Consulenza farmacologica per fluvoxamina, alprazolam e itraconazolo

	∑ Esposizione^a	flu	alp	itr
Fluvoxamina	n.a.¹		1	n.a.
Alprazolam	1.77	1.3		1.74
Itraconazolo	1.44	1.44	1

Punteggi	∑ Punti	flu	alp	itr
Effetti serotoninergici ^a	2	++	Ø	Ø

Punteggi	∑ Punti	flu	alp	itr
Kiesel ^b	3	++	+	Ø

Punteggi	∑ Punti	flu	alp	itr
RISK-PATH ^c	0.5	+	Ø	+

Effetti collaterali	∑ frequenza	flu	alp	itr
Sonnolenza	62.2 %	24.5	49.9	n.a.
Sedazione	45.2 %	n.a.	45.2	n.a.
Nausea	41.4 %	37.0	n.a.	7.0
Fatica	32.8 %	n.a.	31.3	2.3
Vertigini	31.7 %	11.5	20.8	2.6
Problema di coordinamento	24.8 %	n.a.	24.8	n.a.
Compromissione della memoria	24.3 %	n.a.	24.3	n.a.
Xerostomia	23.0 %	12.0	12.4	n.a.
Aumento dell'appetito	19.9 %	n.a.	19.9	n.a.
Costipazione	17.1 %	n.a.	17.1	n.a.

1. Fraser AD et al. Urinary screening for alprazolam and its major metabolites by the Abbott ADx and TDx analyzers with confirmation by GC/MS. Journal of analytical toxicology.

Authors: Fraser AD Bryan W Isner AF
Abstract: Alprazolam is a short-acting triazolobenzodiazepine with anxiolytic and antidepressant properties. It has a half-life of 10-15 hours after multiple oral doses. Approximately 20% of an oral dose is excreted unchanged in the urine. The major urinary metabolites are alpha-OH alprazolam glucuronide and 3-HMB benzophenone glucuronide. The objective of this study was to characterize the reactivity of alprazolam and three metabolites in the Abbott ADx and TDx urinary benzodiazepine assays compared with the EMIT d.a.u. benzodiazepine assay. Alprazolam (at 300 ng/mL) gave an equivalent response as the 300 ng/mL low control (nordiazepam). alpha-OH alprazolam gave an equivalent response to this control between 300-500 ng/mL and 4-OH alprazolam between 500-1000 ng/mL. The 3-HMB benzophenone was not positive even at 10,000 ng/mL. The ADx screening assay was positive in 26 of 31 urine specimens collected from alprazolam-treated patients. All 31 of these specimens were confirmed positive for alpha-OH alprazolam by GC/MS after enzymatic hydrolysis and formation of a TMS derivative. For the TDx, 27 of 31 specimens were positive for benzodiazepines and all 31 were confirmed by GC/MS. All 5 of the negative ADx specimens and 4 of 5 TDx specimens contained 150-400 ng/mL of alpha-OH alprazolam. In conclusion, both the ADx and TDx urine benzodiazepine assays are acceptable screening assays for alprazolam use when the alpha-OH alprazolam concentration is greater than 400 ng/mL.

Pubmed Id: 2046338

2. Fawcett JA et al. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy.

Authors: Fawcett JA Kravitz HM
Abstract: Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.

Pubmed Id: 6133268

3. Smith RB et al. Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration. Psychopharmacology. 1984

Authors: Smith RB Kroboth PD Vanderlugt JT Phillips JP Juhl RP
Abstract: Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.

