Download INTRODUCTION TO PHARMACOLOGY

MUSTAFEEZ BABAR
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General Principles of Pharmacology
Basic Pharmacology
Clinical Pharmacology-(Selected Organ
systems)
Molecular Basis of Pharmacology
Pharmacological Parameters and Calculations
for drug candidate selection
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Sessionals = (15+5)*2
Assignment/ presentation = 10
Terminal = 50
“Poisons in small doses are the best medicines; and
useful medicines in too large doses are poisonous”
(William Withering, “discoverer” of digitalis, 1789)
Paul Insel, M.D. (UCSD) in
Molecular Basis of Drug Action and Disease Therapy
1.
What is pharmacology?
2.
Why are drugs important for human health and scientific research?
3.
How do drug efficacy and toxicity contribute to therapeutic success, therapeutic
failures and medical errors?
4.
What is the “therapeutic partnership”?
5.
What are some major principles of pharmacotherapy?
6.
Where does one obtain reliable information about drugs?
7.
Can drug therapy be individualized/personalized?
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What new efforts in pharmacotherapy and pharmacology are on the horizon?
9.
How are drugs developed and approved?
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What is pharmacology?
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Pharmacology (from pharmakon, the Greek word for drug) is
the study of drugs (substances that produce changes in the
body) and the characterization of their:
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Structure, targets, and mechanisms of action
Distribution in and handling by the body
Effects on the body, including desirable responses (efficacy) and
undesirable side-effects (toxicity)
Drugs include caffeine, nicotine, alcohol in addition to chemicals that
are abused (e.g., cannabis, heroin, etc.), food constituents (vitamins,
minerals, amino acids, etc.) and cosmetics.
Pharmacology can be studied at multiple “levels”: molecular,
(sub)cellular, tissue, whole animal, or population
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Clinical pharmacology is the study of drugs in human patients
Toxicology is the study of harmful rather than therapeutic effects
Pharmacy involves manufacture, preparation, and dispensing of drugs
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Pharmacokinetics (“what the body does to a drug”) and
phamacodynamics (“what a drug does to the body”) are the
two key aspects of pharmacology
In research, many experimentalists in the biological sciences
use drugs to produce or block responses and as a means to
infer mechanisms (of cell, tissue/organ, organismal
responses). In addition, others seek new ways to treat disease
Prescribing drugs is what MD’s “do” and drugs are the raison
d’etre of pharmacists.
Understanding the principles of pharmacology is thus “central”
to the efforts of MD’s, PharmD’s and most biomedical
researchers
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From early in human history, pharmacologically active
substances (e.g., from plants, animals) have been used to
ward off or treat disease
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Drugs can be molecules synthesized in the body (e.g., hormones or
neurotransmitters [e.g. dopamine, epinephrine, acetylcholine]) or
molecules not synthesized in the body (i.e., xenobiotics, from the Greek
xenos, meaning “stranger”)
Poisons are drugs that almost exclusively have harmful effects
Discovery and development of drugs (including
immunotherapy/ vaccinations) has been a major factor that
has increased life span and improved the quality of life
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New scientific insights—in some cases, inferred from novel
mechanisms of action– have been essential to this progress, together
with controlled clinical trials, in particular, randomized, double-blind
trials
In parallel (especially in recent years) has been the promotion of
“alternative” and “complementary” treatments, many (most) of which
have not undergone rigorous scientific validation
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The search for “magic bullets”—agents that treat disease or
produce desirable effects but lack harm— and ways to
improve such agents has driven scientific discovery for >100
years
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There are very few magic bullets* with high benefits and very low risk
The challenge is to identify, test, approve and ultimately use
drugs that maximize efficacy but minimize toxicity
Primum non nocere: “First do no harm”
Because of problems (including deaths) that have occurred,
governments use approval processes (which tend to
emphasize safety>efficacy) before drugs can be marketed and
prescribed.
*Examples: selective toxicity of antimicrobials that target bacterial cell walls
(lacking in animals/humans) or enzymes found only in micro-organisms
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Pharmacodynamics (“drug action”) includes the measurement
of responses to drugs and how such responses relate to drug
dose and concentration at a target site
Effect
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Log Dose
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Pharmacotherapy is the use of drugs to treat disease
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Requires knowledge of drugs, physiology, and pathology (this course
will teach you some of each of these but none can be covered in depth)
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Important “pharmaco” terminology
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Pharmacoepidemiology investigates the effects of drugs
on populations
Pharmacoeconomics examines the cost-effectiveness of
drug treatments
Pharmacogenetics and pharmacogenomics study the
influence of genetic variation on pharmacodynamic and
pharmacokinetic properties of drugs
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The Two Key Aspects of Pharmacology:
Pharmacokinetics and Pharmacodynamics
Drug
Pharmacokinetics
Intended
target
Pharmacodynamics
Unintended
targets
Therapeutic
effects
Toxicokinetics
Toxicodynamics
Toxic
effects
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The Two Key Aspects of Pharmacology:
Pharmacokinetics and Pharmacodynamics
Drug administration
Distribution
Effector
sites
Pharmacodynamics
Excretion
Metabolism
Pharmacokinetics
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Pharmacokinetics and Pharmacodynamics:
A More Complete Schema
Interaction with cellular targets is the focus
of most research regarding drug action
(“Molecular pharmacology”) and includes
studies of receptors, receptor signaling, and
post-receptor responses
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The major goal is rational therapeutics:
Knowing, understanding, and implementing general
principles and specific facts about classes of drugs and
individual drugs
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Rational therapeutics seeks to maximize therapeutic
responses while minimizing therapeutic failures and
medical errors that occur because of “therapeutic
wrongs”:
Prescribing/dispensing/administering the wrong drug
(or wrong dose)
To the wrong patient
At the wrong time
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Patients and health providers (e.g., physicians and pharmacists) are
partners that seek to optimize drug
prescription/dispensing/administration and thereby maximize efficacy
and minimize toxicity, thus increasing the “therapeutic window” (between
beneficial and toxic effects).
