STUDY - Technical - New Dacian's Medicine
Principles
of Drug Therapy (2)
Translation Draft
In my approach I reached the determinants of plasma levels during the equilibrium phase. An important determinant of the plasma level of the drug during the equilibrium phase after a single dose is the extension of the distribution of the drug outside the plasma compartment.
For example, if the distribution of a dose of 3 mg from a bulky macromolecule is limited to a plasma volume of 3 l, then the plasma concentration will di di of 1mg/l. However, if another medicine is distributed so that 90% of it leaves the plasma compartment, then only 0.3 mg will remain in the 3 l plasma volume and its concentration in plasma will be only 0.1 mg/ l. The apparent volume of Vd distribution expresses the relationship between the amount of the drug in the body and its plasma concentration at equilibrium, according to the formula: Vd = the amount of the drug in the body/ plasma concentration.
The amount of medicine in the body is expressed as mass (e.g. milligrams) and plasma concentration is expressed as mass per volume (e.g. milligrams per litre). thus, Vd is a hypothetical volume in which the amount of the drug would be distributed if its concentration in the whole volume were the same as it plasma. Although it is not a real volume, it is an important concept, because through it determines the plasma fraction of the total amount of the drug and thus the fraction available for the purification organs.
An approximation of Vd can be obtained in the equilibrium phase by estimating the plasma concentration of the drug at zero time (Cp0) by retrograde extrapolation of the equilibrium phase representation at zero time. Thus, after intravenous administration, when the dose is the amount in the body at zero time, we have: Vd = dose/ Cp0. For the administration of the above-mentioned voluminous macromolecule, Co0 measured by 1 mg/ l, after a dose of 3 mg, indicates a Vd which is a real volume, plasma volume.
This is an exception, however, because the Vd of most drugs is higher than the plasma volume (many drugs are taken so much by the cells that the tissue levels exceed those of plasma). For such drugs, the hypothetical volume Vd is high, even higher than the volume of water in the body. Since removal is generally carried out by the kidneys and liver, it is useful to look at the elimination of drugs in accordance with the principle of clearance (cleaning). For example, in the kidneys, regardless of the degree to which the treatment of the drug is determined by filtration, secretion or reabsorption, the net result is the reduction of the plasma concentration of the drug as it crosses the organ. The value of this reduction is expressed as the proportion of extraction or E, which is constant as long as an elimination process of order I. E = Ca - CV, where Ca = arterial plasma concentration and CV= venous plasma concentration takes place.
If the extraction is complete, E = 1. If the total renal plasma flow is Q (ml/ min), the total plasma volume from which the drug is completely purified in the unit of time (clearance, Cl) is determined by: Clrenal = QE. if the proportion of renal extraction of penicillin is 0.5 and renal plasma flow is 680 ml/ min, then the renal clearance of penicillin is 340 ml/ min. If the proportion of extraction is high, as is the case with renal extraction of aminohipurat or hepatic extraction of propanolol, then clearance is dependent on blood flow to the organ.
Systemic clearance (Cl) is the sum of the clearances of all disposal organs, being the best measure of the effectiveness of the elimination process. If the drug is purified by both the kidneys and the liver, then: Cl= Clrenal + Clhepatic. Thus, if in a normal person penicillin is eliminated by both renal failure (340 ml/ min) and hepatic clearance (36 ml/ min), the total clearance is 376 ml/ min. If renal clearance is halved, the total clearance is 170 + 36 or 206 ml/ min. In the anuria, total clearance is equal to hepatic clearance.
Only the drug in the vascular compartment can be removed during each passage through an organ. In order to determine the share of plasma clearance by one or more organs relative to the rate of treatment of the drug in the body, clearance should be related to the volume of "plasma equivalences" available to the purification process, which is the volume of distribution. if the volume of distribution is 10 l and the clearance is 1 l/ min, then one tenth of the medicine in the body is removed per minute. This fraction, Cl/ Vd is known as a treatment constant (fractional elimination constant) and is denoted with k, having the formula: k = Cl/ Vd. If the constant k is multiplied by the total amount of the drug in the body, the current rate of elimination can be determined at any time: the elimination rate = k x the amount in the body = Cl x Cp.
