Month: December 2014

How to Choose, Monitor, and Evaluate the Therapeutic Regimen (Pharmacologic Perspective)

December 12, 2014 Adverse Drug Reactions, Pharmacokinetics, Pharmacology, Pharmacotherapy, Therapeutics No comments , , , ,

The relation between drug dose and clinical response is compared with drug concentration/dose and pharmacologic response. The relation between drug concentration and drug response is in carefully controlled systems in vitro, which can be relative simple. Conversely, the relation between dose of a drug and the clinically observed response may be complex (actually it is true). To make rational therapeutic decisions, the prescriber must understand how drug-receptor interactions underline the relations between dose and response in patients, the nature and causes of variation in pharmacologic responsiveness, and the clinical implications of selectivity of drug action.

Relationship Between Dose and Response in Patients

Attention must be paid that the "response" here is different with the "response" in the thread of The Properties of Drugs – Receptor Rationale, where it means the stimulation of a receptor, or inhibition of an enzyme, etc. The term "respond" in this thread means the physiologic effect such as the response of bronchodilatation, lowering of cholesterol, etc.

PS: Drug response can be distinguish among the Pharmacologic Action, the Physiologic Effect, and the Clinical Outcome.


Dose and Response in Patients

1.Graded Dose-Response Relations/Graded Dose-Response Curves

Screen Shot 2014-12-09 at 9.24.10 PMPotency

To choose among drugs and to determine appropriate doses of a drug, the prescriber must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to the desired therapeutic effect. These two important terms, often confusing to students and clinicians, can be explained by referring to the figure at the right side. Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect. Therefore, according to the figure on the right side, potency of drug A is less than that of drug B, despite the drug B is a partial agonist.

Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response (transduce receptor occupancy into cellular response). However, attention must be paid that some doses of drug A can produce larger effects than any dose of drug B, despite the fact that drug B is more pharmacologic potent. The reason for this is that drug A has a larger maximal efficacy.

For clinical use, it is important to distinguish between a drug's potency and its efficacy. The clinical effectiveness of a drug depends not on its potency (EC50/ED50), but on its maximal efficacy and its ability to reach the relevant receptors. This ability can depend on its route of administration, absorption, distribution through the body, and clearance from the blood or site of action. In deciding which of two drugs to administer to a patient, the prescriber must usually consider their relative effectiveness rather than their relative potency. Pharmacologic potency can largely determine the administered dose of the chosen drug. For therapeutic purposes, the potency of a drug should be stated in dosage units, usually in terms of a particular therapeutic end point (e.g., 50 mg for mild sedation, 1 mug/kg/min for an increase in heart rate of 25 bp). Relative potency, the ratio of equip-effective doses (0.2, 10, etc), may be used in comparing one drug with another.

Maximal Efficacy

This parameter reflects the limit of the dose-response relation on the response axis. In the figure on the right, drug A, C, and D have equal maximal efficacy, and all have greater maximal efficacy than drug B. The maximal efficacy (sometimes referred to simply as efficacy) of a drug is obviouslly crucial for making clinical decisions when a large response is needed. It may be determined by the drug's mode of interactions with receptors as with partial agonists or by characteristics of the receptor-effector system involved.

Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blcoks some of the receptor sites (see below). It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist's inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonists, as explained in the figure below.

Screen Shot 2014-12-12 at 11.53.43 PMHowever, clinicians must note that "maximal efficacy," used in a therapeutic context, dose not have exactly the same meaning that the term denotes in the more specialised context of drug-receptor interactions, or more exactly pharmacologic actions. In an idealised in vitro system, efficacy denotes the relative maximal efficacy of agonists and partial agonists that act via the same receptor. In therapeutics, efficacy denotes the extent or degree of an effect (or physical effect) that can be achieved in the intact patient. Thus, therapeutic efficacy may be affected by the characteristics of a particular drug-receptor interaction (pharmacologic action), but it also depends on a host of other factors, for example, a drug's practical efficacy might be limited by the drug's propensity to cause a toxic effect even if the drug could otherwise produce a greater therapeutic effect.

