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KNOWLEDGE OBJECTIVES IN
MEDICAL PHARMACOLOGY
2012 Edition
Chaired and Edited by
Richard Eisenberg, Ph.D. and
Carl Faingold, Ph.D.
Sponsored by the
Association of Medical School Pharmacology Chairs
Table of Contents
Preface
1.
Scope of Pharmacology
2.
General Principles
3.
Drugs Acting at Synaptic and Neuroeffector Junctional
Sites Autonomic and Neuromuscular Pharmacology
4.
Drugs Acting on the Central Nervous System
5.
Autacoids/Nonsteroidal Antiinflammatory/Asthmatic Drugs
6.
Cardiovascular and Respiratory Pharmacology
7.
Diuretics and Drugs Affecting Renal Function, Water, and
Electrolyte Metabolism
8.
Gastrointestinal Drugs
9.
Chemotherapy
10.
Hemostasis and Blood Forming Organs
11.
Endocrine Pharmacology
12.
Toxicology and Therapy of Intoxication
13.
Vitamins
14.
Herbal Medicine
Knowledge Objectives in Medical Pharmacology
2012 Edition
Chaired and Edited by
Richard Eisenberg, Ph.D. and Carl Faingold, Ph.D.
PREFACE
The Knowledge Objectives in Medical Pharmacology was originally the product
of the effort and vision of Dr. James Fisher and other senior Pharmacologists in
1985. The 2012 edition is intended to describe the minimum essential
knowledge and competencies in Pharmacology which should be taught to, and
mastered by, students completing their basic medical education. The Knowledge
Objectives is organized into sections containing specific and detailed knowledge
for each of the major areas of Pharmacology. With the exception of the sections
on “Scope of Pharmacology” and “Principles,” the information in this edition is
presented in the tabular form that was introduced in the last revision. After much
discussion by the members of the Association of Medical School Pharmacology
Chairs (AMSPC) and the contributors to this revision, a decision was reached to
include Clinical Pharmacology aspects in each section. For that, the editors are
especially indebted to Dr. Dan Sitar of the University of Manitoba Medical School.
Embedded in each section and subsection is a list of the relevant drugs (primary
in CAPS, secondary in lower case).
What appears in this document is the consensus of more than 80 Chairs/Course
Directors/Faculty who are specialists in their particular areas. Its significance as
an educational tool in Pharmacology was acknowledged in the recent AAMC
report on “Education In Safe and Effective Prescribing Practices.” Added to each
section in this revision is the direct relevance connection to specific items this
AAMC document and to specific topics detailed by the USMLE.
Pharmacology is accepted as an integrated science. It bridges the gap between
the introductory disciplines, such as physiology and biochemistry, and clinical
medicine. Therapeutics serves as the cornerstone in the practice of clinical
medicine. For this reason, Pharmacology has significant emphasis in the
licensure examinations indicating that mastery is essential. Thus, it is important
for medical educators to make certain that Pharmacology remains a primary
component of every medical school curriculum. In this regard, we hope that the
Knowledge Objectives will serve as a guide to curriculum committees as they
contend with more competition among courses for time in the medical school
curriculum, more diverse and time consuming methods of information delivery,
and more self-study and independent learning. The 2012 edition of the
Knowledge Objectives has undergone significant change. Increased emphasis
on transducing systems effected by receptor activation has been included in
each of the drug categories. The profound influence of genomics in altering
therapeutic application is cited where applicable. The increased use of herbal
medications has resulted in the addition of a new section.
This document is being made available through the AMSPC and its web site, and
is intended to be a dynamic instrument. Users are urged to make suggestions
for change and/or enhancements to the Chair of the selected subcommittee (the
email address is provided). Following approval by the subcommittee, we will
update that section of the Knowledge Objectives.
The editors are grateful to all of the members of AMSPC and their faculties who
participated in revising the Knowledge Objectives.
SCOPE OF PHARMACOLOGY
A.
B.
History - It is of intellectual interest to the physician to know how drugs are
discovered and developed. Often in the past, this was based on folklore or
intelligent observation (e.g. digitalis leaf, penicillin). Nowadays, new drugs are
mostly developed by the organic chemist working with a pharmacologist,
increasingly from basic knowledge about key molecular targets. Usually some sort
of biological screen is used to select among organic molecules for optimum
pharmacological activity.
1.
Francois Magendie (1783-1855), a French physiologist laid down the dictum
"Facts and facts alone are the basis of science." Experimental procedures
with animals are the testing grounds for determination of drug action.
2.
Claude Bernard (1813-1878) worked in Magendie's lab, investigated the
plant extract curare and proposed a site of action for this agent.
3.
Rudolph Buchheim (1820-1879). In 1847 Buchheim established the first
laboratory devoted to experimental pharmacology in the basement of his
home in Dorpat which is known as the cradle of experimental pharmacology.
4.
Oswald Schmiedeberg (1838-1921). In 1872 Schmiedeberg set up an
institute of pharmacology in Strasbourg, France (Germany at that time) which
became a mecca for students who were interest in pharmacological
problems.
5.
J.N. Langley (1852-1925 and Sir Henry Dale (1875-1968) pioneered
pharmacology in England, taking a physiological approach.
6.
John J. Abel (1857-1938) established the first chair of pharmacology in the
U.S.A. (U. Michigan, 1891) after training in Germany. Able went to Johns
Hopkins in 1893, and trained many U.S. pharmacologists. He is known as
"The Father of American Pharmacology".
7.
The second world war was the impetus for accelerated research in
pharmacology (the war time antimalarial program) in the U.S., and introduced
strong analytical and synthetic chemical approaches.
Chemistry - Chemical structures of drugs can provide information about
mechanism of action, pharmacokinetics, stability, and metabolic fate.
1.
Structure-Activity Relationship - A modification of the chemical structure of
a drug may accentuate or diminish its pharmacological effects, often providing
clues as to the mechanism of action. A picture of the biological reactive site
(the receptor) can be developed in such studies. Also, drugs are metabolized
by body systems, which may convert the parent drug to a more active or a
less active form. The drug structure can be modified to enhance or diminish
the rate of metabolic conversion.
2.
Sites of Action - The organ or cellular target of drug action.
3.
Drug Receptors - Macromolecules in cells or cell membranes with which
drugs interact to exert their effects. Usually the interacting forces are
reversible ionic and Van der Waals bonds of relatively low energy, but
sometimes covalent bonds are formed (e.g. organophosphate insecticides).
C.
Pharmacodynamics - The effect of the drug on the body. Pharmaco-dynamics is
the study of the relationship of drug concentration and the biologic effect
(physiological or biochemical). For most drugs it is necessary to know the site of
action and mechanism of action at the level of the organ, functional system, or
tissue. For example, the drug effect may be localized to the brain, the
neuromuscular junction, the heart, the kidney, etc. Often the mechanism of action
can be described in biochemical or molecular terms. Most drugs exert effects on
several organs or tissues, and have unwanted as well as therapeutic effects. There
is a dose-response relationship for wanted and unwanted (toxic) effects. Patient
factors affect drug responses - age, weight, sex, diet, race, genetic factors, disease
states, trauma, concurrent drugs, etc.
D.
Pharmacokinetics - The effect of the body on the drug. To produce its
characteristic effects, a drug must be present in appropriate concentrations at its
sites of action. Thus, it is important to know the interrelationship of the absorption,
distribution, binding, biotransformation, and excretion of a drug and its
concentration at its locus of action.
1.
Absorption (oral or parenteral) - A drug must be absorbed and achieve
adequate concentration at its site of action in order to produce its biological
effects. Thus, when a drug is applied to a body surface (e.g., g.i. tract, skin,
etc.), its rate of absorption will determine the time for its maximal
concentration in plasma and at the receptor to produce its peak effect.
2.
Distribution - The blood, total body water, extracellular, lymphatic and
cerebrospinal fluids are involved in drug movement throughout the body.
Depending upon its chemical and physical properties, the drug may be bound
to plasma proteins or dissolved in body fat, delaying its progress to its sites of
action or excretory mechanism.
3. Metabolism - This is how certain drugs are handled by the body in preparation
for their elimination and includes the fate of drugs-biotransformation (e.g.,
hydrolysis, conjugation, oxidation-reduction).
4. Excretion - The kidney is the most important organ for drug excretion but the
liver, lung and skin are also involved in drug elimination. Drugs excreted in
feces are mostly derived from unabsorbed, orally ingested drugs or from
metabolites excreted in the bile and not reabsorbed by the intestine. The
physical and chemical properties, especially the degree of ionization of the
drug, are important in the rate of excretion.
5. Biological Factors Modifying Pharmacokinetic Aspects - Normal variations
occur in population pharmacokinetic constants (absorption rates, elimination
rates). Other factors include age, weight, obesity, edema, concurrent diseases,
other drugs (various interactions including effects on protein binding or
metabolic rate), diet, dose interval and route of administration, genetic
variations in elimination rate.
E.
Clinical Pharmacology and Therapeutics
1.
Indications and Therapeutic Uses - Emphasis is placed on the therapeutic
use of drugs for the treatment of disease in clinical pharmacology, internal
medicine and therapeutics. There are specific clinic disorders or disease
entities for which a given drug may be prescribed and the physician must
weigh the potential benefit of drug use against the risks of adverse effects.
2.
Contraindications and Factors (e.g., liver disease) May Modify Drug
Action - where detoxification of the drug by the liver is important. It is
important to know that the presence of disease or organ pathology may
influence the actions of a drug. Conditions such as age, pregnancy,
concomitant administration of other drugs and disease may alter the patient's
response to a given drug.
3.
Posology - Is an archaic term describing dosage regimens. Consideration of
dosage schedules is a part of pharmacokinetics.
4.
Bioavailability - The fraction of drug administered which is actually absorbed
and reaches the systemic circulation following oral dosing. Preparations of the
same drug by different manufacturers may have a different bioavailability.
5.
Prescription writing - It is important that the physician write clear, error-free
directions for the drug provider (pharmacist) and for the patient. Physicians
must guard against prescribing too many drugs, or preparations of little value.
Drugs of unproven clinical value should be avoided, as well as potentially
toxic agents if drugs equally effective but less dangerous are available.
Risk-benefit and cost-benefit should be considered. Drugs may be prescribed
by generic name, since often a less expensive drug product can be obtained
in this way. A particular manufacturer may be specified if the physician has
reason to believe a better or more reliable preparation is available from that
manufacturer.
6.
Drug Nomenclature - In addition to its formal chemical name, a new drug is
usually assigned a code name by the pharmaceutical manufacturer. If the
drug appears promising and the manufacturer wishes to place it on the
market, a United States Adopted Name (USAN) is selected by the USAN
Council which is sponsored by:
1)
2)
3)
F.
G.
The American Medical Association
The American Pharmaceutical Association
The United States Pharmacopeial Convention
Toxicology - That aspect of pharmacology that deals with the adverse effects of
chemical agents. Toxicology is concerned not only with drugs used in therapy but
also with the other chemicals that may be responsible for household,
environmental or industrial intoxication.
1.
Forensic Toxicology - Addresses medicolegal aspects of the use of
chemicals that are harmful to animals or man. Analytical chemistry and
fundamental toxicological principles are hybridized to underlie this aspect of
toxicology. Nonetheless accidental poisoning with drugs is a health problem
of major significance. More than 1/4 of the fatalities and about 1/2 of all
poisonings occur in children under 5 years of age. All common household
articles that are poisonous should be made unavailable to children, and
poisonous rodenticides and insecticides should not be placed in the home.
2.
Clinical Toxicology - Focuses on toxic events that are caused by or are
uniquely associated with drugs or other chemicals.
Pharmacovigilance - The area of pharmacology that focuses on the effects of
drugs on patient safety.
It involves the characterization, detection, and
understanding of adverse events associated with drug administration, including
adverse drug reactions, toxicities, and side effects that arise as a consequence of
the short- or long-term use of drugs. Adverse drug reactions, including drug-drug
interactions, are estimated to be a major cause of mortality of inpatients and also
lead to significant increases in duration of hospitalization. No drug is free of toxic
effects. Some untoward effects of drugs are trivial, but others are serious and may
be fatal. Side effects often are predictable from a knowledge of the pharmacology
of a particular drug. Examples of chemicals or drug-induced toxicities are given
below:
1.
Allergic reactions - The number of serious allergic reactions to drugs
involving antigen-antibody reactions is low but when they occur the
physician must have sufficient knowledge to manage these problems.
2.
Blood dyscrasias - These are very serious and sometimes fatal
complications of drug therapy. They include: agranulocytosis, aplastic
anemia, hemolytic anemia, thrombocytopenia and defects in clotting
factors.
3.
Hepatotoxicity and nephrotoxicity - Because many chemicals and
drugs are eliminated and metabolized by the liver and kidney, damage to
these organs is seen commonly.
4.
Teratogenic effects - The thalidomide tragedy dramatically emphasized
that drugs may adversely influence fetal development.
5.
Behavioral toxicity - This is a term used to describe suppression of
normal anxiety, reduction in motivation, impairment of memory and
learning, distortion of judgement, impairment of reflexes, adverse effects
on mood, etc.
6.
Drug dependence and drug abuse - The repeated administration of
some chemicals may lead to drug dependence. Drugs likely to be
abused and upon which drug dependence may develop are the various
psychopharmacological agents such as opiates, barbiturates,
amphetamines, nicotine and ethanol. Dependence on tobacco (nicotine)
is also well known.
7.
Carcinogenesis - Carcinogenesis is a delayed type of toxicity with a
latency of many years.
8.
Pharmacogenetic toxicities - Certain genetically-predisposed
individuals have a markedly toxic reaction to certain otherwise safe
drugs. Examples are prolonged apnea after succinylcholine, or
malignant hyperthermia associated with anesthetics.
GENERAL PRINCIPLES (11)
Subcommittee:
Sitar, Daniel Chair [email protected]
Cooke, William J. [email protected]
Hein, David [email protected]
Lam, Yui-Wing Francis, [email protected]
Prozialeck, Walter [email protected]
Eleven contact hours are recommended at the beginning of the course to provide the
foundation for reinforcement and application of these principles throughout the course.
Relevance
USMLE topic
Principles of therapeutics
Pharmacodynamic and pharmacokinetic
Pharmacokinetics; Mechanisms of drug
processes – general principles
action, structure-activity relationships;
Concentration- and dose-effect
relationships, types of agonists and
antagonists and their actions;
Mechanisms of drug adverse effects;
Mechanisms of drug interactions;
Regulatory issues; Signal transduction;
Cell cycle/cell cycle regulation
AAMC Medical School Objectives
Topic A: Factors that make each patient
Project Report X Patient Safety –
unique
Table 1
Topic B: Principles of clinically important
pharmacokinetics
Topic E: Rules and regulations that
govern prescribing
Topic F: Process and regulations
governing drug discovery and
development
Topic H: How to find and use the most
up-to-date information about drugs,
biologics, and nutraceuticals
Topic J: Adverse drug reactions
Topic K: Drug-drug interactions
1.
Introduction, Roots, and Definition of Terms
a.
Definition of Pharmacology
The discipline that is concerned with understanding the interactions of
chemical substances with living systems, and the application of this
understanding to the practice of medicine.
b.
Relation to Other Disciplines
i.
Basis in Chemistry, Physiology, Biochemistry, Immunology and
Molecular Biology
ii. A foundation of medical practice, including historic perspective
c.
Key Terms and Concepts
i.
Drug - a substance that acts, often by interaction with
regulatorymolecules, to stimulate or inhibit physiologic processes.
ii. Drug Receptors - molecules with which a drug first interacts to
eventually affect biological function. There is often a strict structural
requirement for this interaction. Drug targets include receptors for
endogenous substances (neurotransmitters, hormones, etc.), enzymes,
transport proteins, ion channels, etc. Some pharmacologists prefer the
term "drug targets," and reserve the term "receptor" to describe the
macromolecules that serve as the initiators of signal transduction for
endogenous substances.
iii. Agonist (full, partial, inverse), antagonist (competitive and noncompetitive)
iv. Drug-receptor interactions – affinity, intrinsic activity
v. Selectivity of drug action - all drugs have multiple effects, both desirable
(beneficial) and undesirable (adverse effects, or "side effects").
Selectivity is partly intrinsic to the nature of the drug-receptor
interaction. The astute physician can maximize selectivity by attention
to pharmacologic principles.
vi. Pharmacodynamics - the study of drug effects on the body. The doseresponse relationship(s) and drug-receptor interactions for each drug
are of particular importance.
vii. Pharmacokinetics - the study of the effects of the body on the drug,
including its absorption, distribution and elimination by the organism.
The understanding of plasma drug concentration as a function of time is
of particular importance.
viii. Time-action relationships - function of dosing schedule and a
combination of a drug's pharmacokinetic and pharmacodynamic
properties
ix. Dose-response relationships – graded and quantal
x. Efficacy, potency
xi. Long-term effects of drugs (including tolerance, regulation of gene
expression)
d.
Course Goals
i.
Describe the principles governing drug actions in humans
ii. Describe the specific knowledge related to the different classes of
drugs, and important distinctions among members of each class, in
relation to the organ systems they affect, and the diseases for which
they are used therapeutically.
iii. Develop a basis for continued education in medicine
iv. Establish a foundation on which to build a rational approach to the use
of drugs in clinical practice
v. Develop a foundation to effectively use the medical literature to
evaluate new drugs in the context of evidence-based medical practice
2.
Pharmacokinetics
a.
Chemical Aspects
i.
Weak acids and bases; the Henderson-Hasselbalch equation;
relationship between pH and ionization of drugs
ii. Lipid solubility of drug species; polar and nonpolar drugs
iii. Properties of biological membranes, mechanisms of drug movement
across membranes. Passive (diffusion) and active (transport) processes
iv. Ion trapping of drugs. Specific examples of stomach contents and urine
as ion-trapping compartments
v. Chirality - drugs that exist as mixtures of two or more stereoisomers
b.
Absorption
i.
Concept of therapeutic window
ii. Relationship of lipid solubility, blood flow, and site of drug placement
iii. Effect of pH; absorption of weak acids and bases from stomach vs.
intestine; influence of age; first pass metabolism, factors impairing
absorption
iv. Absorption from oral, IM, SC and other routes
v. Manipulation of absorption: dosage form, depot preparations, modified
release preparations, transdermal patch
vi. Special sites of absorption: buccal, pulmonary, rectal, transcutaneous
sites
vii. Systemic absorption of drugs applied for local effects: intraocular,
intranasal, dermatologic preparations
viii. Concept of bioavailability as a function of absorption and first pass
metabolism
ix. Developmental, age-related and disease-related changes in drug
absorption
c.
Distribution
i.
Plasma protein binding, its effects on distribution
ii. The lymphatic system and drug distribution
iii. Factors affecting distribution: tissue perfusion, ease of access, tissue
binding and solubility coefficients, pKa, partition coefficient
iv. Distribution ("redistribution") as a mode of termination of drug action.
v. Distribution of drugs into special compartments. Nature of the capillary
endothelium at the liver sinusoid, the skeletal muscle and brain. The
blood-brain barrier and tight endothelial junctions. Drug penetration
across the placenta. Importance of membrane transporters for both
entry and efflux.
vi. Concept of apparent volumes of distribution; relationship to
physiological volumes. One and two-compartment drug distribution
models.
vii. Developmental, age-related and disease related changes in drug
distribution.
d.
Metabolism
i.
Importance of drug metabolism for excretion (conversion of non-polar
xenobiotics to polar metabolites which can be excreted in the urine).
ii. Biotransformation: activation vs. inactivation (detoxification) of drugs:
prodrugs, toxic metabolites
iii. Major pathways of metabolism: Phase I vs. Phase II, general properties
(1) oxidation, reduction, hydrolysis
(2) conjugation: glucuronides, glycine, sulfate esters, acetylation,
glutathione, mercapturic acids
iv. The cytochrome P450 system. Organ-selective expression, e.g. Liver,
other tissues. Major P450s involved in drug metabolism: CYP1A2,
CYP2B6, CYP2Cs, CYP2D6, CYP2E1, CYP3A4 and CYP3A5
v. Enzyme induction: mechanisms, time course, clinical implications, and
examples of common inducers (e.g. anticonvulsants, alcohol, rifampin,
polycyclic hydrocarbons, environmental factors)
vi. Enzyme inhibition: clinical implications ((e.g. erythromycin, antifungals,
CYP2D6 interactions)
vii. Developmental (ontogeny), age-related and disease-related changes in
drug metabolism. (For isoforms see section on Pharmacogenetics)
e.
Excretion
i.
Definition of excretion as the loss of drug molecules from the body;
excretion of parent drug vs. excretion of metabolites.
ii. Major sites of drug excretion: renal, biliary/alimentary, pulmonary (a
major route for inhalation agents only). Minor sites of drug excretion:
sweat, milk
iii. Renal excretion: role of filtration, secretion and reabsorption-importance of plasma protein binding, molecular size, polarity, weak
acids/bases, urine pH and transporters
iv. Biliary/alimentary excretion: biliary transport, direct secretion of drugs
from blood to intestine, importance of plasma protein binding, molecular
size, polarity, weak acids and weak bases. Consequences of
enterohepatic circulation.
v. Developmental, age-related, and disease-related changes in drug and
metabolite excretion
vi. Differentiate excretion from pharmacologic concept of elimination (the
sum of metabolism and excretion)
vii. Clearance as the pharmacologic parameter that characterizes the
efficiency of elimination process
(1) general definition of clearance: Cl = rate of elimination/[C]
(2) additivity of organ clearances, e.g Cl tot = Clhepatic + Clrenal +
Clother
(3) organ clearance--extraction ratio and blood flow Cl = E x Q, high
and low extraction ratios and effects of changes in blood flow and
plasma protein binding
f.
