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Drug Administration to Liver Patients: Aspects of Liver Pathophysiology
... Sabe-se que o risco de ocorrência e a gravidade das IM dependem de alguns fatores, entre os quais podem ser citados: número de medicamentos prescritos, duração do tratamento, idade do paciente e estado de doença. Pacientes que requerem uso de grande número de fármacos, longo tempo de tratamento, que possuem alterações fisiológicas provocadas pela idade ou doenças como insuficiência renal, choque, hepatopatias como a cirrose e hepatites virais agudas são considerados de alto risco para interações medicamentosas severas (HANSTEN, 2001;DIPIRO et al., 1992;PARK, 1996;KENNEDY, 1998;WILKINSON, 1984;KEIDING, 1995). Além disso, diversos fatores podem ser responsáveis pela resposta de um medicamento. ...
Interações medicamentosas (IM) são definidas como interferências de um fármaco na ação do outro, trazendo resultados positivos como aumento da eficácia ou negativos como toxicidade e efeitos adversos. As interações podem ser classificadas quanto à gravidade (contraindicada, maior, moderada e menor), à velocidade de ação (rápida, tardia e inespecífica) e quanto à documentação (excelente, boa e razoável). O objetivo do estudo foi conhecer o perfil dos pacientes além de quantificar e classificar as IM potenciais em pacientes internados na Unidade de Terapia Intensiva (UTI) de um hospital universitário federal de Manaus, durante o período de fevereiro a dezembro de 2019. De 78 prescrições analisadas, 210 continham interações, das quais 59,5% foram de maior gravidade, 70,5% com velocidade inespecífica e 73,3% apresentaram documentação razoável. Com relação ao perfil de pacientes, 53% eram do sexo feminino e 29,5% estavam na faixa etária entre 60 e 74 anos. Dentre as hipóteses diagnósticas de internação, 36% foi oncológica. O medicamento mais prescrito foi a dipirona com 63 registros no total. As IMs mais frequentes foram entre os medicamentos insulina regular e metoclopramida e entre metoclopramida e tramadol. O estudo de IMs na UTI é muito importante tanto pelo estado crítico do paciente como pelo uso de grande quantidade de fármacos, sendo o profissional farmacêutico apto a intervir junto à equipe multidisciplinar, minimizando riscos e danos relacionados aos medicamentos e aumentando a segurança do paciente e a efetividade do tratamento.
... 7,8 The liver is the maximal lymphoid organ in humans and is the sole internal organ with the ability to regenerate itself, thus, possessing multiple functional roles. 9 The liver has a unique vascular system supply, 30% of which is derived from the circulation and the remaining 70% from the liver portal venous system, which excretes blood from the gastrointestinal tract, spleen, gallbladder, and pancreas. 10 The liver can sustain acute and chronic injuries, such as acute liver injury caused by drugs, alcohol, acute pathogenic infections, and toxins. ...
The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non‐MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15–20% of the T‐lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell‐based clinical immunotherapeutic approaches. Graphical Abstract: Review on the molecular mechanisms of γδ T cells in liver disease and its implications for clinical immunotherapy.
... Thus, drugs that are dependent primarily on the liver for their systemic clearance are like to have reduced elimination and subsequent accumulation, leading to excessive plasma drug concentration and adverse effects. 2 However the effects of hepatic insufficiency on the pharmacokinetics of the drug are not consistent or predictable. 3 Furthermore the influence of hepatic disease on different drugs can be variable, despite their sharing the same metabolic pathway. The major liver diseases include Cirrhosis, Alcohol abuse, Hepatitis A,B,C,D and E, Fattyliver, Epstein Barrvirus (infectious mononucleosis), Nonalcoholic fatty liver disease, and Hemochromatosis. ...
