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Study of identification and assessment of drug-drug interactions 1Shekar H.S., 2Dr. Chandrashekhar H.R., 1Alirezasahebdel 1. Dept. Of Pharmacy Practice, KIMS Hospital and Research Centre, VIPS, Bangalore. 2. Dept. Of General Medicine, KIMS Hospital and Research Centre, Bangalore. ABSTRACT Introduction Drug –drug interactions can be defined as pharmacological or clinical response to the administration of drugs combination that is different from its known effects of two or more than two medicines. It frequently conjures images of a sudden catastrophic and even fatal outcome. While such an event can occur and it is important to prevent in the clinical set up. Drug interactions can occur by pharmacokinetic & pharmacodynamic interactions. The antipsychotics are known to have drug interactions compared to any other class of drugs hence we aimed for the identification of drug interactions of psychiatric drugs.. Methodology The data was collected from medication chart and discharge medication order of inpatient of psychiatric department and analyzed the interactions using Stockley’s drug interactions, Dipiro etc.. Results and Discussion The study includes 508 samples out of which 368 case were found to have interactions. alcohol with lorazepam accounts for 26.18% and 20.47% respectively . INTRODUCTION Drugs interaction is the phenomenon which occurs when the effects of one drug modified by the prior or concurrent administration of another (or the same) drug(s). Drug interactions may arise either from alteration of the absorption, distribution, biotransformation or excretion of one drug by another, or from combination of their actions or effects.1 Drug-drug interactions (DDIs) occur when the presence of a co-prescribed drug (the perpetrator) alters the nature, magnitude, or duration of the effect of a given dose of another drug (the victim). Altered nature means that the effect produced when the two drugs are used together is qualitatively different than would be expected when either drug is used alone. An example of serotonin syndrome, which consists of marked autonomic instability, can be fatal. This syndrome can occur when a serotonin uptake pump inhibitor is used in combination with a monoamino oxidase inhibitor (MAOI). Altered magnitude, on the other hand, means that the nature of the effect is the same as can be reasonably expected from the victim of drug alone but is either more than or less than what would normally be expected for the specific dose ingested. Altered duration means that the nature of the effect is reasonably the same as can be expected from the victim drug alone, but the effect is either shorter or longer lived than would normally be expected for the dose given.2 DDI can be a consequence of various situations that reflects the growing number of drugs available in the market increasing complexity of polytherapy and the very widespread practice of self-medication makes the situation more severe and difficult. Most of the studies evaluated, analysed and estimated that drug interactions may affects up to 63% of all hospitalized patients.3,4,5 These may occur due to several reasons. For example, accidental misuse or younger people tend to metabolize drugs faster than older people or those who smoke the cigarettes metabolize clonazepam and olanazapine faster than those who do not. Co-morbid medical conditions that decreases the hepatic functions, such as cirrhosis or congestive heart failure, are likely to decrease the rate of drug metabolism. CytochromeP450 enzymes are polymorphic; there exist ethnic differences in hepatic enzymes that influence the pharmacokinetics of drugs and also due to lack of knowledge about the active ingredients involved in the relevant substances. Drug interactions are to be avoided, due to the possibility of poor or unexpected outcomes. A contemporary example of selective serotonin reuptake inhibitors (SSRIs) inhibits the metabolism of tricyclic antidepressants (TCAs) toxicity. (fluoxetine and imipiramine), Co-administration of SSRIs and mono