Adverse Drug Reactions

Variability – Differ in Drug Response

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

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

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

PS: Evidence for interindividual differences in drug response

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

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

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

Why People Differ

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

May 28, 2015 Adverse Drug Reactions, Pharmacoeconomics, Pharmacogenetics, Pharmacokinetics, Pharmacology No comments , ,

470px-Emblem_of_the_United_NationsPharmacokinetic and pharmacodynamic factors

Toxic or exaggerated responses to normal drug doses can lead to drug-induced diseases and other adverse events for two reasons. First, excessively high concentrations of unbound drug or metabolite at the site of action may occur as a result of unusual pharmacokinetics (absorption, distribution, metabolism, excretion) of the drug or metabolites. Second, response to a given concentration of unbound drug or metabolite at the site of action (pharmacodynamics) may be exaggerated or unusual because of many factors, including changes in the number and/or binding affinity of target receptors as well as alternations in signal-transduction pathways. The pharmacokinetic and pharmacodynamic behaviours of drug may be influenced by factors related to concurrent diseases, physiologic status, concomitantly administered drugs or food, lifestyle, and genetic variability.

Concurrent Diseases

The effects of disease on pharmacokinetics have been extensively reviewed. For drugs or drug metabolites that are highly dependent on the kidney or liver for elimination, usual does produce higher-than-normal serum drug concentrations in patients with kidney or liver disease respectively. This results in an exaggerated response, particularly for drugs with narrow therapeutic index.

Cardiovascular diseases, such as acute myocardial infarction or heart failure, may reduce hepatic and/or renal blood flow and decrease the elimination of drugs that are normally highly extracted by the liver. Serum concentrations and response are increased if such drugs are administered intravenously.

Hypothyroidism may be associated with a decrease in both hepatic and renal drug clearances.

Many diseases can also decrease the serum protein binding of drugs. For example, kidney and liver diseases have been associated with decreased albumin binding of some drugs. These changes generally do not result in an altered clinical response, however, because the concentration of unbound drug is unaffected. Nevertheless, misinterpretation of total serum drug concentrations of highly protein-bound drugs that are routinely monitored may lead a clinician to inappropriately increase the dose, thus resulting in toxicity.

Concurrent diseases may also be associated with enhanced pharmacodynamic responses to drugs for a variety of reasons. For example, the incidence of skin rashes and serious dermatologic adverse effects such as Stevens-Johnson syndrome is increased in patients with human immunodeficiency virus (HIV) infection who are taking trimethoprim-sulfamethoxazole. Patients with cytomegalovirus infection who are taking ampicillin are also at increased risk for skin rashes. Although the precise mechanisms are unkown, desensitisation procedures generally reduce the severity of the adverse effect if rechallenge with the drug is necessary.

Physiologic Conditions

The pharmacokinetics of a drug may be affect by age, pregnancy, and sex. In general, the rate of elimination of a drug is impaired in premature newborns, increases in early childhood to more efficient rates than those in adults, and then progressively declines with advancing age. In addition, early patients may also suffer from decreased mental status or diminished physical function. When these physiologic conditions are compounded by decreased elimination of some drugs, the patient is more susceptible to drug-induced falls or physical injury (i.e., benzodiazepines). A variety of physiologic changes during pregnancy may affect the pharmacokinetics of drugs, but no consistent patterns have been identified. The higher serum concentrations of digoxin reported in pregnant patients may be caused by increased bioavailability resulting from decreased gastric emptying time. Women have a higher risk of drug-induced adverse events as compared with men, which has been attributed to the fact that they take more drugs than men, have lower activity of drug-metabolising enzymes, and have estrogen-related effects on drug receptors, as in the case of drug-induced torsades de pointes.

DDIs

Drug-drug interactions may cause altered pharmacokinetics (bioavailability, distribution, clearance) or altered pharmacodynamics by additive or antagonistic effects. Such interactions have been extensively reviewed and are more often a predictable and preventable cause of morbidity and mortality. By far the most frequent contributing factors to drug-induced disease resulting from drug interactions are those that affect bioavailability and drug elimination. A large number of important interactions occur in the liver and gastrointestinal tract because of decreases in the rate of a drug’s metabolism or transport caused by other drugs that are inhibitors of these system.

