Promazine

Promazine Claire Davis University of Wales College of Medicine, Cardiff, UK ã 2007 Elsevier Inc. All rights reserved.

Introduction A major metabolite of chlorpromazine, promazine is categorized as a group 1 aliphatic phenothiazine. Its general properties and therapeutic uses are similar to chlorpromazine. It has pronounced sedative effects and moderate antimuscarinic and extrapyramidal side effects. Promazine is a relatively weak antipsychotic and is therefore not used in the treatment of psychoses, although it may be employed in the short-term adjunctive management of psychomotor agitation. Promazine is used as a tranquilizer in veterinary practice, although it has limited approved uses in humans.

Nomenclature Name of the Clinical Form Related Names Source: EMTREE

Chemical Names CAS Number

Promazine embonate; promazine hydrochloride; promazine chloride A 145; alofen; alophen; ampazine; amprazim; centractil; centractyl; delazin; esparin; lete; liranol; neo hibernex; neuroplegil; piarine; prazine; promantine; promanyl; promilene; promwill; protactil; protactyl; pro tan; romthiazine; romtiazin; rp 3276; sediston; sinophenin; sinophenine; sparine; starazine; talofen; tomil; varophen; verophen; verophene; wy 1094; Promazine; Sparine (trade); 10 (3 dimethylaminopropyl)phenothiazine; promazine chloride; promazine hydrochloride 10-(3-dimethylaminopropyl)phenothiazine; N,N-dimethyl-10Hphenothiazine-10-propanamine 58-40-2

Basic Chemistry Chemical Structure Structure

Chemical Formula Properties Physical Properties

C17 H20 N2 S Promazine hydrochloride is a white to slightly yellow, almost odorless, hygroscopic crystalline powder. It oxidizes with

1

2

Promazine

Molecular Weight Solubility

prolonged exposure to air and develops a blue or pink color. It is stored below 25 C, in an airtight container, and protected from light. Promazine hydrochloride is incompatible with oxidizing agents, alkalis, and heavy metals. Incompatibilities have been reported with aminophylline, barbiturates, benzylpenicillin potassium, chloramphenicol sodium succinate, chlortetracycline, chlorthiazide sodium, dimenhydrinate, heparin, hydrocortisone sodium succinate, nafcillin sodium, phenytoin sodium, prednisolone sodium phosphate, and sodium bicarbonate. It is not recommended that promazine hydrochloride be mixed with other injections, with the exception of pethidine hydrochloride. 284.425 Promazine hydrochloride is very soluble in water, alcohol, and dichloromethane. It is freely soluble in chloroform.

Ionization Constant pKa

Value Salt Conditions Reference Comments 9.4 hydrochloride Dollery (1999)

Human Pharmacokinetics Promazine is a major metabolite of the group 1 phenothiazine, chlorpromazine Sgaragli et al (1986).

Pharmacokinetic Properties Prep. and Route of Value Units Admin. Reference Absorption Bioavailability Distribution Volume of Distribution

Comments

Hu and Curry (1989) Promazine is lipid soluble Dollery (1999) and reaches high concentrations in the brain, lung, liver, and kidneys. It passes readily across the placenta.

Plasma Protein Binding Metabolism Extensively metabolized, producing a large number of metabolites, including promazine sulfoxide, promazine N-oxide, 3-hydroxypromazine, and 3-hydroxydesmonomethylpromazine Essien et al (1975), Beckett et al (1988). Plasma Half-Life Bio Half-Life Clearance Routes of Elimination Urine

Promazine

Targets-Pharmacodynamics Promazine is an antagonist at dopamine, serotonin, alpha-1 adrenergic, histamine H-1, and muscarinic receptors.

Target Name(s): D-1 Dopamine receptor D-2 Dopamine receptor Serotonin receptors Alpha-1 adrenoceptors Histamine H-1 receptors Muscarinic cholinergic receptors

Therapeutics Promazine is a relatively weak antipsychotic and is therefore not used in the treatment of psychoses. It may be employed in the short-term adjunctive management of psychomotor agitation. Promazine is still widely used as a tranquilizer in veterinary practices, although it has limited approved uses in humans.

Indications

Value

Units

Prep. and Route of Admin.

Reference

Short-term adjunctive management of psychomotor agitation Dosage 25-200; 25-50 mg Oral; i.m. Mehta (2001)

Comments

100-200 mg 4 times daily. Children- not recommended. Elderly25-50 mg 4 times daily. 50 mg by intramuscular injection, repeated after 68 hours if necessary. Children- not recommended. Elderly-25 mg by intramuscular injection.

Contraindications Previous known hypersensitivity, depressed level of consciousness, hepatic or renal impairment, cardiovascular disease, Parkinson’s disease, epilepsy, hypothyroidism, prostatic hypertrophy, narrow angle glaucoma, pheochromocytoma, and myasthenia gravis. Special precautions include elderly, pregnancy, lactation, and cerebral arteriosclerosis.

Adverse Effects Promazine is a group 1 phenothiazine, characterized by pronounced sedative effects and moderate extrapyramidal and antimuscarinic adverse effects.