Drug-related problems include medication errors and adverse drug reactions. Liver is the hub of metabolic activity of the body indeed, most drugs are modified or metabolized in liver. Thus, drugs that are dependent primarily on the liver for their systemic clearance are like to have reduced elimination and subsequent accumulation, leading to excessive plasma drug concentration and adverse effects. However the effects of hepatic insufficiency on the pharmacokinetics of the drug are not consistent or predictable. The pharmacokinetic properties of an administered drug may be modified due to alterations in hemodynamics and/or in the so-called intrinsic clearance. Drugs with first pass metabolism require reduction in oral dosages; for high clearance drugs both loading and maintenance dosages need adjustment whereas for low clearance drugs maintenance dose only needs adjustment whenever possible, measuring drug level in the blood and monitoring of adverse events should be done fairly frequently. To sum up thus there are a large category of drugs used for different therapeutic indications which are toxic to the liver and kidney and thus should be cautiously administered; particularly when given at high doses or used for chronic or long term administration. This review pitches light on various drugs which induce renal and hepatotoxicity, with their mechanism of damage and clinical scenario.
... Thus, drugs that are dependent primarily on the liver for their systemic clearance are like to have reduced elimination and subsequent accumulation, leading to excessive plasma drug concentration and adverse effects. 2 However the effects of hepatic insufficiency on the pharmacokinetics of the drug are not consistent or predictable. 3 Furthermore the influence of hepatic disease on different drugs can be variable, despite their sharing the same metabolic pathway. The major liver diseases include Cirrhosis, Alcohol abuse, Hepatitis A,B,C,D and E, Fattyliver, Epstein Barrvirus (infectious mononucleosis), Nonalcoholic fatty liver disease, and Hemochromatosis. ...
... In contrast, generally, compounds with lower extraction ratios tend to be blood flow independent. This area has been reviewed [1,40]. Clearance of many endogenous compounds has not been well studied relative to hepatic blood flow, but clearance of a number of important hormones, including aldosterone and corticosterone [41], is blood flow dependent. ...
More is known about nitric oxide (NO) than is true. The research on NO is proceeding at such a rate that virtually all areas of biological science are being swept into the enthusiastic vortex. Principles that we will espouse in this chapter include the following. In vivo and in vitro observations are often at odds: life is in vivo. Knowledge, or even information, related to NO derived from one tissue cannot necessarily be extrapolated to other systems: NO shows remarkable heterogeneity from tissue to tissue, organ to organ, and cell to cell. Given these philosophical biases, we will describe what we know of the effects of NO in the hepatic circulation.
... 12,13 As such, medications metabolized through glucuronidation, such as lorazepam, oxazepam, and temazepam, are often preferred for this reason. 8 Regarding, phase II reactions, research has led to development of the "sequential progressive model of hepatic dysfunction" to account for observations in which cytochrome P450 (CYP) activity is reduced in a selective and sequential fashion depending on the severity and etiology of liver disease. 9,14,15 For example, research demonstrates non-cholestatic liver disease may reduce the activity of CYP1A2, CYP2C19, and CYP3A4 relative to the activity of CYP2D6, CYP2C9, and CYP2E1. ...
Patients with mental illness often have co-occurring substance abuse which increases the risk for developing cirrhosis, particularly with common etiologies such as hepatitis and alcoholic liver disease. As such, knowledge of how the disease may impact medication prescribing is important. Unfortunately, there is a paucity of data to guide medication prescribing in these patients. Product labeling information should be used in the clinical decision making process. Additionally, clinicians should consider the etiology of disease, adverse effect profile, and pharmacokinetic parameters including solubility, product formulation, protein binding, hydrophilicity, metabolism, bioavailability, extraction ratios, excretion route, and half-life. Thoughtful consideration should be given when prescribing potentially hepatotoxic medications, and those which may increase bleeding risk in patients with coagulopathy. It is essential to ensure every medication has an appropriate indication and carefully evaluate the need for each medication. Overall, more research is necessary to support clinical decision-making with outcomes based research in patients with chronic liver disease.