P-glycoprotein, a transporter protein expressed on the luminal surfaces of intestinal epithelial cells, biliary hepatocytes, and renal tubular cells, transports drug from within the cell to the intestine, bile, or urine, respectively. Inhibition of P-glycoprotein can therefore increase the bioavailability and decrease renal and biliary excretion of affected drugs, thus increasing their serum concentrations. Other interaction mechanisms that may result in reduced renal excretion include reduction of the glomerular filtration rate and increased reabsorption of drug into blood from the renal tubule.

Drugs that displace other drugs from serum protein-binding sites without affecting their metabolism cause only transient increases in unbound drug concentration, and hence do not generally result in adverse effects. Displacement of drugs such as warfarin (long half-life, small volume of distribution, and narrow therapeutic range) can be clinical important, however, and necessitate a temporary reduction in the dose of the affected drug.

Serious drug-drug interactions may also occur when drugs produce additive effects through different mechanisms. Examples include: 1.the combined blood-pressure-lowering effects of calcium channel-blockers and β-blockers; 2.the increased risk of gastrointestinal bleeding resulting from non steroidal anti-inflammatory drug (NSAID)-omdiced gastric erosion in patients taking warfarin; and 3.exaggerated cyclic guanine monophosphate (cGMP)-mediated smooth-muscle relaxation caused by the combination of sildenafil (which inhibits cGMP degradation) and nitrates (which increase GMP production), leading to potentially serious hypotension. An example of a drug-drug interaction involving active or toxic metabolites is the potentiation of acetaminophen hepatotoxicity in patients receiving enzyme inducer such as rifampin, presumably by increasing the formation of toxic acetaminophen metabolites.

Drug-Food Interactions

Drug-food interactions have been extensively reviewed. One of the most serious drug-food interactions occurs with first generation nonselective monoamine oxidase inhibitors and tyramine, an amino acid found in aged or fermented foods and beverages. The suppressed metabolism of large amounts of tyramine may result in hypertensive-crisis, the so-called cheese reaction (tyramine, dopamine, norepinephrine and epinephrine are all monoamines). A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstrictionand increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur (from wiki at http://en.wikipedia.org/wiki/Tyramine).

Components of grapefruit juice are known to suppress the presystemic elimination of certain drugs that are either metabolised in the intestinal wall by the cytochrome P-450 isozyme CYP3A4, are substrates for P-glycoprotein, or both, resulting in increased bioavailability. Drugs for which bioavailability increases dramatically when taken with grapefruit juice include lovastatin, simvastatin, buspirone, and amiodarone.

In general, an increase in drug bioavailability caused by food intake is not a problem if doses throughout the course of treatment are taken consistently at a fixed time relative to a meal. However, a clinically important drug-food interaction was reported for a particular once-daily theophylline product, which has since been reformulated. When taken with high-fat meals, a sudden, rapid release of a large amount of theophylline occurred, leading to excessively hight serum theophylline concentrations.

The salt, protein, or vitamin content of the diet also may affect the renal excretion of drugs. For example, a patient taking lithium who initiates a low-salt diet for treatment of hypertension or heart failure excretes less lithium, resulting in higher serum lithium concentrations and potential toxicity, given this drug’s narrow therapeutic range. A low-protein diet is associated with decreased renal clearance of oxypurinol, apparently through enhanced reabsorption efficiency by the uric acid transporter system.

Lifestyle Factors

Alcohol and caffeine consumption can affect both the pharmacokinetics and the pharmacodynamics of other drugs, leading to serious drug-induced diseases. There are many examples of alcohol exaggerating the central nervous system depressant effects of drugs, including benzodiazepines, phenothiazines, tricyclic antidepressants, opiates, and anthistamines. Caffeine has an additive and potentially dangerous stimulant effect when taken with ephedrine in herbal weight-loss and athletic performance-enhancing supplements.