Shape of Graded Dose-Response Curves

Extremely steep dose-response curves (curve D in Figure 2-15) may have important clinical consequences if the upper portion of the curve represents an undesirable extent of response (e.g., coma caused by a sedative-hypnotic). Steep graded dose-response curves in patients can result from cooperative interactions of several different actions of a drug (e.g., effects on brain, heart, and peripheral vessels, all contributing to lowering of blood pressure).

Quantal Dose-Effect Curves

detail: http://forum.tomhsiung.com/pharmacy-research-study-and-policy/pharmacokinetics-and-pharmacodynamics/600-quantal-dose-effect-curves.html#post981

Graded dose-response curves have certain limitations in their application to clinical decision making. For example, such curves may be impossible to construct if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death. Furthermore, the clinical relevance of a quantitative dose-response relation in a single patient, no matter how precisely defined, may be limited in application to other patients, owing to the great potential variability among patients in severity of disease and responsiveness to drugs.

Therefore, a new type of dose-response curves – Quantal Dose-Effect Curves, is used to overcome these limitations. The curves determines the dose of drug required to produce a specified magnitude of effect in a large number of individual patients or experimental animals and plots the cumulative frequency distribution of responders versus the log dose (the figure above). The specified quantal effect may her chosen on the basis of clinical relevance, or for preservation of safety of experimental subjects, or it may be an inherently quantal event such as death of an experimental animal.

For most drugs, the doses required to produce a specified quantal effect in individuals are log normally distributed; that is, a frequency distribution of such responses plotted against the log of the dose produces a gaussian normal curve of variation. When these responses are summated, the resulting cumulative frequency distribution constitutes a quantal dose-effeec curve of the proportion or percentage of individuals who exhibit the effect plotted as a function of log dose. In the Quantal Dose-Effect Curves, we also use the abbreviation of ED50 to describe the potency of a drug, however the word of ED50 in Quantal Dose-Effect Curves has a different meaning from the one in Graded Dose-Response Curves, which means the dose at which 50% of individuals exhibit the specified quantal effect. Thus, if the ED50s of two drugs for producing a specified quantal effect are 5 and 500 mg, respectively, then the first drug can be said to be 100 times more potent than the second for that particular effect. In the same way, the value of TD50 ("T" means toxic) can be used to compare the risk of two drugs.

PS: the ratio of TD50 to ED50 defines the therapeutic index, which is an index to estimate the potential benefit and risk in therapeutics.

However, the therapeutic index of a drug in humans is almost never known with real precision; instead, drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses. The clinical acceptable risk of toxicity depends critically on the severity of the disease being treated. For example, the dose range that provides relief from an ordinary headache in the majority of patients should be very much lower than the dose range that produce serious toxicity, even if the toxicity occurs in a small minority of patients. However, for treatment of a lethal disease such as Hodgkin's lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller.


Variation in Drug Responsiveness

Individuals may vary considerably in their response to a drug; indeed, a single individual may respond differently to the same drug at different times during the course of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients. The idiosyncratic responses are usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions.

Quantitative variations in drug response are in general more common and more clinically important. An individual patient is hyporeactive or hyperactive to drug in that the intensity of effect of a given dose of drug is diminished or increased compared with the effect seen in most individuals. With some drugs, the intensity of response to a given dose may change during the course of therapy; in these cases, responsiveness usually decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug's effects. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis.

Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times.

1.Alteration in Concentration of Drug That Reaches The Receptor

These alteration factors primarily belong to pharmacokinetic parameters that alter the absorption, the distribution, the metabolism, and the clearing of a drug during the process within in the intact individual. These factors alter the concentration of drug that reaches relevant receptors, as a result, finally the physiologic/clinical response.

