Pharmacokinetics – Distribution Series

November 11, 2017 Pharmacodynamics, Pharmacokinetics, Uncategorized No comments , , , , , , , , ,

As a result of either direct systemic administration or absorption from an extravascular route, drug reaches the systemic circulation, where it very rapidly distributes throughout the entire volume of plasma water and is delivered to tissues around the body. Two aspects of drug distribution need to be considered: how radidly, and to what extent, the drug in the plasma gets taken up by the tissues. A lot of information on the rate of drug disribution can be obtained by observing the pattern of the changes in the plasma concentrations in the early period following drug administration. Information about the extent of drug distribution can be obtained by considering the value of the plasma concentration once distribution is complete. Thus, the plasma concentration constitutes a "window" for obtaining information on the distribution of the bulk of the drug in the body and how it changes over time.

Extent of Drug Distribution

A drug must reach its site of action to produce an effect. Generally, this involves only a very small amount of the overall drug in the body, and access to the site of action is generally a problem only if the site is located in a specialized area or space. The second important aspect of the extent of drug distribution is the relative distribution of a drug between plasma and the rest of the body. This affects the plasma concentration of the drug and is important because: 1) as discussed above, the plasma concentration is the "window" through which we are able to "see" the drug in the body. It is important to know how a measured plasma concentration is related to the total amount of drug in the body; 2) Drug is delivered to the organs of elimination via the blood. If a drug distributes extensively from the plasma to the tissues, the drug in the plasma will constitute only a small fraction of the drug in the body. Little drug will be delivered to the organs of elimination, and this will hamper elimination. Conversely, it a drug is very limited in its ability to distribute beyond the plasma, a greater fraction of the drug in the body will be physically located in the plasma. The organs of elimination will be well supplied with drug, and this will enhance the elimination processes.

Drug distribution to the tissues is driven primarily by the passive diffusion of free, unbound drug along its concentration gradient. Consider the administration of a single intravenous dose of a drug. In the early period after administration, the concentration of drug in the plasma is much higher than that in the tissues, and there is a net movement of drug from the plasma to the tissues; this period is known as the distribution phase. Eventually, a type of equilibrium is established between the tissues and plasma, at which point the ratio of the tissue to plasma concentration remains constant. At this time the distribution phase is complete and the tissue and plasma concentrations rise and fall in parallel; this period is known as the postdistribution phase. It should be noted that after a single dose, true equilibrium between the tissues and the plasma is not achieved in the postdistribution phase because the plasma concentration falls constinuously as drug is eliminated from the body. This breaks the equilibrium between the two and results in the redistribution of drug from the tissues to the plasma. Uptake and efflux transporters in certain tissues may also be involved in the distribution process and may enhance or limit a drug's distribution to specific tissues.

Physiologic Volumes

Three important physiological volumes – plasma water, extracellular fluid, and total body water, are shown in Figure 4.2. In the systemic circulation, drugs distribute throughout the volume of plasma water (about 3 L). Where a drug goes beyond this, including distribution to the cellular elements of the blood, depends on the physicochemical properties of the drug and the permeability characteristics of individual membranes.

The membranes of the capillary epithelial cells are generally very loose in nature and permit the paracellular passage of even polar and/or large drug molecules. Thus, most drugs are able to distribute throughout the volume of extracellular fluid, a volume of about 15 L. However, the capillary membranes of certain tissues, notably delicate tissues such as the central nervous system, the placenta, and the testes, have much more tightly knit membranes, which may limit the access of certain drugs, particularly large and/or polar drugs.

Once in the extracellular fluid, drugs are exposed to the individual cells of tissues. The ability of drugs to penetrate the membrane of these cells is dependent on a drug's physicochemical properties. Polar drugs and large molecular mass drugs will be unable to pass cell membranes by passive diffusion. However, polar drugs may enter cells if they are substrates for specialized uptake transporters. On the other hand, efflux transporters will restrict the distribution of their substrates. Small lipophilic drugs that can easily penetrate cell membranes can potentially distribute throughout the total body water, which is around 40 L.

In summary, drugs are able to pass through most of the capillary membranes in the body and distribute into a volume approximately equal to that of the extracellular fluid (about 15 L). The ability of a drug to distribute beyond this depends primarily on its physicochemical characteristics. Small, lipophilic drug molecules should penetrate biological membranes with ease and distribute throughout the total body water (about 40 L). A drug's distribution to specific tissues may be enhanced by uptake transporters. Conversely, efflux transporters will restrict the tissue distribution of their substrates. Total body water, about 40 L, represents the maximum volume into which a drug can distribute.

