Some Biochemistry of Sedatives by J. CHEM. EDUC. Staff
Antianxiety Agents or Sleep-Inducers Americans now are spending nearly a billion dollars a year 3n sedative drugs. The great majority of these are prescribed by physicians-approximately one prescription in ten is for 3 sedative. A limited number of nonprescription preparations are available and are sold under trade names such as Compoz, Neruine, Nytol, Sleep-Eze and Sominex. Many claim that sedative drugs, especially antianxiety agents, are the most abused of all drugs. Sedatives have two essential roles: (1) they can relieve symptoms of anxiety, and (2) they can induce sleep. Mild tranquilizers, known to the public by registered names such as Valium, Librium, and Serax are primarily relaxants or daytime sedatives. Taken as prescribed, they can reduce anxiety, tension, and agitation without affecting the clarity of consciousness and the quality of psychomotor performance. (Thinking, learning, perception, coordination, and the things we need to do to function effectively in daily work are not adversely affected). Hypnotics or sleep-inducers can also act as relaxants. Given in small amounts, they may act to allay excitement and to reduce motor activity; larger doses can produce a state of drowsiness or induce sleep. Following are Formulas for some substances commonly prescribed as sedatives
Amobarbitai ~mytal@ Intermediate duration of acting sedation. 16-50 mg hypnotic. 100-200 mg
Nonborbiturotes used
He~tabarbital ~edomin@ Short-acting sedation. 50-100 mg hypnotic. 200-400 mg
os Sedotiues CH,-CH,-CH,
0 II
I
Meprobamate
quan nil^. ~ i l t o w n @ Relaxant and Mild Hypnotic Dose: 400 mg every 3-4 hrr
H-N-C-NH-H
II
0 Diazepam ~a~ium@ Dose: 2-10 mg repeated in 3-4 hrs.
Methapyrilene Hydlochloride An antihistamine used in many nonprereription sedatives 50 mg u p t o 4 timer daily
I II I 0 CH /\
CH, CH, Bromirovaium ~rominal@ Daytime sedative Dose: Sedation. 300 mg Hypnotic. 600-900 mg
Discoveries of Sedatives 2hlordiazepoxide H drochloride Librium& 5--10 mg, 3-4 timer daily
Oxarepam
~eraxa 10--15 mg 3-4 times daily
Barbiturates: Hypnotic Sedotiues H
O=C'
I N
'C-OH
402 1 Journal of Chemical Education
Phenobarbital ~uminal@ Long-Acting Dose: sedation. 15-30 mg 3-4 times daily hypnotic. 100 mg at bedtime
Although the sedative properties of alcohol were known and used in China prior to 800 B.C., and in European countries at least as early as the 13th century, other physiological effects of this substance limited its medical use as a sedative. The oldest widely-used sedatives were bromides (NaBr and KBr) introduced into medicine in 1821. In 1853, a Dr. Loekock, having become convinced that epilepsy might be caused hv an overabundance of sexual eniovment, and believing that .. I~rornideswere a sexunl sedntive, twgan using hromides to treat ~:pil~:piy. Although Lorkock's hypothesis was incorrect, bromides did-and do--depreis epileptic a~nvulsions.They were used for many years for this purpose and as a general relaxant. However, because the bromide ion can replace chloride ion in body fluids, giving rise to a poisoning known as bromism, bromides are no longer considered appropriate.
