Plasma concentration effective

There may be several reasons for this pattern to be observed. One obvious reason is distribution, i.e. the drug needs time to reach its site of action, and the time lag between the measured drug concentration in plasma and the drug effect is due to distributional delay. In order to describe such a plasma concentration-effect relationship, a PK-PD model that allows for drug distribution to the site of action, e.g. the effect compartment model may be used. 

Fig. 15. Relationship between the alfentanil plasma concentrations and the probability of needing naloxone to restore adequate spontaneous ventilation. The diagram at the upper part shows the alfentanil plasma concentrations of the patients who required naloxone (upward deflection) or did not require naloxone (downward deflection). The plasma concentration-effect curve for this clinical endpoint (lower part) was defined from the quantal data shown in the upper diagram using logistic regression. Bars indicate SE of C5o%. (From Ausems ME, Hug CC, Stanski DR, Burm AGE. Plasma concentrations of alfentanil required to supplement nitrous oxide anaesthesia for general surgery. Anaesthesiology 1986 65 362-73, reproduced by permission.)...

Meinertz T, Kasper W, Kersting F, Just H, Bechtold H, Jahnchen E. Lorcainide. II. Plasma concentration-effect relationship. Clin Pharmacol Ther 1979 26(2) 196-204. 

The pharmacokinetic interaction of phenytoin with valproate is complicated (78-80). Initially, the total serum phenytoin concentration falls, because valproate displaces phenytoin from protein binding sites and so the unbound fraction increases, with a consequent increase in clearance. Because of the change in unbound fraction the total plasma concentration effect curve is shifted to the left, and a lower total concentration is as effective as the total phenytoin concentration was in the absence of valproate. However, valproate also inhibits the metabolism of phenytoin and so the serum phenytoin concentration then starts to rise and there is a risk of toxicity. 

Another situation in which the plasma concentration-effect relationship may be confounded by time is one where there is very rapid development of tolerance to the drug, even within a single dosing cycle. In this case, for a given plasma concentration, drug effect will be lower as concentrations are falling than when they are rising and will produce clockwise hysteresis this has been demonstrated for nicotine. 

Figure 17.5 Relationship between albuterol plasma concentration, effect (measured by the forced expiratory volume in 1 s [FEV]]) and time, (a) Plasma drug concentration versus time (b) effect versus time (c) effectversus plasma drug concentration.

G. L. Coppoc and S. J. Leger, "Effect of Nitrogen Triduoride on Plasma Concentrations of Lactate, Methemoglobin, and Selected Enzymes," ApriWune 1968, SAM-TR-70-42 (AD 711044), School of Aerospace Medicine, Brooks Air Eorce Base, Texas, July 1970. 

Mexifitene is well absorbed from the GI tract and less than 10% undergoes first-pass hepatic metabolism. In plasma, 60—70% of the dmg is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.5—2.0 lg/mL. The plasma half-life of mexifitene is 10—12 h in patients having normal renal and hepatic function. Toxic effects are noted at plasma concentrations of 1.5—3.0 lg/mL, although side effects have been noted at therapeutic concentrations. The metabolite, /V-methy1mexi1itene, has some antiarrhythmic activity. About 85% of the dmg is metabolized to inactive metabolites. The kidneys excrete about 10% of the dmg unchanged, the rest as metabolites. Excretion can also occur in the bile and in breast milk (1,2). 

Encainide is almost completely absorbed from the GI tract. Eood may delay absorption without altering its bioavailabiUty. The dmg is rapidly metabolized in 90% of the patients to two principal metaboUtes, 0-demethylencainide (ODE) and 3-methoxy-O-demethylencainide (MODE), while the other 10% metabolize encainide slowly with Htde or no ODE or MODE formed. Encainide, ODE, and MODE are extensively protein bound 75—80% for encainide and ODE and 92% for MODE. Peak plasma concentrations are achieved in 30—90 min. Therapeutic plasma concentrations are very low the concentrations of ODE and MODE are approximately five times those of encainide. The findings with the metaboUtes are significant because ODE is 2—10 times and MODE, 1—4 times more effective than encainide as antiarrhythmics. The half-Hves for encainide in fast and slow metabolizers is 1—2 h and 6—12 h, respectively. The elimination half-life for ODE is 3—4 h and for MODE 6—12 h in fast metabolizers. Excretion occurs through the Hver and kidneys (1,2). 

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

After po doses, atenolol is rapidly but incompletely absorbed ( 50%) from the GI tract, and 50% is excreted unchanged in the feces. Six to 16% of the plasma concentration is bound to protein. Atenolol undergoes Httie first-pass metaboHsm. Peak plasma concentrations occur in 2—4 h after po doses. The elimination half-hfe of atenolol is 6—7 h. Excretion of absorbed dmg is mainly by the kidneys and elimination can be impaired in patients having renal failure. The adverse effects of atenolol are similar to those seen for propranolol therapy (98,99,108). 

FIGURE 8.23 Kinetic profiles of the plasma concentrations of three different drags taken by the oral route. If absorption is rapid, toxic effects may ensue (red line). If too slow, a therapeutically effective level may not be attained (blue line). 

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. 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

The co-administration of drugs which induce the metabolic enzymes in the liver or small intestine can reduce the plasma concentrations of drugs which are substrates of the enzyme, leading to reduced drug effects. For example, the plasma concentrations of many drugs which are substrates of the enzyme CYP3A4, such as cyclosporine, are decreased by coadministration of rifampicin, which is an inducer of CYP3A4. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catechol-O-methyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa... 

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... 

Studies of the intoxicating effects of toluene showed that the inhalation of its vapor at a concentration of 200 ppm was associated with the development of mild-to-moderate intoxication, characterized by sedation, paresthesias, and hyporeflexia. Toluene vapor concentrations of 600-800 ppm induced a confusional state, whereas greater concentrations produced an intense euphoria (Benignus 1981 Press and Done 1967). In humans, plasma concentrations of toluene of 10-100 pM have been reported to be intoxicating these concentrations are close to the intoxicating concentrations of alcohol and in-halational anesthetics (Miller 1985). 

These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. 

Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. The prime suspect is OMD which has a half-life of some 20 hours and reaches plasma concentrations three- to fourfold those of dopa. Suggestions that it may compete with dopa for entry across the blood-brain barrier or act as a partial agonist (effective antagonist) have not been substantiated experimentally although it does reduce DA release from rat striatal slices. Also if free radical production through deamination of DA is neurotoxic (see below) then this would be increased by levodopa. 

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