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Pharmacological characteristics of metamizole
Abstract and Figures
Metamizole (dipyrone) is a popular analgetic, non-opioid drug, commonly used in human and veterinary medicine. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug (NSAID). Metamizole is a pro-drug, which spontaneously breaks down after oral administration to structurally related pyrazolone compounds. Apart from its analgesic effect, the medication is an antipyretic and spasmolytic agent. The mechanism responsible for the analgesic effect is a complex one, and most probably rests on the inhibition of a central cyclooxygenase-3 and activation of the opioidergic system and cannabinoid system. Metamizole can block both PG-dependent and PG-independent pathways of fever induced by LPS, which suggests that this drug has a profile of antipyretic action distinctly different from that of NSAIDs. The mechanism responsible for the spasmolytic effect of metamizole is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate. Metamizole is predominantly applied in the therapy of pain of different etiology, of spastic conditions, especially affecting the digestive tract, and of fever refractory to other treatments. Co-administration of morphine and metamizole produces superadditive, antinociceptive effects. Metamizole is a relatively safe pharmaceutical preparation although it is not completely free from undesirable effects. Among these side-effects, the most serious one that raises most controversy is the myelotoxic effect. It seems that in the past the risk of metamizole-induced agranulocytosis was exaggerated. Despite the evidence showing no risk of teratogenic and embryotoxic effects, the drug must not be administered to pregnant women, although it is allowed to be given to pregnant and lactating animals. This paper seeks to describe the characteristics of metamizole in the light of current knowledge.
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... In addition, metamizole is included in the group of nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic and antipyretic effects with spasmolytic properties [2]. The mechanism of analgesic action of MT is complex, but there is a view that it may be related to suppression of a central cyclooxygenase-3 (COX-3) and stimulation of cannabinoid and opioidergic systems [3]. It has been suggested that its antipyretic effect is associated with cyclooxygenase-2 (COX-2) inhibition [4]. ...
... The critical feature of its antipyretic effect is that it reduces fever by inhibiting both prostaglandin-E2 (PGE2)-dependent and independent pathways [5]. The spasmolytic effect of MT is connected with a decrease in intracellular Ca 2+ release through the inhibition of inositol phosphate synthesis [3]. Due to its excellent analgesic, antipyretic, and spasmolytic properties and good gastrointestinal tolerability, MT has been widely used worldwide [5]. ...
... On the contrary, metamizole is banned in some countries due to its severe side effects, such as agranulocytosis [7]. However, studies have suggested that the metamizole-related agranulocytosis risk is exaggerated [3]. In addition, studies have shown no tangible relationship between metamizole and aplastic anemia [8]. ...
Background
Metamizole is banned in some countries because of its toxicity, although it is widely used in some European countries. In addition, there is limited information on its safety profile, and it is still debated whether it is toxic to the heart, lungs, liver, kidneys, and stomach.
Aims
Our study investigated the effects of metamizole on the heart, lung, liver, kidney, and stomach tissues of rats.
Methods
Eighteen rats were divided into three groups, wassix healthy (HG), 500 mg/kg metamizole (MT-500), and 1000 mg/kg metamizole (MT-1000). Metamizole was administered orally twice daily for 14 days. Meanwhile, the HG group received pure water orally. Biochemical, histopathologic, and macroscopic examinations were performed on blood samples and tissues.
Results
Malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) in the lung and gastric tissues of MT-500 and MT-1000 groups were almost the same as those of the HG (p > 0.05). However, MDA levels in the heart and liver tissues of MT-500 and MT-1000 groups were higher (p < 0.05) compared to the HG, while tGSH levels and SOD, and CAT activities were lower (p < 0.05). MDA levels of MT-500 and MT-1000 groups in the kidney tissue increased the most (p < 0.001), and tGSH levels and SOD and CAT activities decreased the most (p < 0.001) compared to HG. Metamizole did not cause oxidative damage in the lung and gastric tissue. While metamizole did not change troponin levels, it significantly increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine levels compared to HG. Histopathologically, mild damage was detected in heart tissue, moderate damage in liver tissue, and severe damage in renal tissue. However, no histopathologic damage was found in any groups’ lung and gastric tissues.