Pubmed Id: 6152055

4. Pohjola-Sintonen S et al. Torsades de pointes after terfenadine-itraconazole interaction. BMJ (Clinical research ed.). 1993

Authors: Pohjola-Sintonen S Viitasalo M Toivonene L Neuvonen P
Abstract: No Abstract available

Pubmed Id: 8382980

5. van Harten J Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clinical pharmacokinetics. 1993

Authors: van Harten J
Abstract: A feature common to all selective serotonin reuptake inhibitors (SSRIs) is that they are believed to act as antidepressant drugs because of their ability to reversibly block the reuptake of serotonin (5-hydroxytryptamine; 5-HT) in the synaptic cleft. From a chemical perspective, however, they show distinct differences. Consequently, the pharmacokinetic behaviour of of the drugs can be very different, and these pharmacokinetic differences may have a major influence on their clinical profiles of action. All SSRIs have a great affinity for the 5-HT reuptake carrier in the synaptic cleft in the central nervous system, with much less affinity for the noradrenaline (norepinephrine) reuptake carrier, and for alpha- and beta-adrenergic, dopamine, histamine, 5-HT and muscarine receptors. Fluoxetine and citalopram are available as racemic mixtures, the isomers of fluoxetine having almost equal affinity to the 5-HT reuptake carrier, while the reuptake inhibitor properties of citalopram reside almost exclusively in the (+)-isomer. Norfluoxetine, one of the metabolites of fluoxetine, has a selectivity for the 5-HT reuptake carrier comparable with that of fluoxetine. Gastrointestinal absorption of the SSRIs is generally good, with peak plasma concentrations observed after approximately 4 to 6h. Absolute bioavailability of citalopram is almost 100%, whereas it is likely that the other compounds undergo (substantial) first-pass metabolism. Apparent oral clearance values after single doses range from 26 L/h (citalopram) to 167 L/h (paroxetine), while after multiple doses oral clearance is markedly reduced, particularly for fluoxetine and paroxetine. Plasma protein binding of fluoxetine, paroxetine and sertraline is > or = 95%; values for fluvoxamine (77%) and citalopram (50%) are much lower. For all compounds, however, protein binding interactions do not seem to be of great importance. Although many attempts were made, to date no convincing evidence exists of a relationship between plasma concentrations of any of the SSRIs and clinical efficacy. Elimination occurs via metabolism, probably in the liver. Renal excretion of the parent compounds is of minor importance. Metabolites of fluvoxamine and fluoxetine are predominantly excreted in urine; larger quantities of metabolites of paroxetine (36%) and sertraline (44%) are excreted in faeces. The half-lives of fluvoxamine, paroxetine, sertraline and citalopram are approximately 1 day. The half-life of fluoxetine is approximately 2 days (6 days after multiple doses), and that of the active metabolite norfluoxetine is 7 to 15 days. The metabolism of paroxetine, and possibly also of fluoxetine, is under genetic control of the sparteine/debrisoquine type. Available data indicate that metabolism of SSRIs is impaired with reduced liver function.(ABSTRACT TRUNCATED AT 400 WORDS)

Pubmed Id: 8384945

6. Bastani JB et al. Serotonin syndrome and fluvoxamine: a case study. The Nebraska medical journal. 1996

Authors: Bastani JB Troester MM Bastani AJ
Abstract: OBJECTIVE: To report a serotonin syndrome reaction in a patient taking fluvoxamine to replace an earlier SSRI agent. CASE REPORT: A female patient with Obsessive Compulsive Disorder on paroxetine after resurgence in her obsessive ruminations was started on fluvoxamine 50 mg daily. One week later she became suicidal and was hospitalized. The fluvoxamine was increased to 50 mg morning and 100 mg bedtime and the paroxetine was discontinued. Over the next few days she began to have trouble with her concentration. A low grade fever set in after she experienced auditory hallucinations. Fluvoxamine was discontinued and she had an uneventful recovery after twenty-four hours. DISCUSSION: Fluvoxamine is a recently approved serotonin selective reuptake inhibitor (SSRI) with few side effect profiles. It is effective in the treatment of Depressive Disorder and Obsessive Compulsive Disorder and is used to potentiate or replace other anti-OCD drugs including already available serotonin specific reuptake inhibitors (SSRI). We wish to draw attention to the potential for serotonin syndrome in patients on fluvoxamine who may have previously been on other SSRIs.

