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Universitatea Stefan cel Mare, Suceava Facultatea de Inginerie Alimentara Depistarea si analiza drogurilor

PINTILEI CRISTINA CEPA 1-b ANUL IV

Barbiturice intravenoase

Abstract Adolf von Baeyer a sintetizat acidul barbituric n 1864 prin reacia cu acid malonic uree. Acidul barbituric este clinic inert, i nu a fost pn la sinteza acidului barbituric dietil n anul 1882 privit ca un sedativ din punct de vedere cand clinic a devenit util. Numit "veronal" de ctre Fischer, el i von Mering au descris pentru prima data utilizarea sa in 1903. Au urmat mai multe derivate ale moleculei barbiturice de baz, i dezvoltarea de anestezie intravenoasa. Dei muli au avut scurte perioade de popularitate, a fost tiopental de sodiu, care le-a surclasat pe toate. Referinte In a doua jumtate a secolului 19, clinica medicala a fost echilibrata, in ateptarea introducerii unei anestezii intravenoasa, cu excepia faptului c nu a existat nici un medicament adecvat. Pierre-Cyprien Ore a experimentat hidratul de cloral intravenoas n 1872, dar din cauza recuperarii lente si mortalitatii ridicta s- intarziat cu dezvoltarea in continuare a metodei. n nceputul secolului 20, mai multe medicamente, inclusiv Hedonal, Paraldehyde, sulfat de magneziu i eter intravenoas de 5%,au realizat popularitate ridicata. Cu toate acestea, nu au fost disponibile pn la introducerea de barbiturice ca o alternativ real la anestezia de inhalaie . Adolf Johann von Baeyer a sintetizat pentru prima data acidul barbituric n 1864 prin reacia cu acid malonic uree (Fig. 1). El a primit Premiul Nobel n chimie pentru activitatea sa ulterioar n chimia organic i vopsele organice. Se spune c el a numit acidul barbituric nou compus dup celebra sa descoperire ntr-o tavern Ghent local.

fig 1 Acidul barbituric este clinic inert i a strnit interes sczut pentru muli ani. Nu a fost descoperit pn la nceputul secolului cnd Hermann Emil Fischer, profesor de chimie la Berlin, i Dilthey asistentul su,au ntreprins cercetri suplimentare cu privire la acidul barbituric dietilic care a fost prima data pregtit n 1882. Fischer a numit chimic"veronal" dup care cltoresc lng Mt. Verona n Italia. Acesta a fost, de asemenea, cunoscut mai trziu ca barbital sau barbitone (fig. 2). Fischer a facut echipa cu Josef von Mering, un medic de la Halle, la cercetarea administrarii orale, scris n 1903 c, din cauza debutului lent, efectul prelungit i insolubilitii, de droguri ar fi nepotrivit pentru utilizare intravenoas. Ca un sedativ oral, veronal a fost popular pentru muli ani, i a fost folosit de o serie de celebritati pentru uitare sau sinucidere.

fig 2 Primul barbituric intravenos a fost o combinaie, n pri egale, de veronal i formai, sau acid diallylbarbituric (fig. 2). Agentul a fost creat la Universitatea din Zurich ctre AT Redonnet n 1920, i numit Somnifene (de asemenea cunoscute ca Somnifen sau Somnifaine). Derivaii de acid barbituric nu se dizolv uor n ap, i Somnifene a fost elaborat ca o soluie n ap, glicerin i alcool. Folosit pentru prima ntr-un salon de munc de ctre Cerne, i la scurt timp dup aceea la Paris, de Fredet i Perlis pentru proceduri chirurgicale, Somnifene a fost apoi folosit timp de muli ani 3

