Tranquilizers and Anesthesia 1966

Martin I. Gold, M.D. 4ssociate Professor, Department of Anesthesiology, University Hospital, University of Maryland, Baltimore, Md.

In order to discuss a subject, defini- the American medical profession tions must be offered and understood. against as a clinically useful Unfortunately, it is impossible to de- tool. The discovery and release of a fine a tranquilizer objectively. The new tranquilizer with all of alcohol's term began in the early 1950's, since properties would excite the medical there was no classification for newer world. central nervous system There is, therefore, no reason why such as the and the alcohol, , narcotics, anti- rauwolfia alkaloids. Soon other and other depressants were promoted as tranquilizers, and might not also be considered tranquil- the term served as a waste basket for izers. They are not advertised as such. many new central nervous system de- Therefore, the basic reasons why the pressants with - ac- drugs to be mentioned are called tran- tivity. quilizers do not involve common Within the past ten years, the tran- pharmacologic properties or even quilizers have become extremely prof- chemical structure, but primarily cus- itable for the pharmaceutical industry tom based on arbitrary reasons. and, until a few years ago when the There are certain characteristics of FDA created more stringent rules, all transquilizers having general ap- new drugs with "tranquilizing" activ- plication. They are basically central ity were being released at the rate of nervous system depressants (excep- approximately ten per year. There tions are the amine oxidase inhibitors are presently about 150 drugs acting and the dibenzapipines) . They are of within the central nervous system pri- recent origin, being nonexistent prior marily which are advertised as tran- to 1945. They are frequently used for quilizers. They have no common char- purposes other than tranquilizing. acteristics. In a general way, they are For instance: phenothiazines are anti- related to barbiturates, emetics, diphenylmethanes are anti- and narcotics. histamines, and rauwolfia derivatives Alcohol could easily be considered are antihypertensives. within this group. In high dosage, it THE PHENOTHIAZINES is an excellent sedative which has rela- These have a complex pharmacol- tively few harmful side effects and no ogy with multiple sites of action and more addictive properties than most clinical effects. They act within the other central nervous system depres- central nervous system, producing: sants. National prohibition and the sedation, antiemetic activity, thermo- exposure of patent medicines contain- regulatory disturbance, ing alcohol seem to have prejudiced activity, alpha blocking ac-

APRIL 1967 75 tivity and adrenergic potentiation, THE AND activity, antiserotonin SUBSTITUTED PROPANEDIOL action, and analgesia. There are ap- DERIVATIVES proximately 25 different derivatives of These may be grouped into: (a) the available, but the dif- tranquilizers and (b) the muscle re- ferences between them are structural laxants. Within this subgroup these and quantitative rather than qualita- agents differ from the phenothiazines, tive. The reason for these many drugs the diphenylmethanes, and rauwolfia is primarily because of competition for many reasons: (a) there are a and not because one agent is better variety of chemical structures in- than another in a particular instance. volved; (b) they are not ganglionic It is very probable that, if these 25 blocking, adrenolytic, antihistaminic, phenothiazines were reduced to five, antiserotonin, or antiemetic and they the spectrum of pharmacologic activ- do not exhibit analgesia; (c) they are ity for this series would be covered. relatively nontoxic and resemble their They interest the anesthesiologist close relations, the barbiturates; and primarily because of their CNS de- (d) generally, these drugs are not con- pressant, antiemetic and temperature sidered antihypertensive in clinical regulatory activities and for the com- dosage. plications occasionally occurring in These drugs exhibit three funda- patients taking them and subsequently