Tissue Binding and Plasma Protein Binding

Given that drug distribution is driven primarily by passive diffusion, it would be reasonable to assume that once distribution has occurred, the concentration of drug would be the same throughout its distribution volume. This is rarely the case because of tissue and plasma protein binding. Drugs frequently bind in a reversible manner to sites on proteins and other macromolecules in the plasma and tissues. At this time it is important to appreciate that bound drug cannot participate in the concentration gradient that drives the distribution process. The bound drug can be considered to be secreted away or hidden in tissue or plasma. Binding has a very important influence on a drug's distribution pattern. Consider a drug that binds extensively (90%) to the plasma proteins but does not bind to tissue macromolecules. In the plasma, 90% of the drug is bound and only 10% is free and able to diffuse to the tissues. At equilibrium, the unbound concentrations in the plasma and tissue will be the same, but the total concentration of drug in the plasma will be much higher than that in the tissues.

Plasma protein binding has the effect of limiting distribution and concentrating drug in the plasma. On the other hand, consider a drug that binds extensively to macromolecules in the tissues but does not bind to the plasma proteins. Assume that overall 90% of the drug in the tissue is bound and only 10% is free. As the distribution process occurs, a large fraction of the drug in the tissues will bind and be removed from participation in the diffusion gradient. As a result, more and more drug will distribute to the tissues. When distribution is complete, the unbound concentrations in the plasma and tissues wil be the same, but the total (bound plus free) average tissue concentration will be much larger than the plasma concentration. Tissue binding essentially draws drug from the plasma and concentrates it in the tissues. Drugs often bind to both the plasma proteins and tissue macromolecules. In this case the final distribution pattern will be determined by which is the dominant process.

Assessment of the Extent of Drug Distribution

Once distribution has gone to completion, the ratio of the total tissue concentration to the total plasma concentration remains constant. The actual tissue concentration (and the ratio) will vary from tissue to tisue, depending on the relative effects of tissue and plasma protein binding. It is not possible to measure individual tissue concentrations, and it is convenient to consider an overall average tissue concentration (Ct). The ratio of Ct to Cp will vary from drug to drug.

It is important to find a way to express a drug's distribution characteristics using a number or distribution parameter that can easily be estimated clinically. The ratio discussed above (Ct/Cp) expresses distribution but cannot be measured easily. Instead, we use the ratio of amount of drug in the body vs. plasma concentration at the same time to express a drug's distribution, that is, the apparent volume of distribution (Vd).

It is important to appreciate that the (apparent) volume of distribution is simply a ratio that has units of volume. It is not physiological volume and, despite its name, it is not the volume into which a drug distributes. The fact that drug A has a Vd value of 20 L does not mean that it distributes into a volume of 20 L, which is greater than extracellular fluid and less than the total body water.

The value of a drug's volume of distribution can be used to estimate the fraction of the drug in the body that is physically present in either the plasma or the tissues. The drug in the body (Ab) may be partitioned into drug in the plasma (Ap) and drug outside the plasma or in the tissues (At):

Ab = Ap + At

the fraction of the drug in the plasma,

fraction in plasma = Ap / Ab

After some algebra, we get

fraction in plasma = Vp / Vd

In a standard 70-kg adult male, Vp = 3 L:

fraction in plasma = 3 / Vd

The fraction of the drug in the body located in the tissues:

fraction in tissue = 1 – fraction in plasma = 1 – 3 / Vd

With this formula we can estimate the fraction of drug in plasma and in tissues, respectively.

Drug in the body is located in either the plasma or the tissues. The amount of drug in either of these spaces is the product of the concentration of drug and the volume of the space. And because Ab = Ap + At, we get

Cp * Vd = Cp *Vp + Ct * Vt

where Cp is the plasma concentration of the drug, Vd the volume of distribution, and Vp the volume of plasma water, Ct the average tissue concentration of the drug, the Vt the overall volume of tissues that the drug distributes.