Quantitative Pharmacokinetics
i.
First order, dose-independent kinetics
(1) single i.v. bolus dose, one and two compartment systems;
noncompartmental model and its clinical utility
(a)
Definition of first order process, explanation of why metabolism
and renal elimination are often first order, distribution and
elimination phases of log C vs. time plot
(b)
Pharmacokinetic parameters that determine the plot and can
be estimated from it, and their interrelationships: Vd1,
Vdextrap, Vdarea, AUC, ke, elimination t1/2, Cl
(2) Single oral (or other non i.v. dose), one compartment
(a)
effect of ka, ke, and dose on Cmax, tmax, and AUC
(b)
estimation of bioavailability by ratio of AUCs
(3) constant i.v. infusion, one compartment
(a)
definition of steady state, the plateau principle, Css = IR/Cl
(b)
time to steady state as a function of half-life and effects of
stopping infusion or changing infusion rate
(c)
calculation of loading dose
(4) repeated dosing one compartment
(a)
drug accumulation and plateau principle: Cssav = DxF/T x Cl,
independent of ka
(b)
peak to trough variation as a function of dose, F, t1/2 , dosing
interval (T), and ka:ke ratio
ii. Deviations from first order (dose-independent) kinetics
(1) Zero order, dose-dependent and "Michaelis-Menten" elimination
kinetics, definition and implications, e.g. phenytoin dosing
(2) Saturation of plasma protein binding, implications e.g. salicylate
overdose
(3) Dose-dependent absorption and bioavailability; intestinal
transporters
3.
Pharmacodynamics
a.
Receptor Theory
i.
Introduction
(1) Historical development
(2) Definition of a receptor (signal transduction)
(3) Occupancy theory: EA/EM = [A]/([A] + KA)
ii. The log concentration-response relationship
iii. Agonists
(1) Interpretation of log concentration-response curves
(2) Potency (ED50 and EC50) vs affinity (KA)
(3) Intrinsic activity vs efficacy
(a)
Partial agonists
(b)
Inverse agonists
iv. Antagonists
(1) Competitive, reversible, surmountable
(2) Non-competitive, irreversible, unsurmountable
v. Receptor reserve: EC50 not necessarily equal to KA
b.
Quantal Response Relationships
i.
ED50 (potency) vs LD50 or TD50
ii. Therapeutic indices
c. Structure-activity relationship (SAR) as a mechanism for modeling
receptors, active sites and developing modified drugs.
d. Types and subtypes of receptors; therapeutic action vs side effects;
receptor superfamilies and mechanisms
i.
Ligand-gated ion channels
(1) Nicotinic ACh receptor
(2) GABA-A receptor
ii. G Protein-coupled receptors
(1) Muscarinic ACh receptors
(2) Three major types of adrenergic receptors (alpha-1, alpha-2, beta)
(3) Guanine nucleotide regulatory binding proteins
iii. Tyrosine kinase receptors
(1) Insulin
(2) PDGF
iv. Transcription factor receptors
(1) Receptors for steroid hormones
e.
Receptor Regulation
i.
Down-regulation and desensitization: inverse relationship between
agonist concentration and receptor levels
ii. Up-regulation and sensitization
f.
Non-receptor targets as sites of drug action
i.
Enzymes - acetylcholinesterase
ii. Nucleic acids as site of action of drugs - actinomycin D
iii. Target uniqueness as a basis for selective chemotherapy - penicillin
4.
Pharmacogenetics/genomics
a.
Definition of pharmacogenetics and pharmacogenomics, and their
clinical Importance.
b.
Genetic polymorphisms include single nucleotide polymorphisms
(SNPs), gene deletions, and gene amplifications that determine protein
structure, configuration, and/or concentration.
c.
Differentiate haplotype, genotype and phenotype. Discuss methods to
determine phenotype and genotype.
5.
6.
d.
Pharmacogenetic polymorphisms affect drug response as well as drug
disposition and toxicity. (e.g., NAT2, CYP2D6, beta adrenergic
receptors).
e.
Monogenic pharmacogenetic traits often discriminate populations into
discrete phenotypes (polymorphic distribution). Polygenic
pharmacogenetic traits usually provide monomorphic distributions.
FDA Regulations require inclusion of pharmacogenetic information
and recommendations for an expanding list of drugs, e.g. warfarin
f.
Frequency of pharmacogenetic polymorphisms often differs with
ethnicity
g.
Illustrate clinical relevance with selected examples, e.g.: NAT2
(isoniazid, procainamide); CYP2D6 (antidepressants, beta-blockers);
CYP2C19 (omeprazole); CYP2C9 (warfarin); serum cholinesterase
(succinylcholine), glucose-6-phosphate dehydrogenase (analgesics;
antimalarials); thiopurine-S-methyltransferase (6-mercaptopurine);
beta-2 adrenergic receptors, (albuterol); dopamine receptors
(antipsychotics; l-DOPA); malignant hyperthermia (inhalation
anesthetics); UGTA1 (irinotecan), ABCB1 (corticosteroids)
Principles of Drug Interactions
a.
Prevalence of multi-drug therapy; importance of complete drug history
including herbal and other complementary medicine and recreational
drugs
b.
Types of interactions by mechanism: pharmaceutic, pharmacokinetic,
pharmacodynamic; with illustrative examples
c.
Types of interactions by outcome: additivity, synergy, potentiation,
antagonism; with illustrative examples
d.
Not all drug interactions are bad: beneficial, planned interactions vs.
unintended adverse interactions
e.
Awareness of drug-food interactions, and drug interference with
diagnostic tests
Development, Evaluation and Control of Drugs
a.
Peclinical Development.
b.
Clinical Trials. Placebo effects. Institutional Review Boards.
Investigator conflict of interest. FDA requirements for efficacy and
safety. Ethics.
c.
Regulatory System. Legal mandates of the FDA and DEA.
Classification (scheduling) of drugs with addiction potential. Influence
of drug scheduling on medical practice.
d.
Post-Marketing Surveillance of Drugs.
e.
Drug Information for Practitioners. Textbooks, journals, FDA alerts,
poison control centers, and electronic databases.
f.
Pharmaceutical Industry: Duration of drug patents; branded verses
generic drugs.
g.
Influence of marketing (from sales representatives to television
advertising) on medical practice.
Footnote: The members of this subcommittee believe that this section already
focuses on Clinical Pharmacology principles and does not require further
elaboration. All examples provided above are clinically relevant and sufficiently
common that students will readily encounter patients where these issues will be
reinforced.
Drugs Acting at Synaptic and Neuroeffector Junctional Sites
Autonomic and Neuromuscular Pharmacology
Subcommittee:
Theobald, Jr., Robert J., Chair [email protected]
Dretchen, L. Kenneth [email protected]
Strandhoy, Jack W. [email protected]
Westfall, Thomas C. [email protected]
Drugs acting at synaptic and neuroeffector junctional sites autonomic and
neuromuscular pharmacology
Recommended Curriculum Equivalent: 1.0 hr
Introduction and History
Neuronal Drugs
BOTULINUM TOXIN
COCAINE
entacapone
metyrosine
reserpine
Learning Objectives
Physiology and pathophysiology
Describe the anatomical projections of the sympathetic and parasympathetic
autonomic nervous system.
Describe the evidence for the development of the concept of neurotransmitters, cotransmitters and end-organ specificity.
Describe homeostasis, fight-or-flight, and rest-and-repair with regard to the autonomic
nervous system.
Describe the central control of the autonomic nervous system.
List and describe the responses of end organs to activation of each division of the
autonomic nervous system.
Describe the concept of dominant tone.
Mechanisms of action
Explain the mechanism and drugs that block uptake of choline into cholinergic
neurons
List drugs that Inhibit Catechol-o-methyl transferase peripherally
List drugs that block storage vesicle transport systems
Describe the mechanism by which drugs Inhibit reuptake of NE into adrenergic
neurons
Describe the mechanism by which drugs deplete NE by interfering with synthesis
Notes
Define words containing the suffixes, -ergic, -mimetic, - lytic, and –ceptive.
Clinical Pharmacology Botulinum toxin only marginally effective for prophylaxis
against chronic migraine headache. Not approved for treatment of episodic migraine
headache.
Relevance
USMLE topic
Principles of therapeutics
Central and peripheral nervous system
Botulinum toxin
Drugs affecting the autonomic nervous
system
Treatment for substance abuse
disorders
Antiparkinsonian drugs
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions
Drugs acting at synaptic and neuroeffector junctional sites autonomic and
neuromuscular pharmacology
Recommended Curriculum Equivalent: 3.0 hr
Drug Classes and Drugs to consider
Direct Acting
Cholinergic EsterAgonists
ACETYLCHOLINE
BETHANECHOL
Direct Acting
Cholinergic Alkaloid
Agonists
Cholinergic Indirect
Acting
PILOCARPINE
ECHOTHIOPHATE
EDROPHONIUM
NEOSTIGMINE
malathion
parathion
physostimine
pyridostigmine
Related Drugs
PRALIDOXIME
obidoxime
sarin
VX series
Learning Objectives
Physiology and pathophysiology
Describe synthesis, storage, release, and inactivation of cholinergic agonists.
List the steps in the synthesis, storage, release and inactivation of acetylcholine, and
drugs that interface with those processes.
List the location of nicotinic and muscarinic receptors and their subtypes.
Compare the two major cholinesterases: acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE) as to anatomical locations, sites of synthesis and
function.
Mechanism of action
Explain the mechanism of actions, including 2nd messenger systems of acetylcholine
and related drugs.
Explain the differences in onset and duration of action and route of administration for
different groups of anticholinesterases.
Explain the chemical makeup of the active site of AChE (anionic and esteratic) as to
attraction, attachment and rates of breakdown of various substrates and
inhibitors.
Distinguish the mechanism by which pralidoxime reactivates phosphorylated AChE.
Actions on organ systems
Describe the responses to activation of these receptors.
Explain the reason why anticholinesterases classified as reversible or irreversible.
Pharmacokinetics
Describe the variations of pharmacokinetics of cholinergic drugs.
Relate the onset of action of anticholinesterases, routes of administration, and the
duration of action of anticholinesterases with sites and type of attachment to the
enzyme.
Explain why anticholinesterases are reversible or irreversible, and indicate which
anticholinesterases are in each category.
Explain the role of cholinesterase “aging” in the enzyme-inhibitor interaction.
Adverse effects, drug interactions and contraindications
List the adverse effects of cholinergic drugs.
List and describe the rationale for contraindications of cholinergic drugs.
Describe the adverse effects, and their relevance, of the two classes of
neuromuscular blocking drugs.
Therapeutic uses
List the therapeutic uses of cholinergic agonists.
Describe the effects of accumulated acetylcholine at muscarinic and nicotinic
receptors in the periphery and the central nervous system.
List therapeutic uses for and adverse side effects of anticholinesterases.
Explain why anticholinesterase agents can be used as insecticides (malathion,
parathion) and chemical warfare agents (sarin, VX series).
Explain why pralidoxime is not effective reactivating all phosphorylated AChE.
Explain the concept of differential toxicity of malathion and parathion in different
species.
Notes
Clinical Pharmacology
Pilocarpine may cause mental impairment when used topically, especially in the
elderly.
Relevance
USMLE topic
Principles of therapeutics
Central and peripheral nervous system
Drugs affecting the autonomic nervous
Pharmacodynamic and pharmacokinetic
system
processes
Neuromuscular junction agonists
Antiglaucoma drugs
Mechanisms of toxicology
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions
Drugs acting at synaptic and neuroeffector junctional sites autonomic and
neuromuscular pharmacology
Recommended Curriculum Equivalent: 2.0 hr
Drug Classes and Drugs to consider
Antagonists at Muscarinic
Antagonists at Nicotinic
Drugs Acting at Autonomic
Receptors
Receptors
Ganglia
ATROPINE
MIVACURIUM
mecamylamine
ipratropium
nicotine
scopolamine
SUCCINYLCHOLINE
tolterodine
TUBOCURARINE
Learning Objectives
Physiology and pathophysiology
List the locations of and the differences between muscarinic and nicotinic receptors.
Explain the rationale for historical uses in treatment of hypertension and autonomic
hyperreflexia.
Mechanism of action
Describe nicotine’s agonist and antagonist properties.
Actions on organ systems
Contrast and compare the depolarizing and the competitive Neuromuscular Junction
blocking drugs.
Adverse effects, drug interactions and contraindications
Explain why muscarinic antagonists cause xerostomia, blurred vision, photophobia,
tachycardia, anhidrosis, difficulty in micturition, hyperthermia, glaucoma and
mental confusion in the elderly.
Explain why muscarinic antagonists are contraindicated in glaucoma, obstructive
disease of the gastrointestinal tract or urinary tract, intestinal atony.
List the adverse side effects of drug acting at autonomic ganglia.
List the adverse side effects and drug interactions at the NMJ.
Therapeutic uses
Explain the rationale for the therapeutic use of muscarinic antagonists in diseases
such as bronchoconstriction, excessive salivation, and motion sickness. Explain
the rationale for the therapeutic use to produce mydriasis and cycloplegia.
Explain why nicotine is not used clinically (except as a smoking deterrent), and its
historical, social and toxicological significance.
Explain the differential uses of competitive versus depolarizing Neuromuscular
Blocking Drugs and their limitations.
Notes
Clinical Pharmacology
All anticholinergic drugs relatively contraindicated in the elderly due to risk of
increased mental impairment.
Relevance
USMLE topic
Central and Peripheral Nervous System
AAMC Medical School Objectives
Project Report X Patient Safety- Table 1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
nervous system – neuromuscular
junction agonist and antagonists
Drugs affecting the autonomic nervous
system
Topic C
Drug treatment of common conditions,
and diseases using frequently
prescribed drugs for the treatment
and prevention of disease
Drugs acting at synaptic and neuroeffector junctional sites autonomic and
neuromuscular pharmacology
Recommended Curriculum Equivalent: 3.5 hr
Drug Classes and Drugs to consider
Nonselective
Selective
Alpha Adrenergic Agonists
Alpha2
Adrenergic Agonists
DOPAMINE
BRIMONIDINE
EPINEPHRINE
CLONIDINE
NOREPINEPHRINE
METHYLDOPA
phenylephrine
pseudoephedrine
Nonselective Alpha1 Alpha2
Selective
Indirect and Mixed Acting
Antagonists
Alpha1 Adrenergic
Agents
Antagonists
phenoxybenzamine
PRAZOSIN
AMPHETAMINE
phentolamine
tamsulosin
ephedrine
terazosin
methamphetamine
tyramine
Learning Objectives
Physiology and pathophysiology
List steps in the synthesis, storage, release and inactivation of norepinephrine and
epinephrine.
Describe types and subtypes of adrenergic receptors, their locations, and physiologic
response to activation.
Describe receptor selectivity of norepinephrine and epinephrine.
Describe the differences between direct and indirect acting adrenergic drugs.
Mechanism of action
Describe the property of intrinsic activity as a characteristic of Direct Agonists binding
to receptors.
Describe the mechanism by which Indirect Agonists release neurotransmitters from
neuron.
Describe the importance of Antagonists binding to receptors without intrinsic activity
Actions on organ systems
Explain why alpha-1 adrenergic antagonists are used to treat hypertension and benign
prostatic hypertrophy.
Explain why alpha-1 adrenergic agonists are important in the treatment of nasal
congestion, hypotension, paroxysmal atrial tachycardia, and are used to cause
mydriasis and vasoconstriction (with local anesthetics).
Explain the mechanism for the use of alpha-2 adrenergic agonists in the treatment of
hypertension, and for topical treatment of glaucoma.
Adverse effects, drug interactions and contraindications
List the adverse side effects of alpha1 and alpha2 agonists.
Explain drug interactions with oxytocic drugs and monamine oxidase inhibitors.
List the contraindications for alpha1 adrenergic agonists.
List the adverse side effects of nonselective alpha and selective alpha adrenergic
antagonists.
Therapeutic uses
Explain why alpha-1 adrenergic agonists are important in the treatment of nasal
congestion, hypotension, paroxysmal atrial tachycardia, and are used to cause
mydriasis and vasoconstriction (with local anesthetics).
Explain the mechanism for the use of alpha-2 adrenergic agonists in the treatment of
hypertension, and for the topical treatment of glaucoma.
Explain the limitations of the use of nonselective alpha-1, alpha-2 adrenergic
antagonists in the treatment of hypertension.
Notes
Clinical Pharmacology
A recent trend to use a combination of methylphenidate and modified release
clodidine to treat ADHD in older children. However, this should not be considered
a first-line drug regimen. Caution in that clonidine should not be discontinued
abruptly due to risk of rebound hypertension. Clonidine use is sometimes
associated with adverse CNS activity including depression and psychosis.
Adverse CNS events have also been observed in patients prescribed methyldopa.
Relevance
USMLE topic
Principles of therapeutics
Central and peripheral nervous system
Mechanisms of action and use of drugs
for treatment of disorders of the
nervous system
Autonomic drugs
Stimulants, amphetamines
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions,
and diseases using frequently
prescribed drugs for the treatment
and prevention of disease
Drugs acting at synaptic and neuroeffector junctional sites autonomic and
neuromuscular pharmacology
Recommended Curriculum Equivalent: 1.5 hr
Drug Classes and Drugs to consider
Nonselective Beta Adrenergic Agonists
Selective Beta Adrenergic Agonists
Isoproterenol
ALBUTEROL
Nonselective Alpha1 Alpha2
Selective Alpha1
Antagonists
Adrenergic Antagonists
phenoxybenzamine
PRAZOSIN
phentolamine
tamsulosin
terazosin
Indirect and Mixed Acting
Agents
AMPHETAMINE
ephedrine
methamphetamine
tyramine
Learning Objectives
Mechanism of action
Compare and contrast the pharmacology of the nonselective beta-adrenergic
agonists, epinephrine and isoproterenol.
Compare and contrast the pharmacology of the beta selective adrenergic agonists,
isoproterenol, albuterol, salmeterol, and dobutamine.
Compare and contrast the pharmacology of the beta-adrenergic antagonists,
propranolol, metoprolol, and atenolol.
Compare and contrast the pharmacology of the nonselective alpha and beta blocking
drug labetalol, with selective beta blocking drugs.
Adverse effects, drug interactions and contraindications
List the adverse side effects of beta2 adrenergic agonists.
List the adverse side effects of beta adrenergic antagonists.
Therapeutic uses
Explain the mechanisms for the use of selective beta-adrenergic agonists in diseases
such as cardiac decompensation, asthma, premature labor, bronchospasm and
emphysema.
Notes
Clinical Pharmacology There is no beta adrenergic blocking drug that has not been
associated with reactive bronchconstriction. Thus caution is advised in adult patients
with a history of pediatric asthma. Use of these agonists as effective tocolytics in
humans is not supported by good clinical evidence.
Relevance
USMLE topic
Principles of therapeutics
Central and peripheral nervous system
Mechanisms of action and use of drugs
for treatment of disorders of the
nervous system
Autonomic drugs
Stimulants, amphetamines
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions,
and diseases using frequently
prescribed drugs for the treatment
and prevention of disease
DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM (21)
Subcommittee:
Eisenberg, Richard, (Chair), [email protected]
Cox, Brian, [email protected]
Faingold, Carl, [email protected]
Goldfarb, Joe, [email protected]
Parkinson, Fiona E., [email protected]
Porrino, Linda, [email protected]
Potter, Pamela E., [email protected]
Prozialeck, Walter, [email protected]
Wecker, Lynn, [email protected]
Introduction to Pharmacology of the Central Nervous System
Understanding how drugs affect the central nervous system depends upon an integral
knowledge of neuroanatomy, biochemistry, physiology, and basic pharmacological
principles. A core medical curriculum in pharmacology of the central nervous system
requires at least 25 hours.
Neurotransmitters, Neuromodulators, and Receptors
Recommended Curriculum Equivalent: 1.5 hr
Learning Objectives
Physiology, pathophysiology and therapeutic actions
List the major neurotransmitters in the brain, their predominant anatomical pathways,
and their associated relevant disorders.
Compare and contrast G protein coupled receptors and ligand-gated ion channels,
and describe the major effector systems coupled to various G-proteins.
List the major classes of receptors for each of the primary
neurotransmitters/neuromodulators and their associated effector systems.
Describe how synaptic function changes in response to chronic administration of
agonists, antagonists and uptake blockers. Describe the processes of receptor
sensitization and desensitization and provide examples of how these processes
may be induced.
Identify the molecular, cellular, and biochemical sites where drugs can act to affect
neuronal function.
Define the blood brain barrier and list the considerations that determine whether a
drug will gain access to the central nervous system. List areas of the brain that are
essentially outside the blood brain barrier and functions of these regions.
Endogenous Agents
Primary agents
Secondary agents
ACETYLCHOLINE (ACH)
adenosine (Ad)
DOPAMINE (DA)
adenosine triphosphate (ATP)
5-HYDROXYTRYPTAMINE (5-HT)
aspartate (Asp)
GAMMA-AMINOBUTYRIC ACID (GABA) beta-amyloid
GLUTAMATE (GLU)
beta-endorphin
HISTAMINE (Hist)
bradykinin
brain derived neurotrophic factor (BDNF)
NOREPINEPHRINE (NE)
endorphins
epinephrine (Epi)
dynorphins
enkephalins
glycine
leptin
nerve growth factor (and other growth
factors) (NGF)
nitric oxide (NO)
orexins
substance P (SP)
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous Systemnormal processes-cell/tissue structure
and function; synthesis, storage,
release, reuptake, and degradation of
neurotransmitters and
neuromodulators; pre- and postsynaptic receptor interactions, trophic
and growth factors; brain homeostasis,
blood-brain barrier
AAMC Medical School Objectives
Project Report X Patient Safety
Topic C
General Anesthetics
Recommended Curriculum Equivalent: 1.5 hr
Drug Classes and Drugs to consider
Inhalational
Primary agents
Secondary agents
DESFLURANE
ISOFLURANE
NITROUS OXIDE
(N2O)
SEVOFLURANE
Intravenous
Primary agents
Secondary agents
ETOMIDATE
methohexital
KETAMINE
thiopental
PROPOFOL
Intravenous Adjuncts
FENTANYL
alfentanil
MIDAZOLAM
remifentanil
MORPHINE
sufentanil
antimuscarinic
agents
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Define the terms “general anesthesia” and “balanced anesthesia.”