Conclusion
Metamizole should be used under strict control in patients with cardiac and liver diseases and it would be more appropriate not to use it in patients with renal disease.
... Metamizole, a pyrazolone derivative and non-opioid analgesic with the N02BB02 Anatomical Therapeutic Chemical code, has been used since 1922 primarily for pain relief, fever reduction, and antispasmodic effects [19][20][21]. The chemical formula of the drug is N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl) [22]. Various studies support its efficacy in managing pain with different origins and intensities, such as postoperative pain, cancer pain, headaches, and migraines. ...
... Notably, it demonstrates safety in short-term use with adverse effects on the lower gastrointestinal, cardiovascular, renal, and neurological systems [19]. Initially considered a non-steroidal anti-inflammatory drug, metamizole was later reclassified as a non-narcotic analgesic given its inhibitory action on central cyclooxygenase(COX)-3 [22]. There are numerous reviews stating the efficacy of the drug, often claiming it to be similar or superior to NSAIDs in some instances [23,24]. ...
... Metamizole, represented by the chemical formula N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl), is a prodrug that spontaneously undergoes breakdown in an aqueous environment [22]. The drug is usually a white or a crystalline white powder that is very soluble in water and alcohol [30]. ...
Metamizole, or dipyrone, has been used for decades as a non-narcotic analgesic, providing pain relief from musculoskeletal disorders and antipyretic and antispasmolytic properties. Despite being in use since the 1920s, its mechanism of action still needs to be discovered. Despite causing fewer adverse effects when compared to other analgesics, its harmful effects on the blood and lack of evidence regarding its teratogenicity make the usage of the drug questionable, which has led to it being removed from the drug market of various countries. This narrative review aims to provide a detailed insight into the mechanism of action and efficacy, comparing its effectiveness and safety with other classes of drugs and the safety profile of metamizole.
... Dzięki swojemu nieselektywnemu działaniu spazmolitycznemu metamizol wykorzystuje się również w przypadku bólów kolkowych mających związek z drogami pokarmowymi, żółciowymi oraz moczowymi. Zaleca się także dawkowanie metamizolu w celu terapii stanów gorączkowych, gdy inne leki nie wykazują skuteczności, szczególnie w przypadku gorączki wywoływanej chorobą nowotworową [1,2]. ...
Przedmiot badań: Lipofilowość związków chemicznych wpływa na ich wchłanianie, dystrybucję, metabolizm, wydalanie oraz toksyczność. Jest więc niezwykle pomocna podczas projektowania nowych struktur potencjalnych substancji o działaniu leczniczym, jak również w procesie optymalizacji już wykorzystywanych związków (leków) w celu uzyskania lepszych parametrów. Ocena właściwości lipofilowych związków jest procesem złożonym i wymaga zastosowania zarówno metod eksperymentalnych (np. chromatograficznych), jak i metod teoretycznych (obliczeniowych). Metody chromatograficzne są obecnie najpopularniejszymi eksperymentalnymi metodami pośrednimi służącymi do wyznaczania lipofilowości leków (szacowania wartości logP). W praktyce klinicznej najczęściej przepisywaną grupą leków stanowią leki przeciwbólowe. Metamizol, propyfenazon i nimesulid są lekami przeciwbólowymi, znanymi od kilkudziesięciu lat, stosunkowo tanimi i powszechnie dostępnymi. W literaturze naukowej jak dotąd nie opisano badań dotyczących oceny lipofilowości ww. leków przeciwbólowych, przy zastosowaniu obu metod, tj. chromatografii cienkowarstwowej w odwróconym układzie faz/wysokosprawnej chromatografii cienkowarstwowej