Genetic Variability

As a result of the rapidly evolving field of pharmacogenomics, interindividual differences in drug related toxicity and therapeutic response are not always considered to be “idiosyncratic” responses. Rther, it is widely recognized that genetic makeup is responsible for a significant portion of drug-induced diseases. Many genes that encode metabolic enzymes or drug transporters are polymorphic, meaning that some groups of patients with certain gene variants have relatively inactive enzymes or transporters, while others have unusually active forms. In addition, the proportion of patients with active or inactive forms may differ among racial groups.

Polymorphisms in metabolising enzymes have been extensively reviewed. Patients with low N-acetyltransferase activities, known as “slow acetylators,” are more likely to suffer from peripheral nerve damage when administered standard isoniazid doses as compared with fast acetylators. Likewise, slow acetylators of hydrazine are more likely to suffer from hydaralazine-induced lupus erythematosus. At least four of the major cytochrome P-450 isozymes (CYP2A6, CYP2C9, CYP2C19, CYP2D6) responsible for oxidative drug metabolism are polymorphic in nature. Patients with gene variants that produce low-activity enzymes for the metabolism of warfarin experience a higher risk of serious bleeding events. Severe and potentially fatal hematologic toxicity occurs in the small percentage of patients receiving azathioprine or mercaptopurine who have a genetic deficiency in the thiopurine methyltransferase enzyme.

Polymorphisms in receptors, ion channels, or other proteins involved in drug response also occur. These result in widely variable pharmacodynamic responses among patients despite similar concentrations of the drug at the site of action. Examples include the polymorphisms in: 1.dopamine receptors, which affect the risk of drug induced tardive dyskinesia; 2.skeletal-muscle ryanodine receptors, which affect the risk of anesthesia-induced malignant hyperthermia; 3.potassium or sodium channels, which affect the risk of potentially fatal tornadoes de points when certain antiarrhythmic drugs are administered; 4.glucose-6-phosphate dehydrogenase, which if deficient, leads to red-cell homeless in patients who take drugs with a high redox potential, such as aspirin, nitrofurantoin, sulfonamides, and quinidine; and 5.the major histocompatibility complex, which mediates hypersensitivity reactions to drugs such as abacavir and nevirapine.


Adherence To Prescribed Therapy

Noncompliance implies that the patient is intentionally or willfully not following directions for medication use, which may or may not be the case. For this reason, some prefer the term non adherence, because it places no blame on either the patient or the health care professional. Common causes of non adherence are listed in Table 1. Regardless of the cause, non adherence can lead to drug-induced disease. Patients may take more or less drug than prescribed or recommended, modify medications in an inappropriate fashion (e.g., crush a sustained-release tablet), or continue to take a prescribed drug even though the underlying medical condition for which the drug was originally prescribed has resolved. Any of these actions can put patients at increased risk for drug-induced disease.

Screen Shot 2015-05-28 at 5.01.13 PMIt is estimated that the prevalence of medication non adherence is 40% to 70%. McDonnell and Jacobs analyzed the cause for hospital admissions from preventable adverse drug reactions. Of 158 drug-related hospital admissions over an 1-month period, patient non adherence with a prescribed medication regimen was the identified cause of 33% of these admissions. Unfortunately, health care providers typically are unable to identify patients at risk for non adherence. Patient age, sex, race, intelligence, and educational background have not been shown to be predictive of adherence or non adherence to a prescribed drug regimen.

Until the most effective strategy or strategies to improve adherence can be identified, it is recommended that healthcare professionals keep drug regimens simple, provide clear and complete instructions, encourage medication adherence by scheduling regular appointments, respond clearly and promptly to patients’ questions and concerns, and reinforce adherence with the prescribed regimen at every opportunity.


Medication Errors

Medication errors contribute significantly to the problem of drug-induced disease. These errors can include a variety of problems involving any step in the drug-use process. In an study, 67% of hospital admissions caused by adverse drug reactions were attributed to inadequate patient monitoring (e.g., failure to order appropriate laboratory tests to monitor drug response or failure to respond appropriately to abnormal laboratory-test results) and 51% were caused by inappropriate drug doses.

