STUDY - Technical - New Dacian's Medicine
Principles
of Drug Therapy (4)
Translation Draft
Let's "discuss" today the effects of liver disease (and others). Unlike the foreseeable decrease in renal clearance of medicinal products in the case of reduced glomerular filtration, there is no general anticipation regarding the effect of liver disease on the biotransformation of medicinal products in the liver. Changes in hepatitis and cirrhosis can range from low to increased drug clearance. Even in advanced hepatocellular diseases, the drug's clearance decreases only about two to five times. However, the amplitude of such changes cannot be foreseen by the usual liver function tests. Therefore, even when we suspect that the elimination of the drug is affected by liver disease, there is no quantitative basis (other than the evaluation of the clinical response and the plasma concentration of the drug) by which to adjust the dosing regimen.
The "turn" of the effects of circulatory insufficiency (heart failure and shock) has come. Under the conditions of a low tissue infusion, the redistribution of cardiac output occurs, to maintain the blood flow of the heart and the brain at the expense of other tissues. As a result, the drug is distributed in a lower volume of distribution, the concentration of the drug in plasma is increased, and the tissues that are best infused are exposed to these high concentrations. If the heart or brain are sensitive to the drug, an alteration of the response may occur. Furthermore, a low infusion of the kidneys or liver may decrease the clearance of the drug in these organs, directly or indirectly.
Thus, in severe congestive heart failure, hemorrhagic shock and cardiogenic shock, the response to the usual dose of the drug may be excessive and it may therefore be necessary to change the dose. For example, lidocaine clearance is reduced by 50% in heart failure and therapeutic plasma levels are achieved at a IV rate of administration. only about half of the dose normally required. It also significantly reduces the volume of distribution of lidocaine, hence the need for a lower loading dose. It is believed that there are similar situations for procainamide, theophylline and possibly quinidine. Unfortunately there are no predictive factors for these types of pharmacokinetic impairment. Therefore, the loading dose should be conservative and continued therapy should be closely monitored, following clinical toxicity indicators and plasma levels.
Another "milestone of influence" is the conditions that induce changes in plasma protein binding. Many drugs circulate in plasma partly related to plasma proteins. Since only the unbound or free medicinal product can be distributed at the pharmacological place of action, the therapeutic response should be associated in particular with the concentration of the free plasma medicinal product, rather than with the total plasma concentration of the circulating medicinal product. In most cases, the degree of binding is approximately constant over the therapeutic concentration range, so the total plasma levels of the drug can be the basis of the dose adjustment, without resulting in significant errors.
However, conditions such as hypoalbuminemia, liver disease and kidney disease may decrease the proportion of binding acidic and neutral medicines, so that, at any total plasma level, there is a higher concentration of free medicine and thus an increased response and a higher toxic risk. Certain clinical situations, e.g. myocardial infarction, surgery, neoplastic diseases, rheumatoid arthritis and burns, leading to an increased plasma concentration of acute phase reaction, alpha1-acid-glycoprotein, increase the binding of basic drugs (which are related to these macromolecules) with inverse consequences.
The drugs for which changes in protein binding are important are those that are normally linked to a large proportion in plasma (more than 90%), because a small change in the degree of binding produces a large change in the amount of free molecules. The consequences of these changes in binding, in particular with respect to the total levels of the drug, are different, as clearance is of interest to the unbound form or both forms. For many medicines, elimination and distribution are largely limited by the unbound fraction, therefore, the decrease in binding leads to increased clearance and distribution of the drug.
The relative size of these changes may be equivalent, as a net effect, to shortening the half-life. In the case of drugs related to alpha1-glycoprotein acid, pathological increases in binding have opposite effects, decreasing the clearance and distribution of the drug. For example, the constant infusion with lidocaine, as an antiarrhythmic, after myocardial infarction, will increase the process of accumulation of the total drug.
There is also a "discussion" here about the variable actions of drugs caused by genetic differences in their metabolism, with the specificities of manifestation embodied in the acetilar as well as in the metabolism by oxidation with mixed function. For example, there are large individual differences in the rate of acetilation of medicinal products (isoniazide, hydralamide, procainamide and a number of other medicinal products being metabolized by the acetilation of the amino or hydrazine group), i.e. a bimodal distribution of the population in "fast acetilators" and "slow acetilates". The rate of acetilation is genetically controlled (slow acetilation being a recessive autosomal trait).