State the objectives of general anesthesia, characteristics of an ideal anesthetic, and
the stages of general anesthesia.
Mechanism of action
List the current theories of the mechanisms of action of inhalation anesthetics, and of
intravenous anesthetics.
Pharmacokinetics
Compare the available inhalation anesthetics with respect to their pharmacokinetic
properties including biotransformation. Explain how the solubility of a gas in a
liquid is defined. List the conditions that must be specified to determine the
concentration of gas in the liquid phase.
Describe how the physical properties of inhalation anesthetics influence the rate of
equilibration of anesthetic in the inspired air to anesthetic in alveoli, blood, brain,
muscle and fat. Explain how this information is related to onset and recovery from
inhalation anesthesia.
Compare and contrast commonly used intravenous induction agents—their speed of
onset, and duration of action. Describe the relative roles of distribution and
metabolism in determining duration of action and how duration of action may
change with repeated administration of an intravenous anesthetic.
Adverse effects, drug interactions and contraindications
List and explain the complications that may ensue with the use of Nitrous Oxide as a
direct result of the high concentrations at which it is administered and its solubility
in blood relative to that of nitrogen.
Describe malignant hyperthermia, list some common triggering agents, and discuss its
prevention and treatment.
Describe the utility and adverse effects of drugs commonly used as pre-anesthetic
medications or in combination with inhalation anesthetics to create a "complete or
balanced anesthetic". Include opioids, benzodiazepines, neuromuscular blocking
agents and antimuscarinic agents in your discussion. Indicate how the
concomitant use of these drugs may affect the concentrations of inhaled
anesthetics used to maintain the anesthetic state.
Describe the pharmacological effects of the drugs in each class on pulmonary,
cardiovascular, endocrine, renal, and CNS function (aside from anesthesia).
Therapeutic uses
Define MAC (minimal alveolar concentration), name the physical property of an
inhalation anesthetic that correlates best with its MAC, and explain how the
concept of MAC is used in anesthesiology.
Discuss relative advantages and disadvantages of intravenous vs. inhalation
anesthesia.
Discuss the factors involved in choosing an anesthetic protocol, including the relative
advantages and disadvantages of inhalation and intravenous anesthesia.
Clinical Pharmacology
One significant issue involves increased risk of cardiovascular mortality with propofol
due to concurrent hypokalemia (increased arrhythmia risk) – this is the result of
not controlling serum potassium when propofol was used as an anesthetic agent.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Mechanisms of action and use of drugs
for treatment of disorders if the
nervous system - anesthetics
AAMC Medical School Objectives
Project Report X Patient Safety- Table 1
Topic C
Drug treatment of common conditions,
and diseases using frequently
prescribed drugs for the treatment
and prevention of disease
Local Anesthetics
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
Primary agents
BENZOCAINE
BUPIVACAINE
LIDOCAINE
PROCAINE
ROPIVACAINE
Secondary agents
articaine
cocaine
prilocaine
tetracaine
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Explain how the actions of clinically used anesthetics might be influenced by the
frequency of impulse transmission in peripheral nerves, size and class of the
peripheral axons, pH, and by the vascularity of the injected area.
Review the concept of weak bases, the Henderson-Hasselbalch equation, and drug
transport across membranes.
Discuss the relevance of isoforms of the voltage-gated sodium channel to the
development of new local anesthetics.
Describe the ionic basis of the action potential.
Mechanism of action
Discuss the mechanism of action of local anesthetics, including a description of how
the action of benzocaine differs from that of other primary agents.
Adverse effects, drug interactions and contraindications
List the common adverse effects of local anesthetics and indicate appropriate
treatments should they occur.
List the significant differences between amide and ester-type local anesthetics.
Therapeutic uses
Describe the common routes of administration of local anesthetics. List anesthetics
that cannot be used topically, that cannot be used for infiltration. Explain why
these routes are not effective.
Describe methods used to restrict local anesthetics to a desired site of action and
indicate how these methods reduce adverse effects.
Compare and contrast the advantages and potential adverse effects of epidural and
intrathecal use of local anesthetics with similar use of opioids (see “opioid
analgesics, agonist-antagonists, and antitussives).
Clinical Pharmacology
There should be caution concerning increased cardiac morbidity and seizures if
significant concentrations are achieved in the circulation.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Mechanisms of action and use of drugs
for treatment of disorders if the
nervous system – local anesthetics
AAMC Medical School Objectives
Project Report X Patient Safety- Table 1
Topic C
Drug treatment of common conditions,
and diseases using frequently
prescribed drugs for the treatment
and prevention of disease
Opioid Analgesics, Agonist-antagonists, and Antitussives
Recommended Curriculum Equivalent: 2 hr
Drug Classes and Drugs to consider
Agonists
Primary
CODEINE
FENTANYL
HYDROCODONE
HYDROMORPHONE
METHADONE
MORPHINE
OXYCODONE
OXYMORPHONE
TRAMADOL
Agonist/Antagonists and Antagonists
Secondary
diphenoxylate
heroin
loperamide
meperidine
combinations opioids plus
acetaminophen
and ASA
Primary
BUPRENORPHINE
NALOXONE
NALTREXONE
Secondary
buprenorphinenaloxone
butorphanol
nalbuphine
nalorphine
nalmefene
pentazocine
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the pharmacological effects and sites of action of the prototype opioid
agonist morphine, and its utility in relieving different types of pain.
Discuss potential therapeutic actions of opioids aside from analgesia in CNS and
other organ systems including cardiovascular, respiratory and GI.
Discuss the salient differences in pharmacology between morphine and each of the
following agonists: meperidine, fentanyl, methadone, and oxycodone.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
List the classes of opioid receptors and their associated functional roles. Explain the
relevance of receptor heterodimers to opioid pharmacology.
Pharmacokinetics
Describe the pharmacokinetic processes affecting morphine, absorption, distribution,
metabolism, excretion and how these are relevant to its therapeutic use. Describe
the distribution of opioids in the body, including their ability to cross the blood-brain
barrier and the placenta.
List opioid agonists that are metabolized to morphine and indicate the salient
differences in their pharmacology from that of morphine.
Adverse effects, drug interactions and contraindications
List adverse effects of morphine on CNS, cardiovascular, GI-biliary, respiratory and
genitourinary systems.
List and explain the major drug interactions of morphine.
List the contraindications for morphine and its surrogates.
Describe the characteristics of opioid tolerance and dependence, including the actions
of morphine that do and do not show significant tolerance. Describe the opioid
abstinence syndrome and how it differs from that for sedative-hypnotics.
Discuss abuse liability for opioids and how it differs among the various drugs.
Describe the signs and symptoms of morphine and heroin overdose and how they are
managed.
Define precipitated abstinence and indicate under what circumstances it might occur
following the clinical use of opioid analgesics or antagonists.
Therapeutic uses
Present the clinical indications for the opioids and opioid antagonists and explain the
basis for their use.
Contrast the analgesic effects of morphine with those of the nonsteroidal
antiinflammatory drugs, with those of antidepressants, and with those of
carbamazepine and gabapentin, particularly in relation to the treatment of
neuropathic pain conditions. Discuss the rationale for using mixtures of opioid
analgesics and NSAIDS.
Discuss selection of appropriate therapeutic agents based on severity and type of
pain; consider abuse potential versus therapeutic benefits of various opioids; and
demonstrate awareness of legal and ethical issues in prescribing of opioids.
Explain how agonist-antagonists and partial agonists differ in their utility and adverse
effect profile when compared to morphine.
Discuss the salient differences between naloxone and naltrexone and how these are
reflected in clinical use of these drugs. Discuss how the combination of naloxone
with opiate analgesics in oral and sublingual preparations permits opiate action,
yet decreases abuse liability.
Explain the rationale for using methadone to treat heroin abusers. List the aspects of
methadone’s pharmacokinetics and pharmacodynamics that make it useful for this
purpose. Discuss the salient differences between maintenance therapy with
methadone and buprenorphine.
Discuss diversion and abuse of prescription opioids and approaches to minimize
these occurrences.
Clinical Pharmacology
The drug of choice in this group remains as morphine. In patients with renal
impairment, accumulation of morphine-6-glucuronide will contribute to the
analgesic response. Under-dosing will aggravate smooth muscle spasm and
actually increase the pain sensation, since this response occurs at lower morphine
doses than that required for analgesia. Codeine is a prodrug. It has no analgesic
efficacy and should never be used alone for significant pain relief. Deficiency in
CYP2D6, whether genetic or induced by a competitive substrate drug, will
decrease or eliminate the analgesic response after a codeine dose.
Fentanyl should only be used in morphine-tolerant patients. Its risk of abuse is
considerably higher than with morphine. If analgesic therapy is switched from
morphine to methadone, there will be a gap in analgesic coverage due to the
slower onset of analgesic efficacy. In patients with heart disease or receiving
concurrent drug therapy that prolongs the QTc interval, methadone is relatively
contraindicated due to increased risk of cardiac arrhythmia induced by the
methadone metabolite.
Tramadol has a slow onset of activity and should be considered as a secondary oral
opioid analgesic treatment only for moderate to severe chronic pain. Oxycodone
has a very high abuse potential and should be considered for pain management
for short-term use only when CYP2D6 genetic deficiency is present or when
concurrent drug therapy requires use of a CYP2D6 substrate.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Mechanisms of action and use of drugs
for treatment of disorders of the
nervous system- analgesics
Treatment for substance abuse
disorders
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
Topic G
Diagnosis and management of patients
with substance abuse problems
Antitussives
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
Primary
Secondary
CODEINE
DEXTROMETHORPHAN
HYDROCODONE
guaifenesin
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the cough reflex and the sites of action of antitussive drugs, expectorants
and mucolytic agents.
Mechanism of action
Discuss the mechanism of action of antitussive drugs.
Relevance
USMLE topic
Principles of therapeutics
Respiratory System
Mechanisms of action and use of drugs
for treatment of disorders of the
respiratory system - cough
suppressants
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
Drugs Used in the Treatment of Motor Disorders and Centrally Acting Muscle
Relaxants
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
Primary
AMANTADINE
BACLOFEN
BENZTROPINE
CARBIDOPA
DANTROLENE
DIAZEPAM
DIPHENHYDRAMINE
DOPAMINE
ENTACAPONE
L-DOPA
PRAMIPEXOLE
RASAGILINE
ROPINEROLE
SELEGILINE (deprenyl)
TETRABENAZINE
Secondary
apomorphine
cyclobenzaprine
propranolol
tizanidine
trihexyphenidyl
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the major anatomical pathways and neurotransmitter systems involved in
control of motor function.
Discuss current hypotheses about the etiology and pathophysiology of Parkinson's
disease. Describe similarities and differences between idiopathic and iatrogenic
Parkinsonism.
Describe Huntington's Chorea and discuss drugs available for its treatment and their
effectiveness.
Discuss the pathophysiological basis of rigidity, spasticity, muscle spasm (if not
previously discussed under motor dysfunction) and the classes of agents that are
used to promote skeletal muscle relaxation (baclofen/GABAB receptors,
tizanidine/alpha2 adrenergic receptors).
Mechanism of action
Describe the molecular mechanism of action of each primary drug.
Adverse effects, drug interactions and contraindications
Describe the similarities and differences in the adverse effect profiles of LDOPA/carbidopa, COMT inhibitors, MAOB inhibitors and direct dopamine
agonists.
Therapeutic uses
Describe the rationale for the use of levodopa in Parkinson's disease and the
rationale for its use in combination with peripheral L-amino acid decarboxylase
inhibitor. Discuss how the drug combination alters levodopa's therapeutic and
adverse effect profiles. Discuss the changes in control of symptoms by levodopa
as disease progresses.
Discuss the use of other classes of drugs in treating Parkinson's disease: direct DA
receptor agonists, anticholinergics, MAO inhibitors, COMT inhibitors, amantadine.
Discuss drugs that can cause parkinsonism and other movement disorders, and how
these drug-induced disorders can be treated.
List drugs useful for treatment of spasticity and compare and contrast the
mechanisms of action and adverse effects of benzodiazepines, baclofen,
cyclobenzaprine and dantrolene when used for this purpose. Explain the rationale for the use of dantrolene in malignant hyperthermia and
neuroleptic malignant syndrome.
Clinical Pharmacology
There is significant potential for drug interaction among drugs in this group, especially
carbidopa and L-DOPA when ingested with vitamins containing transition metals.
The major problem with concurrent iron ingestion is reduced bioavailability of LDOPA and carbidopa. This may be interpreted as disease progression rather than
a drug – metal interaction. Drugs with anticholinergic properties may aggravate
mental deficiencies (memory and cognition) such that the patient is prematurely
institutionalized. Increased risk-taking on patients receiving high dose dopamine
agonists (gambling, psychoses, etc. can occur).
Relevance
USMLE topic
Central & Peripheral Nervous SystemNormal processes- motor system;
basal ganglia; synthesis, storage,
release reuptake and degradation of
neurotransmitters
Abnormal Processes- Parkinson disease,
degenerative disorders
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Principles of therapeutics
Antiparkinsonian drugs
Topic C: Drug treatment of common
conditions
Topic D: Drug treatment of less
common but severe conditions
Antiseizure drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
Primary
CARBAMAZEPINE
DIAZEPAM
ETHOSUXIMIDE
LAMOTRIGINE
LORAZEPAM
PHENOBARBITAL
PHENYTOIN
TIAGABINE
TOPIRAMATE
VALPROIC ACID
Secondary
clonazepam
ezogabine
fosphenytoin
lacosamide
levetiracetam
perampanel
pregabalin
primidone
rufinamide
vigabatrin
zonisamide
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the pathophysiology of seizures, and the types and prevalence of epilepsy.
Discuss briefly each of the following with respect to their possible relevance to the
initiation and spread of seizure activity: mirror foci, kindling, post-tetanic
potentiation, long-term potentiation, paroxysmal depolarizing shift, and
channelopathies.
Mechanism of action
List the major classes of antiseizure drugs, the seizure types against which they are
effective, their cellular mechanisms of action, and how these actions might be
relevant to their roles as antiseizure agents.
Pharmacokinetics
Describe the pharmacokinetic factors relevant to appropriate therapy with antiseizure
drugs. Explain why the clearance of phenytoin changes with dose. Discuss the
rationale for the common practice of monitoring plasma concentrations of many
antiepileptic drugs.
Adverse effects, drug interactions and contraindications
List and describe the adverse and teratogenic effects of the major antiseizure drugs.
List the antiseizure medications that induce hepatic enzymes and describe the
consequences for treatment of epilepsy and for interactions with drugs used for
other conditions.
Therapeutic uses
Describe the use of antiseizure medications.
Define status epilepticus and explain how it is managed pharmacologically.
Discuss the therapeutic use of antiseizure drugs for conditions other than epilepsy,
including their use as analgesics and as mood stabilizers.
Clinical Pharmacology
Differentiate between anticonvulsant and antiepilepsy actions on the basis of
prophylaxis and acute therapy, and differentiate seizures from epilepsy.
Describe the role of anticonvulsant drug blood levels in the therapy of epilepsy.
Describe the principles of antiepileptic therapy to include monotherapy vs. poly drug
therapy, withdrawal of drug therapy and the factors involved in epilepsy treatment
failures.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Mechanisms of action and use of drugs
for treatment of disorders of the
nervous system
Anticonvulsants
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
Drugs Used In The Treatment Of Mental Health Disorders
Drugs For The Treatment of Depression
Recommended Curriculum Equivalent: 1.5 hr
Drug Classes and Drugs to consider
Primary
AMITRIPTYLINE
BUPROPION
DULOXETINE
ESCITALOPRAM
FLUOXETINE
NORTRIPTYLINE
PAROXETINE
ST. JOHN’S WORT
SELEGILINE
SERTRALINE
TRANYLCYPROMINE
VENLAFAXINE
Secondary
citalopram
clomipramine
desipramine
fluvoxamine
imipramine
mirtazapine
phenelzine
trazodone
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the concept of behavioral affect, the current neurochemical and neurotrophic
theories regarding affect and how it can be altered by drugs.
Define depression and list its symptoms, signs and causes.
Mechanism of action
List the major classes of antidepressant drugs and their primary cellular targets.
(Tricyclic ADs, SSRIs, SNRIs, atypical antidepressants, and MAO inhibitors).
Discuss the mechanisms that could account for the delay in therapeutic actions of
antidepressants.
Pharmacokinetics
Contrast the pharmacokinetics of the different classes of antidepressant drugs.
Discuss the importance of active metabolite formation, and how pharmacokinetics
is relevant to switching from one medication to another.
Therapeutic uses
Discuss the utility of the various classes of antidepressants for other indications:
Obsessive compulsive disorder, panic disorder, post-traumatic stress disorder
(PTSD), neuropathic pain, smoking cessation, enuresis and generalized anxiety
disorder.
Discuss the use of herbal antidepressants, such as St. John’s wort.
Describe factors involved in the selection of appropriate drug(s) for a given patient.
Adverse effects, drug interactions and contraindications
Describe and compare the most common adverse effects of the major classes of
antidepressants, and where known, explain the mechanism for these effects.
Identify significant drug and dietary interactions.
Describe the signs and symptoms of tricyclic antidepressant toxicity and serotonin
syndrome and their appropriate treatment.
Discuss possible drug interactions with St. John’s wort.
Clinical Pharmacology
There should be caution in use of St. John’s Wort due to induction of CYP3A4 and
loss of therapeutic efficacy of drugs metabolized by this pathway that are being
administered concurrently. Similarly, there should be caution regarding serotonin
syndrome if St. John’s Wort is used concurrently with prescribed SSRI drugs.
Care should be taken in raising the dose of SSRI abruptly due to increased risk of
a rage reaction, especially within the first 2 weeks of dose change and concurrent
ingestion of ethanol beverages.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Psychopharmacologic agents, drug
induced adverse effects-CNS
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Drugs for treatment bipolar disorder
Drugs to consider
Primary
CARBAMAZEPINE
LAMOTRIGENE
LITHIUM CARBONATE
VALPROIC ACID
ATYPICAL ANTIPSYCHOTICS:
ARIPIPRAZOLE
OLANZAPINE
QUETIAPINE
RISPERIDONE
ZIPRASIDONE
Secondary
clonazepam
clozapine
levetiracetam
paliperidone
primidone
zonisamide
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the concept of behavioral affect, the current neurochemical theories
regarding affect and how it can be altered by drugs.
Define bipolar disorder and its subtypes, and describe its signs and symptoms and its
natural history. Describe manic episodes.
Mechanism of action
Describe the major theories explaining the presumed mechanisms of action of drugs
useful for treating bipolar disorder (lithium, anticonvulsants, antipsychotics). List
effects of lithium on CNS neurotransmitter systems.
Pharmacokinetics
Discuss the pharmacokinetics of lithium and its relationship to the following: alteration
in dietary sodium, effects of exercise, use of diuretics, monitoring of plasma lithium
levels, and treatment of lithium overdose.
Therapeutic uses
Contrast acute treatment of a manic episode and treatment designed to prevent
bipolar cycling.
Discuss the use of antiseizure drugs for treatment of bipolar disorder, their
advantages and disadvantages compared to lithium.
Adverse effects, drug interactions and contraindications
Differentiate adverse side effects of lithium from signs and symptoms of lithium
overdose. Explain why there is a contraindication to the use of lithium in patients
with impaired renal function or cardiovascular disease.
Clinical Pharmacology
See below: the treatment of psychoses
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Psychopharmacologic agents, drug
induced adverse effects-CNS
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Drugs for treatment of psychoses
Recommended Curriculum Equivalent: 1.5 hr
Drugs to consider
Primary
CHLORPROMAZINE
ARIPIPRAZOLE
CLOZAPINE
FLUPHENAZINE
HALOPERIDOL
OLANZAPINE
RISPERIDONE
Secondary
paliperidone
perphenazine
quetiapine
thiothixene
ziprasidone
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe schizophrenia and discuss the theories regarding the underlying
neurochemical/genetic/developmental basis.
Contrast the actions of phenothiazines and haloperidol with those of 2nd and 3rd
generation antipsychotics, and the implications for theories of the mechanisms of
antipsychotic actions.
Mechanism of action
Discuss current theories regarding the therapeutic mechanism of action of
antipsychotic drugs, including acute and chronic effects on major dopaminergic
and serotonergic systems in the CNS.
Therapeutic uses
Compare the effectiveness of classical and atypical antipsychotics in the treatment of
both positive and negative symptoms of schizophrenia.
Discuss cognitive impairments and lack of efficacious treatments.
List uses of antipsychotic drugs for indications other than schizophrenia.
Discuss the use of dopamine antagonists in Tourrette's syndrome.
Adverse effects, drug interactions and contraindications
Differentiate the side effect profile of low potency vs high potency classical (1st
generation) antipsychotics. Provide an explanation for these differences.
Discuss the major area in which atypical (2nd and 3rd generation) antipsychotics‘ side
effect profiles differ from those of classical (1st generation) antipsychotics, the
nature of the differences and the mechanistic basis for the difference.
List the major side effects of each of the primary drugs.
