Clearance

[Clinical Art][Pharmacokinetics] Interpretation of Plasma Drug Concentrations (Steady-State)

November 11, 2016 Clinical Skills, Critical Care, Pharmacokinetics, Practice No comments , , , , , , , , , , , ,

Plasma drug concentration are measured in the clinical setting to determine whether a potentially therapeutic or toxic concentration has been produced by a given dosage regimen. This process is based on the assumption that plasma drug concentrations reflect drug concentrations at the receptor and, therefore, can be correlated with pharmacologic response. This assumption is not always valid. When plasma samples are obtained at inappropriate times or when other factors (such as delayed absorption or altered plasma binding) confound the usual pharmacokinetic behavior of a drug, the interpretation of serum drug concentrations can lead to erroneous pharmacokinetic and pharmacodynamic conclusions and utimately inappropriate patient care decisions. These facors are discussed below.

Confounding Factors

To properly interpret a plasma concentration, it is essential to know when a plasma sample was obtained in relation to the last dose administered and when the drug regimen was initiated.

  • If a plasma sample is obtained before distribution of the drug into tissue is complete, the plasma concentration will be higher than predicted on the basis of dose and response. (avoidance of distribution)
  • Peak plasma levels are helpful in evaluating the dose of antibiotics used to treat severe, life-threatening infections. Although serum concentrations for many drugs peak 1 to 2 hours after an oral dose is administered, factors such as slow or delayed absorption can significantly delay the time at which peak serum concentrations are attained. Large errors in the estimation of Css max can occur if the plasma sample is obtained at the wrong time. Therefore, with few exceptions, plasma samples should be drawn as trough or just before the next dose (Css min) when determining routine drug concentration in plasma. These trough levels are less likely to be influenced by absorption and distribution problems. (slow or delayed absorption)
  • When the full therapeutic response of a given drug dosage regimen is to be assessed, plasma samples should not be obtained until steady-state concentrations of the drug have been achieved. If drug doses are increased or decreased on the basis of drug concentrations that have been measured while the drug is still accumulating, disastrous consequences can occur. Nevertheless, in some clinical situations it is appropriate to measure drug levels before steady state has been achieved. If possible, plasma samples should be drawn after a minimum of two half-lives beause clearance values calculated from drug levels obtained less than one half-life after a regimen has been initiated are very sensitive to small differences in the volume of distribution and minor assay errors. (Whether steady-state attained)
  • The impact of drug plasma protein binding on the interpretation of plasma drug coencentration has been discussed in thread "The Plasma Protein Concentration and The Interpretation of TDM Report" before.

Revising Pharmacokinetic Parameters

The process of using a patient's plasma drug concentration and dosing history to determine patient-specific pharmacokinetic parameters can be complex and difficult. A single plasma sample obtained at the appropriate time can yield information to revise only one parameter, either the volume of distribution or clearance, but not both. Drug concentrations measured from poorly timed samples may prove to be useless in estimating a patient's V or Cl values. Thus, the goal is to obtain plasma samples at times that are likely to yield data that can be used with confidence to estimate pharmacokinetic parameters. In addition, it is important to evaluate available plasma concentration data to determine whether they can be used to estiamte, with some degree of confidence, V and/or Cl. The goal in pharmacokinetic revisions is not only to recognize which pharmacokinetic parameter can be revised, but also the accuracy or confidence one has in the revised or patient-specific pharmacokinetic parameter. In the clinical setting, based on the way drugs are dosed and the recommended time to sample, bioavailability is almost never revised, volume of distribution is sometimes revised, and most often clearance is the pharmacokientic parameter that can be revised to determine a patient-specific value.

Volume of Distribution

A plasma concentration that has been obtained soon after administration of an initial bolus is primarily determined by the dose administered and the volume of distribution. This assumes that both the absorption and distribution phases have been avoided.

C1 = (S) (F) (Loading Dose) x e(-kt1) / V (IV Bolus Model)

When e(-kt1) approches 1 (i.e., when t1 is much less than t1/2), the plasma concentration (C1) is primarily a function of the administered dose and the apparent volume of distribution. At this point, very little drug has been eliminated from the body. As a clinical guideline, a patient's volume of distribution can usually be estimated if the absorption and distribution phase are avoided and t1, or the interval between the administration and sampling time, is less than or equal to one-third of the drug's half-life. As t1 exceeds one-third of a half-life, the measured concentration is increasingly infuenced by clearance. As more of the drug is eliminated (i.e., t1 increases), it is difficult to estimate the patient's V with any certainty. The specific application of this clinical guideline depends on the confidence with which one knows clearance. If clearance is extremely variable and uncertain, a time interval of less than one-third of a half-life would be necessary in order to revise volume of distribution. On the other hand, if a patient-specific value for clearance has already been determined, then t1 could exceed one-third of a half-life and a reasonably accurate estimate of volume of distribution could be obtained. It is important to recognize that the pharmacokinetic parameter that most influences the drug concentration is not determined by the model chosen to represent the drug level. For example, even if the dose is modeled as a short infusion, the volume of distribution can still be the important parameter controlling the plasma concentration. V is not clearly defined in the equation (see it below); nevertheless, it is incorporated into the elimination rate constant (K).

