The Newer Tranquilizing Drugs

The Newer Tranquilizing Drugs ASHTON L. WELSH, M.D.*

Since the review of the "Phenothiazine Tranquilizers, Eight Years of Development," by Ayd 3 in 1961, a number of new tranquilizers have been introduced into medical practice; hundreds of clinical studies have appeared in the medical literature; physicians in the United States have been writing prescriptions (for tranquilizers and other drugs affecting mental health) at the rate of more than 100 million each year, and tranquilizing drugs have been reclassified43 as "major" and "minor" on the basis of certain differences in the pharmacological actions and clinical uses of the chief agents in each group. Discussion, within prescribed space limitations, of the newer tranquilizing drugs (both major and minor), their pharmacological actions, clinical uses, methods of administration, usual daily dosages, side effects, toxic reactions, precautions governing use and therapeutic efficacy, is the purpose of this report. THE MAJOR TRANQUILIZERS

The major tranquilizers are (1) the phenothiazines and (2) Rauwolfia alkaloids and fractions. Major tranquilizers differ from minor ones, primarily, in that they relieve psychotic symptoms. The particular clinical usefulness of these compounds presumably reflects certain quantitative differences in their pharmacological properties from those of the older sedatives and minor tranquilizers. Among those pharmacological characteristics are: antipsychotic activity (e.g., ability to produce emotional calm in aggressive, overactive, disturbed patients); inability of even large doses

* Late Associate Clinical Professor of Dermatology,

University of Cincinnati College of Medicine; Senior Staff, Christ Hospital; Co-Director, Department of Dermatology, Bethesda Hospital; Consulting Dermatologist, Children's Hospital; Attending Dermatologist and Clinician, Cincinnati General Hospital; Associate Attending Staff, Good Samaritan and Jewish Hospitals, Cincinnati, Ohio

459

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to produce deep coma and anesthesia (i.e., animals and patients show both behavioral and electroencephalographic arousal when stimulated); production of reversible effects on the extrapyramidal system leading to development of various signs and symptoms; and lack of any marked tendency to cause psychological or physical dependence. THE PHENOTHIAZINES

It has been pointed out that for versatility of use there is nothing to match the phenothiazines, and to know them is to know pharmacology. Phenothiazine itself has had widespread employment in animals as a vermifuge. Today, certain derivatives of phenothiazine serve not only as major tranquilizers but also as sedatives and antiemetics, while other derivatives of phenothiazine have usefulness in situations which are nonpsychiatric in nature, as antihistaminics, antipruritics, antitussives, antispasmodics, antiemetics and sedatives, for potentiation of hypnotics and narcotics, and for prolongation of ether anesthesia. Derivatives of phenothiazine, which have particular nonpsychiatric uses, are shown in Table 1. Such phenothiazines will be omitted from this discussion.

Table 1. Phenothiazines and Their Nonpsychiatric Uses GENERIC NAME

TRADE NAME

Pipamazine Thiethylperazine maleate Promethazine hydrochloride, D.S.P. Pyrathiazine Methdilazine Trimeprazine Ethopropazine Propriomazine

Mornidine Torecan Phenergan Hydrochloride

Dimethoxanate hydrochloride

Cothera

Pyrro]azote Tacaryl Temaril Parsidol Hydrochloride Largon

PRINCIPAL NONPSYCHIATRIC USES

Antiemetic; sedative Antiemetic Antihistaminic; antiemetic; sedative Antihistaminic An tihistaminic An tipruritic; antihistaminic Antispasmodic Potentiator of hypnotics and narcotics; extender of narcosis of ether anesthesia Antitussive

Derivatives of phenothiazine which are currently classed as tranquilizers43 produce a wide variety of central and peripheral pharmacologic effects; all of these agents are capable of causing undesirable reactions when administered in sufficiently large doses. Differences in the degree to which these varied reactions occur, appear to depend largely on the type of substituted chemical groups which are attached to the basic phenothiazine nucleus, represented by the following structural formula:

461

NEWER TRANQUILIZING DRUGS

These compounds, classified on the basis of the nature of the side chain in position 10 and the substituent in position 2, on the phenothiazine nucleus, together with usual daily dosages, are shown in Table 2. (All of these compounds were described by Ayd,3 plus methoxypromazine, Tentone, which is no longer marketed and which has, therefore, been omitted. Compounds which have been previously described elsewhere by the author66 are so indicated.) Table 2.

Phenothiazine Tranquilizers: Classification and Usual Dosage Range

GENERIC NAME AND TRADE NAME

RiO SUBGROUP

R2 SUBSTITUENT

USUAL DAILY DOSAGE RANGE·

1. Compounds with Propyl Dimethylamino Subgroup at Position RiO and with Various

Chlorpromazine43 . 66 (Thorazine) Promazine43. 66 (Sparine) Triftupromazine43, 66 (Vesprin)

R2 Substituents 3-dimethylaminopropyl

Cl

3-dimethylaminopropyl 3-dimethylaminopropyl

30-1200 mg. 50-1000 mg.

CFa

20-150 mg.

2. Compounds with Alkyl Piperidyl Subgroup at Position Rio and with Various R2 Substituents Mepazine43, 66 I-methyl-3, 50-400 mg. piperidylmethyl (Pacatal)

3. Compounds with Propyl Piperazine Subgroup at Position RiO and with Various R2 Substituents 3-[4-(2-hydroxyethyl) CF3 1-20 mg. Fluphenazine43 piperazinyl] propyl (Permitil; Prolixin) 3-[4-(2-hydroxyethyl) Cl 6-64 mg. Perphenazine43 . 56 piperazinyl] propyl (Trilafon) 3-( I-methyl-4Cl 15-150 mg. Prochlorperazine 43 • 66 piperazinyl) propyl (Compazine) 3-[4-(2-aretoxyethyI) Cl 15-100 mg. Thiopropazate43 piperazinyl] propyl (Dartal) CFa 3-(I-methyl-42-30 mg. Trifiuoperazine43 piperazinyl) propyl (Stelazine)

* The dosage range indicates the amounts usually suggested for the management of patients with conditions varying from mild psychoneurotic disorders to severe psychotic ,disturbances. Smaller doses may sometimes be employed in mild cases, and the maximum amounts indicated for treating severe cases have occasionally been exceeded.

462

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Actions and Uses The phenothiazines produce their primary calming and antipsychotic effects by depressing the central nervous system in a manner which differs from the depression produced by barbiturates and other sedative-hypnotics. This depression, which calms the patient without making him unconscious, offers practical advantages in the management of acute and chronic psychotic states. The phenothiazines are most useful in the treatment of conditions marked by psychomotor activity regardless of the patient's degree of mental illness. Among the psychotic conditions in which improvement often occurs are certain schizophrenic states (e.g., acute catatonic excitement), the manic phase of the manic-depressive psychosis and involutional senile and toxic psychoses. Sedation is most marked with phenothiazines of the dimethylamino and piperidyl subgroups. It seems least likely to occur in patients receiving therapeutic doses of drugs containing the piperazine subgroup (which possesses greater potency than drugs with dimethylamino and piperidyl groupings). The agents with the piperazine subgroup have proved useful in stimulating withdrawn, apathetic patients suffering from chronic schizophrenia, making them more alert, sociable and communicative. Other patients, however, with seemingly similar symptoms, have not always benefited from this "stimulating" action. The phenothiazines have been employed in relatively small doses for suppressing minor manifestations of anxiety, tension and emotional disturbance in psychoneurotic patients, and, as an adjunct in the management of various psychosomatic disorders. Limited benefits of phenothiazine therapy, however, in such cases, do not seem to warrant the risks of adverse reactions inherent in the use of these drugs. Consequently, most clinicians now seem to prefer use of minor tranquilizers for these purposes.