The acetylsalicylic phenotype can be determined by measuring the ratio between dapsone or sulfamethazine aethylated and non-acetilated in plasma or urine after taking a test dose of these acetylsalicylic substrates. In the case of metabolism by mixed-function oxidases, in healthy individuals who do not take other medicines, the major determinant of the rate of metabolism of medicinal products by these mixed-function oxidases in the liver is the genetic one. Many medicines are subject to oxidative metabolism by more than one isoenzyme (from the hepatic endoplasmic reticulum), the plasma concentration of such drugs in the equilibrium state being dependent on the sum of the activities of these isoenzymes and other metabolism enzymes.
When a drug is metabolized in several ways, the catalytic activities of the participating enzymes are regulated by a number of genes, so that the clearance rates and equilibrium concentrations of the drug tend to be distributed unimodally within the population. The degree of activity can differ greatly (ten times or more) between different people, as in the case of chlorpromazine, and there is no way of anticipating it before the start of therapy. For certain metabolic pathways, bimodally distributed activity suggests control by a single gene and several polymorphisms have been identified. as a result, two phenotypic populations are usually present, as in the case of N-aethylation.
The majority of the population is represented by powerful metabolizers (MP phenotype), and a smaller group of people with weak metabolizers (MS phenotype) have a low or absent ability to metabolize the drug. For example, the isoenzyme CYP2D6 is polymorphic lyssed in the population and about 8-10% of the white population has deficiency of this enzyme, this isoenzyme being the main metabolic pathway for some medicines including anti-arrhythmic agents (propafenone, phlecainide), beta-adrenergic blockers (alprenolol, metoprolol, timolol), tricyclic antidepressants (nortriptyline, desipramine, imipramine, clomipramine), neuroleptic drugs (perphenazine, thioridazine and possibly haloperidol), in selective inhibitions of serotonin reuptake (fluoxetine and paroxetine) and certain opiates such as codeine and dextromethorphan.
Thus, the analgesic effect of codeine is much weaker in patients with weak metabolizers, due to a low production of the active metabolite, morphine. Similarly, patients with poor metabolism phenotype experience the effects of blocking beta-adrenergic receptors more strongly after administration of an ophthalmic solution of timolol. The catalytic activity of CYP2D6 can be estimated in humans using a test drug, debrisoquine, which is almost completely purged on the hydroxylation pathway by this isoenzyme. A similar situation occurs in oxidative polymorphism involving mefenitoin metabolism, involving a different isoenzyme, CYP2C19. This enzyme is also involved in the metabolism of omeprazole, proguanil, diazepam and cytoprom. The situation is further complicated due to interracial differences in the frequency of polymorphism.
For example, low mephenitoin hydroxylation is present in 3-5% of whites, but the incidence is approximately 20% in people of Japanese or Chinese descent (similarly, the frequency of the weak metabolizer phenotype for debrisoquine hydroxylation appears to decrease in Western population groups, 8-10%, in eastern ones being only 0-1%). Polymorphism in metabolism capacity can be associated with large individual variations in the mood of medicinal products, especially when the metabolism pathway involved has an important contribution to their overall elimination.
For example, oral mephenitoin clearance differs 100-200 times between people with MP and MS phenotypes. As a result, peak plasma concentration and bioavailability after oral administration may be greatly increased, and the rate of elimination of the drug may be decreased in MS individuals compared to MP. the result in people with the MS phenotype is the accumulation of the drug and the exaggeration of the pharmacological response, including toxicity, when the usual dose of the drug is administered. thus, effective individualization of therapy is especially important when drugs with polymorphic metabolism are used.
Now I will continue (and complete this post) with the use of drugs in the elderly. These people are distinguished by using a disproportionate amount of prescriptions (30%). Also, 70% of the elderly regularly use medicines sold without a prescription, compared to only 10% (?) of the general population. Ageing results in changes in the functions of the organs, especially those organs involved in the disposition of the drug, as well as changes in the size and composition of the body. Therefore, the pharmacokinetic differences often present in older people compared to young people are not surprising.
Unfortunately, there are few generalizations regarding the type, size and clinical importance of age-related changes. Multiple diseases are commonly present in elderly patients and therefore they consume a large number of medicines. Consecutive drug interactions, together with increased vulnerability to morbidity and mortality, contribute to an increased incidence of drug adverse reactions in elderly patients. Increased sensitivity of target organs and deficient physiological control systems, such as that involved in regulating circulation, can also be important factors.
