The department of internal medicine,clinical pharmacology and occupational diseases, BSMU, Chernivtsi Eugene I. Shorikov, Assoc. Prof., PhD The Introduction in treatment science THE PARADIGM OF DRUG THERAPY
Drug Therapy Drug therapy affords an expanding opportunity for preventing and treating disease and for alleviating symptoms. Pharmacologic agents also expose patients to risk. Basic principles of drug therapy provide a conceptual framework for deploying drugs with maximal efficacy while minimizing the risk of adverse effects.
Drug Therapy Optimal therapeutic decisions are based on an evaluation of the individual patient in concert with assessment of the evidence for efficacy and safety of the treatment under consideration. An understanding of the pharmacokinetics and pharmacodynamics of the drug should be integrated with this patient-focused information to guide implementation of therapy.
Drug Therapy Initial determination of the effectiveness and safety of drugs is based predominantly on evaluation of experimental interventions in clinical trials. Well- designed and effectively executed clinical trials provide the scientific evidence that informs most therapeutic decisions. Evidence from clinical trials may be supplemented by observational studies, particularly in assessing adverse effects that elude detection in clinical trials designed to determine efficacy and that do not occur frequently or rapidly enough.
Preclinical Investigation Experiments conducted on animals are essential to the development of new chemicals for the management of disease.The safety and efﬁcacy of new drugs, however, can be established only by adequate and well-controlled studies on human subjects. Since ﬁndings in animals do not always accurately predict the human response to drugs,subjects who participate in clinical trials are put at some degree of risk.The risk comes not only from the potential toxicity of the new drug but also from possible lack of efﬁcacy,with the result that the condition under treatment becomes worse.
Preclinical Investigation Since risk is involved,the primary consideration in any clinical trial should be the welfare of the subject. As a consequence of unethical or questionably ethical practices committed in the past, most countries have established safeguards to protect the rights and welfare of persons who participate in clinical trials.Two of the safeguards that have been established are the institutional review board (IRB) and the requirement for informed consent.
Preclinical Investigation People who volunteer to be subjects in a drug study have a right to know what can and will happen to them if they participate (informed consent). The investigator is responsible for ensuring that each subject receives a full explanation,in easily understood terms,of the purpose of the study,the procedures to be employed, the nature of the substances being tested,and the potential risks, beneﬁts, and discomforts.
Clinical Investigation The clinical development of new drugs usually takes place in steps or phases conventionally described as clinical pharmacology (phase I), clinical investigation (phase II),clinical trials (phase III), and postmarketing studies (phase IV).
Phase I When a drug is administered to humans for the ﬁrst time, the studies generally have been conducted in healthy men between 18 and 45 years of age;this practice is coming under increasing scrutiny and criticism. For certain types of drugs, such as antineoplastic agents, it is not appropriate to use healthy subjects because the risk of injury is too high. The purpose of phase I studies is to establish the dose level at which signs of toxicity ﬁrst appear. The initial studies consist of administering a single dose of the test drug and closely observing the subject in a hospital or clinical pharmacology unit with emergency facilities. If no adverse reactions occur, the dose is increased progressively until a predetermined dose or serum level is reached or toxicity supervenes. Phase I studies are usually conﬁned to a group of 20 to 80 subjects.If no untoward effects result from single doses,short-term multiple-dose studies are initiated.
Phase II If the results of phase I studies show that it is reasonably safe to continue, the new drug is administered to patients for the ﬁrst time. Ideally,these individuals should have no medical problems other than the condition for which the new drug is intended. Efforts are concentrated on evaluating efﬁcacy and on establishing an optimal dose range. Therefore,dose–response studies are a critical part of phase II studies.Monitoring subjects for adverse effects is also an integral part of phase II trials. The number of subjects in phase II studies is
Phase III When an effective dose range has been established and no serious adverse reactions have occurred,large numbers of subjects can be exposed to the drug. In phase III studies the number of subjects may range from several hundred to several thousand,depending on the drug. The purpose of phase III studies is to verify the efﬁcacy of the drug and to detect effects that may not have surfaced in the phase I and II trials, during which exposure to the drug was limited. A new drug application is submitted at the end of phase III. However, for drugs intended to treat patients with life-threatening or severely debilitating illnesses,especially when no satisfactory therapy exists,the WHO has established procedures designed to expedite development,evaluation,and marketing of new therapies. In the majority of cases,the procedure applies to drugs being developed for the treatment of cancer and acquired immunodeﬁciency syndrome (AIDS). Under this procedure, drugs can be approved on the basis of phase II studies conducted in a limited number of patients.
Phase IV Controlled and uncontrolled studies often are conducted after a drug is approved and marketed. Such studies are intended to broaden the experience with the drug and compare it with other drugs.