From 1869 until very recently, chloral hydrate, CClsCH(OH)2, was used extensively as a sedative. Although this suhstance is one of the most reliable and safe sedatives known, mixing it with alcohol produces a combination known as a "Mickey Finn," a very potent and dangerous depressant. As with the bromides and enile~sv.an erroneous idea led t o the use of chloral hydrate i s sedative. I t was known that chloroform induces sleep but that it was slow in entering the blood. Chloral hydrate-because of its polar OH groupsmieht enter the blood faster, and once inside the hody should react to form chloroform. Although no chloroform resulted from its degradation in the human hody, chloral hydrate hecame the first synthetically produced, reliable hypnotic. After more than 100 years, it is still in use. Harhifuric myidand the hnrt)itnrates-the most frequently prrscril)ed hypnoric scdat:\.es-were first prepared by the chemist, ,\rlolph von Haeyrr in 1863. The first harbiturates were inrnduced into clinical practice in 1903.Since then, more than f i f ~ vdifferent harbiturates haw found clinical use at one time or another. The suhstance known as Lihriuma (chlordiazepoxide hydrwhloride,, was first synthesized nt Roche aho oratories in 195;.'l'hi.; tvur ofchemical never had been tested in hiologic systems, a n z t was impossible to anticipate what activity, if any, it might have. When Dr. Leo H. Sternhach, the Roche medicinal chemist who directed the work with Librium," sent the new compound to pharmacologists for testing, he suggested that it might have activity in the central nervous system. He was right! When given to wild monkeys, they acted like tame animals. and could he handled with no difficulties. When given to a Russian lynx, a Sumatra tiger, Australian dineos. marmosets. and other wild animals a t the San Diego zoo, tl;e animals became tame but remained wide awake, playful, and cooperative. With human subjects, Librium'was found to he especially useful when fear, anxiety, and tension were significant features of the disorder. In 1963, Dr. Sternhach's group a t Roche developed and marketed a second mild tranquilizer, diazepam, under the trademark Valium".
Biologic Responses to Anxiety Anxietv-termed the most nervasive nsvcholoeical nhe." nomenon of our times-is characterized by restlessness, tension. and irritahilitv. These can lead t o ~roblemsin slee~inn . and disturhances innormal or everyday functioning. A certain amount of anxiety is inevitable or normal. Allowed to go to an extreme it can become pathological. In essence, anxiety is response to a perceived threat Gust as depression is response to a loss). In a world in which one's existence is continually threatened, anxiety is a normal component of daily life and a universal human experience. Tension is a necessary component of anxiety, though tension also can result from stress caused by overwork, meeting deadlines, etc. Auxietv, tension, and stress can lead to disturbances in our sense bf well-being and to changes in the way we function. At their base, these anxiety-caused disturbances are a result of slight alterations in the chemistry of the brain and other parts of the central nervous system (CNS). Even though much is still to be learned about the ways that anxiety alters the chemistry of the CNS, some conclusions can he drawn. Three components are necessary for the subjective experience of anxiety: arousal, a property mainly responsible for the intensity of anxiety; affect, a factor that refers to the specific qualities of feeling and resportse that characterize anxiety; and awareness, a quality that enables us to perceive anxiety and to evaluate'it in our minds. Arousal is under control of a portion of the CNS located in the hrain stem. The hrain stem connects the hrain to the spinal cord. Nerve signals from all parts of the hody ascend to the hrain through pathways in the hrain stem. Similarly, the brain sends signals to all parts of the body through descending pathways in the brain stem. A component of the hrain stem
monitors and selectively limits all sensory input to the hrain, thereby controllingan,usal of the brain and the intensity uf anxiety or other sensations. Sleep, for example, is chnr;~c~erized bv a diminutim nfacti\.itv in certain aicendinx and descending brain stem pathways. According to present theory, affects (suhjective feelings and responses) are dealt with in the limbic system of the CNS. This svstem is located in the inner brain, where i t is in communicitiou with the body's internal organs and external sensory receivers. The limhic system appears to he responsible for the interpretation of all personal experience in subjective terms of feeling. Awareness and its internretation are reeulated in the neocortex of the brainmatter" located in the u m e r front brain area. The neocortex might he considered hbth a central receptor and effector stricture. It receives stimuli that Droduce anxiety, and it registers anxiety after this has been amplified or elaborated in the brain stem and limhic system. According to one, admittedly overly simplified, model, matters related to the perception of anxiety as an everyday universal human exoerience are dealt with in the neocortex: matters associated with the nervousness and worry aspects of anxietv are elaborated in the limbic svstem: and matters connecteh with tension and stress-induced disturhances arising from anxiety find physiological expression in the hrain stem-more specifically, in the reticular activating system. Within each of these systems in the CNS, the prolonged presence of anxiety can cause alterations in the amounts of and balance among key chemicals, and in the effectiveness with which these chemicals perform their biologic roles.