Therefore, optimization of drug therapy in the elderly, especially in fragile patients, is often difficult, as a variety of factors, often incompletely defined, accentuate the usual interindividual variability of the drug response. Although many people retain good renal function until old age, elderly patients as a group have an increased likelihood of low renal excretion of drugs. Even in the absence of kidney disease, renal clearance is generally reduced to about 35 to 50% in elderly patients. Therefore, dose aids are needed as well as for patients with renal dysfunction (for medicines that are eliminated from the body predominantly by the kidney, for example: digoxin, aminoglycosides, lithium and others). In this regard, it is important that the reduction of muscle mass in the elderly causes a reduction in the production rate of creatinine (so that a normal serum concentration of creatinine can be present even when creatinine clearance is low).
Ageing also causes decreases in liver size, liver blood flow and probably the activity of liver enzymes that metabolize medicines (consequently, hepatic clearance of some drugs is low in the elderly). Unfortunately, there does not appear to be a consistent model of clinical applicability. Moreover, the changes that may exist are often modest compared to inter-individual variability in the patient population. However, even small reductions in liver extraction can cause significant increases in oral bioavailability of drugs with an important hepatic first-passage effect, such as propanolol and labetalol. As a consequence of low clearance and/ or increased distribution, the half-life of medicines may increase with age.
Thus, if a dose change is necessary in the elderly patient, we can often achieve this by decreasing the frequency of taking the drug, possibly together with a dose reduction. Even if the pharmacokinetics of the drug is not modified, elderly patients may require lower doses of the drug, due to increased pharmacodynamic sensitivity. Examples include the greater analgesic effects of opioids, the greater sedative effect of benzodiazepines and other central nervous system depressants, as well as the increased risk of bleeding during anticoagulant therapy, even when the clotting parameters are well controlled. Exaggerated responses to cardiovascular medication are also common, due to low reactivity of normal homeostatic mechanisms. Such age-related changes require careful monitoring of clinical response of patients and appropriate titration of doses. In general, drug therapy of the elderly requires attention to the possibility of moderate reduction of drug clearance and exaggerated pharmacodynamic reactivity.
Next time I'll address the drug interactions.
Let's "discuss" today the effects of liver disease (and others). Unlike the foreseeable decrease in renal clearance of medicinal products in the case of reduced glomerular filtration, there is no general anticipation regarding the effect of liver disease on the biotransformation of medicinal products in the liver. Changes in hepatitis and cirrhosis can range from low to increased drug clearance. Even in advanced hepatocellular diseases, the drug's clearance decreases only about two to five times. However, the amplitude of such changes cannot be foreseen by the usual liver function tests. Therefore, even when we suspect that the elimination of the drug is affected by liver disease, there is no quantitative basis (other than the evaluation of the clinical response and the plasma concentration of the drug) by which to adjust the dosing regimen.
The "turn" of the effects of circulatory insufficiency (heart failure and shock) has come. Under the conditions of a low tissue infusion, the redistribution of cardiac output occurs, to maintain the blood flow of the heart and the brain at the expense of other tissues. As a result, the drug is distributed in a lower volume of distribution, the concentration of the drug in plasma is increased, and the tissues that are best infused are exposed to these high concentrations. If the heart or brain are sensitive to the drug, an alteration of the response may occur. Furthermore, a low infusion of the kidneys or liver may decrease the clearance of the drug in these organs, directly or indirectly.
Thus, in severe congestive heart failure, hemorrhagic shock and cardiogenic shock, the response to the usual dose of the drug may be excessive and it may therefore be necessary to change the dose. For example, lidocaine clearance is reduced by 50% in heart failure and therapeutic plasma levels are achieved at a IV rate of administration. only about half of the dose normally required. It also significantly reduces the volume of distribution of lidocaine, hence the need for a lower loading dose. It is believed that there are similar situations for procainamide, theophylline and possibly quinidine. Unfortunately there are no predictive factors for these types of pharmacokinetic impairment. Therefore, the loading dose should be conservative and continued therapy should be closely monitored, following clinical toxicity indicators and plasma levels.
Another "milestone of influence" is the conditions that induce changes in plasma protein binding. Many drugs circulate in plasma partly related to plasma proteins. Since only the unbound or free medicinal product can be distributed at the pharmacological place of action, the therapeutic response should be associated in particular with the concentration of the free plasma medicinal product, rather than with the total plasma concentration of the circulating medicinal product. In most cases, the degree of binding is approximately constant over the therapeutic concentration range, so the total plasma levels of the drug can be the basis of the dose adjustment, without resulting in significant errors.