Methods of Administration The daily dosage of these drugs varies widely, depending upon severity of the condition and the response of the patient. Even in patients with similar symptoms, dosage may have to be very highly individualized to attain maximum benefit with minimal untoward effects. During maintenance therapy, it is desirable not to exceed the smallest dose effective in keeping the patient's symptoms under controL Compounds containing the piperazine subgroup have the greatest potency. Although certain types of undesirable effects (e.g., autonomic blockade) do seem less likely to occur with these drugs) lower milligram dosage alone does not necessarily mean that drugs of this subgroup are safer or more effective than the less potent agents. Thus low dosage should not, in itself, be considered an advantage, if the margin of safety is not also significantly widened. The phenothiazines are administered orally, rectally and by intramuscular or intravenous injection. Deep intramuscular injection is the preferred parenteral route, as it is less likely to cause severe hypotensive reactions. Certain phenothiazine compounds are available as sustained-release capsules or repeat-action tablets. These products do not appear to offer any significant advantage over ordinary oral forms.

Adverse Reactions and Precautions The phenothiazines are capable of causing a wide variety of untoward effects; some of these are the result of their secondary actions on the central and autonomic nervous system, and others appear to be due to the patient's idiosyncrasy or to his allergic responses. The physician employing a new phenothiazine should be alert to the possible occurrence of any of these effects, even if they may not have

NEWER TRANQUILIZING DRUGS

463

been previously reported to have occurred with the administration of this particular drug. Extrapyramidal symptoms often occur after administration of large doses. Drugs with the dimethylamino-type substitution seem more likely to induce a Parkinson-like syndrome. The piperazine-type compounds also produce these effects, but they are more likely to cause dyskinetic reactions. Profuse sweating, pallor and fever may accompany these symptoms, but consciousness is not lost, and the patient remains fully alert. Akathisia, or motor restlessness and an appearance of continuous agitation, may be produced. It is very important to recognize these dystonic symptoms of possible reactions, for seizure-like syndromes which develop suddenly often have been erroneously diagnosed as acute encephalitis or other neurological disorder and have been treated accordingly. These reactions may be brought under control by the parenteral or oral administration of an antiparkinsonian agent. The patient may be able to continue phenothiazine therapy at a lower dosage level, especially when antiparkinsonian drugs are administered concomitantly. On the other hand, it may be necessary to withdraw the drug completely before symptoms subside. Substitution of a phenothiazine with less likelihood of producing extrapyramidal reactions may be desirable. Certainly, phenothiazines of the piperazine-type should be used only with caution and in low doses for treating patients with a history of convulsive disorders. Other adverse effects and severe toxic reactions include cutaneous and liver disorders and blood dyscrasias, although these may not be related to the dose given. Although skin reactions and jaundice have occurred most commonly in patients treated \vith dimethylamino- and piperidyl-type phenothiazines, it has sometimes been suggested that susceptible patients should be treated with one of the piperazinetype compounds. These drugs are not, however, entirely lacking in their capacity to cause such reactions. Similarly, cross-sensitivity may make it hazardous to try to alter medication from an offending phenothiazine to another agent in a supposedly safer subclass. Physicians should be alert for such symptoms as sore throat, fever and weakness. If these occur, examination of the peripheral blood for leukocyte and differential counts is indicated. Such studies should be carried out periodically in any case, in order to detect early signs of hematopoietic depression, so that the drug can be discontinued before hematotoxicity becomes irreversible. Leukopenia, granulocytopenia, agranulocytosis, purpura and pancytopenia are among the more serious blood dyscrasias. rrhe rnost frequent form of liver disorder during phenothiazine therapy is cholestatic hepatitis which causes an obstructive-type jaundice. If bilirubinuria and signs of impending icterus are detected, further administration of these drugs should be stopped at once. Use of phenothiazines in patients with a history of liver disease or jaundice is certainly undesirable. The phenothiazines, especially in large doses, may produce drowsiness, dizziness and fatigue. Because of the potentiating action of the phenothiazines upon other central nervous system depressants, they should be cautiously used in patients who are under the influence of alcohol or barbiturates: doses of narcotics, analgesics and general anesthetics should be reduced in patients receiving these tranquilizers. The phenothiazines are contraindicated in comatose patients. These drugs produce varying degrees of autonomic blockade. Potentially, the most serious effect is the result of adrenergic blocking action. This effect, which seems more likely to occur with the dimethylamino and piperidyl compounds, than with the piperazine-type drugs, often causes orthostatic hypotension. This reaction Occurs most commonly after parenteral administration; therefore, these drugs should be administered with the patient in a supine position. Patients should be kept recumbent for at least one hour after parenteral administration. Large oral doses may produce postural hypotension and reflex tachycardia in susceptible patients. If ~irculatory collapse occurs, a pressor agent such as levarterenol bitartrate should

464

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be adrninistered. Epinephrine should never be ernployed, because its use in a patient with partial adrenergic blockade may result in vasomotor reversal phenomenon and a further fall in blood pressure. Although tolerance to this hypotensive effect tends to develop during prolonged administration, caution is always required in prescribing these drugs for elderly patients, who have evidence of arteriosclerosis, and others with cardiovascular diseases, in whom a sudden drop in blood pressure would be especially undesirable. Anticholinergic effects may result from the autonomic blocking action of these drugs. These effects, which are most common with the piperidyl derivative, mepazine, include dryness of the mouth, blurring of the vision, urinary retention and constipation. Laxatives may be prescribed concurrently in order to minimize the possibility of intestinal obstruction. T'he use of phenothiazines with a relatively strong anticholinergic action should be avoided in patients with a history of glaucoma or prostatic hypertrophy. Physicians should be alert for signs of heat prostration in patients receiving large doses of these drugs during summer months. Various signs of endocrine imbalance have been caused by phenothiazine depression of hypothalamic function. Among these effects are delayed ovulation and menstruation, and amenorrhea with false-positive results from a pregnancy test. Female patients taking some of these drugs have manifested lactogenic responses. Incidence of abnormal lactation is reported to parallel drug dosage. Weight gain has been ascribed to actions on the endocrine system. Photosensitivity reactions occurring in some patients taking certain phenothiazines suggest that patients should stay out of the sun, or wear protective clothing to prevent sudden development of severe solar erythema. NEWER PHENOTHIAZINE TRANQUILIZERS

Not included in Table 2 are the newer phenothiazine tranquilizers, thioridazine hydrochloride (Mellaril), acetophcnazine dimaleate (Tindal), and carphenazine maleate (Proketazine). These compounds, their usual daily dosages and methods of administration, actions and uses, adverse reactions and precautions governing use are shown in Table 3. NEWER PHENOTHIAZINE-LIKE TRANQUILIZERS

Not included in Tables 2 or 3 are the newer phenothiazine-like tranquilizers: chlorprothixcne (Taractan), a thiaxanthene analogue of chlorpromazine, and prothipendyl hydrochloride (Timovan), an aza analogue of pronlazine. Both compounds have resulted from slight chemical modifications in the basic phenothiazine nucleus and both possess phenothiazinelike activities. The formula for chlorprothixene (Taractan) is: CH 2-CH 2-CH 2- N

0('(\ 11

/

CH 3

""

CH 3

!

'VV'v/ I

I

'

s

A nitrogen has been replaced in the basic phenothiazine nucleus by a carbon.

For treatment, 12.5 to 400 mg., orally. Dosages must be individualized; see package insert. l\tlaximal clinical response wiI] not occur until there have been at least 3 months of continuous medication.

Carphenazine Maleate 1-10-(3-4-(2-Hydroxyethyl) -1-piperaziny1propyl) phenothiazin2-yl-1-propanone bis hydrogen maleate PROKETAZINE (Wyeth L3 b. Div., American Home Products Corp.)

ACTIONS AND USES

Similar to chI 01'promazine.

