Chlorpromazine chemical structure
Find information on thousands of medical conditions and prescription drugs.

Chlorpromazine

Chlorpromazine was the first antipsychotic drug, used during the 1950s and 1960s. Used as chlorpromazine hydrochloride and sold under the tradenames Largactil® and Thorazine®, it has sedative, hypotensive and antiemetic properties as well as anticholinergic and antidopaminergic effects. It has also anxiolytic (alleviation of anxiety) properties. Today, chlorpromazine is considered a typical antipsychotic. more...

Home
Diseases
Medicines
A
B
C
Cabergoline
Caduet
Cafergot
Caffeine
Calan
Calciparine
Calcitonin
Calcitriol
Calcium folinate
Campath
Camptosar
Camptosar
Cancidas
Candesartan
Cannabinol
Capecitabine
Capoten
Captohexal
Captopril
Carbachol
Carbadox
Carbamazepine
Carbatrol
Carbenicillin
Carbidopa
Carbimazole
Carboplatin
Cardinorm
Cardiolite
Cardizem
Cardura
Carfentanil
Carisoprodol
Carnitine
Carvedilol
Casodex
Cataflam
Catapres
Cathine
Cathinone
Caverject
Ceclor
Cefacetrile
Cefaclor
Cefaclor
Cefadroxil
Cefazolin
Cefepime
Cefixime
Cefotan
Cefotaxime
Cefotetan
Cefpodoxime
Cefprozil
Ceftazidime
Ceftriaxone
Ceftriaxone
Cefuroxime
Cefuroxime
Cefzil
Celebrex
Celexa
Cellcept
Cephalexin
Cerebyx
Cerivastatin
Cerumenex
Cetirizine
Cetrimide
Chenodeoxycholic acid
Chloralose
Chlorambucil
Chloramphenicol
Chlordiazepoxide
Chlorhexidine
Chloropyramine
Chloroquine
Chloroxylenol
Chlorphenamine
Chlorpromazine
Chlorpropamide
Chlorprothixene
Chlortalidone
Chlortetracycline
Cholac
Cholybar
Choriogonadotropin alfa
Chorionic gonadotropin
Chymotrypsin
Cialis
Ciclopirox
Cicloral
Ciclosporin
Cidofovir
Ciglitazone
Cilastatin
Cilostazol
Cimehexal
Cimetidine
Cinchophen
Cinnarizine
Cipro
Ciprofloxacin
Cisapride
Cisplatin
Citalopram
Citicoline
Cladribine
Clamoxyquine
Clarinex
Clarithromycin
Claritin
Clavulanic acid
Clemastine
Clenbuterol
Climara
Clindamycin
Clioquinol
Clobazam
Clobetasol
Clofazimine
Clomhexal
Clomid
Clomifene
Clomipramine
Clonazepam
Clonidine
Clopidogrel
Clotrimazole
Cloxacillin
Clozapine
Clozaril
Cocarboxylase
Cogentin
Colistin
Colyte
Combivent
Commit
Compazine
Concerta
Copaxone
Cordarone
Coreg
Corgard
Corticotropin
Cortisone
Cotinine
Cotrim
Coumadin
Cozaar
Crestor
Crospovidone
Cuprimine
Cyanocobalamin
Cyclessa
Cyclizine
Cyclobenzaprine
Cyclopentolate
Cyclophosphamide
Cyclopropane
Cylert
Cyproterone
Cystagon
Cysteine
Cytarabine
Cytotec
Cytovene
Isotretinoin
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z

Chemistry

Chlorpromazine is derived from phenothiazine, its chemical name is 2-chloro-10- phenothiazine monohydrochloride and its molecular formula is C17H19ClN2S•HCl. Chlorpromazine has an aliphatic side chain, typical for low to middle potency neuroleptics. The oral bioavailability is estimated to be 30% to 50% due to extensive first pass metabolization in the liver. Its elemination-halflife is 16 to 30 hours. It has many active metabolites (approx. 75 different ones) with greatly varying halflives and own pharmacological profiles. The CYP-450 isoenzymes 1A2 and 2D6 are needed for metabolization of chlorpromazine and the subtype 2D6 is inhibited by chlorpromazine (NB: possible interactions with other drugs).

Mechanism of action

Central

Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects).

Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use).

Peripheral

Antagonist to H1-receptors (antiallergic effects), H2-receptors (reduction of forming of gastric juice), M1/M2-receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as 'dirty drug', whereas the atypical neuroleptic amisulpride e.g. acts only on central D2/D3-receptors and is therefore a 'clean drug'. This distinction expresses no valuation of the drugs.

Read more at Wikipedia.org


[List your site here Free!]