n Frana i Germania, n pofida tendinei de a provoca hiperactivitate. Acesta nu a fost folosit pe scar larg n afara Europei, dei JH Fjelde a raportat utilizarea sa n Dakota n 1929 pentru chirurgie i obstetric. Tehnica sa a implicat ca componenta intravenoas n episcopie, nainte de un anestezic etilen. "Suntem acum, folosind o doz de 3 cc, n cele mai multe cazuri. Acest lucru face mai multe lucruri. n primul rnd pacientul este pus s doarm chiar n camera lui, un avantaj distinct care l elibereaz de gnduri n continuare a operaiunii . Pacienii apreciau aceasta trasatura.. La trezire sunt din nou n propriul lor pat i nu au nici o amintire de a fi fost la sala de operatie, la toate. O caracteristic minunata! "Utilizarea sa n obstetric prea s-l ncntare n continuare" O femeie de dimensiuni medii, de injectare de 6 cc va dura 6 ore, ca o regula ... la trezire ele nu isi aduc aminte chiar mi-au scos acul. " El a afirmat c munca nu a fost afectat n mod nejustificat, c acel copil ar putea fi somnolente, dar de asemenea afectate, i c nu a existat nici un risc de reflexe modificate. Atunci cnd comentand pe somnolen dup aceea el afirm c "eu nu fac ceea ce privete acest lucru ca un neajuns, ca restul nu pacient bine." De asemenea, el adauga, "Ar fi de dorit s se trezeasc pacientul la scurt timp dupa nastere, o fiol de cafeina benzoat de sodiu se va realiza, de obicei, acest lucru ntr-o jumtate de o or. Pacientul va recunoate apoi rudele i vorbesc raional, dar mai trziu nu poate aminti de aceasta faza. " Barbituricul etil sodiu iso-amil, a fost descris pentru prima data n 1923. In 1928, o form solubil de amital sodiu a fost descris n SUA, care a fost trialed i raportate de ctre Zerfas et al. n 1929. n ciuda faptului c pentru a fi utilizate n termen de 30 de minute de la preparare, Curnd, a devenit extrem de popular, i n urmtorii 4 ani a fost cel mai frecvent intravenos anestezic folosit n America de Nord. Ca si alte barbiturice, aceasta a rmas regionale i a fost rareori folosit n alt parte. John Lundy la clinica Mayo a fost unul dintre primii care au folosit acest medicament..iar recuperarea lent i agitaia au fost dezavantajele amitalului de sodiu. Nembutal, de asemenea, cunoscut sub numele de pentobarbital de sodiu (printre multe alte nume), etil barbituric sodiu metil-butil, nlocuit n mare msur cu

amital de sodiu ca un narcotic bazal, a fost similar instabil n soluie i a provocat agitaie i reacii ocazionale ale pielii. n 1927, obstetrician german, Rudolph Bumm, a introdus Pernocton, sodiu secbutil (2-bromoallyl)-barbituric. De asemenea, cunoscut sub numele de Pernoston, acest medicament a devenit foarte popular, mai ales n Germania. Pernocton hiperactivitate au artat mai puin postoperatorii i agitaie dect alte barbiturice, i a fost stabil n soluie. Comercializate sub form de soluie apoas de 10%, aceasta nu necesita amestecare. Helmuth Weese (1897-1954) a absolvit in medicina de la Universitatea din Munchen, dar a schimbat direcia n curnd pentru a deveni un farmacolog. Pn n 1928 el a fost ef al departamentului de farmacologie la Bayer lucrrile n WuppertalElberfeld. El a devenit mai trziu profesor de farmaciologie la Kln, i apoi Dusseldorf. Trebuie remarcat faptul c aceste lucrri ale lui Bayer au fost site-ul original a ceea ce este acum o industrie chimic la nivel mondial. Cu toate acestea, dei ele au de lucru importante n dezvoltarea de barbiturice intravenos, compania nu are nici o legtur cu Adolf von Baeyer. Cercetarea considerabil n barbiturice a nceput n acest moment, cu muli compui pentru a fi testate. Prin schimbarea Lanurilor de pe partea moleculei de baz, anumite efecte previzibile ar putea fi realizate (fig. 3). n cazul n care lanul de alchil laturi de la C5 sunt prea lungi, activitatea hipnotica este redusa, iar activitatea convulsanta poate crete.Cresterea solubilitatii lipidelor duce la potenta hipnotica crescuta, mpreun cu o durat sczuta de aciune i laten de debut, precum i metabolism mai rapid.

fig 3 Hexobarbitone primul barbituric cu adevarat de durat scurt de aciune, (Evipan, Evipal), sodiu 5-cyclohexenyl 1,5 dimetil-barbituric, a fost sintetizat sub direcia Weese, iar utilizarea sa la prima clinic au fost raportate de Weese i Scharpff W. n iulie 1932. Adugarea unui grup de metil pe unul dintre atomii de azot a dus la solubilitate lipidic crescut. Astfel, hexobarbitone a devenit extrem de popular ca un agent de inducie datorit induciei sale rapide i aciune de scurt durata, i prin 1944 a fost estimat c acesta a fost folosit pe mai mult de 10 milioane de pacieni. Acesta a fost pregtit n stare proaspt de la o pulbere alb i efecte secundare in principal a micrilor musculare excitator pe inducie, o trstur comun a tuturor barbiturice metilat. O serie de alte barbiturice de scurt durat intravenoas au aparut in jurul anului acest moment. Eunarcon, sodiu 1-metil barbituric 5-5-izopropil--bromallyl, de asemenea, cunoscut sub numele de Eunarkon a fost disponibil ca o soluie stabil de 10% n fiole. Rapida injectare a fost nsoit de spasme musculare, altfel era foarte asemntoare cu hexobarbitone n afar de o inciden mai mic de dureri de cap postoperatorii. Narconumal, 1-metil-5-5-izopropil alil acid barbituric, a trebuit s fie proaspt preparat i injectat lent (mai puin de 1 cm3/min). A fost foarte similar cu hexobarbitone n aciune, cu un factor de siguran cu reputaie mare. Nici una dintre aceste barbiturice nu ar mai putea concura cu hexobarbitone toate acestea, care a rmas extrem de popular, mai ales n Europa, mult timp dup introducerea de tiopental.

