Identifying high risk medications causing potential drug-drug interactions in outpatients: A prescription database study based on an online surveillance system.

BACKGROUND: Drug-drug interactions (DDIs) are a significant cause for adverse drug events (ADEs). DDIs are often predictable and preventable, but their prevention and management require systematic service development. Most DDI studies focus on interaction rates in hospitalized patients. Less is known of DDIs in outpatients, particularly how community pharmacists could contribute to DDI management by applying their surveillance systems for identifying high-risk medications. OBJECTIVES: The study was related to the implementation of the first online DDI surveillance system in Finnish community pharmacies. The goal was to demonstrate how community pharmacies can utilize their prospective surveillance system 1) for identifying high risk medications causing potential DDIs in outpatients, 2) for collaborative service development with local physicians, and 3) for academic risk management research purposes. METHODS: All DDI alerts given by the online surveillance system were collected during a one-month period in 16 out of 17 University Pharmacy outlets in Finland, covering approximately 10% of the national outpatient prescription volume. The surveillance system was based on the FASS database, which categorizes DDIs into four classes (A-D) according to their clinical significance. RESULTS: Potential drug-drug DDIs were analyzed for 276,891 dispensed community pharmacy prescriptions. Potential DDIs were associated with 10.8%, or 31,110 of these prescriptions. Clinically significant interaction alerts categorized as FASS classes D (most severe, should be avoided) and C (clinically significant but controllable) were associated with 0.5% and 7.0% of the prescriptions, respectively. Methotrexate and warfarin had the highest risk of causing potentially serious (class D) interactions. These interaction alerts were most frequently between methotrexate and NSAIDs and warfarin and NSAIDs. In general, NSAIDs were the most commonly interacting drugs in this study. CONCLUSIONS: This study demonstrates that community pharmacies can actively contribute to DDI risk management and systematically use their surveillance systems for identifying patients having clinically significant DDIs. The findings also indicate that the majority of potentially serious interactions in outpatients involve a limited number of drugs, particularly NSAIDs, warfarin and methotrexate. Further research should focus on community pharmacists' involvement in DDI risk management in collaboration with local health care providers.

Effects of repeated morphine treatment on metabolism of cerebral dopamine and serotonin in alcohol-preferring AA and alcohol-avoiding ANA rats.

The alcohol-preferring AA (Alko Alcohol) rats are more rapidly sensitized to the locomotor activity-stimulating effects of small doses of morphine than the alcohol-avoiding ANA (Alko Non-Alcohol) rats. To study the involvement of dopaminergic and serotonergic transmission in this behaviour, the effects of acute morphine (1 mg/kg) challenge on the concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT, serotonin) and their metabolites were estimated in three dopaminergic areas in AA and ANA rats on the fourth day after a 3-day morphine or saline treatment. Acute administration of morphine enhanced DA metabolism in the caudate-putamen in the AA, but not in the ANA, rats; in the nucleus accumbens and in the olfactory tubercle the acute effect of morphine was similar in rats of both lines. Morphine pretreatment did not significantly enhance acute morphine's effects on DA metabolites in any of the brain areas studied in rats of either line. Acute administration of morphine enhanced brain 5-HT metabolism in the AA rats but not in the ANA rats, but after repeated treatment it induced no enhancement of 5-HT metabolism. With the methods used, no significant differences were found between the AA and ANA rats in the effects of repeated morphine on cerebral dopaminergic or serotonergic mechanisms which could account for the different behavioural sensitization found previously in rats of these lines. However, both monoamines studied might be involved in the acute locomotor stimulatory effects of morphine.

Effects of repeated cocaine treatment on striatal dopamine release in alcohol-preferring AA and alcohol-avoiding ANA rats.

Modulation of striatal dopamine (DA) release by acute or repeated cocaine treatment was studied in the nucleus accumbens and caudate-putamen of alcohol-preferring (AA, Alko Alcohol) and alcohol-avoiding (ANA, Alko Non-Alcohol) rats. Cocaine (5-10 mg/kg i.p.) was administered daily for 4 days and the concentrations of extracellular DA measured by in vivo microdialysis on days 1 and 4 in the freely moving rats. The first administration of cocaine increased DA concentration similarly in rats of both lines in both the nucleus accumbens and caudate-putamen. On the 4th day, the effect of cocaine was significantly larger in the nucleus accumbens of AA than in that of ANA rats, whereas no such enhanced effect of cocaine was found in the caudate-putamen of either line. The results suggest that mesolimbic DA release in response to cocaine is sensitized more readily in AA than in ANA rats, which would not only render the former more susceptible to alcohol, but to other drugs of abuse, and might explain our previous findings that AA rats are more susceptible to psychomotor sensitization than ANA rats.

The effects of nicotine on locomotor activity and dopamine overflow in the alcohol-preferring AA and alcohol-avoiding ANA rats.