Umweltstoffe, gewerbliche Toxine, häusliche und pflanzliche Gifte und schließlich Medikamente bergen Risiken seit alters, und in neuerer Zeit gesellen sich Verunreinigungen von Luft, Wasser und Nahrung hinzu. Die meisten dieser Stoffe und Medikamente insbesondere, treffen vornehmlich und zuerst die Leber als das wesentliche Stoffwechselorgan. Um immer möglichen Schädigungen zu begegnen, hat man sich gewöhnt, jedenfalls die industriellen und pharmakologisch definierten Substanzen auf ihre Toxizität zu überprüfen, im Tierversuch zu testen und — nach ihrer Freigabe — auf unerwartete Wirkungen und Nebenwirkungen besonders zu achten. Trotz alledem sind wir häufig nicht in der Lage, selbst schwere Leberschäden innerhalb einzelner Subpopulationen vorauszusagen, sie, wo sie einmal auftreten, hinreichend rasch zu entdecken und — nach einem Zwischenfall — jeweils einvernehmlich zu klären, was genau sich ereignet, welche abnorme Reaktion stattgefunden hat. Zweifellos wird sich daran auch zukünftig nichts Entscheidendes ändern können; dies umso weniger angesichts einer offenbar zunehmenden Neigung zu Selbstbehandlung, womöglich mit undeklarierten pflanzlichen Zubereitungen (Georgii et al. 1988; Perharic
Walton u. Murray 1992; Kane et al. 1995; Larrey u. Pageaux 1995), wodurch es im Ernstfall vollends ausgeschlossen ist, brauchbare Übersicht zu gewinnen.
Patients with renal or liver failure have a high risk of developing adverse effects of pharmacotherapy, since they are usually treated with many drugs and elimination of these drugs may be impaired. In this article, dose adjustment of the most important drugs used in these groups of patients is discussed. While clear guidelines for dose adjustment can be worked out for patients with renal failure this is more difficult for patients with liver failure since the metabolic capacity of the liver cannot be reliably quantified. Thus, despite dose adjustment, pharmacotherapy must be constantly monitored for adverse effects in these groups of patients.
microcirculation;hepatocytes;sinusoids;blood concentration;caffeine
OBJECTIVE. The aim of our study was to determine if hepatic perfusion parameters measured with CT change in relation to disease severity in patients with chronic liver disease.
SUBJECTS AND METHODS. Dynamic contrast-enhanced single-section CT scans of the liver were obtained in 40 individuals who included six control subjects, 16 patients with noncirrhotic chronic liver disease, and 18 patients with cirrhosis. Hepatic, aortic, and portal venous time—density curves were fitted to a dual-input one-compartment model to calculate the liver perfusion, arterial fraction, distribution volume, and mean transit time.
RESULTS. Liver perfusion decreased in patients with cirrhosis (67 ± 23 mL · min⁻¹ · 100 mL⁻¹ versus 108 ± 34 mL · min⁻¹ · 100 mL⁻¹ in control subjects [p = 0.009] and 98 ± 36 mL · min⁻¹ · 100 mL⁻¹ in patients with noncirrhotic chronic liver disease [p = 0.003]), and the arterial fraction and the mean transit time increased (41 ± 27% and 51 ± 79 sec versus 17 ± 16% and 16 ± 5 sec in control subjects, and 19 ± 6% and 17 ± 8 sec in patients with noncirrhotic chronic liver disease [p < 0.05]). A significant correlation was seen between these three perfusion parameters and the severity of chronic liver disease based on clinical and biologic data (p < 0.001). No significant change in distribution volume was observed.
CONCLUSION. Hepatic perfusion parameters measured with CT were significantly altered in cirrhosis and correlated with the severity of chronic liver disease.
Attempts to quantitate the blood flow rate through possible intrahepatic shunting versus the flow rate through so-called functioning liver sinusoids by means of measurements of hepatic clearance of a test substance (eg, sorbitol) and measurement of total liver blood flow rate is not possible with current methods. A reduced hepatic extraction fraction can be due to both reduced liver cell function and intrahepatic shunting, the effects of which cannot be separated by any flow or clearance measurements. Direct and individual estimates of the hepatic removal capacity,V
max, and of the halfsaturation concentration,K
m, for the liver cell process involved must be made. Only then can an approximation of a hepatic clearance measurement to liver blood flow rate be evaluated from the values ofV
max,K
m, andQ according to the sinusoidal perfusion model.Only for substances with a high value of the (V
max/K
m)/Q ratio (in practice >2.3) will the hepatic clearance be useful as a measure of the flow rate through functioning sinusoids. With such a determination, and an independent measure of total hepatic blood flow, the blood flow rate through possible intrahepatic shunting could be determined.