3

4

Promazine

Agent-Agent Interactions Agent Name

Mode of Interaction

ACE inhibitors Angiotensin-II antagonists Alcohol General Anesthetics Analgesics Antacids and adsorbents Antiarrhythmics Antidepressants

Severe postural hypotension. Severe postural hypotension.

Antidiabetics Antiepileptics Antihypertensives Antimuscarinics Antivirals Anxiolytics and hypnotics Beta-blockers Calcium-channel blockers Cocaine Diuretics Dopamine receptor agents Lithium Sympathomimetics Tetrabenazine Tobacco smoking Ulcer-healing drugs

Enhanced sedative effect. Enhanced hypotensive effect. Enhanced sedative and hypotensive effect. Reduced absorption of phenothiazines. Increased risk of ventricular arrhythmias due to prolonged QT interval. Increased risk of ventricular arrhythmias with tricyclic antidepressants. Coadministration increases plasma concentration and enhances antimuscarinic effects. Monoamine oxidase inhibitors may enhance hypotensive effects. Hypoglycaemic effect of sulphonylureas antagonized. Reduce seizure threshold and reduce efficacy of anticonvulsants. Enhanced hypotensive effect. Antimuscarinic side effects increased, but plasma concentration decreased. May increase plasma concentration of antipsychotics. Enhanced sedative effect. Increase risk of ventricular arrhythmias. Enhanced hypotensive effect. Increased risk of antipsychotic-induced dystonic reactions. Hypokalaemia increases risk of ventricular arrhythmias. Antagonism of hypoprolactinaemic and antiparkinsonian effects of bromocriptine and cabergoline. Antagonism of effect of apomorphine, levodopa, lisuride, and pergolide. Increased extrapyramidal effects and neurotoxicity. Antagonize pressor action. Increased extrapyramidal effects. Clearance of phenothiazine may be increased. Cimetidine may enhance antipsychotic effects.

Pre-Clinical Research Promazine is a nonselective dopamine receptor antagonist. As such, it blocks the action of amphetamine and apomorphine in several animal models Janssen and Van Bever (1978).

Promazine

Pharmacokinetics Potency

Organ/ Value Units Tissue Rat LD50

300

mg/kg

ID50

9.2

mg/kg

Dog ID50

9.2

mg/kg

Prep. and Route of Admin.

Cell Line/ Type Effects

Exp. End Point Reference

Comments

Subcutaneous injection Subcutaneous injection

Janssen and Van Bever (1978) Janssen and Van ED50 value for Bever (1978) amphetamine antagonism test. Refer to reference for ED50 values for other tests, including norepinephrine antagonism, catalepsy, palpebral ptosis, jumping box, apomorphine antagonism, and food intake inhibition tests.

Subcutaneous injection

Janssen and Van ED50 value for apomorphine Bever (1978) antagonism test. Refer to reference for ED50 values for jumping box test.

Journal Citations Sgaragli, G., Ninci, R., Della Corte, L., et al. 1986. Promazine. A Major Plasma Metabolite of Chlorpromazine in a Population of Chronic Schizophrenics. Drug Metabolism and Disposition, 14, 263–266. Hu, O.Y., Curry, S.H., 1989. Stability, Human Blood Distribution and Rat Tissue Localization of Promazine and Desmonomethylpromazine. Biopharmaceutics and Drug Disposition, 10, 537–548. Essien, E.E., Cowan, D.A., Beckett, A.H., 1975. Metabolism of Phenothiazines: Identification of NOxygenated Products by Gas Chromatography and Mass Spectrometry. Journal of Pharmacy and Pharmacology, 27, 334–342. Beckett, A.H., Navas, G.E., Hutt, A.J., 1988. Metabolism of Chlorpromazine and Promazine in Vitro: Isolation and Characterization of N-Oxidation Products. Xenobiotica, 18, 61–74.

Book Citations Dollery, C., 1999. Dollery, C. (Ed.), Therapeutic Drugs, pp. P236–P238, Churchill Livingstone, Edinburgh. Mehta, D.K., 2001. Central Nervous System. Mehta, D.K. (Ed.), British National Formulary, Edition 41, pp. 165–250, British Medical Association, London. Janssen, P.A., Van Bever, W.F.M., 1978. Preclinical Psychopharmacology of Neuroleptics. Clark, Del Giudice (Ed.), Principles of Psychopharmacology, Edition 2, pp. 279–295, Academic Press, New York.

Further Reading Anxiolytic Sedatives Hypnotics and Psychotics. In Martindale-The Complete Drug reference, K. Parfitt (Ed.), Edition 32, Pharmaceutical Press, London, 1999, pp. 635–700

5

6

Promazine Baldessarini, R.J., Drugs and the Treatment of Psychiatric Disorders. In J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. G. Gilman (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Edition 9, McGraw-Hill, New York, 1996, pp. 399–459 McGee, J. L. and Alexander, M.R., Phenothiazine Analgesia-Fact or Fantasy?, American Journal of Hospital Pharmacy, 36 (1979) 633–640 Davis, J.M., Recent Developments in the Drug Treatment of Schizophrenia, American Journal of Psychiatry, 133 (1976) 208–214