C2 =[(S) (F) (Dose/tin) / Cl]*(1-e-ktin)(e-kt2)

Although one would not usually select this equation to demonstrate that the drug concentration is primarily a function of volume of distribution, it is important to recognize that the relationship between the observed drug concentration and volume is not altered as long as the total elapsed time (tin + t2) does not exceed one-third of a half-life.

Our assumption in evaluating the volume of distribution is that although we have not sampled beyond one-third of a t1/2, we have waited until the drug absorption and distribution process is complete.

Clearance

A plasma drug concentration that has been obtained at steady state from a patient who is receiving a constant drug infusion is determined by clearance.

Css ave = (S) (F) (Dose / tau) / Cl

So, the average steady-state plasma concentration is not influenced by volume of distribution. Therefore, plasma concentrations that represent the average steady-state level can be used to estimate a patient's clearnace value, but they cannot be used to estimate a patient's volume of distribution. Generally, all steady-state plasma concentrations within a dosing interval that is short relative to a drug's half-life (tau =<1/3 t1/2) approximate the average concentration. Therefore, these concentrations are also primarily a function of clearance and only minimally influenced by V.

Also the below equation could be used,

Css 1 =[(S)(F)(Dose)/V]/(1-e-kτ)*(e-kt1)

the expected volume of distribution should be retained and the elimination rate constant adjusted such that Css1 at t1 equals the observed drug plasma concentration.

Sensitivity Analysis

Whether a measured drug concentration is a function of clearance or volume of distribution is not always apparent. When this is difficult to ascertain, one can examine the sensitivity or responsiveness of the predicted plasma concentration to a parameter by changing one parameter while holding the other constant. For example, for maintenance infusion, a plasma concentration (C1) at some time intervnal (t1) after a maintenance infusion has been started should be:

C1=[(S)(F)(Dose/τ)/Cl]*(1-e-kt1)

when the fraction of steady that has been reached (1-e-kt1) is small, large changes in clerance are frequently required to adjust a predicted plasma concentration to the appropriate value. If a large percentage change in the clearance value results in a disproportionately small change in the predicted drug level, then something other than clearance is controlling (responsible for) the drug concentration. In this case, the volume of distribution and the amount of drug administered are the primary determinants of the observed concentration. Also in cases where the drug concentration is very low, it might be assay error or sensitivity that is the predominant factor in determining the drug concentration making the ability to revise for any pharmacokinetic parameter limited if not impossible.

This type of sensitivity analysis is useful to reinforce the concept that the most reliable revisions in pharmacokinetic parameters are made when the predicted drug concentration changes by approximately the same percentage as the pharmacokinetic parameter undergoing revision.

When a predicted drug concentration changes in direct proportion, or inverse proportion to an alteration in only one of the pharmacokinetic parameters, it is likely that a measured drug concentration can be used to estimate that patient-specific parameter. But when both clearance and volume of distribution have a significant influence on th prediction of a measured drug concentration, revision of a patient's pharmacokinetic parameters will be less certain because there is an infinite number of combinations for clearance and volume of distribution values that could be used to predict the observed drug concentration. When this occurs, the patient's specific pharmacokinetic characteristics can be estimated by adjusting one or both of the pharmacokinetic parameters. Nevertheless, in most cases additional plasma level sampling will be needed to accurately predict the patient's clearance or volume of distribution so that subsequent dosing regimens can be adjusted.

When the dosing interval is much shorter than the drug's half-life, the changes in concentration within a dosing interval are relatively small, and any drug concentration obtained within a dosing interval can be used as an approximation of the average steady-state concentration. Even though Css max and Css min exist,

Css max =[(S)(F)(Dose)/V]/(1-e-kτ)

and

Css min =[(S)(F)(Dose)/V]/(1-e-kτ)*(e-kτ)

and could be used to predict peak and trough concentrations, a reasonable approximation could also be achieved by using the Css ave, that is

Css ave =(S)(F)(Dose/τ)/Cl

This suggests that even though Css max and Css min do not contain the parameter clearance per se, the elimination rate constant functions in such a way that the clearance derived from Css max or Css min and Css ave would all essentially be the same.

In the situation in which the dosing interval is greater than one-third of a half-life, the use of Css max and Css min are appropriate as not all drug concentrations within the dosing interval can be considered as the Css ave. However, as long as the dosing interval has not been extended beyond one half-life, clearance is still the primary pharmacokinetic parameter that is responsible for the drug concentrations within the dosing interval. Although the elimination rate constant and volume of distribution might be manipulated in Css max and Css min, it is only the product of those two numbers (i.e., clearance) that can be known with any certainty: Cl = (K) (V).

If a drug is administered at a dosing interval that is much longer than the apparent half-life, peak concentrations may be primarily a function of volume of distribution. Since most of the dose is eliminated within a dosing interval, each dose can be thought as something approaching a new loading dose. Of course for steady-state conditions, at some point within the dosing interval, the plasma concentration (Css ave) will be determined by clearance. Trough plasma concentrations in this situation are a function of both clearance and volume of distribution. Since clearance and volume of distribution are critical to the prediction of peak and trough concentrations when the dosing interval is much longer than the drug t1/2, a minimum of two plasma concentrations is needed to accurately establish patient-specific pharmacokinetic parameters and a dosing regimen that will achieve desired peak and trough concentrations.


