Medical Interventions in Elderly

Najčešća medicinska intervencija u populaciji starijih ljudi (>65 godina) jest propisivanje lijekova. S obzirom na to da je udio starijih ljudi i u našem društvu sve veći, ono postaje uz medicinski i farmakoekonomski problem. Starenjem se mijenjaju farmakokinetske i farmakodinamske karakteristike lijekova, ali ne jednako za svaki lijek ili skupinu lijekova. Nuspojave lijekova u ovoj su dobnoj skupini češće, a često se one interpretiraju kao novonastala bolest koja se počinje liječiti novim lijekom. Među važnijim lijekovima koji se propisuju starijim bolesnicima jesu analgetici (NSAR, opiodni analgetici), antireumatici, antidepresivi, antihipertenzivi, antikoagulansi, antipsihotici, antiparkinsonici i hipoglikemici. Prije nego πto se starijemu bolesniku propiše lijek, treba uzeti potpunu anamnezu o lijekovima koje bolesnik uzima, lijekove ne davati prije vremena, ne davati lijek predugo, opetovano reevaluirati kroničnu terapiju, treba dobro poznavati lijek koji se propisuje, početi s niskom dozom i postepeno je povisivati, osigurati da bolesnik razumije kako lijek valja uzimati, a nove lijekove ovoj skupini bolesnika treba propisivati s posebnim oprezom.The most common medical intervention in elderly (>65 years) is prescribing of drugs. The number of elderly in this country is also increasing and becoming a medical and pharmacoeconomic problem. The pharmacokinetic and pharmacodynamic characteristics of drugs are changed in the elderly, but not always in the same way in all drugs of a ceartain drug group. Adverse events in elderly are more frequent and often interpreted as a new disease, so new drugs will be added for its treatment. Drugs most frequently prescribed for this age population are analgesics (NSAR, opiod analgesics), antirrheumatics, antidepressants, antihypertensives, anticoagulants, antipsychotics, antiparkinsonics and antidiabetic drugs. Before prescribing a drug to an elderly patient, a thorough case history should be taken with special emphasis given to drugs that he/she is taking. When prescribing a new drug to elderly it is most important to know all its characteristics, drugs should not be prescribed too early or too long, long-term prescriptions should be frequently revaluated, starting with small doses and gradually increasing the dosage, making sure that the patient understands the correct way of taking the drug. New drugs should be prescribed to elderly with utmost caution and care

Clinical application of genotype-guided dosing of warfarin in patients with acute stroke

BACKGROUND: Patients with certain types of stroke need urgent anticoagulation and it is extremely important for them to achieve fast and stable anticoagulant effect and receive individualized treatment during the initiation of warfarin therapy. ----- METHODS: We conducted a prospective study among 210 acute stroke patients who had an indication for anticoagulation and compared the impact of CYP2C9 and VKORC1 genotype-guided warfarin dosing (PhG) with fixed dosing (NPhG) on anticoagulation control and clinical outcome between groups. ----- RESULTS: PhG achieved target INR values earlier, i.e., on average in 4.2 (4.1-4.7, 95% CI) days compared to NPhG (5.2 days [4.7-6.4, 95% CI]) (p = 0.0009), spent a higher percentage of time in the therapeutic INR range (76.3% [74.7-78.5, 95% CI] vs. 67.1% [64.5-69.6, 95% CI] in NPhG), and spent less time overdosed (INR > 3.1) (PhG 0.4 [0.1-0.7, 95% CI], NPhG 1.7 [1.1-2.3, 95% CI] days; p >0.000). PhG reached stable maintenance dose faster (10 [9.9-10.7, 95% CI] vs. 13.9 [13.3-14.7, 95% CI] days in controls; p = 0.0049) and had a better clinical outcome in relation to neurological deficit on admission as compared to NPhG. ----- CONCLUSION: We confirmed that warfarin therapy with genotype-guided dosing instead of fixed dosing reduces the time required for stabilization and improves anticoagulant control with better clinical outcome in early stages of warfarin therapy introduction among acute stroke patients, which is essential for clinical practice

Pain Relief in Medical Patients: Does Clinical Judgment and Prescribing Knowledge Suffice?