This is the general equation for all processes of order I and expresses the fact that in such a process the elimination rate is proportional to the decrease in quantity. Since half-life is a temporal expression of the exponential process of order I, half-life (t1/2) can be reported to k as follows: t1/2 = 0.693/k and because k = Cl/Vd then t1/2 = 0.693 Vd/Cl. The linear relationship between k or Cl and clearance makes k a useful parameter for estimating changes in the elimination of the drug with the reduction of clearance.
The half-life is not linearly dependent on clearance. The important relationship t1/2 = 0.693 Vd/ Cl clearly indicates the dependence of half-life (one measure of elimination rate) on two independent physiological variables, the volume of distribution and clearance, the latter expressing the efficiency of elimination. For example, the half-life is shortened when phenobarbital induces the release of enzymes responsible for hepatic clearance of the drug and is prolonged in renal failure, when renal clearance of the drug is diminished. Also, the half-life of certain drugs is shorter when their volume of distribution is reduced. In the treatment of patients after an overdose of the drug, the effects of hemodialysis on the elimination of the drug depend on its volume of distribution.
When the volume of distribution is high, as is the case for tricyclic antidepressants (Vd desipramine exceeds 1,500 l), the drug's purification proceeds slowly, even at a dialysis with a high-performance clearance. The extent to which a drug is linked to plasma proteins also influences the fraction extracted from the elimination organs. Binding defects significantly alter the excretion rate, but only when removal is limited to the unbound (free) drug in plasma.
The extent to which binding influences elimination depends on the relative affinities of the drug for plasma binding and for the extraction process. The high affinity of the tubular renal system of anionic transport for many drugs causes the extraction of the bound or unbound drug, and the effective process by which the liver purifies propanolol extracts most of this bound drug from the blood. In the case of drugs with low extraction ration by the organ, only unbound molecules are available for disposal.
In the steady state, at a continuous IV infusion of the drug, the rate of administration is equal to the rate of elimination.. Therefore, the administration rate (qty/unit time) = Cpss (cant/ vol) x Cl (vol/ unit of time) when units of measure for quantity, volume and time are compatible. Thus, if clearance (Cl) is known, it is possible to calculate the rate of administration required to achieve a certain constant plasma level.
When the dose is administered intermittently instead of an infusion, the above relationship between the plasma concentration and the administered dose, for each interval between doses, can be expressed as follows: Dose = Cpm x Cl x interval between doses. Because the average plasma concentration is rendered as an average value (Cpm), plasma levels may be higher or lower at different times in the interval between doses. When a drug is administered orally, the F fraction of the administered dose that reaches the systemic circulation is the expression of the bioavailability of the drug.
The reduction of bioavailability may be due to the inadequate pharmaceutical form, which does not allow the disintegration or dissolution of the drug in gastrointestinal juices. Standard regulations have reduced the importance of this problem. Drug interactions may also decrease absorption after oral administration. Bioavailability may also be reduced due to the metabolism of the drug in the gastrointestinal tract and/ or liver during the absorption process, a process called a first-passage effect.
This is a peculiarity of drugs that are extracted from plasma extensively by organs, so there is often considerable individual variability in bioavailability. Lidocaine, used as an antiarrhythmic, is not given orally because of the first-passage effect. Medications that are injected intramuscularly may also have reduced bioavailability, an example being phenytoin. An unforeseen drug response should lead to the consideration of bioavailability as a possible factor. Calculation of the dosage regimen may require correction for bioavailability as follows: Oral dose = (Cpm x Cl x interval between doses)/ F.
We have come to the presentation of elements related to the location of the drug action. Direct intra-arterial administration of selected medicinal products can be considered as a measure to achieve a targeted pharmacological effect on a specific organ. In order for such a strategy to be effective, the medicinal product must exercise an action in the target organ, which is broader than in the case of oral or intravenous administration, without accentuating systemic adverse effects (i.e. a higher therapeutic index).