A Ranking of the Quality of Comparative Studies Randomized, controlled trials Double blinded Single blinded Unblinded Observational studies Prospective cohort study Prospective case-control study Retrospective cohort study Retrospective case control study
A Ranking of the Quality ofComparative Studies Similarity of the control group with the group receiving the intervention is key to obtaining valid information in all experimental science. In clinical trials, this similarity is best achieved by random assignment of patients or volunteers to the control group or the group receiving the experimental therapy. Such randomization is the optimal method for distributing between the treatment and control groups the known and unknown variables that could affect outcome. Recognizing that a randomized clinical trial is the "gold standard" of clinical trials, it nonetheless may be impossible to use this design to study all disorders; for patients who cannot - by regulation, ethics, or both - be studied with this design (e.g., children, fetuses, or some patients with psychiatric disease) or for disorders with a typically fatal outcome (e.g., rabies), it may be necessary to resort to historical controls.
A Ranking of the Quality of Comparative Studies A second important element of study design is concealment of the outcome of randomization from the study participants and investigators. Concealing whether participants are assigned to the control or the treatment group is referred to as blinding or masking the study. In therapeutic investigations, participants in the control group will receive an inactive replica of the drug, e.g., a tablet or capsule containing inert ingredients that is identical in appearance to the active agent. This inert replica of the drug is designated as a placebo. When only the study participants are blinded to treatment assignment but investigators know whether the active agent is being given, this is designated as a single-blind study. In a double- blind study, neither the study participants nor the investigators knows whether the active agent is being given.
A Ranking of the Quality of Comparative Studies Blinding the investigators not only removes bias in interpreting the outcomes and in decisions regarding management of the patient but also eliminates selectivity in the enthusiasm for therapy typically conveyed by clinicians. By eliminating participant and observer bias, the randomized, double-blind, placebo-controlled trial provides the highest likelihood of revealing the truth about the effects of a drug. The double-blind, placebo-controlled design permits evaluation of subjective end points, such as pain, that are powerfully influenced by the administration of placebo. Striking instances in which placebo effects are observed include pain in labor, where a placebo produces approximately 40% of the relief provided by the opioid analgesic meperidine with a remarkably similar time course, and angina pectoris, where as much as a 60% improvement in symptoms is achieved with placebo. The response to placebo in patients with depression is often 60% to 70% as great as that of an active antidepressant drug; this complicates clinical trials of efficacy.
End Points of Trial A clear hypothesis for the trial should guide the selection of a primary end point, which should be specified before the trial is initiated. Ideally, this primary end point should measure a clinical outcome, either a disease-related outcome, such as improvement of survival or reduction of myocardial infarction, or a symptomatic outcome, such as pain relief or quality of life. Examination of a single, prospectively selected end point is most likely to yield a valid result from the study. A few additional (secondary) end points also may be designated in advance; the greater the number of end points that are examined, the greater is the likelihood that apparently significant changes in one of them will occur by chance. The least rigorous examination of trial results comes from retrospective selection of end points after viewing the data. Because this introduces a selection bias and increases the probability of a chance result, retrospective selection should be used only as the basis to generate hypotheses that then can be tested prospectively.
End Points of Trial In some instances, therapeutic decisions must be based on trials evaluating surrogate end points - measures such as clinical signs or laboratory findings that are correlated with but do not directly measure clinical outcome. Such surrogate end points include measurements of blood pressure (for antihypertensive drugs), plasma glucose (for diabetic drugs), and levels of viral RNA in plasma (for antiretroviral drugs). The extent to which surrogate end points predict clinical outcomes varies, and two drugs with the same effect on a surrogate end point may have different effects on clinical outcome. Of greater concern, the effect of a drug on a surrogate end point may lead to erroneous conclusions about the clinical consequences of drug administration. One compelling example of the danger of reliance on surrogate end points emerged from the Cardiac Arrhythmia Suppression Trial (CAST). Based on their ability to suppress the surrogate markers of ventricular premature contractions and nonsustained ventricular tachycardia, antiarrhythmic drugs such as encainide, flecanide, and moricizine frequently were used in patients with ventricular ectopy after myocardial infarction The CAST study showed that despite their ability to suppress ventricular ectopy, the drugs actually increased the frequency of sudden cardiac death. Thus, the ultimate test of a drugs efficacy must arise from actual clinical outcomes rather than surrogate markers
Observational Studies Important but infrequent adverse drug effects may escape detection in the randomized, controlled trials that demonstrate efficacy. In controlled trials that form the basis for approval of drugs for marketing, the number of patient-years of exposure to a drug is small relative to exposure after it is marketed. Also, some adverse effects may have a long latency or may affect patients excluded from the controlled trials. Therefore, nonexperimental or observational studies are used to examine those adverse effects that only become apparent with widespread, prolonged use of the drug in the practice of medicine. For example, such observational studies identified peptic ulcers and gastritis as serious adverse effects of nonsteroidal antiinflammatory drugs and aspirin.