Tiobarbituricele nlocuind oxigen la C2 cu un atom de sulf sa creat tiobarbituricele. Barbituricele dei nu este adevrat, ele sunt de obicei incluse n clasa de generic. Tiobarbituricele sunt lipide mai solubile, i prin urmare, sunt mai scurte i acioneaz mai puternic. Barbituricele de sulf au fost descrise de Fisher i Mering von n 1903. Ei au administrat o doz unic la un caine care a murit cu promptitudine. Acest lucru i-au condus la concluzia c sulful are proprieti toxice i au ntrerupt cercetarea. Barbituricele de sulf nu au fost studiate din nou pn la nceputul anilor 1930. La o reuniune a American Chemical Society, n august 1935, chimiti Ernest Volwiler i Donalee Tabern, de la Abbott Laboratories, a descris activitatea lor cu barbiturice mai mult sulf. Ellis Miller si colegii sai, de asemenea, au descris tiobarbituricele in acelai an. (Volwiler a fost mai trziu a devenit vice-preedinte al Abbott Laboratories n 1940, preedinte n 1950 i preedinte n 1958.) Potrivit Adams, studiile clinice primul rezultat de la locul de munc nedeclarat experimentale pe iepuri de Spruth i Tabern. De sodiu de alil-sec-butil-thiobarbiturate i sodiu thiobarbiturate etil metil-butil-au fost apoi prezentate pentru John Lundy de Abbott pentru munca de investigaie suplimentar. Acesta din urm a acestor dou medicamente este derivat de sulf din pentobarbitone (Nembutal) si a fost cunoscut la momentul ca "tiobarbiturate 8064". Lundy mai trziu numit-Thionembutal i i sa dat denumirea comercial de sodiu Pentothal. Acest medicament, pe care tim acum ca

tiopental, a fost preferat de Lundy datorita actiunii sale rapide i de scurt durat. Alte medicamente a fost cunoscut sub numele de Thiosebutal. Rapoartele indic faptul c Ralph Apelor a fost primul care a folosit tiopental din punct de vedere clinic, dar John Lundy a fost responsabil pentru o mare parte din cercetare clinic precoce i de raportare. El a publicat experienta sa cu 2207 de pacieni, n decembrie 1936 n Jurnalul American de Chirurgie. Tehnica sa a implicat oferind o medie de 15 ml de soluie 5% peste aproximativ 15 min. Observaia lui principala a fost c injecia rapida a condus la depresie respiratorie i el a pzit mpotriva acestei inregistrari cu o bucata de vata la buza superioar a pacientului care a monitorizat respiraie continu. Acest aparat a fost denumit fluture Lundy i a fost utilizat pe scar larg timp de muli ani. Aceste prime zile ale agenilor anestezic intravenos au fost un moment de mare schimbare n anestezie. Nu numai ca au fost acesti anesteziti experimentarea cu noi medicamente, dar cu tehnici complet noi. Sir Ivan Magill descrie agenii intravenosi n 1931 a susinut c au oferit "o metod plcut de reducerea decalajului dintre contiin i incontient nainte de anestezie general". Iniial, acestea au fost cele mai utilizate n acest fel, ca ageni de inducie, dar anesteziti s-au grbit s vad alte avantaje poteniale ale anesteziei intravenoase-aproape n detrimentul tehnicii. n 1943, FJ Halford a scris "n timp ce anestezia intravenoasa ar prea a fi ideal pentru leziunile de rzboi din cauza compactului sau, uurina de preparare i caracteristicile nonexplosive, acesta ar trebui s fie recunoscut n mod clar c, n rzboi anestezic, cu condiii ca nu poate fi administrat de ctre medicul anestezist cu nalt calificare, dar au n loc s se acorde de ctre medici, asistente medicale i infirmieri, pentru care arta este ciudat ... "El continu s descrie un numr de pacieni anesteziai cu barbiturice, la 7 decembrie 1941 n Honolulu. Muli dintre aceti pacieni au fost grav ocati i au murit pe un numr de inducie. Nu a fost echipament foarte puin, un minim de lichide intravenos, i o lips de oxigen. barbiturice intravenos timp ce prea o soluie bun, acest lucru nu a fost n mod evident cazul. Autorul conchide, "Ca-amiralul Gordon Taylor a Marinei britanice a spus acest lucru pe bun dreptate," anesteziei spinale este forma ideal de eutanasiei n rzboi 8

