STUDY - Technical - New Dacian's Medicine
Principles
of Drug Therapy (1)
Translation Draft
A series of typical pharmacological posts follow in which I will focus, first, on the elements of pharmaco-kinetics and, subsequently, on certain elements characteristic of allopathic medicine (the new medicine has little "job" however but cannot be removed from the whole). And since they all have their purpose, I have to point out to you that this series of posts (under the name of the principles of drug therapy) can only be pursued by "medical craftsmen". Thanks for understanding!
I'll start with a few elements about the quantitative determinants of drug action. Safe and effective drug therapy requires that it be distributed to the target tissues in such a concentration that it falls within the range of non-toxicity efficacy. The concentration of the drug within this "therapeutic window" can be obtained with regimens that are based on the kinetics of its availability at the target sites. I will address here the principles of the elimination and distribution of medicines, which form the basis of loading and maintenance regimes for an ordinary individual, taking into account also situations where the excretion of the drug is reduced (e.g. in renal failure). The principles for optimal use of data obtained by studying the plasma level of the drug will also be discussed.
Obviously, it is good to start with plasma levels after a single dose. The plasma level of lidocaine after intravenous administration decreases in two stages (this biphasic decline being typical for many drugs): 1. distribution phase and 2. balance or elimination phase. Immediately after rapid injection, virtually all the drug is in the plasma compartment, with the high initial plasma concentration (CPO) reflecting its limitation in this sector.
Subsequently, the drug is transferred to the extravascular compartment, during a period called the distribution phase. For lidoicain, the distribution phase is virtually complete in 30 minutes. Then comes the slower rate of decline phase, called the balance or elimination phase. During the latter, plasma levels of the drug change in parallel with tissue levels. Although this mood profile is common to many intravenously administered drugs, the characteristic parameters vary depending on the drug.
To approach the distribution phase. Pharmacological processes during the distribution phase depend on the existence of a concentration of the drug in receptors similar to plasma. In this case, pharmacological effects (either favorable or adverse) may be intense at this stage, due to initially high plasma levels. For example, after a low dose in the bolus (50 mg) of lidocaine, the antiarrhythmic effects may be evident during the initial distribution phase, but disappear when the plasma level drops below the minimum effective one, even before the balance between plasma and tissues is reached.
Thus, in order to maintain the drug balance during the equilibrium phase, either a single high dose or small multiple doses should be administered. Toxicity resulting from high concentrations of some medicinal products during the distribution phase excludes intravenous administration of a single dose of loading, which would reach therapeutic levels during the equilibrium phase. For example, administering a total dose of phenytoin loading into the intravenous bolus may cause cardiovascular collapse due to high levels during the distribution phase. If a high dose of phenytoin loading is administered intravenously, it should be divided at sufficient intervals to allow for a substantial distribution between doses (e.g. 100 mg every 3-5 minutes).
For similar reasons, the loading (attack) dose of many high potency drugs, which quickly balance with their receptors, is either divided into fractional doses given at intervals or given as an infusion over a similar period of time. After an oral dose providing an equivalent amount of the drug in the systemic circulation, plasma levels during the initial period after administration are not as high as after a dose in the intravenous bolus. Because after oral administration the drug is not absorbed instantly and is released into the systemic circulation more slowly, much of the drug is already distributed when absorption is complete.
Thus, procainamide, which is almost totally absorbed after oral administration, can be administered orally in a single loading dose of 750 mg, with a low risk of hypotension (in contrast, injecting the drug into an intravenous loading dose is much less risky by splitting the dose into 100 mg at 5-minute intervals or by introduction into a slow infusion , to avoid hypotension during the distribution phase). Some drugs are distributed slowly at their places of action during the distribution phase.
For example, the concentration of digoxin in the receptors (and its pharmacological effect) does not reflect its plasma level during the distribution phase. Digoxin is transported (or fixed) slowly by its cardiac receptors through a process that works throughout the distribution phase. Thus, plasma levels decrease during the distribution phase within a few hours, while the concentration at the site of action and the pharmacological effect increase. Only at the end of the distribution phase, when the drug has reached balance with the receptor, the plasma concentration of digoxin reflects the pharmacological effect. For this reason, to control therapy, there must be 6-8 hours of rest after administration before plasma levels of digoxin are measured.