0 Chemistry of Sedatives Before anxiety-blocking or sleep-inducing drugs can perform their functions, they must reach the brain or other parts of the CNS. However, the brain possesses a unique and specialized mechanism for excludine manv suhstances resented to it by the circulating blood. ~ t k i l lo,"f ~ o u r s e , ~ l l oxygen, ok glucose, and a few other essential compounds and ions to he transported across the blood-brain harrier. Other than these, only a few un-ionized molecules that are' soluble in lipids (nonpolar suhstances) are able to pass. Included among these are certain weak organic acids (such as the barbiturates), and certain weak organic bases (such as the tranquilizers). Recent studies show that the mild tranquilizers such as Valiuma and Libriuma exert most oftheir action on the limhic system. Certain nonharhiturates with hypnotic properties, such as menrobamate (Miltown". Eauanil"), mav act ~ r i marily in the brain stem where they' canbring about;elaxation of skeletal muscles. Barbiturates a . m.e a r to he active in all three systems. These locations of ~rincioalaction can account for some of the differences in the effects produced by the several classes of sedatives. For example, drugs that inhibit processes in the neocortex can produce a state of drowsiness by slowing down our awareness and responsiveness. In larger doses, they might induce sleep; in still larger doses they could cause a virtual shut-down of the central nervous system, resulting in death. Drugs that inhibit processes primarily in the hrain stem can cause relaxation of muscles, and in this way also produce a state of lowered tension. In larger doses, they might create drowsiness and facilitate sleep. Excessive doses might cause too much inhibition of muscle activity, leading to disturhances in normal function. Drugs that act primarily in the limhic system, might be able to alter our sense of well-being without greatly affecting clarity of consciousness or quality of psychomotor performance. Some such drugs might tend to lessen our aggressions, others to intensify them. Among the most important chemicals in the hrain and in other parts of the CNS are the hiogenic amines, represented by acetylcholine and norepinephrine Volume 56. Number 6, June 1979 1 403
central stimulant effect of norepinephrine and related suhstances. HO
Norepinephrine (Noradrenaline)
I
CH,
I
0
Acetylcholine
These substances, and others closely related to them, transmit nerve signals from one nerve terminal (synapse) to another throughout the nervous system. They also appear to he importantly involved in the body's response to tension, anxiety, and depression. A deficiency of norepinephrine in the hrain and CNS appears to accompany depression. An excess of this substance may produce tension and anxiety. In fact, our readiness for "fight or flight" corresponds precisely to an increase in the secretion of norepinephrine in the CNS. By contrast, the acetylcholine content of the hrain is higher during sleep than during the waking state. Limited experimental evidence1 indicates that most sedative drugs may play their ultimate biologic role in the chemistry of norepinephrine and related hiogenic amines. The mild tranquilizers, the barbiturates, and compounds like meprobamate and brumisovalum all appear either to induce a decrease in the excretion of biogenic amines or to oppose the
Toxicity and Side Effects As might he expected of chemical substances powerful enough to reach the hrain and to alter its chemistry, these drugs have many and sometimes unpredictable side effects. Most are extremely toxic; many are addictive. They should be used only under the supervision of a physician. Although the mild tranquilizers are relatively safe-no deaths have been reported when these are taken alone in overdose, and studies have failed to show patterns of physical dependence-two adverse effects of these drugs have emerged: (1) Mixing them with alcohol and other drugs can create a life-threatening situation-900 deaths attributable to this cause were reported between May 1976 and April 1977; (2) Frequent intake of gradually increasing doses, especially among young adults has led to drug abuse problems, some of which are described by physicians as psychological dependence, personality changes, and alteration of normal drives. Widespread use of mild tranquilizers has made it clear that medication cannot "cure" anxiety and severe stress. To remain healrhy, ind~vidudlic.xp4mring surh rlitiiculries muct adjust th(,ir nrtit~~rles and lite styles so th.31 anxwty and stress can be minimized or used to advantage. Literature Cited Lehman. H. E.,and Ban. T. A . "Pharmacatherapy dTension and Anxiety,'C. E. Thomas. Springfield. Illinois. 1970. Wiln~n.?. 0..Cisuold. 0..end Iherge, I