Fortunately, not all medication errors result in clinically significant problems. In one study of hospitalized patients, only 7 to 100 medication errors were thought to be serious enough to cause harm (all adverse effects are harm and might not be preventable, whereas all medication errors are preventable and do not necessarily cause harm). However, in a view of the overall frequency of medication errors that occur each year, a 7% proportion of serious medication errors may result in many affected lives.

Medication errors and drug-induced diseases may result from the limitations of an individual practitioner, from problems latent in the system or setting in which the practitioner operates, or from a combination of the above. In most cases, medication errors are caused by system-related problems including the absence of redundancies and system defenses needed to detect and counter an error in an individual’s judgment before the medication reaches the patient.

 

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

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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.

 

Make a provider and patient education for levothyroxine

February 13, 2013 Adverse Drug Reactions, Cardiology, Drug Informatics, Drug Interactions, Pharmacokinetics, Pharmacotherapy, Pharmacy Education, Therapeutics 3 comments , , , ,

Today I would like to write something about levothyroxine. My hospital uses levothyroxine often. Everyday there are lots of patients prescribed with levothyroxine. I do believe it is necessary to write below for education, which is not only for patients but also providers. The reference I use comes from U.S. FDA’s official drug information database.

Indications and Usage

Levothyroxine sodium is used for the following indications:

Hypothyroidism – As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

Pituitary TSH Suppression – In the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Contraindications

Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids. Finally, levothyroxine is contraindicated in patients with hypersensitivity to any of the inactive ingredients in levothyroxine.

Dosage and Administration

  • The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state.
  • The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue.

To acheive the two goals above, it depends on variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions (e.g., pregnancy, concomitant medications, and the specific nature of the condition being treated). As a result Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters.

Levothyroxine sodium tablets are administered as a single daily dose.

Table 1 The Indication and Dosages of Levothyroxine

Indication and UsageDosage
1HypothyroidismIndividuals who are at low risk of coronary artery diseaseStarting at 1.7 mcg/kg/day (Full dose). Adjusting dosage in 12.5-25 mcg increments until clinically euthyroid and serum TSH has normalized.
If myxedema coma, administer intravenously rather than orallyIndividuals older than 50 yrs or under 50 yrs with underlying cardiac diseaseStarting from 25-50 mcg/day, with increments of 12.5-25 mcg/day at 6-8 week intervals until clinical euthyroid and the serum TSH has normalized
Elderly individualsStarting from 12.5-25 mcg/day, with increments of 12.5-25 mcg/day at 4-6 week intervals until clinical euthyroid and the serum TSH has normalized
Individuals with severe hypothyroidismStarting from 12.5-25 mcg/day, with increments of 25 mcg/day at 2-4 week intervals until clinical euthyroid and the serum TSH has normalized
Secondary or tertiary hypothyroidismDosage as above but titrated until clinically euthyroid and serum free-T4 level is restored to the upper half of the normal range
2TSH Suppression – various types of euthyroid goiters and thyroid cancerWell-differentiated thyroid cancer> 2 mcg/kg/day (Target: TSH suppressed to <0.1 mU/L)
Contraindicated if the serum TSH is already suppressedWell-differentiated thyroid cancer (high risk)Target: TSH suppressed to <0.01 mU/L
Benign nodules and nontoxic multinodular goiter (controversial)Target: TSH suppressed to between 0.1 to either 0.5 or 1.0 mU/L

 

The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels alone may be used to monitor therapy. The frequence of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization.

Monitor (more…)

Complications of The Care of Multiple Myeloma

November 29, 2012 Adverse Drug Reactions, Chemotherapy, Hematology, Infectious Diseases, Pharmacology, Pharmacotherapy 2 comments , , , , , ,

As a clinical pharmacist you should always know the adverse effect of the pharmacotherapy. That is why we are trained again and again. That is we are educated for. This is more important for oncology pharmacists because the chemotherapy always is relevant to adverse reactions which are commonly grade 3/4.

Last post we talked about the care of multiple myeloma (MM). Today let’s talk about the comlications and toxicities of the treatement of MM.