amino oxidaze inhibitors (MAOIs) causes severe depression, Combination of SSRIs with pimozide or Tramadol hydrochloride causes seizure and hepatic failure. SSRIs with lithium, diuretics and CNS depressants increases the toxicity and NSAIDS interferes with SSRIs decreases its efficiency.6 Drug-drug interactions (DDIs) are a concern for the prescriber because they have the potential for causing untoward outcomes for everyone involved, morbidity and even mortality for the patients, liability for the prescriber and increased costs for the healthcare system. The risk of unintended and untoward DDIs is increasing in concert with both the increasing number of pharmaceuticals available and the number of patients on multiple medications. Health and Human Services research in the year of 2004 reports around 7% of Americans more than 18 years of age and more than 20% of Americans more than 65 years of age had taken 5 prescriptions medications in a week preceding the survey. Many studies have found that patients on psychiatric medications, such as antidepressants, are on more medications than patients not on psychiatric medications. It is important for prescribers to appreciate that medications interact not on the basis of their therapeutic use but on the basis of their pharmacodynamic and pharmacokinetic characters. For these reasons, the prescriber must consider all the medications prescribed and the patient consuming, this educational review emphasizes the role of pharmacologic principles to guide the safe and effective use of multiple medications when such use is necessary.2 IMPORTANCE OF DRUG-DRUG INTERACTIONS It is easy to understand the occurrence of DDIs and can mimic virtually any clinical presentation imaginable from catastrophic to the everyday problems seen in practice. DDIs can present in the following ways: A multitude of different types of serious adverse events (SAEs), such as sudden death,seizures, cardiacrhythm disturbances, serotonin syndrome, malignant hypertension, neuroleptic malignant syndrome, and delirium. 7-17 Poor tolerability (ie, patients ―sensitive‖ to adverse drug effect )1822 Lack of efficacy (ie, patient is ―resistant‖ to beneficial drug effect) 23 Symptoms that mimic or lead to a misdiagnosis of a new disease 24-26 The apparent worsening of the disease being treated. 18-20 Withdrawal symptoms or drug-seeking behavior on the part of the patient.6 The term DDI frequently conjures images of a sudden catastrophic and even fatal outcome. While such an event can occur and is important to prevent, DDIs can present as virtually anything, including the worsening of the illness being treated or the emergence of a new illness. For this reason, such ―masked‖ DDIs can ironically lead to the use of more medications to treat the apparent worsening of the primary condition or to treat the apparent emergence of a new condition. As psychiatric drugs are more rationally developed to affects brain, their adverse effects will not be on peripheral systems. Thus, the result of psychiatric DDIs could present as changes in mentation, reality testing, emotional control, inter-personal relationships and memory function. The prescribers must be a good behavioral pharmacologist as well as a good diagnosticians and must also keep in mind that changes in these outputs of the human brain may be because of the medications that the patients receiving rather in spite of them.27 Guide to Psychiatric Drug Interactions The prescriber should be aware of generic names of medications of their personal formulary, without which it is impossible to search the medical literature on them. As medicine becomes more international and the world becomes smaller, the physician must be aware that medications have different brand names in different countries and frequently have multiple brand names. The use of generic drugs decreases total count of the patients when they are available, Despite claims to the contrary, there are only a small number of examples where an approved generic drugs are not an effective sub- stitutes for the brand name drug.28 Special Considerations for How DDIs Present in Psychiatric patients All drugs, except anti-infectives, are administered to change human physiology. 