RP-TLC/HPTLC oraz metod teoretycznych, wykorzystujących różne algorytmy obliczeniowe. W niniejszej pracy oprócz powszechnie wyznaczanego, w oparciu o metodę Soczewińskiego-Wachtmeistera chromatograficznego parametru lipofilowości RMWS, wyznaczono również dodatkowy chromatograficzny parametr lipofilowości RMWO, w oparciu o równanie Ościka. Cel badań: Celem pracy była ocena możliwości zastosowania obu metod, tj. eksperymentalnej RP-TLC/HPTLC oraz teoretycznych (obliczeniowych) do określenia właściwości lipofilowych metamizolu, propyfenazonu i nimesulidu. Uzyskane dla badanych związków wartości RMWS i RMWO zostały następnie porównane z teoretycznymi wartościami logP uzyskanymi z użyciem różnych algorytmów obliczeniowych oraz wartościami logPexp wyznaczonymi doświadczalnie w układzie n-oktanol-woda. Meteriał i metody: Roztwory analizowanych związków o stężeniu 1mg/mL sporządzono w metanolu w przypadku metamizolu i propyfenazonu oraz w acetonie dla nimesulidu. Jako fazy ruchome zastosowano mieszaniny metanolu z wodą, dioksanu z wodą, acetonitrylu z wodą oraz acetonu z wodą o różnej zawartości modyfikatora organicznego zmieniającej się co 5% w przypadku płytek RP-8F254 i RP-18F254, oraz co 10% w przypadku płytek RP-18WF254. Wartości parametru RM uzyskane metodą RP-TLC/HPTLC w różnych układach chromatograficznych, tj. czterech fazach ruchomych (metanol-woda, dioksan-woda, acetonitryl-woda, aceton-woda) i trzech faz stacjonarnych (RP-8F254, RP-18F254, RP-18WF254) zostały zastosowane do wyznaczenia chromatograficznych parametrów lipofilowości wg. równania Soczewińskiego-Wachtmeistera (RMWS) oraz wg. równania Ościka (RMWO). Uzyskane dla badanych związków wartości RMWS i RMWO zostały następnie porównane z parametrami teoretycznymi (AlogPs, AClogP, AlogP, MlogP, xlogP2, xlogP3, miLogP, logPKOWWIN, ACD/logP) i eksperymentalną wartością współczynnika podziału (logPexp). Wyniki: Stwierdzono, że najniższą lipofilowość wykazuje metamizol, a największą nimesulid. Dla metamizolu brak jest danych dotyczących wartości logPexp oraz obserwuje się zróżnicowanie w wartościach teoretycznych współczynników podziału logP. Dla propyfenazonu parametrem najbardziej zbliżonym do wyznaczonego eksperymentalnie logPexp jest parametr teoretyczny AlogPs oraz chromatograficzne parametry lipofilowości tj. RMWO(DRP18), RMWO(DRP8), RMWO(ARP18W), RMWS(MRP18W) i RMWS(ARP8). Ponadto wartości zbliżone do logPexp i AlogPs wykazują chromatograficzne parametry lipofilowości RMWS(MRP18W) i RMWS(ARP8). Dla nimesulidu parametrem najbardziej zbliżonym do wyznaczonego eksperymentalnie logPexp jest parametr teoretyczny xlogP3 oraz chromatograficzne parametry lipofilowości tj. RMWS(ARP18), RMWS(ACNRP18) i RMWS(MRP8). Ponadto wartości zbliżone przyjmują teoretyczne współczynniki podziału takie jak: AlogPs, xlogP2 oraz AlogP. Wnioski: Prosta, szybka i efektywna technika RP-TLC/HPTLC oraz parametry lipofilowości oznaczone jako RMWS i RMWO mogą być z powodzeniem stosowane jako alternatywne do klasycznej ekstrakcji w układzie n-oktanol-woda w opisie lipofilowego charakteru metamizolu, propyfenazonu oraz nimesulidu. Mogą one być w przyszłości wykorzystane w procesie ich optymalizacji w celu uzyskania lepszych parametrów, np. biodostępności badanych związków i ich pochodnych, jak również mogą być przydatne w procesie projektowania nowych i bardziej skutecznych terapeutycznie preparatów lub pochodnych metamizolu, propyfenazonu oraz nimesulidu. Wykazano, że technika RP-TLC/HPTLC oraz internetowe bazy danych są użytecznym narzędziem w wyznaczaniu lipofilowości związków biologicznie aktywnych, do których należą metamizol, propyfenazon oraz nimesulid. Ponadto wykazano, że techniki chemometryczne są pomocne w ocenie lipofilowości metamizolu, propyfenazonu oraz nimesulidu wyznaczonej za pomocą różnych metod.
