Drugs Affecting the Central Nervous System 1. Depressant Drugs 1.1. General Anesthetics General anesthesia is a depression of the central nervous system carried out under controlled and reversible conditions so that loss of sensation and consciousness results. Drugs given to induce or maintain general anesthesia are either given as: - Gases or vapors (inhalational anesthetics) - Injections (intravenous anesthetics) Most commonly these two forms are combined, with an injection given to induce anesthesia and a gas used to maintain it, although it is possible to deliver anesthesia solely by inhalation or injection. 1.1.a. Inhalation Inhalational anesthetic substances are either volatile liquids or gases and are usually delivered using an anesthesia machine. An anesthesia machine allows composing a mixture of oxygen, anesthetics and ambient air, delivering it to the patient and monitoring patient and machine parameters. Liquid anesthetics are vaporized in the machine. Many compounds have been used for inhalation anesthesia, but only a few are still in widespread use. Desflurane, isoflurane and sevoflurane are the most widely used volatile anesthetics today. They are often combined with nitrous oxide. Dr. Amged 1 Older, less popular, volatile anesthetics, include halothane, enflurane, and methoxyflurane. 1.1.b Injection Injection anesthetics are used for induction and maintenance of a state of unconsciousness. Anesthetists prefer to use intravenous injections as they are faster, generally less painful and more reliable than intramuscular or subcutaneous injections. Among the most widely used drugs are: 1.2. Sedative & Hypnotics A Sedative drug is a CNS depressant that decreases excitability but does not induce sleep. On the other hand, a hypnotic drug is a CNS depressant that produces sleep; used to induce sleep when natural sleep is impossible. Sedative-hypnotics often are referred to as sleeping pills and are used to treat insomnia. This class of drugs causes drowsiness and facilitates the initiation maintenance of sleep. The observed pharmacological effects of most drugs in this class usually are dose related. Small doses cause sedation, larger doses cause hypnosis (sleep), and still larger doses may bring about surgical anesthesia. Insomnia can be classified as primary (pathogenesis unknown) or secondary (from other causes). The latter is more common and can be the result of situational stress, Dr. Amged 2 lifestyle habits, drugs, and psychiatric or medical disorders. The drugs currently used as hypnotics are effective, but there is ample need for newer and safer hypnotics. The ideal sedative-hypnotic should: 1) Cause transient decrease in the level of consciousness for the purpose of sleep without lingering effects (sleep induction and sleep maintenance). 2) Have no potential for decreasing or arresting respirations (even at relatively high doses). 3) Produce no abuse, addiction, tolerance or dependence. 1.2.1 Physiology of Sleep 1.2.1.a Sleep Cycle Sleep is studied using related techniques that permit electronic monitoring of the head and neck muscle and eye movements. Form these and related studies, three states have been defined: (1) Wakefulness. (2) Nonrapid eye movement [NREM] sleep. (3) Rapid eye movement [REM] sleep. 1.2.1.b Sleep Factors The involvement of many autonomic, physiologic, and biochemical changes are associated with these wakefulness, NREM sleep, and REM sleep. The relationship of cause and effect in relation to these systems is still somewhat controversial and a rapidly changing area of research. Several brain regions that regulate sleep have now been identified; however, the specific contribution on any one region to sleep is still controversial. The roles of the major systems are important to be familiar with in relation to sleep. This not only helps one to understand the mechanism by which hypnotics work but also provides some understanding of why unrelated drugs, such as neuroleptics, Dr. Amged 3 antihistamines, antidepressants, and antimanic drugs, occasionally are used as hypnotics to facilitate sleep. Every neurotransmitter has, at one time or another, been implicated in sleep or wake fullness, for examples: (1) Catecholamines. (2) Serotonin. (3) Histamine (4) Acetylcholine. (5) Adenosine. (6) γ-Aminobutyric acid: it probably represents the most important inhibitory transmitter of the mammalian CNS. Both types of GABAergic inhibition (pre- and postsynaptic) use the GABAA receptor subtype, which acts by regulation of the chloride channel of the neuronal membrane. A second GABAergic type, GABAB, that is a G protein-coupled receptor is not considered to be important in understanding the mechanism of hypnotics. Activation of a GABAA receptor by an agonist increases the inhibitory synaptic