Another important mechanism influencing drug availability is active transporters which can put the drug back outside the area where the drug take effect, including the cell level (efflux of drug from cytoplasm), the tissue level (efflux of drug from gastrointestinal epithelium back to the lumen), and the organ level (efflux of drug from BBB). For example, up-regulation of MDR gene-encoded transporter expression is a major mechanism by which tutor cells develop resistance to anticancer drugs.

2.Variation in Concentration of an Endogenous Receptor Ligand

This mechanism contributes greatly to variability in responses to pharmacologic antagonists. Two examples available here. Propranolol, a β-adrenoceptor antagonist, markedly slows the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but dose not affect the resting heart rate of a well-trained marathon runner. In the same way, Saralasin, a weak partial agonist at angiotensin II receptors, lowers blood pressure in patients with hypertension caused by increased angiotensin II production and raises blood pressure in patients who produce normal amounts of angiotensin. Well, I did not find any detail information from references about this view. However, I have made my own theory or rationale for it.

To understand why the responses are so that result in the two example above, I drew a draft to show the theory or rationale. Here I only explain the example of propranolol and the other example is in the same way. OK, in the figure below, the patient with pheochromocytoma is on the left and the well trained marathon runner is on the right. The small circles represent the β1 receptors on the heart, and the black brushing means catecholamine-receptor binding, whereas the red brushing means propranolol-receptor binding. Let's assume that the physiologic effect per receptor activating is E. Therefore, before the administrations of propranolol in both individuals, respectively, the physiologic effects/responses in two individuals should be 9E and 3E respectively.

Because the amount of unbound receptors in the marathon runner is significantly more than unbound receptors in the patient of pheochromocytoma, so after the administration of some doses of propranolol, the amount of catecholamine-receptor binding replaced by propranolol-receptor binding in the patient is significantly more than that of the marathon runner (resting status). As a result, the physiologic effects after the administration of propranolol should be 4E and 2E, in the patient and the marathon runner respectively. Therefore, the ΔE in two individuals should be 5E and 1E respectively. As a result, the change in the physiologic response (the decrease of the heart rate) is much more significant in the patient with pheochromocytoma than in the well trained marathon runner (resting status).

3.Alterations in Number and/or Function of Receptors

Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. Generally, hormones, genetic parameters, and the ligand itself can induce the change of number and/or the function of specific receptors (i.e., thyroid hormones, analgesics, etc.)

This factor correlates very closely to the former threads talking about the drug receptor interaction, or the pharmacologic action. We have discuss this topic very detail in those threads. If you want to know detail please refer to these threads on this blog.

4.Changes in Components of Response Distal to The Receptor

Although a drug initiates its actions by binding to receptors, the response observed in a patient depends on the functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems. Clinically, changes in these post receptor processes represent the largest and most important class of mechanisms that cause variation in responsiveness to drug therapy.

Factors in this category includes patient characteristics such as the age and the general health of the patient, the severity and pathophysiologic mechanism of the disease the patient facing. The most important potential cause of failure to achieve a satisfactory response is that the diagnosis is wrong or physiologically incomplete. Drug therapy is always most successful when it is accurately directed at the pathophysiologic mechanism responsible for the disease.

When the diagnosis is correct and the drug is appropriate, an unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihypertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic result.


Clinical Selectivity: Beneficial Versus Toxic Effects of Drugs

Although we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific effect. Why is this so? It is exceedingly unlikely that any kind of drug molecule will bind to only a single type of receptor molecule, if only because the number of potential receptors in every patient is astronomically large. Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in many cell types and would be coupled to many other biochemical functions; as a result, the patient and the prescriber would probably receive more than one drug effect.

Accordingly, drugs are only selective – rather than specific – in their actions, because they bind to one or a few types of receptor more tightly than to others and because these receptors control discrete processes that result in distinct effect.

Selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo. In therapeutics, selectivity is usually considered by separating effects into two categories: beneficial or therapeutic effects versus toxic or adverse effects.