In order to obtain a higher therapeutic index in the case of intraarterial administration, the drug must be marked extracted by the organ during the first passage of its circulation. Furthermore, the local pharmacological effect should be supported by the duration required to achieve the therapeutic effect. Intracoronary administration of nitroglycerin meets these criteria. Nitroglycerin is marked extracted during the first passage through an organ (it is a prodrug and its metabolism to nitric oxide in the arterial wall locates its vasodilating action at the level of this metabolic activation).
Experimentally, liposomes are investigated as a targeted transportation of drugs, as they are marked extracted during the first passage through an organ. Objective data on the fact that a medicinal product meets the criteria for achieving a higher therapeutic index by intra-arterial administration must be strong enough to justify the risk of the necessary invasive procedure.
I will complete this post with the elimination of drugs by a process other than that of Order I. Elimination of drugs such as phenytoin, salicylates, propaphenone and theophylline does not follow a kinetic scan of order I when the amount of the drug in the body is within the therapeutic range. For these medicines, clearance decreases with the decrease in the amount of the drug in the body by elimination or after dose modification. This treatment model is called dose dependent. Appropriately, the time it takes to halve the concentration becomes shorter with the reduction of plasma levels (this half-reduction time is not a true half-life, as the half-life applies to the first-order kinetics and is a constant).
When a drug is eliminated by a mechanism of order I, the plasma level at steady state depends directly on the maintenance dose, and doubling the dose will cause the plasma equilibrium level to double. For dose-dependent kinetic drugs, increasing the dose may cause a disproportionate increase in plasma levels. The degree of increase is not foreseeable, primarily due to individual variability, in so far as elimination is no longer of order I. Changes in the dosage regimen for dose-dependent kinetic drugs, such as phenytoin, salicylates and ethanol, should always be accompanied by careful monitoring of adverse effects and measurement of the plasma concentration of the medicinal product after sufficient time to establish the new state of equilibrium. Mechanisms involved in dose-dependent kinetics may include saturation of a limiting step of metabolism or a feedback inhibition of the limiting enzyme by a reaction product.
That's it for today... Next time!
In my approach I reached the determinants of plasma levels during the equilibrium phase. An important determinant of the plasma level of the drug during the equilibrium phase after a single dose is the extension of the distribution of the drug outside the plasma compartment.
For example, if the distribution of a dose of 3 mg from a bulky macromolecule is limited to a plasma volume of 3 l, then the plasma concentration will di di of 1mg/l. However, if another medicine is distributed so that 90% of it leaves the plasma compartment, then only 0.3 mg will remain in the 3 l plasma volume and its concentration in plasma will be only 0.1 mg/ l. The apparent volume of Vd distribution expresses the relationship between the amount of the drug in the body and its plasma concentration at equilibrium, according to the formula: Vd = the amount of the drug in the body/ plasma concentration.
The amount of medicine in the body is expressed as mass (e.g. milligrams) and plasma concentration is expressed as mass per volume (e.g. milligrams per litre). thus, Vd is a hypothetical volume in which the amount of the drug would be distributed if its concentration in the whole volume were the same as it plasma. Although it is not a real volume, it is an important concept, because through it determines the plasma fraction of the total amount of the drug and thus the fraction available for the purification organs.
An approximation of Vd can be obtained in the equilibrium phase by estimating the plasma concentration of the drug at zero time (Cp0) by retrograde extrapolation of the equilibrium phase representation at zero time. Thus, after intravenous administration, when the dose is the amount in the body at zero time, we have: Vd = dose/ Cp0. For the administration of the above-mentioned voluminous macromolecule, Co0 measured by 1 mg/ l, after a dose of 3 mg, indicates a Vd which is a real volume, plasma volume.
This is an exception, however, because the Vd of most drugs is higher than the plasma volume (many drugs are taken so much by the cells that the tissue levels exceed those of plasma). For such drugs, the hypothetical volume Vd is high, even higher than the volume of water in the body. Since removal is generally carried out by the kidneys and liver, it is useful to look at the elimination of drugs in accordance with the principle of clearance (cleaning). For example, in the kidneys, regardless of the degree to which the treatment of the drug is determined by filtration, secretion or reabsorption, the net result is the reduction of the plasma concentration of the drug as it crosses the organ. The value of this reduction is expressed as the proportion of extraction or E, which is constant as long as an elimination process of order I. E = Ca - CV, where Ca = arterial plasma concentration and CV= venous plasma concentration takes place.