... Many of the pharmacological agents used as part of a general anaesthetic or those employed within a critical care, for example, propofol [50] and opioid receptor agonists [ [51][52][53], may mask symptoms of alcohol withdrawal syndrome independent of study medications. Gipson et al. [37] reported the number of patients in receipt of concomitant medications, including dexmedetomidine, phenobarbital, and clonidine and wilkens et al. [42] discussed the use of metamizole [54] (a multi-modal analgesic and antispasmodic analgesic) and piritramide (an opioid analgesic [55]) for post-operative analgesia [42]. However, the influence of these were not considered at the symptom assessment or analysis stage. in addition to the use of adjunct medications in a critical care setting masking symptoms of withdrawal, the use of tools to detect symptoms in this setting also warrants discussion. ...
Introduction
Alcohol withdrawal is typically managed using benzodiazepines. However, modulation of both γ-aminobutyric acid-A and N-methyl-d-aspartate-receptors through ethanol provision may provide an alternative management strategy. This systematic review critically analyses the evidence surrounding the use of oral or intravenous ethanol for the management of alcohol withdrawal syndrome.
Methods
Systematic searches of ProQuest – American Psychological Association, PsycInfo, MEDLINE and PubMed Central, Web of Science and Embase were performed (Prospero registration number: CRD42023425224). Search criteria were: Population = Patients receiving pharmacological interventions to treat or prevent alcohol withdrawal in a healthcare setting. Intervention = intravenous or enteral ethanol. Comparator = standard care, benzodiazepines, carbamazepine, adjunct medications including sedatives, or no comparator. Outcomes = complication rates, symptom scores, length of stay in healthcare settings. Exclusions were: preclinical studies, participants less than 18 years old, non-peer reviewed literature, poor study design or poor data quality. Study quality was assessed using an adapted National Institute for Health and Care Research quality tool. A narrative data synthesis approach was adopted.
Results
Eight thousand two hundred and four studies were retrieved. Ten were included in the final analysis. Overall study quality was poor. Seven studies reported treatment outcomes that were comparable to a control arm or in which ethanol conferred no detrimental effect. Three studies reported positive outcomes, and one study reported worse outcomes following ethanol administration.
Discussion
The review identified heterogeneity in study design and limited reporting surrounding patient demographics, patient alcohol use history and the practicalities of ethanol administration. As such, implementation of ethanol prescribing for the management of alcohol withdrawal is currently limited due to the quality and translatability of existing data surrounding its use.
Conclusions
Further studies are required with more transparent and complete outcome reporting and practical implementation recommendations in order to facilitate the translation of ethanol prescribing for the management of alcohol withdrawal syndrome.
... Medications with anti-inflammatory, analgesic, and antipyretic properties serve multiple physiological functions, often overlapping in their efficacy. While certain drugs may excel in one aspect over another, their shared mechanism of action-primarily the inhibition of cyclooxygenases (COX-1 and COX-2) and subsequent suppression of prostaglandin synthesis allow them to effectively address pain, inflammation, and fever across the spectrum [1]. ...
