Variability – Differ in Drug Response

April 13, 2017 Adverse Drug Reactions, Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Therapeutics No comments , , , , , , , , , , , , , ,

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Substantial differences in response to drugs commonly exist among patients. Such between or interindividual variability is often reflected by various marketed dose strengths of a drug. Because variability in response within a subject from one occasion to another (intraindividual variability) is generally smaller than interindividual variability, there is usually little need to subsequently adjust an individual’s dosage regimen, once well-established, unless the condition or treatment of the patient changes. Clearly, if intraindividual variability were large and unpredictable, finding and maintaining dosage for an individual would be an extremely difficult task, particularly for a drug with a low therapeutic index (e.g., warfarin).

Many patients stabilized on one medicine receive another for the treatment of the same or concurrent condition or disease. Sometimes, the second drug affects the response to the first. The change in response may be clinically insignificant for most of the patient population, with the recommendation that no adjustment in dosage be made. However, a few individuals may exhibit an exaggerated response, which could prove fatal unless the dosage of the first drug given to them is reduced. The lesson is clear: Average data are useful as a guide; but ultimately, information pertaining to the individual patient is all-important.

PS: Evidence for interindividual differences in drug response

  • Variability in the dosage required to produce a given response – daily dose of warfarin
  • Variability in pharmacokinetics – phenytoin’s wide scatter in plateau plasma concentration
  • Variability in pharmacodynamics – levels of endogenous agonists or antagonists

Clearly, variability exists in both pharmacokinetics and pharmacodynamics, and measurement of drug in plasma is a prerequisite for separating the two. The characterization of pharmacokinetic and pharmacodynamic variabilities within the population is called population pharmacokinetics and population pharmacodynamics, respectively.

The dependence on dose and time in the assignment of variability is minimized by expressing variability not in terms of observations but rather in terms of the parameter values defining pharmacokinetics and pharmacodynamics, that is, in F, ka, Cl, and V for pharmacokinetics, and in Emax, C50, and the factor defining the steepness of the concentration-response relationship for pharmacodynamics.

Why People Differ

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The reasons why people differ in their responsiveness to a given dose of a drug are manifold and include genetics, disease, age, gender, body weight, drugs given concomitantly, and various behavioral and environmental factors. Age, body weight, disease, and concomitantly administered drugs are important because they are measurable sources of variability that can be taken into account. Gender-linked differences in hormonal balance, body composition, and activity of certain enzymes manifest themselves in differences in both pharmacokinetics and responsiveness, but overall, the effect of gender is small. Although inheritance accounts for a substantial part of the differences in response among individuals for many drugs, much of this variability is still largely unpredictable, particularly in regard to pharmacodynamics.
Pharmaceutical formulation and the process used to manufacture a product can be important because both can affect the rate and extent of release, and hence entry, into the body. A well-designed formulation diminishes the degree of variability in the release characteristics of a drug in vivo.
Heavy cigarette smoking tends to reduce clinical and toxic effects of some drugs, including theophylline, caffeine, and olanzapine. The drug affected are extensively metabolized by hepatic oxidation catalyzed by CYP1A2; induction of this enzyme is the likely cause.
Although on average the body maintains homeostasis, many biological functions and many endogenous substances undergo temporal rhythms. The period of the cycle is often circadian, approximately 24 hr, although there may be both shorter and longer cycles upon which the daily one is superimposed. The menstrual cycle and seasonal variations in the concentrations of some endogenous substances are examples of cycles with a long period. Drug responses and pharmacokinetics may therefore change with time of the day, day of the month, or season of the year.
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Factors Affecting Metabolism

March 30, 2016 Medicinal Chemistry No comments , , , , , , , ,

Drug therapy is becoming oriented more toward controlling metabolic, genetic, and environmental illnesss rather than short-term therapy associated with infectious disease. In most cases, drug therapy lasts for months or even years, and the problems of drug-drug interactions and chronic toxicity from long-term drug therapy have become more serious. Therefore, a greater knowledge of drug metabolism is essential. Several factors influencing xenobiotic metabolism include:

1.Genetic factors. Individual differences in drug effectiveness (drug sensitivity or drug resistance), drug-drug interactions, and drug toxicity can depend on racial and ethnic characteristics with the population frequencies of the many polymorphic genes and the expression of the metabolizing enzymes. Pharmacogenetics focuses primarily on genetic polymorphisms (mutations) responsible for interindividual differences in drug metabolism and disposition. Genotype-phenotype correlation studies have validated that inherited mutations result in two or more distinct phenotypes causing very different responses following drug administration. The genes encoding for CYP2A6, CYP2C9, CYP2C19, and CYP2D6 are functionally polymorphic; therefore, at least 30% of P450-dependent metabolism is performed by polymorphic enzymes. For example, mutations in the CYP2D6 gene result in poor, intermediate, or ultrarapid metabolizers of more than 30 cardiovascular and central nervous system drugs. Thus, each of these phenotypic subgroups experiences different responses to drugs extensively metabolized by CYP2D6 pathway ranging from severe toxicity to complete lack of efficacy. For example, ethnic specificity has been observed with the sensitivity of the Japanese and Chinese to ethanol as compared to Caucasians, CYP2C19 polymorphism (affects ~20% of Asians and ~3% of Caucasians) and the variable metabolism of omeprazole (proton pump inhibitor) and antiseizure drugs, and the polymorphic paraoxonase-catalyzed hydrolysis of the neurotoxic organophosphates and lipid peroxides (atherosclerosis).

2.Physiologic factors. Age is a factor as both very young and old have impaired metabolism. Hormones, sex differences, pregnancy, changes in intestinal micro-flora, diseases (espeically those involving the liver), and nutritional status can also influence drug and xenobiotic metabolism.

Beause the liver is the principal site for xenobiotic and drug metabolism, liver disease can modify the pharmacokinetics of drugs metabolized by the liver. Several factors identified as major determinants of the metabolism of a drug in the diseased liver are:

  • the nature and extent of liver damage
  • hepatic blood flow
  • the drug involved
  • the dosage regimen
  • the degree of participation of the liver in the pharmacokinetics of the drug

Liver disease affects the elimination half-life of some drugs but not of others, although all undergo hepatic biotransformation. Some results have shown that the capacity for dug metabolism is impaired in chronic liver disase, which could lead to drug overdosage. Consequently, as a result of the unpredictability of drug effects in the presence of liver disorders, drug therapy in these circumstances is complex, and more than usual caution is needed.

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to reduced hepatic microsomal protein and lipid metabolism; oxidative metabolism is decreased due to an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body.

3.Pharmacodynamic factors. Dose, frequency, and route of administration, plus tissue distribution and protein binding of a drug, affect its metabolism.

4.Environmental factors. Competition of ingested environmental substances with other drugs and xenobiotics for metabolizing enzymes, and poisoning of enzymes by toxic chemicals such as carbon monoxide or pesticide synergists alter metabolism. Induction of enzyme expression (in which the number of enzyme molecules is increased, while the activity is constant) by other drugs and xenobiotics is another consideration.

Such factors (genetic, physiologic, pharmacodynamic, and environmental factors) can change not only the kinetics of an enzyme reaction but also the whole pattern of metabolism, thereby altering bioavailability, pharmacokinetics, pharmacologic activity, or toxicity of a xenobiotic.