STUDY - Technical - New Dacian's Medicine
Principles
of Drug Therapy (3)
Translation Draft
We've come to individualize drug therapy. Optimal drug therapy requires the exact administration of the appropriate amount of medicine with the patient's particularities (too low a dose may be ineffective and too high a dose may increase the risk of undesirable effects). When the desired response is a well-determined clinical effect, such as changes in blood pressure or clotting time, then optimal dosing can be done in an empirical way.
However, for potentially toxic medicines, dose modification should involve modest changes in quantity (less than or equal to 50%) and not be more common than at 2-3 half-lifes. In most cases, drug therapy should be conducted according to the concept of the "therapeutic window", in which the concentration of the drug should be maintained. If the therapeutic window is wide, which means that dose-dependent toxicity is reduced, then the maximum, desired and achievable efficiency can be achieved by taking an over-efficient dose.
Such a strategy is often used for penicillin and for many beta-adrenergic blockers. In these circumstances, it is also possible to usefully extend the duration of the action of the drug, especially when it is quickly removed from the body. Thus, the administration of 75 mg of captopril causes the reduction of arterial pressure for more than 12 hours, although the half-life of the conversion enzyme inhibitor is about 2 hours. The therapeutic window for most medicines is much narrower and, in some cases, would be twice as much as the difference between the dose of the drug that produces the desired response and that which produces the adverse effect.
In these cases, the application of pharmacokinetic principles is decisive for achieving defined therapeutic objectives. During long-term therapy, the most important pharmacokinetic factor is clearance, as it determines the steady state of plasma concentration. Thus, after an oral dose, taking into account that this clearance is a constant regardless of dose, we have: Cpm = dosage rate/ clearance = (F x oral dose)/ (Cl x interval between doses). Consequently, the levels of the drug at the steady state and therefore the intensity of the response, can be adjusted by changing the dosage rate. In most cases, this is achieved by modifying the dose of the drug and maintaining the same interval between doses (e.g. 250 mg every 8 hours compared to 200 mg every 8 hours).
A change of this kind will change the levels of the drug proportionately, but the relative fluctuations between the maximum and minimum values will remain the same. Such an approach is acceptable if the maximum concentration obtained is not toxic and the minimum concentration does not fall below the minimum effective one for too long. Alternatively, the level of equilibrium may be changed by changing the frequency of intermittent administration, with the maintenance of the same amounts of the drug at each administration. In this case, the size of the relative fluctuation of the average equilibrium concentrations will change (the shorter the interval between doses, the greater the difference between maximum and minimum levels).
Let's see now what's with the effects of kidney failure! Since renal excretion is an important route of elimination, renal failure has the effect of a low clearance of the drug and therefore a slow purification of it from the body, so the administration of the usual doses leads to high accumulations and an increased probability of the occurrence of toxicity. The objective, in such cases, is to modify the dosing schedule so that in the plasma of the patient with renal impairment a concentration of the drug similar to the normal one (in a given time) and the steady state is achieved after a necessary time interval with the variable one in the patient with normal renal function. Carefully modifying the dosing schedule is important for medicines with high half-life and limited therapeutic index (e.g. digoxin) - whereas Cpm = (dose/ interval between doses) x F/ Cl = F/ kVd. CPM in patients with normal renal function can be achieved in patients with impaired renal function (i.e., with low clearance) either by taking lower doses, or by extending the interval between doses, or in both ways.
The change factor for the dosing regimen is dependent on the relationship between the clearance of the drug or the rate of elimination in the patient with renal failure and the one with normal function. If only the dose is changed, then it is necessary to calculate the fraction of the normal dose to be administered (at a normal interval between doses). This fraction can be determined either from the clearance of the drug or from the fractional elimination constant (k), as both values are proportional to creatinine clearance (Cl cr). Creatinine clearance is best determined directly. Serum creatinine (C cr) can be used to estimate this value by means of the following equation (valid in men): Cl cr = [(140-age) x weight (kg)]/ [72 x C cr (mg/ dl)] (ml/ min). For women, the correct estimate is 85% of that obtained in men. This approach does not apply in severe renal failure (C cr greater than 5 mg/ dl) or in case of rapid variations in renal function.
