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.


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

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.


Pharmacoeconomic Evaluating Methods

April 14, 2013 Pharmacoeconomics 1 comment , , , ,

The pharmacoeconomic methods of evaluation are listed in Figure 1. These methods or tools can be separated into two distinct categories: economic and humanistic evaluation techniques.

Economic Evaluation

Figure 1 Components of pharmacoeconomics.


The basic task of economic evaluation is to identify, measure, value, and compare the costs and consequences of the alternatives being considered.

Basic concepts

Costs: Cost is defined as the value of the resources consumed by a program or drug therapy of interest. Example of healthcare cost include direct medical costs, direct nonmedical costs, indirect costs, intangible costs, opportunity costs, and incremental costs.

Consequence (or outcome): Consequence is defined as the effects, outputs, or outcomes of the program or drug therapy of interest.

Consequences can be categorized as positive or negative.

Consequences also can be discussed in terms of intermediate and final outcomes.

Outcomes can be separate into three categories: economic, clinical, and humanistic. Economic outcomes are the direct, indirect, and intangible costs compared with the consequences of medical treatment alternatives. Clinical outcomes are the medical events that occur as a result of disease or treatment. Humanistic outcomes are the consequences of disease or treatment on patient functional status or quality of life along several dimensions.

Economic Evaluation Methods

There are four types of economic evaluation methods shown in Table 1.

Table 1 Summary of Pharmacoeconomic Methodologies

Table 1-2 Summary of Pharmacoeconomic Methodologies
MethodDescriptionApplicationCost UnitOutcome Unit
COIEstimates the cost of a disease on a defined populationUse to provide baseline to compare prevention/treatment options against$$$NA
CMAFinds the least expensive cost alternativeUse when benefits are the same$$$Assume to be equivalent
CBAMeasures benefit in monetary units and computes a net gainCan compare programs with different objectives$$$$$$
CEACompares alternatives with therapeutic effects measured in physical units; computes a cost-effectiveness ratioCan compare drugs/programs that differ inclinical outcomes and use the same unit of benefit$$$Natural units
CUAMeasures therapeutic consequences in utility units rather than physical units; computes a cost-utility ratioUse to compare drugs/programs that are life extending with serious side effects or those producing reductions in morbidity$$$QALYs
QOLPhysical, social, and emotional aspects of patient’s well-being that are relevant and important to the patientExamines drug effects in areas not covered by laboratory or physiologic measurementsNAQOL score


Humanistic Evaluation

Methods for humanistic evaluation including the assessment for QoL (quality of life), patient preferences, and patient satisfaction.

Basic concepts

Humanistic Outcomes: Humanistic outcomes are the consequences of the disease and/or its treatment as perceived and reported by the patient.

Health-Related Quality of Life (HRQoL): HRQoL is defined as the subjective assessment of the impact of a disease and treatment across the physical, psychological, social, and somatic domains of functioning and well-being. HRQoL include three domains which are (1) physical health and functioning;(2) mental/emotional health and functioning;(3) social and role functioning.

Humanistic Evaluation Methods (Quality of Life)

Table 2 provides a taxonomy of the different types of instrument of HRQoL.

Table 2 Taxonomy of Health-Related Quality of Life Instruments

TABLE 2-1 Taxonomy of Health-Related Quality of Life Instruments
Generic instruments
Health profiles
Preference-based measures
Specific instruments
Disease specific (e.g., diabetes)
Population specific (e.g., frail older adults)
Function specific (e.g., sexual functioning)
Condition or problem specific (e.g., pain)


Here three methods are used to measure health state preferences directly. They are (1) Visual Analog Scales;(2) Standard Gamble;and (3) Time Trade-Off.

Visual Analog Scales (VAS)

The VAS is a line, typically 10 to 20 cm in length, with the end points well-defined (e.g., 0 = worst imaginable heath state and 100 = best imaginable heath state). The respondent is asked to mark the line where he or she would place a real or hypothetical health state in relation to the two end points. In addition, because death may not always be considered the worst possible health state, the subject’s placement of death on the scale in relation to the other health states must be explicitly elicited. If a subject has placed death at 0 and rates a health state at the midpoint between 0 and 100 on the scale, that subject’s preference for that health state is 0.5.

Standard Gamble

The standard gamble offers a choice between two alternatives: choice A, living in health state i with certainty, or choice B, taking a gamble on a new treatment for which the outcome is uncertain.

Figure 2 shows this gamble. The subject is told that hypothetical treatment will lead to perfect health, for a defined remaining lifetime, with a probability of P or immediate death with a probability of 1 – P. The subject can choose between remaining, for the same defined lifetime, in state i, which is intermediate between healthy and dead, or taking the gamble and trying the new treatment. The probability P is varied until the subject is indifferent between choices A and B. For example, if a subject is indifferent between the choices A and B when P = 0.75, the preference of state i is 0.75.

Figure 2 The Standard Gamble


Time Trade-Off

Figure 3 represents the time trade-off (TTO) technique for a chronic disease state. Here, the subject is offered a choice living for a variable amount of time x in perfect health or a defined amount of time t in a health state i that is less desirable. By reducing the time x of being healthy (at 1.0) and leaving the time t in the suboptimal health state fixed, an indifference point can be determined (hi = x/t). For example, a subject may indicate that undergoing chronic hemodialysis for 2 years is equivalent to perfect health for 1 year. Therefore, the value of that health state would be 0.5.

