20. Sedative/hypnotics death surgical anesthesia coma unconsciousness sleep sedation Drug dose Most non-benzodiazepine sedative/hypnotics Benzodiazepines, Zolpidem, Zaleplon
Sleep is subdivided into : rapid eye movement (REM) sleep, which is characterized by high-frequency electroencephalogram (EEG) recordings and muscle atonia non-REM (slow-wave) sleep, characterized by low frequency EEG recordings and body rest
During sleep, the brain generates a patterned rhythmic activity that can be monitored bymeans of the electroencephalogram (EEG). Internal sleep cycles recur 4–5 times per night, each cycle being interrupted by a rapid eye movement (REM) sleep phase (A). The REMstage is characterized by EEG activity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of individual muscle groups against a background of generalized atonia of skeletal musculature. Normally, the REM stage is entered only after a preceding non-REM cycle.
GABA neuron ending release GABA ， agitate GABAA receptors on postsynaptic membrane . GABAA receptor is constructed by two αsubunits and two βsubunits . GABA binds to GABAA receptorβsubunit and open Cl channel ， resulting in Cl － inflow , postsynaptic neurons potential decline and membrane hyperpolarization . The cell is hard to be excited . When GABA exhausted ， the role of the drugs disappear ， indicating that the role depends on GABA but not the receptor
Graded dose-dependent depression of central nervous system function is a characteristic of most sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of central nervous system depression. The linear slope for drug A (most non benzodiazepine drugs) is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments to achieve central nervous system depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.
Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects. At higher dosage, both groups promote the onset of sleep or induce it (C). At low doses, benzodiazepines have a predominantly anxiolytic effect. Unlike barbiturates, benzodiazepine derivatives administered orally lack a general anesthetic action; cerebral activity is not globally inhibited (the virtual impossibility of respiratory paralysis negates suicidal misuse) and autonomic functions, such as blood pressure, heart rate, or body temperature,are unimpaired. Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates. Zolpidem (an imidazopyridine), zaleplone (a pyrazolopyrimidine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, can bind to the benzodiazepine site on the GABAA receptor (p. 222). However, their effects do not appear to be identical to those of benzodiazepines. Thus, compared with benzodiazepines, zolpidem exerts a weaker effect on sleep phases, supposedly carries alower risk of dependence, and appears to have less anxiolytic activity. Heterogeneity of GABAA receptors may explain these differences in activity. GABAA receptors consist of five subunits that exist in several subtypes
Shortening of REM sleep (normally~ 25% of total sleep duration) results in increased irritability and restlessness during the daytime. With undisturbed night rest, REM deficits are compensated by increased REM sleep on subsequent nights Hypnotic drugs can shorten REM sleep phases With repeated ingestion of a hypnotic on several 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 tapers off only over many days Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unrefreshing. Thus, the attempt todiscontinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic drug dependence.
Sedative-hypnotic drugs. In: Basic and clinical pharmacology, 8 th edition. Katzung BG. USA: The McGraw Hill Companies, Inc, 2001:364–381. Benzodiazepines (BDZs) bind to the gamma sub-unit of the GABA-A receptor. Their binding causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. BDZs do not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential A model of the GABA A receptor-chloride ion channel macromolecular complex. The complex consists of five or more membrane-spanning subunits. GABA appears to interact with alpha or beta subunits triggering chloride channel opening with resultant membrane hyperpolarization . Binding of BZs to gamma subunits facilitates the process of channel opening
The speed of Absorption and the extent of plasma binding are in equilibrium with liposolubility . More than 90 % bind -> absorbed quickly, such as diazapam , etc. Liver metabolism : metabolised to a range of active substances by liver drug enzyme , t1 / 2 longer than the mother nuclide . Demethyldiazapam is metabolised to a wide range of active metabolins, t1/2 20-100 hr.