Aims: To analyze the use of anti-inflammatory drugs and the associated factors, including educational level, number of prenatal visits, and food insecurity, during pregnancy. Study Desing: Population-based cross-sectional study. Place and Durationof Study: The sample were recruited in two maternity hospitals of Rio Branco, Acre, Brazil. The Santa Juliana Hospital and Maternity (HSJ) and the Bárbara Heliodora Maternity in April 6 and July 10, 2015 Methodology: Demographic, socioeconomic, reproductive, maternal habits, prenatal care, and newborn status were investigated. Multivariate analysis with logistic regression was performed, considering p<0.05 for association. Results: 1190 postpartum women were interviewed. Anti-inflammatories were not used by only 13.2% of pregnant women. The prevalence of dipyrone use was 72.7%, paracetamol 50.3%, nimesulide 16.1%, and diclofenac 5.2%. Women with lower educational levels (up to high school OR=1.55, 95% CI 1.07-2.25), those who consumed alcohol (OR=1.96, 95% CI 1.03-3.73), and those with a higher number of living children (more than 4 children OR=1.6, 95% CI 1.06-2.24, 2 to 3 children OR=1.52, 95% CI 1.10-2.27) had a higher chance of using anti-inflammatories during pregnancy. Primiparous women (OR=0.66, 95% CI 0.47-0.93), those with more than eight prenatal visits (OR=0.55, 95% CI 0.35-0.85), and those experiencing moderate to severe food insecurity (OR=0.42, 95% CI 0.25-0.69) had a lower chance of using anti-inflammatories during pregnancy. After adjusted analysis, alcohol consumption and the number of living children lost statistical significance and were not included in the final model as independent variables. Conclusion: The prevalence of anti-inflammatory use was high. Alternative therapies and restricting prescriptions to necessary cases could be proposed to reduce the use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy.
... Sweden, the USA, Japan, the UK, Australia and Iran), metamizole is still widely used in many countries (some European countries and those in Asia and South America) in both human and veterinary medicine (Baumgartner et al., 2009;Wessel et al., 2006). Following prolonged administration, there is some evidence indicating that metamizole can perturb the blood count and cause leukopenia, agranulocytosis, and even aplastic anaemia (Basak et al., 2010;García-Martínez et al., 2003;Hedenmalm & Spigset, 2002), which has led to its recall from the market in many countries (Basak et al., 2010;Baumgartner et al., 2009;Jasiecka et al., 2014;Schug & Manopas, 2007;Wessel et al., 2006). ...
Drug use during pregnancy is an important issue that must be investigated due to its adverse effects on maternal and foetal health. This study aimed to determine the embryotoxic and teratogenic effects of in-ovo administered metamizole (dipyrone), which can be used when needed during pregnancy and has potent analgesic, antipyretic, anti-inflammatory, and long bone (tibia and femur) effects. This study used 240 fertile eggs from Atak S breed chickens, divided into eight equal groups: control, vehicle control, and 15.62, 31.25, 62.5, 125, 250 and 500 mg/kg metamizole. The eggs were hatched on the 21st day of incubation, and the chicks' body weights and mortality rates were determined. The right and left femur and tibia bones were resected from the chicks. Anatomical reference points were determined after removing the soft tissues of the bones, and necessary morphometric measures were taken from these points with a 0.01 mm precision using digital callipers. The 100% lethal dose (LD100) was identified in the highest examined dose (500 mg/kg) in the Chicken Embryotoxicity Screening Test (CHEST)-I stage. The CHEST-II stage determined the 50% lethal dose (LD50). High-dose metamizole affected skeletal development, significantly decreasing tibia and femur lengths and corpus thicknesses and increasing mortality.
... Ao fim do procedimento diminuiu-se as dosagens de fármacos de infusão continua, o que proporcionou uma recuperação calma e rápida. Além disso para analgesia pós cirúrgica utilizou-se a dipirona, seu mecanismo responsável pelo efeito analgésico é complexo e muito provavelmente se baseia na inibição de uma ciclooxigenase-3 central e na ativação do sistema opioidérgico e do sistema canabinóide [11]. E ainda aliado ao uso da dipirona, em associação usou-se o tramadol, um medicamento analgésico que exerce um modo duplo de ação: é um agonista dos receptores m-opioides e inibe recaptação de serotonina e noradrenalina [12]. ...
Anestesiologia veterinária tem como objetivo primordial induzir a inconsciência e a amnésia, prevenir a percepção da dor, garantir a contenção e a imobilização do animal, além de promover o relaxamento muscular. Uma abordagem comum para manter a anestesia geral é a administração de fármacos por via intravenosa, conhecida como Anestesia Intravenosa Total (TIVA). Essa técnica envolve a combinação de anestésicos parenterais que, em resumo, satisfazem todos os critérios essenciais para uma anestesia eficaz. Em situações em que a utilização de uma técnica inalatória não é viável ou contraindicada, é fundamental que todos os anestesistas sejam capazes de conduzir com competência e segurança a TIVA. Este estudo de caso tem como propósito investigar a aplicação da anestesia intravenosa total em uma cirurgia de hérnia diafragmática como exemplo prático.