Similar to chlorpromazine.

Similar to chlor.. promazine, prototype of the phenothiazine tranquilizers.

* See also under the major discussion of the phenothiazines.

For treatment, 40 to 80 mg. oraUy in divided doses. For patients who have difficulty sleeping, the last tablet should be given 1 hour before retiring.

For treatment, 300 mg. to 1.6 gm.; for maintenance, 30 to 100 mg., orally.

USUAL DAILY DOSAGES AND METHODS OF ADMINISTRATION

Aceto:!)henazine Dimaleate 1- (2- Hydroxyethyl) -4-3(2-acetyl-10-phenothiazinyl)-propyl-pipera zine dimaleate TINDAL (Schering Corp.)

"r

2-l\ilethylmercapto-10 2(N-methyl-2-piperidyl) ethyl phenothiazine hydrochloride M ELLARIL (Sandoz Pharmaceuticals Div., Sandoz Chemical orks)

Thioridozine Hydrochloride, N.N.D.43

GENERIC NAME, CHEMICAL DESCRIPTION, TRADE NA:\iE AND CO!\lMERCIAL SOURCE

Table 3.

Allergic Phenomena Edema 45 Alteration in cephalin flocculation 45 Cardiovascular Complications Hypotension: dizziness, weakness, fatigue 45 Central Nervous System Effects Akathisia; akinesia; dyskinesia45 Drowsiness; somnolence 15 Parkinsonism 15

Allergic Phenomena Persistent pruritus 54 Central Nervous System Effects Agitation 54 Akathisia15 Depression15 Drowsiness; sedation 15

Allergic Phenomena Edema 30 ,31 Nasal congestion 30 , 43 Toxic liver changes; jaundice~, 43 Cardiovascular Complications Hypotension: dizziness, weakness, fatigue43, 51 Central Nenrous System Effects Ataxia; vertigo 21 • 51 Drowsiness: sedation 21 , 31, 43 Drvness of nasal and oral mucosa 21 . 31 Hallucinations 21 Headache; insomnia 21 Parkinsonism30 Ocular manifestations: toxic retinitis. Patients taking large doses, above 1.6 gm. per day, have developed pigmen tary retinopathy; others, who have received smaller doses, have also experienced visual

Dermal Reactions Dermatitis medicamentosa45 Gastrointestinal Disturbances Nausea 45 Vomiting 45

Central Nervous System Effects (Coni'd.) Dryness of oral mucosa Hi 54 Headache 54 Parkinsonism15 Urinary frequency15 Visual difficul ties l5

Central Nervous System Effeds (Cont'd.) impairment, but no detectable retinal changes occurred. Thus, patients should be closely ohserved for deposition of pigment and signs of diminished visual acuity, impaired night vision and a brownish discoloration to objects viewed. Although this condition seems to be reversible, use of some other phenothiazine is probably preferred for patients requiring large doses of the drug for prolonged periods, 10, 23. 43 Dermal Reactions Dermatitis medicamentosa: sun sensitization 30 . 31. 43 Endocrine Imbalances Amenorrhea: galactorrhea31 , 43, 60 Inhibition of ejaculation 18 , 43 Hematopoietic Changes Leukopenia 4 Agranulocytosis 43

ADVERSE REACTIONS AND PRECAUTIONS*

Newer Phenothiazine Tranquilizers

>

~

~ ~

U2

d Cl

N

Z o o ~

E

d

,0

Z

~

~

~

~

~

t:rj

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466

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WELSH

The formula for prothipendyl hydrochloride (Timovan) is:

c66

CH 2-CH 2-CH 2-N

I

/

CH 3 ·HCI·H 20

"'" CH,

s

An extra nitrogen appears in the basic phenothiazine nucleus. Phenothiazine tranquilizers have been found to possess pronounced sedative effects, as described previously. Slight chemical modifications in the basic phenothiazine nucleus lend support to the claims that phenothiazine-like tranquilizers offer relief from agitation, tension and unrest (sleeplessness) by exerting activity which improves the "sleep pattern." Phenothiazine-like tranquilizers, their usual daily dosages, methods of administration, actions and uses, adverse reactions and precautions governing use are shown in 'fable 4. Since hesitant introduction of chlorpromazine in 1954, search has been (and is still being) made for compounds possessing at least equal, perhaps greater potency, with fewer side effects and toxic reactions. As each new compound has become available, hopes for greater therapeutic efficacy have been high. Expectations, however, have not been fulfilled. When the newer phenothiazine and phenothiazine-like tranquilizers are reviewed critically, and compared with chlorpromazine, it would seem that they are about equipotent and equitoxic. Pharmaceutically and therapeutically, there is little to choose between them-except in price. RAUWOLFIA ALKALOIDS AND FRACTIONS

Summarized below are the chemistry, actions and uses, usual daily dosages, methods of administration, adverse reactions and precautions governing use of the Rauwolfia species. These compounds were previously described elsewhere by the author. 56 , 57

Rauwolfia Serpentina Whole Root, N.F.

(IlAUDIXIN, RAUSERPA, RAUVAL)

The powdered whole root of Rauwolfia serpentina (Benth.) produces the surn of the actions of the total alkaloids contained in the whole root. The component alkaloids exhibit the sedative, antihypertensive-bradycrotic action characteristic of reserpine. The whole root contains only insignificant arllounts of yohimbine and other adrenolytic alkaloids. Thus, Rauwolfia powdered whole root is useful for the same purposes, and with the same precautions, as reserpine. Rauwolfia powdered \vhole root is administered orally; for adults, 200 mg. in divided doses. Larger amounts rnay be required for the sedation of gross psychotic disturbances than for anxiety-tension states associated with mild labile hypertension. (OraUy, 200 to 300 rllg. of powdered whole root is equivalent to 0.5 mg. of reserpine.)

Prothipendyl Hydrochloride

Similar to chlorpromazine.

Similar to chlorpromazine.

ACTIONS AND USES

* See also under the major discussion of the phenothiazines.

4-Dimethylaminopropylpyrido-(3, 2{J) (1, 4) benzothiazine hydrochloride-monohydrate TIMOVAN (Ayerst Lab. Div., American Home Products Corp.)

For treatment, 25 to 400 mg. orally.

2-Chloro-9- (3-dimethylaminopropylidene) thiaxanthene TARACTAN (Roche Lab. Div., HoffmannLaRoche)

OF ADMINISTRATION

USUAL DAILY DOSES AND METHODS

For treatment, 10 to 600 mg. orally. When potent, rapid, calming action is required, 25 to 200 mg. intramuscularly. Dosages must be individualized.

Chlorprothixene

CHEMICAL DESCRIPTION, TRADE NAME AND COMMERCIAL SOURCE

GENERIC NAME,

Table 4.

Cardiovascular Complications Hypotension: dizziness, weakness, fatigue 41 Tachycardia47 Central Nervous System Effects Catatonia41 Drowsiness: sedation 41

Central Nervous System Effects (Cont'd.) Allergic Phenomena Increase in alkaline phosphatase22 , 35 DrYness of oral mucosa; bitter taste in the mouth21 Excitement 32 Edema 16 Headache21, 32 Cardiovascular Complications Insomnia16 ,21 Hypotension: dizziness, weakness, fatigue5, 29, 32 Parkinsonism5, 85 Central Nervous System Effects Thirst35 5 Akathisia; dystonia Endocrine Imbalances Anxiety32 Increased libido35 Ataxia; vertigo21 , 35 Hematopoietic Changes Leukopenia 22 Convulsions; seizures5 Drowsiness; sedation 16 , 21,29,32,35 Although no evidence of changes in thyroid function has been noted in patients receiving chlorprothixene, nevertheless certain animal data suggest the advisability of examining the status of the thyroid gland during prolonged administration. Changes, such as increase in size or development of nodules within the gland should be noted, as well as any alteration in basal metabolic rate. 52

ADVERSE REACTIONS AND PRECAUTIONS*

Phenothiazine-like Tranquilizers

-.::J

~ ~

w

'0

d

~

tJ

ts

Z o

~

I-l

§

>-Z

~

1-3

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t:tj

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468

ASHTON

L.

