Azmat Rasheed ( Faculty of Pharmacy, Punjab University, Lahore. )
Muhammad Afzal Javed ( Department of Psychiatry, Mayo Hospital, Lahore. )
Samia Nazir ( Faculty of Pharmacy, Punjab University, Lahore. )
Obaidullah Khawaja ( Department of Pharmacology, K.E. Medical College, Lahore. )
Interaction of Chiorpromazine with tricydlic antidepressants was investigated in twenty schizophrenic patients after their concurrent administration. A significant increase in serum chlorpromazine concentration was observed when administered in combination with both amitriptyline and imipramine with chiorpromazine. If combined therapy is indicated, the dose of chiorpromazine should be reduced or the time of administration of other two drugs should be adjusted to maintain therapeutic levels of chlorpromazine (JPMA 44:233, 1994).
Chlorpromazine is a versatile, prototype neuroleptic drug having variety of actions. It is a synthetic phenothiazine derivative that affects the pharmacological actions of a number of drugs, e.g., antacid1, antimalarial2, phenobarbitone3, Cimetidine4 and Lithium carbonate5 due to different drug interactions. It acts on the hypothalamus and brainstem reticular formation. It has a remarkable ability to control hyperactive and hypomanic states without seriously impairing consciousness. It modifies abnormal behaviours in schizophonic states associated with increase dopaminergic activity in the limbic system of the brain6. Tricyclic antidepressants like arnitriptyline and imipramine are chemically and structurally related to phenothiazines. These drugs contrary to chlorpromazine, enhance the neurotransmitter activity in the brain by blocking the reuptake of amine neurotransmitters. They increase the availability of adrenaline, noradrenaline and serotonine in thea central nervous system7. Although neuroleptics are mainly used in the treatment of schizophrenia, yet antidepressants are also prescribed for the treatment of depression. A number of treatment studies have been undertaken to investigate the utility of adjunctive antidepressant medication in schizophrenia with secondary depression8,9. The present study was carried out to investigate the effects/interactions of amitripty line and imipramine, two commonly used tricyclic antidepressants, on serum concentration of chlorpromazine after their concurrent administration to a group of schizophrenic patients.
Patients and Methods
Selection Criteria for Patients
Twenty male (between 3 0-50 years of age) schizophrenic patients diagnosed as per Diagnostic and Statistical Manual of Mental Health Disorders10, were selected for this study. They were resident members of Fountain House, a rehabilitation centre situated in Lahore. Patients enrolled in the study were made drug free and all the medications were discontinued ten days prior to the start of the study. The study was done in three stages. After 10 days of initial drug holiday, Chiorpromazine, Amitriptyline and Imipratnine were administrated orally in a sequence to the patients.
Stage I: Each patient was given chlorpromazine (200 mg). Blood samples were collected at 0,2,4,12 and 24 hours after the administration of drug for the determination of serum chloipromazine concentration.
Stage II: After a week interval the blood samples from each patient was taken at zero hour in the morning. Each patient was given chloipromazine (200 mg) and amitriptyline (100 mg) concomitantly. Blood samples were then collected at 0,2,4,12 and 24 hours after the administration of both the drugs for the determination of serum chlorpmmazine concentration.
Stage III: After an interval of another week the blood samples from each patient was taken at zero hour in the morning. Each patient was given chlorpromazine (200 mg) and imipramine (100 mg) concomitantly; blood samples were then collected at 0,2,4,12 and 24 hours after the administration of both the drugs for the determination of serum chlorpromazine level. Serum chlorpromazine concentration was determined according to the method adopted by Rasheed et al. 11 using Perkin Elmer 1320 Infrared Spectrophotometer at a wave length 273 nm.
Serum chlorpronrnzine level increased after concurrent administration of amitriptyline or imipraniine and was maximum at 2 hours of administration. Although it gradually decreased at intervals of 4,12 and 24 hours yet its concentration remained consistently high as compared to the group receiving chlorpromazine alone. A significant increase in the serum chlorpromazine concentration was however observed ranging between 23.44±1.40, 32.29±0.48 and 31.36±0.56 ug/mI at 2 hours interval after the administration of drugs in stage I, H and Ill respectively (Table).
A significant increase in chiorpromazine was observed as compared to the base line levels at 2,4,12 and 24 hours among patients taking chlorpromazine and a.mitriptyline or imipramine concurrently than patients taking chiorpromazine alone. These results correlate with the findings of Grammer and Rolfe12 and Lofa et al13 that the concurrent administration of Chlorpromazine with tricyclicantide pressants significantly increase the serum chiorpromazine concentration in Schizophienic patients at all time intervals. There may be many explanations for this increase, since chlorpromazine shares a common pathway for metabolism involving hepatic microsomal enzymes with imipramine and amitriptyline. Concurrent administration of these agents slows down the degradation of chlorpromazine resulting in prolongation of its plasma half life and a rise in therapeutic level of drut in the blood. It can be speculated that the levels of the active drug inthe blood may also be elevated on account of its displacement from its binding sites with plasma albumin. Chlorpromazine, imipramine andamitriptyline are lipophilic drugs and have a high binding.capacity and are thus capable of binding with plasma albumin to a significant extent. As the total binding capacity of plasma albumin is limited, concurrent presence of the drugs may result in mutual displacement of each other from their binding sites. As a result of which the fraction of active drug is elevated and the pharmacological or therapeutic effect of chlorpromazine is potentiated. The increase in serum Chlorpromazine concentration observed after concurrent administration of Chlorpromazine andantide pressants might also be due to similarity of chemical structure. Chlorpromazine is metabolized in liver to cause induction of bepatic microsomal enzyme. It is more firmly bound to plasma protein and replaces the less bound tricyclic antidepressants resulting in its accumulation in the body. The practical implication of the interaction between chlorpromazine and amitriptyline or imipramine need special attention. Such type of drug interaction may enhance the therapeutic effects of chiorpromazine. Care should, therefore, be taken when chlorpromazine is prescribed with aniitriptyline or imipramine. It is therefore recommended that when chlorpromazine and tricycle antidepressants are prescribed together, the dose of chlorpromazine may be reduced or the timing of the administration of both the drugs should be adjusted in order to achieve the intended the rapeutic response with minimum side effects.
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