And because the unbound (free) drug concentration equals the total drug concentration multiplying fraction of unbound, while the unbound drug concentrations between plasma and tissues (extraceullar space) must be the same after reaching distribution equilibrium, we get,

Cp*fu = Ct * fut

After some algebra, we have

Vd = Vp + Vt * fu / fut

where fu is the fraction of unbound drug in plasma and fut is the fraction of unbound drug in tissues. This final equation shows that a drug's volume of distribution is dependent on both the volume into which a drug distributes and on tissue and plasma protein binding. It also shows that increased tissue binding (fut gets smaller) or decreased plasma protein binding (fu gets larger) will result in an increase in the volume of distribution. Also, if a drug binds to neither the plasma proteins (fu = 1) nor the tissues (fut = 1), its volume of distribution will be equal to that of the volume into which the drug distributes (physiologic volume).


  • Vd is a ratio that reflects a drug's relative distribution between the plasma and the rest of the body.
  • It is dependent on the volume into which a drug distributes and a drug's binding characteristics.
  • It is a constant for a drug under normal conditions.
  • Conditions that alter body volume may affect its value.
  • Altered tissue and/or protein binding may alter its value.
  • It provides information about a drug's distribution pattern. Large values indicate extensive distribution of a drug to the tissues.
  • It can be used to calculate the amount of drug in the body if a drug's plasma concentration is known.

Plasma Protein Binding

A very large number of therapeutic drugs bind to certain sites on the proteins in plasma to form drug-protein complexes. The binding process occurs very rapidly, it is completely reversible, and equilibrium is quickly established between the bound and unbound forms of a drug. If the unbound or free drug concentration falls due to distribution or drug elimination, bound drug dissociates rapidly to restore equilibrium. Clinically, although the total drug concentration is measured routinely, pharmacological and toxicological activity is thought to reside with the free unbound drug (Cpu). It is only this component of the drug that is thought to be able to diffuse across membranes to the drug's site of action and to interact with the receptor. Binding is usually expressed using the parameter fraction unbound (fu), and the unbound pharmacologically active component can be calculated:

Cpu = Cp * fu

The three primary plasma proteins combining drugs include albumin, 𝛼1-acid glycoprotein (AAG), and the lipoproteins. AAG is present in lower concentration than albumin and binds primarily neutral and basic drugs. It is referred to as an acute-phase reactant protein because its concentration increases in response to a variety of unrelated stressful conditions, such as cancer, inflammation, and acute myocardial infarction. Given that the unbound concentration is the clinical important fraction and that it is the total concentration that is routinely measured, it is important to know how and when the unbound fraction may change for a drug.

The binding of drug and plasma protein could be regarded as a drug and "receptor" interaction (occupation). So the pharmacodynamic Emax model could be used to describe this interacton mathematically. After some algebra modifications, we get


where PT is the serum concentration of plasma binding protein, Kd the equilibrium dissociation constant, and the Cpu the plasma concentration of unbound (free) drug.

At low concentrations, binding increases in direct proportion to an increase in the free drug (fu remains constant as Cpu increases, where Cpu < Kd). As the free drug concentration increases further, some saturation of the proteins occurs, and proportionally less drug can bind (fu will increase as Cpu increases further). Eventually, at high drug concentrations, all the binding sites on the protein are taken and binding cannot increase further.

The Changes of fu

  • Affinity

The affinity of the drug for the protein is the main determinant of fu. Affinity is expressed by Kd, which is a reciprocal form of affinity. As affinity increases, Kd gets smaller. Drugs with small Kd values bind extensively, whereas those with large Kd values will not bind extensively.

  • Free drug concentration

Because the therapeutic plasma concentrations of most drugs are much less than their Kd values, binding is able to increase in proportion to increases in the total concentration: fu remains constant over therapeutic plasma concentrations. There are, however, a few drugs that have therapeutic plasma concentrations that are around the range of their Kd values. These drugs, which tend to be drugs that have very high therapeutic plasma concentrations, include valproic acid and salicylates, both of which bind to albumin, and disopyramide, which binds to AAG. The binding of these drugs uses a substantial amount of protein, and as a result they display concentration-dependent binding. As the drug concentration increases, some degree of saturation is observed, and the fraction unbound gets larger.

  • Plasma binding protein concentration

As predicted by the law of mass action, changes in the protein concentration will produce changes in the degree of binding. In the case of AAG, increases in the concentration are more common. Physiological stress caused by myocardial infarction, cancer, and surgery can lead to four- to fivefold increases in the AAG concentration. Lipoprotein concentrations vary widely in the population. They can decrease as a result of diet and therapy with HMG-CoA reductase inhibitors (statins), and increase due to alcoholism and diabetes mellitus.