WELSH

AIseroxylon (RAUWILOID) Alseroxylon is a fat-soluble alkaloidal fraction extracted from the root of Rauwolfia serpentina (Benth.), containing reserpine and other nonadrenolytic alkaloids. Alseroxylon has the action of the sedative-antihypertensive-bradyerotic alkaloids of Rauwolfia serpentina (of which reserpine is the most potent). Alseroxylon, therefore, has the same uses and limitations as the whole root, Rauwolfia, and its chief component alkaloid, reserpine. Alseroxylon is administered orally. For adults the average dose usually is 2 to 4 mg. Higher oral dosages may be required for sedation of gross psychotic disturbances than for anxiety-tension syndromes associated with mild labile hypertension. (Orally, 1 mg. is approximately equivalent to 0.2 mg. of reserpine.) Rescinnamine, N.F. (MODERIL) Rescinnamine is the 3,4,5-trimethoxy cinnamic acid ester of methyl reserpate, structural formula for which is:

/~-~

cHao-lJNAJ~

~ ~~~

CHao-e-l ~

/O-CHa

0

)-O-~-CH=CH-Q' -O-CH

~(

O-CHa

s

-

O-CH:~

The pharmacologic properties of rescinnamine are similar to those of reserpine, although, in some respects, rescinnamine seems to be the weaker, producing less sedation and less bradycardia (in proportion to hypotensive dose) than does reserpine. Rescinnamine is administered orally, in highly individualized dosages: initially, 0.5 mg. twice daily for one week, with adjustment to 0.25 mg. once daily, for patients with anxiety states associated with labile essential hypertension.

Syrosingopine (SINGOSERP) Syrosingopine, a chemically modified reserpine derivative, is represented by the following structural formula:

N

469

NEWER TRANQUILIZING DRUGS

Syrosingopine possesses pharmacologic properties similar to those of reserpine, but there is less sedation and less bradycardia in proportion to hypotensive dose. Syrosingopine is administered orally, in dosages of 1 mg. two or three times daily, for mild anxiety states.

Deserpidine

(HARMONYL)

Deserpidine, an alkaloid extracted from the root of Rauwolfia canescens Linn., is closely related, in chemical structure and pharmacological actions, to reserpine. The structural formula for deserpidine is:

~I-()

~NA~

J

lJ", I

I

0 1I

0--

/ O-CH,

CH,O-ry/-o-c- ~ ( O-CH s

O-CH,

o-eR a

Deserpidine produces mild, gradual and sustained lowering of blood pressure, a tranquilizing effect (usually without hypnosis), and slowing of the heart rate. Deserpidine is administered orally in anxiety-tension states in dosages of 0.25 mg., three or four times daily, with reduction of dosage as indicated after 10 days. For many patients with mild symptoms, daily maintenance dosage is 0.25 mg.

Reserpine, U.S.. P.

(RAULOYDIN, RAURINE, RAU-SED, RESERPOID, SANDRIL,

SERFIN, SERPASIL, SERPATE, VIO-SERPINE)

Reserpine is the 3,4,5-trimethoxybenzoic acid ester of reserpic acid. Its struc.. tural formula follows:

Reserpine is considered to be one of the most potent of the Rauwolfia alkaloids, which exhibit a sedative action and antihypertensive effect, accompanied by bradycardia. (The antihypertensive effect of reserpine is variable and ineffective in some patients.) Studies in experimental animals indicate that the drug acts on the J'entral nervous system, producing a psychotherapeutic nonhypnotic sedation,
470

ASHTON

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WELSH

the gastrointestinal tract, and a variable lowering of mean arterial blood pressure. The latter effect is attributed to a decrease in peripheral vasomotor mechanism, and is not associated with a significant alteration of cardiac output or renal plasma flow. Some effects of the drug suggest an action on the autonomic nervous system, although it does not exhibit either peripheral adrenolytic or peripheral parasympathomimetic activity, and it does not block autonomic ganglions. Effects of the drug are presumed to result from a central partial suppression of sympathetic predominance near the level of the hypothalamus, where autonomic nervous functions are integrated. Reserpine has a rather low toxicity, but may be associated with undesirable or toxic side effects, especially at high dosage levels. Reserpine is administered orally. (Intramuscular and intravenous methods of administration not required for the treatment of anxiety-tension states are omitted here.) In anxiety or tension psychoneuroses, the daily dosage is 0.5 to 2.0 mg., although, in some cases as little as 0.05 mg. may be required. With daily oral administration, effects of the drug usually are not manifest for several days to 2 weeks, and may persist for as long as 4 weeks after oral medication is discontinued. Tolerance to the drug does not develop with continuous administration. The drug must be administered for a period of 1 (usually) or 2 weeks before the optimal level of dosage can be determined. The tranquilizing effect of reserpine must be carefully observed in order to avoid development of an oblique attitude of indifference or detachment, which may induce a paradoxical form of anxiety, and an adverse reactive depression. Other oide effects, commonly observed following reserpine therapy, are: nasal stuffiness, weight gain and diarrhea, and less frequently, dryness of the mouth, insomnia, nervousness, increased gastrointestinal activity, chronic fatigue or sense of weakness in the extremities, muscular aching, epistaxis, nightmares, agitated or paranoid depression, skin eruptions and peptic ulceration. A paralysis agitans-like syndrome, which is reversible and which apparently results from excessive dosage, has been encountered. Postural hypotension may occur occasionally after parenteral administration, and, rarely, after oral administration, except with large dosages. Sodium retention and the development of edema associated with reserpine therapy have been reported. Mechanism of these reactions is unknown.

THE MINOR TRANQUILIZERS

The minor tranquilizers are considered useful mainly for suppressing the less severe manifestations of anxiety and tension. They may help to control mild to moderate degrees of emotional upset in various psychoneuroses, in somatic disorders and in normal individuals who react adversely to environmental stress. 43 They are often employed alone, or concomitantly with more specific agents, such as antispasmodics, analgesics, vasodilators, adrenal steroids and estrogens. Used in this way, they may favorably influence the emotional component in certain gastrointestinal, musculoskeletal, cardiovascular and dermatological disorders, and in the menopause. When administered in large oral and parenteral doses, some of these drugs occasionally have helped to overcome more severe states of psychomotor hyperexcitability. Sometimes they have rapidly reduced acute psychotic agitation in schizophrenics, and have helped to counteract the