Pubmed Id: 8628448

7. van Harten J Overview of the pharmacokinetics of fluvoxamine. Clinical pharmacokinetics. 1995

Authors: van Harten J
Abstract: The pharmacokinetics of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties, are well established. After oral administration, the drug is almost completely absorbed from the gastrointestinal tract, and the extent of absorption is unaffected by the presence of food. Despite complete absorption, oral bioavailability in man is approximately 50% on account of first-pass hepatic metabolism. Peak plasma fluvoxamine concentrations are reached 4 to 12 hours (enteric-coated tablets) or 2 to 8 hours (capsules, film-coated tablets) after administration. Steady-state plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single dose data. Fluvoxamine displays nonlinear steady-state pharmacokinetics over the therapeutic dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma fluvoxamine concentrations show no clear relationship with antidepressant response or severity of adverse effects. Fluvoxamine undergoes extensive oxidative metabolism, most probably in the liver. Nine metabolites have been identified, none of which are known to be pharmacologically active. The specific cytochrome P450 (CYP) isoenzymes involved in the metabolism of fluvoxamine are unknown. CYP2D6, which is crucially involved in the metabolism of paroxetine and fluoxetine, appears to play a clinically insignificant role in the metabolism of fluvoxamine. The drug is excreted in the urine, predominantly as metabolites, with only negligible amounts ( < 4%) of the parent compound. Fluvoxamine shows a biphasic pattern of elimination with a mean terminal elimination half-life of 12 to 15 hours after a single oral dose; this is prolonged by 30 to 50% at steady-state. Plasma protein binding of fluvoxamine (77%) is low compared with that of other SSRIs. Fluvoxamine pharmacokinetics are substantially unaltered by increased age or renal impairment. However, its elimination is prolonged in patients with hepatic cirrhosis. Fluvoxamine inhibits oxidative drug metabolising enzymes (particularly CYP1A2, and less potently and much less potently CYP3A4 and CYP2D6, respectively) and has the potential for clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants (tertiary, but not secondary, amines), alprazolam, bromazepam, diazepam, theophylline, propranolol, warfarin and, possibly, carbamazepine. Fluvoxamine is a second generation antidepressant that selectively inhibits neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT). Fluvoxamine exhibits antidepressant activity similar to that of the tricyclic antidepressants, but has a somewhat improved tolerability profile, particularly with respect to a lower incidence of anticholinergic effects and reduced cardiotoxic potential. However, gastrointestinal adverse effects, especially nausea, are seen more frequently with fluvoxamine than with the tricyclic antidepressants. Fluvoxamine does not have an asymmetric carbon in its structure (fig. 1) and therefore does not exist as optical isomers. For this reason, the potentially confounding problem of stereoisomerism does not arise with fluvoxamine.

Pubmed Id: 8846617

8. Gill M et al. Serotonin syndrome in a child after a single dose of fluvoxamine. Annals of emergency medicine. 1999

Authors: Gill M LoVecchio F Selden B
Abstract: Serotonin syndrome, a potentially fatal iatrogenic complication of psychopharmacologic therapy, is most commonly reported with combinations of serotonergic medications. Serotonin syndrome is characterized by alterations in cognition, behavior, autonomic, and central nervous system function as a result of increased postsynaptic serotonin receptor agonism. We present the first reported case of serotonin syndrome after a single dose of fluvoxamine in a pediatric patient after ingestion of a single supratherapeutic dose of fluvoxamine.

Pubmed Id: 10092727

9. Isoherranen N et al. Role of itraconazole metabolites in CYP3A4 inhibition. Drug metabolism and disposition: the biological fate of chemicals. 2004