Describe the time course, signs and symptoms of antipsychotic drug-induced
dyskinesias (dystonia, akathesia, parkinsonism, tardive dyskinesia), and their
management and treatment.
Describe neuroleptic malignant syndrome and its management and treatment.
Clinical Pharmacology
Care should be taken as metabolic disorders may be observEd with the second
generation drugs, especially in patients with metabolic syndrome and/or a family
history of diabetes.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System- Psychopharmacologic agents
Normal processes- cognition
Abnormal Processes- psychopathologic
disorders; schizophrenia and other
psychotic disorders
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety-Table 1
conditions
Topic D: Drug treatment of less
common but severe conditions
Drugs For Treatment Anxiety And Sleep Disorders
Recommended Curriculum Equivalent: 2 hr
Drugs to consider
Primary
ALPRAZOLAM
DIAZEPAM
DULOXETINE
ESCITALOPRAM
ESZOPICLONE
FLUMAZENIL (ANTAGONIST)
FLUOXETINE
LORAZEPAM
MIDAZOLAM
RAMELTEON
SERTRALINE
VENLAFAXINE
ZOLPIDEM
Secondary
buspirone
chloral hydrate
dexmedetomidine
diphenhydramine
gamma-hydroxybutyrate
hydroxyzine
lorazepam
oxazepam
temazepam
zaleplon
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Briefly describe the concepts of sedation, hypnosis, anesthesia, coma. List and
describe the stages of sleep.
Define anxiety, its relationship to the amygdala and differentiate the major anxiety
disorders.
Discuss the GABAA receptor channel complex, the heterogeneity of its subunits and
the physiological and therapeutic implications.
Describe translocator protein (18kD)-TSPO, its relationship to benzodiazepines and
its possible relevance to drug treatment of anxiety.
Mechanism of action
Describe the effects of various sedative/hypnotic/anxiolytic drugs on GABAA function,
their selectivity for different receptors with different subunit subtypes, and
differences in their sites of action on the GABAA receptor channel complex.
Define inverse agonist at the GABAA receptor channel complex.
List sedatives, hypnotics and anxiolytics whose mechanism of action does not involve
enhancement of GABAA function, and describe their molecular targets.
Adverse effects, drug interactions and contraindications
List the signs and symptoms of barbiturate and benzodiazepine overdose and its
treatment. Explain how flumazenil might be used, and the rationale for its use.
Describe the interactions of the various classes of drugs used as hypnotics, sedatives
and anxiolytics with other CNS depressants.
Compare the dependence liability, and withdrawal syndromes of the various classes
of drugs used as hypnotics, sedatives and anxiolytics.
Discuss the interactions with alcohol.
Therapeutic uses
Compare and contrast the effects of barbiturates, benzodiazepines, and nonbenzodiazepine agonists at the benzodiazepine site on induction and maintenance
of sleep (including effects on sleep stages), and the adverse effects of these
classes of drugs. Explain why drugs acting at the benzodiazepine receptor have
virtually totally replaced barbiturates as hypnotics.
List the therapeutic uses of benzodiazepines, and prototypes for each use. Explain
how pharmacokinetics of various benzodiazepines relates to their therapeutic
utility.
Compare and contrast the hypnotic action of ramelteon and the anxiolytic action of
buspirone with those of drugs acting at the benzodiazepine site of the GABAA
receptor channel complex, and describe how their adverse effects including abuse
potential differ.
Compare and contrast the sedative action of chloral hydrate, hydroxyzine and
dexmedetomidine with those of drugs acting at the benzodiazepine site of the
GABAA receptor channel complex, and describe how their adverse effects
including abuse potential differ.
List drugs that are used for treating anxiety disorders other than generalized anxiety:
panic disorder, obsessive-compulsive disorder, specific phobias. Can these drugs
be used for generalized anxiety disorder as well?
Compare time course of anxiety relief with benzodiazepines vs SS/SNRIs.
Clinical Pharmacology
SSRIs are considered to have a higher benefit:risk ratio than the benzodiazepine or
benzodiazepine-like drugs to treat anxiety states. Use as sedative-hypnotics of
the benazodiazepine class is considerably abused. This therapeutic intervention
is justified only for short-term administration. If benzodiazepines are to be used,
intermediate-acting agents with primary elimination by Phase 2 drug metabolism
are preferred due to reduced probability of a “hangover” effect. The only justifiable
use of midazolam is part of a conscious sedation protocol prior to an
uncomfortable diagnostic intervention.
Diazepam use in the elderly patient is problematic in that the terminal disposition halflife approximates age in the adult patient. However, this change is not related to a
reduction in drug clearance but to an increase in apparent volume of distribution.
Since its primary metabolite, desmethyldiazepam, has an even longer terminal
half-life than diazepam, there is increased risk of hangover and reduced mental
function with chronic use. When indicated, shorter acting benzodiazepines
(lorazepam or oxazepam) are safer alternatives.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Psychopharmacologic agents, drug
induced adverse effects-CNS,
hypnotic sedatives
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic A
Factors that make each patient unique
Topic C
Drug treatment of common conditions
Stimulants and Anorexigenic Drugs
Recommended Curriculum Equivalent: 0.5 hr
Drugs to consider
Primary agents
AMPHETAMINES
ATOMOXETINE
CAFFEINE
METHYLPHENIDATE
MODAFINIL
PHENTERMINE
Secondary agents
ephedrine
theophylline
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Discuss the presumed physiological basis for the use of stimulants as anorexigenics,
to enhance wakefulness, and in attention deficit hyperactivity disorder.
Mechanism of action
Describe the cellular mechanisms of action of the various stimulant drugs.
Adverse effects, drug interactions and contraindications
Discuss the adverse effects of stimulants with particular attention to cardiovascular
problems and substance abuse.
Therapeutic uses
Discuss the use of stimulants for attention deficit hyperactivity disorder, narcolepsy,
other sleep disorders, obesity, and apnea in the newborn.
Discuss the limitations of using stimulants for weight loss.
Clinical Pharmacology
This should not be a first line treatment intervention for facilitation of weight loss due
to increased cardiovascular risk in a population with a high likelihood of
underlying cardiovascular disease. Tolerance and rebound weight gain upon
cessation of use of these agents diminishes a rational justification of their use in
management of obesity, given the risk of dependence and diversion for
recreational use.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Mechanisms of action of drugs for
treatment of disorders of the
nervous system-stimulants,
amphetamines
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Topic G
Diagnosis and management of patients
with substance abuse problems
Drug and Substance Abuse
Recommended Curriculum Equivalent: 3 hr
Drug dependence, general principles
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Define and differentiate tolerance to, physical dependence on and substance
dependence (DSM-IVR) on drugs.
Discuss the roles of drug craving and reward vs. avoidance of withdrawal in initiation
and maintenance of substance dependence.
Define conditioned withdrawal and precipitated withdrawal and indicate their
relevance to substance dependence and its treatment.
Discuss how pharmacokinetics influences abuse liability and withdrawal syndromes.
Compare patterns and effects of substance abuse for stimulants, opioids, sedativehypnotics and anxiolytics.
Drugs to consider - Psychostimulants
Primary
AMPHETAMINES
BUPROPION
COCAINE
METHAMPHETAMINE
METHYLPHENIDATE
NICOTINE
VARENICLINE
Secondary
cathinone and analogs
ephedrine
phentermine
Learning Objectives
Mechanism of action
Discuss current theories of the mechanisms of action of the stimulant drugs listed
above.
Adverse effects, drug interactions and contraindications
Compare abuse liability among the various listed stimulants and among available
preparations of each drug.
Discuss adverse effects of misused and abused stimulants.
Discuss the addictive properties of nicotine, and the adverse effects of nicotine and
other constituents of tobacco.
Compare and contrast patterns of substance misuse and abuse of stimulants with
those of other drugs of abuse.
Compare and contrast morbidity and mortality of misuse and abuse of stimulants with
those of other drugs of abuse.
Compare and contrast patterns of tolerance and dependence, and the withdrawal
syndromes for stimulants with those of other drugs of abuse.
Therapeutic uses
Discuss the use of varenicline, bupropion, and various formulations of nicotine to treat
nicotine dependence.
Describe the treatment for overdose on stimulant drugs.
Discuss current thoughts on potential treatments for stimulant drug dependence.
Clinical Pharmacology
The use of amphetamines with tricyclic antidepressants is contraindicated due to
increased risk of cardiovascular morbidity and mortality.
Relevance
USMLE topic
Central and Peripheral Nervous System
Principles of therapeutics
Treatment for substance abuse
disorders, amphetamines,
psychopharmacological agents
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Topic G
Diagnosis and management of patients
with substance abuse problems
Drugs to Consider - Ethanol and alcoholism
Primary
ETHANOL
FOMEPIZOLE
METHANOL
NALTREXONE
Secondary
acamprosate
ethylene glycol
topiramate
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe the acute CNS actions of ethanol and discuss their relationship to blood
alcohol levels.
Describe the effects of chronic alcohol on sleep.
Mechanism of action
Discuss current theories about the mechanism of action of alcohol in the CNS.
Pharmacokinetics
Describe the pharmacokinetics of ethanol, its absorption, distribution, metabolism and
excretion.
List the effects of chronic (moderate or high) alcohol use on alcohol metabolism and
organ function.
Adverse effects, drug interactions and contraindications
Describe the acute and chronic organ toxicities of ethanol methanol and higher
alcohols (e.g. ethylene glycol).
List drugs with which ethanol shows cross-tolerance and cross-dependence.
List drugs, both prescription and over the counter, that would entail a patient refraining
from the use of alcoholic beverages. Explain the nature of the potential
interactions.
List the signs and symptoms of chronic alcoholism and the ethanol abstinence
syndrome. Compare and contrast the latter with abstinence syndromes following
chronic use of barbiturates, benzodiazepines, or opioids.
Compare and contrast morbidity and mortality of ethanol use with that for other drugs
of abuse.
Therapeutic uses
Summarize the therapeutic applications of ethanol.
Discuss the treatment options for acute intoxication by ethanol or other alcohols, and
for the ethanol abstinence syndrome.
Discuss the use of disulfiram, naltrexone and acamprosate in the treatment of chronic
alcoholics. Describe their effects and the mechanistic rationale for their use.
Clinical Pharmacology
For the most part, there is no longer an acceptable therapeutic use of ethanol. It was
sometimes used in older patients to stimulate gastric acid production prior to a
meal. Acutely, it can be used as a second line treatment by injection for trigeminal
neuralgia.
Fomepizole has evolved into the treatment of choice for overdose with methanol or
ethylene glycol. In the absence of fomepizole, ethanol may be a reasonable
treatment for methanol or ethylene glycol overdose, but control of concentration
after ingestion is problematic, and exacerbation of CNS depression is a major
concern.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Treatment for substance abuse
disorders, amphetamines,
psychopharmacological agents
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Topic G
Diagnosis and management of patients
with substance abuse problems
Drugs to Consider - Hallucinogens and Designer Drugs
Primary
Secondary
LYSERGIC ACID DIETHYLAMIDE (LSD) atropine
MDMA (methylene
bath salts (methylenedioxypyrovalerone)
dioxymethamphetamine)
bufotenin
MESCALINE
ketamine
PHENCYCLIDINE (PCP)
psilocin
salvia
scopolamine
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Describe salient differences among the behavioral and hallucinogenic effects of the
various drugs and compare and contrast the drug-induced states with endogenous
psychoses and with amphetamine-induced psychosis.
Discuss the variability in inter-individual responses to hallucinogens and the
interaction between the social setting in which hallucinogens are taken and their
behavioral effects.
Mechanism of action
List the hallucinogens with primary actions on 5HT2A receptors, and those that are
NMDA receptor antagonists, and muscarinic receptor antagonists and describe
their mechanisms of action.
Pharmacokinetics
Describe how the pharmacokinetics of different drugs may influence their duration of
action and their detection by screening tests for illicit drug use.
Adverse effects, drug interactions and contraindications
Discuss tolerance to and cross-tolerance among the various hallucinogens.
Describe the toxidromes expected for LSD, MDMA, PCP, and belladonna alkaloids.
Discuss general principles of treatment for patients with known ingestion of
hallucinogens.
Clinical Pharmacology
For the most part, treatment of consequences relating to acute ingestion of these
drugs defaults to supportive care and patient placement in a quiet, nonthreatening
environment.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Treatment for substance abuse
disorders, amphetamines,
psychopharmacological agents
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Topic G
Diagnosis and management of patients
with substance abuse problems
Drugs to Consider - Marijuana
Primary
DELTA-9-TETRAHYDROCANNABINOL
(THC)
DRONABINOL
MARIJUANA
Secondary
designer cannabinoids
hashish
K-2
nabilone
spice
Learning Objectives
Physiology, pathophysiology and therapeutic actions
Discuss the endogenous cannabinoids, how they differ from classical
neurotransmitters/neuromodulators, their receptors, and the current hypotheses
about their functional roles.
List the psychological, physiological and pharmacologic effects of smoking marijuana;
of taking dronabinol.
Compare and contrast patterns of marijuana use with that of other drugs of abuse.
Compare and contrast morbidity of marijuana use with that of other drugs of abuse.
Compare and contrast tolerance and dependence on marijuana with that for other
drugs of abuse.
Therapeutic uses
List the approved therapeutic indications for dronabinol. Discuss the current
controversy over the use of medical marijuana vs. the use of dronabinol or
nabilone, and proposed therapeutic actions aside from those currently approved
for dronabinol.
Describe the effects of cannabinoid receptor antagonists and their potential uses.
Clinical Pharmacology
With currently available clinical trial evidence, cannabinoids are probably indicated
only as second-line treatment for nausea and vomiting associated with cancer
chemotherapy that is unresponsive to other more conventional antiemetics. There
is suggestive evidence for its efficacy as a co-analgesic to manage terminal pain in
a palliative care setting. Clinical trials to assess efficacy and toxicity in patients
with severe pain are currently ongoing. Robust clinical trial data to support other
claimed human therapeutic indications are currently lacking.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Treatment for substance abuse
disorders, amphetamines,
psychopharmacological agents
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Topic G
Diagnosis and management of patients
with substance abuse problems
Drugs to Consider - Inhalants/Organic solvents and gases
Primary
Secondary
GASOLINE
carbon tetrachloride
fire extinguisher accelerants
fluorocarbons
gasoline
glue
nitrous oxide
toluene
Learning Objectives
Adverse effects, drug interactions and contraindications
Discuss the epidemiology of abuse of inhalants.
Describe, in general terms, the effects of organic solvents and their toxicities
Drugs to Consider - Opioids
Agonists
Antagonists
BUPRENORPHINE
NALOXONE
BUPRENORPHINE/NALOXONE
NALTREXONE
HEROIN
METHADONE
MORPHINE
OXYCODONE (and abuse of prescribed
opioids)
Learning Objectives
Adverse effects, drug interactions and contraindications
Discuss the development of substance dependence (addiction) on opioids during their
use for treatment of pain, differentiating physical dependence from addiction.
Describe patterns of opioid abuse, compare and contrast them with those of other
classes of abused drugs.
Describe opioid tolerance and indicate differences in degree of tolerance achieved for
various responses.
Discuss the opioid abstinence syndrome, list the signs and symptoms and compare
and contrast these with withdrawal from CNS depressants including ethanol and
benzodiazepines.
Therapeutic uses
Discuss treatment of opioid overdose in a chronic user of these drugs.
Discuss approaches used in drug formulation to limit the abuse and diversion of
prescription opioids.
Describe the rationale and implementation of methadone maintenance for treatment
of opioid abuse.
Explain the major differences between the use of methadone and buprenorphine for
maintenance therapy. Explain why after initiating buprenorphine therapy,
maintenance is commonly effected using a combination of buprenorphine and
naloxone.
Discuss the rationale and limitations of the use of naltrexone for treating patients with
opioid substance dependence.
Clinical Pharmacology
Use of methadone is particularly problematic in that it prolongs the QTc interval and is
dangerous in the patient with underlying cardiac disease and/or receiving therapy
with other drugs concurrently that also prolong the QTc interval. Since
buprenoprhine is a partial agonist, it should not be used concurrently for chronic
pain management with a full opioid agonist due to the increased risk of
precipitating an acute opioid withdrawal reaction. Buprenorphine also prolongs the
QTc interval.
There is no rationale for the use of heroin as an analgesic, since its therapeutic
activity occurs as a result of its conversion to morphine.
Many jurisdictions are removing oxycodone from their formularies due to its enhanced
risk:benefit profile and the availability of safer oral opioid analgesic formulations
with a lesser tendency for abuse. Oxycodone use is probably only justified for
short-term acute pain management as a second line drug, and only in patients with
suppression of CYP2D6 activity.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Treatment for substance abuse
disorders, amphetamines,
psychopharmacological agents
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
Topic G
Diagnosis and management of patients
with substance abuse problems
Drugs to Consider – CNS general depressants
Primary
Secondary
BUTALBITAL
DIAZEPAM
ALPRAZOLAM
FLUNITRAZEPAM
secobarbital
zolpidem
Learning Objectives
Adverse effects, drug interactions and contraindications
Discuss the relative abuse potential of drugs within this class.
Compare and contrast patterns of barbiturate and benzodiazepine abuse with that of
other drugs of abuse.
Compare and contrast morbidity and mortality of barbiturate abuse, benzodiazepine
abuse, and abuse of other classes of drugs.
Compare and contrast tolerance and dependence, and the nature of the withdrawal
syndrome for barbiturates, benzodiazepines, and that for other drugs of abuse.
Therapeutic uses
Discuss treatment of barbiturate and benzodiazepine overdose in a chronic user of
these drugs.
Clinical Pharmacology
Benzodiazepines abuse represents one of the largest problems in Clinical
Pharmacology. There is substantial diversion for recreational use, especially in
combination with alcohol. Diazepam by mouth is a reasonable therapy for
management of the alcohol withdrawal syndrome. Its long half-life serves to
reduce the severity of the withdrawal reaction, and serves as a self-tapering
mechanism when drug doses are stopped.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System
Treatment for substance abuse
disorders, amphetamines,
psychopharmacological agents
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic G
Diagnosis and management of patients
with substance abuse problems
Drugs and the law
Therapeutic uses
Define the characteristics of drugs in each of the Drug Enforcement Administration
classification of controlled substances into Schedules I, II, III, and IV, and give
examples of some specific drugs that are included in each schedule. Discuss the
ways in which this classification affects the clinical use of drugs.
Driving under the influence of alcohol, marijuana, others.
Relevance
USMLE topic
Principles of therapeutics
Pharmacodynamic and Pharmacokinetic
Processes – regulatory issues
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic E
Rules and regulations that govern
prescribing
Treatment of Alzheimer’s Disease.
Recommended Curriculum Equivalent: .3 hr
Drugs to consider
Primary
Secondary
DONEPEZIL
GALANTAMINE
MEMANTINE
RIVASTIGMINE
Learning Objectives
Mechanism of action
Discuss the drugs used for the treatment of Alzheimer's disease, their mechanisms of
action, their efficacy and their adverse effects.
Relevance
USMLE topic
Principles of therapeutics
Central and Peripheral Nervous System- Drugs for dementia, Alzheimer type
Normal processes- cognition; memory;
limbic system
Abnormal Processes- degenerative
disorders
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety-Table 1
conditions
Topic D: Drug treatment of less
common but severe conditions
Autacoids/Nonsteroidal Antiinflammatory/Asthmatic Drugs
Subcommittee:
Szarek, John, (Chair), [email protected]
Cox, Brian [email protected]
Malik, Asrar B. [email protected]
Histamine and Antagonists
Recommended Curriculum Equivalent: 1.5 hr
Drug Classes and Drugs to consider
H1 Receptor Antagonists
First Generation
DIMENHYDRINATE
DIPHENHYDRAMINE
PROMETHAZINE
chlorpheniramine hydroxyzine
Endogenous Substances
HISTAMINE
Second Generation
FEXOFENADINE
LORATADINE
cetirizine
H2 Receptor Antagonists
CIMETIDINE
FAMOTIDINE
RANITIDINE
nizatidine
Histamine Release
Modifiers
CROMOLYN
omalizumab
Learning Objectives
Physiology and pathophysiology
Describe the synthesis, storage and release of histamine.
Describe the metabolism and elimination of histamine.
Identify the major classes of histamine receptors - H1, H2 (with mention of H3 and H4)
and discuss their tissue distribution and function.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the pharmacological effects of the drugs in each class on various organ
systems.
Differentiate the histamine receptor subtypes responsible for mediating the effects of
histamine in each organ system.
Pharmacokinetics
Describe the pharmacokinetics of the second generation antihistamines.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs in each class.
Describe the clinically important drug interactions of the drugs in each class.
Describe the principal contraindications of the drugs in each class.
Therapeutic uses
Differentiate the use of the antihistamines in allergies, sedation, and motion sickness.
Clinical Pharmacology
Of the first generation antihistamines, chlorpheniramine is the least sedating and is
often preferred because of this characteristic
Dimenhydrinate and diphenhydramine have a relatively narrow therapeutic index and
are often used recreationally as over-the-counter hallucinogens.
Cimetidine is no longer recommended as an H2 receptor antagonist due to its
property of being a suicide substrate for CYP 3A4 and the potential for toxicity of
concurrently ingested drugs that are metabolized by this CYP isoform.
Relevance
USMLE topic
Principles of therapeutics
Respiratory System-Abnormal Processes- Decongestants, cough suppressants,
Immunological Disorders and
expectorants, mucolytics & other
Inflammatory Disorders
therapeutic modalities
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
and disease
Notes
Objectives for H2-receptor antagonists are covered in Gastrointestinal Drugs.
Objectives for Histamine Release Modifiers are covered in Asthma Drugs.