The aim of this study was to evaluate the quality of pain management in hospitalised patients. A cross-sectional study design that included all medical patients experiencing pain was used. Out of 167 patients hospitalized at the Department of Medicine at the University Hospital Zagreb, 41 patients were experiencing pain and 40 out of them received analgesics. Twenty-two out of 38 patients were treated for malignant pain, 16 for non-malignant pain, and 2 patients could not be classified. Adequate pain relief was reported in less than 25% of patients in both groups. Our study revealed under-prescribing of combination therapy, low utilization rates of strong opioids and prevailing »as needed« prescribing practice. In conclusion, unsatisfactory pain management in medical patients is often present if left solely to the clinical judgement and knowledge of the prescribing physician. Regular pain assessment, evidence-based guidelines, education and regular audits of implementation of these measures are a prerequisite for effective pain treatment, and should all be employed in patients experiencing pain

ADVERSE DRUG REACTIONS OF HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS REPORTED TO AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL DEVICES

Inhibitori 3-hidroksi-3-metil-glutaril koenzim A reduktaze (statini) lijekovi su koji se primjenjuju u liječenju kroničnih bolesti i često u istodobnoj terapiji s mnogim drugim lijekovima te je mogućnost nastanka nuspojava, posebice onih uzrokovanih interakcijama, velika. Cilj ovog istraživanja bio je analizirati sve nuspojave statina prijavljene Agenciji za lijekove i medicinske proizvode od ožujka 2005. godine do 31. 12. 2008. te istaknuti moguće razloge njihova nastanka. Prijavljeno je 136 slučaja nuspojava statina. 12% svih prijavljenih nuspojava statina bilo je uzrokovano interakcijama, što je više od postotka nuspojava (5,6%) uzrokovanih interakcijama svih lijekova prijavljenih u 2005. i 2006. godini. Udio ozbiljnih nuspojava koje su povezane s primijenjenom dozom i prema tome se mogu spriječiti bio je veći od udjela svih prijavljenih ozbiljnih nuspojava statina (p=0,003). Najveći broj ozbiljnih nuspojava statina mogao je biti spriječen boljim poznavanjem interakcija te primjenom farmakogenomike koja može identificirati bolesnike koji su zbog genske predispozicije osjetljiviji na standardne doze lijeka.Hydroxymethylglutaryl-CoA reductase inhibitors (statins) are drugs used in the treatment of chronic diseases and frequently in concomitant therapy with many other drugs. Therefore, the risk of adverse drug reactions (ADRs), especially those caused by interactions is high. Aim of the study was to describe and analyze ADRs caused by statins reported to Croatian Agency from March 2005 to December 2008, and to emphasize reasons of their occurrence. 136 of statin ADRs were reported. 12 % of all reported statins’ ADRs were caused by interactions, which is higher than percent (5.6%) of interactions caused by all other drugs in 2005 and 2006. Proportion of serious ADRs related to administered dose and thus preventable was higher than proportion of all ADRs caused by statins (p=0.003). Most serious ADRs could have been prevented with better understanding of interactions and by use of pharmacogenomics in identifying patients that are because of genetic predisposition more sensitive to standard doses

Use of gastroprotective agents in recommended doses in hospitalized patients receiving NSAIDs: a drug utilization study