However, conditions such as hypoalbuminemia, liver disease and kidney disease may decrease the proportion of binding acidic and neutral medicines, so that, at any total plasma level, there is a higher concentration of free medicine and thus an increased response and a higher toxic risk. Certain clinical situations, e.g. myocardial infarction, surgery, neoplastic diseases, rheumatoid arthritis and burns, leading to an increased plasma concentration of acute phase reaction, alpha1-acid-glycoprotein, increase the binding of basic drugs (which are related to these macromolecules) with inverse consequences.
The drugs for which changes in protein binding are important are those that are normally linked to a large proportion in plasma (more than 90%), because a small change in the degree of binding produces a large change in the amount of free molecules. The consequences of these changes in binding, in particular with respect to the total levels of the drug, are different, as clearance is of interest to the unbound form or both forms. For many medicines, elimination and distribution are largely limited by the unbound fraction, therefore, the decrease in binding leads to increased clearance and distribution of the drug.
The relative size of these changes may be equivalent, as a net effect, to shortening the half-life. In the case of drugs related to alpha1-glycoprotein acid, pathological increases in binding have opposite effects, decreasing the clearance and distribution of the drug. For example, the constant infusion with lidocaine, as an antiarrhythmic, after myocardial infarction, will increase the process of accumulation of the total drug.
There is also a "discussion" here about the variable actions of drugs caused by genetic differences in their metabolism, with the specificities of manifestation embodied in the acetilar as well as in the metabolism by oxidation with mixed function. For example, there are large individual differences in the rate of acetilation of medicinal products (isoniazide, hydralamide, procainamide and a number of other medicinal products being metabolized by the acetilation of the amino or hydrazine group), i.e. a bimodal distribution of the population in "fast acetilators" and "slow acetilates". The rate of acetilation is genetically controlled (slow acetilation being a recessive autosomal trait).
The acetylsalicylic phenotype can be determined by measuring the ratio between dapsone or sulfamethazine aethylated and non-acetilated in plasma or urine after taking a test dose of these acetylsalicylic substrates. In the case of metabolism by mixed-function oxidases, in healthy individuals who do not take other medicines, the major determinant of the rate of metabolism of medicinal products by these mixed-function oxidases in the liver is the genetic one. Many medicines are subject to oxidative metabolism by more than one isoenzyme (from the hepatic endoplasmic reticulum), the plasma concentration of such drugs in the equilibrium state being dependent on the sum of the activities of these isoenzymes and other metabolism enzymes.
When a drug is metabolized in several ways, the catalytic activities of the participating enzymes are regulated by a number of genes, so that the clearance rates and equilibrium concentrations of the drug tend to be distributed unimodally within the population. The degree of activity can differ greatly (ten times or more) between different people, as in the case of chlorpromazine, and there is no way of anticipating it before the start of therapy. For certain metabolic pathways, bimodally distributed activity suggests control by a single gene and several polymorphisms have been identified. as a result, two phenotypic populations are usually present, as in the case of N-aethylation.
The majority of the population is represented by powerful metabolizers (MP phenotype), and a smaller group of people with weak metabolizers (MS phenotype) have a low or absent ability to metabolize the drug. For example, the isoenzyme CYP2D6 is polymorphic lyssed in the population and about 8-10% of the white population has deficiency of this enzyme, this isoenzyme being the main metabolic pathway for some medicines including anti-arrhythmic agents (propafenone, phlecainide), beta-adrenergic blockers (alprenolol, metoprolol, timolol), tricyclic antidepressants (nortriptyline, desipramine, imipramine, clomipramine), neuroleptic drugs (perphenazine, thioridazine and possibly haloperidol), in selective inhibitions of serotonin reuptake (fluoxetine and paroxetine) and certain opiates such as codeine and dextromethorphan.
Thus, the analgesic effect of codeine is much weaker in patients with weak metabolizers, due to a low production of the active metabolite, morphine. Similarly, patients with poor metabolism phenotype experience the effects of blocking beta-adrenergic receptors more strongly after administration of an ophthalmic solution of timolol. The catalytic activity of CYP2D6 can be estimated in humans using a test drug, debrisoquine, which is almost completely purged on the hydroxylation pathway by this isoenzyme. A similar situation occurs in oxidative polymorphism involving mefenitoin metabolism, involving a different isoenzyme, CYP2C19. This enzyme is also involved in the metabolism of omeprazole, proguanil, diazepam and cytoprom. The situation is further complicated due to interracial differences in the frequency of polymorphism.