The aim of the study was to investigate the importance of the interaction between central dopaminergic and cholinergic mechanisms for ethanol reinforcement. This was done by comparing the effects of nicotine on locomotor activity and release of dopamine in the nucleus accumbens of the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding alko non-alcohol (ANA) rats. Nicotine was administered acutely (0.25, 0.50 or 0.75 mg/kg, s.c.) or repeatedly once daily (0.5 mg/kg, s.c.) for 8 days. An acute dose of nicotine increased locomotor activity and the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) measured with in vivo microdialysis suggesting stimulation of dopamine release by nicotine. No difference in the stimulation of locomotor activity or in the increase in the extracellular concentrations of dopamine or its metabolites by nicotine was found between the rat lines. The concentrations of nicotine in the plasma were also identical. The rats treated repeatedly with nicotine showed a progressive increase in locomotion. On the challenge day, 1 week after termination of nicotine or saline injections, rats previously treated with nicotine were activated more by nicotine than saline-treated rats. This behavioral sensitization was not accompanied by an increase in the amplitude of the neurochemical response to nicotine, but the duration of the increase in the levels of DOPAC was longer in the nicotine than saline-treated animals. The increases in locomotor activity and metabolite levels were, however, similar in both rat lines. These data suggest that differences in the interaction of central dopaminergic and cholinergic mechanisms probably do not contribute to the difference in ethanol self-administration between the AA and ANA rat lines.

Effects of repeated morphine on cerebral dopamine release and metabolism in AA and ANA rats.

Cerebral dopaminergic mechanisms were studied in the nucleus accumbens and caudate-putamen of alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko Non-Alcohol) rats after 4-day repeated morphine treatment. This treatment has been shown to enhance the locomotor activity stimulating effect of morphine in the AA but not in the ANA rats. Morphine (1 or 3 mg/kg) or saline was administered subcutaneously once daily and the extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured, in freely moving rats by in vivo microdialysis on days 1 and 4. Morphine increased accumbal DA, DOPAC and HVA similarly in rats of both lines, and no sensitization of DA release or metabolism was seen in rats of either line given morphine repeatedly. In the caudate-putamen, morphine increased DA, DOPAC and HVA significantly only in the AA rats. During repeated treatment, the morphine-induced elevation of DA metabolites, but not that of DA, was enhanced similarly in rats of both lines. These results suggest that the effects of acute morphine administration on nigrostriatal dopaminergic mechanisms are stronger in the AA than in the ANA rats, whereas the effects of morphine on mesolimbic dopaminergic systems do not differ. Furthermore, in rats of both lines, repeated morphine treatment enhanced the responses of the nigrostriatal dopaminergic systems similarly, but no enhancement occurred in the mesolimbic systems of rats of either line. These findings do not support the critical role of accumbal dopaminergic systems in morphine-induced behavioural sensitization.

Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration.

The effect of intrastriatally-administered morphine on striatal dopamine (DA) release was studied in freely moving rats. Morphine (1, 10 or 100 microM) was given into the striatum by reversed microdialysis, and concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously measured from the striatal dialysates. Intrastriatally-administered morphine significantly and dose-dependently decreased the extracellular concentration of DA, the concentrations of the acidic DA metabolites were only slightly decreased. The effect of morphine was antagonized by naltrexone (2.25 mg kg(-1), s.c.). Pretreatment with a preferential kappa-opioid receptor antagonist, MR2266 [(-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane; 1 mg kg(-1), s.c.], had no effect on the decrease of extracellular DA evoked by intrastriatal morphine (100 microM). Intrastriatal administration of the selective micro-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO; 1 microM), significantly decreased the extracellular concentration of DA in the striatum. When the rats were given morphine repeatedly in increasing doses (10-25 mg kg(-1), s.c.) twice daily for 7 days and withdrawn for 48 h, the decrease of extracellular DA induced by morphine (100 microM) was significantly less than that seen in saline-treated controls. Our results show that besides the well-known stimulatory effect there is a local inhibitory component in the action of morphine on striatal DA release in the terminal regions of nigrostriatal DA neurones. Tolerance develops to this inhibitory effect during repeated morphine treatment. Furthermore, our results suggest that the effect of intrastriatally-administered morphine is mediated by the micro-opioid receptors.

Involvement of opioid mu1-receptors in opioid-induced acceleration of striatal and limbic dopaminergic transmission.

The role of mu1-opioid receptors in the acceleration of cerebral dopaminergic transmission induced by morphine and the putative mu1-opioid agonist, etonitazene, was studied in rats by measuring the tissue levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal striatum and nucleus accumbens. The striatal extracellular concentrations of DA and its metabolites in freely moving rats were estimated as well. Morphine (3 mg/kg) and etonitazene (2.5 microg/kg) increased the striatal and accumbal dopamine metabolism as measured by the tissue ratios of DOPAC/DA and HVA/DA. The mu1-opioid receptor antagonist, naloxonazine (15 mg/kg), significantly antagonized these elevations except the morphine-induced elevation of striatal HVA/DA ratio. Both morphine (3 mg/kg) and etonitazene (1, 2.5, and 5 microg/kg) elevated the striatal extracellular DA, DOPAC, and HVA. Naloxonazine antagonized the effects of morphine and etonitazene on striatal extracellular DA concentration as well as etonitazene's effects on DOPAC and HVA, but not morphine's effects on DOPAC and HVA. As we previously showed concerning morphine, the conditioned place preference induced by etonitazene was inhibited by naloxonazine. These findings emphasize the role of mu1-opioid receptors in opioid reward, in which the mesolimbic dopaminergic system is considered to be importantly involved. Our results clearly show that in addition to the mesolimbic dopaminergic system the mu1-opioid receptors are also involved in the control of nigrostriatal DA release and metabolism. However, the effects of etonitazene on the striatal DA differ from those of morphine, suggesting that the opioid mechanisms regulating these two DA systems differ.