Observational Studies The quality of information derived from observational studies varies with the design and depends highly on the selection of controls and the accuracy of the information on medication use. Cohort studies compare the occurrence of events in users and nonusers of a drug; this is the more powerful of the observational study designs. Case-control studies compare drug exposure among patients with an adverse outcome with that in control patients. Because the control and treatment groups in an observational study are not selected randomly, there may be unknown differences between the groups that determine outcome independent of drug use. Because of the limitations of observational studies, their validity cannot be equated with that of randomized, controlled trials. Rather, the role of observational studies is to raise questions and pose hypotheses about adverse reactions. However, if it is not feasible to test these hypotheses in controlled clinical trials, then replicated findings from observational studies may form the basis for clinical decisions
ADVERSE REACTION SURVEILLANCE Almost all drugs have adverse effects associated with their use;these range in severity from mild inconveniences to severe morbidity and death. Some adverse effects are extensions of the drug’s pharmacological effect and are predictable, for example, orthostatic hypotension with some antihypertensive agents, arrhythmias with certain cardioactive drugs,and electrolyte imbalance with diuretics. Other adverse effects are not predictable and may occur rarely or be delayed for months or years before the association is recognized. Examples of such reactions are aplastic anemia associated with chloramphenicol and clear cell carcinoma of the uterus in offspring of women treated with diethylstilbestrol during pregnancy. Postmarketing surveillance programs and adverse reaction reporting systems may detect such events. The best defense against devastating adverse actions is still the vigilance and suspicion of the physician.
PATIENT-CENTERED THERAPEUTICS Optimal treatment decisions are based on an understanding of the characteristics of the individual patient that will determine the response to the drug. Interindividual differences in drug delivery to its site(s) of action can profoundly influence therapeutic effectiveness and adverse effects. A thorough drug history is a key element in individualizing therapy, and information on concurrent therapy must be accessible at each encounter to guide safe and effective treatment. Documentation of current prescription drug use is a starting point in the drug history. Despite increasing use of computerized drug lists, it often is very helpful for patients to bring all current medications with them to the clinical encounter. Specific prompting is required to elicit the use of over-the-counter drugs and herbal medications, both of which may affect therapeutic decisions. Information about medications that are used only sporadically may not be volunteered without a specific query. With cognitively impaired patients, it may be necessary to go beyond the interview to include caregivers and pharmacy records; as noted earlier, requests to examine the actual medications also can be invaluable.
PATIENT-CENTERED THERAPEUTICS Before writing a prescription, review the patients drug therapy, even if you are rewriting a drug chart in hospital. Ask yourself the following questions: How will the new drug fit in with the existing therapy for this disease? Will it add to symptom relief? Will it modify the pathophysiology of the disease? Will it prevent the disease or its progression? Will the drug have an effect on any other diseases? Diuretics given for heart failure can worsen gout; beta-blockers can precipitate and worsen asthma. Will the drug interact with any other drugs that the patient is taking? Remember: Drugs prescribed by others (doctors, nurses, pharmacists) Over-the-counter drugs including herbal remedies and other non-prescribed drugs
PATIENT-CENTERED THERAPEUTICS Repeat prescriptions Many drug treatments need to be taken long-term and will therefore require a repeat prescription. About 75% of all prescriptions issued by GPs are repeat prescriptions. Computer systems have made the practicalities of issuing a repeat prescription easier, but before doing so consider the following: Is long-term treatment required or justified (e.g. corticosteroids, antidepressants, benzodiazepines)? Each of these should be given for a defined period with a clinical review at the end. See individual articles for more information. The duration of each repeat prescription should be no longer than 3 months. All long-term therapy should be reviewed with the patient in person at least once a year. Take the opportunity to review all the patients medication. Computer systems can alert you to possible drugвЂ“drug interactions, but consider drugвЂ“disease interactions as well. Ask whether you have clear targets for the patients treatment, and whether the drug regimen is optimal. If you are discharging a patient from hospital, make clear which drugs should be continued long-term and whether any further dose titration is required.
PATIENT-CENTERED THERAPEUTICS Cautionary and advisory labels Most medicines are dispensed by pharmacists. They will always label a medicine with essential details (the name of the medicine, the dose, and the frequency of administration), and in some cases will add cautionary and advisory labels. Standard labels offer advice but are not exhaustive. Remember that labels are not a substitute for adequate counselling by prescribers and dispensers but are intended to reinforce essential information. Recommended label wording can offer advice about: Timing of doses in relation to food. Completing the course of treatment. What to do if a dose is missed. The correct storage of a medicine. Dissolution of the medicine in water before taking it. Limits to the number of tablets that should be taken in a given time. Recommended label wording can offer warnings about: Effects of the medicine on driving or work (e.g. through drowsiness). Foods or medicines that should be avoided. Avoidance of exposure of the skin to sunlight or sun lamps. Medicines that can discolour the urine. Medicines that can stain clothes or skin.