  • Displacement

The binding of one drug may displace a second drug from its binding site. This displacement occurs because two drugs compete for a limited number of binding sites on the protein. Not surprisingly, displacers tend to be those drugs that achieve high concentrations in the plasma, use up a lot of protein, and display concentration-dependent binding.

  • Renal and hepatic disease

The binding of drugs to ablumin is often decreased in patients with severe renal disease. This appears to be the result of both decreased albumin levels and the accumulation of compounds that are normally eliminated, which may alter the affinity of drugs for albumin and/or compete for binding sites. The binding of several acidic drugs, including phenytoin and valproic acid, is reduced in severe renal disease. Plasma protein binding may also be reduced in hepatic disease.

Clinical Consequences of Changes in Plasma Protein Binding

Changes in fu as a result of altered protein concentration or displacement will result in a change in the fraction of the total drug that is unbound. Two issues need to be addressed when considering the clinical consequences of this: the potential changes in the unbound drug concentration at the site of action, and the interpretation and evaluation of the routinely measured total plasma concentrations.

When binding decreases, the pharmacologically active unbound component increases, and in theory, the response or toxicity could increase. However, the clinical consequences of altered plasma protein binding are minimized by two factors: 1) increased elimination and 2) little change in drug concentrations outside the plasma.

In many cases, only the unbound drug is accessible to the organs of elimination. This is known as restrictive elimination because elimination is restricted by protein binding and is limited to the unbound drug. For drugs display restrictive clearance, the increase in the unbound concentration that occurs when binding decreases results in an increase in elimination of the drug. The increase in elimination is usually proportional to the increase in unbound concentration. As a result, the unbound drug concentration in the plasma eventually falls to exactly the same value as that before the change in binding. In other words, the increase in the unbound concentration is canceled out by increased elimination.

The time it takes for the unbound concentration to return to its normal level is determined by the rate of elimination of the drug (the elimination half-life). If the drug is eliminated rapidly, the unbound concentration returns to its original level quickly. If the drug is eliminated slowly, it takes a long time for the unbound concentration to return to its original level. The time it takes to return can be important for drugs that have a narrow therapeutic index.

The plasma comprises a relative small physiological volume (3 L). Even when plasma protein binding is extensive, the fraction of the drug in the body that is located in the plasma is much less than that in the tissues. As a result, when the fraction unbound increases, the extra drug that distributes to the tissue is often very small in comparison to the amount of drug already present. This is particularly the case for drugs that have large volumes of distribution, where the majority of the drug in the body is in the tissues and only a very small fraction resides in the plasma.

Interpreting Cp

In clinical practice, drug therapy may be monitored by ensuring that plasma concentrations lie within the therapeutic range. The therapeutic range of a drug is expressed most conveniently in terms of concentration routinely measured, the total plasma concentration (Cp). But since the unbound concentration is the pharmacologically active component, the therapeutic range should more correctly be expressed in terms of this unbound concentration. Formulas have been developed for some drugs that will convert a measured plasma concentration of a drug to the value that it would be if the protein concentration were normal. We can prove the below formula with algebra modification.

 (when plasma drug concentration << Kd)

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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Drug Interactions to Warfarin

March 22, 2017 Drug Informatics, Drug Interactions, Pharmacodynamics, Pharmacokinetics No comments , , , , , , ,

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Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.


  • Synergism
  • Competitive antagonism
  • Alteration of vitamin K cycle and metabolism


  • Enzyme induction
  • Enzyme inhibition
  • Reduced plasma protein binding

CYP450 Interactions

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CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Antibiotics and Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Botanical (Herbal) Products and Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium. Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

[Endocrinology] The Agonist-Receptor Interaction and Pharmacodynamics of Thyroid Hormone

October 14, 2016 Endocrinology, Pharmacodynamics, Pharmacology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , ,

rs_634x1024-160907091929-634-justin-chambers-greys-anatomy-abcThyroid Hormone Receptors and Cellular Events

Thyroid hormone receptors are expressed in virtually all tissues and affect multiple cellular events. The cellular actions of thyroid hormones are mediated by multiple thyroid hormone receptor isoforms derived from 2 distinct genes (alpha and beta) encoding thyroid hormone receptors. The functional significance of the different isoforms has not yet been elucidated. Thyroid hormone recetpors are nuclear receptors intimately associated wtih chromatin. Thyroid hormone receptors are DNA-binding transcription factors that function as molecular switches in response to hormone binding. The hormone receptor can activate or repress gene transcription, depending on the promoter context and ligand-binding status. Unoccupied thyroid hormone receptors are bound to DNA thyroid hormone response elements and are associated with a complex of proteins containing corepressor proteins. Hormone binding to the receptor promotes corepressor dissociation and binding of a coactivator, leading to modulation of gene transcription. Thyroid hormone receptors bind the hormone with high affinity and specificity. They have low capacity but high affinity for T3. The majority (85%) of nuclear-bound thyroid hormone is T3, and approximately 15% is T4.