29 Those changes can present in every way clinically imaginable. For this reason, the prescriber should keep in mind that the patient may not be doing well because of the medications he is receiving rather than despite the medications receiving.30 Understanding and identifying DDIs with psychiatric medications is perhaps more challenging than in any other area of medicine. The reason is complexity of the organ they affect and its output. 31 Every identified neurotransmitter has 2-17 receptor subtypes. Thus, the human brain may contain thousands of receptors, which are the primary targets of drug action. There are different enzymes for the synthesis and degradation of these neurotransmitters, different uptake pumps and storage mechanisms. These regulatory proteins can be the target for drug action. Thus, current drugs may interact pharmacodynamically in ways that are neither understood nor predictable at the present time. 32 Their detection is dependent on the careful assessment at the time of a medication prescribed by the prescriber.28 Mechanism of drug-drug interactions Two types of mechanism: 1-Pharmacodynamic interactions 2-Pharmacokinitic interactions. Drugs are approved and generally considered from the perspective of their therapeutic use; however, they interact on the basis of their pharmacodynamics and pharmacokinetic properties. They are frequently used for reasons other than their initial labeled indication. For example, selective serotonin reuptake inhibitors were initially approved as antidepressants, but several have subsequently gained approved labeling for the treatment of a variety of anxiety disorders.2 Pharmacodynamic DDIs Number of neuropsychiatric medications including tertiary amines and atypical antipsychotics affect more than one mechanism of action under clinically relevant dosing conditions. For example, quetiapine binds most avidly to the α1-adrenergic receptor and binds almost as avidly to the histamine H1-receptor33-36, but requires 23-fold increase in dose to bind to the dopamine D2 receptor That indicates why do low doses of quetiapine can be used for sedative effects and higher doses are needed for antipsychotic efficacy. For the same reason, quetiapine can have the same pharmacodynamic DDIs as other potent H -receptor antagonists even though those other drugs might not have any efficacy as an antipsychotic medication.2 Pharmacokinetic DDIs These outline potential CYP enzyme-mediated DDIs. Parenthetically, CYP-mediated DDIs are the most common, clinically meaningful type of pharmacokinetic DDIs. 37-38 The chelation of drugs in the gastrointestinal tract formed by iron salts prescribed to treat anemia or by antacids with high aluminum content; interactions that occur prior to the administration of intravenous (IV) drugs due to the incompatibility of IV solutions; interaction with drug-secreting transporters that line the renal tubules and the blood-brain barrier (eg, lithium intoxication due to co-administration with ibuprofen and possibly other nonsteroidal anti-inflammatory drugs); and nutritional interactions that deplete the cofactors required for the phase II metabolism of some drugs (ie, reduced acetylation and glycosylation due to persistent hypoglycemia or clinically significant malnutrition).33 potential mechanisms underlying pharmaceutics‘ drug-drug interactions are Protein binding/ Phase I enzymes / CYPs and non CYPs / Phase II enzymes / ABC transporters / Nuclear receptors. 