mental pharmacologic properties: (1) undergoing anesthesia. These compli- CNS depression; (2) muscle relaxa- cations are: hypotension and postanes- tion; and (3) action. thetic lethargy. The prototype, , is an The phenothiazines may be classi- interneuronal blocker. It will block fied into the nontranquilizing and the the crossed extenser reflex but not the tranquilizing agents. The nontran- knee jerk. All of the tranquilizing quilizing phenothiazines consist of mephenesin and substituted propane- anti-Parkinsonian, antihistamine, anti- diol derivatives have been used as pre- pruritic, and analgesic drugs. The medicants with variable tranquilizers may be classified as success. Clinically, none are available promazines, and miscel- parenterally. laneous. The group of drugs resembles the tranquilizers in many DERIVATIVES respects and exhibits the same basic These somewhat ineffective drugs pharmacologic properties, with heavy are structurally similar and frequently emphasis on muscle relaxant activity. pharmacologically different. Most are Many of the muscle relaxants have weak central nervous system depres- been withdrawn from the market be- sants. They are related to various cause of toxicity , antihistamines, anti- emetics, narcotics and even muscle re- THE NONBARBITURATE laxants which have the diphenylme- , INCLUDING thane structure. They have multiple THE side effects (e.g., is a po- Clinically, these mild CNS depres- tent ). is sants might conveniently be classified the most popular, having been pub- with and . licized as an effective anesthetic pre- Most have been available for more medicant with little toxicity. than ten years. They differ somewhat 76 ANESTHESIA PROGRESS structurally. The infamous thalido- adrenergic blocking activity, antieme- mide, which had teratogenic activity, tic action, are central nervous system is included, as is Megimideg, an ana- depressants and good potentiators. leptic. There is close chemical struc- They supposedly exhibit little respira- tural resemblance- of these drugs to tory or circulatory depression, but in Doriden®. overdosage cause tremors, ataxia and These drugs have been used as pre- depression of most vital functions. anesthetic sedatives with relatively few has been combined with side effects. They offer no unique ad- a new narcotic, Fentanyl®, to create vantage when compared with barbitu- a polypharmacologic phenomenon rates. All are potentially addictive and known as "neuroleptanalgesia." In reasonably successful suicide agents. truth, similar combinations of nar- This is especially true of , cotics and other central nervous sys- a rather insoluble agent, which after tem depressants include "twilight ingestion, remains in the gastrointes- sleep" which is a combination of mor- tinal tract serving to maintain blood phine and , and the "lytic levels. cocktail" which included combina- The three benzodiazepines cur- tions of meperidine and phenothi- rently available include the original azines. No fundamental difference and most popular, exists between "neuroleptanalgesia" (Librium®). They are extremely po- and these mixtures of drugs. tent agents and again basically seda- tive, anticonvulsant and skeletal mus- (sernyl) and keta- cle relaxant in activity. They have men (CI-581) are two experimental supposedly weak hypnotic activity. drugs which are extremely rapid act- They create postanesthetic lethargy ing analgesics when administered in- and respiratory depression in patients travenously. They produce a catalep- ingesting them and receiving general tic-like state with the patient having anesthesia. They seem to create an in- eyes open and nystagmus. He is un- creased sensitivity to alcohol and have responsive and in a state of "sus- been accused of being causative in pended animation." These drugs are automobile accidents. central nervous system depressants; they increase blood pressure. They NEWER CENTRAL NERVOUS create excess salivation and have anti- SYSTEM DEPRESSANTS convulsant activity. Unfortunately, The majority of these drugs have they are hallucinogenic, although little structural similarity to each ketamen, which is presently