Non-obligatory presentation

1. 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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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).

9. 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.

10. 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

11. 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.

12. 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.

13. 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

14. A Ranking of the Quality of
Comparative 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.

15. 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.

16. 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.

17. 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.

18. 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 drug's
efficacy must arise from actual clinical outcomes rather than surrogate markers

19. 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.

20. 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

21. 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.

22. 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.

23. PATIENT-CENTERED THERAPEUTICS
 Before writing a prescription, review the patient's 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

24. 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 patient's medication. Computer systems can alert you
to possible drug–drug interactions, but consider drug–disease interactions as well.
 Ask whether you have clear targets for the patient's 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.

25. 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.

26. 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.

27. 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.

28. 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)

29. Guidelines and EBM

30. Guidelines and EBM

31. 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)

32. 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)

33. 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.

34. THANK YOU