Photoaddition to DNA by nonintercalated chlorpromazine molecules
From Photochemistry and Photobiology, 11/1/98 by Kochevar, Irene E

Irene E. Kochevar*1, Carmelo Garcia^1, and Nicholas E. Geacintov2

ABSTRACT

Chlorpromazine (CPZ) forms photoadducts with DNA and photosensitizes DNA strand breaks. These reactions may be responsible for the reported photomutagenicity of CPZ and for the well-known cutaneous and ocular phototoxicity associated with this drug. We have investigated whether CPZ molecules that are intercalated between base pairs in double-stranded (ds) DNA are the absorbing species for the photoaddition reaction. Quenching of CPZ fluorescence by ds-DNA gave nonlinear Stern-Volmer plots, indicating that more than one type of complex is formed. Linear dichroism spectra of CPZ in the presence of ds-DNA showed a minimum at 345 nm, indicating that the absorption maxima of intercalation complex(es) are red-shifted compared to the absorption maximum of free CPZ at 307 nm. The sum of the absorption of all CPZ complexes with ds-DNA, obtained from dialysis experiments, was broadened and maximized at about 315 nm, indicating that complexes not involving intercalation dominate the absorption spectrum at lambda

INTRODUCTION

The mechanism whereby certain drugs cause adverse sunlight-induced cutaneous and ocular responses, a condition called drug phototoxicity, may involve photoreactions of the drug with cellular DNA. The most well-studied of these drugs are the psoralens that undergo [2 + 2] photocycloaddition reactions with pyrimidine bases when the planar psoralen molecule is intercalated between DNA base pairs. This photochemistry is believed to be a mechanism for the highly effective treatment for psoriasis and other cutaneous diseases using psoralens and UVA radiation. Reactions with DNA may be responsible for the phototoxicity of other drugs including chlorpromazine (CPZ)^^ (1,2), certain nonsteroidal anti-inflammatory drugs (3) and the recently reported fluoroquinolone antibiotics (4).

The wavelength dependence for photoaddition cannot be used to distinguish between externally bound CPZ and free CPZ as the chromophore for the photoaddition reaction although the slight red shift in the action spectrum from the absorption spectrum of free CPZ may favor the former species. The involvement of nonintercalated CPZ complexes in the photoaddition mechanism is supported by previous reports that CPZ photoadded more efficiently to single-stranded DNA, where intercalation is not possible, than to ds-DNA (8,11,13,17).

The apparent low reactivity of intercalated CPZ toward photoaddition contrasts with the requirement for intercalation prior to photoaddition found for psoralens. This difference cannot be rationalized solely on the basis of differences in the photoaddition mechanisms. The detailed mechanism for the formation of CPZ-base adducts is not known, although from the structure of one characterized adduct (6), the nominal mechanism involves dechlorination and subsequent addition of the phenothiazine radical to the 7-8 bond of the purine base. Unless intercalation does not allow the CPZ molecule to orient properly for this reaction, this reaction should be allowed because other molecules that intercalate into DNA undergo photoaddition by mechanisms involving (or likely to involve) free radical reactions with pyrimidines (27-28).

The more likely reason for the lack of photoadduct formation by intercalated CPZ molecules is that efficient nonradiative decay processes occur at these binding sites; the low fluorescence yields associated with CPZ-DNA intercalation complexes (Fig. 3) are consistent with this explanation. A thorough exploration of these interesting issues was beyond the scope of this work.

Acknowledgements-We gratefully acknowledge preliminary experiments by F.-L. Chung, many fruitful discussions with Mr. Rolando Oyola and support of this research by NIH grant S06-GM08216.

^^Abbreviations: CPZ, 2-chlorpromazine; ds-DNA, double-stranded DNA; LD, linear dichroism.

REFERENCES

Ljunggren, B., S. R. Cohen, M. Carter and S. I. Wayne (1980) Chlorpromazine phototoxicity: growth inhibition and DNA-interaction in normal human fibroblasts. J. Invest. Dermatol. 75, 253-256.

2. Kochevar, I. E. (1987) Mechanisms of drug photosensitization. Photochem. Photobiol. 45, 891-895.

3. Artuso, T., J. Bernadou, B. Meunier, J. Piette and N. Paillous (1991) Mechanism of DNA cleavage mediated by non-steroidal antiinflammatory drugs. Photochem. Photobiol. 54, 205-213.

4. Lietman, P. S. (1995) Fluoroquinolone toxicities. An update. Drugs 49 (Suppl. 2), 159-173.

5. Buettner, G. R., A. G. Motten, R. D. Hall and C. F. Chignell (1986) Free radical production by chlorpromazine sulfoxide. An ESR spin-trapping and flash photolysis study. Photochem. Photobiol. 44, 5-10.

6. Ciulla, T. A., G. A. Epling and I. E. Kochevar (1986) Photoaddition of chlorpromazine to guanosine-5'-monophosphate. Photochem. Photobiol. 43, 607-613.

7. Epstein, S. (1968) Chlorpromazine photosensitivity; phototoxic and photoallergic reactions. Arch. Dermatol. 98, 354-363.

8. Fujita, H., H. Hayashi and K. Suzuki (1981) Spectrofluorometric study on photochemical interaction between chlorpromazine and nucleic acids. Photochem. Photobiol. 34, 101-105.