Choosing A Model to Revise or Estimate A Patient's Clearance at Steady State

As previously discussed, a drug's half-life often determines the pharmacokinetic equation that should be used to make a revised or patient-specific estimate of a pharmacokinetic parameter. A common problem encountered clinically, however, is that the half-life observed in the patient often differs from the expected value. Since a change in either clearance or volume of distribution or both may account for this unexpected value, the pharmacokinetic model is often unclear. One way to approach this dilemma is to first calculate the expected change in plasma drug concentration assocaited with each dose:

delta C = (S) (F) (Dose) / V

where delta C is the change in concentration following the administration of each dose into the patient's volume of distribution. This change in concentration can then be compared to the steady-state trough concentration measured in the patient.

(S) (F) (Dose) / V versus Css min

or

delta C versus Css min

When the dosing interval (tau) is much less than the drug half-life, delta C will be small when compared to Css min. As the dosing interval increases relative to tau, delta C will increase relative to Css min. Therefore, a comparison of delta C or (S) (F) (Dose) / V to Css min can serve as a guide to estimating the drug t1/2 and the most appropriate pharmacokineitc model or technique to use for revision. With few exceptions, drugs that have plasma level monitoring are most often dosed at intervals less than or equal to their half-lives. Therefore, clearance is the pharmacokinetic parameter most often revised or calculated for the patient in question. The following guidelines can be used to select the pharmacokinetic model that is the least complex and therefore the most appropriate to estimate a patient-specific pharmacokientic parameter.

Condition 1

When, (S) (F) (Dose) / V =< 1/4 Css min

Then, tau =<1/3 t1/2

Under these conditions, Css min ≈ Css ave

And Cl can be estimated by Cl = (S) (F) (Dose / tau) / Css ave

Rules/Conditions: Must be at steady state.

Condition 2

When, (S) (F) (Dose) / V =< Css min

Then, tau =< t1/2

Under these conditions, Css min + (1/2) (S) (F) (Dose) / V ≈ Css ave

And Cl can be estimated by Cl = (S) (F) (Dose / tau) / Css ave

Rules/Conditions: Must be at steady state; C is Css min; Bolus model for absorption is acceptable (dosage form is not sustained release; short infusion model is not required, that is, tin =<1/6t1/2)

Conditon 3

When, (S) (F) (Dose) / V > Css min

Then, tau > t1/2

Under these conditions: Css min + (S) (F) (Dose) / V = Css max

where V is an assumed value from the literature.

K is revised (Krevised):

Krevised = ln {[(Css min + (S) (F) (Dose / V)] / Css min} / tau = ln (Css max / Css min) / tau

Rules/Conditions: Must be at steady state; C is Css min; Bolus model for absorption is acceptable (dosage form is not sustained release; short infusion model is not required, that is, tin =< 1/6 t1/2)

Note that the approaches used become more complex as the dosing interval increases relative to the drug half-life. If a drug is administered at a dosing interval less than or equal to one-third of its half-life and the technique in Condition 3 is used to revise clearance, the revised clearance would be correct. The calculation is not wrong, just unnecessarily complex. However, if a drug is administered at a dosing interval that exceeds one half-life and the technique in Condition 1 is used to revise clearance, the revised clearance value would be inaccurate because Css min cannot be assumed to be approximately equal to Css ave. While it could be argued that the technique used in Condition 3 would suffice for all the previous conditions, it is more cumbersome and tends to focus on the intermediate parameters, K and V rather than Cl. One should also be ware that as the dosing interval increases, relative to the drug's half-life, the confidence in a revised clearance diminishes because the volume of distribution, which is an assumed value from the literature, begins to influence the revised clearance to a greater degree. As a general rule, the confidence in Cl is usually good when the dosing interval is < t1/2, steady state has been achieved, and drug concentrations are obtained properly.

[Endocrinology] The Regulation and Clinical Art of Thyroid Hormones

October 13, 2016 Clinical Skills, Endocrinology, Pharmacokinetics, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

Thyroid Hormone Synthesis Process

The Source Components of Thyroid Hormone

Thyroglobulin (Tg), plays an important role in the synthesis and storage of thyroid hormone. Tg is a glycoprotein containing multiple tyrosine residues. It is synthesized in the thyroid follicular epithelial cells and secreted through the apical membrane into the follicular lumen, where it is stored in the colloid. A small amount of noniodinated Tg is also secreted through the basolateral membrane into the circulation. Although circulating levels of Tg can be detected under normal conditions, levels are elevated in diseases such as thyroiditis and Graves disease.

screen-shot-2016-10-13-at-3-48-24-pmTg can be considered a scaffold upon which thyroid hormone synthesis takes place. Once Tg is secreted into the follicular lumen, it undergoes major posttranslational modification during the production of thyroid hormones. At the apical surface of the thyroid follicular epithelial cells, multiple tyrosine residues of Tg are iodinated, followed by coupling of some of the iodotyrosine residues to form T3 and T4.

The iodide required for thyroid hormone synthesis is readily absorbed from dietary sources, primarily from iodized salt, but also from seafood and plants grown in soil that is rich in iodine. Following its absorption, iodide is confined to the extracellular fluid, from which it is removed primarily by the thyroid (20%) and the kidney (80%). The total excretion of iodide by the kidneys is approximately equal to daily intake. The balance between dietary intake and renal excretion preserves the total extracellular pool of iodide.

