BIOM 255: Molecular basis of drug action and disease therapy

BIOM 255: Molecular basis of drug action and disease therapy
The human need for medicines to alleviate
suffering, cure disease, and even delay aging
is both timeless and personal. Indeed, the
critical goal of personalized medicine is to
address this need for each individual.
Identifying the right drug for the right patient
at the right dose and time promises to
revolutionize the treatment of disease while
also improving drug safety. Pharmacologythe scientific discipline that seeks to describe
the actions of drugs on living systems-has
begun to provide us with answers to these
age-old questions.
-William W. Chin
From the Recommended reading: Principles of Pharmacology: The
Pathophysiologic Basis of Drug Therapy, Golan, et al., 3rd Edition (2011)
BLOCK 1: General principles of pharmacology
Block Leader: Paul Insel
1. Jan 10: Paul Insel: Introduction to principles of pharmacology2. Jan 12: Alexandra Newton: Dose-response relationships
3. Jan 17: James Halpert: Drug Metabolism and Disposition
4. Jan 19: Palmer Taylor: Pharmacokinetics & Pharmacodynamics
BLOCK 2: Inflammation and inflammatory diseases
Block Leader: Tony Yaksh
5. Jan 24: Tony Yaksh: Inflammatory mediators and their treatment
6. Jan 26: Michael Karin: Inflammatory bowel disease
7. Jan 31: Tony Yaksh et al: Class discussion (papers)
8. Feb 2: Gary Firestein: Rheumatoid arthritis: therapeutic approaches
BLOCK 3: The Autonomic Nervous System, Asthma and Hypertension
Block Leader: Paul Insel
9. Feb 7: Paul Insel: Principles of autonomic pharmacology
10.Feb 9: Volker Vallon: Hypertension and its therapy
11.Feb 14: Fiona Murray: Asthma and its therapy
12.Feb 16: Fiona Murray/Volker Vallon - Class Discussion (papers)
BLOCK 4: Diabetes, Obesity & Metabolic Syndrome
Block Leader: Nick Webster
13. Feb 21: Nick Webster: Diabetes mellitus and obesity: Pt 1
14. Feb 23: Nick Webster: Diabetes mellitus and obesity: Pt 2
15. Feb 28: Steven Chessler: Treatment of diabetes and metabolic syndrome
16. Mar 1: Nick Webster, et al. - Class Discussion (papers)
BLOCK 5: Cancer: Carcinogens, metastases and chemotherapy
Block Leader: Bob Tukey
17. Mar 6: Bob Tukey: Carcinogens and carcinogenesis
18. WED, Mar 7* (1 -3): Steve Howell: Cancer chemotherapy
19. Mar 13: Tannishtha Reya: New Targets in Cancer including metastases?
20. Mar 15: Bob Tukey et al.-Class Discussion (papers)
Principles of Pharmacology
Paul A. Insel, MD
Tuesday, January 10, 2012
“Poisons in small doses are the best medicines; and
useful medicines in too large doses are poisonous”
(William Withering, “discoverer” of digitalis, 1789)
Lecture Outline
This lecture will answer the following questions:
What is pharmacology?
Why are drugs important for human health and scientific research?
How do drug efficacy and toxicity contribute to therapeutic success,
therapeutic failures and medical errors?
What is the “therapeutic partnership”?
What are some major principles of pharmacotherapy?
Where does one obtain reliable information about drugs?
Can drug therapy be individualized/personalized?
What new efforts in pharmacotherapy and pharmacology are on the horizon?
How are drugs developed and approved?
What is pharmacology?
• 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:
– 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
– 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
What is pharmacology?
• Pharmacokinetics (“what the body does to a drug”) and
phamacodynamics (“what a drug does to the body”) are the
two key aspects of pharmacology
• Prescribing drugs is what MD’s “do” and drugs are the raison
d’etre of pharmacists.
• 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
Understanding the principles of pharmacology is thus
“central” to the efforts of MD’s, PharmD’s and most
biomedical researchers
Why are drugs important for health and scientific
• From early in human history, pharmacologically active
substances (e.g., from plants, animals) have been used to ward
off or treat disease
– 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
– 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
Why are drugs important for health and scientific
• 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
– 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
Important Terminology
• Pharmacodynamics (“drug action”) includes the measurement
of responses to drugs and how such responses relate to drug
dose and concentration at a target site
Log Dose
• Pharmacotherapy is the use of drugs to treat disease
– Requires knowledge of drugs, physiology, and pathology (this course will
teach you some of each of these but none can be covered in depth)
Important “pharmaco” terminology
• 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
The Two Key Aspects of Pharmacology:
Pharmacokinetics and Pharmacodynamics
The Two Key Aspects of Pharmacology:
Pharmacokinetics and Pharmacodynamics
Drug administration
Pharmacokinetics and Pharmacodynamics:
A More Complete Schema
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
How do drug efficacy and toxicity contribute
to therapeutic success, therapeutic failures,
and medical errors?
• The major goal is rational therapeutics:
Knowing, understanding, and implementing general principles
and specific facts about classes of drugs and individual drugs
• 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
What is the “therapeutic
• 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 :
Simplification of medication regimens
Patient/caregiver education
Ongoing assessment of adherence and outcomes
Novel formulations, delivery methods, monitoring/assessment
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)
Therapeutic Window:
Tx effect
Rx effect
Log Dose
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
What are some major principles of
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
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
Can one achieve selectivity in
• Drugs are “selective” (rarely “specific”) in their sites of action
• Selectivity depends on several factors
• Chemical nature of drug
• Dose and route of administration
• Patient characteristics (e.g., genetics, age, gender, co-existing disease)
• Selective toxicity for drugs used as chemotherapeutic
(antimicrobial, anticancer) agents or pesticides (e.g.,insecticides)
that kill targets without harming the host
• 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:
• 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”?