Useful here is the clearance approach. The calculation of the dose of the drug, with the highest accuracy, is based on the clearance of the drug. From the values of the clearance of the drug can be calculated the dose in renal failure (Ir dose) as follows: Dota ir = dose x (Cl ir/ Cl) where ir = renal failure, Cl = systemic clearance with normal renal function, Cl ir = systemic clearance from renal failure, Dose = maintenance dose for normal renal function (Cl cr approximately equal to 100 ml/ min). in patients with renal impairment, for a range between doses, the dose thus calculated will produce an average plasma concentration equal to that produced by the normal dose given in a patient with normal renal function.
However, fluctuations between peaks and minimums may be more pronounced, peak value may be below therapeutic level, and minimum concentration higher. In order to partially compensate for the flattening of the plasma concentration curve, the interval between doses, e.g. for gentamicin, in renal failure, administration every 12 hours for Cl cr greater than 50, every 24 hours for Cl cr between 10 and 49 and 48 hours for Cl cr less than 10 ml/ min may be changed (thus, the above formula is based on the appropriate dose for the usual interval between doses, in a patient with normal renal function). For certain medicines, in renal failure, it is recommended to change the interval between doses, maintaining the same dose used when renal function is normal: Interval between doses x (Cl/ Cl ir) = Interval between doses ir.
With this strategy, the possibility that plasma levels are subtherapeutic for critical time periods must be evaluated. In some cases, it is desirable to calculate a dose that determines a certain constant plasma level. This approach is more appropriate for constant intravenous infusions, where 100% of the dose is released into the systemic circulation. When the clearance of a drug in a patient with renal failure is calculated as above, then the ir dose (cant/ unit of time) = Cl ir (vol/ unit of time) x Cp (cant/ vol), where units of time, quantity and volume are compatible. If in a patient with a creatinine clearance of 25 ml/ min, the plasma concentration of carbenicillin of 100 microg/ ml is the therapeutic objective, the rate of intravenous infusion is calculated as follows. The clearance of carbenicillin is Cl ir = [68 x (25/ 100)] + 10 = 27 ml/ min. Therefore, carbenicillin should be injected at a rate of 2,700 microg/ min.
I should also present something about the approach of the fractional elimination constant (k). Clearance data in renal failure are not available for many medicines. In these cases, the fraction of the normal dose required in a patient with renal impairment may be approximated from the ratio between the fractional elimination constant in the body with renal failure (k ir) and the constant in the body with normal renal function (k). This approach assumes that the distribution of the drug (Vd) is not affected by kidney disease.
Such interpretation is equivalent to the one using the clearance data: Dose ir = dose x (k ir/ k). Since the K ir/ K ratio is the fraction of the usual dose used for a certain degree of renal failure, it is called the dose fraction. The elimination of many medicines is rapid enough in patients with normal renal function for the time needed to achieve a steady state of equilibrium, which usually means that a loading dose is not required. In renal failure, where half-life can be significantly prolonged, this accumulation period could become unacceptably long. In such cases, a loading dose may be indicated (the same loading dose of the medicine as in cases with normal renal function may be indicated).
Now, a little bit about general considerations for determining dosage in renal failure. Due to differences in distribution volumes and metabolism rates in patients, the calculation of the drug dose in renal failure should be regarded as a valid approximation, which prevents the use of excessively high doses, inadequate for most patients. However, maintenance doses are most accurately determined when plasma level data are used to adjust them. Active or toxic metabolites of medicinal products may also accumulate in renal failure.
For example, meperidine is purified largely by metabolism and its plasma concentration of one of its metabolites, normperidine, is increased when its renal elimination is low. Since normperidine has higher convulsive activity than meperidine, its accumulation in patients with renal impairment is probably responsible for signs of excitation of the central nervous system, such as irritability, jerky and seizures, which occur after several doses of meperidine in patients with renal impairment.
We'll continue next time with the effects of liver disease.