Figure 3 Time Trade-Off

Fidaxomicin Beats Vancomycin for C difficile in Cancer

July 21, 2012 Hematology, Infectious Diseases, Pharmacoeconomics, Therapeutics No comments , , ,

I have read a similar article before. It was about Fidaxomicin and CDAD too. But today this newer one describes more exactly. This article compares fidaxomicin to vancomycin in aspects of cure rate in terms of initial clinical cure, recurrence, and sustained response. According to this article fidaxomicin appears to be better than vancomycin in treating Clostridium difficile-associated diarrhea (CDAD). However, vancomycin also can treat CDAD effiaciously, according to the data shown in these studies.

According to the North American study, clinical cure rate of fidaxomicin was 87.7% and that of vancomycin was 86.8%. From this point both fidaxomicin and vancomycin are able to treat CDAD satisfactorily. However, differ between the two drugs does exist. The incidence of recurrence with vancomycin over fidaxomicin were 26.9% vs 12.7%. And the sustained response rates of fidaxomicin over vancomycin were 76.6% vs 63.4%. Thus from these two aspects fidaxomicin appears to be better than vancomycin.

I want to emphasize that we should compare these two drugs in the specific group population – the cancer survivors. According to the studies, those with cancers treated with fidaxomicin had significantly higher clinical cure and sustained clinical cure rates and significantly lower rates of recurrence than patients treated with vancomycin.

One more thing is that the price of these two drug is not considered in this article. I check the price of fidaxomicin and vancomycin. The dosage of fidaxomicin is 200 mg po Bid, that of vancomycin is 125 mg po Qid. The cheapest vancomycin capsule’s unit price is $27.78 (per 125 mg/capsule, Vancocin-VIROPHARMA INCO), and that of fidaxomicin tablet is $135 (per 200 mg/tablet). So a 10-day course we need $2700 for fidaxomicin vs $1111.2 for vancomycin. From this perspective I think we should use vancomycin to treat CDAD first, fidaxomicin should be the alternative. However considering the lower recurrence rate and higher sustained response rate, the fidaxomicin regimen’s cost may be less than vancomycin’s.


  1. Becky McCall. Fidaxomicin Beats Vancomycin for C difficile in Cancer. Medscape News. 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). 2012 Apr 3. Poster 2289 and abstract O670.
  2. Jason W. Lancaster, PharmD, BCPS. Economic Impact of Fidaxomicin on CDI Treatment in United States. The American Journal of Pharmacy Benefits. 2012 May; 4: 114-117.

April 4, 2012 (London, United Kingdom) — Fidaxomicin (Dificid, Optimer Pharmaceuticals) treatment was superior to vancomycin for initial cure, recurrence, and sustained response, according to a subanalysis of patients with cancer and Clostridium difficile–associated diarrhea (CDAD).

In addition, concomitant antibiotics had less effect on clinical cure rate with fidaxomicin than with vancomycin, according to data from a phase 3 clinical trial conducted in Europe and North America. Both studies were presented here at the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Oliver A. Cornely, MD, oncologist/hematologist and infectious diseases physician from the University Hospital Cologne in Germany, led the European/North American phase 3 study (OPT-80-004). He presented the results of a subanalysis of data from both studies.

The European/North American multicenter, randomized, controlled, double-blind, noninferiority study was published in February (Lancet Infect Dis. 2012;12:281-289). An earlier phase 3 study of fidaxomicin conducted in the United States and Canada was published last year (N Engl J Med. 2011;364:422-431).

The subanalysis of cancer patients with CDAD was presented here at ECCMID for the first time.

Fidaxomicin is a novel macrocyclic antibiotic with a narrow spectrum of activity against Gram-positive bacteria and minimal activity against normal gut flora. “Fidaxomicin is not absorbed, which makes it like a magic bullet because it stays where it is needed in extremely high concentrations,” Dr. Cornely told Medscape Medical News.

Further to the North American study, results of the second phase 3 trial in 509 patients from Europe and North America also demonstrated that clinical cure for fidaxomicin was noninferior to vancomycin in the modified intent-to-treat population (87.7% vs 86.8%).

Dr. Cornely emphasized the recurrence rates with fidaxomicin. “This is the first point at which we see a difference in the 2 antibiotics, and it is a large difference,” he said. “We see double the incidence of recurrence with vancomycin over fidaxomicin [26.9% vs 12.7%; difference, 14.2%; 95% confidence interval [CI], –21.4% to –6.8%; P < .001]. It cuts the recurrence rate in half. A high recurrence rate is expected with vancomycin in a very sick population, but this is still an extreme.”

These findings were also reflected in the sustained response rates, which showed fidaxomicin was superior to vancomycin (76.6% vs 63.4%; difference, 13.2%; 95% CI, 5.2% to 20.9%; P = .001).

Cancer Patients a Special Population

The subanalysis in cancer patients was drawn from data derived from the 2 phase 3 trials. “Patients with cancer are a population of special interest because of their lower response rates, and they are very prone to recurrent disease,” Dr. Cornely told Medscape Medical News. (more…)