surgery'-apoi s se fi spus c anestezie intravenoasa este, de asemenea, o metod ideal de eutanasie. A fost un consens al tuturor chirurgilor civile ngrijorat de faptul c, lund n considerare toate pericolele de pacient, anestezist i eter anestezic, pictur deschide nc mai pstreaz supremaia! " Din fericire pentru tiopental, editorii au alt articol publicat n aceeai revist n cazul n care o femeie a fost cu succes anesteziai cu tiopental dup un foc de arm rana. Acest caz a fost evident diferit, n sensul c nu a fost un prejudiciu de rzboi, iar pacientul a fost n mod corespunztor transfuzat. Anestezic constat de 1 cm3 creteri de 2,5% tiopental dat afar 1 min. Dup 5 cm3, ea a fost intubat si a continuat sa respire spontan pentru restul de funcionare de 90 de minute pe un amestec de oxigen 50% / protoxid de azot. O alte 11 cm3 de tiopental a fost dat n total pe parcursul anestezic i n cele din urm pacientul s-a recuperat, n ciuda traumatismelor extinse abdominale i toracice. Autorii acestui articol, Charles Adams si Howard Gray, a concluzionat c tiopental ar putea fi administrat n siguran la pacienii in stare de soc unde resuscitarea adecvata a fost disponibila. Barbituricele n timp ce mai devreme sa bucurat de popularitate , aceasta a fost tiopental care a devenit universal acceptabil. n primul rnd folosit ca o soluie de 10%, sa constatat ca si cauza de deprimare respiratorie i iritarea perivasculare. Mai trziu a fost folosit ca o soluie de 5% i n cele din urm a recomandat ca o soluie de 2,5%. Dup preparare a rmas stabil pentru mai multe zile. Un numr de alte thiobarbiturates au fost introduse. Acestea includ urmtoarele. Venesetic, thiobarbiturate sodiu etil iso-amil, omologul de sulf din amytal de sodiu. Sa spus de a aciona ntr-un mod foarte asemntor cu tiopental. Kemithal de sodiu, sodiu cyclohexenyl-5-alil-2-thiobarbiturate, de asemenea, utilizat ca o soluie de 10%, a fost stabil n soluie pentru 4-5 h. Kemithal a fost observat de a provoca depresie respiratorie mai puin dect tiopental, i s fie mai puin susceptibile de a provoca laringospasm, sau ca rezultat apariia de hiperactivitate. Cu toate acestea, sa observat ca produce aritmii mai frecvent. 9

Thiamylal (thioquinalbarbitone, Surital de sodiu), sodiu 5-alil-5 (1methyl butil) thiobarbiturate, a fost descris de Volwiler i Tabern n 1935. O serie de studii au sugerat c Surital a fost la fel de sigure i la fel de eficace ca tiopental, cu efect mai puin cumulativ. Buthalitone de sodiu, sodiu thiobarbiturate 5-alil-5-iso-butil, a fost sintetizat de Miller i introduse de ctre Helmuth Weese i Koss Ferdinad n 1954. Acesta a fost, de asemenea, cunoscut sub numele de Baytenal sau Baytinal, i mai trziu, Transithal i Ulbreval. Acesta a fost stabil timp de 36 de ore n soluie de carbonat de sodiu cu 6%. Ea a avut se pare un timp de recuperare mai rapid dect hexobarbitone, dar a fost abandonat n cele din urm, din nou, din cauza o inciden ridicat de miscari musculare. Thiobutobarbitone, sodiu 5-etil-5-secbutyl-thiobarbiturate, a fost introdus pentru prima dat de Karl Horatz i Sturtzbecher Fritz n 1952, dup ce primul a fost descris de ctre Volwiler i Tabern n 1935. Este mai puin potent dect tiopental, dar altfel este foarte asemntoare. Acesta a fost utilizat pe scar larg pe continent, i a fost deosebit de populare n Germania, unde a fost comercializat ca Inaktin. n alt parte a fost cunoscut sub numele de Inactin. Thionarcex, thiobarbiturate etil de sodiu 5-etil-5-butil, a fost uor mai puternic dect tiopental, cu un timp de recuperare un pic mai scurt. Zima, von Werder i Hotovy a introdus un grup thioethyl metil n poziia 5 din lanul de barbituric n ncercarea de a accelera de degradare i de a preveni deteriorarea ficatului cauzat de doze toxice. Aceast cercetare a condus la dezvoltarea de methitural, sodiu thioethyl metil thiobarbiturate pentil-2, care a fost foarte scurt de aciune. Acesta a fost utilizat pentru scurt timp n Statele Unite ale Americii, ca Nereval, i Germania, ca Thiogenal, dar nu a fost la fel de eficace ca i altor ageni i posed proprieti mai mare parasimpatomimetice. A fost curnd abandonat. Grupul de metil n hexobarbitone a fost responsabil pentru instalarea rapid a aciunii i n continuare cercetri n barbiturice metilate a continuat pentru acest motiv. n cele din urm, de cercetare de Chernish et al. Lilly la Laboratoarele de Cercetare a condus la dezvoltarea n 1956 a Lilly 22451, un medicament mai puternic dect tiopental, cu o rat de recuperare mai rapid, dar cu proprieti nefericite 10