This review emphasizes the need for well-defined models for hepatic pharmacokinetics and discusses the interpretation of hepatic clearance measurements. Such recent approaches are subjected to theoretical and experimental comparisons. The pharmacokinetic consequences, including a classification of drugs according to hepatic clearance, are outlined.
The kinetics of ethanol elimination in intact liver was studied in human livers and pig livers in situ, examined by means of hepatic vein catheterization, and in perfused pig livers. The elimination kinetics was analyzed by a mathematical model of the sinusoidal perfusion. It assumes that parallel liver sinusoids are perfused in a parallel manner with unidirectional flow with a single common transit time and that one-way metabolic removal in the hepatocytes follows Michaelis-Menten kinetics. Ethanol was given as successive constant infusions so that successive steady-state periods were obtained with mean ethanol concentrations from about 50-11,000 μM. The ethanol concentration was determined in input and output blood samples, and the hepatic blood flow rate was measured by means of a constant infusion of indocyanine green. The mathematical model fitted the data to within the measurement uncertainty. The estimated maximal elimination rate, V max, ranged from 0.80 to 1.26 mmolxmin-1xkg-1 liver in three human subjects (estimated liver wt = 2% of body wt), from 0.62 to 1.63 mmolxmin-1xkg-1 liver in eight in situ pig livers, and from 0.46 to 0.65 mmolxmin-1xkg-1 liver in five perfused pig livers. The half saturation concentration, Km, ranged from 0.09 to 0.26 mM in the human liver, from 0.10 to 0.80 mM in the in situ pig liver, and from 0.14 to 0.92 mM in the perfused pig liver.
Enzymatic elimination of a class of substrates by the liver is analyzed in terms of a convective model of the microcirculation carrying the substrates. The elimination generates concentration gradients of the substrates which in turn affect the elimination rate through Michaelis-Menten saturation kinetics. The interplay of biochemical, anatomical and haemo-dynamic factors results in a variety of limiting regimes of elimination which are given a quantitative discussion and classification. The kinetic parameters of the enzymatic elimination reaction are expressed in terms of quantities observable on the intact liver. An overall elimination efficiency is defined by comparison with a homogenous process and evaluated for all elimination regimes, with clinical implications. Examples of two types of experiments supporting the validity of the model are presented.
The feasibility of measuring caffeine clearance from saliva (SCI) was assessed in ambulatory patients with liver disease and in a control group, and the results were compared with quantitative liver function tests. For this purpose, the subjects were given 280 mg caffeine p.o. in decaffeinated coffee powder between noon and 4 p.m., and caffeine concentrations were measured in saliva (using an enzyme immunoassay) before bedtime and upon arising. In the cirrhotics (n = 29), SCI was 0.58 ± S.D. 0.45 ml per min × kg, thus being reduced to approximately one-third of drug-free, nonsmoking controls (1.53 ± 0.46, n = 18); although patients with non-cirrhotic liver disease showed intermediate values (0.95 ± 0.47), their reduction in SCI was significant (p < 0.001). SCI was correlated with indocyanine green fractional clearance, galactose elimination capacity and aminopyrine breath test; however, the closest relationship (Rs = 0.80) was observed with the aminopyrine breath test. It is suggested that the measurement of SCI represents a noninvasive and innocuous procedure for quantifying hepatic microsomal function, and is suitable for routine use. Since a.m. saliva concentrations of caffeine are highly correlated (Rs = −0.94) with SCl, further simplification of the test to a single-point measurement appears possible.
We studied the influence of posterior pituitary extract, vasopressin, and somatostatin on hepatic elimination function. Hepatic clearance and its two biological determinants, hepatic blood flow and metabolic activity (clearance Vmax/Km), were determined from hepatic indocyanine green elimination at steady-state in cirrhotic patients. Intravenous infusion of posterior pituitary extract (oxytocin, 59%; vasopressin, 41%) at the constant rate of 0.3 unit per kg per hr decreased hepatic clearance (p < 0.05) and Vmax/Km (p < 0.05) but did not change hepatic blood flow. Intravenous infusion of vasopressin (0.3 unit per kg per hr) decreased hepatic clearance (p < 0.05), Vmax/Km (p < 0.05) and hepatic blood flow (p < 0.05). Intravenous infusion of somatostatin (250 μg per hr following a bolus i.v. injection of 250 μg) decreased hepatic clearance (p < 0.05), Vmax/Km (p < 0.05), and hepatic blood flow (p < 0.05). This study shows that the vasoactive agents used in the management of upper digestive bleeding in cirrhotic patients may have deleterious effects on the metabolic activity of the liver in addition to their effects on hemodynamics. The results suggest that the vasoactive substances either increased the fraction of total hepatic blood which bypassed intact hepatocytes or directly impaired metabolic activity of hepatocytes. Reduction in the metabolic activity of the liver produced by vasoactive agents may have important implications in therapy of portal hypertension.