For example, low mephenitoin hydroxylation is present in 3-5% of whites, but the incidence is approximately 20% in people of Japanese or Chinese descent (similarly, the frequency of the weak metabolizer phenotype for debrisoquine hydroxylation appears to decrease in Western population groups, 8-10%, in eastern ones being only 0-1%). Polymorphism in metabolism capacity can be associated with large individual variations in the mood of medicinal products, especially when the metabolism pathway involved has an important contribution to their overall elimination.
For example, oral mephenitoin clearance differs 100-200 times between people with MP and MS phenotypes. As a result, peak plasma concentration and bioavailability after oral administration may be greatly increased, and the rate of elimination of the drug may be decreased in MS individuals compared to MP. the result in people with the MS phenotype is the accumulation of the drug and the exaggeration of the pharmacological response, including toxicity, when the usual dose of the drug is administered. thus, effective individualization of therapy is especially important when drugs with polymorphic metabolism are used.
Now I will continue (and complete this post) with the use of drugs in the elderly. These people are distinguished by using a disproportionate amount of prescriptions (30%). Also, 70% of the elderly regularly use medicines sold without a prescription, compared to only 10% (?) of the general population. Ageing results in changes in the functions of the organs, especially those organs involved in the disposition of the drug, as well as changes in the size and composition of the body. Therefore, the pharmacokinetic differences often present in older people compared to young people are not surprising.
Unfortunately, there are few generalizations regarding the type, size and clinical importance of age-related changes. Multiple diseases are commonly present in elderly patients and therefore they consume a large number of medicines. Consecutive drug interactions, together with increased vulnerability to morbidity and mortality, contribute to an increased incidence of drug adverse reactions in elderly patients. Increased sensitivity of target organs and deficient physiological control systems, such as that involved in regulating circulation, can also be important factors.
Therefore, optimization of drug therapy in the elderly, especially in fragile patients, is often difficult, as a variety of factors, often incompletely defined, accentuate the usual interindividual variability of the drug response. Although many people retain good renal function until old age, elderly patients as a group have an increased likelihood of low renal excretion of drugs. Even in the absence of kidney disease, renal clearance is generally reduced to about 35 to 50% in elderly patients. Therefore, dose aids are needed as well as for patients with renal dysfunction (for medicines that are eliminated from the body predominantly by the kidney, for example: digoxin, aminoglycosides, lithium and others). In this regard, it is important that the reduction of muscle mass in the elderly causes a reduction in the production rate of creatinine (so that a normal serum concentration of creatinine can be present even when creatinine clearance is low).
Ageing also causes decreases in liver size, liver blood flow and probably the activity of liver enzymes that metabolize medicines (consequently, hepatic clearance of some drugs is low in the elderly). Unfortunately, there does not appear to be a consistent model of clinical applicability. Moreover, the changes that may exist are often modest compared to inter-individual variability in the patient population. However, even small reductions in liver extraction can cause significant increases in oral bioavailability of drugs with an important hepatic first-passage effect, such as propanolol and labetalol. As a consequence of low clearance and/ or increased distribution, the half-life of medicines may increase with age.
Thus, if a dose change is necessary in the elderly patient, we can often achieve this by decreasing the frequency of taking the drug, possibly together with a dose reduction. Even if the pharmacokinetics of the drug is not modified, elderly patients may require lower doses of the drug, due to increased pharmacodynamic sensitivity. Examples include the greater analgesic effects of opioids, the greater sedative effect of benzodiazepines and other central nervous system depressants, as well as the increased risk of bleeding during anticoagulant therapy, even when the clotting parameters are well controlled. Exaggerated responses to cardiovascular medication are also common, due to low reactivity of normal homeostatic mechanisms. Such age-related changes require careful monitoring of clinical response of patients and appropriate titration of doses. In general, drug therapy of the elderly requires attention to the possibility of moderate reduction of drug clearance and exaggerated pharmacodynamic reactivity.
Next time I'll address the drug interactions.
Until then (and after),
Love, Gratitude and Understanding!
Dorin, Merticaru