convulsive. De sodiu 1-metil, barbituric 5-5 alil-(1-metil, 2-pentynyl) sa dovedit a avea patru izomeri, ca urmare a doi atomi de carbon asimetrice. Ar putea fi fracionat n perechi, fie cu puncte de topire nalt i joas. Separarea izomerilor ridicat punctul de topire a condus la dezvoltarea de Lilly 25398, sau methohexitone, utilizat pentru prima clinic de Dundee i Moore in 1960 [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 i 12].

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The intravenous barbiturates

R. N. Westhorpe, and C. Ball Geoffrey Kaye Museum of Anaesthetic History and Australian and New Zealand College of Anaesthetists Melbourne, Melbourne, Australia Available online 7 February 2003. Abstract Adolf von Baeyer synthesised barbituric acid in 1864 by reacting malonic acid with urea. Barbituric acid is clinically inert, and it was not until the synthesis of diethyl barbituric acid in 1882 that a clinically useful sedative became available. Named Veronal by Fischer, he and von Mering first described its use in 1903. There followed many derivatives of the basic barbiturate molecule, and the development of intravenous anaesthesia. Although many had brief periods of popularity, it was sodium thiopentone which outlasted them all. Author Keywords: Barbiturate; Barbituric acid; Thiobarbiturate; Thiopentone; Methohexitone 1. The thiobarbiturates References In the latter half of the 19th century, the medical climate was poised, waiting for the introduction of an intravenous anaesthesia, except that no suitable drug existed. Pierre-Cyprien Or experimented with intravenous chloral hydrate in 1872, but slow recovery and high mortality delayed further development of the method. In the early 20th century, several drugs achieved limited popularity, including Hedonal,

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Paraldehyde, Magnesium Sulphate and intravenous 5% ether. However, it was not until the introduction of barbiturates that a true alternative to inhalation anaesthesia became available. Adolf Johann von Baeyer first synthesised barbituric acid in 1864 by reacting malonic acid with urea (Fig. 1). He later received the Nobel Prize in chemistry for his subsequent work in organic chemistry and organic dyes. It is said that he named the new compound barbituric acid after celebrating his discovery in a local Ghent tavern, where some artillery officers were celebrating the day of their patron saint, St. Barbara. The amalgamation of Barbara and urea thus gave rise to the name barbiturate.

fig.1

Barbituric acid is clinically inert and aroused little interest for many years. It was not until the turn of the century when Hermann Emil Fischer, Professor of Chemistry in Berlin, and his assistant Dilthey, undertook further research on diethyl barbituric acid which had first been prepared in 1882. Fischer named the chemical Veronal after traveling near Mt. Verona in Italy. It was also known later as barbital or barbitone (Fig. 2). Fischer teamed up with Josef von Mering, a physician from Halle, to research oral administration, writing in 1903 that because of the slow onset, prolonged effect and insolubility, the drug would be unsuitable for intravenous use. As an oral sedative, Veronal was popular for many years, and was used by a number of celebrities for oblivion or suicide.

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fig.2 The first intravenous barbiturate was a combination, in equal parts, of Veronal and dial, or diallylbarbituric acid (Fig. 2). The agent was created at the University of Zurich by T.A. Redonnet in 1920, and named Somnifene (also known as Somnifen or Somnifaine). The barbituric acid derivatives do not dissolve readily in water, and Somnifene was prepared as a solution in water, glycerine and alcohol. First used in a labour ward by Cerne, and shortly afterwards in Paris, by Fredet and Perlis for surgical procedures, Somnifene was then used for many years in France and Germany despite its tendency to cause hyperactivity. It was not used widely outside Europe although J.H. Fjelde reported its use in Dakota in 1929 for surgery and obstetrics.