Let's get to the equilibrium phase. After distribution it has gone to the point where the concentration of the drug in plasma is in dynamic equilibrium with that in the tissues, the plasma and tissue levels decrease in parallel as the drug is removed from the body. Therefore, the equilibrium phase is also called the elimination phase. Measuring the plasma concentrations of the drug provides the best reflection of its level in tissues during this phase. Most drugs are eliminated by a kinetic process of order I. During the equilibrium phase, a characteristic of the order I process is that the time required to decrease to half the initial plasma level of the drug (half-life, t1/2) is the same, regardless of the point chosen on the plasma level curve as the starting point for measurement. Another feature of the order I process is that the semilogarithmic representation of plasma concentration according to time during the equilibrium phase is linear.
From such a chart it can be observed that the half-life of lidocaine is 108 minutes. If t1/2 is known, it can be calculated how much of the administered dose remains in the body at any time after taking the drug. Clinically, elimination is virtually complete when it reaches 90%. Therefore, for practical purposes, a process of elimination of order I is completed after 3-4 half-lifes.
If we know what the phases are, it's time to find out what it is with the accumulation of the drug referring to loading (attack) and maintenance doses. With repeated administration of a medicinal product at shorter intervals than the time required to eliminate the dose, both the amount of the medicine in the body and the pharmacological effect increase with the continuation of administration until a plateau is reached. I will give as an example, the accumulation of digoxin administered in repeated maintenance doses (without a loading dose). Since the half-life of digoxin is approximately 1.6 days in a patient with normal renal function, 65% of digoxin remains in the body at the end of the first day.
The second dose will increase the amount of digoxin in the body (and the average plasma concentration) to 165%. Each subsequent dose will produce an increase, until a steady state is achieved. At this point, the absorption of the drug per unit of time is done at the same rate as the rate of elimination, keeping the fluctuation of peak and baseline plasma levels constant. If the dose is changed later, a new state of equilibrium will be achieved. Continuous injection of a drug at a constant rate will also lead to progressive accumulation, up to a state of predictable equilibrium.
In this case, the constant plasma level (Cpss) is between the maximum and the minimum of the value reached when the same dose of the drug is intermittently administered over the same period of time. For all first-order kinetic drugs, the time required to achieve the stable state can be calculated from the half-life, since accumulation is also a process of order I, with a half-life identical to that of elimination. Thus, the accumulation reaches 90% of the level of equilibrium at the end of 3-4 tmpi of half-life. This also applies to intermittent and continuous administration. The time required to achieve the equilibrium state can be shortened by taking a loading dose (a quantity of medicine that quickly achieves constant plasma concentration at the desired level).
The loading dose (attack) can be estimated if both the desired plasma level (Cpss) and the proportion of the extravascular distribution of the drug at equilibrium (apparent volume of distribution or Vd) are known, which can be determined according to the formula: the loading dose = the desired plasma level x the volume of distribution in the stable state = Cpss x Vd. Loading can be achieved by administering the total load quantity as a single dose (if there is a high toxic risk , the load quantity is administered fractionally). The division of the attack dose into fractions is recommended for many drugs that have a low therapeutic index (the therapeutic index is the ratio between the toxic dose and the therapeutic dose). this allows for a better individualisation of the load quantity administered and minimizes adverse effects.
The attack dose required to achieve the desired constant plasma level can be calculated according to the fraction of the drug removed in the interval between the doses and the maintenance dose (in the case of intermittent administration of the drug). For example, if the daily digoxin fraction is 35% and the planned maintenance dose is 0.25 mg/ day, then the load dose required to reach the plasma equilibrium level will be: 100/35 x the maintenance dose, so approximately 0.75 mg. Thus: loading dose = [100/ (% of the drug removed in the interval between doses)] x maintenance dose. The fraction of the drug removed during any interval between doses can be determined using a semilogarithmic graph, in which the total amount of the drug in the body at 0 (zero) is 100% and the remaining fraction at the end of a half-life is 50%.
To calculate the loading dose intended to reach the steady plasma concentration, for a certain infusion rate, the loading dose = administration rate/ k, where k notes the fractional elimination constant describing the rate of elimination of the drug. Regardless of the size of the loading dose, after a maintenance therapy that was administered for 3-4 half-lifes, the amount of the drug in the body is determined by the maintenance dose. Non-dependence of plasma balance levels on the loading dose shows us that the elimination of the loading dose is virtually complete after 3-4 half-lifes.