5-Hydroxytryptamine (5-HT, Serotonin): Agonists & Antagonists
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
Drugs used for Migraine
Abortive Agents
Prophylactic Agents
Triptans
Ergot Alkaloids
SUMATRIPTAN
ergotamine
AMITRIPTYLINE
zolmitriptan
PROPRANOLOL
TOPIRAMATE
Serotonin Agonists and Antagonists
Antiemetic
SEROTONIN
ONDANSETRON
cyproheptadine
Learning Objectives
Physiology and pathophysiology
Describe the synthesis, storage and release of serotonin.
Describe the metabolism and elimination of serotonin.
Identify the major types of serotonin receptors relevant to therapeutic drugs acting in
the brain, the vasculature and the g.i. tract.
Describe the roles of serotonin in migraine, carcinoid syndrome, and in the CNS
(emesis; mood disorders and other psychiatric conditions, covered with CNS
drugs).
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the pharmacological effects of the drugs in each class on various organ
systems.
Pharmacokinetics
Describe the pharmacokinetics of abortive therapy for migraine.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs in each class
Describe the clinically important drug interactions of the drugs in each class.
Describe the principal contraindications of the drugs in each class.
Therapeutic uses
Differentiate the use of these drugs in migraine (prophylaxis vs. abortive therapy) and
as antiemetic agents.
Note the use of the 5HT2A and H1 antagonist cyproheptadine in carcinoid syndrome.
Clinical Pharmacology
A combination of aspirin, acetaminophen and caffeine in clinically effective doses
should be tried prior to use of triptan drugs for the treatment of migraine
headaches. This drug combination is available as an over-the-counter product and
has been demonstrated to be effective in the majority of migraine headache
attacks.
Relevance
USMLE topic
Central and Peripheral Nervous SystemNormal processes: cell/tissue structure
and function-synthesis, storage,
release, reuptake, and degradation of
neurotransmitters and neuromodulators
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
nervous system-antimigraine agents
Topic C
Drug treatment of common conditions
and disease
Nitric Oxide and Drugs for Erectile Dysfunction
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
Agonist
NITRIC
OXIDE
PDE inhibitor
SILDENAFIL
NO Donors
SODIUM
NITROPRUSSIDE
nitroglycerin
Learning Objectives
PGE1 Analog
alprostadil
Physiological roles of NO and cGMP
Describe the mechanisms and cellular site of endogenous synthesis of NO and its
interactions with guanylate cylcase to regulate cellular levels of cGMP.
Explain the roles of NO and cGMP in local control of blood flow, erectile dysfunction
and relaxation of the pulmonary vasculature .
Mechanism of action
Explain the molecular mechanism of action of NO, guanyl cyclase and each drug in
each class.
Actions on organ systems
Describe the pharmacological effects of the drugs in each class on various organ
systems.
Pharmacokinetics
Describe the synthesis (constitutive vs. inducible) and release of nitric oxide.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs in each class.
Describe the clinically important drug interactions of the drugs in each class.
Describe the principal contraindications of the drugs in each class.
Therapeutic uses
Differentiate the use of these drugs in erectile dysfunction.
Describe the use of NO gas to induce pulmonary vasodilation in persistent pulmonary
hypertension in newborn and in adult respiratory distress syndrome.
Clinical Pharmacology
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System
Mechanisms of action, use, and
Reproductive System
adverse effects of drugs for
Pharmacodynamic and Pharmacokinetic
treatment of disorders of the
Processes-general principles
cardiovascular system
antihypertensive drugs, coronary
and peripheral vasodilators
Restoration of potency
Signal transduction
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions
and disease
Notes
Objectives for NO donors are covered under Cardiac Drugs.
Objectives for drugs related to prostaglandins in ED are covered under Eicosanoids.
Eicosanoids: Agonists & Antagonists
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
Prostanoids
Endogenous
PGE2
PGF2Α
PROSTACYCLIN
THROMBOXANE A2
Leukotrienes
Analogs
ALPROSTADIL
MISOPROSTOL
Latanoprost
Endogenous
LTB4
LTC4,D4,E4
Leukotriene Modifiers
ZAFIRLUKAST
Montelukast
Zileuton
Learning Objectives
Physiology and Pathophysiology
Describe the synthesis of prostaglandins, thromboxanes, leukotrienes from
arachidonic acid.
Explain physiologic and pathophysiologic roles of esicosanoids in regulation of local
blood flow, airway resistance, inflammation and nociception.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the pharmacological effects of the drugs in each class on various organ
systems.
Differentiate drugs inhibiting leukotriene synthesis (zileuton) from leukotriene action at
CysLT1 receptors (zafirlukast).
Pharmacokinetics
Describe the metabolism and elimination of eicosanoids
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs in each class.
Describe the clinically important drug interactions of the drugs in each class.
Describe the principal contraindications of the drugs in each class.
Describe the shunting of arachidonic acid metabolism to the production of
leukotrienes by inhibition of COX enzymes, leading to bronchoconstriction.
Therapeutic uses
Describe the clinical utility of prostaglandin analogs.
Clinical Pharmacology
The leukotriene antagonists remain as secondary choices for the management of
patients with asthma.
Prostaglandin analogs are contraindicated in women of child-bearing age who are or
are likely to become pregnant.
Misoprostol is most often used together with an NSAID (most often diclofenac) to
reduce the risk of a GI bleed in patients requiring chronic drug therapy with an antiinflammatory analgesic.
Relevance
USMLE topic
Principles of therapeutics
Musculoskeletal System
Mechanisms of action and use of drugs
for treatment of disorders of the
musculoskeletal system
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic D
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
Notes
Objectives for the Leukotriene Modifiers are covered under Asthma Drugs.
Bioactive Peptides
Recommended Curriculum Equivalent: 0.25 hr
Drug Classes and Drugs to consider
Neuropeptides
Kinins
Endogenous
Antagonist
BRADYKININ
CGRP
aprepitant
substance P
VIP
Physiology and Pathophysiology:
Describe the synthesis and metabolism of kinins, and the pathological factors that can
trigger kinin formation.
Describe the roles of substance P, neurokinins and CGRP in pain perception and local
inflammation, and the probable role of substance P in emesis.
Describe briefly the receptors activated by bradykinin, and substance P and other
neurokinins.
Therapeutic uses:
Describe the use of the neurokinin antagonist, aprepitant, as an anti-emetic.
Drug interactions
Describe the effects of ACE inhibitors on the metabolism of bradykinin and the
production of cough related to ACE inhibitor therapy.
Clinical Pharmacology
Where cough is induced by treatment with an ACE inhibitor, this side effect may be
eliminated by substitution with an angiotensin receptor antagonist. There is no
good clinical evidence for the concurrent use of an ACE inhibitor and an
angiotenson receptor antagonist.
Relevance
USMLE topic
Pharmacodynamic and Pharmacokinetic
Processes-general principles
Gastrointestinal System
Principles of therapeutics
Signal transduction
Mechanisms of action and use of drugs
for treatment of disorders of the
gastrointestinal system
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions
and disease
Drugs used for treating Asthma and COPD
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Antiinflammatory Drugs
Leukotriene Modifiers
Modulators of mast cell
Leukotriene receptor
Steroids
5-LO inhibitor
degranulation
antagonists
BECLOMETHASONE
CROMOLYN
ZAFIRLUKAST
zileuton
FLUTICASONE
omalizumab
montelukast
Bronchodilators
β2 Agonists
Methylxanthines
Muscarinic receptor antagonists
ALBUTEROL
THEOPHYLLINE
IPRATROPIUM
PIRBUTEROL
aminophylline
tiotropium - now preferred due to
SALMETEROL
once daily dosage
terbutaline
Learning Objectives
Physiology and Pathophysiology
Describe the disease processes of asthma and COPD including airway inflammation, bronchial
smooth muscle constriction, and mast cell degranulation.
Describe the role of various mediators (histamine, acetylcholine, proteases, leukotrienes C4, D4;
prostaglandins; cytokines) in asthma and COPD.
Mechanisms of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Differentiate the effects on the lung of the quick relief drugs and the drugs used for long-term control.
Pharmacokinetics
Describe the routes of administration of each drug.
List the main drugs and clinical situations that can alter the pharmacokinetics of theophylline.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class.
Describe the principal contraindications of the drugs of each class.
Therapeutic uses
Differentiate the use of these drugs in asthma (short term relief and long term control) and their use in
COPD.
Clinical Pharmacology
Long-acting beta-2 receptor agonists are not to be used alone, due to down-regulation of the beta-2
receptor. These drugs are to be used only concurrently with inhaled steroids. Many clinicians
prefer beclomethasone as an inhaled steroid therapy because of its high first pass metabolism for
that portion of the dose that is swallowed during the inhalational ingestion.
There is no good evidence for superiority of any of the short-acting beta-2 receptor agonist
congeners.
Theophylline remains an effective bronchodilator, but the recommended dose has been lowered in
recent times.
Tiotropium has supplanted ipratropium as an antimuscarinic bronchodilator strategy due to its more
convenient once daily dosage recommendation. Anticholinergic and antileukotriene drug therapy
remain secondary drug management strategies.
USMLE topic
Respiratory System
AAMC Medical School Objectives Project
Report X Patient Safety-Table 1
Relevance
Principles of therapeutics
Mechanisms of action and use of drugs for
treatment of disorders of the respiratory
system-bronchodilator drugs
Topic C
Drug treatment of common conditions and
disease
Notes
Objectives for steroids are covered under Adrenal Cortex
Cytotoxic drugs
AZATHIOPRINE
Hypersensitivity and Immunopharmacology
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Immunosuppressants
Drugs acting on
Drugs acting on
cytokines or on
Lymphotoxic drugs Immunocompetent
Other
cytokine
cells
receptors
PREDNISONE
CYCLOSPORINE
DACLIZUMAB Rho(D) immune
Antithymocyte
TACROLIMUS
INFLIXIMAB
globulin
immunoglobulin
MYCOPHENOLATE Lenalidomide
MOFETIL
Etanercept
Muromonab
Thalidomide
Sirolimus
Immunostimulants and colony stimulating factors
EPOETIN ALFA
FILGRASTIM (G-CSF)
INTERFERONS
SARGRAMOSTIM (GM-CSF)
ldesleukin
BCG vaccine
Learning Objectives
Physiology and Pathophysiology
Describe the role of immunoglobulins (IgE, IgG, IgM) and cytokines in the immune response.
Differentiate different types of allergic reactions (Type I-IV) and factors (e.g. cytokines, MHC) involved
Describe the release of allergic mediators and processes leading to hypersensitivity.
Mechanisms of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Relate the main effects of each drug to its molecular mechanism of action.
Pharmacokinetics
Describe the route of administration and the relevant pharmacokinetic features of each drug in each
drug class.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class.
Describe the principal contraindications of the drugs of each class.
Therapeutic uses
Outline the main therapeutic uses of the drugs of each class.
Clinical Pharmacology
These drugs are almost always used in combinations. Emphasize the increased risk of activation of
latent infection and increased susceptibility to tuberculosis. Some of these drugs suspected to
increase the risk of cancer.
Relevance
USMLE topic
Immune System
Principles of therapeutics
Mechanisms of action and use of drugs that
specifically affect immune functionimmunomodulating drugs
AAMC Medical School Objectives Project
Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions and
disease
Notes
Objectives for Corticosteroids are covered under Adrenal Cortex.
Analgesic, Antipyretic, Antiinflammatory
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Nonsteroidal Antiinflammatory Drugs (NSAIDS)
Salicylic acid
Nonselective
Selective
derivatives
COX inhibitors
COX-2 inhibitors
ACETYLSALICYLIC ACID
IBUPROFEN
CELECOXIB
mesalamine sodium
INDOMETHACIN - NO
salicylate
LONGER A FIRST CHOICE
NSAID DUE TO ITS GI TOXICITY
NAPROXEN
diclofenac
ketorolac
piroxicam sulindac
Analgesic, Antipyretic Drugs
Antidote for acetaminophen
ACETAMINOPHEN
acetylcysteine
Physiology and Pathophysiology of pain, inflammation & hyperthermia
Outline the physiological basis of temperature control and peripheral sensory pain fibers.
Describe the role of eicosanoids and bradykinin in causing local pain, edema and fever.
Outline the pathophysiology of acute and chronic inflammation.
Mechanisms of action
Explain the molecular mechanism of action of each drug in each drug class.
Differentiate the mechanisms of action of acetylsalicylic acid, acetaminophen, and
NSAIDS.
Actions on organ systems
Differentiate the effects on pain, fever, and inflammation of the drugs in each class.
Pharmacokinetics
Describe the metabolism of and mechanism of toxicity of acetaminophen. - Why? This
Is not an NSAID and is not included in the list above. No acceptable evidence for
clinically Important anti-inflammatory activity - can be used together with an NSAID to
treat acute pain before turning to opioids - See above for migraine headache therapy
strategies.
Describe the factors that affect the renal elimination of acetylsalicylic acid. Emphasize
the dose-dependent disposition within the therapeutic dose range and the ability to
dose less than QID if administered as a 900 mg dose.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs of each class.
Describe consequences of protein binding, zero order metabolism, and irreversible
inhibition related to acetylsalicylic acid.
Describe the clinically important drug interactions of the drugs of each class.
Describe the principal contraindications of the drugs of each class.
Therapeutic uses
Differentiate the use of these drugs in treatment of pain, fever, and inflammation.
Describe the principles of treatment for acetaminophen toxicity.
Describe the principles of treatment for salicylate toxicity.
Clinical Pharmacology
Never use two NSAIDs concurrently. Naproxen is indicated in patients resistant to
other propionic acid congeners because it is the only congener that is present in the
pure active isomer. Resistance may include a component of inability to convert the
inactive isomer to its active form, since this metabolic pathway is highly variable
among patients.
Sulindac should be included, since it is the only member of this class where
inactivation of the active sulfide metabolite occurs in the kidney of the majority of
patients, and may allow use of an NSAID in a patient with impaired renal function.
Selective COX-2 inhibitor drugs have a slower onset of analgesia and should not be
used for management of acute pain. Remember that COX-2 is the primary
isoenzyme in the kidney and the brain. One should emphasize the danger when two
highly-bound drugs are used together – e.g. most NSAIDs and sulfonylureas.
Important also is the risk of bleeds with warfarin + an NSAID due to different
mechanisms of anticoagulant effect.
Relevance
USMLE topic
Principles of therapeutics
Musculoskeletal System
Mechanisms of action and use of drugs
for treatment of disorders of the
musculoskeletal system-non-steroidal
anti-inflammatory drugs and
analgesics
AAMC Medical School Objectives
Topic D
Project Report X Patient Safety-Table I
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
Notes:
Objectives for glucocorticoids are covered under Adrenal Cortex.
Objectives for opiates are covered under CNS.
15
COX Inhibitors
ASPIRIN
IBUPROFEN
NAPROXEN
celecoxib
Antirheumatic Drugs
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
DMARDS (Disease Modifying Antirheumatic Drugs)
Biologics
Traditional
ANAKINRA
METHOTREXATE
ETANERCEPT
hydroxychloroquine
INFLIXIMAB
leflunomide
abatacept
sulfasalazine
adalimumab
rituximab
Learning Objectives
Mechanism of action
Explain the molecular mechanism of action common to all nonsteroidal
antiinflammatory drugs (NSAIDs).
Describe the likely mechanisms of antirheumatic action of the DMARDS.
Pharmacokinetics
List the routes of administration of drugs in each class.
Recognize the time required before the onset of action of the DMARDS.
Adverse effects, drug interactions and contraindications
Describe the main adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class.
Describe the principal contraindications or precautions of the drugs of each class.
Therapeutic uses
Outline the use of the NSAIDS and DMARDS in arthritic disorders.
Clinical Pharmacology
Relevance
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
musculoskeletal system- antigout
therapy and immunosuppressive
drugs
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
USMLE topic
Musculoskeletal System
Notes
Objectives for COX inhibitors are covered under Analgesic, Antipyretic,
Antiinflammatory Drugs.
Rasburicase is used in pediatric patients receiving cancer chemotherapy.
16
Gout
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
Drugs for the gouty attack
Decrease urate formation
Increase urate excretion
INDOMETHACIN
ALLOPURINOL
PROBENECID
Colchicine
Febuxostat
Sulfapyryrazone
Rasburicase
Learning Objectives
Physiology and Pathophysiology
Describe the causes and pathophysiology of acute gouty arthritis and chronic
tophaceous gout.
Mechanisms of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the pharmacological effects of each drug in each class.
Differentiate the effects of the drugs in the treatment of gout.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class
Describe the principal contraindications of the drugs of each class.
List the drugs that interfere with the renal excretion of uric acid.
Describe the mechanism of gouty flare-up associated with the treatment of chronic
tophaceous gout.
Therapeutic uses
Differentiate the use of these drugs in the treatment of acute gout attacks and as
prophylactic therapies.
Clinical Pharmacology
Probably Indomethacin is no longer the preferred NSAID due to its GI toxicity. Almost
all NSAIDs will manage the acute symptoms of gout. Importance of colchicine is
noted as an alternate drug therapy for chromic gout in patients allergic to allopurinol.
In the elderly, probenecid is probably no longer indicated due to decreased renal
function.
Relevance
USMLE topic
Principles of therapeutics
Musculoskeletal System
Mechanisms of action and use of drugs
for treatment of disorders of the
musculoskeletal system- antigout
therapy and immunosuppressive
drugs
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
17
Notes
18
Drugs for specific clinical entities
Drugs for headaches
Drug Classes and Drugs to consider
Acute or Abortive Treatment
Prophylaxis
Ergot
Analgesics
Triptans
β-Blockers
Antiepileptics Others
alkaloids
acetaminophen
sumatriptan ergotamine propranolol valproate
amitriptyline
aspirin
verapamil
ibuprofen
(NSAIDS)
(N-acetylcysteine)
Therapeutic uses
Outline the use of these drugs in the acute and prophylactic treatment of headaches
including migraine, tension and cluster headaches.
Outline the management of treatment of overdose to acetaminophen.
Drugs Used for Treating Alopecia
Drug Classes and Drugs to consider
Alopecia Areata
Androgenetic Alopecia
cyclosporine
finasteride
glucocorticoids
minoxidil
Therapeutic uses
Outline the use of these drugs in the treatment of alopecia areata and androgenic
alopecia.
Drugs Used for Treating HPV & Molluscum, Actinic Keratoses,
BCC and SCC, and Psoriasis
Drug Classes and Drugs to consider
Psoriasis
HPV & Molluscum, Actinic
Keratoses, BCC and SCC
Topical
Systemic
5-fluorouracil
calcipotriene
acitretin
imiquimod
glucocorticoids
adalimumab
podofilox
tazarotene
alefacept
cyclosporine
etanercept
infliximab
methotrexate
Therapeutic uses
Outline the use of these drugs in the treatment of HPV & molluscum, actinic keratoses,
BCC and SCC, and psoriasis.
Drugs Used for Treating Inflammatory Bowel Disease
Drug Classes and Drugs to consider
Drugs altering
Mesalamine-based
ImmunoSteroids
Biologicals balance of enteric
therapy
suppressives
bacteria
19
balsalazide
mesalamine
olsalazine
sulfasalazine
budesonide
azathioprine
infliximab
ciprofloxacin
hydrocortisone mercaptopurine natalizumab metronidazole
prednisone
methotrexate
lactobacillus spp.
saccharomyces
boulardii
Therapeutic uses
Outline the use of these drugs in treating ulcerative colitis and Crohn’s disease.
Drugs used for Nausea and Vomiting
Drug Classes and Drugs to consider
Substance P/NK1
Corticosteroids
Others
5-HT Antagonists
Antagonist
granisetron
aprepitant
dexamethasone
metoclopramide
ondansetron
nabilone
olanzapine
prochlorperazine
scopolamine
Therapeutic uses
Outline the use of these drugs in treating nausea and vomiting associated with
chemotherapy, radiation, and postoperative.
Drugs used for treating Peptic Ulcer Disease and GERD
Drug Classes and Drugs to consider
Inhibitors of Acid Secretion
Drugs for
Mucosal
Antacids
eradicating H.
H2RAs
PPIs
Protectants
pylori
cimetidine
omeprazole
bismuth salts
amoxicillin
CaCO3
famotidine
misoprostol
bismuth
Al(OH)3
nizatidine
sucralfate
clarithromycin
Mg(OH)2
ranitidine
metronidazole
NaHCO3
tetracycline
inhibitors of acid
secretion
Therapeutic uses
Differentiate between the use of these drugs in peptic ulcer disease and GERD.
Drug Treatment for Erectile Dysfunction
Drug Classes and Drugs to consider
PDE5 Inhibitors
sildenafil
tadalafil
vardenafil
Prostaglandin
Analog
alprostadil
Testosterone
Replacement
methyltestosterone
testosterone topical
testosterone enanthate
Therapeutic uses
Outline the use of these drugs in treating erectile dysfunction.
Drugs for Allergic Reactions
20
Others
papaverine
phentolamine
Drug Classes and Drugs to consider
Glucocorticoids
fluticasone
prednisone
Decongestants
Anticholinergics Anaphylaxis
phenylephrine
ipratropium
pseudoephedrine
epinephrine
Autacoid
Antagonists
antihistamines
modulators of
histamine
release
lt receptor
antagonists
Therapeutic uses
Outline the use of the drugs in each class in treating allergic disorders.
Pharmacology of Tocolytics, Antenatal Drugs and Abortives
Drug Classes and Drugs to consider
Tocolytics
Antenatal/Neonatal
Abortives
++
Therapy
Ca Blockers
β-Agonists COX inhibitors
magnesium sulfate terbutaline indomethacin
methotrexate betamethasone
nifedipine
mifepristone
indomethacin
misoprostol
Therapeutic uses
Outline the clinical uses of the drugs used in preventing preterm labor and in abortion.
