鎮靜安眠藥：成癮性與其研究現況   全文下載

Sedative-Hypnotics: Addiction and Current Research Status

酒精，巴比妥類藥劑和benzodiazepines等中樞神經系統抑制藥，在人類和動物均具有同等效力。依使用劑量的不同，這些藥劑對中樞神經系統會產生不同程度的抑鬱作用。當小劑量給藥時，這些鎮靜安眠藥可減輕病人的焦慮和降低其自發性動作。中等劑量則引發嗜睡，相反的，大量服用時則導致嚴重的中樞神經系統抑鬱，進而引起麻木、昏迷甚至死亡。這種依據劑量不同所引致的中樞神經系統抑鬱上的差異也是鎮靜安眠藥分級的一個共同特性。這類藥物，除了引起中樞神經系統抑鬱外，尚含有藥理學上的某些性質，例如：促進肌肉鬆弛，抗痙攣作用，和緩呼吸及降低體溫等。長期的服用鎮靜安眠藥，往往造成服用者對這將藥劑產生耐受性和依賴性，所謂的耐受性就是對這些藥物作用的感受性因繼續的使用而降低，或者需服用更高劑量才能達到最初服用時的效果。至於藥物耐受性歸結可分成兩種型態，一種是傾向性藥物耐受性（屬藥物動力的），另一種則是功能性的藥物耐受性（屬藥效的）。藥物依賴性則導因於生理功能的一種修飾作用，病人必需繼續不斷的使用該類藥劑才能阻止脫癮徵狀的出現，長期服用者如果突然戒除該類藥物則會產生焦慮、暈眩、噁心、嘔吐、失眠、抽動、發熱、譫妄、顫抖、全身痙攣，甚或死亡。証據顯示，鎮靜安眠藥，例如benodiazepines，巴比妥類藥劑和酒精等，其某些藥理學上的作用可能是藉著模擬γ-胺基酪酸（GABA）的傳遞來達成，然而，這些藥劑在GABA系統上的作用機轉則仍待探討，即使如此，benzodiazepines的受體已經被証實係GABA受體的一部分。關於巴比妥類藥劑，雖然其在GABA系統上確切的結合位置尚未被定出，但是許多有力証據顯示巴比妥類藥劑和發厥藥劑係結合在不同位置上，但這兩個結合位卻彼此藉著異位立體形式（allosteric）相互影響。至於酒精可能是影響在多數的神經傳導系統上。GABA胞突接合（synapse）在這些鎮靜安眠藥之藥理效用上扮演一個重要的角色，然而這些中樞神經抑制藥對GABA胞突接合之藥理上和生化上的影響則有所異同。這類藥物對GABA胞突接合影響又會因不同腦部區域而有所差異。文獻上對這方面的報導頗不一致，這些差異可能是研究者（a）使用不同的動物模式（b）使用不同腦部區域（c）不同的動物處理條件或（d）不同技術所致。

Central nervous system depressants, e.g. alcohol, barbiturates, and benzodiazepines, have a wide spectrum of activity in human and animals. These depressants produce varying degrees of CNS depression, depending mainly upon the dose used. In small doses, they can alleviate anxiety and/or reduce spontaneous activity; in moderate doses, they induce sleep; with large doses, severe CNS depression progresses to anesthesia, coma or even death. This graded, dose-dependent CNS depression is a common feature of these agents. In addition to causing CNS depression, these agents also possess other pharmacological properties, e. g. muscle relaxation, anticonvulsant activity, respiratory depression, hypothermia, etc. Tolerance-dependence developing to sedative-hypnotics is a common feature following continuous administration of sedative-hypnotics. Tolerance is defined as a decreasing response to repeated administration of the same dose of a sedative-hypnotic or as a necessary increase of the dosage to obtain the initial response. There are two types of tolerance-one dispositional (pharmacokinetic), the other functional (pharmacodynamic). Dependence is defined as a modification of physiological functions that require continuous drug administration to prevent the appearance of withdrawal symptoms. Abrupt withdrawal from long-term usage of these drugs may produce anxiety, dizziness, nausea and vomiting, insomnia, muscular twitching, hyperthermia, delirium, tremors, convulsions, and death. Evidence accumulated suggests that some of the pharmacological actions exerted by sedativehypnoties, e.g benzodiazepines, barbiturates and alcohol, may be mediated through the GABA system by mimicking GABAergic transmission. However, the mechanisms of the actions of these agents on the GABA system remain to be elucidated. Benzodiazepines have been demonstrated to have receptors which arc parts of the GABAA receptors (GABA benzodiazepine receptor chloride ionophore complexes). Although a definitive barbiturate binding site has not yet been identified, the available evidence strongly suggests that barbiturate binding sites and convulsant binding sites are separate but allosterically affect each other. As far as ethanol is concerned, it is likely that multiple neurotransmitter systems are affected. Therefore, it is still unclear how alcohol, barbiturates, and benzodiazepines are functionally associated with the GABA system. The evidence summarized demonstrates that the GABA synapse plays an important role in the pharmacologic effects of barbiturates, alcohol and benzodiazepines. There are similarities and differences in the effects of these CNS depressants on the pharmacology and biochemistry of the GABA synapse. The effects of alcohol, barbiturates and benzodiazepines on GABA synapses are different in different brain regions. Furthermore, the results which have been reported in the literature are inconsistent. This may be due to differences in (a) animal models used, (b) brain regions used, (c) protocols used in treating the animals (dose, duration, form and route of administration, etc.) and/or (d) techniques used (pharmacological, biochemical, physiological, etc.).