Drug Tolerance and Placebo Effects PDF

Given that disturbances in electrolyte balance can have widespread effects on cell physiology, we might expect that electrolyte imbalances would cause profound and widespread effects on responses to drugs. However, this does not seem to be the case; examples in which electrolyte changes have a signi...

Given that disturbances in electrolyte balance can have widespread effects on cell physiology, we might expect that electrolyte imbalances would cause profound and widespread effects on responses to drugs. However, this does not seem to be the case; examples in which electrolyte changes have a significant effect on drug responses are rare. An exception is digoxin in the presence of hypokalemia. When potassium levels are low, the ability of digoxin to induce dysrhythmias is greatly increased. Accordingly, all patients receiving digoxin must undergo regular measurement of serum potassium to ensure that levels remain within a safe range. Tolerance Tolerance is a decreased responsiveness to a drug as a result of repeated drug administration. Patients who are tolerant to a drug require higher doses to produce effects equivalent to those that could be achieved with lower doses before tolerance developed. There are three categories of drug tolerance: (1) pharmacodynamic tolerance, (2) metabolic tolerance, and (3) tachyphylaxis. Pharmacodynamic Tolerance The term pharmacodynamic tolerance refers to the familiar type of tolerance associated with long-term administration of drugs such as morphine and heroin. Pharmacodynamic tolerance is the result of adaptive processes that occur in response to chronic receptor occupation. Because increased drug levels are required to produce an effective response, the minimum effective concentration (MEC) of a drug becomes abnormally high. Metabolic Tolerance Metabolic tolerance is defined as tolerance resulting from accelerated drug metabolism. This form of tolerance is brought about by the ability of certain drugs (e.g., barbiturates) to induce the synthesis of hepatic drug-metabolizing enzymes, thereby causing rates of drug metabolism to increase. Because of increased metabolism, dosage must be increased to maintain therapeutic drug levels. Unlike pharmacodynamic tolerance, which causes the MEC to increase, metabolic tolerance does not affect the MEC. Tachyphylaxis Tachyphylaxis is a reduction in drug responsiveness brought on by repeated dosing over a short time. This is unlike pharmacodynamic tolerance and metabolic tolerance, which take days or longer to develop. Transdermal nitroglycerin provides a good example of tachyphylaxis. When nitroglycerin is administered using a transdermal patch, effects are lost in less than 24 hours if the patch is left in place around the clock. As discussed in Chapter 44, the loss of effect results from depletion of a cofactor required for nitroglycerin to act. When nitroglycerin is administered on an intermittent schedule, rather than continuously, the cofactor can be replenished between doses, and no loss of effect occurs. Placebo Effect A placebo is devoid of intrinsic pharmacologic activity; therefore any response that a patient may have to a placebo is based solely on the patient\'s psychological reaction to the idea of taking a medication and not to any direct physiologic or biochemical action of the placebo itself. The primary use of the placebo is as a control preparation during clinical trials. In pharmacology, the placebo effect is defined as the component of a drug response that is caused by psychological factors and not by the biochemical or physiologic properties of the drug. It is widely believed that with practically all medications, some fraction of the total response results from a placebo effect. Although placebo effects are determined by psychological factors and not physiologic responses to the inactive placebo, the presence of a placebo response does not imply that a patient\'s original pathology was imaginary. Not all placebo responses are beneficial. If a patient believes that a medication is going to be effective, then placebo responses are likely to help promote recovery. Conversely, if a patient is convinced that a particular medication is ineffective or perhaps even harmful, then placebo effects are likely to detract from his or her progress. Because the placebo effect depends on the patient\'s attitude toward medicine, fostering a positive attitude may help promote beneficial effects. In this regard, it is desirable that all members of the health care team present the patient with an optimistic (but realistic) assessment of the effects that therapy is likely to produce. Variability in Absorption Both the rate and extent of drug absorption can vary among patients. As a result, both the timing and intensity of responses can be changed. Bioavailability The term bioavailability refers to the amount of an active drug that reaches the systemic circulation from its site of administration. Different formulations of the same drug can vary in bioavailability. Factors such as tablet disintegration time, enteric coatings, and sustained-release formulations can alter bioavailability and can thereby make drug responses variable. Differences in bioavailability occur primarily with oral preparations rather than parenteral preparations. Fortunately, even with oral agents, when differences in bioavailability do exist between preparations, those differences are usually so small that they lack clinical