Outline the uses of betamethasone and indomethacin in antenatal and neonatal therapy,
respectively.
Clinical Pharmacology
Evidence for efficacy of tocolytics in humans is less than Impressive.
ACE inhibitors also contraindicated In pregnancy.
21
Cardiovascular and Respiratory Pharmacology
Subcommittee:
Taylor, David, Chair, [email protected]
Caldwell, R. William [email protected]
Karpa, Kelly [email protected]
Kass, Robert S. [email protected]
Kerecsen, Laszlo [email protected]
Marcus, Philip
In memoriam
We dedicate this edition of the Cardiovascular and Respiratory Pharmacology section of
the Knowledge Objectives to Dr. Philip Marcus who died unexpectedly on April 9, 2012.
Dr. Marcus made valuable contributions to several editions of the Knowledge Objectives
and his valuable input will be missed.
CARDIOVASCULAR AND RESPIRATORY PHARMACOLOGY
Recommended Total Curriculum Equivalent: 15 hrs.
Learning Objectives for Introduction to Cardiovascular Drugs
Physiology and Pathophysiology: Review of Cardiovascular Physiology (2 hrs
equivalent)
Review the properties of the heart including contractility (e.g. excitation-contraction
coupling) and electrical activity (e.g. the action potential, automaticity, excitability,
refractory period, conduction and the relationship to the electrocardiogram).
Review the concepts of inotropism, chronotropism, dromotropism and lusitropism
as they pertain to mechanism of action of commonly used drugs. Discuss the
mechanisms by which the autonomic nervous system regulates heart rate and
contractility.
Review the neuroendocrine properties of the heart (both response and output).
Discuss mechanisms of myocardial growth, hypertrophy and signal transduction.
Review the intrinsic and extrinsic regulation of the cardiovascular system.
Describe cardiac and vascular smooth muscle cellular pathobiology including
mechanisms of apoptosis and responses to hypoxia, reperfusion, ischemia and
mechanical and oxidative stress.
Antiarrhythmic Agents
Recommended Curriculum Equivalent: 3.0 hr
Drug Classes and Drugs to Consider (Major or Prototype Drugs Capitalized)
CLASS I
CLASS II
β-ADRENOCEPTOR
Class IA
Class IB
Class IC
ANTAGONISTS
QUINIDINE
LIDOCAINE
flecainide
ESMOLOL
PROCAINAMIDE mexiletine
propafenone
METOPROLOL
disopyramide
PROPRANOLOL
atenolol
CLASS III
CLASS IV
Others
Prolongation of Action
Calcium Channel Blockers
Potential Duration
AMIODARONE
DILTIAZEM
ADENOSINE
dronedarone
VERAPAMIL
atropine
sotalol
digoxin
dofetilide
ibutilide
Learning Objectives for Management of Cardiac Arrhythmias
Physiology and pathophysiology: Introduction to Cardiac Electrophysiology
and Pathophysiology
Describe the ionic basis of the cardiac action potential.
Discuss the role of specific ions and ionic conductances in the production and
propagation of the cardiac action potential with emphasis on fast (sodium
dependent) and slow (calcium dependent) responses and their relevance to
specific cardiac tissue types.
Review the electrophysiological differences between normal atrial and ventricular
cardiac muscle cells and between specialized and normal cardiac cells.
Describe how cardiac electrical activity is altered in the production of cardiac
arrhythmias.
Discuss the relationship between cellular cardiac electrical activity and the
electrocardiogram.
Describe the pathophysiologic mechanisms of cardiac arrhythmias (abnormal
automaticity, triggered rhythms, reentrant rhythms and abnormal impulse
conduction).
Discuss the pharmacogenomics of long QT syndrome and the relationship of genetics
to drug selection.
Describe the two forms of this disorder (i.e. drug-induced [or acquired LQT] and
congenital) and which ion channels are responsible for each.
Mechanism of action
Classify antiarrhythmic drugs according to the Vaughn-Williams classification into
classes I, II, III and IV including miscellaneous agents not otherwise classified,
though recognizing the limitations of this classification system.
Explain the molecular mechanism of action of each drug in each drug class.
Describe the electrophysiologic actions of antiarrhythmic drugs in normal and
abnormal myocardial and conduction tissue, and their effect on the phases of the
cardiac action potential.
Describe the alteration of slow (calcium-dependent) and fast (sodium-dependent)
responses by antiarrhythmic drugs and how that relates to the use of specific
agents in arrhythmias of different origins (ventricular vs. supraventricular).
Describe the indirect autonomic actions of these drugs.
Describe the effect of age on fast and slow channels and on the agents affecting these
channels.
Actions on organ systems
Describe the relevant extracardiac actions of antiarrhythmic drugs with special
reference to the actions of amiodarone.
Describe the indirect autonomic actions of these drugs.
Pharmacokinetics
Describe the routes of administration, biotransformation and excretion of selected
antiarrhythmic drugs.
Describe the pharmacokinetics and time-course of the cardiac actions of
antiarrhythmic drugs (onset and duration of action).
Discuss the impact of reduced cardiac output due to myocardial infarction and
cardiomyopathy on pharmacokinetics (including half-life) and pharmacodynamics.
Describe the influence of age on pharmacokinetic parameters, i.e., liver metabolism
(lidocaine, procainamide, and propranolol) and elimination through kidney (digoxin
and sotalol).
Describe the pharmacogenetic confounding effect of NAT2 pharmacogenetics on the
choice of procainamide as an antiarrhythmic drug, especially in patients with renal
impairment.
Adverse effects, drug interactions and contraindications
Describe the cardiac and extracardiac manifestations of toxicity from antiarrhythmic
drugs.
Describe the beneficial and adverse interactions among antiarrhythmic drugs and
between antiarrhythmic drugs and digoxin.
Describe the significance of electrolyte and acid-base imbalance in arrhythmia
generation and their influence on antiarrhythmic drug action.
Describe the possible contraindications of antiarrhythmic drugs in the presence of
heart block or congestive heart failure, and the precautions and contraindications
in other conditions.
Know the classes of drugs (both antiarrhythmic and non antiarrhythmic) that can
produce acquired Long QT Syndrome (LQTS).
Therapeutic uses
Describe the use of antiarrhythmic drugs in supraventricular arrhythmias (atrial flutter,
atrial fibrillation, paroxysmal atrial tachycardia, junctional arrhythmias).
Describe the use of antiarrhythmic drugs in ventricular arrhythmias (ventricular
premature beats, ventricular tachycardia, and ventricular fibrillation).
Discuss the utility of antiarrhythmic drugs in combination with electrical cardioversion
or implantable cardioverter-defibrillators and ablation procedures.
Recognize that the therapeutic management of congenital Long QT Syndrome
depends on the genotype, despite a uniform phenotype.
Notes
Objectives for Calcium-Channel Blockers are covered under Management of
Hypertension.
Objectives for β-Adrenoceptor Antagonist Agents are covered under Autonomic
Nervous System.
Clinical Pharmacology
The CAST study has changed our understanding of the risk of using sodium channel
blockers post myocardial infarction in the management of cardiac arrhythmias.
The use of antiarrhythmic drugs is being impacted considerably by data arising
from studies of the pharmacogenomics of inherited channelopathies of ion
transporters. As well as the long QT syndrome, there is now an appreciation of the
existence of a short QT syndrome that is associated with atrial fibrillation and
sudden death. Both phenotypes predispose an affected individual to cardiac
arrhythmias, and can be induced by drug therapy for other disease states.
Quinidine has provided benefit in lengthening the QT interval in the short QT
syndrome. Disopyramide may also be effective in this pathological state.
Currently, beta-adrenoreceptor blocking drugs are perceived to be the treatment of
choice for long QT syndrome.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System-Abnormal
Antiarrhythmic Drugs
Processes- Metabolic and Regulatory
Disorders (dysarrhythmias, ischemic
heart disease, myocardial infarction)
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C: Drug treatment of common
conditions
Management of Acute and Chronic Heart Failure
Recommended Curriculum Equivalent: 2.0 hr
Drug Classes and Drugs to Consider (Major or Prototype Drugs Capitalized)
Renin-Angiotensin Aldosterone System
Other Peptide Systems
Angiotensin
Aldosterone
ACE Inhibitors
ANP Agents
Receptor Blockers
Antagonists
CAPTOPRIL
LOSARTAN
SPIRONOLACTONE nesiritide
ENALAPRIL
valsartan
EPLERENONE
LISINOPRIL
candesartan
C. Sympathetic Agents
D. PDE Inhibitors
E. Vasodilators
Antagonists
Agonists
CARVEDILOL
DOBUTAMINE
inamrinone
HYDRALAZINE
METOPROLOL
dopamine
milrinone
ISOSORBIDE DINITRATE
bisoprolol
NITROGLYCERIN
Combination of hydralazine
and isosorbide dinitrate
(BiDil) used in African
Americans
nitroprusside
F. Diuretics
G. Cardiac Glycosides
FUROSEMIDE
DIGOXIN
Thiazides
Principles and Learning Objectives for Management of Heart Failure
Physiology and pathophysiology: Introduction to cardiac inotropism
Describe the acute inotropic, dromotropic, and chronotropic effects of catecholamines (e.g.
epinephrine, norepinephrine, dopamine, isoproterenol).
Discuss the lusitropic actions of the catecholamines as they relate to normal and abnormal
cardiac function.
Compare and contrast the management of acute and chronic heart failure.
Discuss preventing cardiac remodeling at the onset of heart failure.
Describe the basic pathophysiology of heart failure and the cardiac and extracardiac
compensatory mechanisms that are activated.
Discuss the role of genetics and ethnicity in the pathophysiology of heart failure and in the
regulation of responsiveness to agents used in heart failure.
Mechanism of action
Describe the effects of digoxin on myocardial contractility.
Explain the ionic basis for the mechanism of action of digoxin: discuss the roles of Na+, K+ATPase inhibition and the Na+/Ca2+ exchanger.
Describe the electrophysiologic effects of digoxin on atrial and ventricular muscle and
specialized conducting tissue.
Explain the significance of direct and indirect (autonomic) actions of digoxin.
Describe the positive inotropic effects of the β-adrenoceptor-agonists and phosphodiesterase
inhibitors.
Explain the effects of adrenoceptor antagonists and ACE-inhibitors on cardiac function and
ventricular remodeling in the setting of heart failure.
Actions on organ systems
Describe the hemodynamic actions of digoxin in the failing and the normal heart.
Describe the extracardiac actions of digoxin.
Explain the effects of vasodilators, loop diuretics and β-blockers on preload and afterload.
Explain the effects of vasodilators on renal and coronary perfusion.
Describe the extracardiac actions of the adrenoceptor agonists, adrenoceptor antagonists,
phosphodiesterase inhibitors and ACE-inhibitors.
Pharmacokinetics
Describe the routes of administration, the extent of oral absorption and bioavailability, the
routes of elimination and extent of biotransformation of digoxin and other drugs used in
heart failure.
Contrast the pharmacokinetics of digoxin in young and old patients.
Describe the time-course of the cardiac actions of digoxin (onset and duration of action).
Explain the concept of digitalization (loading dose) and maintenance therapy.
Review the "plateau principle" with regard to maintenance therapy without a loading dose.
Adverse effects, drug interactions and contraindications
Describe the cardiac (delayed depolarizations and arrhythmias) and extracardiac
manifestations of digoxin toxicity (digoxin levels > 2.0 ng/mL are associated with toxicity).
Discuss the potential for low levels (0.4-0.8 ng/mL) to reduce mortality in acute decompensated
heart failure.
Describe the significance of changes in serum electrolyte levels (potassium, sodium, calcium,
magnesium) with regard to digoxin toxicity.
Discuss the potential adverse effects with concomitant use of diuretics (both potassium-sparing
and potassium depleting) in the elderly or in patients with congestive heart failure,
hypothyroidism and renal disease.
Describe the interactions of digoxin and quinidine, verapamil, and other relevant drugs.
Describe the cardiac and extracardiac side effects and limitations of the antagonist agents,
vasodilators, phosphodiesterase inhibitors, and ACE-inhibitors.
Therapeutic uses
Describe the use of digoxin in congestive heart failure and in atrial arrhythmias.
Describe the role of adrenoceptor agonists, adrenoceptor antagonists, vasodilators, diuretics
and ACE-inhibitors in the treatment of acute and chronic heart failure.
Discuss the use of atrial natriuretic peptide agonists in the management of acute severe heart
failure unresponsive to other agents.
Notes
Objectives for Renin-angiotensin aldosterone agents are covered under vasoactive peptides.
Objectives for Sympathetic nervous system drugs are covered under Autonomic Nervous
System.
Clinical Pharmacology
The latest Cochrane Review indicates that ACE inhibitors and ARB drugs do not reduce total
morbidity and mortality in patients with heart failure. With the increased likelihood of
impaired renal perfusion in association with heart failure, a loop diuretic (furosemide) is
likely to be a prudent choice to relieve congestion. There is a reasonable consensus that
beta-receptor adrenergic blocking drugs are becoming the pharmacological treatment of
choice for this pathological state.
Relevance
USMLE topic
Cardiovascular System; Renal/Urinary
System- Abnormal Processes- Metabolic
and Regulatory Disorders (Systolic and
diastolic dysfunction, low-and high output
heart failure, systemic hypertension)
AAMC Medical School Objectives Project
Report X Patient Safety-Table 1
Principles of therapeutics
Mechanisms of action, use, adverse effects of
drugs for treatment of disorder of
cardiovascular system-Inotropic agents
and treatment of heart failure
Topic C: Drug treatment of common
conditions
Management of Hypertension
Recommended Curriculum Equivalent: 4.0 hr
Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized)
Renin-Angiotensin Aldosterone System
Endothelin
Antagonists
Angiotensin
Angiotensin
Aldosterone
Renin
Converting
Receptor Blockers
Antagonists
Inhibitor
Enzyme
Inhibitors
ENALAPRIL
LOSARTAN
SPIRONOLACTONE
aliskiren
ambrisentan
CAPTOPRIL
VALSARTAN
eplerenone
bosentan
LISINOPRIL
candesartan
fosinopril
olmesartan
Sympathetic Antagonist Agents
Alpha
Beta
Mixed α and β
Non-selective
α1 Selective
Nonselective
PRAZOSIN
doxazosin
Diuretics
amiloride
CHLORTHALIDONE
eplerenone
furosemide
Vasodilators
Venous
Arterial
ISOSORBIDE DINITRATE CALCIUM BLOCKERS
nitroglycerin
(DIHYDROPYRIDINES,
DILTIAZEM, VERAPAMIL)
HYDRALAZINE
diazoxide
minoxidil
HYDROCHLOROTHIAZIDE
spironolactone
triamterene
Centrally Acting
Agents
CLONIDINE
methyldopa
PROPRANOLOL
nadolol
pindolol
timolol
β1 Selective
phenoxybenzamine
phentolamine
METOPROLOL
atenolol
nebivolol
Pulmonary Hypertension
Endothelin
PDE 5
Prostaglandins
Antagonists Inhibitors
(Prostacyclin)
ambrisentan sildenafil
epoprostenol
bosentan
tadalafil
iloprost
treprostinil
CARVEDILOL
LABETALOL
Both
NITROPRUSSIDE
ANGIOTENSIN
CONVERTING
ENZYME
INHIBITORS
ANGIOTENSIN
RECEPTOR
BLOCKERS
alpha blockers
Combination of
hydralazine and
isosorbide dinitrate
(BiDil)
Hypertensive Emergency
and Urgency
NITROPRUSSIDE
clevidipine
esmolol
fenoldopam
nicardipine
trimethaphan (Historical)
Principles and Learning Objectives for Management of Hypertension
Introduction to the Vascular System and its Regulation
Review the determinants of systemic arterial blood pressure including the role of the autonomic
nervous system, the regulation of fluid volume and the renin-angiotensin aldosterone system.
Describe the role of the central nervous system in the regulation of blood pressure.
Discuss the role of vascular endothelium and locally released regulators of vascular tone in the
maintenance of blood pressure.
List the types of hypertension and the relative prevalence of each.
Describe the current views for the etiology of essential hypertension.
Mechanism of action
Discuss the mechanism of action of each of the several classes of agents used to manage
hypertension according to the site of action within the pathogenesis of hypertension.
Describe the mechanism by which each antihypertensive drug or drug class exerts its therapeutic
function.
Actions on organ systems
Review the end organ effects of untreated hypertension and the beneficial effects achieved by
therapeutic management of the disease.
Describe the actions of antihypertensive drugs on the heart, renal blood flow and renal function.
Describe the relevant actions of antihypertensive drugs in other organ systems (CNS, other).
Pharmacokinetics
Describe the time-course of their antihypertensive activity (onset and duration of action) for each class
of agents.
Adverse effects, drug interactions and contraindications
Describe the cardiac and extracardiac side effects of antihypertensive drugs, including reflex effects.
Describe the beneficial and adverse interactions between antihypertensive drugs and between
antihypertensive drugs and other therapeutic agents.
Therapeutic uses
Discuss the role of non-pharmacological treatment modalities in the management of hypertension.
Describe the use of antihypertensive drugs in mild, moderate and severe essential hypertension.
Describe the use of antihypertensive drugs in hypertensive emergencies and in pregnancy (e.g.
eclampsia).
Describe the use of antihypertensive drugs in pheochromocytoma.
Discuss the pathophysiology of pulmonary hypertension and describe the use of prostacyclin agonists,
phosphodiesterase 5 inhibitors and endothelin receptor antagonists in the management of this form
of hypertension.
Discuss population subgroups with special antihypertensive drug considerations (e.g. AfricanAmericans, diabetics, isolated systolic hypertension esp. in elderly patients, renal failure patients).
Notes
Objectives for Renin-angiotensin aldosterone agents are covered under vasoactive peptides
Objectives for Sympathetic nervous system drugs are covered under Autonomic Nervous System
Clinical Pharmacology
ACE inhibitors are becoming a first line drug choice, especially in patients with diabetes. Usually a low
dose of diuretic is added to inhibit the upregulation of aldosterone when ACE inhbitiors are used
alone. In diabetic patients, a target diastolic blood pressure of 80 mm Hg is chosen rather that the
conventional target of 90 mm Hg. ARB’s are a consideration when cough occurs in patients
prescribed ACE inhibitor drugs. There is no evidence for improved efficacy of using ACE inhibitors
and ARB drugs concurrently. No beta-adrenergic receptor blocking drug is sufficiently selective to
prevent bronchoconstriction in patients with a history of reversible airways constriction. When
cardiac perfusion is a concurrent pathological issue, beta-adrenoreceptor blockers and long-acting
calcium channel blocking drugs are reasonable choices for the management of hypertension.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System-Abnormal ProcessesMechanisms of action, use, adverse effects of
Metabolic and Regulatory Disorders (Systemic
drugs for treatment of disorder of
hypertension)
cardiovascular system-Antihypertensive drugs
AAMC Medical School Objectives
Topic C: Drug treatment of common conditions
Project Report X Patient Safety-Table 1
Drugs for the Treatment of Angina and Coronary Artery Disease
Recommended Curriculum Equivalent: 1.0 hr
Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized)
Beta
Calcium
Metabolic
Adrenoceptor
Channel
Organic Nitrates
Modulators
Antagonists
Blockers
ATENOLOL
AMLODIPINE
ISOSORBIDE MONONITRATE ranolazine
METOPROLOL
NICARDIPINE
NITROGLYCERIN
PROPRANOLOL NIFEDIPINE
isosorbide dinitrate
diltiazem
verapamil
Principles and Learning Objectives for Management of Angina and Coronary Artery
Disease
Introduction to Coronary Blood Flow and its Regulation
Describe the normal regulation of coronary blood flow and the relationship to the events of the
cardiac cycle
Describe the normal determinants of cardiac oxygen consumption and supply.
Describe the basic pathophysiology of myocardial ischemia.
Explain the significance of atherosclerotic coronary artery disease and coronary artery spasm
(Prinzmetal's) in the production of myocardial ischemia and angina pectoris.
Mechanism of action
Describe the hemodynamic actions of antianginal drugs, including their coronary and
peripheral vasodilator actions.
Describe the effects of each antianginal drug or drug class on the determinants of myocardial
oxygen consumption (heart rate, myocardial wall tension, etc.) and/or oxygen supply
(coronary blood flow).
Describe the effects of the antianginal drugs at the cellular level.
Actions on organ systems
Describe the cardiac actions of antianginal drugs (electrophysiologic, coronary vasodilator,
inotropic actions).
Describe the actions of antianginal drugs on the peripheral circulation (arterial, venous) and
their effects on ventricular preload and afterload.
Pharmacokinetics
Describe the routes of administration, biotransformation and excretion of antianginal drugs.
Describe the significance of a "first-pass effect" for orally administered antianginal drugs and
the rationale underlying sublingual and transdermal administration of nitrates.
Describe the time-course of antianginal activity (onset and duration of action).
Describe the problem of dose intervals and tolerance development with the nitrates.
Adverse effects, drug interactions and contraindications
Describe the cardiac and extra-cardiac side effects of antianginal drugs with special reference
to the interaction with drugs used to treat erectile dysfunction (PDE 5 inhibitors).
Describe the beneficial and adverse interactions between antianginal drugs and between
antianginal drugs and other cardiovascular drugs.
Therapeutic uses
Describe the use of antianginal drugs in classic (effort-related) angina pectoris and
vasospastic angina pectoris.
Describe the concept of "myocardial preservation" and discuss the use of antianginal drugs in
the context of acute myocardial infarction with particular emphasis on adrenoceptor
antagonists.
