Download Pharmacodynamics

Introduction to the Course of
Pharmacology
Prof. Ushkalova Elena Andreevna
Pharmacology
• Basic
• Clinical
Basic pharmacology
An area of medical science which
deals with the study of drugs
(medicine)
that interact with the living system
through chemical processes
specially by binding to regulatory
molecules and activating or
inhibiting body processes.
Clinical pharmacology is
the scientific discipline
that involves all aspects of
the relationship between
drugs and humans.
Pharmacology
• Parmacokynetics • Pharmacodynamics
Movement of the drug in
the organism
• Where the drug acts
• How it acts
• The result of its action
PHARMACOKINETICS
Pharmacodynamics
• Pharmacodynamics is
the study of the
biochemical and
physiological effects of
drugs and the
mechanisms of drug
action and
the relationship
between drug
concentration and
effect.
Pharmacodynamics
•
•
•
•
Drug actions and effects
Sites of action
Mechanisms of action
Development of therapeutic
response:
- Onset – the time it takes for the
drug to elicit a therapeutic response
- Peak - the time it takes for the drug
to reach its maximum therapeutic
response
- Duration - the time the drug
concentration is sufficient to elicit a
therapeutic response
• Agonists - they stimulate and activate the
receptors
• Antagonists - they stop the agonists from
stimulating the receptors
Agonists stimulate and activate the receptors
Antagonists stop the agonists from stimulating the receptors
Causes of Variability in Drug
Response
• Those related to the conditions of administration
1. Dose, formulation, route of administration.
2. Resulting from repeated administration of drug:
drug resistance; drug tolerance-tachyphylaxis; drug allergy
(hypersensitivity )
3. Drug interactions:
chemical or physical;
GI absorption;
protein binding/distribution;
metabolism (stimulation/inhibition);
excretion (pH/transport processes);
receptor (potentiation/antagonism);
changes in pH or electrolytes.
Factors that Influence Drug Action
• Age
Pediatric patients and elderly
patients may need a reduced dose
because of smaller size or inability
of liver to metabolize medication
• Disease
Specific diseases may hinder the
pharmacokinetic process of some
drugs
• Mental State, Genes, Gender
Age-related
pharmacokinetics
Pediatric Age Groups
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•
•
•
•
•
Premature: gestational age < 36 weeks
Full-term: gestational age ≥ 36
Neonates: 0–1 months
Infants: 1 months – 2 years
Children: 2 –12 years
Adolescent: 12–16 (18) years
Geriatric Considerations
• Altered Drug Responses
• Adverse Drug Reactions
(ADRs)
• Polypharmacy
• Noncompliance
B («best»), C («caution»), D («dangerous»)
Rational use of drugs
The World Health Organization in Nairobi in 1985 defined that,
«Rational use of drugs requires that patients receive medications
appropriate to their clinical needs, in doses that meet their own
individual requirements for an adequate period of time, and the
lowest cost to them and their community».
• The definition implies that rational use of drugs, especially rational
prescribing should meet certain criteria as follows:
• appropriate indication
• appropriate drug
• appropriate patient
• appropriate information
• appropriate monitoring
WHO booklet “Assessing the problems of irrational use of drugs” 2003, ISBN 92 4 156234X
2. Ambwani S & Mathur, A, Rational drug use, health administrator, vol 19, 2006 p.5-7.
3. Sharma HL, Sharma KK. Concept of essential medicine & rational use of drugs in Principle
of Pharmacology, Pras publication 2001:9, 106-107
“Rights” for Drug Administration
Right Drug
Right Patient
Right Time
Right Strength
Right Route
Risk/benefit ratio
• The benefit-risk balance of a drug must be positive in order to gain and
maintain product approval.
• Benefits are commonly expressed as the proven therapeutic good of a
product, but should also include the patient’s subjective assessment of its
effects
• Risk is the probability of harm being caused, usually expressed as a
percent or ratio of the treated population; the probability of an
occurrence
• Regulatory authorities accept different degree of risks for different
pharmacological classes
• It is necessary to monitor benefits and risks during the life cycle of a
medicine
• The assess of this ratio can be changed:
• If new information about this medicine appears
• If new drugs with better risk/benefit ratio are approved
Efficacy, Effectiveness, Efficiency
• Efficacy - the power or capacity to
produce a desired result
Efficacy is used to express the extent to
which a drug works under ideal
circumstances (i.e., in clinical trials).
• Effectiveness means the capability of
producing an effect.
Effectiveness is used to express the
extent to which a drug works under real
world circumstances, i.e., clinical
practice (not clinical trials).
• Efficiency – economic efficiency
(evaluates clinical efficacy/safety/cost of
treatment)
Side effects occur when drug is used in therapeutic doses, toxic
– in supratherapeutic doses
ADR Classification
• Type A: Augmented pharmacologic
effects - dose dependent and
predictable
• Type B: Bizarre effects
(or idiosyncratic) - dose independent
and unpredictable
• Type C: Develop during long-term
therapy (tolerance, addiction,
cumulative and withdrawal
symptoms)
• Type D: Delayed effects (mutagenic,
carcinogenic, teratogenic)
Therapeutic Window and Therapeutic
Ratio
• Measure “how safe” drug is
• Higher (wider) = safer
Therapeutic window is the
range of doses of between the
amount that gives an effect
(effective dose) and the amount
that gives more adverse
effects than desired effects
(minimal therapeutic and
minimal toxic doses)
Tolerability and Safety
• Tolerability - the ability to
tolerate drug therapy
• Safety – low risk (incidence) of
developing serious ADR
Serious ADR
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•
•
•
•
•
Life-threatening
Requires hospitalization
Prolongs hospitalization
Causes disability
Causes congenital anomalies
Causes medically important
events
Serious  Severe
International Pharmaceutical Market
• More than 8000 INN - International
Nonproprietary Names
• Annually 150-200 INN are launched
Drug Names
• Chemical Name
– Chemical makeup
• Generic name
– Name the manufacturer gives a drug (according
with «Procedure for the Selection of
Recommended International Nonproprietary
Names for Pharmaceutical Substances»,
WHOEB15.R7)
– USAN, BAN, DCF, DCIt, JANn etc
– Nonproprietary drug, not protected by trademark
• Brand name
– Trade name
– Copyrighted and used exclusively
Archie Cochrane
(1909–1988)
Scottish doctor and epidemiologist , founder of
evidence-based medicine
His advocacy of randomized controlled trials eventually led to the development of the
Cochrane Library database of systematic reviews, the establishment of the UK
Cochrane Centre in Oxford and the international Cochrane Collaboration.