The influence of intracellular and extracellular protein binding on the hepatic storage and biliary elimination of dibromosulfophthalein (DBSP) was studied in isolated perfused rat liver. Under first order kinetic conditions the amount of DBSP in the liver at a given plasma concentration (hepatic storage) was determined by extracellular binding to albumin and intracellular binding to the cytosolic Y and Z proteins as well as concentrative membrane transport from plasma into the liver. At higher doses, extensive binding of DBSP to intracellular organelles also occurred while liver cytosol/plasma concentration gradients of unbound DBSP were much lower. Hepatic storage increased with decreasing albumin concentration in the perfusate of isolated perfused rat livers. However, it was shown that this parameter is dose-dependent, and errors can be introduced in its calculation if nonlinearity of sinusoidal and canalicular transport processes as well as nonlinear protein binding are not taken into account. The influence of another organic anion, indocyanine green (ICG) on the hepatic storage, subcellular distribution, and elimination of DBSP was subsequently studied. At equimolar amounts the presence of ICG resulted in a 50% decrease in hepatic clearance and hepatic distribution volume of DBSP. It was inferred that these changes are due to an inhibition of carrier-mediated transport across the sinusoidal and canalicular membrane and preferential displacement from intracellular binding sites. In contrast DBSP in equimolar amount enhanced the initial disappearance rate and biliary excretion of ICG, probably due to increasing its free fraction in plasma. It is concluded that the level and mechanism of interaction of two drugs within the eliminating organ can be characterized by combining clearance studies with data on subcellular and extracellular binding.
The hepatic clearance ofd-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction ofd-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-today reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (sd) hepatic clearance in the normal subjects (911137 ml/min) was significantly greater (P<0.001) than that of the cirrhotics (456181 ml/min).
The kinetics of a drug eliminated by first-order processes in a perfusion-limited isolated perfused organ system are examined. In this model, the mean clearance, determined by dividing the dose by the area under the blood concentration profile, and the steady-state clearance are shown to be equal. The perfusion model and the compartmental model are compared and contrasted. Effects of blood flow and reservoir size on drug clearance are examined. Similarities and differences between the isolated and the in vivoorgan system are explored. The virtue of using clearance, instead of half-life, as a correlative parameter between these systems is stressed.
The disposition of Propranolol in blood has been investigated in 9 normal subjects and 7 patients with biopsy proven, well compensated cirrhosis using a protocol which allowed the estimation of the steady-state systemic availability of propranolol after oral administration. In addition, the systemic clearances of both antipyrine and indocyanine green (ICG) have been measured.
The mean steady-stale free (unbound) Propranolol concentration in patients with cirrhosis was increased 3-fold in comparison with controls. This augmentation was due to an increase in systemic availability from 38 ± 3% in controls to 54 ± 6%, a decrease in systemic clearance from 860 ± 90ml/min to 580 ± 140ml/min and an increase in free fraction of drug in blood from 0.06 ± 0.04 to 0.102 ± 0.65. The increase in the free fraction of drug also led to the volume of distribution increasing from 290 ± 17L to 380 ± 41L. As a consequence of both clearance and distribution changes, propranolol half-life increased from 4.0 ± 0.3h to 11.2 ± 3.2h.
It is concluded that the reduced intrinsic clearance and/or portasyslemic vascular shunts in cirrhosis, permits more of the absorbed drug to reach the circulation and that elimination of the drug from the systemic blood is also impaired. Furthermore, more of the drug in the systemic circulation is in the unbound form and potentially available to exert an increased pharmacological response.