Authors: Isoherranen N Kunze KL Allen KE Nelson WL Thummel KE
Abstract: Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro Ki, and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied. Three metabolites were detected: hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). OHITZ and keto-ITZ were also substrates of CYP3A4. Using a substrate depletion kinetic approach for parameter determination, ITZ exhibited an unbound K(m) of 3.9 nM and an intrinsic clearance (CLint) of 69.3 ml.min(-1).nmol CYP3A4(-1). The respective unbound Km values for OH-ITZ and keto-ITZ were 27 nM and 1.4 nM and the CLint values were 19.8 and 62.5 ml.min(-1).nmol CYP3A4(-1). Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction. Both ITZ and OH-ITZ were competitive inhibitors of CYP3A4, with unbound Ki (1.3 nM for ITZ and 14.4 nM for OH-ITZ) close to their respective Km. ITZ, OH-ITZ, keto-ITZ and ND-ITZ exhibited unbound IC50 values of 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively, when coincubated with human liver microsomes and midazolam (substrate concentration < Km). These findings demonstrate that ITZ metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself, and thus may contribute to the inhibition of CYP3A4 observed in vivo after ITZ dosing.

Pubmed Id: 15242978

10. Park JY et al. Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects. Clinical pharmacology and therapeutics. 2006

Authors: Park JY Kim KA Park PW Lee OJ Kang DK Shon JH Liu KH Shin JG
Abstract: OBJECTIVE: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.

Pubmed Id: 16765147

11. Templeton IE et al. Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clinical pharmacology and therapeutics. 2008

Authors: Templeton IE Thummel KE Kharasch ED Kunze KL Hoffer C Nelson WL Isoherranen N
Abstract: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

Pubmed Id: 17495874

12. Kato M et al. The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling. Pharmaceutical research. 2008

Authors: Kato M Shitara Y Sato H Yoshisue K Hirano M Ikeda T Sugiyama Y
Abstract: PURPOSE: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable. METHOD: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration. RESULTS: The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods. CONCLUSION: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.

Pubmed Id: 18483837

13. Orlando R et al. Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure. British journal of clinical pharmacology. 2010

Authors: Orlando R De Martin S Andrighetto L Floreani M Palatini P
Abstract: AIMS: To investigate the effects of age and chronic heart failure (CHF) on the oral disposition kinetics of fluvoxamine. METHODS: A single fluvoxamine dose (50 mg) was administered orally to 10 healthy young adults, 10 healthy elderly subjects and 10 elderly patients with CHF. Fluvoxamine concentration in plasma was measured for up to 96 h. RESULTS: With the exception of apparent distribution volume, ageing modified all main pharmacokinetic parameters of fluvoxamine. Thus, peak concentration was about doubled {31 +/- 19 vs. 15 +/- 9 ng ml(-1); difference [95% confidence interval (CI)] 16 (3, 29), P < 0.05}, and area under the concentration-time curve was almost three times higher [885 +/- 560 vs. 304 +/- 84 ng h ml(-1); difference (95% CI) 581 (205, 957), P < 0.05]; half-life was prolonged by 63% [21.1 +/- 6.2 vs. 12.9 +/- 6.4 h; difference (95% CI) 8.2 (2.3, 14.1), P < 0.01], and oral clearance was halved (1.12 +/- 0.77 vs. 2.25 +/- 0.66 l h(-1) kg(-1); difference (95% CI) -1.13 (-1.80, -0.46), P < 0.001]. A significant inverse correlation was consistently observed between age and oral clearance (r=-0.67; P < 0.001). The coexistence of CHF had no significant effect on any pharmacokinetic parameters in elderly subjects. CONCLUSIONS: Ageing results in considerable impairment of fluvoxamine disposition, whereas CHF causes no significant modifications. Therefore, adjustment of initial dose and subsequent dose titrations may be required in elderly subjects, whereas no further dose reduction is necessary in elderly patients with CHF.