Compliance, adherence, and concordance It has been estimated that about half of those for whom medicines are prescribed do not take them in the recommended way. Until recently this was termed non-compliance, which was sometimes regarded as a manifestation of irrational behaviour or wilful failure to observe instructions, although forgetfulness is probably a more common reason. We prefer to talk about adherence to a regimen rather than compliance. There are many reasons why patients do not take medicines in the ways that health professionals expect them to, for example: Lack of agreement that a prescription medicine is the best treatment for an illness Concern about the effectiveness of a treatment or about possible adverse effects Failure to appreciate the reasons for therapy Forgetfulness There have been many studies of the effects of different strategies in improving adherence to therapy. These include reducing the frequency of administration during the day and reducing the numbers of medicines the patient has to take. However, evidence that such measures are effective is lacking. Nevertheless, it seems likely that adherence can be improved by taking care to explain the benefits and adverse effects of a drug; in a busy clinic it is all too easy to issue a prescription with little or no explanation. Reducing the frequency of administration to once or, at most, twice a day also makes sense, despite lack of convincing evidence that this is effective. Concordance is a term that has been coined to reflect the changing nature of the relationship between patients and prescribers. It encapsulates the notion that there should be an explicit agreement between the patient and the prescriber; an impression that agreement has been reached is not enough. It recognizes that patients should have the casting vote and may decide not to take a medicine, even when it appears to be in their best interests. The corollary of this is that patients should take greater responsibility for their treatment and the consequences of their actions.
Guidelines and EBM Clinical guidelines are intended to improve the quality of healthcare by implementing the best available information. They are not a substitute for thought; prescribers should always consider the extent to which the guidelines apply to their clinical problem. Clinical guidelines vary in quality: some are based on a careful review of all the available data, others represent little more than the opinion of a small group. Do not forget that political and economic consider ations can influence the ways in which guidelines are written and their contents. The scope of guidelines varies: some consider clinical effectiveness only, while others consider cost as well. This can lead to contradictory recommendations. Guidelines are produced by many different bodies, and there is no single repository of the best.
Guidelines and EBM The Basis of guidelines is EBM EBM (evidence based medicine) is an approach to medical practice that uses the results of patient care research and other available objective evidence as a component of clinical decision making.Similarly, evidence-based pharmacotherapy,deﬁned by Etminan and colleagues,is an approach to decision making whereby clinicians appraise the scientiﬁc evidence and its strength in support of their therapeutic decisions. Patients care reseach are special trials (the principle of trial deal with principles of EBM (randomisation, masking, control, end points, observation, pharmacoepidemiology etc)
An approach to rational prescribing Prescribing should follow a rational algorithm. All too often, however, it is a reflex decision taken at the end of a consultation. Principles When planning therapy consider your interventions in the following categories: Treatments that relieve symptoms of the disease. Treatments that modify the pathophysiology of the disease. Treatments that are aimed at secondary (and primary) prevention. These treatments can be both pharmacological and non-pharmacological. Drug selection Do I need a drug at all? If I need a drug : What sort of drug do I need? What is the target? (receptor, enzyme, transport protein, etc.) Where is the target found? Does the drug reach its site of action? (e.g. vancomycin is not absorbed when given by mouth)
An approach to rational prescribing Can I focus my treatment on one subtype or location? Pharmacodynamic targeting (receptor subtypes) (e.g. a relatively beta1-selective beta- blocker) Pharmacokinetic targeting (routes of delivery) (e.g. beta2 agonists given by inhalation) Is the onset of action of this drug appropriate for the indication? Some drugs take days to act, is this fast enough? (e.g. antidepressant drugs take at least 2 weeks to act) How will I deliver this drug? Route (e.g. by inhalation) Formulation (e.g. modified-release) Have I taken into account any important kinetic factors? Renal or hepatic insufficiency Have I considered any interactions: With the disease/physiology (e.g. a sulphonylurea will not work in most cases of type I diabetes the islet cells have been destroyed) With drugs Metabolic interactions (enzyme induction) Pharmacological interactions (e.g. beta-blockers and verapamil)
Monitoring therapy Having selected a drug, it is essential to set targets for your therapy. Make a note of the effect you expect the drug to have (e.g. by how much you want the blood pressure to fall). Warn the patient about any predictable adverse effects and other points to note Arrange appropriate follow-up. At follow-up, assess the success of your intervention. This should include assessment of both the therapeutic and adverse effects. Set a new target for your therapy and repeat the process. Do not give patients drugs without a clear idea of what you are hoping to achieve.