His technique involved giving the intravenous component in the ward prior to an ethylene anaesthetic. We are now using a 3 cc dose in most cases. This does several things. In the first place the patient is put to sleep right in his room, a distinct advantage which relieves him of further thoughts of the coming operation. Patients appreciate this feature. When awakening they are back in their own bed and have no recollection of having been to the operating room at all. A wonderful feature! Its use in obstetrics seemed to delight him further In the average sized woman, the injection of 6 cc will last 6 h, as a rule On awakening they do not even remember me having taken out the needle. He stated that labour was not unduly affected, that the child may be somnolent but otherwise unaffected, and that there was no risk of haemorrhaging or altered reflexes. When commenting on the drowsiness afterwards he states that I do not regard this as a drawback, as the rest does the patient good. He also adds, Should it be desirable to awaken the patient shortly after delivery, an

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ampoule of caffeinesodium benzoate will usually accomplish this in one-half to one hour. The patient will then recognize relatives and talk rationally, but later may not remember this phase.Sodium amytal, sodium iso-amyl ethyl barbiturate, was first described in 1923. In 1928, a soluble form of sodium amytal was described in the US which was trialed and reported on by Zerfas et al. in 1929. Despite having to be used within 30 min of preparation, it soon became extremely popular, and over the next 4 years it was the most common intravenous anaesthetic used in North America. Like other barbiturates, it remained regional and was seldom used elsewhere. John Lundy at the Mayo clinic was one of the first to use this drug. Slow recovery and restlessness were disadvantages of sodium amytal.Nembutal, also known as Pentobarbital sodium (among many other names), sodium ethyl methylbutyl barbiturate, largely replaced sodium amytal as a basal narcotic, but was similarly unstable in solution and caused restlessness and occasional skin reactions.

In 1927, the German obstetrician, Rudolph Bumm, introduced Pernocton, sodium sec-butyl (2-bromoallyl)-barbiturate. Also known as Pernoston, this drug became very popular, especially in Germany. Pernocton showed less postoperative hyperactivity and restlessness than other barbiturates, and was stable in solution. Marketed as a 10% aqueous solution, it did not require mixing.Sodium soneryl, Butobarbitone, or Butobarbital sodium, sodium butylethyl barbiturate, was primarily an oral sedative which was used briefly intravenously as a 5% solution. Prolonged recovery was a problem. Helmuth Weese (18971954) graduated in medicine from Munich University but soon changed direction to become a pharmacologist. By 1928 he was head of the department of pharmacology at the Bayer works in Wuppertal-Elberfeld. He later became Professor of Pharmacology in Cologne, and then Dusseldorf. It should be noted that these Bayer works were the original site of what is now a worldwide chemical industry.

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However, although they did significant work into the development of intravenous barbiturates, the company has no connection with Adolf von Baeyer.Considerable research into barbiturates began at this time, with many compounds being tested. By changing the side chains on the basic molecule, certain predictable effects could be achieved (Fig. 3). If the alkyl sides chain at C5 are too long, hypnotic activity is reduced, and convulsant activity may increase. Increasing lipid solubility leads to increased hypnotic potency, together with decreased duration of action and latency of onset, as well as more rapid metabolism.

fig.3

The first truly short acting barbiturate, hexobarbitone (Evipan, Evipal), sodium 5-cyclohexenyl 1,5-dimethyl barbiturate, was synthesized under the direction of Weese, and its first clinical use was reported by Weese and W. Scharpff in July 1932. The addition of a methyl group onto one of the nitrogen atoms resulted in increased lipid solubility. Thus, hexobarbitone soon became extremely popular as an induction agent due to its rapid induction and short action, and by 1944 it was estimated that it had been used on over 10 million patients. It was prepared fresh from a white powder and the main side effect was excitatory muscle movement on induction, a feature common to all methylated barbiturates. Several other short-acting intravenous barbiturates appeared around this time. Eunarcon, sodium 1-methyl 5-5-isopropyl--bromallyl barbiturate, also known as Eunarkon was available as a stable 10% solution in ampoules. Rapid injection was