significance. Differences in bioavailability are of greatest concern for drugs with a narrow therapeutic range, because with these agents, a relatively small change in drug level can produce a significant change in response: a small decline in drug level may cause therapeutic failure, whereas a small increase in drug level may cause toxicity. Under these conditions, differences in bioavailability could have a significant effect. Individual Causes of Variable Absorption Individual variations that affect the speed and degree of drug absorption affect bioavailability and can thereby lead to variations in drug responses. Alterations in gastric pH can affect absorption through the pH partitioning effect. For drugs that undergo absorption in the intestine, absorption will be delayed when gastric emptying time is prolonged. Diarrhea can reduce absorption by accelerating the transport of drugs through the intestine. Conversely, constipation may enhance the absorption of some drugs by prolonging the time available for absorption. Genetics and Pharmacogenomics A patient\'s unique genetic makeup can lead to drug responses that are qualitatively and quantitatively different from those of the population at large. Adverse effects and therapeutic effects may be increased or reduced. Idiosyncratic responses to drugs may also occur. This topic is explored extensively in Chapter 7. Gender- and Race-Related Variations Gender- and race-related differences in drug responses are, ultimately, genetically based. However, a general discussion is warranted. Gender Men and women can respond differently to the same drug. A drug may be more effective in men than in women, or vice versa. Likewise, adverse effects may be more intense in men than in women, or vice versa. Unfortunately, for most drugs, we do not have adequate knowledge about gender-related differences because before 1997, when the FDA pressured drug companies to include women in trials of new drugs, essentially all drug research was done in men. Since that time, research has demonstrated that significant gender-related differences really do exist. Here are four examples: When used to treat heart failure, digoxin may increase mortality in women while having no effect on mortality in men. Alcohol is metabolized more slowly by women than by men. As a result, a woman who drinks the same amount as a man (on a weight-adjusted basis) will become more intoxicated. Certain opioid analgesics (e.g., pentazocine, nalbuphine) are much more effective in women than in men. As a result, pain relief can be achieved at lower doses in women. Quinidine causes greater QT interval prolongation in women than in men. As a result, women given the drug are more likely to develop torsades de pointes, a potentially fatal cardiac dysrhythmia. Although there is still a lack of adequate data related to drug effects in women, information generated by these drug trials, coupled with current and future trials, will permit drug therapy in women to be more rational than is possible today. In the meantime, clinicians must keep in mind that the information currently available may fail to accurately predict responses in female patients. Accordingly, clinicians should remain alert for treatment failures and unexpected adverse effects. Race In 2005, BiDil, a fixed-dose combination of two vasodilators (isosorbidide dinitrate \[ISDN\] and hydralazine), became the first drug product approved by the FDA for treatment of a single racial group. Approval was based on results of the African American Heart Failure Trial (A-HeFT), which demonstrated that, in self-described black patients, adding ISDN plus hydralazine to standard therapy of heart failure reduced 1 year mortality by 43%---a very impressive and welcome result. The approval was controversial; however, because populations other than self-described black patients were excluded from clinical trials. Hence, there is no evidence that BiDil will not work just as well (and possibly even better) among some other group. The greatest concern surrounding race-based therapy has to do with genetic variability. We know there is great diversity within and among racial groups; therefore, a "one fits all" approach based on race is unwise. Still, we can use known associations to guide choices. For example, differences in metabolism between people with East Asian and European heritage are common. The provider can use this knowledge to guide initial dosing (with adjustment, as indicated based on response) if genetic testing is not feasible or warranted. Comorbidities and Drug Interactions Individuals often have two or more medical conditions or disease processes. When this occurs, drugs taken to manage one condition may complicate management of the other condition. As an example, if a person who has both asthma and hypertension is prescribed a nonselective β-adrenergic antagonist (β blocker) to control blood pressure, this may worsen the patient\'s asthma symptoms if the dose is sufficient to cause airway constriction. This illustrates the necessity for the provider to consider the whole patient, not only the disease being treated, when selecting drug therapy. Because patients with comorbidities often take multiple medications, there is the increased likelihood of drug interactions. Drug interactions can be an important source of variability. The mechanisms by which one drug can alter the effects of another and the clinical consequences of drug interactions are discussed at length in Chapter 4.