receiving other. Some are similar to phenothia- a great deal of attention in pediatric zines, while others, such as trimetho- surgery, has much less such activity. benzamide, (Tigan®) are unique and These analgesic anesthetic agents do have novel chemical structure. Those not create respiratory depression nor related to the phenothiazines are truly do such patients require oral airways. the result of "molecular manipula- tion" and it is suspected that more of MONOAMINE OXIDASE such agents will soon become avail- INHIBITORS able. These are not CNS depressants, but The buterophenones include halo- stimulants, and are used in psychotic peridol and droperidol, two experi- states. Iproniazid, the first, mental agents which have interesting was originally developed as a tubercu- properties. They exhibit weak alpha lostatic agent. APRIL 1967 77 TRANQUILIZING AND OTHER CNS DEPRESSANT DRUGS

PHENOTHIAZINES - TRANQUILIZERS THE MEPHENESIN AND SUBSTITUTED Pipamazine (Mornidine®) PROPANEDIOL DERIVATIVES (Largon®) A. Tranquilizers Mepazine (Pacatal®) \[enrobamate (Miltown®, Equanil®) (Quide®) (Capla®) Methiomeprazine (Striatran®) (Mellaril®) Hydroxyphenmate (Listica®) Win 13,645-5 (Dimethylane®) (Quiacting) PHENOTHIAZINE TRANQUILIZERS: Phenaglycodol (Ultram®) PROMAZINES (Trepidone®) (Sparine®) Amphenidone (Dornwal®) (Thorazine®) B. Muscle Relaxants (Vesprin®) (Soma®, Rela®) Methoxypromazine (Tentone®) Mephenesin PHENOTHIAZINE TRANQUILIZERS: Zoxazolamine (Flexin®, ' discontinued) Proclorperazine (Compazine®) Chlorzoxazone (Paraflex®) (Torecan®) Methocarbomal (Robaxin®) (Stelazine®) Styramate (Synaxar®) (Dartal®) Phenyramidol (Analexin®) (Trilafon®) (Trancopal®) (Permitil®, Prolixin®) NON- CNS DEPRESSANTS (Tindal®) (Quaalude®) Carphenazine (Proketazine®) (Valmid8) (Placidyl®) PHENOTHIAZINE DERIVATIVES - Methyl Parafynol (Dormison®) NON-TRANQUILIZING DRUGS (Nodular®) Phenothiazine Glutethimide (Doriden®) 3-Ethyl 3-Methyglutarimide Diethazine (Diparcol®) (Megimide®) (Parsidol®9) Thalidomide (Kevadon®, Pyrathiazine (Pyrrolazate®) discontinued) (Phenergan®) 2-Ethylcrotonyl Urea (Nostyn®) Trimeprazine (Temaril®) (Tacaryl®) Methotrimeprazine BENZODIAZEPINES Oxasepam (Serax®) DIPHENYLMETHANE DERIVATIVES - Chlordiazepoxide (L.ibrium®) TRANQUILIZERS (Valium®) Pipradrol (Meretran®) NEW DRUGS ACTING ON CNS Hydroxyzine (Atarax®, Vistaril®) Trimethobenzamide (Tigan®) Azacyclanol (Frenquel®) Isothipendyl (Theruhistin®) (Softran®) (Timovan®) Benactyzine (Suavitil®) (Taractan®) Pipethanate (Sycotrol®9) Captodiamine (Suvren®) Droperidol 78 ANESTHESIA PROGRESS Gamma Aminobutyric Acid (Gaba®) Nortryptyline (AventylO) Gama Hydroxybutyric Acid (Surmantil®) (Gamma@) (Periactin®) Phencyclidine (Sernyl) Ci-58 1 (Ketamen) RAUWOLFIA ALKALOIDS AND DERIVATIVES THE AMINE OXIDASE INHIBITORS (Serpasil®9) Tranylcypromine (Parnate®, (Harmonyl®) discontinued) (Moderil®) Iproniazid (Marsilid®, discontinued) (Singoserp®) (Catron®, Serpentine discontinued) Tetrabenazine (Nitoman®) (Nardil®) SU-1 1279 Isocarboxazid (Marplan®9) Benzquinamide (Quantril®) (Eutonylg) Ethyltryptamine (Monase®) ANTIHYPERTENSIVES Nialamide (Niamid®) Hydralazine (Apresoline®9) (Ansolysen®) IMINODIBENZYL AND Guanethedine (Ismelin®) DERIVATIVES (Aldomet®) (Tofranil®) Bretyliurn Amitryptyline (Elavil®') (Pertofrane®) (Regitine®)

Several related hydrazine and non- serious morbidity and the combina- hydrazine derivatives have since been tion of them and general anesthesia introduced. They are complex in may be hazardous. Prolonged sleep and have prolonged ef- time may occur in these patients and fects which are cumulative. Their if they become hypotensive, use of a long duration of action has been ex- vasopressor may markedly elevate plained on the basis of their being ir- blood pressure. The combination of reversible inhibitors of monoamine narcotics and monoamine oxidase in- oxidase. They may produce postural hibitors may also produce serious com- hypotension and central stimulation. plications including convulsions and In patients ingesting such drugs, the death. Meperidine has been particu- effects of anesthetic agents, narcotics larly guilty here. There are