NEWER TRANQUILIZING DRUGS

471

confusion, hallucinosis, disorientation and delusions which often occur in patients with toxic psychoses. Despite their use in the management of such symptoms of acute psychosis and their occasional employment for premedication prior to electroshock therapy, however, the minor tranquilizers are not generally recommended for the long-term treatment of chronic schizophrenia or other psychoses. 43 In some respects, the minor tranquilizers resemble the classic sedatives. For example, they may produce psychological and even physical dependence in individuals who take them in excessive amounts for long periods of time. They differ from the older sedatives mainly in that a somewhat lower incidence of drowsiness is induced when equally effective calming doses are given. The margin between doses which produce clinically desirable degrees of sedation and those which adversely affect consciousness and psychomotor activity is relatively limited in most of these compounds. The minor tranquilizers share a somewhat similar central depressant action, the ability to produce mild sedation in doses unlikely to cause soporific effects. or to adversely affect the clarity of consciousness and the quality of psychomotor performance. They vary somewhat in the nature of their secondary central and peripheral effects, and such effects form the basis for grouping the minor tranquilizers into three subclasses43 as outlined below. 1. Drugs of the First Subclass. Drugs belonging to this subclass are chlordiazepoxide hydrochloride, chlormezanone, emylcamate, hydroxyphenamate, mephenoxalone, meprobamate and oxanamide. Of these, the newer tranquilizers are chlordiazepoxide hydrochloride, chlormezanone, emylcamate, hydroxyphenamate and mephenoxalone. Actions of these drugs are limited largely to the central nervous system. In addition to calming action, these drugs also produce a partial blockade of certain central interneuronal connections involved in motor reflex activity. This may account for the marked skeletal muscle relaxant and anticonvulsant actions often seen in experimental animals after large doses have been given. The clinical usefulness of the anticonvulsant property of these drugs in the treatment of epilepsy has been limited. Numerous attempts have been made to apply their central muscle relaxant effects in the management of a wide variety of neuromuscular and musculoskeletal disorders; however, results are difficult to evaluate. They may be useful as adjuncts in the management of some types of patients, especially those in whom anxiety and tension tend to intensify the symptoms of a spastic condition. 2. Drugs of the Second Subclass. Drugs belonging to this subclass are buclizine hydrochloride and hydroxyzine (hydrochloride and pamoate). Buclizine hydrochloride is one of the newer tranquilizers. These drugs produce antihistaminic and other peripheral effects (anticholinergic, antiarrhythmic, etc.), in addition to their central calmative action. Their antihistaminic and antiemetic actions appear to be of clinical

~ ~ N

Hydrochloride~

0

""OHs

/-

S02

_/-Cl

/

0

OH3

I

CH3CH20-0-C-NH2

I

C2H5

l-Ethyl-1-methylpropyl carbamate

Emylcamate, N.N.D.43

TRANCOPAL C\Yinthrop Laboratories)

o

""

/ - "" C" rN

2· (4-Chlorophenyl)-3-methyl-4-metathiazanone-l, l-dioxide

Chlormezanone, N.N.D. 43

LIBRIOM (Roche Laboratories Div., Hoffmann-La Roche)

(~ ,,/

\-N""

01-"/,,,,_

( ",,(N=>I ·HCI

NHCH 3

4-benzodiazepine 4-oxide hydrochloride

7-Chloro-2-methylamino-5~phenyl-3H-l,

N.N.D.43

Chlordiazepoxide

GENERIC NAME, CHEMICAL DESCRIPTION, STRUCTURAL FORMULA, TRADE NAME AND COMMERCIAL SOURCE ACTIOXS AND USES 43

Minor Tranquilizers

of the First Subclass ADVERSE REACTIOKS AND PRECAUTIOXS*

_

Orally, for adults, 200 mg., given 3 or 4 times immediately before meals.

fa-

Gastrointe~tina] Di~turbances

Central Nervous Svstem Effects (Cont'd.) Drowsiness: somnolence39, 43, 50 Dryness of the mouth 39 , 43 Dermal Reactions Dermatitis medicamentosa43 Endocrine Imbalances Impotence EO

Similar to meprobamate. (Appears to be, milli- Central Nervous System Effects Gastrointestinal Disturbances gram for milligram, twice as potent as Drowsiness, somnolence, lethargy43 Nausea and vomiting 43 meprobamate, and to produce a lesser de"Gastric intolerance"36 DrynesR of the oral mucosa43 43 gree of drowsiness.) Headache (Gastrointestinal distress may be avoided, Results from one toxicity study in dogs re- Dermal Reactions usually, by taking the drug just before vealed that dailv administration of 100 to Dermatitis medicamentosa43 meals.) 200 mg./kg. body weight produced elevation of plasma alkaline phosphatase and Routine hemograms and liver function tests are advisable when the drug is given in large dosages, or for extended periods, particularly in patients with hepatic disease. 43

Nausea43 Although no serious adverse effects have been noted in p\\tients treated for as long as 18 months, more experience and better controlled studies will be necessary, to determine any possible undesirable effects which may occur from long-term administration. 43 •

Orally, for adults, 300 to 800 Similar to meprobamate. Allergic Phenomena mg:.; for children, 150 to Pruritus50 200 mg. Studies in laboratory animals suggest some Cardiovascular Complications skeletal muscle relaxant properties, as well Flushing43 Hypotension: dizziness, weakness, as sedative and mild analgesic actions. Clintigue 39 ,4J,50 ical studies have failed, however, to demonstrate any objective effect on spasticity, in Central Nervous System Effects humans. Blurred vision39

Orally, for adultp, 15 to 40 Similar to meprobamate. Central Nervous System Effects (Cont'd.) Allergic Phenomena Edema 9 Urinary frequency 53 mg.; for elderly or debili- Animal studies have shown sedative, anticonvulsant and skeletal muscle relaxant properElevation of serum glutamic oxalopyruvic 'Yithdrawal symptoms after abrupt discontat,ed patients, 10 to 20 mg.; ties. Drug is rapidly absorbed from the transaminase: jaundice1?, 25 tinuation of drug, taken in large doses for for children, 5 mg. 2 to 4 gastrointestinal tract and excreted very Eosinophilia~25 several months: convulsions one week after timeB, or 10 mg. 2 or 3 times. Parenterally (intravenously or slowly. Its plasma half-life is 20 to 24 hours. Cardiovascular Complications therapy was discontinued43 intramuscularly), for Hypotension: dizziness, weakness, fatigue, Dermal Reactions Clinical studies have demonstrated some desyncope25 , 43,53 Dermatitis medicamentosa43, 53 adults: 50 to 100 mg. Total gree of effectiveness in musculoskeletal disorders associated with emotional disturb- Central Nervous System Effects Fixed drug eruptions20 dose should not exceed 300 Ataxia25 ,43,53 Urticaria 9 mg. ances, and little or no effect upon muscle 43 Minimal effective dose should spasm of a purely organic nature. There is Decreased tolerance to alcoho1 Endocrine Imbalances Drowsiness: somnolence: lethargy25, 43, 53 Altered libido 53 insufficient evidence to assess value of drug be determined in all cases. in convulsive disorders. Headache 53 Changes in menstrual cyc1e 53 Insomniq25 V\Teight gain 53 Irrihbility: paradoxical rage, excitement, Gastrointestinal Disturbances stimulation, hostility, depersonalizaNausea43 ,53 tion34 , 43, 53 Constipation43. 53 Ocular manifestations: anisometropia: eso- Hematopoietic Changes phoria for distance and exophoria for near Agranulocytosis43 vision: poor depth perception40 Leukocytosis25 Concomitant administration of other psychotropic agents, particularly phpnothiazines or monoamine oxidase inhibitors, which are known to potentiate action of other drugs, should be avoided. 43

USUAL DAILY D03AGES AND METHODS OF ADMINISTRATION43

Table 5.