Notes
Objectives for Sympathetic nervous system drugs are covered under Autonomic Nervous
System.
Clinical Pharmacology
Nitroglycerin remains the initial treatment of choice for acute anginal attacks. Patients must
be reminded that exposure to moisture will destroy a sublingual tablet formulation and
potentially be misinterpreted as worsening of the disease. For chronic angina, long-acting
nitrates are a reasonable next step, but tolerance is a problem when the drug is used at
evenly spaced time intervals over 24 hours. For chronic stable angina, beta-adrenergic
receptor blocking drugs remain a reasonable choice with calcium channel blocking drugs
as a secondary choice. Calcium channel-blocking drugs are preferred for vasospasminduced angina, but the long-acting formulations are indicated as an appropriate
treatment.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System- Abnormal
Mechanisms of action, use, adverse effects of
Processes- Metabolic and Regulatory
drugs for treatment of disorder of
Disorders (Ischemic heart disease,
cardiovascular system-coronary and
Myocardial infarction)
peripheral vasodilators, drugs to treat
peripheral arterial diseases
AAMC Medical School Objectives
Topic C: Drug treatment of common conditions
Project Report X Patient Safety-Table 1
Drugs for the Treatment of Hyperlipidemias
Recommended Curriculum Equivalent: 1.0 hr
Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized)
BILE ACID
FIBRIC ACID
HMG CoA REDUCTASE
OTHERS
SEQUESTRANTS
DERIVATIVES
INHIBITORS
CHOLESTYRAMINE GEMFIBROZIL
ATORVASTATIN
EZETIMIBE
colesevelam
fenofibrate
FLUVASTATIN
nicotinic acid
colestipol
LOVASTATIN
omega-3 fatty acids
PRAVASTATIN
ROSUVASTATIN
SIMVASTATIN
Principles and Learning Objectives for the Management of Hyperlipidemias
Physiology and Pathophysiology: Lipid Interactions with the Cardiovascular System
Discuss cholesterol synthesis, transport, export, excretion, and receptor mediated cellular
uptake.
Review “normal” values for lipid levels.
Discuss the relevant hypotheses regarding the etiology of hyperlipidemias (e.g. intrinsic versus
extrinsic elevations in plasma lipids).
Describe the basic pathophysiology of atherosclerotic vascular disease and its relationship to
the hyperlipidemias (“cholesterol” or “infectious agent”).
Describe the types of hyperlipidemias (I, II, III, IV, and V) and the alterations in serum lipids in
each type (triglycerides, cholesterol, LDL, HDL, LDL, lipoproteins).
Discuss the lipid profile characteristic of insulin-resistant diabetics.
Discuss genetic conditions leading to hyperlipidemia.
Describe the concept of “plaque stability”.
Mechanisms of action
Describe the actions of each drug class on serum lipids, and compare and contrast the
mechanism of each of these actions.
Characterize these agents according to their action to reduce lipid synthesis or enhance
removal.
Discuss the advantages of combinations of agents in the management of hyperlipidemia.
Identify the putative role of antioxidants in the management of hyperlipidemia.
Actions on organ systems
Describe the relevant actions of these drugs, other than on lipid metabolism (e.g. pleiotropic
effects).
Discuss drug-induced alterations in plasma lipids (e.g. protease inhibitor-induced
hyperlipidemia; estrogen-induced hypolipidemia).
Review the role of thyroid hormone in affecting serum lipids and the findings in hyper- and
hypothyroidism.
Discuss the role of the HMG CoA reductase inhibitors in preventing acute coronary events and
stroke and as possible adjuncts in the management of dementia and other pathological
disorders. Consider the potential anti-inflammatory effects of “statins” on other disease
states.
Pharmacokinetics
Describe the absorption, distribution, metabolism and excretion of drugs used for
hyperlipidemias.
Compare and contrast the pharmacokinetics of nicotinic acid (niacin) and fibric acids.
Adverse effects, drug interactions and contraindications
Describe the cardiovascular and other systemic side effects of these drugs with special
reference to the muscle and liver toxicities.
Describe the beneficial and adverse interactions between these drugs, and their interactions
with digoxin, oral anticoagulants, and other relevant drugs.
Therapeutic uses:
Describe the non-pharmacological management of hyperlipidemia (i.e. life style modifications
and natural remedies that may benefit patients).
Describe the use of these agents in familial and acquired hyperlipidemias, and their efficacy in
atherosclerotic vascular disease.
Discuss important multicenter clinical trial data documenting efficacy in multiple patient groups.
Discuss new National Cholesterol Education Program (NCEP) guidelines for lowering LDL.
Discuss the apparent lack of a threshold effect (lower is always better, even in the normal range
of LDL).
Notes
Objectives for nicotinic acid (niacin) are also found under Vitamins.
Clinical Pharmacology
The statin class of drugs has become the de facto primary choice for treatment of
hyperlipidemias. Choice of agent is often based on potential drug interactions, since their
bioavailability is very low. Accumulation may be problematic with inhibition of first-pass
elimination mechanisms. It is still controversial as to whether or not use of this drug class in
elderly patients has an acceptable risk:benefit ratio.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System-Abnormal ProcessesDrug affecting cholesterol and lipid
Metabolic and Regulatory Disorders &
metabolism
Vascular Disorders
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions and
diseases
Thrombolytic and Anticoagulant Agents in the Management of ST-Elevation Myocardial
Infarction (STEMI)/Myocardial Infarction/Acute Coronary Syndrome and Chronic Treatment of
Cardiovascular Diseases including Atrial Fibrillation
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized)
ANTIPLATELET AGENTS
ADP Receptor Antagonists
Glycoprotein IIb/IIIA Receptor
Others
Antagonists
CLOPIDOGREL
ABCIXIMAB
ASPIRIN
PRASUGREL
Eptifibatide
Dipyridamole
Ticlopidine
Tirofiban
Cilostazol
Ticagrelor
ANTICOAGULANTS
Heparins
Oral Anticoagulants
Thrombin Inhibitors
Factor Xa Inhibitors
HEPARIN
ENOXAPARIN
dalteparin
tinzaparin
WARFARIN
DABIGATRAN (oral)
argatroban
bivalirudin
lepirudin
desirudin
fondaparinux
rivaroxaban (oral)
FIBRINOLYTICS
ALTEPLASE
UROKINASE
Anistreplase
Reteplase
Streptokinase (Historical)
Tenecteplase
Mechanisms of action
Understand the mechanisms involved in coagulation.
Describe the mechanisms of platelet activation and aggregation
Know the mechanism of action of antiplatelet agents, their major routes of administration and
elimination and adverse effects.
Know the mechanism of action of anticoagulant agents.
Understand the differences in the mechanisms and actions of heparin, warfarin and thrombin and
factor Xa inhibitors, respectively.
Describe the use of thrombolytic agents as first-line in the therapy of acute myocardial infarction and
stroke. Discuss the role of acute catheter-mediated intervention as an alternative or
complementary strategy.
Consider the spectrum of agents available for cardioprotection and plaque stabilization in the setting
of acute coronary syndrome.
Actions on organ systems
Discuss the long-term use of antiplatelet agents (e.g. ASPIRIN and clopidogrel) in patients with
claudication associated with chronic occlusive peripheral arterial disease, stroke and following
percutaneous coronary interventions (e.g. angioplasty and stents).
Describe the use of thrombolytic agents as first-line agents in the acute therapy of post-myocardial
infarction and as adjuncts in the nonpharmacological management of coronary artery disease
(e.g. surgical stent implantation with drug-eluting stents).
Consider the proper use of morphine in the pain of MI, the long-term use of aspirin (antiplatelet
activity) as prophylaxis and the use of adrenergic blocking agents for cardiac protection.
Pharmacokinetics
Discuss the appropriate use of parenteral versus oral anticoagulants.
Discuss the route and time of administration of thrombolytic agents.
Adverse effects, drug interactions and contraindications
Discuss the treatment of warfarin overdose and excessive effect of warfarin. Review the role of
Vitamin K in such an event.
Discuss the management of heparin-induced thrombocytopenia (HIT) and the potential for heparininduced thrombocytopenic thrombosis (HITT).
Therapeutic uses
Describe the use of thrombolytic and anticoagulant agents in the acute management of myocardial
infarction.
Discuss the use of anticoagulant agents in the management of DVT and in total hip and knee
replacement surgery.
Discuss the use of antiplatelet drugs, anticoagulant drugs, nitroglycerin, adrenergic blocking agents
and angiotensin converting enzyme inhibitors as adjunctive agents in the management of
myocardial infarctions.
Notes
See Section I Drugs Acting on the Blood and Blood-forming Organs for Objectives on Thrombolytics,
Anticoagulants and Antithrombotic Drugs.
Clinical Pharmacology
Many new agents are rapidly reaching the market to treat STEMI. Therapy with low dose aspirin
plus clopidogrel appears to have reasonable evidence for efficacy. Alternately, low molecular
weight heparin therapy with addition of a glycoprotein IIb/IIIa receptor antagonist is also
considered acceptable. There is increasing evidence that low molecular weight heparins are
more effective and safer than the previously used standard intervention with unfractionated
heparin. Use of combination endpoints to assess safety and efficacy of alternative drug
treatments has clouded the ability to compare alternative strategies. In the management of
atrial fibrillation, warfarin still appears to be the drug treatment of choice, in spite of difficulties
with control of INR. The hope that pharmacogenetic diagnostic tools would resolve this problem
has provided only a modest incremental improvement in the safety and efficacy of using warfarin
as a drug intervention.
Relevance
USMLE topic
Principles of therapeutics
Hematopoietic and Lymphoreticular SystemsDrug affecting blood coagulation, thrombolytic
Abnormal Processes-Hemorrhagic and
agents, and antiplatelet agents
Hemostatic Disorders
Cardiovascular System-Abnormal ProcessesTraumatic and Mechanical Disorders &
Vascular Disorders
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C: Drug treatment of common conditions
Topic D: Management of less common but
severe medical conditions and emergencies
Drugs Used for the Management of Asthma and COPD
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized)
Antiinflammatory Drugs
Leukotriene Modifiers
Inhaled Steroids
Modulators of Mast Cell
Leukotriene
5-LO Inhibitor
Degranulation
Receptor
Antagonists
Mast Cell Stabilizer
Anti-IgE
BUDESONIDE
CROMOLYN
OMALIZUMAB zafirlukast
ZILEUTON
BECLOMETHASONE
MONTELUKAST
FLUTICASONE
MOMETASONE
ciclesonide
Bronchodilators
β2 Agonists
Methylxanthines Muscarinic Receptor Phosphodiesterase 4
Antagonists
Inhibitors
Short-Acting
Long-Acting THEOPHYLLINE
IPRATROPIUM
roflumilast
aminophylline
TIOTROPIUM
ALBUTEROL SALMETEROL
levalbuterol
FORMOTEROL
pirbuterol
INDACATEROL
Principles and Learning Objectives for the Management of Respiratory Diseases
Physiology and Pathophysiology: Introduction to Respiratory Physiology
Describe the endogenous chemical mediators and their receptors that function to regulate bronchial
smooth muscle tone.
Describe the role of cyclic AMP, cyclic GMP, leukotrienes and nitric oxide in regulation of bronchiolar
smooth muscle and pulmonary vasculature.
Describe the role of phosphodiesterases and the various isoenzymes of PDE (i.e. PDE4) in the
function of bronchiolar smooth muscle and in the inflammatory process.
Identify the relationship of bronchial smooth muscle reactivity to the pathogenesis of asthma.
Characterize the role of inflammation in the pathogenesis of asthma and chronic obstructive
pulmonary disease (COPD).
Describe the similarities and differences between asthma and chronic obstructive pulmonary disease
and the treatments of each disorder.
Recognize the allergic basis of asthma and its association with other atopic disorders (e.g. allergic
rhinitis).
Mechanisms of action
Describe the mechanism of action of each of the major classes of agents relative to the component of
pathogenesis to distinguish between agents that modify the disease process versus those that
relieve symptoms.
Describe the putative mechanism of action of theophylline.
Discuss the use of combinations of agents (e.g. fluticasone and salmeterol) in the chronic
management of asthma.
Describe the use of agents to treat acute episodes of asthma and in the treatment of exerciseinduced asthma.
Describe the use of various agents in the treatment of COPD.
Discuss the role of agents in reducing COPD exacerbations and improving outcomes.
Actions on organ systems
Describe the actions of agents used to treat asthma on smooth muscle versus inflammatory
processes.
Describe the relevant actions of these drugs on other physiological systems.
Pharmacokinetics
Identify the factors that influence the plasma levels of theophylline.
Know the appropriate route of administration of the various bronchodilators relative to the physicochemical characteristics and the pharmacological action of the drug.
Discuss the relative merits of inhalant administration versus oral or parenteral administration for the
management of both episodic and chronic asthma as well as COPD.
Identify the potential role of single-isomers in the management of airway diseases (e.g. levalbuterol
and arformoterol).
Adverse effects, drug interactions and contraindications
Discuss the adverse effects and potential contraindications for each class of agents.
Therapeutic uses
Compare and contrast the management of acute and chronic asthma and chronic obstructive
pulmonary disease.
Discuss the management of asthma in special patient populations (e.g. pediatric and pregnant and/or
lactating females).
Discuss the emerging therapies for the management of asthma and chronic obstructive pulmonary
disease (e.g. monoclonal antibodies).
Discuss the non-pharmacologic approaches to the management of asthma and COPD (e.g. smoking
cessation and oxygen).
Discuss recently introduced guidelines for management of asthma (National Heart, Lung and Blood
Institute) and COPD (Global Initiative for Obstructive Lung Disease [GOLD]).
Notes
For additional information and objectives see Management of Asthma and COPD in Autocoids
Section.
Clinical Pharmacology
The availability of inhaled short-acting beta-2 receptor agonists has transformed the management
of mild to moderate asthma. Inhaled corticosteroids have become the cornerstone of
management of inflammation of the bronchioles in patients with chronic disease. An inhaled
steroid with extensive first-pass elimination is preferred to limit the systemic effects of that
portion of the administered dose that is swallowed. The addition of long-acting beta-2 receptor
drug formulations has not solved the issue of management of chronic bronchoconstriction. Due
to down regulation of beta-2 receptors with the long-acting formulations, they should be used
only concurrently with an inhaled steroid in patients with chronic moderate to severe reversible
bronchoconstriction. Theophylline remains an effective and economical oral therapy for persons
with mild to moderate disease, especially in countries where cost limits availability of alternative
drug treatments. The drug management of obstructive lung disease remains controversial.
Outside of North America, a prodrug of terbutaline [bambuterol] offers an alternative and
effective oral therapy for patients with reversible bronchoconstriction who have difficulty in
inhaling their prescribed bronchodilators. Other drugs for management of bronchiolar
obstruction remain for the most part second-line alternative choices.
USMLE topic
Respiratory system
Relevance
Principles of therapeutics
Bronchodilator drugs
AAMC Medical School Objectives
Project Report X Patient Safety – Table 1
Topic C
Drug treatment of common conditions and
diseases
Summary of Classes and Specific Cardiovascular and Respiratory Drugs for
Consideration
Primary Agents to be considered in each class are indicated by CAPITALIZATION.
Drugs only used outside the US are identified by boldface print and brackets.
Important drugs of historical significance are identified as (historical).
1. Adenosine Diphosphate Receptor Antagonists
CLOPIDOGREL
PRASUGREL
ticlopidine
2. Adrenoceptor Agonists
β-Adrenoceptor Agonists
β2-Adrenoceptor Selective Agonists
DOBUTAMINE
ALBUTEROL (salbutamol)
dopamine
bitolterol
EPINEPHRINE
FORMOTEROL
isoproterenol
indacaterol
levalbuterol
pirbuterol
SALMETEROL
terbutaline
[bambuterol]
3. Adrenoceptor Antagonists
Alpha-Adrenoceptor Antagonists
Beta-Adrenoceptor Antagonists
Nonselective
α1-selective
Mixed
Nonselective
β1-selective
phentolamine
doxazosin
CARVEDILOL
nadolol
acebutolol
phenoxybenzamine
PRAZOSIN
LABETALOL
penbutolol
ATENOLOL
terazosin
pindolol
betaxolol
PROPRANOLOL
bisoprolol
sotalol
ESMOLOL
timolol
METOPROLOL
nebivolol
4. Aldosterone Antagonists
SPIRONOLACTONE
eplerenone
5. Direct Renin Inhibitors
aliskiren
6. Angiotensin Converting Enzyme Inhibitors (ACEIs)
BENAZEPRIL
CAPTOPRIL
ENALAPRIL
FOSINOPRIL
LISINOPRIL
QUINAPRIL
RAMIPRIL
enalaprilat
moexipril
perindopril
trandolapril
7. Angiotensin Receptor Antagonists (ARBs)
IRBESARTAN
LOSARTAN
VALSARTAN
azilsartan
candesartan
eprosartan
olmesartan
telmisartan
8. Antiarrhythmic Agents (Miscellaneous Mechanisms)
ADENOSINE
AMIODARONE
DRONEDARONE
LIDOCAINE
PROCAINAMIDE
QUINIDINE
disopyramide
dofetilide
flecainide
ibutilide
mexiletine
propafenone
9. Antiasthmatic Agents (Miscellaneous Mechanisms)
Mast Cell Stabilizers
Anti-IgE Agents
CROMOLYN
omalizumab
Bile Acid Sequestrants
CHOLESTYRAMINE
colestipol
colesevelam
10. Anticholesterolemic Agents
HMG CoA
Fibric Acid
Reductase
Derivatives
Inhibitors
ATORVASTATIN
GEMFIBROZIL
FLUVASTATIN
fenofibrate
LOVASTATIN
PRAVASTATIN
ROSUVASTATIN
SIMVASTATIN
Miscellaneous
Mechanisms
EZETIMIBE
niacin
nicotinic acid
omega-3 ethyl esters
11. Anticholinergic Agents
Nicotinic Receptor Antagonists
Muscarinic Receptor Antagonists
(Ganglionic Blockers)
trimethaphan (historical)
ATROPINE
hexamethonium (historical)
IPRATROPIUM
tiotropium
Oral Anticoagulants
WARFARIN
Miscellaneous
Mechanisms
ASPIRIN
dipyridamole
12. Anticoagulant Agents
Heparins
Thrombin Inhibitors
ENOXAPARIN
argatroban
HEPARIN
bivalirudin
dalteparin
DABIGATRAN (oral)
tinzaparin
LEPIRUDIN
Factor Xa Inhibitor
fondaparinux
rivaroxaban (oral)
13. Antiplatelet Agents
Phosphodiesterase
Glycoprotein IIb/IIIA ADP Receptor
Inhibitors
Inhibitors
Antagonists
cilostazol
ABCIXIMAB
CLOPIDOGREL
eptifibatide
PRASUGREL
tirofiban
ticlopidine
ticagrelor
14. Atrial Natriuretic Peptide Agonists
nesiritide
15. Calcium Channel Blockers (Calcium Entry Blockers)
Dihydropyridines
Phenylalkylamine
Benzothiazepines
AMLODIPINE
VERAPAMIL
DILTIAZEM
FELODIPINE
NIFEDIPINE
clevidipine
isradipine
nicardipine
nimodipine
nisoldipine
Others
bepridil
flunarizine
16. Cardiac Glycosides
DIGOXIN
digitoxin (historical)
17. Centrally Acting Antihypertensive Drugs
CLONIDINE
Guanfacine
Guanabenz
methyldopa
reserpine (historical)
18. Corticosteroids (Inhaled)
BECLOMETHASONE
BUDESONIDE
FLUTICASONE
ciclesonide
mometasone
Loop Diuretics
ETHACRYNIC ACID
FUROSEMIDE
bumetanide
torsemide
19. Diuretics
Thiazide Diuretics
HYDROCHLOROTHIAZIDE
INDAPAMIDE
chlorothiazide
chlorthalidone
metolazone
Potassium-Sparing Diuretics
EPLERENONE
SPIRONOLACTONE
amiloride
triamterene
20. Endothelin Receptor Antagonists
ambrisentan
bosentan
21. Fibrates
fenofibrate
GEMFIBROZIL
22. Fibrinolytics
ALTEPLASE
UROKINASE anistreplase
reteplase
streptokinase (historical)
tenecteplase
23. Glycoprotein IIb/IIIa Receptor Antagonists
ABCIXIMAB
eptifibatide
tirofiban
24. Leukotriene Modifiers
Leukotriene Receptor Antagonists
5’-Lipoxygenase Inihibitors
MONTELUKAST
zileuton
zafirlukast
25. Metabolic Modulators
ranolazine
26. Methylxanthines
THEOPHYLLINE aminophylline
pentoxyphylline (only for intermittent claudication with peripheral vascular disease)
PDE 3 Inhibitors
cilostazol
inamrinone
milrinone
27. Phosphodiesterase Inhibitors
PDE 4 Inhibitors
roflumilast
Organic Nitrates
ISOSORBIDE MONONITRATE
NITROGLYCERIN
amyl nitrite
isosorbide dinitrate
PDE 5 Inhibitors
sildenafil
tadalafil
28. Vasodilators
Others (Miscellaneous Mechanisms)
HYDRALAZINE
NITROPRUSSIDE
diazoxide
minoxidil
combination of isosorbide dinitrate and hydralazine
(BiDil) use to treat HF in African Americans
Diuretics and Drugs Affecting Renal Function, Water,
and Electrolyte Metabolism
Subcommittee:
Strandhoy, Jack W., Chair, [email protected]
Jeffries, William B.