OBJECTIVE: In recent years, studies investigated to what extend recommendations for co-prescribing gastroprotective agents in prevention of NSAID-induced gastrointestinal complications are followed in clinical practice. However, only a few studies have also taken into consideration the recommended dose of gastroprotectives prescribed in NSAID-induced ulcer prophylaxis. The aim of our study was to evaluate the prevalence of concomitant use of gastroprotectives with NSAIDs in hospitalized patients, with emphasis on the recommended dose of gastroprotectives for ulcer prophylaxis. - - - - - METHOD: This observational, cross-sectional, drug utilization study included all adult patients receiving NSAIDs hospitalized in the Clinical Hospital Center Zagreb on the day of the study. Data on age, sex, comorbidities, indications for NSAID use, type/dose of NSAIDs and gastroprotectives, history of gastrointestinal events, active gastrointestinal symptoms and risk factors were evaluated. - - - - - MAIN OUTCOME MEASURE: Study outcomes were: (1) prevalence of prescription of gastroprotectives among NSAID-users at risk; (2) prevalence of prescription of gastroprotective in recommended dose; (3) association between risk factors and prescription of GPAs. - - - - - RESULTS: The rates of gastroprotectives prescription were significantly higher in NSAID-users with concomitant risk factors as compared to patients without risk factors [47/70 (67.1%) and 8/22 (36.4%), respectively; p = 0.01072]. However, gastroprotection in recommended ulcer-preventive dose was low in both groups [8/70 (11.4%) and 9/92 (9.8%), respectively]. The number of concomitant risk factors did not increase the odds of receiving anti-ulcer therapy (odds ratio 0.7279). Thirty-three percent of patients with concomitant risk factors were not prescribed gastroprotectives. Ibuprofen, NSAID with the lowest risk of inducing gastrointestinal complications, was prescribed in only two patients. - - - - - CONCLUSION: The results indicate high awareness among hospital physicians about possible NSAID-induced gastrointestinal complications, but insufficient knowledge about risk factors related to NSAID-induced gastrointestinal toxicity, recommended dose of gastroprotectives in NSAID-induced ulcer prophylaxis and gastrointestinal toxicity of different types of NSAIDs

Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study

Aim To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence. Methods In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them. Results HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drugdrug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n = 4) was significantly higher (P < 0.001) than among the remaining reports (580 out of 1982; n = 2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter. Conclusion The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care educatio

ADVERSE DRUG REACTIONS OF PSYCOPHARMACS

Background: The objective of analysis of ADRs caused by drugs that pertain to the ATC group N (nervous system), as reported to the Croatian Agency for Medicinal Products and Medical Devices for the period from March 2005 to December 2008, was to examine the types of ADRs collected in said period, the profile of reporters and the possible impacts this could have on prescribing this group of medicinal products in the future. Subjects and methods: A retrospective observational study of ADRs was performed. Drugs causing ADRs were grouped according to the ATC drug classification, and subsequently entered into a database. Data were analyzed in respect of total number, gender, age, type, seriousness, expectedness, outcome, system organ class, suspected drug and reporter. Results: The findings showed that 15% of all reported ADRs were caused by drugs from the ATC group N. 60% of these were caused by drugs belonging to the ATC subgroups N05 (psycholeptics) and N06A (antidepressants). A significant increase in the percentage of serious ADRs in the examined groups of medicinal products was observed. Analysis of expectedness showed that the share of unexpected ADRs is very high. Conclusion: The distribution of reporters is not satisfactory. The Agency, as regulatory authority, cannot undertake certain measures to improve the safe use of medicinal products without having reports. Only reporting of ADRs can result in changes to benefit all patient populations. Our joint aim should be avoiding a great number of ADRs and maintaining overall safe use of medicinal products

Vaccine Regulations in Croatia

In this paper legal prerequisites for vaccine licensure in Croatia are discussed. The Croatian legislation concerning vaccine licensing, marketing authorisation and utilization is reviewed. The procedures for including a vaccine into the Mandatory Childhood Vaccination Programme are also discussed with focus on Human papillomavirus (HPV) vaccines. Non-obligatory vaccination recommendations are given when according to professional opinion; vaccination is beneficial for the vaccinee. There is little doubt that HPV vaccines should be recommended for preadolescent girls in Croatia. However, reaching a decision on its possible introduction into the Childhood Vaccination Programme will require careful consideration of the larger picture and a comparison of the cost-effectiveness of a mandatory vaccination against other competing public health priorities