The Uptake and Iodination of Iodine

Iodine uptake

Iodide is concentrated in thyroid epithelial cells by an active, saturable, energy-dependent process mediated by a Na+/I symporter located in the basolateral plasma membrane of the follicular cell. Additional tissues that express the Na+/I symporter include the salivary glands, the gastric mucosa, the placenta, and the mammary glands. However, transport of iodine in these tissues is not under TSH regulation.

Iodine efflux (after the transformation from anion cation?, see below)

The iodination of Tg residues is a process that occurs at the apical membrane. Thus, once inside the cell, iodine must leave the follicular cell through apical efflux by an iodide-permeating mechanism consisting of a chloride-iodide transporting protein (iodide channel) located in the apical membrane of the thyroid follicular cell. The uptake, concentration, and efflux of iodide through the iodide channel are all a function of TSH-stimulated transepithelial transport of iodide.

Organification and coupling

In the follicular lumen, tyrosine residues of Tg are iodinated by iodine (I+; formed by oxidation of I by TPO). This reaction requires hydrogen peroxide, which is generated by a flavoprotein Ca++-dependent reduced nicotinamide adenine dinucleotide phosphate oxidase at the apical cell surface and serves as an electron acceptor in the reaction process. Iodine bonds to carbon 3 or to carbon 5 of the tyrosine residues on Tg in a process referred to as the organification of iodine. This iodination of specific tyrosines located on Tg yields monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT) residues that are enzymatically coupled to form triiodothyronine (T3) or tetraiodothyronine (T4). The coupling of iodinated tyrosine residues, either of 2 DIT residues or of 1 MIT and 1 DIT residues, is catalyzed by the enzyme thyroid peroxidase. Because not all of the iodinated tyrosine residues undergo coupling, Tg stored in the follicular lumen contains MIT and DIT residues as well as formed T3 and T4.

Release of Thyroid Hormone

The synthesis of thyroid hormone takes place in the colloid space. As mentioned previously, the apical surface of the follicular epithelial cell faces the colloid and not the interstitial space, and thus has no access to the bloodstream. Therefore, thyroid hormone release involves endocytosis of vesicles containing Tg from the apical surface of the follicular cell. The vesicles fuse with follicular epithelial phagolysosomes, leading to proteolytic digestion and cleavage of Tg. In addition to the thyroid hormones T4 and T3, the products of this reaction include iodinated tyrosine residues (MIT and DIT). MIT and DIT are deiodinated intracellularly, and iodide is transported by apical efflux into the follicular colloid space, where it is reused in thyroid hormone synthesis. T4 and T3 are released from the basolateral membrane into the circulation. The thyroid gland releases greater amounts of T4 than T3, so plasma concentrations of T4 are 40-fold higher than those of T3 (90 vs 2 nM). Most of the circulating T3 is formed peripherally by deiodination of T4, a process that involves the removal of iodine from carbon 5 on the outer ring of T4. Thus, T4 acts as a prohormone for T3. Although this deiodination occurs predominantly in the liver, some occurs in the thyroid follicular epithelial cell itself. This intrathyroidal deiodination of T4 is the result of TSH stimulation of the type I deiodinase.

Two additional facts regarding thyroid hormone activity and storage should be noted. First, at physiologic levels, T4, is relatively inactive because it possesses 100-fold lower affinity than T3 for binding to the thyroid receptor and does not enter the cell nucleus at high enough concentrations to occupy the ligand-binding site of the thyroid hormone receptor. Second, in contrast to most endocrine glands, which do not have storage capacity for their product, the thyroid gland is able to store 2-3 months' supply of thyroid hormones in the Tg pool.


Transport and Tissue Delivery of Thyroid Hormones

Once thyroid hormones are released into the circulation, most of them circulate bound to protein. Approximately 70% of T4 and T3 is bound to thyroid-binding globulin. Other protein involved in thyroid binding include transthyretin, which binds 10% of T4, and albumin, which binds 15% of T4 and 25% of T3. A small fraction of each hormone (0.03% of T4 and 0.3% of T3) circulates in its free form. This fraction of the circulating hormone pool is bioavailable and can enter the cell to bind to the thyroid receptor. Of the 2 thyroid hormones, T4 binds more tightly to binding proteins than T3 and thus has a lower metabolic clearance rate and a longer half-life (7 days) than T3 (1 day). The kidneys readily excrete free T4 and T3. Binding of thyroid hormones to plasma proteins ensures a circulating reserve and delays their clearance.

The release of hormone from its protein-bound form is in a dynamic equilibrium. Although the role of binding proteins in delivery of hormone to specific tissues remains to be fully understood, it is known that drugs such as salicylate may affect thyroid hormone binding to plasma proteins. The binding-hormone capacity of the individual can also be altered by disease or hormonal changes. The changes in total amount of plasma proteins available to bind thyroid hormone will impact the total amout of circulating thyroid hormone because of a constant homeostatic adjustment to changes in free hormone levels. A decrease in free thyroid hormone because of an increase in plasma-binding proteins will stimulate the release of TSH from the anterior pituitary, which will in turn stimulate the synthesis and release of thyroid hormone from the thyroid gland. In contrast, a decrease in binding-protein levels, with a resulting rise in free thyroid hormone levels, will suppress TSH release and decrease thyroid hormone synthesis and release. These dynamic changes occur throughout the life of the individual, whether in health or disease. Disruption in these feedback mechanisms will result in manifestations of excess or deficient thyroid hormone function.