Nitrogen-containing heterocycles have been desirable targets for synthesis for many years because of their structural diversity and biological significance. Five-membered heterocyclic rings, or pyrazole, are a flexible starting point for the design of effective bioactive compounds and are widely used in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry. Pyrazole derivatives have played an important role in heterocyclic chemistry and have been extensively studied owing to their ease of access, diversified chemical reactivity, and broad biological properties, including antibacterial, anti-inflammatory, anticancer, analgesic, anticonvulsant, anthelmintic, antioxidant, and herbicidal properties. Pyrazole nuclei are synthesized via a variety of methods, including the multicomponent approach, dipolar cycloaddition, cyclocondensation of hydrazine with a carbonyl system, heterocyclic system, and multicomponent approach. The current review is an attempt to understand the chemistry and medicinal importance of the pyrazole-containing marketed drugs reported to date, which will undoubtedly assist the scientific community in making further advances in the isolation and synthesis of pyrazole-based novel bioactive compounds.
A selective, precise, and accurate reversed HPLC method has been developed and validated for simultaneous separation and determination of two veterinary drugs, dipyrone and hyoscine, in their combined dosage form in the presence of their official impurities, namely 4-aminoantipyrine and tropic acid, in addition to the formulated preservative: phenol. The linearity range was found to be (1.00–35.00 µg/mL) for dipyrone and (2.50–50.00 µg/mL) for hyoscine. It exhibited a satisfactory linearity regression R (0.9999) for both drugs with LOD 0.22 µg/mL and 0.72 µg/mL and LOQ 0.65 µg/mL and 2.19 µg/mL for dipyrone and hyoscine, respectively. Additionally, the two cited drugs were also determined in the presence of dipyrone active metabolite 4-aminoantipyrine using diclofenac as an internal standard in bovine urine. The linearity range was found to be (15–75 µg/mL) for dipyrone, (2.5–60 µg/mL) for hyoscine, and (2.5–60 µg/mL) for 4-aminoantipyrine with linearity regression R (0.9999–0.9998). The LLOQ (15, 2.5, 2.5 µg/mL), LQC (45, 7.5, 7.5 µg/mL), MQC (55, 25, 25 µg/mL), and HQC (60, 50 50 µg/mL) were determined for dipyrone, hyoscine and 4-aminoantipyrine, respectively. UV detection was carried out at 220 nm. The method was validated according to the ICH guidelines, as well as according to FDA guidelines for determining both drugs in bioanalytical matrices and both proved accuracy and precision. A statistical comparison was made between the results obtained and those obtained by the reported method, showing no significant difference in accuracy and precision at p = 0.05. The suggested method was proved eco-friendly through a greenness assessment using two different tools (The analytical eco-scale scored 83, and the AGREE-Analytical Greenness Metric approach scored 0.83). The suggested method can be used in the routine work of quality control labs, screening for drug abuse, and ensuring clean sport for horse racing.
Metamizole, a nonnarcotic analgesic, has been used to treat pain and fever for almost 90 years in some countries, while in others it is completely unknown or forgotten. It was synthesized by the German company Hoechst AG in 1920, and its mass production started in 1922. Metamizole remained freely available worldwide until the 1970s, when it was found that the drug poses a risk of causing agranulocytosis. Soon after that, metamizole was banned in the United States, Japan, Australia, and part of the European Union. However it is still widely used in some European countries, Turkey, Israel, India, Brazil, and Third World countries. Metamizole is available over-the-counter and remains one of the most popular analgesics in Bulgaria. The objective of this study is to review the pharmaceutical and pharmaco-toxicological aspects of the drug. In Part II, the clinical profile of the drug will be discussed.
