Plasma concentrations, steady state

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Elecainide is weU absorbed and 90% of the po dose is bioavailable. Binding to plasma protein is only 40% and peak plasma concentrations are attained in about 1—6 h. Three to five days may be requited to attain steady-state plasma concentrations when multiple doses are used. Therapeutic plasma concentrations are 0.2—1.0 lg/mL. Elecainide has an elimination half-life of 12—27 h, allowing twice a day dosing. The plasma half-life is increased in patients with renal failure or low cardiac outputs. About 70% of the flecainide in plasma is metabolized by the Hver to two principal metaboUtes. The antiarrhythmic potency of the meta-O-dealkylated metaboUte and the meta-O-dealkylated lactam, relative to that of flecainide is 50 and 10%, respectively. The plasma concentrations of the two metaboUtes relative to that of flecainide are 3—25%. Elecainide is mainly excreted by the kidneys, 30% unchanged, the rest as metaboUtes or conjugates about 5% is excreted in the feces (1,2). 

Theoretical volume of distribution (Vj) of a chemical is the volume in which the chemical would be distributed if its concentration were equal to a theoretical steady-state plasma concentration (Cq) at time zero. The volume of distribution is thus obtained quite similarly as the steady state concentration of a compound in the workroom air ... 

FIGURE 8.25 Repeated oral administration of drags leads to steady-state plasma concentrations. If elimination is rapid and administration not often enough, then an elevated and therapeutically effective steady-state concentration may not be achieved (green lines). In contrast, if elimination is very slow (or administration too often), then an accumulation of the drag may be observed with no constant steady state (red line). Bine line shows a correct balance between frequency of administration and elimination. 

Ciraulo DA, Sands BE, Shader RI Critical review of liability for benzodiazepine abuse among alcoholics. Am J Psychiatry 145 1501-1506, 1988b Ciraulo DA, Barnhill JG, Ciraulo AM, et al Parental alcoholism as a risk factor in benzodiazepine abuse a pilot smdy. Am J Psychiatry 146 1333-1335, 1989 Ciraulo DA, Antal EJ, Smith RB, et al The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol 10 27—32, 1990 Ciraulo DA, Sarid-Segal O, Knapp C, et al Liability to alprazolam abuse in daughters of alcoholics. Am J Psychiatry 153 956-958, 1996 Ciraulo DA, Barnhill JG, Ciraulo AM, et al Alterations in pharmacodynamics of anxiolytics in abstinent alcoholic men subjective responses, abuse liability, and electroencephalographic effects of alprazolam, diazepam, and buspirone. J Clin Pharmacol 37 64-73, 1997... 

In humans, peak plasma or serum concentrations of lutein occurred 11 to 16 hr after administration of a single oral dose. During daily supplementation with 20 mg of lutein, steady-state plasma concentrations were reached in about 30 days. This is consistent with an elimination half-life of 5 to 7 days. 

If the infusion is maintained for a sufficiently long time x, one obtains the condition for a steady-state plasma concentration which no longer changes with time. The condition follows immediately from eq. (39.34), by setting rto infinity ... 

Note that the steady-state plasma concentration varies proportionally with the rate of infusion and inversely with the plasma clearance C/p, the definition of... 

In practice, one will seek to obtain an estimate of the elimination constant kp and the plasma volume of distribution Vp by means of a single intravenous injection. These pharmacokinetic parameters are then used in the determination of the required dose D in the reservoir and the input rate constant k (i.e. the drip rate or the pump flow) in order to obtain an optimal steady state plasma concentration... 

In this special case when the time between dosings is equal to the half-life time of the drug, we can deduce that the minimum (steady-state) plasma concentration with repeated dosing is equal to the peak concentration, obtained from a single dose. Under this condition, the corresponding maximum (steady-state) concentration is twice as much as the minimum one. 

A recent study compared the differences in dosage and steady state plasma concentrations of sertraline, in Chinese versus Caucasian depressed outpatients. 

The plasma concentration will continue to rise until it reaches a plateau, or steady state. At this time, the plasma concentration will fluctuate between a maximum (Cmav) and a minimum (CrnLn) level, but, more important, the amount of drug eliminated per dose interval will equal the amount of drug absorbed per dose. When a drug is given at a dosing interval that is equal to its elimination half-life, it will reach 50% of its steady-state plasma concentration after one half-life, 75% after two half-lives, 87.5% after three, 93.75% after four, and 96.87% after five. Thus, from a practical viewpoint,... 

Several cases of sudden death have been reported in children and adolescents taking desipramine. A baseline electrocardiogram (ECG) is recommended before initiating a TCA in children and adolescents, and an additional ECG is advised when steady-state plasma concentrations are achieved. TCA plasma concentration monitoring is critical to ensure safety. 