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accompanied by muscle twitching, otherwise it was very similar to hexobarbitone apart from a lower incidence of postoperative headache . Narconumal, 1-methyl-5-5-allyl isopropyl barbituric acid, had to be freshly prepared and injected slowly (less than 1 cm3/min). It was very similar to hexobarbitone in action, with a reputedly high safety factor. None of these other barbiturates could compete with hexobarbitone however, which remained extremely popular, especially in Europe, long after the introduction of thiopentone. 1. The thiobarbiturates Substituting oxygen at C2 with a sulphur atom created thiobarbiturates. Although not true barbiturates, they are commonly included in the generic class. Thiobarbiturates are more lipid soluble, and are therefore shorter acting and more potent.Sulphur barbiturates were first described by Fisher and von Mering in 1903. They administered a single dose to a dog that promptly died. This led them to conclude that the sulphur had toxic properties and they discontinued their research. Sulphur barbiturates were not studied again until early 1930s. At a meeting of the American Chemical Society in August 1935, chemists Ernest Volwiler and Donalee Tabern, from Abbott laboratories, described their work with several sulphur barbiturates. Ellis Miller and colleagues also described the thiobarbiturates the same year. (Volwiler was later to become Vice President of Abbott laboratories in 1940, President in 1950 and Chairman in 1958.)According to Adams, the first clinical trials resulted from unreported experimental work on rabbits by Spruth and Tabern. Sodium allyl-secbutyl-thiobarbiturate and sodium ethyl methylbutyl thiobarbiturate were then presented to John Lundy by Abbott for further investigative work. The latter of these two drugs is the sulphur derivative of pentobarbitone (Nembutal) and was known at the time as thiobarbiturate 8064. Lundy later named it Thionembutal and it was given the trade name Pentothal sodium. This drug, which we now know as thiopentone, was preferred by Lundy because of its rapid action and short duration. The other drug was known as Thiosebutal.

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Reports indicate that Ralph Waters was the first to use thiopentone clinically, but John Lundy was responsible for much of the early clinical research and reporting. He published his experience with 2207 patients in December 1936 in the American Journal of Surgery. His technique involved giving an average of 15 ml of a 5% solution over about 15 min. His principal observation was that rapid injection led to respiratory depression and he guarded against this by taping a piece of cotton wool to the patient's upper lip which monitored continuing respiration. This device was referred to as Lundy's butterfly and was widely used for many years.These early days of intravenous anaesthetic agents were a time of great change in anaesthesia. Not only were these anaesthetists experimenting with new drugs, but with entirely new techniques. Sir Ivan Magill describing intravenous agents in 1931 claimed that they provided a pleasant method of bridging the gap between consciousness and unconsciousness before general anaesthesia. Initially, they were mostly used this way, as induction agents, but anaesthetists were quick to see other potential advantages of intravenous anaesthesiaalmost to the detriment of the technique.

In 1943, F.J. Halford wrote While intravenous anaesthesia would seem to be ideal for war injuries because of its compactness, ease of preparation and nonexplosive characteristics, it should be clearly recognized that under war conditions anaesthetics cannot be administered by highly skilled anaesthesiologists, but have instead to be given by doctors, nurses and orderlies, to whom the art is strange He goes on to describe a number of patients anaesthetized with barbiturates on 7 December 1941 in Honolulu. Many of these patients were badly shocked and a number died on induction. There was very little equipment, a minimum of intravenous fluids, and a lack of oxygen. Whilst intravenous barbiturates seemed a good solution, this was obviously not the case. The author concludes, As Admiral Gordon-Taylor of the British Navy has so aptly said, Spinal anaesthesia is the ideal form of euthanasia in war surgerythen let it be said that intravenous anaesthesia is also an ideal method of euthanasia. It was the consensus of all civilian surgeons concerned that, considering all the hazards of patient, anaesthetist and anaesthetic, open drop ether still retains the primacy!

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Fortunately for thiopentone, the editors published another article in the same journal where a woman was successfully anaesthetized with thiopentone after a gunshot wound. This case was obviously different, in that it was not a war injury, and the patient was adequately transfused. The anaesthetic consisted of 1 cm3 increments of 2.5% thiopentone given 1 min apart. After 5 cm3, she was intubated and continued to breathe spontaneously for the rest of the 90-min operation on a mixture of 50% oxygen/nitrous oxide. A further 11 cm3 of thiopentone was given in total throughout the anaesthetic and the patient eventually recovered, despite extensive abdominal and thoracic trauma. The authors of this article, Charles Adams and Howard Gray, concluded that thiopentone could safely be administered in shocked patients where adequate resuscitation was available. While earlier barbiturates enjoyed some popularity, it was thiopentone that became universally acceptable. First used as a 10% solution, it was noted as the cause of respiratory depression and perivascular irritation. It was later used as a 5% solution and eventually recommended as a 2.5% solution. After preparation it remained stable for several days.A number of other thiobarbiturates were introduced. They include the following.Venesetic, sodium iso-amyl ethyl thiobarbiturate, the sulphur homologue of sodium amytal. It was said to act in a very similar way to thiopentone. Kemithal sodium, sodium cyclohexenyl-5-allyl-2-thiobarbiturate, also used as a 10% solution, was stable in solution for 4 to 5 h. Kemithal was noted to cause less respiratory depression than thiopentone, and to be less likely to cause laryngospasm, or result in the emergence of hyperactivity. However, it was noted as producing arrhythmias more frequently. Thiamylal (thioquinalbarbitone, Surital sodium), sodium 5-allyl-5 (1methyl butyl) thiobarbiturate, was described by Volwiler and Tabern in 1935. A number of studies suggested that Surital was as safe and as effective as thiopentone, with slightly less cumulative effect. Buthalitone sodium, sodium 5-allyl-5-iso-butyl thiobarbiturate, was first synthesised by Miller and introduced by Helmuth Weese and Ferdinad Koss in 1954. It was also known as Baytenal or Baytinal, and later, Transithal and Ulbreval. It was stable for 36 h in solution with 6% sodium carbonate. It reportedly had a faster 19