~

0

2-Methyl-2-n-propyl-l. 3-propanediol dicarbamate

Orally, for adults, 400 mg.• Prototype of the minor tranquilizers with psy- Allergic Phenomena Central Nervous System Effects (Cont'd.) Headache43, 56 given 3 or 4 times. The bedHypersensitivity reactions include urticaria, chosedative, anticonvulsant and central Muscular paralysis43, Sf time dose may be doubled maculopapular eruptions, erythema, edeskeletal muscle relaxant actions, found useto facilitate onset of sleep. ful for suppressing less severe manifestations Ocular manifestations: paralysis of extrama: occasionally. fever, intense pruritus, ocular muscles; diplopia43 , 56 All dosages must be indiof anxiety and tension, and for helping to acute nonthrombocytopenic purpura with o C3H7 0 Paradoxical excitement 43 , 56 vidualized. control mild-to-moderate degrees of emocutaneous petechiae and ecchymoses. tional upset in various psychoneuroses, in More severe reactions include chills, fever, Dermal Reactions 11 1 11 HaN-C-0-CH2-C-CH20-C- NH2 See 11 Allergic Phenomena" somatic disorders, and in normal individsyncope, angioneurotic edema and bronFixed drug eruptions27 , 55 chia.l spasm. 43 , 56 uals, who react adversely to environI CHs mental stress. Often employed alone, or conStomatitis and proctitisll There may be cross-sensitization between Carbromal and meprobamate;37 between Gastrointestinal Disturbances comitantly with more specific agents, such See "Dermal Reactions" carisoprodol and meprobamate: 27 beas antispa.smodics, analgesics, vasodilators,

Meprobamate, U.S.P., N.N.D.43

Orally, for adults, 400 mg., ad- Similar to meprobamate. Dermal Reactions Cardiovascular Complications ministered 4 times. For chil- Onset of action, although relatively rapid, is Dermatitis medicamentosa43 Hypotension: dizziness, weakness. fatigue 48 dren, dosages should be advariable, ranging from 30 minutes to 4 Central Nervous System Effects Urtiearia48 48 justed on the basis of weight Agitation hours. Peak blood levels are achieved in 4 Endocrine Imbalances and age. Drowsiness: somnolence43 , 48 hours after oral administration. Relation of Diminution of lil;ido48 blood levels to psychopharmacological effect Extrapyramidal reactions48 Gastrointestinal Disturbances Constipation: cramps: diarrhea, nausea43 , 48 is not known. Drug appears to be quickly Headache4 3 and almost completely metabolized. Insomnia43 In one chronic toxicity study on dogs,615 times Until greater experience is obtained, rourine hemograms and liver function tests are advisable, the usual human dose, daily produced severe when the drug is given in large doses, or for extended periods. hemolytic anemia with granulo- and reticulocytosis and with siderosis of the liver and kidneys. A slight hemolytic anemia was demonstrated, also, in dogs when five times the usual daily dose for humans was given. In no case, to date, has hemolytic anemia, in humans. been encountered. 43

Orally, for adults, 600 to 800 Similar to meprobamate. Central Nervous System Effects (Cont'd.) Cardiovascular Complications Increased irritabilityl mg. Available data are incomplete and provide no Hypotension: dizziness, weakness, fatiguel ,28,43 "Shakiness"] evidence that drug is unique; that it has a selective action; or that it acts by selectively Central Nervous System Effects Dermal Reactions inhibiting transmission of nerve impulses Drticaria43 Ataxia l over internuncial pathways. Gastrointestinal Disturbances Blurred vision l l Drowsiness, somnolence , 28, 43 Anorexia l Feeling of being "overmedicated"l "Gastrointestinal upset"28

slightly enlarged livers. (A minor amount of pigment was noted in liver parenchymal cells.) No evidence is yet available, however, that emylcamate has altered liver function in humans. In the absence of adequately controlled studies, there is no convincing evidence that drug has more than sedative or calming effect.

~----------------------------------------------------------------------

"

0

LENETRAN (Lakeside Laboratories) TREPIDONE (Lederle Laboratories Div., American Cyanamid Co.) TRANPOISE (Whittier Laboratories)

V

5-Co-Methoxyphenoxymetbyl)-2oxazolidinone OCH2 ! I-NH /"'- 0 CH I 1 I 1- ~"'- /~

Mephenoxalone, N.N .D. 43

OH LISTICA (Armour Pharmaceutical Co. Div., Armour & Co.)

I -I' _/-r-CH20-C-NH2

C ""

Hydroxyphenamate, N.N.D.43 2-Hydroxy-2-phenylbutyl carbamate C2Hs 0

STRIATRAN CMerck Sharp & Dohme Div., Merck & Co.)

I

0

ADVERSE REACTIONS AND PRECAUTIONS*

Evaluation of oxanamide by the Council on Drugs of the American Medical Association contains this statement: "Relatively few adverse effects have been reported."43 Drowsiness has been observed. occasionally, during the first few weeks of medication. 44 Two experiments concerning the effects of moderate doses on 6 behavioral variables involved in complete acts, such as driving a car. have been conducted. Under the conditions described, performance was impaired no more by oxanamide than by a placebo, while alcohol produced much greater impairment than both.sS The authorM reported previously the following observations of response to oxanamide, administered to patients with dermatoses. complicated or exacerbated by factors of anxiety, tension and emotional upset: "In patients. who had been under therapy with other tranquilizing agents, such as phenothiazines, Rauwolfia alkaloids and fractions. substit,uted propanediols and the like. we observed gradual disappearance of all of the unpleasant subjectiye symptoms of previously-used medicationf'; for example, 'tired all of the time,' 'logginess,' 'grogginess,' 'hangover,' 'don't want to move. just want to sit.' nasal congestion, bad dreams and nightmares. The disappearance of these side effects of previous therapy, in some cases, took as long as two to four weeks..•." "In our experience to date. oxanamide appears to be the only tranquilizing agent which can be administered in high dosages (400 mg. tablets, 3 or 4 times daily) during a prolonged interval (as long as 6 months) without producing any toxic reactions or side effects. such as photosensitivity. dermatitis, allergic phenomena. liver damage. depression and suicidal tendencies, extrapyramidal dysfunction. convulsions or seizures:' Experience since that time has been identical, with one exception: some patients have now received continuous therapy with oxanamide during intervals as long as 18 months, without any toxic reactions or side effects.

adrenal steroids and estrogens for influenc· tween hydroxyzine and meprobamate (see Intestinal hyperperistalsis with rice-water stools41'.56 Table 6, "Hydroxyzine"). ing the emotional component in certain gastrointestinal. musculoskeletal. cardio- Cardiovascular Complications Nausea, vomiting. anorexia. discomfort, flatulence, cramps4.3, 56 vascular and dermatological disorders, in Hypotension: dizziness. weakness. fatigue43 ,56 the menopause, in idiopathic petit mal Hematopoietic Changes epilepsy. and to lessen abnormal motor ac- Central Nervous System Effects See"Allergic Phenomena" tivity in athetoid and dyskinetic patients. 4s Addiction: withdrawal reactions: conAplastic anemia38 vulsions26. 43 ,56 69 Decreased tolerance to alcohol Depression: suicide (actual, as well as attempted)43,56 Drowsiness: somnolence43 ,56

ACTIONS AND USES 4S

Orally. 400 mg., given 4 times. Similar to meprobamate. The bedtime dose may be Like mephenesin. administration of large doses to experimental animals produces skeldoubled to facilitate the onetal muscle relaxation. as a result of partial set of sleep. All dosages blockade of internuncial neurons. Theoretmust be adjusted to meet ically. this action might make the drug use· the needs of the patient. ful as an adjunct in the management of muscle spasm. in humans. In practice, however, it is probable that any antispastic effect which occurs after ordinary dosage is secondary to relief of anxiety and tension. 43

USUAL DAILY DOSAGES AND METHODS OF ADMINISTRATION43

* See previous discussion of adverse effects and precautions which should govern use of minor tranquilizers.

QUIACTIN (Wm.

S. Merrell Co. Div.• Richardson-Merrell)

o

CH3CH2CH2-C-C-C-NH2 ""'-/ ~

I

2-Ethyl-3-propy19lycidamide C2H5 H

Oxanamide, N.N.D.43

(Wallace Laboratories)

MILTOWN. MEPROSPAN. MEPROTABS

EQUANIL, EQUANIL

L-A, WYSEALS (Wyeth Laboratories Div., American Home Products Corp.)