33 METHODOLOGY The 508 patients who have fulfilled study criteria were included for the study, among which 200 patients were from psychiatric in patient department and 308 were from MRD, the data was collected form the discharged case notes at KIMS hospital and research centre. The study was conducted for a period of 9 months. The data was collected from medication chart, discharge patients medication order, Patient attenders. The patients who are admitted to psychiatric department with the clinical conditions and treated with two or more than two drugs and fulfils study criteria at KIMS Hospital and research centre. Patient discharge against medical advice. Patients who disagree with consent form MATERIAL AND METHODS: A prospective study is conducted on inpatients of psychiatric department at KIMS hospital & research center who have fulfilled inclusion criteria and on therapy. The patient consent form is taken from the patient care taker. The Medical records, case sheets of patients is reviewed and the drug data was collected. Any identified DDIs assessment was done for their mild, moderate and severity of reactions and analyzed the mechanism and time of onset of DDIs using recourses like Stockley‘s drug drug interaction, patient drug facts etc. Ethical clearance was obtained from the ethical committee and submitted to RGUHS before starting the study. RESULTS The work illustrate the drug drug interactions at psychiatric depatment in kims hospital and research centre, Bangalore. Around 508 patients were included for the study, among this 368 patients were found to have drug interactions in 17 different forms has been observed as shown in the table-1 and figure-1. SERIAL NO NAME OF DRUG DRUG INTRACTION WITH DDRU-DRUG INTERACTION NUMBER OF THE PATIENT OUT OF 508 26 PERCENTAGE OUTCOME % 1 CHLORDIA ZPOXIIDE DISULFIRAM CHLORDIAZPOXIDE +DISULFIRAM=INCREASE SERUMLEVEL OF CHLORDIAZPOXIDE AND CAUSE DROWSNESS (STOCKLY’S DDLs PAGE 725) 2 PANTAPRAZOL 3 INJ NEUROBIO N/VIT B12 ALCOHOL VIT B12+PANTAPRAZOL=DECREASE EFFECT OF VIT B12 133 26.18% LORAZPAM ALCOHOL+LORAZEPAM=AGGRESION/ANXIE TY/AMNESIA/IMPAIRED PERFORMANCE(STOCKLY’S DDLs PAGE 53) ALCOHOL+CLONAZPAM=POOR CONCENTRATION/DIZZINESS/SEXUAL DISFUNCTION DIPIRO PAGE 1302 104 20.47% 4 ALCOHOL CLONAZPPAM 1 0.19% 5 ALCOHOL olanzapine POSTURAL HYPOTENSION DROWSNESAS/INCREASE HEART RATE/CNS DEPPRESION (STOCKLY’S DDLs PAGE 72) ALCOHOL+DISULFIRAM=FLUSHING &FULLNESS OF THE FACE/TACHYCARDIA/BRADYCARDIA/GID DINESS/HYPOTENSION (STOCKLY’S DDLs PAGE 61) 3 0.59% 6 ALCOHOL DISULFIRAM 6 1.18% 7 ALCOHOL QUITIPIN ALCOHOL +QUITIPIN=POSTURAL HYPOTENSION&DROWSNESS(STOCKLY’S DDLs PAGE 76) 1 0.19% 9 ALCOHOL NSAIDs MAY INCREASE GIT HAEMORHAGE(STOCKLY’S DDLs PAGE 71) 1 0.19% 10 OLENAZPI LORAZPAM OLANAZPINE+LORAZPAM=ADDITIVE 31 6.10% 5.18% NE 11 TOXICITY OF LORAZPAM/CNS DEPPRESION/SEIZURE/HF/STROKE (STOCKLY’S DDIs page 756) DIVALPOR AX SODIUM(V APORIC cid) DIVALPOR AX SODIUM(V APORIC cid) DIVALPOR AX SODIUM(V APORIC cid) DIVALPOR AX SODIUM(V APORIC cid) RISPERIDO N LORAZPAM DIVALPORAX+LORAZEPAM=INCREASE LORAZPAM CLEARANCE AND DECREASE THE VALPORIC ACID CLEARANCE HF/STROKE (STOCKLY’S DDLs PAGE 719) 10 1.96 % OLENAZPINE DIVALPORAX+OLANAZPINE=ADDITIVE TOXICITY /TACHY CARDIA/AGITATION/COMADYSTHERMIA( STOCKLY’S DDLs PAGE 719 ) 7 1.37% CLONAZPAM DIVALPORAX+CLONAZEPAM=INCREASE CLONAZPAM CLEARANCE AND DECREASE THE VALPORIC ACID CLEARANCE(STOCKLY’S DDLs PAGE 719) 11 2.16% RISPERIDON VALPORIC ACID + RESPERIDON = OEDEMA (STOCKLY’S DDLs PAGE 767) 4 0.78% HALOPERIDOL REPERIDONE + HOLOPERIDOL=NEUROLEPTIC MALIGNANT SYNDROM(STOCKLY’S DDLs PAGE 755) 19 3.70% 16 RISPERIDO N FLOUXETIN RESPERIDON+FLOUXETIN= AKATASIAPAINFUL BILATERAL BREAST ENLARGMENT/OBSSESIVE AND COMPULSIVE DISORDER/SEDATIVE AND CONSTIPATION(STOCKLY’S DDLs PAGE 766) 7 1.37% 17 BUPRION HALOPERIDOL BUPRION INCREASE PLASMA LEVEL OF HALOPERIDOL(STOCKLY’S DDLs PAGE 1206) 1 .019 18 FLOUXETIN OLENAZPINE FLOUXETIN+OLENAZPINE=SEROTONIN SYNDROM(STOCKLY’S DDLs PAGE 754) 3 0.59 12 13 14 15 30 26.18 percentage 25 20.47 20 15 10 5 5.8 0.19 6.1 3.7 2.16 1.37 1.96 0.781.370.59 0.19 0.19 0.59 0.19 1.18 0 DISCUSSION 26 patients were treated with Anxiolytics (chlordiazpoxide) with antidotes and detoxifying agent (disulfiram), accounts for 5.18 % of drug drug interactions by increasing concentration of Chlorodiazapoxide and causes drowsiness . Antipsychotics(Bioprion) with antidotes/detoxifier is given to one patient out of 508 patients acoounts for 0.19 % of DDIs and Buprion is reported to increase plasma concentration of haloperidol . Out of 368 patients 133 patients