Thyroid Hormone Metabolism

As already mentioned, the thyroid releases mostly T4 and very small amounts of T3, yet T3 has greater thyroid activity than T4. The main source of circulating T3 is peripheral deiodination of T4 by deiodinases (I, II and III). Approximately 80% of T4 produced by the thyroid undergoes deiodination in the periphery. Approximately 40% of T4 is deiodinated at carbon 5 in the outer ring to yield the more active T3, principally in liver and kidney. In approximately 33% of T4, iodine is removed from carbon 5 in the inner ring to yield reverse T3 (rT3). Reverse T3 has little or no biologic activity, has a higher metabolic clearance rate than T3, and has a lower serum concentration than T3. Following conversion of T4 to T3 or rT3, these are converted to T2,  a biologically inactive hormone. Therefore, thyroid hormone peripheral metabolism is a sequential deiodination process, leading first to a more active form of thyroid hormone (T3) and finally to complete inactivation of the hormone. Thus, loss of a single iodine from the outer ring of T4 produces the active hormone T3, which may either exit the cell, enter the nucleus directly, or possibly even both. Thyroid hormones can be excreted following hepatic sulfo- and glucuronide conjugation and biliary excretion.

Type I deiodinase catalyzes outer- and inner-ring deiodination of T4 and rT3. It is found predominantly in the liver, kidney, and thyroid. It is considered the primary deiodinase responsible for T4 to T3 conversion in hyperthyroid patients in the periphery. This enzyme also converts T3 to T2. The activity of type I deiodinase expressed in the thyroid gland is increased by TSH-stimulated cAMP production and has a significant influence on the amount of T3 released by the thyroid. Propylthiouracil and iodinated x-ray contrast agents such as iopanoic acid inhibit the activity of this enzyme and consequently the thyroidal production of T3.

Type II deiodinase is expressed in the brain, pituitary gland, brown adipose tissue, thyroid, placenta, and skeletal and cardiac muscle. Type II deiodinase has only outer-ring activity and converts T4 to T3. This enzyme is thought to be the major source of T3 in the euthyroid state. This enzyme plays an important role in tissues that produce a relatively high proportion of the receptor-bound T3 themseleves, rather than deriving T3 from plasma. In these tissues, type II deiodinases are an important source of intracellular T3 and provide more than 50% of the nuclear receptor-bound T3. The critical role of type II deiodinases is underscored by the fact that T3 formed in the anterior pituitary is necessary for negative feedback inhibition (long loop) of TSH secretion.screen-shot-2016-10-13-at-9-21-09-pm

Type III Deiodinase is expressed in the brain, placenta, and skin. Type III deiodinase has inner-ring activity and converts T4 to rT3, and T3 to T2, thus inactivating T4 and T3. This process is an important feature in placental protection of the fetus. The placental conversion of T4 to rT3, and of T3 to T2 reduces the flow of T3 from mother to fetus. Small amounts of maternal T4 are transferred to the fetus and converted to T3, which increases the T3 concentration in the fetal brain, preventing hypothyroidism. In the adult brain, the expression of type III deiodinases is enhanced by thyroid hormone excess, serving as a protective mechanism against high thyroid hormone concentrations.


The Hypothalamic-pituitary-thyroid Axis

Hypothalamic Regulation of Thyroid-Stimulating Hormone Release (releasing factor)

Thyroid hormone synthesis and release are under negative feedback regualtion by the hypothalamic-pituitary-thyroid axis. TRH is a tripeptide synthesized in the hypothalamus and released from nerve terminals in the median eminence from where it is transported through the portal capillary plexus to the anterior pituitary. TRH binds to cell membrane Gq/11 receptors on thyrotrophs of the anterior pituitary gland, where it activates phospholipase C, resulting in the hydrolysis of phosphatidylinositol bisphosphate and the generation of inositol triphosphate and diacylylycerol. This process leads to an increase in the intracellular Ca2+ concentration, resulting in stimulation of exocytosis and release of TSH into the systemic circulation.

Thyroid-Stimulating Hormone Regulation of Thyroid Hormone Release (tropic effect)

TSH is transported in the bloodstream to the thyroid gland, where it binds to the TSH receptor located on the basolateral membrane of thyroid follicular epithelial cells. The TSH receptor is a cell membrane G protein-coupled receptor. Binding of TSH to its receptor initiates signaling through cyclic 3', 5'-adenosine monophosphate (cAMP), phospholipase C, and the protein kinase A signal transduction systems. Activation of adenylate cyclase, formation of cAMP, and activation of protein kinase A regulate iodide uptake and transcription of Tg, thyroid peroxidase (TPO), and the activity of the sodium-iodide (Na+/I) symporter. Signaling through phospholipase C and intracellular Ca2+ regulate iodide efflux, H2O2 production, and Tg iodination. The TSH receptor is an important antigenic site involved in thyroid autoimmune disease. Autoantibodies to the receptor may act as agonists mimicking the actions of TSH, or antagonists in the case of autoimmune hypothyroidism.