Infectious Complications of Myeloma Treatment

As we talked before, bortezomib is a novel agent which reversibly inhibits the chymotrypsin-like activity of the 26S proteasome in mammalian cells. While the clinical outcome is improved, side effects accompany. In one study it was found that infection rate of herpes zoster was higher in bortzeomib group than the dexamethasone group (13% vs 5%;P = .0002). However the incidence of grade 3/4 herpes zoster infection was not significantly different for the 2 groups, nor was the incidence of serious infections. One thing to emphasize is that patients in this study didn’t recevie prophylaxis against herpes simplex virus (HSV) reactivation.

At least 4 different mechanisms have been proposed to explain the increased risk of HSV reactivation in patients receiving bortezomib: (1) bortezomib is thought to produce its therapeutic effect at least partly as a result of decreased cell-mediated immunity,3 which could promote viral replication; (2) bortezomib may specifically inhibit the immunoproteasome that is responsible for the suppression of latent varicella zoster virus (VZV)4; (3) bortezomib may alter the function and viability of dendritic cells, which are important antigen-presenting cells involved in the initiation of an antiviral response5,6; and (4) bortezomib is known to affect the dorsal root ganglia, which is where latent VZV resides.7,8

Recent retrospective studies have demonstrated that patients who receive acyclovir prophylaxis are less likely to experience bortezomib-related HSV reactivation. In a study performed at the Roswell Park Cancer Center, investigators reviewed medical charts for 100 consecutive patients who were treated with bortezomib-based therapy for MM, including 59 patients treated as initial therapy and 41 patients for recurrent or refractory disease; and 87 patients receiving bortezomib as part of a combination regimen and 13 patients receiving bortezomib monotherapy.9 All patients received acyclovir, which was initiated before bortezomib and continued until 4 weeks after the last bortezomib dose. All patients but 1 received a fixed dose of acyclovir 400 mg twice daily regardless of renal function. Compliance was evaluated by review of the medical record. Of the 100 patients enrolled in the study, none developed VZV reactivation. In another study patients receiving steroids, no episodes of VZV were observed in patients who received antiviral prophylaxis.

These studies demonstrate that antiviral prophylaxis reduces the incidence of herpes zoster-related complications;the specific antiviral agent is less important.

Venous Thromboembolism (VTE) Complication 

Factor that are associated with increased risk include:

The use of thalidomide or lenalidomide;

Steroid use (especially high-dose steroids);

Concomitant chemotherapy (especially anthracycline-based therapy);

The use of erythropoiesis-stimulating agents (ESAs).

A review of VTE risk factors and prophylaxis for patients receiving thalidomide or lenalidomide for MM recommended aspirin prophylaxis for patients with no more than 1 VTE risk factor. LMWH (equivalent to enoxaparin 40 mg/d) was recommended for patients with 2 or more risk factors, and for patients receiving high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting an INR of 2 to 3 was recommended as an alternative to LMWH.

In a phase III, randomized clinical trial that compared lenalidomide plus standard-dose or low-dose dexamethasone in patients with newly diagnosed MM, high-dose dexamethasone was associated with higher rates of a number of adverse event which included deep vein thrombosis/pulmonary embolism (DVT/PE) (26% vs 12%). For patients who received antithrombotic prophylaxis with aspirin, the incidence of DVT/PE decreased to 14% for the high-dose dexamethasone group and 5% for low-dose dexamethasone group.

Hematologic Toxicity in Renal Insufficiency Patients

In patients receiving lenalidomide for MM, renal insufficiency has been associated with significantly shorter time to the onset of myelosuppression such as thrombocytopenia. In one study of 72 patients with MM, 8 of 14 patients with myelosuppression of grade 3 or worse had baseline creatinine clearance (CrCl) values of 40 mL/min or lower.

The elimination of lenalidomide is primarily renal. Follow a single oral administration of [14C]-lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive doseis eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively.

Above describes the reason why the hematologic toxicity of lenalidomide is enhanced is patients with renal insufficiency. So dose adjustment is needed. Recommendations for dose adjustment are shown in table below.

The Complication of Neuropathy in MM patients

Nearly all patients receiving bortezomib develop some degree of neuropathy. (more…)