If the extraction is complete, E = 1. If the total renal plasma flow is Q (ml/ min), the total plasma volume from which the drug is completely purified in the unit of time (clearance, Cl) is determined by: Clrenal = QE. if the proportion of renal extraction of penicillin is 0.5 and renal plasma flow is 680 ml/ min, then the renal clearance of penicillin is 340 ml/ min. If the proportion of extraction is high, as is the case with renal extraction of aminohipurat or hepatic extraction of propanolol, then clearance is dependent on blood flow to the organ.
Systemic clearance (Cl) is the sum of the clearances of all disposal organs, being the best measure of the effectiveness of the elimination process. If the drug is purified by both the kidneys and the liver, then: Cl= Clrenal + Clhepatic. Thus, if in a normal person penicillin is eliminated by both renal failure (340 ml/ min) and hepatic clearance (36 ml/ min), the total clearance is 376 ml/ min. If renal clearance is halved, the total clearance is 170 + 36 or 206 ml/ min. In the anuria, total clearance is equal to hepatic clearance.
Only the drug in the vascular compartment can be removed during each passage through an organ. In order to determine the share of plasma clearance by one or more organs relative to the rate of treatment of the drug in the body, clearance should be related to the volume of "plasma equivalences" available to the purification process, which is the volume of distribution. if the volume of distribution is 10 l and the clearance is 1 l/ min, then one tenth of the medicine in the body is removed per minute. This fraction, Cl/ Vd is known as a treatment constant (fractional elimination constant) and is denoted with k, having the formula: k = Cl/ Vd. If the constant k is multiplied by the total amount of the drug in the body, the current rate of elimination can be determined at any time: the elimination rate = k x the amount in the body = Cl x Cp.
This is the general equation for all processes of order I and expresses the fact that in such a process the elimination rate is proportional to the decrease in quantity. Since half-life is a temporal expression of the exponential process of order I, half-life (t1/2) can be reported to k as follows: t1/2 = 0.693/k and because k = Cl/Vd then t1/2 = 0.693 Vd/Cl. The linear relationship between k or Cl and clearance makes k a useful parameter for estimating changes in the elimination of the drug with the reduction of clearance.
The half-life is not linearly dependent on clearance. The important relationship t1/2 = 0.693 Vd/ Cl clearly indicates the dependence of half-life (one measure of elimination rate) on two independent physiological variables, the volume of distribution and clearance, the latter expressing the efficiency of elimination. For example, the half-life is shortened when phenobarbital induces the release of enzymes responsible for hepatic clearance of the drug and is prolonged in renal failure, when renal clearance of the drug is diminished. Also, the half-life of certain drugs is shorter when their volume of distribution is reduced. In the treatment of patients after an overdose of the drug, the effects of hemodialysis on the elimination of the drug depend on its volume of distribution.
When the volume of distribution is high, as is the case for tricyclic antidepressants (Vd desipramine exceeds 1,500 l), the drug's purification proceeds slowly, even at a dialysis with a high-performance clearance. The extent to which a drug is linked to plasma proteins also influences the fraction extracted from the elimination organs. Binding defects significantly alter the excretion rate, but only when removal is limited to the unbound (free) drug in plasma.
The extent to which binding influences elimination depends on the relative affinities of the drug for plasma binding and for the extraction process. The high affinity of the tubular renal system of anionic transport for many drugs causes the extraction of the bound or unbound drug, and the effective process by which the liver purifies propanolol extracts most of this bound drug from the blood. In the case of drugs with low extraction ration by the organ, only unbound molecules are available for disposal.
In the steady state, at a continuous IV infusion of the drug, the rate of administration is equal to the rate of elimination.. Therefore, the administration rate (qty/unit time) = Cpss (cant/ vol) x Cl (vol/ unit of time) when units of measure for quantity, volume and time are compatible. Thus, if clearance (Cl) is known, it is possible to calculate the rate of administration required to achieve a certain constant plasma level.