Small Animal Clinical Pharmacology is a practical, clinically-oriented pharmacology text designed to provide the veterinary student and practitioner with all the relevant information needed when designing drug treatment regimens for pets in small animal veterinary practice. Comprehensively updated and revised, the second edition of this core text covers essential new information on drugs used in the management of a range of presenting conditions including heart disease and cardiac arrhythmias. For the second edition new authors, superb new illustrations and a second colour have all been introduced. With its unique approach combining a thorough understanding of the pharmacological action of drugs with a basic understanding of the relevant physiology and pathophysiology of systems and tissues affected, Small Animal Clinical Pharmacology continues to be an indispensable book for all veterinary students and practitioners. Organised by drug class in a uniform and detailed structure which means it is easy to locate key information on dose rates, routes of administration, drug interactions and special considerations at a glance Key chapters based around treatment of disorders of particular body systems, eg cardiovascular and thyroid disorders Essential introductory chapters covering pharmacokinetics, general pharmacological principles and adverse reactions for a thorough basic grounding in the subject All authors are experienced clinicians and recognised experts in their field who bring a down to earth and practical approach to the text.
This article reviews the approval process for new animal drugs in the United States, including the minor use drug program; lists drugs currently approved and marketed for goats and sheep; and reviews regulations concerning extralabel use of drugs. Other regulations for drug use are also discussed, including compounding guidelines. Methods of establishing withdrawal times are briefly covered. Several specific drugs and drug groups are discussed as to their status and legal and illegal uses.
Cannabinoids exert their biological influence by two types of cannabinoids receptors: CB1 and CB2. CB1 receptors are located mainly in the central nervous system (CNS). CB2 receptors are found primarily on cells of the immune system. Both types of receptors inhibit cAMP formation, via Gi/o proteins, and activate mitogen-activated-protein kinase. Five endocannabinoids have been described to date, anandamide (N-arachidonoylethanoloamine), 2-arachidonoylglycerol, noladin ether (2-arachidonoylglycerol ether), virodhamine (O-arachidonolylethanoloamine) and N-arachidonoyldopamine. Endocannabinoids, by activating presynaptic CB1 receptors, can modulate the release of both excitatory and inhibitory neurotransmitters. The role of central cannabinoid system in variety physiological functions such as appetite, emotional states, pain transmission, sleep, learning, memory and regulation of motoric activity and related to them pathologic states as follows: obesity, anxiety, depression, schizophrenia, neurodegenerative diseases was presented in this paper.
Small Animal Clinical Pharmacology is a practical, clinically-oriented pharmacology text designed to provide the veterinary student and practitioner with all the relevant information needed when designing drug treatment regimens for pets in small animal veterinary practice. Comprehensively updated and revised, the second edition of this core text covers essential new information on drugs used in the management of a range of presenting conditions including heart disease and cardiac arrhythmias. For the second edition new authors, superb new illustrations and a second colour have all been introduced. With its unique approach combining a thorough understanding of the pharmacological action of drugs with a basic understanding of the relevant physiology and pathophysiology of systems and tissues affected, Small Animal Clinical Pharmacology continues to be an indispensable book for all veterinary students and practitioners. Organised by drug class in a uniform and detailed structure which means it is easy to locate key information on dose rates, routes of administration, drug interactions and special considerations at a glance Key chapters based around treatment of disorders of particular body systems, eg cardiovascular and thyroid disorders Essential introductory chapters covering pharmacokinetics, general pharmacological principles and adverse reactions for a thorough basic grounding in the subject All authors are experienced clinicians and recognised experts in their field who bring a down to earth and practical approach to the text.
In a model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test), simultaneous administration of subanalgesic doses of metamizol (150 mg/kg) and morphine (0.2 mg/kg) resulted in a potent analgesia (19±1 vs. 2.3±0.8 writhes; P<0.05). While the analgesic effect of morphine (2 mg/kg) was antagonized by naloxone (1 mg/kg), the opioid antagonist did not reverse the analgesia induced by the combination of metamizol and morphine. Potentiation by metamizol was also observed as a bilateral decrease in stimulus-evoked c-Fos induction in superficial laminas (I–II) of the dorsal spinal cord after drug combination compared to single administration (66.5±2.2 vs. 80.7±4.2; P<0.05). Conversely, the number of nuclei immunostained with an antibody that recognizes all proteins of the Fos family was not modified by the same dose combination compared to single treatment (21.1±1.3 vs. 20.2±1.2). Furthermore, in a model of somatic pain consisting of peripheral thermal stimulation of the paws, simultaneous administration of metamizol (100–250 mg/kg) and morphine (0.5 mg/kg) failed to modify flexor reflex latency.