9. Hasei, K., M. Ichihashi and M. Mojamdar (1984) Investigations

on the mechanism of chlorpromazine phototoxicity: effects on lysosomes of cultured human fibroblasts. Photochem. Photobiol. 40, 273-276.

10. Kelly-Garvert, F. and M. S. Legator (1973) Photoactivation of chlorpromazine: cytogenetic and mutagenic effects. Mutat. Res. 21, 101-105.

11. Kochevar, I. E., F.-L. Chung and A. M. Jeffrey (1984) Photoaddition of chlorpromazine to DNA. Chem.-Biol. Interact. 51, 273-284.

12. Kochevar, I. E. (1985) Influence of prior complex formation on the photoaddition of chlorpromazine to calf thymus deoxyribonucleic acid. J. Photochem. 28, 197-203.

13. Merville, M. P., J. Piette, J. Decuyper, C. M. Calberg-Bacq and A. van de Vorst (1983) Phototoxicity of phenothiazine derivatives. II. Photosensitized cross-linking of erythrocyte membrane proteins. Chem.-Biol. Interact. 44, 275-87.

14. Rosenthal, I., E. Ben-Hur, A. Prager and E. Riklis (1978) Photochemical reactions of chlorpromazine: chemical and biochemical implications. Photochem. Photobiol. 28,

15. Schothorst, A. A., D. Suurmond and R. Schouten (1983) Photochemical damage to DNA treated with chlorpormazine and near UV radiation under aerobic and anaerobic conditions. Photochem. Photobiol. 38, 659-664.

16. Jose, J. G. (1979) Photomutagenesis by chlorinated phenothiazine tranquilizers. Proc. Natl. Acad. Sci. USA 76, 469472.

17. Kahn, G. and B. P. Davis (1970) In vitro studies on longwave ultraviolet light-dependent reactions of the skin photosensitizer chlorpromazine with nucleic acids, purines and pyrimidines. J. Invest. Dermatol. 55, 47-53.

18. Fujita, H., A. Endo and K. Suzuki (1981) Inactivation of bacteriophage lambda by near-ultraviolet irradiation in the presence of chlorpromazine. Photochem. Photobiol. 33, 215-222.

19. Norden, A. B., M. Kubista and T. Kurucsev (1992) Linear dichroism spectroscopy of nucleic acids. Q. Rev. Biophys. 25, 51170.

20. Geacintov, N. E., V. Ibanez, M. Rougee and R. V. Bensasson (1987) Orientation and linear dichroism characteristics of porphyrin-DNA complexes. Biochemistry 26, 3087-3092. 21. Lamola, A. A., D. Landon, I. E. Kochevar and L. C. Harber (1982) An instrument for action spectrum studies in dermatology. Photochem. Photobiol. 35, 285-290.

22. Hatchard, C. G. and C. A. Parker (1956) A new sensitive chemical actinometer II. Potassium ferrioxalate as a standard chemical actinometer. Proc. R. Soc. (Lond.), A 235, 518-536.

23. McDowell, J. J. H. (1969) Crystal and molecular structure of chlorpromazine. Acta Crystallogr. Sect. B Struct. Crystallogr. Cryst. Chem. 25, 409-411.

24. Dewar, M. J., E. G. Zoebisch, E. F. Healy and J. J. Steward (1985) AMI: a new general purpose quantum mechanical molecular model. J. Am. Chem. Soc. 107, 3903-3909. 25. Fronza, G., E. Raggy and R. Mondelli (1981) Dynamic aspects of the stereochemistry of phenothiazine solutions. Actual. Chim. Ther. 8, 245-264.

26. Geacintov, N. E. (1987) Principles and applications of fluorescence techniques in biophysical chemistry. Photochem. Photobiol. 45, 547-553.

27. Hardwick, J. M., R. S. von Sprecken, K. L. Yielding and L. W. Yielding (1984) Ethidium bromide binding sites in plasmid DNA determined by photoaffinity labeling. J. Biol. Chem. 259, 1109011097.

28. Daugherty, P., S. C. Hixon and K. L. Yielding (1979) Direct in vitro photoaffinity labeling of DNA with daunorubicin, adriamycin and rubidazone. Biochim. Biophys. Acta 565, 13-21.

'Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA and

2Department of Chemistry, New York University, New York, NY, USA Received 28 May 1998; accepted 5 August 1998

* To whom correspondence should be addressed at: Wellman Laboratories of Photomedicine, Massachusetts General Hospital, WEL-224, 37 Fruit Street, Boston, MA 02114, USA. Fax: 617726-3192; e-mail: kochevar@helix.mgh.harvard.edu ^ Permanent address: University of Puerto Rico Humacao, Department of Chemistry, Humacao, PR 00791, USA.

Copyright American Society of Photobiology Nov 1998
Provided by ProQuest Information and Learning Company. All rights Reserved

Return to Chlorpromazine
Home Contact Resources Exchange Links ebay