response of central neurons to GABA through hyperpolarization. Because many, if not all, central neurons receive some GABAergic input, this leads to a mechanism by which CNS activity can be depressed. For example, if the GABAergic interneurons are activated by an agonist that inhibits the monoaminergic structures of the brain stem, hypnotic activity will be observed. Some hormones have been found to have a significant effect on sleep and circadian rhythmcity, for examples: (1) Growth hormone. (2) Prolactin. (3) Melatonin Dr. Amged 4 1.2.3 Classification of Hypnotics: The hypnotic drugs are not characterized by common structural features. Instead, a wide variety of chemical compounds have been used in clinical therapy. 1) Chloral. 2) Barbiturates. 3) Benzodiazepines. 4) Nonbenzodiazepines 5) Melatonin receptor agonists. 6) Antihistamines. 7) Antidepressants. 1.2.3.a Chloral Hydrate It was introduced as a sedative in 1869. During the 1950s and 1960s, chloral hydrate was widely promoted as a hypnotic. Today, it still finds use as a sedative in nonoperating room procedures for pediatric patients. Chloral is a unique aldehyde because of the electron-withdrawing effect of CCl3 group. When chloral (an oily liquid) is treated with water or alcohol, a crystalline solid, chloral hydrate, is formed. Chloral hydrate is stable, but as indicated below, when it is dissolved in water, it is in equilibrium with the chloral form (equilibrium strongly favoring the chloral hydrate structure). The CCl3 group is sufficiently electron-withdrawing that chloral hydrate is a weak acid (pKa = 10.04). This acidity makes it quite irritating to mucous membranes, such as in the stomach. Dr. Amged 5 Chloral hydrate is readily absorbed from the gastrointestinal tract following oral or rectal doses and is quickly reduced to trichloroethanol, its active metabolite, by alcohol dehydrogenase in the liver and erythrocytes. Trichloroethanol is metabolized by alcohol dehydrogenase oxidation to chloral and then to the inactive metabolite trichloroacetic acid via ldehyde dehydrogenase. Trichloroacetic acid is excreted in the urine as a glucuronic acid conjugate. Cl O alcohol Cl OH dehydrogenase Cl C Cl C H Cl H Cl H Chloral Trichloroethanol active metabolite aldehyde dehydrogenase Cl O Cl C Conjugation Cl OH Trichloroacetic acid inactive metabolite 1.2.3.b Barbiturates Older medications, such as the barbiturates, are used as sedative-hypnotics, but toxicity limits their widespread use. For example, they can cause significant central nervous system (CNS) depression, physical dependence, and tolerance. Additionally, they are potent inducers of liver enzymes, which can lead to clinically significant drug interactions when these medications are administered with other drugs extensively metabolized by the liver. Barbiturates are cyclic ureides and are formed when a dicarboxylic acid reacts with urea. The acids used are generally in the form of ester and are condensed in the presence of sodium ethoxide (C2H5ONa). Dr. Amged 6 Parabanic acid is a cyclic ureide containing five membered ring, which on hydrolysis by alkali may regenerate the corresponding acid and urea. The cyclic ureides are acidic owing to enolization and hence, they may form metallic salts by replacing the H atom of the –OH group as shown below: Or Many cyclic ureides are derived from malonic acid or malonic esters. They are collectively known as barbiturates because of their relationship of barbituric acid (malonyl urea). Barbituric acid is prepared by the following two methods: (a) By the interaction of urea and malonyl dichloride Dr. Amged 7 (b) By the interaction of urea and diethyl malonate Barbituric acid like parabanic acid exhibits keto-enol tautomerism as illustrated below: In thiobarbiturate the oxygen of the carbonyl group of the urea residue is replaced by a sulfur atom (thiourea). However, it is interesting to observe that the barbituric acid itself does not possess any hypnotic properties, but such characteristic is conferred only when the hydrogen atoms at C-5 are replaced by organic groups (alkyl or aryl). Dr. Amged 8 The barbiturates are 5,5-disubstituted barbituric acids. The following scheme shows how the 5,5-dialkyl compounds are synthesized. Substitution of thiourea for urea produces the 2-thiobarbiturates, useful as induction anesthetics. 1.2.3.b.1 Clinical applications A prescription for long-term use of barbiturates as hypnotics rarely is indicated. The currently available barbiturates are shown below: Hypnotic Onset Duration Barbiturate R5 R5 Dose (mg) (min) (hours) Amobarbital C2H5– (CH3)2CHCH2CH2– 100–200 45–60 6–8 Aprobarbital CH2=CHCH2– (CH3)2CH– 40–160 45–60 6–8 Butabarbital C2H5– CH3CH2CH(CH3)– 50–100 45–60 6–8 Pentobarbital C2H5– CH3(CH2)2CH(CH3)– 100 10–15 3–4