Nuspojave lijekova supstrata metaboličkog enzima citokroma P450 CYP2C9 i transportnog P-glikoproteina

Polymorphic metabolic enzymes and transport proteins can significantly modulate the pharmacokinetic parameters of medicinal products and therefore be a reason for the appearance of type A adverse reactions. The objective of this study was to test the adverse reactions to medicinal product substrates of the metabolic enzyme cytochrome P450 CYP2C9 and the transport P-glycoprotein (Pgp). Based on the retrospective and current collection of data on adverse drug reactions of the substrates CYP2C9 and Pgp, the role of polymorphism in the appearance of adverse reactions was estimated. All adverse reactions reported to the National database in the period 2005–2011 were analysed. Reports pertaining to drug substrates CYP2C9, CYP2C9 and Pgp, i.e. drugs with a substrate of the transport protein Pgp, were analysed if the drugs had a clearance via the said enzyme of greater than 10%, or if the clearance via CYP2C9 was between 5 and 10%, and there are drugs commonly used in combination with other drugs simultaneous, as is the case, for example, with acetylsalicylic acid. A group of 158 subjects with serious adverse reactions to drugs with a substrate of the metabolic enzyme CYP2C9 were selected from the adverse reactions database. The selected subjects experienced adverse reactions to drugs that were, for the most part, metabolised via the enzyme CYP2C9. These were primarily anticoagulants of the coumarin type, i.e. warfarin (n=30 subjects), nonsteroidal anti-inflammatory drugs ibuprofen, indomethacin, diclofenac, pyroxicam (n=32), anti-epileptics phenytoin, phenobarbitone and valproic acid (n=44), fluvastatin (n=46), and oral anti-diabetics glyburide and glibenclamide (n=6). In addition to the group of subjects with adverse reactions, a second group was selected of subjects without adverse reactions (n=155) and who corresponded to the adverse reaction group in terms of gender, diseases and concomitant therapy. Genotypisation of CYP2C9*2*3 and ABCB1 2677G>T/A, 3435C>T was conducted. An analysis of the National Adverse Reactions Database (kept by HALMED), and subsequent pharmacogenetic analysis established the following: • Adverse reactions to drugs (excluding vaccines) appear in women in more than 60% of cases, which has also been shown for drugs with the substrate CYP2C9, substrate CYP2C9 &Pgp, and substrate Pgp. • 60% of all reported adverse reactions in the database and adverse reactions to drug substrates were reported for adults (aged 17 to 69 years). • 8% of all drugs are based on the substrates CYP2C9, CYP2C9&Pgp or only the transport protein Pgp, while 69% of all reaction reports pertain to these drugs. • Adverse reactions from the entire group of drug substrates CYP2C9 have a statistically significant higher incidence of serious adverse reactions in comparison to other reports in the database (p<0.0004). • Adverse reactions from the drug group nonsteroidal anti-inflammatory drugs that have drug substrate CYP2C9 had a statistically significant higher incidence of serious adverse reactions in comparison to other reports in the database (p<0.006). • The higher the number of drug substrates CYP2C9 in simultaneous use, the greater the number of adverse reactions relating to gastrointestinal disorders, with a statistically significant high incidence of serious adverse reactions in comparison to other drugs in the database (p<0.006). • Of the substrates that are partially metabolised via CYP2C9 and which simultaneously have the substrate Pgp, the highest number of reports was received for diazepam and alprazolam which, in relation to other reports in the database, have a statistically significantly higher incidence of serious adverse reactions that is expected for other drugs, and that this increases with the number of drugs with the active compound diazepam taken simultaneously (p<0.002). • An analysis of the adverse reactions in terms of their severity also shows a statistically significant increase in the number of serious adverse reactions to warfarin (substrate CYP2C9 and PGP) in relation to other drugs in the database (p<0.00001). • In the case of cyclosporin (substrate Pgp) in combination with fluvastatin (CYP2C9 and Pgp), the largest number of reports were regarding adverse reactions from the group of skeleto-muscular disorders. The increased number of serious adverse reactions