Pubmed Id: 20233199

14. O'Brien FE et al. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. British journal of pharmacology. 2012

Authors: O'Brien FE Dinan TG Griffin BT Cryan JF
Abstract: The drug efflux pump P-glycoprotein (P-gp) plays an important role in the function of the blood-brain barrier by selectively extruding certain endogenous and exogenous molecules, thus limiting the ability of its substrates to reach the brain. Emerging evidence suggests that P-gp may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. Despite some inconsistency in the literature, clinical investigations of potential associations between functional single nucleotide polymorphisms in ABCB1, the gene which encodes P-gp, and antidepressant response have highlighted a potential link between P-gp function and treatment-resistant depression (TRD). Therefore, co-administration of P-gp inhibitors with antidepressants to patients who are refractory to antidepressant therapy may represent a novel therapeutic approach in the management of TRD. Furthermore, certain antidepressants inhibit P-gp in vitro, and it has been hypothesized that inhibition of P-gp by such antidepressant drugs may play a role in their therapeutic action. The present review summarizes the available in vitro, in vivo and clinical data pertaining to interactions between antidepressant drugs and P-gp, and discusses the potential relevance of these interactions in the treatment of depression.

Pubmed Id: 21718296

15. Funk KA et al. A comparison of the risk of QT prolongation among SSRIs. The Annals of pharmacotherapy. 2013

Authors: Funk KA Bostwick JR
Abstract: OBJECTIVE: To report QT prolongation potential in selective serotonin reuptake inhibitors (SSRIs) in order to advise clinicians on safe use of SSRIs other than citalopram in light of citalopram warnings. DATA SOURCES: Primary literature and case reports were identified through a systematic search. Data from drug manufacturers, package inserts, and the ArizonaCERT database were also utilized. STUDY SELECTION AND DATA EXTRACTION: English-language studies and case reports were included. DATA SYNTHESIS: Studies demonstrate possible dose-related clinically significant QT prolongation with escitalopram. Fluoxetine, fluvoxamine, and sertraline at traditional doses demonstrate a lack of clinically significant increases in QTc in the majority of studies. Further, paroxetine monotherapy shows a lack of clinically significant QTc prolongation in all studies. However, case reports or reporting tools still link these SSRIs with QTc prolongation. Fluoxetine, escitalopram, and sertraline used in post-acute coronary syndrome patients did not demonstrate risk of QTc prolongation. CONCLUSION: For clinicians who choose not to use citalopram due to recent Food and Drug Administration (FDA) recommendations, other antidepressants within this class may be considered. When citalopram is not utilized based on risk factors for TdP, use of escitalopram is not likely the safest alternative. Based on current literature, fluoxetine, fluvoxamine, and sertraline appear to have similar, low risk for QT prolongation, and paroxetine appears to have the lowest risk. However, there are significant limitations in interpreting the studies, including varying definitions of significant QT prolongation. Therefore, choice of an alternative SSRI should be based on individual risk factors for arrhythmias and other patient-specific factors.

Pubmed Id: 24259697

16. Ivanyuk A et al. Renal Drug Transporters and Drug Interactions. Clinical pharmacokinetics. 2017

Authors: Ivanyuk A Livio F Biollaz J Buclin T
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.

Pubmed Id: 28210973

17. Yoshida K et al. Accurate Estimation of In Vivo Inhibition Constants of Inhibitors and Fraction Metabolized of Substrates with Physiologically Based Pharmacokinetic Drug-Drug Interaction Models Incorporating Parent Drugs and Metabolites of Substrates with Cluster Newton Method. Drug metabolism and disposition: the biological fate of chemicals. 2018

Authors: Yoshida K Maeda K Konagaya A Kusuhara H
Abstract: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.

Pubmed Id: 30135241

18. Kiesel EK et al. An anticholinergic burden score for German prescribers: score development. BMC geriatrics. 2018

Authors: Kiesel EK Hopf YM Drey M
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.

Pubmed Id: 30305048

Farmacocinetica	-5%
Fluvoxamina
Alprazolam
Itraconazolo

Punteggi	-16%
Estensione di tempo QT
Effetti anticolinergici
Effetti serotoninergici

Consulenza farmacologica per fluvoxamina, alprazolam e itraconazolo

Sommario info 55%

Varianti ✨

Aree di applicazione

Farmacocinetica info -5%

Effetti serotoninergici info -8%

Effetti anticolinergici info -7%

Estensione di tempo QT info -1%

Effetti collaterali generali info -24%

Limitazioni

Riferimenti letterari

epha.ch AG

Generale

Lingue