The most commonly used drugs against pain act by inhibiting the cyclooxygenases (COXs). Metamizol (dipyrone) inhibits the COXs and is widely used in Europe and Latin America as a non-opioid analgesic. One target of metamizol and other non-opioid analgesics is the periaqueductal grey matter (PAG), where they trigger descending inhibition of spinal nociceptive transmission. Also, cannabinoids exert an analgesic action at several structures in the peripheral and central nervous system, including the PAG. The present study investigates whether the antinociceptive action of metamizol in the lateral-ventrolateral (LVL) PAG during inflammation is related to endocannabinoids. In anaesthetized rats, unitary action potentials were recorded from spinal nociceptive neurons with receptive fields in the ipsilateral hind paw. Inflammation of the paw induced neuronal hyperexcitability, which was attenuated by intra-LVL-PAG microinjection of metamizol either at the beginning of inflammation or when hyperexcitability was fully established. In both cases, the antinociceptive effect of metamizol was reduced by a microinjection of AM251, an antagonist at the CB1 cannabinoid receptor, either into the LVL-PAG or into the rostral ventromedial medulla (RVM). The RVM is a downstream structure that funnels PAG-derived descending inhibition into the spinal cord. These results show that endocannabinoids and their CB1 receptor (1) contribute at the LVL-PAG to the antinociceptive effects of metamizol, and possibly other non-opioid analgesics; and (2) participate in the PAG-derived activation of RVM descending antinociceptive influences.
Dipyrone is a common antipyretic drug and the most popular non-opioid analgesic in many countries. In spite of its long and widespread use, molecular details of its fate in the body are not fully known. We administered dipyrone orally to mice. Two unknown metabolites were found, viz. the arachidonoyl amides of the known major dipyrone metabolites, 4-methylaminoantipyrine (2) and 4-aminoantipyrine (3). They were identified by ESI-LC-MS/MS after extraction from the CNS, and comparison with reference substances prepared synthetically. The arachidonoyl amides were positively tested for cannabis receptor binding (CB(1) and CB(2)) and cyclooxygenase inhibition (COX-1 and COX-2 in tissues and as isolated enzymes), suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain.
To evaluate the post-operative analgesic effect of metamizol (dipyrone) administered intravenously at three different doses (15 mg kg(-1), 25 mg kg(-1) and 35 mg kg(-1)) compared to placebo in dogs undergoing ovariohysterectomy.
Prospective, comparative, randomized, blinded trial.
Forty healthy bitches, aged 1-6 years, weighing 10-35 kg
The animals were randomly divided into four groups and received their respective treatments immediately after surgery: placebo group (0.9% saline solution), D15 group (metamizol 15 mg kg(-1) IV), D25 group (metamizol 25 mg kg(-1) IV), D35 group (metamizol 35 mg kg(-1) IV). The following variables were measured: sedation, pulse rate (PR), respiratory rate (f(R)), arterial blood pressure (ABP), plasma catecholamines, serum cortisol, blood urea nitrogen (BUN) and creatinine metabolites, albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), hemogram, platelet counts and level of analgesia which was assessed by visual analog (VAS), descriptive and behavioral scales. Patients were monitored for 48 hours after the administration of the analgesic agent. Rescue analgesia (tramadol, 2 mg kg(-1), intramuscularly) was provided for animals with pain scores ≥4, as determined by the VAS or descriptive scale.
The D25 and D35 groups showed equivalent post-operative analgesia, as shown by decreased pain scores, according to the three different pain scales, and fewer animals that required rescue analgesia. Significantly lower serum cortisol concentrations were observed in the D25 and D35 groups when compared to the placebo and D15 groups. No hematologic, renal, hepatic or clinical adverse effects were observed during the treatment.
Metamizol administered intravenously at 25 or 35 mg kg(-1) can provide adequate post-operative analgesia in bitches undergoing ovariohysterectomy.