TSH receptor activation results in stimulation of all of the steps involved in thyroid hormone synthesis, including 1) iodine uptake and organification, 2) production and release of iodothyronines from the gland, and 3) promotion of thyroid growth. Specifically, the biologic effects of TSH include stimulation of gene transcription of the following: 1) Na+/I symporter, the protein involved in transporting and concentrating iodide in the thyroid epithelial cell; 2) Tg, the glycoprotein that serves as a scaffold for tyrosine iodination and thyroid hormone synthesis, as well as storage of thyroid hormone; 3) TPO, the enzyme involved in catalyzing the oxidation of iodide and its incorporation into thyrosine residues of Tg; and 4) thyroid hormones T4 and T3 (triiodothyronine).

TSH control the energy-dependent uptake and concentration of iodide by the thyroid gland and its transcellular transport through the follicular epithelial cell. However, iodine metabolism within the thyroid can also be reglated independently of TSH. This mechanism is important when plasma iodide levels are elevated (15-20-fold above normal) because this elevation inhibits the organic binding of iodine within the thyroid. This autoregulatory phenomenon consisting of inhibition of the organification of iodine by elevated circulating levels of iodide is known as the Wolff-Chaikoff effect. This effect lasts for a few days and is followed by the so-called escape phenomenon, at which point the organification of intra-thyroidal iodine resumes and the normal synthesis of T4 and T3 returns. The escape phenomenon results from a decrease in the inorganic iodine concentration inside the thyroid gland from downregulation of the Na+/I symporter. This relative decrease in intrathyroidal inorganic iodine allows the TPO-H2O2 system to resume normal activity. The mechanisms responsible for the acute Wolff-Chaikoff effect have not been elucidated but may be caused by the formation of organic iodocompounds within the thyroid.

Thyroid Hormone Regulation of Thyroid-Stimulating Hormone Release (long loop)

The production and release of thyroid hormones are under negative feedback regulation by the hypothalamic-pituitary-thyroid axis. The release of TSH is inhibited mainly by T3, produced by conversion of T4 to T3 in the hypothalamus, and in the anterior pituitary by type II deiodinase. The contribution of this intracellularly derived T3 in producing the negative feedback inhibition of TSH release is greater than that of T3 derived from the circualtion. Other neuroendocrine mediators that inhibit TSH release include dopamine, somatostatin, and glucocorticoids at high levels, which produce partial suppression of TSH release.

The TDM of Vancomycin

August 16, 2016 Critical Care, Infectious Diseases, Pharmacokinetics No comments , , , , ,

Question #1. B.C., a 65-year old, 45-kg man with a serum creatinine concentration of 2.2 mg/dL, is being treated for a presumed hospital-acquired, MRSA infection. Design a dosing regimen that will produce peak concentration less than 40 to 50 mg/L and through concentrations of 5 to 15 mg/L.

Target Plasma Concentration

Screen Shot 2016-08-16 at 10.37.03 AM

Clearance and Volume of Distribution

The first step in calculating an appropriate dosing regimen for B.C. is to estimate his pharmacokinetic parameters (i.e., volume of distribution, clearance, elimination rate constant, and half-life).

The volume of distribution for B.C. can be calculated by using Equation 13.1.

V (L) = 0.17 (age in years) + 0.22 (TBW in kg) + 15

So, B.C.'s expected volume of distribution would be: V (L) = 0.17 (65 yrs) + 0.22 (45 kg) + 15 = 36.0 L [Equation 13.1]

Using Equation 13.2 and Equation 13.4 to calculated B.C.'s expected creatinine clearance and vancomycin clearance.

Clcr for males (mL/min) = (140 – Age)(Weight in kg) / [(72)(SCrss)] [Equation 13.2]

Vancomycin Cl ≈ Clcr [Equation 13.4]

For B.C. the vancomycin Cl ≈ (140 – 65 yrs)(45 kg) / [(72)(2.2 mg/dL)] = 21.3 mL/min = 1.28 L/hr

The calculated vancomycin clearance of 1.28 L/hr and the volume of distribution of 36.0 L then can be used to estimate the elimination rate constant of 0.036 hr-1. And the corresponding vancomycin half-life can be calculated, which equals (0.693)(V) / Cl = 19.5 hr.

Loading Dose

In clinical practice, loading doses of vancomycin are seldom administered. This is probably because most clinicians prescribe about 15 mg/kg as their maintenance dose.

C0 = (S)(F)(Loading Dose) / V = (1)(1)(15 mg/kg x 45 kg) / 36 L = 18.8 mg/L ≈ 20 mg/L (Equation 13.8)

If you want to administer a loading dose, the loading dose = (V)(C) / [(S)(F)] = (36.0 L)(30 mg/L) / [(1)(1)] = 1080 mg or ≈ 1000 mg.

Steady-State

During the steady-state, Css max = Css min + [(S)(F)(Dose) / V] (Equation 13.5). This equation is based on several conditions including: 1) Steady state has been achieved; 2) the measured plasma concentration is a trough concentration; and 3) the bolus dose is an acceptable model (infusion time <1/6 half-life).

In the clinical setting, trough concentrations are often obtained slightly before the true trough. Because vancomycin has a realtive long half-life, most plasma concentrations obtained within 1 hour of the true trough can be assumed to have met condition 2 above.