STRUCTURAL FORMULA, TRADE NAME AND COMMERCIAL SOURCE

Table 5. Minor Tranquilizers of the First Subclass (Continued) ~----------------------------------------------------GENERIC NAME. CHEMICAL DESCRIPTION,

~

~

~

OHs

2 HCl

CH2CH20H

ACTIONS AND USES43 ADVERSE REACTIONS AND PRECAUTIONS*

I'

Orally, for adults: 25 to 100 Hydroxyzine is a prototype of those minor Allergic Phenomena Central Nervous System Effects4S ,56 mg., given 3 or 4 times. Acute hypersensitivity reaction in a 39 tranquilizers which also possess other poFor most children over 6 year old man, who had no history of alDrowsiness, somnolence tentially useful central and peripheral years of age, a total dose lergy except for the migraine synDryness of the mouth and actions, including antiemetic and antiof 50 to 100 mg., and for drome, and who was recovering from a throat histaminic effects. In addition to use as children under 6 years of an adjunct in the symptomatic treatdermatosis due to meprobamate. Headache age, no more than 50 mg. Shortly after ingestion of the second ment of anxiety, tension and agitation, M uscular weakness, undose of hydroxyzine (prescribed as Parenteral administration hydroxyzine has been employed alone, in steadiness Vertigo should be reserved for substitute therapy for meprobamate), the management of acute and chronic emergencies requiring he experienced tightness in the chest, Dermal Reactions urticaria and other manifestations of more rapid onset of acAngioneurotic edema allergic dermatoses. difficult breathing, edema of the face, tion. It should be re- The pamoate salt is thought to be conhands and feet, angioneurotic edema, Dermatitis medicamentosa placed by oral therapy as followed by a generalized skin erupUrticaria verted by gastric acid to the hydrochlorsoon as is practicable. Intion and painful arthralgia of the Gastrointestinal Disturbances ide, but there is no adequate evidence tramuscularly, 50 to 100 wrists and ankles. Recovery followed Increased intestinal perithat it produces a more sustained theramg., every 4 to 6 hours: epinephrine subcutaneously, intrapeutic effect than does the hydrostalsis intravenously, the initial venous infusions of AOTH and other chloride. dose, injected at a rate supportive measures. of no more than 25 mg. PruritusiG per minute, should not Rhinorrhea 511 exceed 100 mg. It may be followed by maintenance doses of 25 to 50 mg. every 4 to 6 hours, as required.

Orally, for adults: 50 to The drug exerts central nervous system de- Central Nervous System Effects Drowsiness7, 19 150mg. pressant, antiemetic and antihistaminic The suggested dose, orally, effects (similar to those of hydroxyzine, Certain early reports indicate that incifor children 3 years and to which, chemically, there is close reladence is low: but, according to evaluaolder: 25 to 50 mg. No tionship). Sedation is its most prominent tion by the Council on Drugs, drowsiclinical evidence has been action, and this forms the basis for the ness occurs in approximately 25% of presented, however, to drug's most common clinical use. patients. It could make driving a car or substantiate this pro- Buclizine hydrochloride has been proposed operation of machinery dangerous. 43 posed dosage. Dryness of the mouth43 for use to alleviate mild-to-moderate anxiety, tension and senile agitation. Headache43 In the absence of carefully controlled N ervousness43 studies or adequate comparison, with Gastrointestinal Disturbances other tranquilizing agents, however, the Nausea43 evidence to support these claims is not impressive.

* See previous discussion of adverse effects and precautions which should govern use of minor tranquilizers.

ATARAX HYDROCHLORIDE (J. B. Roerig & Co. Div., Ohas. Pfizer & Co.) VISTARIL PARENTERAL (Hydrochloride), VISTARIL (Pamoate) (Pfizer Lab. Div., Chas. Pfizer & 00.)

v/"'CH-N<~N-OH20H20

CI-O",

Hydroxyzine (Hydrochloride, N.F., and Pamoate), N.N.D.43 1-(p-Chlorobenzhydryl)-4-2-(2-hydroxyethoxy) ethyl piperazine

SOFTRAN (Stuart Co.)

""../

(11

CI-<>-OH-N<-)N-CH~<;-6-CH3' -/ 1 . - / I

OH3

I-p-Chlorobenzhydryl-4-p-(t)-butybenzylpiperazine dihydrochloride

Buclizine Hydrochloride, N.N.D.43

GENERIC NAME, CHEMICAL DESCRIPTION, STRUCTURAL FORMULA, TRADE NAME AND COMMERCIAL SOURCE

Minor Tranquilizers of the Second Subclass

USUAL DAILY DOSAGES AND METHODS OF ADMINISTRATION43

Table 6.

C")

~

USUAL DAILY DOSAGES AND METHODS OF ADMINISTRATION43 ACTIONS AND USES43

Minor Tranquilizers

of the ADVEllSE REACTIONS AND PRECAUTIONS*

Third Subclass _

V

0",

'"

2-Diethylaminoethyl benzilate hydrochloride

Benactyzine Hydrochloride, N.N.D.43

Central Nervous System Effects (Cont'd.) Orally, for adults, the suggested Benactyzine is an anticholinergic corn· Allergic Phpnomena Paresthesia13, 43, 46, i6, 58 Headache13, 43, 46 pound proposed for use in the maninitial dose is 1 mg. given 3 Hypersensitivity reactioniG• 58 Inappropriate behavior17, 58 agement of psychoneurotic disorders. times, for 2 or 3 days. This Muscular rehx3.tion marked by feeling of Its usefulness for this purpose, and Cardiovascular Complications may be gradually increased to 13 Palpations: throbbing sensations ,43, 58 heaviness in the limbs13, 43, 46, &6,58 for the treatment of obsessive com3 mg., given 3 times, if smaller Syncope: generalized weaknesg43, 46,56,58 Ocular manifestations: difficulty in reading pulsive reactions or mild depressive doses produce no therapeutic OH 0 CH2CHa fine print, blurring of the visiont 13. 43, 58 reactions has not been established Central Nervous System Effects response. Doses of more than "'IC-C-Q-CH2CH2N / / Anxiety, uneasiness, fear, fright13 , 43, 46, 56, 58 micropsia, nystagmus, pupillary dilataconclusively. The drug appears to 10 mg. are considered undesir• HCI 43 tionl3. 68 Apathy, indifference , 46,56,58 have no effect in the treatment of able. The drug should be given Ataxia, dizziness, giddiness, clumsi- Dermal Reactions psychotic symptoms. after meals to reduce the rate / CH2CH3 nessl3, 43,46, 56, &8 Dermatitis medicamentosaf6, 08 of absorptIOn, and thus lessen Blocking of thought, retarded mental Endocrine Imbalances systemic adverse effects. activity, loss of memory, forgetful.. Modification of menstrual cycles8 ness 13 , 43, 46, £i6, 58 Psychosexual disorders must be carefully apPHOBEX (Lloyd, Dabney &; Westerfield) proached. Drowsmess: not so much sleepiness as a SUAVITIL (Merck Sharp & Dohme Div., Merck "lazy feeling, want to lie down and shut During therapy with benactyzine hydro& Co.) my eyes"13. 43, 46, 56, 68 chloride, homosexual relationships have been established, without feelings ofshame46 Dryness of the mouth, huskiness of the voice1s , 43, 46, 66, 58 Gastrointestinal Disturbances EEG change~ in normal subjects17•68 Bloating, heartburn46 , 56,58 Euphoria: "couldn't care less," "slapMetallic taste in the mouth06 , 58 happy"l;.43, 56, 68 Nausea, vomiting, gastric distress43, 46,56, 68 Benactyzine hydrochloride is contraindicated in patipnts with frankly hostile attitudes: their condition tends to deterIorate under therapy. The drug should not be administered to patients about to receive electroshock therapy. The drug should not be administered to patients with glaucoma. All patients should be carefully observed for untoward effects.43

o/C-0N-HoHCl

~OH

Azacyclonol Hydrochloride, N.F., N.N.D.43

Orally, the proposed dosage for Clinically, azacyclonol differs from Dermal Reactiollil other agents in this class because it Maculopapular eruptions2 treatment of schizophrenia has been proposed primarily for convaries from 20 to 100 mg., trol of psychotic symptoms rather given 3 times. a,a- Diphenyl-4-piperidinemethanol hydrothan mild-to-moderate aruriety and Intravenously, for schizophrenic chloride tension. (It is not a typical central patients in whom oral medicanervous system depressant, as even tion is not feasible, and for large doses do not produce sedative treatment of toxic psychoses, or hypnotic effects.) such as delirium tremens, the drug may be administered in Reports on its effectiveness in the treat"'I ment of patients with hallucinations, doses of 100 mg. every 8 hours delusions and other signs of schizofor 1 to 7 days. phrenia and toxic psychoses have The above dosages should be been highly varIable. The drug seems considered experimental until less useful in chronic schizophrenia more evidence can be accumuthan in acute psychotic states. It has lated to support the theraFRENQUEL HYDROCHLORIDE (Wm. S. Merrell no plac~ in the therapy of depresshre peutic value of the drug. Co. Div., Richardson-Merrell) disorderEl, obsessive-compulsive neurosefl, or anxiety reactions.