in this combination in comparison to other drugs in the database is statistically significant (p<0.01). • Amlodipin has the substrate Pgp and is a drug with the highest number of reported adverse reactions in the National database for tested substrates. In relation to the severity of reported adverse reactions for amlodipin, the adverse reactions reported for this drug in comparison to other drugs in the database are significantly lower in terms of the severity of adverse reactions (p<0.0001). • The group of subjects receiving therapy with drugs containing the substrates of the metabolic enzyme CYP2C9 and who developed one of the serious adverse reactions characteristic for these drugs, in comparison to the subjects without adverse reactions, were more often carriers of mutated alleles that determine reduced enzyme function, i.e. they belonged to the intermediate or slow metabolic phenotype that represents a predisposition for accumulation of the drug in the body and the development of adverse reactions. • In the homogeneously separated groups of subjects receiving therapy of warfarin, nonsteroidal anti-inflammatory drugs, and anti-epileptics phenytoin, fenobarbiton or valproic acid, and who developed one of the serious adverse reactions, again these subjects were often intermediate and slow metabolic phenotypes in comparison to the group without adverse reactions receiving the same therapy. • From the study, it can be concluded that the polymorphism of the metabolic enzymes CYP2C9*2 and *3 could be considered a pharmacogenetic predisposition for the appearance of serious adverse reactions to drugs that are primarily metabolised via the enzyme CYP2C9. That means that these adverse reactions could be predicted with the genotypisation of CYP2C9 prior to taking the drugs. The therapy for these patients should be adapted to the genotype, and the dose reduced according to the algorithms and recommendations. This is especially important for drugs with a narrow therapeutic index, such as warfarin and phenytoin. • The study did not prove that polymorphisms of Pgp (ABCB1) could serve as a pharmacogenetic marker. Though in some variations of the gene ABCB1 a difference in the distribution of alleles and genotypes was observed between groups of subjects with adverse reactions in comparison to those without adverse reactions, the difference was not statistically significant, with the exception of warfarin and fluvastatin; however, this indicates that it would be worthwhile expanding the research to larger homogenous groups of subjects. • The National Pharmacovigilance Centre could be a good starting point for pharmacogenetic studies, as data from different sources could be brought together in the assessment of causal relationships between medicine use and adverse reasons. Also, as the regulatory body changes the medicinal product documentation, i.e. Summary of Product Characteristics and Patient Instructions for Use, the Centre could therefore contribute to reducing the appearance of serious adverse reactions and enable the safest possible use of medicinal products and doses in long-term use

Pain relief in medical patients: does clinical judgment and prescribing knowledge suffice? [Liječenje boli u internističkih bolesnika: da li su klinička procjena i znanje o propisivanju analgetika dovoljni?]

The aim of this study was to evaluate the quality of pain management in hospitalised patients. A cross-sectional study design that included all medical patients experiencing pain was used. Out of 167 patients hospitalized at the Department of Medicine at the University Hospital Zagreb, 41 patients were experiencing pain and 40 out of them received analgesics. Twenty-two out of 38 patients were treated for malignant pain, 16 for non-malignant pain, and 2 patients could not be classified. Adequate pain relief was reported in less than 25% of patients in both groups. Our study revealed under-prescribing of combination therapy, low utilization rates of strong opioids and prevailing "as needed" prescribing practice. In conclusion, unsatisfactory pain management in medical patients is often present if left solely to the clinical judgement and knowledge of the prescribing physician. Regular pain assessment, evidence-based guidelines, education and regular audits of implementation of these measures are a prerequisite for effective pain treatment, and should all be employed in patients experiencing pain