There are three aspects to understand the beneficial and toxic effects.

1.Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism

Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug. In some of these cases (e.g., bleeding caused by anticoagulant therapy; hypoglycemic coma due to insulin), toxicity may be avoid by judicious management of the dose of drug administered, guided by careful monitoring of effect (to monitor the blood coagulation or the serum glucose level) and aided by ancillary measures (avoiding tissue trauma that may lead to haemorrhage; regulation of carbohydrate intake).

In still other cases, the toxicity may be avoided by not administering the drug at all, if the therapeutic indication is weak or if other therapy is available. And in certain situations, a drug is clearly necessary and beneficial but produces unacceptable toxicity when given in dose that produce optimal benefit. In such situations, it may be necessary to add another drug to the treatment regimen (in oder to reduce the dose of the first drug required).

2.Beneficial and Toxic Effects Mediated by Identical Receptors but in different Tissues or by Different Effector Pathways

Many drugs produce both their desired effects and adverse by acting on a single receptor type in different tissues. Three therapeutic strategies are used to avoid or mitigate this sort of toxicity. First, the drug should always be administered at the lowest dose that produces acceptable benefit. Second, adjunctive drugs that act through different receptor mechanisms and produce different toxicities may allow lowering the dose of the first drug, thus limiting tis toxicity. Third, selectivity of the drug's actions may be increased by manipulating the concentrations of drug available to receptors in different parts of the body.

3.Beneficial and Toxic Effects Mediated by Different Types of Receptors

This issue is not only a potentially annoying in treating patients but presents a continuing challenge to pharmacology and an opportunity for developing new and more useful drugs.

 

Ligand- and Voltage-Gated Channels (Receptors)

December 7, 2014 Pharmacology No comments , ,

Screen Shot 2014-12-07 at 10.48.47 PMLigand-Gated Channels

Some ligands including natural and agents regulate the flow of ions through plasma membrane channels which could be understood as ligand-gated receptors/channels. The natural ligands are acetylcholine, serotonin, GABA, and glutamate and all are synaptic transmitters. Each of their receptors transmits it signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane.

The mechanism of the action of ligand-gated receptors is simple. When a ligand binds to sites on the ligand-gated receptor, a conformational change occurs that results in the transient opening of a central aqueous channel through which the relative ions (e.g., sodium, calcium, etc) penetrate from the extracellular fluid into the cell or outflow from intracellular cytoplasm into extracellular fluid.

The time elapse between the binding of the agonist to a ligand-gated channel and the cellular response can often be measured in milliseconds. The rapidity of this signalling mechanism is crucially important for moment-to-moment transfer of information across synapses.

Ligand-gated ion channels can be regulated by multiple mechanisms, including phosphorylation and endocytosis. In the CNS, these mechanisms contribute to synaptic plasticity involved in learning and memory.

Voltage-Gated Channels

Voltage-gated ion channels do not bind ligands directly but are controlled by membrane potential; such channels are also important drug targets. For example, verapamil inhibits voltage-gated calcium channels that are present in the heart and in vascular smooth muscle, producing anti arrhythmic effects and reducing blood pressure without mimicking or antagonising any known endogenous transmitter.

The Plasma Protein Concentration and The Interpretation of TDM Report

December 5, 2014 Pharmacokinetics, Therapeutics No comments , ,

Most clinical laboratory reports of drug concentrations in plasma (C) represent drug that is bound to plasma protein plus drug that is unbound of free. It is the free or unbound drug that is in equilibrium with the receptor site and is, therefore, the pharmacologically active moiety. Thus, in the case of a drug with significant plasma binding, the reported plasma drug concentration indirectly reflects the concentration of free or active drug. Some disease state are associated with decreased plasma proteins or with decreased binding of drugs to plasma proteins. In these situations, drugs that are usually highly protein bound have a larger percentage of free or unbound drug present in plasma. Therefore, a greater pharmacologic effect can be expected for any given drug concentration in plasma (C). Clinicians must always consider altered protein binding and whether the fraction of free drug concentration or fraction unbound (fu) is altered when interpreting or establishing desired plasma concentrations.

