HABITUAL USE OF BARBITURIC ACID DERIVATIVES IN INDIA By R. N. CHOPRA, C.I.E., m.a., m.d. (Cantab.) LIEUTENANT-COLONEL, I.M.S. and G. S. CHOPRA, m.b., b.s. {Drug Addiction Enquiry, Indian Research Fund Association. Series No. 22) Introduction.?During recent years a large number of barbituric acid derivatives have been introduced into therapeutics; the follow- ing are some of the important compounds known to the profession in this country :? (1) Barbitone, or veronal (di-ethyl-barbituric acid), (2) sodium barbitone, or medinal (sodium salt of barbitone), (3) proponal (di-propyl-barbituric acid), (4) neonal, or soneryl (N. butyl-etliyl-barbituric acid), (5) dial (di-allyl-barbituric acid), (6) phenobarbitone, or luminal (di-phenyl-barbiturie acid), (7) sodium luminal, (8) phanodorn (cyclo-hexenyl-ethyl-barbituric acid), (9) evipan (N. methyl-cyclo-hexenyl-methyl- barbituric acid), (10) sodium evipan, (11) pento- barbitone (ethyl-methyl-butyl-barbituric acid) and (12) its sodium salt, nembutal, (13) ipral (calcium ethyl iso-propyl-barbituric acid), (14) allonal (a com- bination of allyl-iso-propyl-barbituric acid with amido- pyrin), (15) veramon (a combination of veronal with amidopyrin), (16) somnifain> (a combination of dial and amidopyrin), (17) cibalgin (a combination of dial and amidopyrin), (these last four all produce a reddish- brown colour in urine on account of the presence of amidopyrin), (18) gardenal (phenyl-ethyl-barbituric acid), (19) sodium hebaral (sodium salt of hexyl- barbituric acid), (20) beatol (a proprietary preparation said to be a mixture of veronal with extracts of valerian and jusquiame), (21) quadronox (a propri- etary preparation said to contain 80 per cent veronal with phenacetin, phenazone, etc.; urine may be coloured reddish-brown from the phenazone present), (23) amytal (iso-amyl-ethyl-barbiUiric acid), (24) pernocton (2 butyl-brom-ethyl-barbituric acid), (the sodium salts of both these are used by the intravenous route to produce anaesthesia), (25) nastal (iso-propyl-brom- allyl-barbituric acid), and (26) sandoptal (iso-butyl- allyl-barbituric acid). The addition of alkyl or aryl radicles of higher mole- cular weight than ethyl adds to the toxicity of the substance, thus luminal, dial, proponal, gardenal, soneryl and nembutal are all more toxic than veronal. Launoy and Contiere, taking veronal as unity, have found that the relative toxicity for dial is 3.1, for soneryl 4.7, and for both amytal and nembutal 10.1. It is therefore safer to use for hypnotic purposes barbitone or its sodium salt than the more complex derivatives. Although these drugs as a rule are not very toxic and the average minimum fatal dose for barbitone (veronal) is 3 to 4 grammes (45 to 60 grains) deaths have occurred from much smaller doses, e.g., 1 gramme or 15 grains given in one dose. On account of their easy availability they have been used for suicidal purposes. The combination of a barbituric acid compound with an analgesic drug, such as amidopyrin, phenacetin, etc., occurs in veramon, allonal, cibalgin, ^Omnifaine and quadronox. Such combinations are likely to have more toxic effects on the organism and frequent repetition of therapeutic doses may produce serioua effects. Wagner (1933) has divided the barbituric acid com- pounds into two groups, (1) the shorter-acting drugs, which are eliminated rapidly and whose cumulative effects are not marked; to this category belong pento- barbital sodium, amytal and secondary butyl beta ABUSE OF BARBITURIC ACID DERIVATIVES: R. N. & G. S. CHOPRA 189 brom-allyl-barbituric acid sodium salt, and (2) the without unpleasant after-effects. There is more longer-acting drugs, which are eliminated slowly, have certainty of action than with most of the other marked cumulative effects and lead to delirious re- hypnotics, with the exception of opiates, and action or other toxic to this symptoms: category belong this is the reason for the of this phenobarbital, neonal, ipral, a barbital derivative with popularity of of the men- amidopyrin, dial and barbital. It may be generally group hypnotics. Many drugs said that combination with sodium makes the com- tioned have been used for basal anaesthesia, pounds more rapid in their action. The degree of those which are most commonly used at the toxicity of these compounds according to this author present time being nembutal, starting from the highest is as follows : pernocton, amytal secondary and On account of their effective butyl beta brom-allyl-barbituric acid sodium salt, evipan. barbital, phenobarbital, amytal, neonal, a barbital sedative properties, they are used in the treat- derivative with amidopyrin, dial and pentobarbital ment of chorea and sodium. hysteria, neurasthenia, epilepsy. Action and use.?The physiological effects of Toxic effects and habit formation.?In a these compounds comprise not only a specific paper in the Lancet, Sir James Purves-Stewart hypnotic action on the