Since vancomycin follows a multicompartmental model, it is difficult to avoid the distribution phase when obtaining peak plamsa concentrations. If peak levels are to be measured, samples should be obtained at least 1 or possibly 2 hours after the end of the infusion period. It is difficult to evaluate the appropriateness of a dosing regimen that is based on plasma samples obtained before steady state. Additional plasma concentrations are required to more accurately estimate a paient's apparent clearance and half-life, and to ensure that any dosing adjustments based on a non-steady-state trough concentration actually achieve the targeted steady-state concentrations.

Maintenance Dose

The maintenance dose can be calculated by a number of methods. One approach might be to first approximate the hourly infusion rate required to maintain the desired average concentration. Then, the hourly infusion rate can be multiplied by an appropriate dosing interval to calculate a reasonable dose to be given on an intermittent basis. For example, if an average concentraion of 20 mg/L is selected (approximately halfway between the desired peak concentration of ≈ 30 mg/L and trough concentration of ≈ 10 mg/L), the hourly administration rate would be 25.6 mg/hr.

Maintenance Dose = (Cl)(Css ave)(tau) / [(S)(F)] 

For this patient the 24 hour dose should be (1.28 L/hr)(20 mg/L)(24 hr) / [(1)(1)] = 614 mg ≈ 600 mg

– or –

Maintenance delivery rate = Dose/tau = (Cl)(Css ave) / [(S)(F)]

For this patient the maintenance deliver rate = (1.28 L/hr)(20 mg/L) / [(1)(1)] = 25.6 mg/hr

The second approach that can be used to calculate the maintenance dose is to select a desired peak and trough concentration that is consistent with the therapeutic range and B.C.'s vancomcin half-life. For example, it steady-state peak concentrations of 30 mg/L are desired, it would take approximately two half-lives for that peak level to fall to 7.5 mg/L. Since the vancomycin half-life in B.C. is approximately 1 day, the dosing interval would be 48 hours. The dose to be administered every 48 hours can be calculated as follows using Equation 13.5:

Dose = (V)(Css max – Css min) / [(S)(F)] = (36.0 L)(30 mg/L – 7.5 mg/L) / [(1)(1)] = 810 mg ≈ 800 mg

The peak and trough concentrations that are expected using this dosing regimen can be calcualted by using Equations 13.12 and 13.14, respectively.

Css max = (S)(F)(Dose) / {V x [1- e(-k*tau)]} = 27.0 mg/L (Equation 13.12)

Note that although 27 mg/L is an acceptable peak, the actual clinical peak would normally be obtained approximately 1 hour after the end of a 1-hour infusion, or 2 hours after this calculated peak concentration, and would be about 25 mg/L, as calculated by Equation 13.13.

C2 = C1[e(-k*t)] = 25.1 mg/L (Equation 13.13)

The calculated trough concentration would be about 5 mg/L.

Css min = (S)(F)(Dose / V)[e(-k*tau)] / [1 – e(-k*tau)] = (Css max)[e(-k*tau)] = 4.8 mg/L (Equation 13.14 and 13.15)

This process of checking the expected peak and trough concentrations is most appropriate when the dose or the dosing interval has been changed from a calculated value (e.g., twice the half-life) to a practical value (e.g., 8, 12, 18, 24, 36, or 48 hours). Many institutions generally prefer not to use dosing intervals of 18 or 36 hours because the time of day whent the next dose is to be given changes, potentially resulting in dosing errors. If different plasma vancomycin concentrations are desired, Equations 13.12 and 13.14 can be used target specific vancomycin concentrations by adjusting the dose and/or the dosing interval.

A third alternative is to rearrange Equation 13.14, such that the dose can be calculated:

Dose = (Css min)(V)[1 – e(-k*tau)] / {(S)(F)[e(-k*tau)]} (Equation 13.16)

Pharmacokinetics Series – Clearance and Maintenance Dose

March 14, 2015 Pharmacokinetics, Pharmacotherapy, Therapeutics No comments , , , , ,

UCSFClearance and Maintenance Dose

Clearance can be thought of as the intrinsic ability of the body or its organs of elimination (usually the kidneys and the liver) to remove drug from the blood or plasma. Clearance is expressed as a volume per unit of time. It is important to emphasise that clearance is not an indicator of how much drug is being removed; it only represents the theoretical volume of blood or plasma which is completely cleared of drug in a given period. The amount of drug removed depends on the plasma concentration of drug and the clearance.

As steady state, the rate of drug administration (RA) and the rate of drug elimination (RE) must be equal, so that, RA = RE. Because RA can be described as (S)(F)(Dose/τ), and the RE equals to (Cl)(Css ave), we get the formula for Cl as Cl = (S)(F)(Dose/τ)/(Css ave) [Equation 1].

If an estimate for clearance is obtained from the literature, the clearance formula of [Equation 1] can be rearranged and used to calculate the rate of administration or maintenance dose that will produce a desired average plasma concentration of (Css ave) at steady state: Maintenance Dose = (Cl)(Css ave)(τ)/[(S)(F)] [Equation 2].

Attention must be paid that the units of all factors in these formulas must be consistent.