Basis and History
• 1972 г. - Cochrane A L
«Effectiveness and Efficiency:
Random Reflections on Health
Services»
• 1993 г. - The Cochrane
CollaborationThe Cochrane
Library
Cochrane Electronic Library
• The Cochrane Database of
Systematic Reviews (Cochrane
Reviews)
• The Database of Abstracts of Reviews
of Effects (DARE)
• The Cochrane Central Register of
Controlled Trials (CENTRAL)
• The Cochrane Methodology Register
(Methodology Register).
• Health Technology Assessment
Database (HTA).
• NHS Economic Evaluation Database
(NHS EED)
Clinical Trials
• Phase I
– Studied in 20-100 healthy people (safety)
• Phase II
– Studied in patients who have the condition it is
intended to treat ( efficacy )
• Phase III
– Compared to commonly used treatments
• Phase IV
– Continuation of testing after approved for
marketing (effectiveness and safety in real
practice)
Limitations of Premarketing
Clinical Trials
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•
•
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Strict criteria of inclusion/exclusion
Homogeneous groups of patients
Proper guidance
Research is often limited with respect to duration and size. For this
reason, in order to demonstrate efficacy, use is often made of
surrogate outcome measures and not of clinical endpoints such as
a decrease in mortality and morbidity
• It is not possible to adequately distinguish rare adverse effects or
ones that only occur after long-term use
• This ideal-trial situation differs from the real-life situation. In
clinical practice medicines are undeniably be used in more
heterogeneous groups of patients, often with comorbidity and
frequently for longer periods
ADR incidence
1:100
1:200
1:1000
1:2000
1:3000
Number of participants
1 ADR
2 ADR
(signal)
3 ADR
300
600
3000
6000
30000
480
960
4800
9600
48000
650
1300
6500
13000
65000
Definition of
Pharmacovigilance
Pharmacovigilance is defined as the science and activities
relating to the detection, assessment, understanding
and prevention of adverse effects or any other drugrelated problem, including medical errors.
The IMPORTANCE of
PHARMACOVIGILANCE.
Safety Monitoring of medicinal products.
World Health Organization 2002
Frances Kelsey
(born 1914, July
24)
2010 • FDA Kelsey Award
Medical Errors as Important
Cause of Morbidity and Mortality
• Experts estimate that only in the USA as many as 98,000 people
die in any given year from medical errors that occur in hospitals.
That's more than die from motor vehicle accidents, breast cancer,
or AIDS «(To err is human: building a safer health system»
(Washington (DC): National Academy Press, 1999.,An
organisation with a memory . London: Department of Health,
2000.)
• Several studies have estimated that around 4% to 17% of patients
have experienced an adverse event, and that up to half of these
incidents could have been prevented
Sousa P. Acta Med Port. 2006 Jul-Aug;19(4):309-17.
WHY PHARMACOVIGILANCE?
• The information collected during the pre-marketing
phase of a medical drug is inevitably incomplete with
regard to possible adverse reactions :
• tests in animals are insufficiently predictive of
human safety
• in clinical trials patients are selected and limited in
number, the conditions of use differ from those in
clinical practice and the duration of trials is limited
• information about rare but serious adverse
reactions, chronic toxicity, use in special groups
(such as children, the elderly or pregnant women) or
drug interactions is often incomplete or not available.
Safety
Monitoring
of
Medicinal
Products:
Guidelines for Setting Up and
Running
a
Pharmacovigilance Centre.
WHO 2000.
VigiBase
• VigiBase, is the source of worldwide post-marketing
case safety reports.
• More than 100 countries are currently contributing to
the database by submitting ICSRs collected at their
national pharmacovigilance centres (NCs)
• January 2012 - 7 million ADR reports
• April 2012 - 7,160,190 reports
• 1997 - Russia was admitted as official member of the
WHO Programme
VigiBase: Number of Reports (per million inhabitants)
from Different Countries (2006-2011)
WHO Recommendations
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Pharmacovigilance is needed in every country, because there are differences
between countries (and even regions within countries) in the occurrence of
adverse drug reactionsand other drug-related problems. This may be because
of differences in:
drug production
distribution and use (e.g. indications, dose, availability)
genetics, diet, traditions of the people
pharmaceutical quality and composition (excipients) of locally produced
pharmaceutical products
the use of non-orthodox drugs (e.g. herbal remedies) which may pose special
toxicological problems, when used alone or in combination with other drugs.
Data derived from within the country or region may have greater relevance and
educational value and may encourage national regulatory decision-making.
International monitoring such as the WHO International Drug Monitoring
Programme may provide information on possible safety issues which may not
yet have emerged within the country‘s data.
SAFETY MONITORING of MEDICINAL PRODUCTS. Guidelines for setting up and running a Pharmacovigilance CentreWHO Collaborating Centre
for International Drug Monitoring. 2000.
ADR Reporting Form