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Outpatient Management of Stable Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Leah Reid, Jonathan Murrow, Kent Nilsson, Catherine Marti
Furosemide is the most widely used loop diuretic with an oral bioavailability of about 50% in patients with normal renal function. The onset of action after an oral dose is within 30–60 min and has a duration of action of six hours.42 In renal insufficiency, the elimination half-life can be prolonged and there is reduced drug delivery to the main site of action within the tubule.43 In HF patients, the absorption of oral furosemide can be delayed, which prolongs the time to peak concentration as well as efficacy. Bumetanide is 40 times more potent than furosemide with a bioavailability of 80%. The duration of action is between three and six hours for most patients. Torsemide differs from other loop diuretics as 80% of the drug is metabolized in the liver, so that its half-life is less altered by renal dysfunction. It is absorbed rapidly and has a bioavailability of 80%. The natriuretic response following dosing of torsemide is not affected by route of administration.44 The onset of action is one to two hours after administration with a half-life of 3.3 hours, but this can be prolonged in the setting of cirrhosis.41,45 When selecting an oral agent for patients with HF, torsemide may be advantageous as its absorption is unimpaired and more consistent than that of furosemide.41
Medicines in neonates
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
At birth, anatomical and functional immaturity of the kidney limit glomerular and tubular functional capacity, which results in inefficient drug elimination and a prolonged elimination half-life [76,77]. Rapid improvements in glomerular and tubular functions occur during the postnatal period, greatly enhancing renal drug elimination. The main factors involved in the development of renal function are gestational age and the dramatic sequential haemodynamic changes after birth, in a situation initially dominated by high vascular resistance and extremely low blood flow. At birth, the GFR is 2–4 ml/min in term neonates and it may be as low as 0.6–0.8 ml/min in preterm infants. The increase in GFR after birth is important and usually greater in term than in preterm infants [78–81]. This increase is due to the increase in cardiac output which is associated with specific changes in renal vascular resistances, resulting in an increase in renal blood flow, changes in renal blood flow distribution, and a higher permeability of the glomerular membrane.
Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Meprobamate is well absorbed and undergoes metabolization in the liver by hydroxylation and glucuronidation. The elimination half-life of the drug is directly proportional to the amount of drug administered. There is increase in plasma half-life of meprobamate due to the cumulative effects of the drug given for a prolong duration. The adverse drug effects are drowsiness, ataxia, impair learning, motor incoordination, and prolong reaction time. Its abrupt discontinuation leads to withdrawal syndrome in the form of anxiety, insomnia, tremors, hallucinations, etc. (Ramchandani et al., 2006).
Dose-dependent pharmacokinetics of midazolam in rats: influence of hepatic first-pass metabolism
Published in Xenobiotica, 2023
Run Li, Qingqing Wang, Zihou Liu, Like Xie, Zhipeng Diao, Ying Peng, Guangji Wang, Jianguo Sun
It is interesting that the half-life values in low doses prolonged compared to high dose after hepatic portal vein administration (Figure 3). And we performed a compartment model analysis on the data and we found that the elimination rates of the central chamber at 1 and 2 mg/kg were slower than that at 0.2 and 0.5 mg/kg (Table S1). This means that the elimination half-life in high dose was longer than in low doses. We envision a possibility for this observation is that the half-life of central chamber rather than the terminal half-life could be designated as the elimination half-life in this case. The terminal half-life is frequently referred to as the elimination half-life, as is often the case in pharmacokinetics. However, Riegelman et al. pointed out that the rate constant in the terminal phase could not be taken as the elimination rate constant (Riegelman et al. 1968), as is the same in Flip-flop pharmacokinetics.
Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent
Published in Expert Review of Neurotherapeutics, 2023
Justin Faden, Meghan Musselman, Leslie Citrome
Dexmedetomidine is highly protein-bound, with 94% bound to albumin and alpha-1-glycoprotein. Dexmedetomidine has been shown to distribute widely throughout the body and crosses the blood-brain and placental barriers[30]. The fraction of the drug bound to protein in individuals with hepatic impairment was decreased compared to healthy subjects, and hepatic impairment impacts the mean elimination half-life of the drug [26,30]. Both prolonged and shortened elimination half-lives have been reported in patients with hypoalbuminemia, though clearance is largely unaffected[30]. Dexmedetomidine pharmacokinetics are not significantly different in patients with creatinine clearance <30 mL/minute as compared to those patients with normal renal functioning[26]. Studies of the intravenous formulation of dexmedetomidine have evaluated the impact of physical factors on drug pharmacokinetics. Reduced cardiac output has demonstrated an impact on clearance of the drug. Racial differences in pharmacokinetics of the drug have not been demonstrated. Age and height are also unlikely to impact pharmacokinetics, though body weight is expected to impact the steady state and peak concentration of the drug in an inverse fashion[30].
Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain
Published in Expert Opinion on Pharmacotherapy, 2022
Qiu Qiu, Joshua CJ Chew, Michael G Irwin
M6G has four-times less affinity for the MOP receptor [74]. Both the volume of distribution and clearance of M6G is lower than morphine. M6G is less lipophilic resulting in a slower distribution into the central nervous system and this confers a slower onset compared with morphine [75,77–79]. After oral administration of M6G, two peak concentrations are observed (3.5 hours and 21.3 hours after 50 mg). A potential mechanism is that M6G was hydrolyzed into morphine within the colon, and this morphine was subsequently reabsorbed and metabolized back into M6G, producing a second peak [80]. Clinically effective doses of M6G were shown to be greater than 0.15 mg/kg. Doses of less than 5 mg, used in early trials, showed no analgesic effect over placebo. The duration of action of M6G was 12–24 hours, as compared to 2–4 hours for morphine [77,81]. Unlike morphine, M6G is almost exclusively eliminated through the kidneys with minimal enterohepatic circulation. Thus, the elimination half-life is significantly increased in patients with renal impairment, potentially to more than 24 hours [82,83].