We'll keep going!
A series of typical pharmacological posts follow in which I will focus, first, on the elements of pharmaco-kinetics and, subsequently, on certain elements characteristic of allopathic medicine (the new medicine has little "job" however but cannot be removed from the whole). And since they all have their purpose, I have to point out to you that this series of posts (under the name of the principles of drug therapy) can only be pursued by "medical craftsmen". Thanks for understanding!
I'll start with a few elements about the quantitative determinants of drug action. Safe and effective drug therapy requires that it be distributed to the target tissues in such a concentration that it falls within the range of non-toxicity efficacy. The concentration of the drug within this "therapeutic window" can be obtained with regimens that are based on the kinetics of its availability at the target sites. I will address here the principles of the elimination and distribution of medicines, which form the basis of loading and maintenance regimes for an ordinary individual, taking into account also situations where the excretion of the drug is reduced (e.g. in renal failure). The principles for optimal use of data obtained by studying the plasma level of the drug will also be discussed.
Obviously, it is good to start with plasma levels after a single dose. The plasma level of lidocaine after intravenous administration decreases in two stages (this biphasic decline being typical for many drugs): 1. distribution phase and 2. balance or elimination phase. Immediately after rapid injection, virtually all the drug is in the plasma compartment, with the high initial plasma concentration (CPO) reflecting its limitation in this sector.
Subsequently, the drug is transferred to the extravascular compartment, during a period called the distribution phase. For lidoicain, the distribution phase is virtually complete in 30 minutes. Then comes the slower rate of decline phase, called the balance or elimination phase. During the latter, plasma levels of the drug change in parallel with tissue levels. Although this mood profile is common to many intravenously administered drugs, the characteristic parameters vary depending on the drug.
To approach the distribution phase. Pharmacological processes during the distribution phase depend on the existence of a concentration of the drug in receptors similar to plasma. In this case, pharmacological effects (either favorable or adverse) may be intense at this stage, due to initially high plasma levels. For example, after a low dose in the bolus (50 mg) of lidocaine, the antiarrhythmic effects may be evident during the initial distribution phase, but disappear when the plasma level drops below the minimum effective one, even before the balance between plasma and tissues is reached.
Thus, in order to maintain the drug balance during the equilibrium phase, either a single high dose or small multiple doses should be administered. Toxicity resulting from high concentrations of some medicinal products during the distribution phase excludes intravenous administration of a single dose of loading, which would reach therapeutic levels during the equilibrium phase. For example, administering a total dose of phenytoin loading into the intravenous bolus may cause cardiovascular collapse due to high levels during the distribution phase. If a high dose of phenytoin loading is administered intravenously, it should be divided at sufficient intervals to allow for a substantial distribution between doses (e.g. 100 mg every 3-5 minutes).
For similar reasons, the loading (attack) dose of many high potency drugs, which quickly balance with their receptors, is either divided into fractional doses given at intervals or given as an infusion over a similar period of time. After an oral dose providing an equivalent amount of the drug in the systemic circulation, plasma levels during the initial period after administration are not as high as after a dose in the intravenous bolus. Because after oral administration the drug is not absorbed instantly and is released into the systemic circulation more slowly, much of the drug is already distributed when absorption is complete.
Thus, procainamide, which is almost totally absorbed after oral administration, can be administered orally in a single loading dose of 750 mg, with a low risk of hypotension (in contrast, injecting the drug into an intravenous loading dose is much less risky by splitting the dose into 100 mg at 5-minute intervals or by introduction into a slow infusion , to avoid hypotension during the distribution phase). Some drugs are distributed slowly at their places of action during the distribution phase.
For example, the concentration of digoxin in the receptors (and its pharmacological effect) does not reflect its plasma level during the distribution phase. Digoxin is transported (or fixed) slowly by its cardiac receptors through a process that works throughout the distribution phase. Thus, plasma levels decrease during the distribution phase within a few hours, while the concentration at the site of action and the pharmacological effect increase. Only at the end of the distribution phase, when the drug has reached balance with the receptor, the plasma concentration of digoxin reflects the pharmacological effect. For this reason, to control therapy, there must be 6-8 hours of rest after administration before plasma levels of digoxin are measured.