physicians and ganglionic blockers are markedly who believe that a delay in elective potentiated. Such enhancement has surgery in patients taking such drugs been attributed to an inhibition of should be a policy. the oxidative enzyme system associ- ated with biotransformation of the CNS depressant, possibly in liver mi- These include imipramine and crosomes. others. They are closely related to These drugs have extreme hepatic phenothiazines chemically but are cen- and neurologic toxic potential and tral nervous system stimulants rather three have been discontinued. Pa- than depressants. They are not mono- tients for general anesthesia who are amine oxidase inhibitors, but re- taking these drugs have encountered semble them overtly. They exert a APRIL 1967 79 complex type of central motor stimu- suggested that a "middle of the road lation and create euphoria in de- philosophy" be practiced by anesthesi- pressed patients. These effects often ologists. do not appear until the agent has These drugs are different from most been given for from two to four weeks. other agents. Their action is indirect, There is some hazard of a wide va- delayed and, once obtained, long-last- riety of side effects and toxicity but ing. Their effects are not proportional less so than with the monoamine oxi- to their tissue concentration. It is dase inhibitors. These include Park- presently believed that they release insonian-like symptoms, cholestatic various amines from the brain and jaundice, granulocytopenia and sei- peripherally in order to exert activity. zures in epileptics. They have atro- Reserpine depletes norepinephrine, pine-like side activity and should not epinephrine and dopamine from va- be used in wide-angle glaucomatous rious tissues. patients. They should also not be used Combinations of these alkaloids in combination with a monoamine with diuretics and other antihyperten- oxidase inhibitor. sives serve to confuse the clinician. In RAUWOLFIA ALKALOIDS AND addition, newer antihypertensives DERIVATIVES such as , methyldopa, These agents were introduced in and bethanidine, the phar- the early 1950's and the alkaloids be- macology of which is extremely com- came available a few years later. They plicated, have created a new group of are used as antihypertensives prima- drugs to harass the anesthesiologist. rily, but have a distinct central nerv- Such potent agents which act within ous system depressant quality. The the block- alkaloids include: reserpine, deserpi- ing sympathetic nerve terminations dine, rescinnamine and syrosingopine, and exhibiting adrenolytic and ad- but there are also synthetic derivatives renergic blocking action are extremely such as tetrabenazine and benzquina- potent. The complete pharmacology mide. The chemistry and pharmacol- of these agents needs to be elucidated. ogy of these agents are complex. And more will become available to They have many autonomic nerv- introduce further problems. ous system side effects such as: miosis, CONCLUSION bradycardia, hypotension and in- The pharmaceutical industry, in re- creased gastrointestinal activity. They sponse to patient and physician de- are of no value to anesthesiologists, mand, has created new and wonderful but create circulatory problems dur- agents to alleviate symptoms. These ing and after anesthesia. Presently it agents in turn have created a "Pan- is believed that such patients may be dora's Box" of iatrogenic complica- managed safely, since there is no tions. Unless the physician, nurse and higher incidence of hypotensive com- pharmacist comprehend the enormity plications in hypertensives taking of the problem and are able to classify these drugs than in those not in- each tranquilizer and antihyperten- gesting them. A well controlled and sive within its own group the prob- uncontroversial study in humans lems mentioned will continue to remains to be done to resolve this plague the patient. problem. Since we occasionally en- counter severe hypotension in such (The above article was reprinted, with per- mission, from Hospital Formulary Management, patients ingesting these alkaloids it is vol. 1:11, 1966.) 80 ANESTHESIA PROGRESS