Luckily, the fraction of drug that is unbound (fu) does not vary with the drug concentration for most drugs that are bound primarily to albumin. This is because the number of protein binding sites far exceeds the number of drug molecules available for binding. When the plasma concentrations for drugs bound to albumin exceed 25 to 50 mg/L, however, albumin binding sites can start to become saturated. As a result, fu, or the fraction of drug that is free, will change with the plasma drug concentration.

For those drugs that do not reach serum concentrations capable of saturating protein binding sites, the plasma protein concentration (in many cases, this is albumin) and the binding affinity of the drug for the plasma protein are the two major factors that control the fraction unbound (fu).


Plasma Protein Concentration

Low plasma protein concentrations decrease the plasma concentration of bound drug (C bound); however, the concentration of free drug (C free) generally is unaffected. Therefore, the fraction of drug that is free (fu) increases as plasma protein concentrations decrease. Free or unbound drug concentrations are not significantly increased because the free drug that is released into plasma secondary to low plasma protein concentrations equilibrates with the tissue compartment (see the figures below). Therefore, if the volume of distribution (V) is relatively large, only a minor increase in C free will result.Screen Shot 2014-12-03 at 12.17.45 AM

Screen Shot 2014-12-03 at 12.48.31 AMThe relationship between the new plasma drug concentration (C’), the normal plasma drug concentration (C Normal Binding), the new plasma protein concentration (P’), and the normal plasma protein concentration (P NL) can be expressed as follows:

[Equation 1] C’/C Normal Binding = (1 – fu)[P’/P NL] + fu, whereas fu is the free fraction of the drug associated with “normal plasma protein binding”, or more precisely, associated with the situation when the plasma protein concentration is normal. So when the clinician receives the report of the plasma concentration for a drug, he or she should consider the plasma protein concentration as well. For example, if a drug’s normal free fraction (fu) is 0.1, and a patient with a low serum albumin of 2.2 g/dL (normal albumin, 4.4 g/dL) and an apparently low plasma drug concentration of 5.5 mg/L still has a therapeutically acceptable plasma drug concentration when it is adjusted for the low serum albumin. That is the reported value of actual plasma concentration of phenytoin should be adjusted by [Equation 1] under the condition of low plasma protein concentration. So the adjusted plasma concentration of phenytoin (the normal plasma drug concentration) is,

[Equation 2] C Normal Binding = C’/{ (1 – fu)[P’/P NL] + fu} = 5.5 / [(1 – 0.1 )*(2.2/4.4) + 0.1] = 10 mg/L

While [Equation 2] could be used to adjust for any drug significantly bound to albumin, the degree to which the drug concentration will be adjusted or “normalized” for the alteration in serum albumin between 3.5 and 5.5/dL will be minimal and is generally unwarranted. For example, in the same patient above is given another drug with normal free fraction (fu) of 0.95, and the lab report value of the actual plasma drug concentration is also 5.5 mg/L, then the adjusted plasma drug concentration should be 5.5 / [(1 – 0.95 )*(2.2/4.4) + 0.95] = 5.64 mg/L.

Many other drugs are bound primarily to globulin rather than albumin. Adjustments of plasma drug concentrations for these drugs based on serum albumin concentrations would, therefore, be inappropriate. Unfortunately, adjustments for changes in globulin binding are difficult because drug usually bind to a specific globulin that is only a small fraction of total globulin concentration.