Thyroid hormones enter cells by a carrier-mediated energy-, temperature-, and Na+-dependent process. Several transporters have been identified to be involved in their entry into the cell, including those belonging to the sodium taurocholate cotransporting polypeptide (NTCP), the sodium-independent organic anion transporting polypeptide (OATP), L- and T-type amino acid transporters, and members of the monocarboxylate transporter family. Two transporters have been demonstrated to have particular specificity for thyroid hormone transport, the OATP1C1, which shows preference for T4 and the MCT8 which shows preference for T3. Mutations or deletions in the MCT8 gene have been linked to psychomotor retardation and thyroid hormone resistance, indicating their contribution to optimal thyroid hormone function.

Cellular Events of Thyroid Hormone

  • Transcription of cell membrane Na+/K+-ATPase, leading to an increase in oxygen consumption
  • Transcription of uncoupling protein, enhancing fatty acid oxidation and heat generation without production of adenosine triphosphate
  • Protein synthesis and degradation, contributing to growth and differentiation
  • Epinephrine-induced glycogenolysis, and insulin-induced glycogen synthesis and glucose utilization
  • Cholesterol synthesis and low-density lipoprotein receptor regulation

Physiologic Effects of Thyroid Hormone

Thyroid hormones are essential for normal growth and development; they control the rate of metabolism and hence the function of practically every organ in the body (remember that the thyroid hormone receptors are expressed in virtually all tissues). Their specific biologic effects vary from one tissue to another.

The effects of thyroid hormone are mediated primarily by the transcriptional regulation of target genes, and are thus known as genomic effects. Recently, it has become evident that thyroid hormones also exert nongenomic effects, which do not require modification of gene transcription. Some of these effects include stimulation of activity of Ca2+ adenosine triphosphatease (ATPase) at the plasma membrane and sarcoplasmic reticulum, rapid stimulation of the Na+/H+ antiporter, and increases in oxygen consumption. The nature of the receptors that mediate these effects and the signaling pathways involved are not yet completely elucidated. However, T3 exerts rapid effects on ion fluxes and electrophysiologic events, predominantly in the cardiovascular system.


Thyroid hormone is essential for bone growth and development through activation of osteoclast and osteoblast activities. Deficiency during childhood affects growth. In adults, excess thyroid hormone levels are associated with increased risk of osteoporosis.

Cardiovascular System

Thyroid hormone has cardiac inotropic and chronotropic effects, increases cardiac ouput and blood volume, and decreases systemic vascular resistance. These responses are mediated through thyroid hormone changes in gene transcription of several proteins including Ca2+-ATPase, phospholamban, myosin, beta-adrenergic receptors, adenylyl cyclase, guanine-nucleotide-binding proteins, Na+/Ca2+ exchanger, Na+/K+-ATPase, and voltage-gated potassium channels.


Thyroid hormone induces white adipose tissue differentiation, lipogenic enzymes, and intracellular lipid accumulation; stimulates adipocyte cell proliferation; stimulates uncoupling proteins; and uncouples oxidative phosphorylation. Hyperthyroidism enhances and hypothyroidism decreases lipolysis through different mechanisms. The induction of catecholamine-mediated lipolysis by thyroid hormones results from an increased beta-adrenoceptor number and a decrease in phosphodiesterase activity resulting in an increase in cAMP level and hormone-sensitive lipase activity.


Thyroid hormone regulates triglyceride and cholesterol metabolism, as well as lipoprotein homeostasis. Thyroid hormone also modulates cell proliferation and mitochondrial respiration.


Thyroid hormone regulates the synthesis of pituitary hormones, stimulates growth hormone production, and inhibits TSH.


Thyroid hormone controls expression of genes involved in myelination, cell differentiation, migration, and signaling. Thyroid hormone is necessary for axonal growth and development.