We've come to individualize drug therapy. Optimal drug therapy requires the exact administration of the appropriate amount of medicine with the patient's particularities (too low a dose may be ineffective and too high a dose may increase the risk of undesirable effects). When the desired response is a well-determined clinical effect, such as changes in blood pressure or clotting time, then optimal dosing can be done in an empirical way.
However, for potentially toxic medicines, dose modification should involve modest changes in quantity (less than or equal to 50%) and not be more common than at 2-3 half-lifes. In most cases, drug therapy should be conducted according to the concept of the "therapeutic window", in which the concentration of the drug should be maintained. If the therapeutic window is wide, which means that dose-dependent toxicity is reduced, then the maximum, desired and achievable efficiency can be achieved by taking an over-efficient dose.
Such a strategy is often used for penicillin and for many beta-adrenergic blockers. In these circumstances, it is also possible to usefully extend the duration of the action of the drug, especially when it is quickly removed from the body. Thus, the administration of 75 mg of captopril causes the reduction of arterial pressure for more than 12 hours, although the half-life of the conversion enzyme inhibitor is about 2 hours. The therapeutic window for most medicines is much narrower and, in some cases, would be twice as much as the difference between the dose of the drug that produces the desired response and that which produces the adverse effect.
In these cases, the application of pharmacokinetic principles is decisive for achieving defined therapeutic objectives. During long-term therapy, the most important pharmacokinetic factor is clearance, as it determines the steady state of plasma concentration. Thus, after an oral dose, taking into account that this clearance is a constant regardless of dose, we have: Cpm = dosage rate/ clearance = (F x oral dose)/ (Cl x interval between doses). Consequently, the levels of the drug at the steady state and therefore the intensity of the response, can be adjusted by changing the dosage rate. In most cases, this is achieved by modifying the dose of the drug and maintaining the same interval between doses (e.g. 250 mg every 8 hours compared to 200 mg every 8 hours).
A change of this kind will change the levels of the drug proportionately, but the relative fluctuations between the maximum and minimum values will remain the same. Such an approach is acceptable if the maximum concentration obtained is not toxic and the minimum concentration does not fall below the minimum effective one for too long. Alternatively, the level of equilibrium may be changed by changing the frequency of intermittent administration, with the maintenance of the same amounts of the drug at each administration. In this case, the size of the relative fluctuation of the average equilibrium concentrations will change (the shorter the interval between doses, the greater the difference between maximum and minimum levels).
Let's see now what's with the effects of kidney failure! Since renal excretion is an important route of elimination, renal failure has the effect of a low clearance of the drug and therefore a slow purification of it from the body, so the administration of the usual doses leads to high accumulations and an increased probability of the occurrence of toxicity. The objective, in such cases, is to modify the dosing schedule so that in the plasma of the patient with renal impairment a concentration of the drug similar to the normal one (in a given time) and the steady state is achieved after a necessary time interval with the variable one in the patient with normal renal function. Carefully modifying the dosing schedule is important for medicines with high half-life and limited therapeutic index (e.g. digoxin) - whereas Cpm = (dose/ interval between doses) x F/ Cl = F/ kVd. CPM in patients with normal renal function can be achieved in patients with impaired renal function (i.e., with low clearance) either by taking lower doses, or by extending the interval between doses, or in both ways.
The change factor for the dosing regimen is dependent on the relationship between the clearance of the drug or the rate of elimination in the patient with renal failure and the one with normal function. If only the dose is changed, then it is necessary to calculate the fraction of the normal dose to be administered (at a normal interval between doses). This fraction can be determined either from the clearance of the drug or from the fractional elimination constant (k), as both values are proportional to creatinine clearance (Cl cr). Creatinine clearance is best determined directly. Serum creatinine (C cr) can be used to estimate this value by means of the following equation (valid in men): Cl cr = [(140-age) x weight (kg)]/ [72 x C cr (mg/ dl)] (ml/ min). For women, the correct estimate is 85% of that obtained in men. This approach does not apply in severe renal failure (C cr greater than 5 mg/ dl) or in case of rapid variations in renal function.