When the dose is administered intermittently instead of an infusion, the above relationship between the plasma concentration and the administered dose, for each interval between doses, can be expressed as follows: Dose = Cpm x Cl x interval between doses. Because the average plasma concentration is rendered as an average value (Cpm), plasma levels may be higher or lower at different times in the interval between doses. When a drug is administered orally, the F fraction of the administered dose that reaches the systemic circulation is the expression of the bioavailability of the drug.
The reduction of bioavailability may be due to the inadequate pharmaceutical form, which does not allow the disintegration or dissolution of the drug in gastrointestinal juices. Standard regulations have reduced the importance of this problem. Drug interactions may also decrease absorption after oral administration. Bioavailability may also be reduced due to the metabolism of the drug in the gastrointestinal tract and/ or liver during the absorption process, a process called a first-passage effect.
This is a peculiarity of drugs that are extracted from plasma extensively by organs, so there is often considerable individual variability in bioavailability. Lidocaine, used as an antiarrhythmic, is not given orally because of the first-passage effect. Medications that are injected intramuscularly may also have reduced bioavailability, an example being phenytoin. An unforeseen drug response should lead to the consideration of bioavailability as a possible factor. Calculation of the dosage regimen may require correction for bioavailability as follows: Oral dose = (Cpm x Cl x interval between doses)/ F.
We have come to the presentation of elements related to the location of the drug action. Direct intra-arterial administration of selected medicinal products can be considered as a measure to achieve a targeted pharmacological effect on a specific organ. In order for such a strategy to be effective, the medicinal product must exercise an action in the target organ, which is broader than in the case of oral or intravenous administration, without accentuating systemic adverse effects (i.e. a higher therapeutic index).
In order to obtain a higher therapeutic index in the case of intraarterial administration, the drug must be marked extracted by the organ during the first passage of its circulation. Furthermore, the local pharmacological effect should be supported by the duration required to achieve the therapeutic effect. Intracoronary administration of nitroglycerin meets these criteria. Nitroglycerin is marked extracted during the first passage through an organ (it is a prodrug and its metabolism to nitric oxide in the arterial wall locates its vasodilating action at the level of this metabolic activation).
Experimentally, liposomes are investigated as a targeted transportation of drugs, as they are marked extracted during the first passage through an organ. Objective data on the fact that a medicinal product meets the criteria for achieving a higher therapeutic index by intra-arterial administration must be strong enough to justify the risk of the necessary invasive procedure.
I will complete this post with the elimination of drugs by a process other than that of Order I. Elimination of drugs such as phenytoin, salicylates, propaphenone and theophylline does not follow a kinetic scan of order I when the amount of the drug in the body is within the therapeutic range. For these medicines, clearance decreases with the decrease in the amount of the drug in the body by elimination or after dose modification. This treatment model is called dose dependent. Appropriately, the time it takes to halve the concentration becomes shorter with the reduction of plasma levels (this half-reduction time is not a true half-life, as the half-life applies to the first-order kinetics and is a constant).
When a drug is eliminated by a mechanism of order I, the plasma level at steady state depends directly on the maintenance dose, and doubling the dose will cause the plasma equilibrium level to double. For dose-dependent kinetic drugs, increasing the dose may cause a disproportionate increase in plasma levels. The degree of increase is not foreseeable, primarily due to individual variability, in so far as elimination is no longer of order I. Changes in the dosage regimen for dose-dependent kinetic drugs, such as phenytoin, salicylates and ethanol, should always be accompanied by careful monitoring of adverse effects and measurement of the plasma concentration of the medicinal product after sufficient time to establish the new state of equilibrium. Mechanisms involved in dose-dependent kinetics may include saturation of a limiting step of metabolism or a feedback inhibition of the limiting enzyme by a reaction product.
That's it for today... Next time!
Happy New Year, Romania!!!
Happy birthday to all Romanians!!! Plus, Understanding, Love and
Gratitude!!!
Dorin, Merticaru