Let's get to the equilibrium phase. After distribution it has gone to the point where the concentration of the drug in plasma is in dynamic equilibrium with that in the tissues, the plasma and tissue levels decrease in parallel as the drug is removed from the body. Therefore, the equilibrium phase is also called the elimination phase. Measuring the plasma concentrations of the drug provides the best reflection of its level in tissues during this phase. Most drugs are eliminated by a kinetic process of order I. During the equilibrium phase, a characteristic of the order I process is that the time required to decrease to half the initial plasma level of the drug (half-life, t1/2) is the same, regardless of the point chosen on the plasma level curve as the starting point for measurement. Another feature of the order I process is that the semilogarithmic representation of plasma concentration according to time during the equilibrium phase is linear.
From such a chart it can be observed that the half-life of lidocaine is 108 minutes. If t1/2 is known, it can be calculated how much of the administered dose remains in the body at any time after taking the drug. Clinically, elimination is virtually complete when it reaches 90%. Therefore, for practical purposes, a process of elimination of order I is completed after 3-4 half-lifes.
If we know what the phases are, it's time to find out what it is with the accumulation of the drug referring to loading (attack) and maintenance doses. With repeated administration of a medicinal product at shorter intervals than the time required to eliminate the dose, both the amount of the medicine in the body and the pharmacological effect increase with the continuation of administration until a plateau is reached. I will give as an example, the accumulation of digoxin administered in repeated maintenance doses (without a loading dose). Since the half-life of digoxin is approximately 1.6 days in a patient with normal renal function, 65% of digoxin remains in the body at the end of the first day.
The second dose will increase the amount of digoxin in the body (and the average plasma concentration) to 165%. Each subsequent dose will produce an increase, until a steady state is achieved. At this point, the absorption of the drug per unit of time is done at the same rate as the rate of elimination, keeping the fluctuation of peak and baseline plasma levels constant. If the dose is changed later, a new state of equilibrium will be achieved. Continuous injection of a drug at a constant rate will also lead to progressive accumulation, up to a state of predictable equilibrium.
In this case, the constant plasma level (Cpss) is between the maximum and the minimum of the value reached when the same dose of the drug is intermittently administered over the same period of time. For all first-order kinetic drugs, the time required to achieve the stable state can be calculated from the half-life, since accumulation is also a process of order I, with a half-life identical to that of elimination. Thus, the accumulation reaches 90% of the level of equilibrium at the end of 3-4 tmpi of half-life. This also applies to intermittent and continuous administration. The time required to achieve the equilibrium state can be shortened by taking a loading dose (a quantity of medicine that quickly achieves constant plasma concentration at the desired level).
The loading dose (attack) can be estimated if both the desired plasma level (Cpss) and the proportion of the extravascular distribution of the drug at equilibrium (apparent volume of distribution or Vd) are known, which can be determined according to the formula: the loading dose = the desired plasma level x the volume of distribution in the stable state = Cpss x Vd. Loading can be achieved by administering the total load quantity as a single dose (if there is a high toxic risk , the load quantity is administered fractionally). The division of the attack dose into fractions is recommended for many drugs that have a low therapeutic index (the therapeutic index is the ratio between the toxic dose and the therapeutic dose). this allows for a better individualisation of the load quantity administered and minimizes adverse effects.
The attack dose required to achieve the desired constant plasma level can be calculated according to the fraction of the drug removed in the interval between the doses and the maintenance dose (in the case of intermittent administration of the drug). For example, if the daily digoxin fraction is 35% and the planned maintenance dose is 0.25 mg/ day, then the load dose required to reach the plasma equilibrium level will be: 100/35 x the maintenance dose, so approximately 0.75 mg. Thus: loading dose = [100/ (% of the drug removed in the interval between doses)] x maintenance dose. The fraction of the drug removed during any interval between doses can be determined using a semilogarithmic graph, in which the total amount of the drug in the body at 0 (zero) is 100% and the remaining fraction at the end of a half-life is 50%.
To calculate the loading dose intended to reach the steady plasma concentration, for a certain infusion rate, the loading dose = administration rate/ k, where k notes the fractional elimination constant describing the rate of elimination of the drug. Regardless of the size of the loading dose, after a maintenance therapy that was administered for 3-4 half-lifes, the amount of the drug in the body is determined by the maintenance dose. Non-dependence of plasma balance levels on the loading dose shows us that the elimination of the loading dose is virtually complete after 3-4 half-lifes.
We'll keep going!
Until then, Love,
Gratitude and Understanding!!!
Dorin, Merticaru