnotics fall into different catego- ries, including the benzodiazepines (e.g., triazolam, temazepam, clotiaze- pam, nitrazepam), barbiturates (e.g., hexobarbital, pentobarbital), chloral hy- drate, and H 1 -antihistamines with seda- tive activity (p. 114). Benzodiazepines act at specific receptors (p. 226). The site and mechanism of action of barbitu- rates, antihistamines, and chloral hy- drate are incompletely understood. All hypnotics shorten the time spent in the REM stages (B). With re- peated ingestion of a hypnotic on sever- al successive days, the proportion of time spent in REM vs. non-REM sleep returns to normal despite continued drug intake. Withdrawal of the hypnotic drug results in REM rebound, which ta- pers off only over many days (B). Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unre- freshing. Thus, the attempt to discon- tinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic drug dependence. Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects, the former group also being anxiolytic. At higher dosage, both groups promote the onset of sleep or induce it (C). Unlike barbiturates, benzodiaze- pine derivatives administered orally lack a general anesthetic action; cere- bral activity is not globally inhibited (respiratory paralysis is virtually impos- sible) and autonomic functions, such as blood pressure, heart rate, or body tem- perature, are unimpaired. Thus, benzo- diazepines possess a therapeutic margin considerably wider than that of barbitu- rates. Zolpidem (an imidazopyridine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, possess agonist ac- tivity at the benzodiazepine receptor (p. 226). Due to their narrower margin of safety (risk of misuse for suicide) and their potential to produce physical de- pendence, barbiturates are no longer or only rarely used as hypnotics. Depen- dence on them has all the characteris- tics of an addiction (p. 210). Because of rapidly developing tol- erance, choral hydrate is suitable only for short-term use. Antihistamines are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine, p. 114), in which case their sedative side effect is used as the princi- pal effect. 222 Hypnotics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypnotics 223 C. Concentration dependence of barbiturate and benzodiazepine effects B. Effect of hypnotics on proportion of REM/NREM A. Succession of different sleep phases during night rest REM Waking state Sleep stage I Sleep stage IV Sleep stage III Sleep stage II REM-sleep= Rapid Eye Movement sleep NREM = No Rapid Eye Movement sleep Ratio NREM 5 10 15 20 25 30 Nights without hypnotic Nights with hypnotic Nights after withdrawal of hypnotic Paralyzing Anesthetizing Hypnogenic Hypnagogic Calming, anxiolytic Triazolam Pentobarbital Effect Concentration in blood Pentobarbital Triazolam Barbiturates: Benzo- diazepines: REM Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Sleep–Wake Cycle and Hypnotics The physiological mechanisms regulat- ing the sleep-wake rhythm are not com- pletely known. There is evidence that histaminergic, cholinergic, glutamater- gic, and adrenergic neurons are more active during waking than during the NREM sleep stage. Via their ascending thalamopetal projections, these neu- rons excite thalamocortical pathways and inhibit GABA-ergic neurons. During sleep, input from the brain stem de- creases, giving rise to diminished tha- lamocortical activity and disinhibition of the GABA neurons (A). The shift in balance between excitatory (red) and inhibitory (green) neuron groups underlies a circadian change in sleep propensity, causing it to remain low in the morning, to increase towards early afternoon (midday siesta), then to de- cline again, and finally to reach its peak before midnight (B1). Treatment of sleep disturbances. Pharmacotherapeutic measures are in- dicated only when causal therapy has failed. Causes of insomnia include emo- tional problems (grief, anxiety, “stress”), physical complaints (cough, pain), or the ingestion of stimulant substances (caffeine-containing beverages, sympa- thomimetics, theophylline, or certain antidepressants). As illustrated for emo- tional stress (B2), these factors cause an imbalance in favor of excitatory influ- ences. As a result, the interval between going to bed and falling asleep becomes longer, total sleep duration decreases, and sleep may be interrupted by several waking periods. Depending on the type of insomnia, benzodiazepines (p. 226) with short or intermediate duration of action are in- dicated, e.g., triazolam and brotizolam (t 1/2 ~ 4–6 h); lormetazepam or temaze- pam (t 1/2 ~ 10–15 h). These drugs short- en the latency of falling asleep, lengthen total sleep duration, and reduce the fre- quency of nocturnal awakenings. They act by augmenting inhibitory activity. Even with the longer-acting benzodiaz- epines, the patient awakes after about 6–8 h of sleep, because in the morning excitatory activity exceeds the sum of physiological and pharmacological inhi- bition (B3). The drug effect may, howev- er, become unmasked at daytime when other sedating substances (e.g., ethanol) are ingested and the patient shows an unusually pronounced response due to a synergistic interaction (impaired abil- ity to concentrate or react). As the margin between excitatory and inhibitory activity decreases with age, there is an increasing tendency to- wards shortened daytime sleep periods and more frequent interruption of noc- turnal sleep (C). Use of a hypnotic drug should not be extended beyond 4 wk, because tol- erance may develop. The risk of a re- bound decrease in sleep propensity af- ter drug withdrawal may be avoided by tapering off the dose over 2 to 3 wk. With any hypnotic, the risk of sui- cidal overdosage cannot be ignored. Since benzodiazepine intoxication may become life-threatening only when other central nervous depressants (etha- nol) are taken simultaneously and can, moreover, be treated with specific ben- zodiazepine antagonists, the benzo- diazepines should be given preference as sleep remedies over the all but obso- lete barbiturates. 224 Hypnotics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypnotics 225 B. Wake-sleep pattern, stress, and hypnotic drug action Waking state NREM-sleep Neurons with transmitters: Histamine Acetylcholine Glutamate Norepinephrine GABA A. Transmitters: waking state and sleep C. Changes of the arousal reaction in the elderly Hypnotic Hypnotic 1 2 3 1 2 Emotional stress Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. . Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs. These drugs are eliminated within minutes after being adminster- ed, irrespective of the duration of anesthesia. 216 General Anesthetic Drugs Lüllmann, Color