By simultaneous monitoring of tidal volume and respiratory rate, or minute volume, and the concentration of an inhaled vapor in the bloodstream and the vapor in the exposure atmosphere, pharmacokinetic studies on the C t relationship have shown that the effective dose was nearly proportional to the exposure concentration for vapors such as 1,1,1-trichloroethane (Dallas et al., 1986), which has a saturable metabolism, found that the steady-state plasma concentrations were disproportion-ally greater at higher exposure concentrations. 

Ishida, M., Otani, K., Kaneko, S., Ohkubo, T., Osanai, T., Yasui, N., Mihara, K., Higuchi, H. and Sugawara, K. (1995) Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. International Clinical Psychopharmacology, 10 (3), 143-146. 

PK Following an oral dose, plasma peak concentration is achieved in approximately 6 hours. About 40% is eliminated through first pass metabolism. The half-life is from 21 to 54 hours and plasma clearance is from 12 to 47 hours. Daily administration will lead to a steady-state plasma concentration in about a week with concentration twice that of the single dose. Metabolism of Zyprexa is by the cytochrome P-450 oxidation. 

Varsaldi, F., MigUo, G., Scordo, M.G., et al. (2006) Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer s disease patients. Eur. J. Clin. Pharmacol., 62, 721-726. 

Increasing the infusion rate will mean the concentrations will climb until a new steady state value is obtained. Thus doubling the infusion rate doubles the steady state plasma concentration as illustrated in Figure 2.5. 

Metformin is negligibly bound to plasma proteins steady-state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 mcg/mL. 

Adjust dosage gradually, allowing 3 days between dosing increments to attain steady-state plasma concentrations and allow monitoring of QT intervals. 

Absorption-The oral bioavailability at steady-state is estimated to be 15% and 19% for 7.5 and 15 mg tablets, respectively. Peak plasma concentrations are reached approximately 7 hours after multiple dosing, and steady-state plasma concentrations are achieved by the sixth day of dosing. 

Dosage individualization Once therapy is initiated, pain relief and other opioid effects should be frequently assessed. Titrate patients to adequate effect (generally mild or no pain with the regular use of no more than 2 doses of supplemental analgesia per 24 hours). Patients who experience breakthrough pain may require dosage adjustment or rescue medication. Because steady-state plasma concentrations are approximated within 24 to 36 hours, dosage... 

Metabolism/Excretion- Bupropion is extensively metabolized in the liver. Steady-state plasma concentrations of bupropion and its metabolites are reached within 5 and 8 days, respectively. 

Renal function impairment The following table is designed to yield steady-state plasma concentrations of 0.7 to 1 mcg/mL. 

Absorption - The absolute bioavailability of acamprosate is approximately 11%. Steady-state plasma concentrations are reached within 5 days of dosing. Steady-state peak plasma concentrations after acamprosate doses of two 333... 

Oral solution/Injectlon The oral bioavailability is maximal when itraconazole oral solution is taken without food. Steady state is reached after 1 to 2 weeks during chronic administration. Peak plasma levels are observed 2 hours (fasting) to 5 hours (with food) following oral administration. Steady-state plasma concentrations are approximately 25% lower when the oral solution is taken with food. 

Fig. 9. Relationship between amelioration scores in depressed patients and steady-state plasma concentrations of the antidepressant nortriptyline. Both low and high concentrations are associated with minimum therapeutic effect. (From Asherg M, Cronholm B, Sjoqvist F, Tuck D. Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J 1971 3 331-4, with permission from the BMJ Publishing Group.)...

Nebert DW, Dieter MZ (2000) The evolution of drngmetabolism. Pharmacology 61 124-135 O Reilly RL, Bogue L, Singh SM (1994) Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry 36 467-471 Ozdemir V, Tyndale RF, Reed K, et al (1999) Paroxetine steady-state plasma concentration in relation to CYP2D6 genotype in extensive metabolizers. J Clin Psychopharmacol 19 472-475... 

Mechanism of Action An alcohol abuse deterrent that appears to interact with glutamate and gamma-aminobutyric acid neurotransmitter systems centrally, restoring their balance. Therapeutic Effect Reduces alcohol dependence. Pharmacokinetics Slowly absorbed from the G1 tract. Steady-state plasma concentrations are reached within 5 days. Does not undergo metabolism. Excreted in urine. Half-life 20-33 hr. 

Because of the possibility of increased seizure frequency, discontinuance of lamotrigine should be done gradually over a period of 2 weeks. Addition of DVP to lamotrigine therapy reduces lamotrigine clearance and increases steady-state plasma lamotrigine concentrations by 50% (AHFS, 2000). Conversely, steady-state plasma concentrations of lamotrigine are de-... 

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