brain, but also on the and Sir William Willcox (1934) have described lungs, heart and kidneys. The heart rate is a series of cases of poisoning by barbitone and quickened, vasodilatation is produced and the allied drugs. Besides the toxic effects produced blood pressure falls partly owing to vasodilata- by massive doses of these compounds they also tion and partly to the toxic action of the drugs produce dangerous cumulative effects when on the myocardium; the pulse may become inter- repeated in therapeutic doses and there is a mittent. In severe cases death may occur from tendency to habit formation. These facts have heart failure. In certain patients, such as those not been sufficiently appreciated by the medical suffering from hyperthyroidism, exophthalmic profession in India. During recent years the goitre or severe toxaemia, sepsis, etc., the toxic use of barbituric acid derivatives has consid- effects of barbituric acid compounds are greatly erably increased in India and a number of com- enhanced so that even an ordinary therapeutic pounds, particularly luminal, veronal, medinal, dose veramon are may produce dangerous symptoms or even and adaline, being largely used fatal results. by medical practitioners. On account of their marked hypnotic and analgesic properties, less a tem- They produce slight fall in the body disagreeable taste and irritant effects, they are the basic metabolic rate is little perature; preferred to the chloral and sulphonal group affected; they have no appreciable effect on of drugs. The lay public have also begun to blood the calcium content of the blood sugar; use them, without medical advice, for the pur- is of this definitely decreased. All members poses of producing sleep or relieving pain, with series the and depress respiratory system pro- the result that in quite a number of cases habit duce physical signs of broncho-pneumonia. The J formation have occurred. output is diminished but urinary appreciably The of habit formation with these the flow returns to normal within about 24 question drugs has been discussed by (1934) hours; drugs like nembutal are said to Gillespie produce and he has forward certain a suppression of urine. Some workers have brought priori considerations against the likelihood of the found a slight but transient to the liver, damage | frequent occurrence of this. others consider very little action on the hepatic function. The tone of the gastro-intestinal While engaged in the study of drug habits muscle is decreased. So far as the nervous in India we have been making enquiries is system concerned the threshold for painful regarding the use of these drugs by the public stimuli is decidedly increased and during deep and have found that habit formation does narcosis no response to painful stimuli can be sometimes follow the use of members of this obtained. The pain has been controlled in group of drugs. Our enquiries show that addic- patients with or tabetic crises. Large doses, tion is still uncommon, as there are no in J but, susceptible individuals even small doses, may restrictions to the sale of these drugs, there is cause a drowsy condition accompanied by fever likelihood of the extension of this practice. and rapid development of coma. The psycho- Instances of abuse of these drugs are at present logical effects of these compounds have been confined to large towns only. We have been forked out; after administration of these drugs informed that certain members of this group there a is striking change in the emotional are being employed by young licentious individ- of attitude the subjects and a definite uals and for their sexual of feeling by prostitutes effects, euphoria is said to be obtained. and it has been alleged that they have been for im- The barbituric acid derivatives are perhaps employed for stupefying young girls We not the most commonly used hypnotics at the moral purposes. have, however, been case of this use Present day. When taken by the mouth they able to trace any nature. The are is at to the quickly absorbed and within an hour or so of barbiturates present confined a educated because have after clinical dose sleep usually ensues. After classes, probably they a of notices in the medical single therapeutic dose a period of sleep opportunities reading and the the and lasting from six to twelve hours usually occurs. lay press extolling hypnotic 190 THE INDIAN MEDICAL GAZETTE [April, 1935 analgesic properties and alleged freedom from only partly overcome by other measures for a few toxic and harmful effects of these drugs, and weeks. The patient then secretly bought a bottle of and started in doses of thus start self-medication. sodium barbitone taking it they 7$ grains daily. One pill was enough to produce The following cases which have come to our sound sleep in the beginning, but after some time he notice are typical examples of the abuse of had to resort to 2 pills to obtain the desired effect.