Useful here is the clearance approach. The calculation of the dose of the drug, with the highest accuracy, is based on the clearance of the drug. From the values of the clearance of the drug can be calculated the dose in renal failure (Ir dose) as follows: Dota ir = dose x (Cl ir/ Cl) where ir = renal failure, Cl = systemic clearance with normal renal function, Cl ir = systemic clearance from renal failure, Dose = maintenance dose for normal renal function (Cl cr approximately equal to 100 ml/ min). in patients with renal impairment, for a range between doses, the dose thus calculated will produce an average plasma concentration equal to that produced by the normal dose given in a patient with normal renal function.
However, fluctuations between peaks and minimums may be more pronounced, peak value may be below therapeutic level, and minimum concentration higher. In order to partially compensate for the flattening of the plasma concentration curve, the interval between doses, e.g. for gentamicin, in renal failure, administration every 12 hours for Cl cr greater than 50, every 24 hours for Cl cr between 10 and 49 and 48 hours for Cl cr less than 10 ml/ min may be changed (thus, the above formula is based on the appropriate dose for the usual interval between doses, in a patient with normal renal function). For certain medicines, in renal failure, it is recommended to change the interval between doses, maintaining the same dose used when renal function is normal: Interval between doses x (Cl/ Cl ir) = Interval between doses ir.
With this strategy, the possibility that plasma levels are subtherapeutic for critical time periods must be evaluated. In some cases, it is desirable to calculate a dose that determines a certain constant plasma level. This approach is more appropriate for constant intravenous infusions, where 100% of the dose is released into the systemic circulation. When the clearance of a drug in a patient with renal failure is calculated as above, then the ir dose (cant/ unit of time) = Cl ir (vol/ unit of time) x Cp (cant/ vol), where units of time, quantity and volume are compatible. If in a patient with a creatinine clearance of 25 ml/ min, the plasma concentration of carbenicillin of 100 microg/ ml is the therapeutic objective, the rate of intravenous infusion is calculated as follows. The clearance of carbenicillin is Cl ir = [68 x (25/ 100)] + 10 = 27 ml/ min. Therefore, carbenicillin should be injected at a rate of 2,700 microg/ min.
I should also present something about the approach of the fractional elimination constant (k). Clearance data in renal failure are not available for many medicines. In these cases, the fraction of the normal dose required in a patient with renal impairment may be approximated from the ratio between the fractional elimination constant in the body with renal failure (k ir) and the constant in the body with normal renal function (k). This approach assumes that the distribution of the drug (Vd) is not affected by kidney disease.
Such interpretation is equivalent to the one using the clearance data: Dose ir = dose x (k ir/ k). Since the K ir/ K ratio is the fraction of the usual dose used for a certain degree of renal failure, it is called the dose fraction. The elimination of many medicines is rapid enough in patients with normal renal function for the time needed to achieve a steady state of equilibrium, which usually means that a loading dose is not required. In renal failure, where half-life can be significantly prolonged, this accumulation period could become unacceptably long. In such cases, a loading dose may be indicated (the same loading dose of the medicine as in cases with normal renal function may be indicated).
Now, a little bit about general considerations for determining dosage in renal failure. Due to differences in distribution volumes and metabolism rates in patients, the calculation of the drug dose in renal failure should be regarded as a valid approximation, which prevents the use of excessively high doses, inadequate for most patients. However, maintenance doses are most accurately determined when plasma level data are used to adjust them. Active or toxic metabolites of medicinal products may also accumulate in renal failure.
For example, meperidine is purified largely by metabolism and its plasma concentration of one of its metabolites, normperidine, is increased when its renal elimination is low. Since normperidine has higher convulsive activity than meperidine, its accumulation in patients with renal impairment is probably responsible for signs of excitation of the central nervous system, such as irritability, jerky and seizures, which occur after several doses of meperidine in patients with renal impairment.
We'll continue next time with the effects of liver disease.
Love, Gratitude and
Understanding!
Dorin, Merticaru