Write Again – Receptor Rationale – Pharmacodynamics

April 22, 2016 Pharmacodynamics, Pharmacology No comments , , , , , , , , , , , , , , , , , , , ,

Screen Shot 2016-08-23 at 8.19.15 PMType of Drug Receptors

The effects of must drugs result from their interaction with macromolecular components of the organism. These interactions alter the function of the pertinent component and initiate the biochemical and physiological changes that are characteristic of the response to the drug. The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular response, i.e., change in cell function.

From a numerical standpoint, proteins form the most important class of drug receptors. Examples include the receptors for hormones, growth factors, transcription factors, and neurotransmitters; the enzymes of crucial metabolic or regulatory pathways; proteins involved in transport processes; secreted glycoproteins; and structural proteins. Specific binding of drugs to other cellular constituents such as DNA is also exploited for therapeutic purposes.

Drugs commonly alter the rate or magnitude of an intrinsic cellular response rather than create new responses. Drug receptors are often located on the surface of cells, but may also be located in specific intracellular compartments such as the nucleus. Many drugs also interact with acceptors (e.g., serum albumin) within the body. Acceptors are entities that do not directly cause any change in biochemical or physiological response. However, interactions of drugs with acceptors such as serum ablumin can alter the pharmacokinetics of a drug's action.

A major group of drug receptors consists of proteins that normally serve as receptors for endogenous regulatory ligands. These drug targets are termed physiological receptors. Many drugs act on physiological receptors and are particularly selective because physiological receptors have evolved to recognize and respond to individual signaling molecules with great selectivity.

Type of Drugs – From Perspective of Pharmacodynamics

Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists. If the drug binds to the same recognition site as the endogenous agonist the drug is said to be primary agonist. Allosteric (allotopic) agonists bind to a different region on the receptor referred to as an allosteric or allotopic site.

Drugs that block or reduce the action of an agonist are termed antagonists. Antagonism most commonly results from competition with an agonist for the same or overlapping site on the receptor (a syntopic interaction, or "primary" antagonism, or competitive antagonism), but can also occur by interacting with other sites on the receptor (allosteric antagonism), by combining with the agonist (chemical antagonism), or by functional antagonism by indirectly inhibiting the cellular or physiological effects of the agonist.

Agents that are only partly as effective as agonists regardless of the concentration employed are termed partial agonists.

Many receptors exhibit some constitutive activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed inverse agonists.

Drug Specificity

The chemical structure of a drug contributes to the drug's specificity. A drug that interacts with a single type of receptor that is expressed on only a limited number of differentiated cells will exhibit high specificity. If, however, a receptor is expressed ubiquitously on a variety of cells throughout the body, drugs acting on such a widely expressed receptor will exhibit widespread effects, and could produce serious side effects or toxicities if the receptor serves important functions in multiple tissues.

Quantitative Aspects of Drug Interactions with Receptors

Screen Shot 2016-04-18 at 8.36.23 PMReceptor occupancy theory asumes that response emanates from a receptor occupied by a drug, a concept that has its basis in the law of mass action. The basic currency of receptor pharmacology is the dose-response (or concentration-response) curve, a depiction of the observed effect of a drug as a function of its concentration in the receptor compartment. Figure 3-2 shows a typical dose-response curve; it reaches a maximal asymptotic value when the drug occupies all the receptor sites.

In general, the drug-receptor interaction is characterized by 1.binding of drug to receptor and 2.generation of a response in a biological system, as illustrated in Equation 3-1 where the drug or ligand is denoted as L and the inactive receptor as R. The first reaction, the reversible formation of the lignad-receptor complex LR, is governed by the chemical property of affinity. LR* is produced in produced in proportion to [LR] and leads to a response. This simple relationship illustrates the reliance of the affinity of the ligand (L) with receptor (R) on both the forward or association rate (k+1) and the reverse or dissociation rate (k-1). At any given time, the concentration of ligand-receptor complex [LR] is equal to the product of k+1[L][R], the rate of formation of the bi-molecular complex LR, minus the product k-1[LR], the rate dissociation of LR into L and R. At equilibrium, k+1[L][R] = k-1[LR]. Because the equilibrium dissociation constant (KD) is then described by ratio of the off and on rate constants (KDk-1/k+1), thus at equilibrium KD = k-1/k+1 = [L][R] / [LR] (Equation 3-2).