A worldwide problem of overuse of
drugs: Antibiotic usage can enhance
microbial resistance and ultimately,
lead to failure of treatment
Where does one obtain reliable
information about drugs?
• 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
– Clinical Pharmacology (Online Clinical Library @ BML)
– Micromedex (Online Clinical Library @ BML)
– The Medical Letter (E-Journals @ BML)
• Physician’s Desk Reference (PDR)
– Drug company-generated compilation of FDA-approved package inserts +
pictures of drugs
Drug Names/Classifications
• Drugs have many names: chemical, generic (scientific,
officially approved), and commercial (trade, brand)
– Brand names differ in different countries and with different products
– Scientists (and physicians) should use generic and not trade names
• Generic names are those in national pharmacopeias
– Pharmacopeias originally were books for medical materials (materia
medica) with information about sources, extraction methods, assays
but now usually contain info about pure drugs
• Increased harmonization in choosing generic names and in
using common endings for certain drug classes
– -olol for β-blockers, -caine for local anesthetics, -clovir for antiviral
(herpes) drugs, -prils for ACE inhibitors, etc
Drug Names/Classifications
• Efforts are underway (by the World Health Organization
[WHO] and IUPHAR [Intl Union of Pharmacology]) for new,
worldwide systems for classifying drugs
– Many classification systems are possible (e.g., based on therapeutic
indication, site of action, mechanism of action, or chemical class)
– Diseases are being reclassified based on genetic/molecular
“signatures”; this information may lead to the reclassification of
based on their targets and effects and these “signatures”
• Current pharmacologic classification emphasizes the site
and nature of action (e.g., agonist/antagonist), the molecular
target (receptor, channel, enzyme), and mode of interaction (e.g.,
reversible/irreversible; competitive/non-competitive)
Can drug therapy be
• Much current interest in the individualization of drug therapy
and taking into account genetic and environmental factors
– There has been some success but progress toward individualized
therapy has been slow—especially as related to drug action
• Many key questions remain, including:
– 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
What new efforts in pharmacotherapy
and pharmacology are on the horizon?
• In addition to “genetically informed” understanding of
disease, drug development/prescribing, other aspects of
pharmacotherapy that will likely change are:
– ”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
To Err Is Human: Building a Safer Health System
Linda T. Kohn, Janet M. Corrigan, and Molla S.
Donaldson, Editors; Committee on Quality of Health
Care in America, Institute of Medicine (IOM)
National Academy Press
April 2000
Anywhere from 44,000 to 98,000 deaths/yr are caused by
medical errors…~10% from drugs
The IOM Roundtable on Quality of Care categorized threats to quality in 3
broad families: overuse (receiving treatment of no value), underuse (failing to
receive needed treatment), and misuse (errors and defects in treatment). In its
narrowest form, a focus on safety addresses only the third family, that is, a subset
of the whole domain of quality of care.
How are drugs developed and
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..
Accumulated evidence suggests that the placebo effect is a genuine psychobiological
event attributable to the overall therapeutic context. This psychosocial context can
consist of individual patient and clinician factors, and the interaction between the
patient, clinician, and treatment environment …The placebo intervention is
designed to simulate a therapeutic context such that the effect of the intervention
(placebo effect) is attributable to the way in which this context affects the patient's
brain, body, and behavior. When an active treatment is given, the overall response
is the result of the treatment itself and the context in which it is given. (Finniss DG,
Kaptchukb TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of
placebo effects Lancet 375: 686-695 [2010]).
Drug discovery and approval:
Preclinical research and Phases 1-4
J.Molzon.The common technical document: the changing face of the New
Drug Application. Nature Reviews: Drug Discovery. 2:71-4 (2003)
Drug discovery, development and
approval: the industry perspective
Preclinical and clinical drug development: Phases and
success (with an optimistic timeline and success rate)
IND= Investigational New Drug; NDA: New Drug Application
Preclinical and clinical drug development:
Another view (and longer timeline)
Are drug approvals by the FDA slowing down?
Wall Street Journal: 12/31/10
Drug Approvals Slipped in 2010
Some Potential Blockbusters Suffered Delays Amid FDA's Tougher Safety Stance
The Food and Drug Administration approved about 21 drugs in 2010, a relatively
modest figure that shows the pharmaceutical industry hasn't yet escaped its
drought in recent years. A few potential blockbusters won approval during the
year, but some of the most highly anticipated new products got delayed into next
year or beyond. That partly reflects a tougher environment at the FDA, with
regulators stepping up their scrutiny of safety issues in drugs for obesity,
diabetes and other conditions.
According to monthly drug-approval reports on the FDA's website, 21 new drugs
were approved in 2010, down from 25 in 2009 and 24 in 2008, but higher from a
recent low of 18 in 2007.
Remember: Drugs are developed to treat people-- not cells or experimental animals!!
Patient (public) advocacy can influence drug approval:
Drugs for HIV and certain other diseases (e.g. especially
infections) can be “fast-tracked” and given “priority review”
Another schematic of drug approval process