Adherence (compliance) to drug regimens is a major problem in
therapeutics: many patients do not take the correct drug/dose at the
correct time/frequency for the correct period of time). Thus, new
approaches are needed to solve this problem and will likely include :
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Simplification of medication regimens
Patient/caregiver education
Ongoing assessment of adherence and outcomes
Novel formulations, delivery methods, monitoring/assessment
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Therapeutic Window
[Drug] in blood
[Drug] in Blood and Relation to Effects
Oertel, W. et al. Neurology 2007;69:S4-S9
Note the need to achieve effective concentration (efficacy) without exceeding levels that
increase side effects (toxicity)
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Therapeutic Window:
Tx effect
Effect
Rx effect
Log Dose
Effect
Effect
Relationship between Rx and Tx Doses
Rx effect
Tx effect
Log Dose
Rx effect
Log Dose
Tx effect
Rx effect = Therapeutic effect
Tx effect = Toxic effect
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Use of scientific method and application of fundamental
principles must guide drug prescription/administration
and the monitoring/evaluation of drug administration
Each patient’s prescription is a scientific experiment (but is not
usually thought of in this way):
Hypothesisdrug treatmentassessment of
outcomeinterpretation?make changes for next experiment
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Since there are few “magic bullets”, it is critically
important for those who prescribe, dispense and
administer drugs to be knowledgeable and those who
discover drugs must seek to optimize efficacy and
minimize toxicity
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Drugs are “selective” (rarely “specific”) in their sites of action
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Selectivity depends on several factors
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Selective toxicity for drugs used as chemotherapeutic
(antimicrobial, anticancer) agents or pesticides (e.g.,insecticides)
that kill targets without harming the host
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Chemical nature of drug
Dose and route of administration
Patient characteristics (e.g., genetics, age, gender, co-existing disease)
Difficult to achieve selective toxicity if the “target” resembles the host
Risk-benefit ratio describes adverse vs. beneficial effects of a
drug; acceptable risk/benefit ratios depend on:
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Severity of the disease being treated (or prevented)
Economic and societal factors: many new drugs are VERY expensive
and raise concerns about “rationed care” that will only be available for
the world’s most wealthy citizens: is this “moral”?
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A worldwide problem of overuse of
drugs: Antibiotic usage can enhance
microbial resistance and ultimately,
lead to failure of treatment
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Textbooks of pharmacology (but most have “dated” info
even at time of publication): Recommended text is this
course provides a good overview on topics that will be
covered
Journals and especially from on-line sources that provide
regular updates
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Clinical Pharmacology (Online Clinical Library @ BML)
Micromedex (Online Clinical Library @ BML)
The Medical Letter (E-Journals @ BML)
Physician’s Desk Reference (PDR)
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Drug company-generated compilation of FDA-approved package inserts +
pictures of drugs
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Much current interest in the individualization of drug therapy
and taking into account genetic and environmental factors
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There has been some success but progress toward individualized
therapy has been slow—especially as related to drug action
Many key questions remain, including:
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Are the most important inter-individual differences in
pharmacokinetics or pharmacodynamics?
Will knowing a person’s genome improve the choice among and
dosing of drugs?
Will/should clinical trials be “genomically stratified” such that drugs
are tested and then approved for genomic sub-populations? Should
basic research studies emphasize such issues during drug
development?
Bottom line: This is a work in progress that will likely
drive research and changes in drug approval and
prescribing
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In addition to “genetically informed” understanding of
disease, drug development/prescribing, other aspects of
pharmacotherapy that will likely change are:
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”New” disease/drug targets based on evolving information from
genetic, biochemical, molecular biological, and imaging studies [as
will be discussed in this course]
New formulations with an increased number of “biological drugs”
(e.g., antibodies, binding proteins, ?antisense, ?siRNA, ?gene
therapy)
Alternative methods of drug delivery (less pain and other side
effects, better/more consistent delivery and bioavailability)
Less-invasive but increased assessment of efficacy and toxicity
Better methods and their wider use to assess compliance/adherence
Efforts to create errorless drug prescribing/administration—these
are a major source of medical errors, which in spite of much publicity
are still seen as a serious, unsolved problem
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Answer: Following discovery of new chemical entities (NCEs) in academia or
industry, studies are conducted in animals and humans. Randomized, placebocontrolled, double-blind clinical trials are the gold standard for demonstration of
efficacy and determining benefit/harm..