recovery time than hexobarbitone, but was eventually abandoned, once again because of a high incidence of muscle movements. Thiobutobarbitone, sodium 5-ethyl-5secbutyl-thiobarbiturate, was first introduced by Karl Horatz and Fritz Sturtzbecher in 1952 after it had first been described by Volwiler and Tabern in 1935. It is slightly less potent than thiopentone but is otherwise very similar. It was widely used on the continent, and was particularly popular in Germany where it was marketed as Inaktin. Elsewhere it was known as Inactin. Thionarcex, sodium 5-ethyl-5-butyl ethyl thiobarbiturate, was slightly more potent than thiopentone, with a slightly shorter recovery time. Zima, von Werder and Hotovy introduced a methyl thioethyl group at the 5 position of the barbiturate chain in an attempt to accelerate breakdown and prevent liver damage due to toxic doses. This research led to the development of methitural, sodium methyl thioethyl-2 pentyl thiobarbiturate, which was very short acting. It was used briefly in the USA, as Nereval, and Germany, as Thiogenal, but it was not as effective as other agents and possessed greater parasympathomimetic properties. It was soon abandoned.The methyl group in hexobarbitone was responsible for the rapid onset of action and further research into the methylated barbiturates continued for this reason. Eventually, research by Chernish et al. at the Lilly Research Laboratories led to the development in 1956 of Lilly 22,451, a drug more potent than thiopentone, with a more rapid recovery rate, but with unfortunate convulsive properties. Sodium 1methyl, 5-5-allyl (1-methyl, 2-pentynyl) barbiturate was shown to have four isomers, due to the two asymmetrical carbon atoms. It could be fractionated into pairs with either high and low melting points. Separation of the high melting point isomers led to the development of Lilly 25,398, or methohexitone, first used clinically by Dundee and Moore in 1960 [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12].

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References 1. R.C. Adams, Intravenous Anaesthesia. , Harper and Brothers, London (1944). 2. R.C. Adams and H.K. Gray, Intravenous anaesthesia with pentothal sodium in the case of gunshot wound associated with accompanying severe traumatic shock and loss of blood: report of a case. Anesthesiology 4 (1943), pp. 7073. 3. C. Ball and R.N. Westhorpe, The history of intravenous anaesthesia: the barbiturates. Part 1. Anaesth. Intensive Care 29 (2001), p. 97. View Record in Scopus | Cited By in Scopus (1) 4. C. Ball and R.N. Westhorpe, The history of intravenous anaesthesia: the barbiturates. Part 2. Anaesth. Intensive Care 29 (2001), p. 219. View Record in Scopus | Cited By in Scopus (2) 5. C. Ball and R.N. Westhorpe, The history of intravenous anaesthesia: the barbiturates. Part 3. Anaesth. Intensive Care 29 (2001), p. 323. View Record in Scopus | Cited By in Scopus (1) 6. J. Dundee, Intravenous anaesthesia. , Churchill Livingstone (1988). 7. J. Dundee and P. McIlroy, The history of the barbiturates. Anaesthesia 37 (1982), pp. 726734. View Record in Scopus | Cited By in Scopus (8) 8. Editorial, The question of intravenous anaesthesia in war surgery. Anesthesiology 4 (1943), pp. 7477. 9. F.J. Halford, A critique of intravenous anaesthesia in war surgery. Anesthesiology 4 (1943), pp. 6769. 10. J. Schulte am Esch and M. Goerig, Anaesthetic Equipment in the History of German Anaesthesia. , Drager Druck, Lubeck (1997).

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11. P. White, Textbook of Intravenous Anaesthesia. , Williams and Wilkins (1997).

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