GENERIC NAME, CHEMICAL DESCRIPTION, STRUCTURAL FORMULA, TRADE NAME AND COMMERCIAL SOURCE

Table 7.

-.:a

-l

~

Ectylurea, N.N.D.43

11

0

~

0

0

* See prpvious discussion of adverse effects and precautions which should govern use of minor tranquilizers.

SYCOTROL

(Reed & Carnrick Div., Block Druf! Co.)

\:;/

HO/C-C-o-CH2CH~N

(>'" - '"

Central Nervous System Effects (Cant'd.) Orally, 150 to 300 mg., 3 or 4 Ectylurea, a mild depressant which has Allergic Phenomena been used for treating simple anxiety Jaundice due to cholangiolitic hepatitis24 Nervousness times. and tension, does not have anticon- Central Nervous System Effects43 • 56 Urinary frequency. dribbling Dizziness Dermal Reactions43 , 56 vulsant, skeletal muscle relaxant, or analgesic a('tiom~, nor ia there e\'iDrowsiness. somnolence Dermatitis medicamentosa dence that it is of benefit t.o alcoholic Dryness of nasal and oral mucosa Gastrointestinal Disturbances43 , 56 patients or to those with frank psyHeadache Anorexia: nausea choses. Potential clinical usefulness appears to be as a sedative, but not Ectylurea is contraindicated in patients with hepatic disease. Use should be discontinued, as a hypnotic; however, its ultimate at once, if jaundice or other signs of liver dysfunction appear. usefulness remains to be establil'lhed by further, controlled. clinical studies.

Orally. the proposed dosage for Proposed for use in the management of Central Nervous System Effects anXIety and tension accompanying adults is 3 to 6 mg., adminDrowsiness is the only untoward reaction reported to date.43 peptic ulcer, and other somatic comistered 3 times. plaints. Further controlled studies, however, are required to support present claims for effeCl,iveness, which are based on limited, uncontrolled experience. • HCI Toxicity studies in animals and humans, reported to date are inadequate.

2-(l-Pippridino) ethyl benzilate hydrochloride

Pipethanate Hydrochloride, N.N.D.43

LEVANIL (Upjohn Co.) NOSTYN (Ames Co.)

H-C-CHa

11

CHaCH2-C-C-NH-C-NH2

11

o

2-EthyJ-cis-crotonylurea

478

ASHTON

L.

WELSH

use in the management of allergic conditions and of the nausea and vomiting of motion sickness and pregnancy. Attempts have been made to utilize their antiarrhythmic action in the management of cardiac arrhythmias. Favorable results have sometimes been reported in the treatment of extrasystoles and tachycardia of sudden onset and short duration. The clinical effectiveness of this property, however, has not been established. Any clinical benefits in cardiac conditions may be the results of sedation rather than of a direct cardiac action. These drugs are also claimed to have anticholinergic actions resulting in antispasmodic and antisecretory effects. They have not been proved clinically useful, however, in the control of gastrointestinal hypermotility and hypersecretion. 3. Drugs of the Third Subclass. Drugs belonging to this subclass are azacyclonol hydrochloride, benactyzine hydrochloride, ectylurea and pipethanate hydrochloride. These drugs are grouped together mainly because of the heterogeneity of chemical constitution, pharmacologic activity and clinical indications, which keep them from being classed with either of the two foregoing subgroups.

Safety, Adverse Effects and Precautions The minor tranquilizers seem relatively safe when employed in small doses required for the symptomatic relief of anxiety and tension. Incidence of drowsiness and other undesirable effects seems lower with these agents, than with equally effective doses of the older sedatives. Similarly, overdosage with these drugs is less likely to result in severe coma, vasomotor collapse and respiratory failure than with the barbiturates. Prolonged administration does not produce signs of autonomic imbalance as frequently, or as severely, as seen with the major tranquilizers. Numerous instances of adverse effects following use of the minor tranquilizers have been reported. Most commonly, these are drowsiness, ataxia, dizziness, headache (especially during the first few days of therapy), gastrointestinal discomfort, dryness of the mouth, nausea and vomiting, as well as rash, fever, chills and other signs of drug idiosyncrasy or hypersensitivity. Blood dyscrasias have been reported, rarely. Although relatively uncommon in comparison with older sedatives, acute and chronic toxicity results from abuse of these drugs. Suicidal attempts have led to coma, shock and death. Patients prone to take excessive amounts for prolonged periods have become dependent. Certain precautions,43 which are listed below, must be observed by the physician who prescribes minor tranquilizers. 1. Patients should be advised not to drive cars and not to operate dangerous machinery while taking these drugs. 2. Patients should be warned that minor tranquilizers may reduce tolerance to alcohol, and this may result in unexpected slowing of reaction time and impairment of judgment and motor co-ordination. 3. Amounts of minor tranquilizers prescribed for patients with a

479

NEWER TRANQUILIZING DRUGS

history of alcoholism, drug addiction or psychoneuroses should be limited, in order to prevent dependence. If patients are found to have been taking large amounts of these drugs for prolonged periods, they should not be abruptly withdrawn. Sudden withdrawal may lead to restlessness, convulsions and other signs of psychomotor hyperexcitability. 4. Caution is required in prescribing some of these drugs for patients with histories of allergic dermatoses, marked capillary fragility, blood dyscrasias or hepatic disease. If skin rash or other symptoms of hypersensitivity occur, administration of an offending drug should be stopped immediately, and symptomatic therapy instituted. 5. Hemograms, at regular intervals, should be required of patients undergoing therapy with minor tranquilizers. Patients with liver ailments should have regular examinations of hepatic functions. 6. Concomitant administration of other psychotropic agents, particularly phenothiazines and monoamine oxidase inhibitors, which are known to potentiate the action of other drugs, should be avoided. The minor tranquilizers, arranged by subclass, usual daily dosages, methods of administration, actions and uses, adverse reactions and specific precautions governing use are shown in Tables 5, 6 and 7. (Minor tranquilizers which have been previously described by the author elsewhere are so designated.) The following statement appeared in the evaluation,43 made by the Council on Drugs of the American Medical Association, of six of the newer minor tranquilizers (chlordiazepoxide hydrochloride, hydroxyphenamate, emylcamate, mephenoxalone, buclizine hydrochloride and chlormezanone): "On the basis of the current evidence, the Council can find no general advantage in the use of these newer agents; thus, the physician should use discretion when prescribing any of these in place of an older, wellestablished drug of similar therapeutic range and safety ratio with which he may already be thoroughly familiar."

REFERENCES 1. Abbott, J. A., Scholl, M. L., Schwab, R. S. and England, A. C., Jr.: Report on the

2.

3. 4.

5. 6. 7

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