drug interactions were between cobalamine and proton pump inhibitors which accounts for 26.18 % of the total sample size. Pantaprazole was found to decreases the effects of vitamin B 12 . Alcohol and anxiolytics / anticonvulsants were prescribed for 105 patients, accounts for 20.66 % of drug interactions. Out of 105 cases 104 patients wereprescribed with alcohol+lorazepam causes aggression/anxiety/amnesia/impaired performance accounts for 20.47 % and 1 patient was treated with alcohol+clonazpam which causes poor concentration/dizziness/sexual dysfunction accounts for 0.19 % drug interaction . The combination of Alcohol and analgesics prescribed to one patient accounts 0.19 % of drug interaction which increases gastrointestinal hemorrhage. The combination of Alcohol and antipsychotics were prescribed for 4 patients, out of 508 patients, accounts for 0.78 % of drug interactions and Causes postural hypotension, drowsiness, increased heart rate and CNS depression. 3 patients were prescribed with olenzapine with alcohol causes postural hypotension, drowsiness/increased heart rate/CNS depression accounts 0.59% of drug interactions and one patient was treated with alcohol and quitipin which accounts 0.19% of interaction, causes postural hypotension & drowsiness . The administration of Alcohol with antidotes/detoxifiers (disulfiram) prescribed for 6 patients, accounts 1.18 % of drug interactions and causes flushing & facial puffiness, tachycardia, bradycardia, giddiness and hypotension . The combination of antipsychotics /anticonvulsants with anxiolytics /anti convulsants were prescribed with 52 patients, which accounts 10.22 % of drug interactions. Among 52 patients 31 patients were with olanazpine+lorazpam which causes additive toxicity of lorazpam, CNS depression, seizures, stroke accounts 6.10% of interactions. Ten patients were prescribed with valproic acid +lorazepam which causes increased lorazpam clearance and decreases the valporic acid clearance, which account for 1.96 % of drug –drug interaction. The 11 patients were treated with valproic acid +clonazepam accounts for 2.16% causes increased clonazpam clearance and decreases valproic acid clearance accounts 2.16 % of drug interactions. The co-administration of Antipsychotics /anticonvulsants with antipsychotics were prescribed for 30 patients out of 508 patients accounts 5.85% of total DDIs. the 7 patients were treated with valproic acid and olanzapam which accounts for 1.37% of DDIs, causes additive toxicity, tachycardia, agitation, comadysthermia and 4 patients were treated with valproic acid and risperidon which causes edema accounts for 0.78 % of DDIs and 19 patients were treated with risperidone and holoperidol which causes neuroleptic malignant syndrome accounts 3.70 % of drug- drug interactions . The co-administration of Antipsychotics /anticonvulsants with antidepressants were 10 patients out of 508 cases accounts for 1.96 % of DDIs. The 7 patients were treated with risperidon and flouxetin which causes akatasia, painful bilateral breast enlargement, obcessive and compulsive disorder. Three patients were prescribed with sedatives and constipation accounts 1.37% of (flouxetin+olenazpine) drug drug interactions causes serotonin syndrome . CONCLUSION Drug drug interactions are more serious around the world, to be avoided unintended and untoward DDIs. The prescriber must understand the fundamental principles of pharmacology and good clinical practice and must follow the knowledge of the pharmacokinetic and pharmacodynamic characteristics of the drugs prescribed to patients. This educational review has addressed these principles summarizing the major pharmacodynamic and pharmacokinetic interactions affecting and/or caused by commonly used neuropsychiatric medications. REFRENCES: 1. The annals of pharmacotherapy, Drug Interaction: 1. General Considerations,(home page on internet) available from; http://www.theannals.com. 2. Sheldon H, Preskorn, and David F. Guide to Psychiatric Drug Interactions. April; 2006;13(4):35-64. 3. 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