Factors Affecting Clearance

Body Surface Area/Weight

Most literature values for clearance are expressed as volume/kg/time or as volume/70 kg/time. There is some evidence, however, that drug clearance is best adjusted on the basis of BSA rather than weight. BSA can be calculated using BSA in m2 = (Patient’s Weight in kg/70 kg)0.7(1.73 m2) [Equation 3] or it can be obtained from various charts and nomograms. The value of a patient’s weight divided by 70 taken to the 0.7 power is an attempt to scale or size a patient as a fraction of the average 1.73 m2 or 70-kg individual. Weight divided by 70 taken to the 0.7 power has no units and should be thought of as the fraction of the average-size person.

As an example, a 7-kg patient has a weight ratio relative to 70 kg of 0.1 and, therefore, may be thought of as having a size and thus a metabolic and renal capacity that is one-tenth of the average 70-kg person (7 kg/70 kg = 0.1). If the same weight individual was compared to the 70-kg standard using weight to the 0.7 power, the ratio becomes 0.2 or 20%, (7 kg/70 kg)0.7 = 0.2. Therefore in these two examples, the difference between  0.1 and 0.2 is large. However, when patients do not differ significantly from 70 kg, the difference between using weight versus weight to the power 0.7 (BSA) becomes less significant.

The underlying assumption in using weight or surface area to adjust clearance is that the patient’s liver and kidney size (and hopefully function) vary in proportion to these physical measurements (weight or BSA). However, this may not always be the case; therefore, clearance values derived from the patient population having a similar age and size should be used whenever possible. When a patient’s size is substantially greater or less than the standard 70 kg, or 1.73 m2, a careful assessment should be made to determine if the patient’s body stature is normal, obese, or emaciated. In obese and emaciated patients, neither weight nor surface area is likely to be helpful in predicting clearance, since the patient’s body size will not reflect the size or function of the liver and kidney.

Plasma Protein Binding

For highly protein-bound drugs, diminished plasma protein binding is associated with a decrease in reported steady-state plasma drug concentrations (total of unbound plus free drug) for any given dose that is administered. According to Equation 1, a decrease in the denominator, (Css ave), increases the calculated clearance. This actually would be misleading, however, to assume that because the calculated clearance is increased, the amount eliminated of drug per unit of time has increased. Equation 1 assumes that when (Css ave) changes, the free drug concentration, which is available for metabolism and renal elimination, changes proportionately. In actuality the free or unbound fraction of drug in the plasma generally increases with diminished plasma protein binding. As a result, the amount of free drug eliminated per unit of time remains unchanged. This should be apparent if one considers that at steady state, the amount of drug administered per unit of time (RA) must equal the amount eliminated per unit of time (RE). If RA has not changed, RE must remain the same.

In summary, when the same daily dose of a drug is given in the presence of diminished protein binding, an amount equal to that dose will be eliminated from the body each day at steady state despite a diminished steady-state plasma concentration (Css ave) and an increase in the calculated clearance (Cl). This lower plasma concentration (C bound + C free) is associated with a decreased C bound, no change in C free, and as a result there is an increase in the fraction of unbound drug (fu). Therefore, the pharmacologic effect achieved will be similar to that produced by the higher serum concentration observed, under normal protein binding conditions. This example re-emphasizes the principle that clearance alone is not a good indicator of the amount of drug eliminated per unit of time (RE).

Extraction Ratio

The direct proportionality between calculated clearance and fraction unbound (fu) does not apply to drugs that are so efficiently metabolised or excreted that some (perhaps all) of the drug bound to plasma protein is removed as it passes through the elimination organ. In this situation the plasma protein acts as a “transport system” for the drug, carrying it to the eliminating organs, and clearance becomes dependent on the blood or plasma flow to the eliminating organ. To determine whether the clearance for a drug with significant plasma binding will be influenced primarily by blood flow or plasma protein binding, its extraction ratio is estimated and compared to its (fu) value.

The extraction ratio is the fraction of the drug presented to the eliminating organ that is cleared after a single pass through that organ. It can be estimated by dividing the blood or plasma clearance of a drug by the blood or plasma flow to the eliminating organ. If the extraction ratio exceeds the (fu), then the plasma proteins are acting as a transport system and clearance will not change in proportion to (fu). If, however, the extraction ratio is less than (fu), clearance is likely to increase by the same proportion that (fu) changes. This approach does not take into account other factors that may affect clearance such as red blood cell binding, elimination from red blood cells, or changes in metabolic function.

Renal and Hepatic Function

Drugs can be eliminated or cleared as unchanged drug through the kidney and by metabolism in liver. These two routes of clearance are assumed to be independent of one another and additive. A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination. However, as the major elimination pathway becomes increasingly compromised, the “minor” pathway becomes more significant because it assumes a greater proportion of the total clearance. For example, a drug that is usually 67% eliminated by the renal route and 33% by the metabolic route will be 100% metabolised in the event of complete renal failure; the total clearance, however, will only be one-third of the normal value.

Cardiac Output

Cardiac output also affects drug metabolism. Hepatic or metabolic clearances for some drugs can be decreased by 25% to 50% in patients with CHD. For example, the metabolic clearances of theophylline and digoxin are reduced by approximately one-half in patients with CHD. Since the metabolic clearance for both of these drugs is much lower than the hepatic blood or plasma flow (low extraction ratio), it would not have been predicted that their clearances would have been influenced by cardiac output. The decreased cardiac output and resultant hepatic congestion must, in some way, decrease the intrinsic metabolic capacity of the liver.