Fig. 3 : demonstrates the short-acting drugs are those that are metabolised directly by conjugation with glucuronide. gradual bild-up and slow disappearance of nordazepam from the plasma gives long-acting drugs. Remember AGE: advancing age affects the rate of oxidative reactions more than that of conjugation. the effect of long-acting BZs tends to increase with age (drowsiness and confusion)
reduction of anxiety and agression : Note: BZ may paradoxically produce an increase in irritability and aggression in some individuals (particularly if short- acting drugs are given (triazolam) Advantages : high selectivity , wide safety margin , slow elimination , lasting effects ,low dependence and light withdrawal symptoms. Clinical applications : anxiety with obsessive-compulsive disorder , gastrointestinal neurosis ,heart neurosis . Strychnine and other drugs cause seizures. sedation and induction of sleep BZs decrease the time taken to get to sleep increase the total duration of sleep (only in subjects who normally sleep for less than about 6 hours each night) REM sleep ( rapid eye movement) is less affected if compared with the same effect of other hypnotics. Is that important? Yes , artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced). Clinical applications ： Narcotic administration —— calm Treat insomnia —— difficult to fall asleep , wake up easily and early reduction of muscle tone and coordination may be clinically useful: increased muscle tone is a common feature of anxiety states and may contribute to pains (headache). Influence of manual skills (!) anticonvulsant effects (GABA A receptors) clonazepam to treat epilepsy diazepam (i.v.) status epilepticus to control life-threatening seizures anterograde amnesia BZs obliterate memory of events experienced while under their influence Lapsus memoriae ： damage in recent memory (reversible)
At low doses symptoms can include sedation, drowsiness, ataxia, lethargy, mental confusion, motor and cognitive impairments, disorientation, slurred speech, amnesia, dementia, etc. At high doses mental and psychomotor dysfunction can progress to hypnosis (i.e., pass out) o Respiration is not seriously depressed, unless benzo is taken concurrently with another CNS depressant (i.e., alcohol) o Short-acting agents taken at bedtime can result in both early-morning wakening and rebound insomnia the following night o Long-acting agents taken at bedtime can result in daytime sedation the following day Cognitive impacts are considerable: o Inhibition of learning behaviors, academic performance, and psychomotor functioning common These symptoms can persist long after treatment is discontinued Ethanol strengthen toxicity Through the placenta : teratogenicity role
Reputation for causing only a low incidence of abuse and dependence, however, when taken for prolonged periods of time, dependence can develop and result in withdrawal Withdrawal symptoms include: Return (and possible intensification) of anxiety state, increases in rebound insomnia, restlessness, agitation, irritability, etc.
Clinical Pharmacology
The centrol role is related to the activation of GABAA receptors . Barbiturates can function as GABA in the absence of GABA , which can increase the permeability of Cl － channel , leading to the cell membrane hyperpolarization . Different from BZ drugs which increase Cl － channel opening frequence ， barbiturates mainly extend the Cl － channel opening time . In addition ， barbiturates can weaken or block the excited reaction resulted from depolarization caused by the glumatic acids and inhibit the CNS .
Oral and intramuscular injection absorption->distribution all over the body , body fluid ->brain High liposolubility （ metabolised by liver drug enzyme ）-> eliminated in urine （ short maintenance time ） Low liposolubility-> eliminated in original form （ long maintenance time ）
Barbiturates generally inhibit the CNS . It has sedative , hypnotic , anticonvulsant , antiepileptic and anaesthetic effect at different doses from low to large , respectively . Inhibit cardiovascular system at large dose . 10 times of hypnosis dose can cause respiratory paralysis and death . Poor safety ， easy to cause dependence . The application has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia .
Clinical Pharmacology
After effect :dizziness , drowsiness , fine uncoordinate movement Allergic response : nettle rash , angioneuroedema , erythema mlutiforme Tolerance Dependence Acute intoxication :significant inhibit respiration center
The drug is a inducer of liver drug-metabolizing enzymes and promote metabolism of other drugs . The main cause of death of barbiturates is deep respiratory inhibition . In pregnant and lactant period , the thyroid function is low . Patients who have fever , anaemia , hypotension , hemorrhagic shock , heart , liver , kidney dysfunction and old people with mental disease should take the drug with caution . Patients with respiratory inhibition caused by bronchial asthma and head injury , severe liver dysfunction , uncontrolled diabetes and who is allergic are forbidden to take
Clinical Pharmacology
binds selectively to the BZ 1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition like the BZs, the actions of zolpidem are antagonised by f l u m a z e n i l minimal muscle relaxing and anticonvulsant effects the risk of development of tolerance and dependence with extended use is less than with the use of hypnotic BZs
Short half-life hypnotics , e.g., triazolam, zolpidem, and zaleplon, are essentially gone from the blood within 8 hours. Thus, they cause little hangover, but may not help patients with early awakening. Indeed, triazolam (and zolpidem cause early awakening for some patients, particularly with prolonged usage. These drugs may also produce daytime agitation or anxiety. Hypnotics with half lives of 8-12 hours, e.g., temazepam, help promote sleep at the end of the night, but they may still have significant blood concentrations in the morning. Accordingly, they cause considerable hangover. Eszopiclone, with a half-life of 6-9 hours, is somewhere between the short and intermediate half-life drugs, as is Ambien CR. None of these drugs will accumulate, since they are largely gone by the following bedtime. Drugs such as flurazepam with long-lasting active metabolites (and active metabolites of diazepam) have a half-life of several days. Thus, they will accumulate night after night. In the elderly, the half-lives of these drugs may extend to a week or more. Accordingly, patients who take these drugs (especially elders) may experience insidious obtundation, confusion, or impaired behavior. Because of the long half-life, it may take a week or two for patients to recover from these drugs. On the other hand, stopping these drugs causes no immediate withdrawal symptoms.
Simulated absorption and metabolism of hypnotics is shown, when a sleeping pill is taken at bedtime. Low concentrations 5-8 hours after bedtime may lead to withdrawal and early awakening. After getting out of bed, residual concentrations of the sleeping pill will produce possible hangover. The curve for eszopiclone shows metabolism estimated for a person about 60-70 years old. For a younger adult, the eszopiclone curve would be closer to the Ambien CR curve.
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