Elevated plasma albumin concentrations are uncommon in the clinical setting, thus the use of [Equation 2] for high serum albumin would be rare. Many basic drugs, however, are bound to the acute phase reactive protein, α1-acid glycoprotein (AAG). This plasma protein has been known to be significantly decreased and increased under certain clinical conditions. For example, increases in plasma quinidine concentrations have been observed following surgery or trauma. The change in the quinidine concentration is the result of increased concentrations of the plasma binding proteins (AAGs) and increased bound concentrations of quinidine. There appears to be little or no change in the free quinidine level because re-equilibration with the larger tissue stores occurs. In this situation, there would be a decrease in unbound free fraction (fu), and the therapeutic levels of free or unbound drug should correlate with higher-than-usual drug concentration (bound plus free).

Other basic compounds with significant binding to AAGs would be expected to be similarly affected. Unfortunately, AAG concentrations are seldom assayed in the clinical setting, making it difficult to evaluate the relationship between the total drug concentration and the unbound or free fraction. For this reason, evaluation of plasma levels for basic drugs that are significantly protein bound is often difficult. A careful evaluation of the patient’s clinical response to a measured drug level, as well as an evaluation of any concurrent medical problems (such as surgery, trauma, or inflammatory disease) that could influence plasma protein concentrations and drug binding, is required.

Patients with cirrhosis vary considerably in their plasma protein binding characteristics. Some patients have significantly elevated binding capabilities, whereas others have significantly decreased binding capabilities. This variation probably reflects the fact that some cirrhotic patients have a strong stimulus for the production of AAGs, whereas others with more serious hepatic disease are unable to manufacture these binding proteins.

Binding Affinity

The binding affinity of plasma protein for a drug also alter the fraction of drug which is free (fu). For example, the plasma proteins in patients with uraemia (severe end-stage renal failure) have less affinity for phenytoin than do proteins present in nonnumeric individuals (different from general drug-receptor binding, other factors except binding affinity such as efficiency of the occupancy-response, degree of spareness [please refer detail at http://www.tomhsiung.com/wordpress/2014/06/the-properties-of-drugs-receptor-rationale/]). As a result, the fu for phenytoin in ureic patients is estimate to be in the range of 0.2 to 0.3 in contrast to the normal value of 0.1. However, the plasma concentration of free or unbound drug is little changed (due to the same reasons as previously discussed). So the total drug concentrations (free or unbound plus bound drug) are decreased compared to that in nonnumeric patients and the fu is increased.Screen Shot 2014-12-05 at 10.16.26 PM

Let’s see this example. In normal individuals, the fu of phenytoin is 0.1 and when a TDM report of 10 mg/L is achieved, the free or unbound drug should be 10*0.1 = 1 mg/L. So in the same patient if he or she were with low binding affinity (uremic syndrome) and with the same dose which achieves 10 mg/L of phenytoin just as said before, the serum concentration of free or unbound phenytoin is nearly the same – 1 mg/L. Because the low binding affinity and according to the references the fu should be 0.3 here, so the total serum drug concentration or the TDM report should be 1/0.3 = 3.3 mg/L. As a general rule, if fraction unbound is increased in any given situation, the clinician should reduced the desired C by the same proportion.

So to clinicians, a careful interoperation of the lab report for therapeutic drug monitor is very necessary. In patients with low plasma concentration protein, or elevated plasma concentration protein, or in patients with significant change in protein binding affinity, the lab report value for a specific drug may puzzle clinicians’ sight.


Plasma Protein Binding and Clearance

Clearance can be thought of as the intrinsic ability of the body or its organs of elimination 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.

For highly protein-bound drugs, diminished plasma protein binding is associated with a decrease in reported steady-state plasma drug concentration (total of unbound plus free drug) for any given dose that is administered. According to this equation of Cl=(S)(F)(Dose/τ)/(Css ave) [Equation 3], a decrease in the denominator, Css ave, increases the calculated clearance. It would be misleading, however, to assume that because the calculated clearance is increased, the amount eliminated per unit of time has increased. Equation 3 assumes that when Css ave (total of bound plus free drug) 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 drug administered per unit of time remains unchanged.

This (low plasma protein binding) lower plasma concentration (C bound plus 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).

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.