Screen Shot 2016-04-18 at 9.04.40 PMThe affinity constant or equilibrium association constant (KA) is the reciprocal of the equilibrium dissociation constant (KA = 1/KD); thus a high-affinity drug has a low KD and will bind a greater number of receptor at a low concentration than a low concentration than a low-affinity drug. As a practical matter, the affinity of a drug is influenced most often by changes in its off-rate (k-1) rather than its on-rate (k+1).

Screen Shot 2016-04-18 at 9.20.47 PMEquation 3-2 permits us to write an expression of the fractional occupancy (f) of receptors by agonist, Equation 3-3. This can be expressed in terms of KA (or KD) and [L]: f = [L]/([L] + KD). This relationship illustrate that under the condition of equilibrium and when the concentration of drug equals the KD, f = 0.5, that is, the drug will occupy 50% of the receptors. Note that this relationship describes only receptor occupancy, not the eventual response that is often amplified by the cell.

  • Occupation 

The second reaction shown in Equation 3-1 is the reversible formation of the active ligand-receptor complex, LR*. The ability of a drug to activate a receptor and generate a cellular response is a reflection of its efficacy. A drug with high efficacy may be a full agonist, eliciting, at some concentration, a full response. A drug with a lower efficacy at the same receptor may not elicit a full response at any dose. When it is possible to describe the relative efficacy of drugs at a particular receptor, a drug with a low intrinsic efficacy will be a partial agonist. A drug that binds to a receptor and exhibit zero efficacy is an antagonist. When the response of an agonist is measured in a simple biological system, the apparent dissociation constant, Kapp, is a macroscopic equilibrium constant that reflects both the ligand binding equilibrium and the subsequent equilibrium that results in the formation of the active receptor LR*.

Potency and Efficacy


When the relative potency of two agonists of equal efficacy is measured in the same biological system, and downstream signaling events are the same for both drugs, the comparison yields a relative measure of the affinity and efficacy of the two agonists (Figure 3-3). It is convenient to describe agonist response by determining the half-maximally effective concentration (EC50) for producing a given effect. Thus, measuring agonist potency by comparison of EC50 values is one method of measuring the capability of different agonists to induce a response in a test system and for predicting comparable activity in another. Another method of estimating agonist activity is to compare maximal asymptotes in systems where the agonists do not produce maximal response (Figure 3-3B). The advantage of using maxima is that this property depends solely on efficacy, whereas drug potency is a mixed function of both affinity and efficacy.Screen Shot 2016-04-22 at 7.52.20 PM

PS: Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect.


For antagonists, characteristic patterns of antagonism are associated with certain mechanisms of blockade of receptors. One is straightforward competitive antagonism, whereby a drug with affinity for a receptor but lacking instrinsic efficacy competes with the agonist (i.e., endogenous ligands) for the primary binding site on the receptor. The characteristic pattern of such antagonism is the concentration-dependent production of a parallel shift to the right of the agonist dose-response curve with no change in the maximal response. The magnitiude of the rightward shift of the curve depends on the concentration of the antagonist and its affinity for the receptor. A partial agonist similarly can compete with a "full" agonist for binding to the receptor. However, increaseing concentrations of a partial agonist will inhibit response to a finite level characteristic of the drug's intrinsic efficacy; in contrast, a competitive antagonist will reduce the response to zero. Partial agonists thus can be used therapeuticallu to buffer a response by inhibiting excessive receptor stimulation without totally abolishing receptor stimulation.

An antagonist may dissociate so slowly from the receptor that its action is exceedingly prolonged, as with the opiate partial agonist buprenorphine and the Ca2+ channel blocker amlodipine. In the presence of a slowly dissociating antagonist, the maximal response to the agonist (i.e., endogenous ligand) will be depressed at some antagonist concentrations. Operationally, this is referred to as noncompetitive antagonism, although the  molecular mechanism of action really cannot be inferred unequivocally from the effect. An antagonist may also interact irreversibly (covalently) with a receptor to produce relatively irreversible effects. Noncompetitive antagonism antagonism can also be produced by another type of drug, referred to as an allosteric or allotopic antagonist. This type of drug produces its effect by binding to a site on the receptor distinct from that of the primary agonist, thereby changing the affinity of the receptor for the agonist. In the case of an allosteric antagonist, the affinity of the receptor for the agonist is decreased by the antagonist. In contrast, a drug binding at an allosteric site could potentiate the effects of primary agonists; such as drug would be referred to as an allosteric agonist or co-agonist.