[email protected]
Diuretics
Recommended Curriculum Equivalent: 2 hrs Carbonic
Anhydrase
Inhibitor
acetazolamide
Drug Classes and Drugs to Consider
Osmotic
Diuretic
mannitol
FUROSEMIDE
bumetanide
Distal tubule
Diuretics
CHLORTHALIDONE
HYDROCHLOROTHIAZIDE
metolazone
Loop
Diuretics
K-sparing
Diuretics
AMILORIDE
SPIRONOLACTONE
TRIAMTERENE
eplerenone
Learning Objectives Physiology and Pathophysiology
Describe the location and function of major ion transporters and channels on renal
epithelial membranes.
Explain how sodium transport influences the reabsorption of other ions and water in the
kidney.
Explain how abnormal renal function can cause hypertension or edema.
Mechanism of Action
Describe the changes that occur with electrolyte transport, water reabsorption and
hemodynamics when specific diuretics inhibit kidney function.
Actions on organ systems
Describe the hemodynamic, ion transport and excretory effects of different classes of
diuretic drugs.
Pharmacokinetics
Explain the importance of the organic anion transporters and protein binding to the renal
action of diuretics.
Provide examples of how other drugs or diseases can interfere with the effects of
diuretics.
Adverse effects, drug interactions and contraindications
Explain how thiazides and loop diuretics can cause a metabolic alkalosis.
Explain how diuretic therapy can lead to hyponatremia.
Describe the metabolic imbalances with diuretic therapy on glucose, urate, lipids,
calcium, magnesium and potassium. Explain the underlying mechanisms involved.
Describe the clinical consequences of interactions between diuretics and drugs such as
cardiac glycosides, oral hypoglycemics, uricosurics, aminoglycosides, amphotericin,
NSAIDs and angiotensin inhibitors.
Describe why reduced renal perfusion can limit the use of thiazide diuretics.
Therapeutic uses
Explain the renal and extra-renal mechanisms by which diuretics are useful in treating
hypertension and edema.
Explain how osmotic drugs can reduce toxic nephropathy.
Clinical Pharmacology
In salicylate overdose, failure of urine alkalinization with intravenous bicarbonate then
allows for the use of a carbonic anhydrase inhibitor to increase urine pH and allow for
increased urinary clearance of salicylic acid in the absence of access to dialysis.
Hydrochlorothiazide can be used in a 12.5 mg dose (1/2 tablet) to counteract the
increase in circulating aldosterone secondary to use of an ACE inhibitor for the
management of hypertension. Hydrochlorothiazide is indicated as the only diuretic
that spares calcium in patients with osteopenia. Furosemide is the only effective oral
diuretic in patients with a creatinine clearance less than 60 ml/min. Potassium-sparing
diuretics are relatively contraindicated in patients receiving ACE inhibitor therapy due
to the increased potential for hyperkalemia. Caution with interaction between thiazide
diuretics and concurrent acute NSAIDs due to increased potential for interstitial
nephritis.
Relevance USMLE topic
Principles of therapeutics
Cardiovascular System-Abnormal
Diuretics, antidiuretic drugs
Processes- Metabolic and Regulatory
Disorders & Vascular DisordersPrinciples of Therapeutics:
Antihypertensive Drugs.
Renal/Urinary System-Abnormal Processes AAMC Medical School Objectives Project Topic C:
Drug treatment of common conditions Report X Patient Safety - Table 1 Notes
Objectives for diuretics as antihypertensive drugs are covered in Cardiovascular Drugs.
Objectives for renin inhibitors, ACE inhibitors and angiotensin-receptor blockers are
covered in Cardiovascular drugs.
Objectives for drugs used in renal transplantation and some renal diseases are covered
in Immunosuppressive Drugs.
Agents Affecting the Renal Conservation of Water
Recommended Curriculum Equivalent: 1 hr.
Drug Classes and Drugs to Consider Vasopressin
Vasopressin
Agonists
Antagonists
DESMOPRESSIN (V2)
conivaptan (V1aR, V2R)
vasopressin (V1, V2)
tolvaptan (V2R)
Learning Objectives
Physiology and Pathophysiology Explain the mechanisms by which the kidney makes a concentrated or dilute urine.
Describe the roles of vasopressin, aquaporins, V1 and V2 receptors, cyclic AMP and
prostaglandins in regulating renal epithelial water permeability.
Mechanisms of Action
Describe how drugs can mimic or interfere with the cellular mechanisms of vasopressin.
Actions on organ systems Compare and contrast the renal and extrarenal effects of vasopressin and
desmopressin.
Pharmacokinetics
Explain how altering the structure of vasopressin affects its pharmacokinetics and
pharmacodynamics.
Adverse effects, drug interactions and contraindications Explain the mechanism of vasoconstriction produced by vasopressin.
Explain how NSAIDs and clonidine can alter water reabsorption by the kidney.
Describe the hazards of correcting hyponatremia with vasopressin antagonists too
rapidly.
Explain how drugs such as clonidine, chlorpropamide, demeclocycline, lithium, and
NSAIDs can modify the action of vasopressin.
Explain how blocking the V1 receptor can alter ACTH secretion.
Therapeutic uses
Compare and contrast the therapy of central and nephrogenic diabetes insipidus.
Describe the pharmacological treatment of the syndrome of inappropriate ADH
secretion.
Explain the mechanism of lithium carbonate interference with renal water reabsorption.
Clinical Pharmacology Caution in use of conivaptan and tolvaptan concurrently with drugs inhibiting CYP3A or
P-gp due to increased risk of toxicity associated with overly rapid correction of
hyponatremia.
Relevance USMLE topic
Renal/Urinary System
Principles of therapeutics
Drugs and fluids used to treat volume,
electrolyte, and acid-base disorders
AAMC Medical School Objectives Project
Report X Patient Safety - Table 1
Topic D
Management of less common but
severe medical conditions and
emergencies
Notes
Objectives for desmopressin-enhanced clotting factor release are covered in
Hematological Drugs.
Gastrointestinal Drugs
Subcommittee:
Prozialeck, Walter (Chair) [email protected]
Escher, Emanuel [email protected]
Garrison, James C. [email protected]
Henry, Matthew, [email protected]
Weber, Donna R [email protected]
Recommended Curriculum Equivalent: 1.5 h
Acid Reducers and Drugs for the Treatment of Peptic Ulcer Disease
Proton pump inhibitors
First generation
OMEPRAZOLE
Second generation
ESOMEPRAZOLE
LANSOPRAZOLE
PANTOPRAZOLE
RABEPRAZOLE
Learning Objectives
Physiology and pathophysiology
Describe the synthesis and mechanism of H+ secretion by the parietal cells
Mechanism of action
Describe the mechanism of action of proton pump inhibitors and why they are
selective for the parietal cell proton pump.
Actions on organ systems
Describe the pharmacological effects of the drugs on gastric function.
Are there effects on other organ systems?
Pharmacokinetics
Describe the pharmacokinetics of proton pump inhibitors?
Are there significant differences among the different drugs in this class?
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of proton pump inhibitors.
Describe the clinically important drug interactions of proton pump inhibitors.
Describe the principal contraindications of proton pump inhibitors.
Therapeutic uses
Describe the current therapeutic uses of proton pump inhibitors.
1
Clinical Pharmacology
Omeprazole is perceived to be the most potent of this drug class in inhibiting
CYP2C19 activity and is proposed to have potential drug interactions with other
drugs metabolized by this P450 isoform. Concern has been raised about potential
inhibition of clopidogrel activation in patients taking both drugs concurrently.
Current consensus is that in such patients clopidogrel with pantoprazole may be a
safer choice to reduce the probability of a drug interaction involving CYP2C19.
Prolonged used of PPI drugs is associated with hypomagnesemia. This possibility is
a concern in debilitated patients especially in those having underlying cardiac
arrhythmias and/or oesteoporosis where associated muscle weakness might
increase risk of a fall and subsequent fracture.
Relevance
USMLE topic
Principles of therapeutics
Gastrointestinal System, Normal
Mechanisms of action and use of drugs
Processes – organ structure and
for treatment of disorders of the
function including digestion; cell/tissue
gastrointestinal system; treatment
structure & function including endocrine
and prophylaxis of peptic ulcer
and neural regulatory functions;
disease and gastroesophageal reflux
gastrointestinal secretory products
AAMC Medical School Objectives
Topic C—Drug treatment of common
Project Report X Patient Safety-Table 1
conditions and diseases, using
frequently prescribed classes of drugs
for the treatment and prevention of
disease
2
Acid Reducers and Drugs for the Treatment of Peptic Ulcer Disease
Endogenous
Substance
histamine
H2 Receptor Antagonists
First Generation
Second Generation
cimetidine
FAMOTIDINE
NIZATIDINE
RANITIDINE
Learning Objectives
Physiology and pathophysiology
Describe the neurohumoral control of H+ secretion by gastric parietal cells.
Describe the role of histamine in the different phases H+ secretion.
Describe the causes of H+ hypersecretion.
Mechanism of action
Explain the molecular mechanism of action H2 receptor antagonists.
Actions on organ systems
Describe the pharmacological effects of the drugs on the stomach.
Do these anatagonists have effects on other organ systems?
Pharmacokinetics
Describe the pharmacokinetics of the H2 receptor antagonists.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of each H2 receptor antagonist.
Describe the clinically important drug interactions of H2 receptor antagonists.
Describe the principal contraindications of H2 receptor antagonists.
Therapeutic uses
Identify current therapetutic uses of H2 receptor antagonists.
Clinical Pharmacology
Tolerance and loss of efficacy occurs with prolonged use of drugs in this class. Due
to its ability to inhibit activity of many CYP isoforms, cimetidine is not the preferred
drug in this class when administered concurrently with other drugs whose
elimination is cytochromes P450-dependent. Use of ranitidine or famotidine is
considered preferable in such patients.
Relevance
USMLE topic
Principles of therapeutics
Gastrointestinal System, Normal
Mechanisms of action and use of drugs
Processes – organ structure and
for treatment of disorders of the
function including digestion; cell/tissue
gastrointestinal system; treatment
structure & function including endocrine
and prophylaxis of peptic ulcer
and neural regulatory functions;
disease and gastroesophageal reflux
gastrointestinal secretory products
Abnormal Processes – idiopathic
disorders
3
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C—Drug treatment of common
conditions and diseases, using
frequently prescribed classes of
drugs for the treatment and
prevention of disease
Notes
4
Acid Reducers and Drugs for the Treatment of Peptic Ulcer Disease
Acid Neutralizers (Classic Antacid preparations)
Endogenous
substance
H+
Single agent
Mixed preparations
ALUMINUM HYDROXIDE
ALUMINUM HYDROXIDE
MAGNESIUM HYDROXIDE/
CALCIUM CARBONATE
MAGNESIUM HYDROXIDE
sodium bicarbonate
Learning Objectives
Physiology and Pathophysiology
Describe the mechanisms of H+ secretion in the stomach
Mechanism of action
Describe the mechanism of action of antacid medications.
Describe the differences in onset and duration of action of each antacid preparation.
Actions on organ systems
Describe the pharmacological effects of the drugs in each class on the stomach.
Pharmacokinetics
Describe the absorption and systemic actions of antacid preparations
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of each antacid preparation.
Describe the clinically important drug interactions with antacids.
Describe the principal precautions and contraindications in the use of antacids.
Therapeutic uses
Describe the primary indication of antacid use.
Clinical Pharmacology
The main concern with these antacids is chelation of co-administered drugs that may
be interpreted as disease progression due to reduction of systemic bioavailability
of these other agents.
Some older patients ingest calcium carbonate tablets as a cheap source of calcium
supplementation as a means to preserve bone mass.
There is no good evidence to support the claim that long-term use of antacids
prevents to occurrence of peptic ulcers.
Relevance
5
USMLE topic
Gastrointestinal System, Normal
Processes – organ structure and
function including digestion; cell/tissue
structure & function including endocrine
and neural regulatory functions;
gastrointestinal secretory products
Abnormal Processes – idiopathic
disorders
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
gastrointestinal system; treatment
and prophylaxis of peptic ulcer
disease and gastroesophageal
reflux
Topic C
Drug treatment of less common but
severe conditions
Notes
Drugs for the Treatment of Peptic Ulcer Disease
Cytoprotectant agents
Endogenous
substance
PGE2
Analog
Surface protectant
MISOPROSTOL
SUCRALFATE
Learning Objectives
Physiology and Pathophysiology
Describe the mechanisms for production of the gastric cytoprotective barrier.
Describe causes for disruption of the cytoprotective barrier.
Mechanism of action
Explain the mechanism of action of each drug.
Actions on organ systems
Describe the pharmacological effect of the each drug on the cytoprotective barrier.
Pharmacokinetics
Describe the absorption, distribution metabolism and excretion of each drug.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of each drug.
Describe clinically important drug interactions of the drugs in each class.
Therapeutic uses
Describe the primary indications for use of each drug.
Clinical Pharmacology
As a prostaglandin analog, misoprostol is contraindicated in pregnancy. Its doserelated GI toxicity has relegated its use to second-line strategy.
In patients with renal impairment, hypophosphatemia and aluminum intoxication
become a concern with prolonged use of sucralfate.
Relevance
6
USMLE topic
Gastrointestinal System, Normal
Processes – organ structure and
function including digestion; cell/tissue
structure & function including endocrine
and neural regulatory functions;
gastrointestinal secretory products;
gastrointestinal defense mechanisms
Abnormal Processes – drug-induced
adverse effects on the gastrointestinal
system
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
gastrointestinal system; treatment of
peptic ulcer disease
Topic C
Drug treatment of less common but
severe conditions
Notes
7
Drugs for the Treatment of Peptic Ulcer Disease
Helicobacter pylori eradication
Triple therapy
Antibiotics
AMOXICILLIN
CLARITHROMYCIN
METRONIDAZOLE
TETRACYLCINES
Acid
suppression
PPI
Quadruple therapy
Antibiotics
CLARITHROMYCIN
TETRACYLCINES
Acid
suppression
H 2BLOCKERS
PPI
other
BISMUTH
SUBSALICYLATE
Physiology and Pathophysiology:
Describe the role of H. pylori in peptic ulcer disease.
Describe tests for evaluating H. pylori infection.
Therapeutic uses:
Describe the use of triple and quadruple therapy regimens used for H. pylori eradication.
Describe factors to be used in selecting the best therapeutic options for a given patient.
Mechanism of action:
Describe the contribution of each agent in triple or quadruple therapy regimens in H.
pylori eradication.
Drug interactions
Describe potential drug interactions.
Describe potential for antibiotic resistant strains of H. pylori.
Clinical Pharmacology
Amoxicillin, clarithromycin and a PPI is the most commonly recommended triple therapy
regimen. With initial treatment failure, bismuth subsalicylate is often added to the
second attempt at eradication and the approach is then referred to as quadruple
therapy. Bismuth subsalicylate ingestion has been associated with salicylate
intoxication, especially in children, and in adults ingesting other salicylate-containing
drug preparations concurrently.
Relevance
USMLE topic
Gastrointestinal System, Normal
Processes – organ structure and
function including digestion; cell/tissue
structure & function including endocrine
and neural regulatory functions;
gastrointestinal secretory products
Abnormal Processes – infectious
disorders
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Principles of therapeutics
Mechanisms of action and use of drugs for
treatment of disorders of the
gastrointestinal system; treatment and
prophylaxis of peptic ulcer disease
Topic C
Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
8
Prokinetic Drugs and Laxatives
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Drugs used to treat upper GI
motility disorders (Gastroparesis,
dyspepsia, GERD)
METOCLOPRAMIDE
cisapride
domperidone
erythromycin
tegaserod
Drugs used to treat lower GI motility disorders
(Constipation)
Receptor mediated
ALVIMOPAN
LUBIPROSTONE
METHYLNALTREXONE
bethanechol
neostigmine
renzapride
tegaserod
Laxatives
DOCUSATE
LACTULOSE
METHYLCELLULOSE
POLYETHYLENE GLYCOL
SODIUM PHOSPATE
SODIUM CITRATE
PSYLIUM
castor oil, bisacodyl, senna,
cascara, mineral oil
Learning Objectives
Physiology and Pathophysiology
Describe the neural and hormonal mechanisms controlling stomach and intestinal motility
Describe the changes in neural and hormonal control of stomach and intestinal motility that
lead to delayed gastric emptying or accommodation.
Mechanisms of action
Explain the molecular mechanism of action of each drug.
Actions on organ systems
Describe why some drugs are selective for upper GI motility disorders and why others are
selective for lower GI motility disorders.
Pharmacokinetics
Describe the relevant pharmacokinetic features of each drug
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class
Describe the principal contraindications of the drugs of each class
Therapeutic uses
Outline the main therapeutic uses of the drugs of each class.
9
Clinical Pharmacology
Cisapride is no longer favored because of its potent inhibition of CYP3A, the cytochrome
P450 isoform responsible for metabolism of a large proportion of drugs ingested by
patients, and the fact that it is associated with prolongation of the QTc interval.
Drugs to treat constipation are frequently abused by the general population. Use should
be progressive from stool softeners (ducosate) to fibre supplementation
(methylcellulose) and finally to propulsive agents. Recently polyelectrolyte lavage
solution has been found to be acceptable with less cramping than seen with the use of
castor oil.
Relevance
USMLE topic
Principles of therapeutics
Laxatives: Gastrointestinal System,
Laxatives: mechanisms of action and use
Normal Processes – organ structure
of drugs for treatment of disorders of the
and function including motility, digestion
gastrointestinal system; drugs to alter
and absorption; cell/tissue structure &
gastrointestinal motility
function including endocrine and neural Prokinetics: mechanisms of action and use
regulatory functions; gastrointestinal
of drugs for treatment of disorders of the
defense mechanisms and normal flora
gastrointestinal system; drugs to alter
Abnormal Processes – infection,
gastrointestinal motility; treatment and
inflammatory and immunologic
prophylaxis of gastroesophageal reflux
disorders; systemic disorders affecting
the gastrointestinal system; druginduced adverse effects on the
gastrointestinal system; idiopathic
disorders
Prokinetics: Gastrointestinal System,
Normal Processes – organ structure
and function including motility;
cell/tissue structure & function including
endocrine and neural regulatory
functions Abnormal Processes –
systemic disorders affecting the
gastrointestinal system; idiopathic
disorders
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
Notes
Cisapride is available in the U.S. only in special cases.
Tegaserod has been removed from the U.S. market and is now available only in emergency
cases requiring special FDA approval.
Domperidone is available in Europe and Canada but not the U.S. However, patients in the
U.S. have access to this drug via the internet or by travel to Europe and Canada.
10
Anti-diarrheal drugs
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
SerotonergicAdrenergic
Opioid- compounds
compounds
compounds
LOPERAMIDE
alosetron
clonidine
diphenoxylate
cilansetron
somatostatin analog
octreotide
muscarinic antagonists
ATROPINE
DICYCLOMINE
hyoscyamine
scopolamine
Probiotics
bifidobacterium
infantis
other
BISMUTH SUBSALICYLATE
bismuth citrate
Learning Objectives
Physiology and Pathophysiology:
Describe the neural and hormonal mechanisms controlling colonic motility and water and
electrolyte absorption and secretion.
Describe the conditions under which neural mechanisms controlling colonic motility and
water and electrolyte absorption and secretion are impaired.
Describe the neural mechanisms of visceral sensation and visceral pain.
Describe the importance of maintaining normal gut flora and how disruption can lead to
altered motility and absorption and secretion in the colon.
Mechanisms of action:
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems:
Describe the effects of each drug on the colon and also on other organ systems.
Pharmacokinetics:
Describe the absorption distribution metabolism and secretion of each drug.
Adverse effects, drug interactions and contraindications:
Describe the principal adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class
Describe the principal contraindications of the drugs of each class
Therapeutic uses
Identify the specific therapeutic applications of each class of drug.
11
Clinical Pharmacology
Adequate replacement of fluid and electrolytes remains the primary approach to
management so that clearance of the offending intestinal stimulant is removed.
Loperamide represents the primary opioid receptor agonist drug intervention that has
minimal effects on the central nervous system. It is often useful in patients with
chronic diarrhea secondary to treatment with chemotherapeutic drugs.
Use of bismuth subsalicylate is discouraged because of its potential to cause salicylate
intoxication if it is used chronically. Other drug interventions are considered second
line and rarely used because of associated adverse reactions.
Relevance
USMLE topic
Principles of therapeutics
Gastrointestinal System, Normal
Mechanisms of action and use of drugs for
Processes – organ structure and
treatment of disorders of the
function including motility, digestion and
gastrointestinal system; drugs to alter
absorption; cell/tissue structure &
gastrointestinal motility
function including endocrine and neural
regulatory functions; gastrointestinal
defense mechanisms and normal flora
Abnormal Processes – infection,
inflammatory and immunologic
disorders; systemic disorders affecting
the gastrointestinal system; druginduced adverse effects on the
gastrointestinal system; idiopathic
disorders
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
Notes:
12
Drugs used for the Treatment of Inflammatory Bowel Disease
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
Salicylates
Steroids
Anti-mitotic agents
5-AMINO SALICYLIC
ACID
SULFAPYRIDINE
SULFASALAZINE
balsalazide
HYDROCORTISONE
METHYLPREDNISOLONE
PREDNISONE
budesonide
6-mercaptopurine
azathioprine
cyclosporine
methotrexate
Antibiotics
Monoclonal
antibodies
INFLIXIMAB
Probiotics
ciprofloxacin
clarithromycin
metronidazole
VSL #2
lactobacillus
Learning Objectives
Pathophysiology:
Describe the differences between ulcerative colitis and Crohn’s disease.
Describe the mechanisms responsible of intestinal and extraintestinal symptoms of
inflammatory bowel disease.
Describe the contribution of intestinal bacteria to the pathophysiology of inflammatory bowel
disease.
Mechanism of action
Describe the mechanism of action of each of the major classes of drugs.
Pharmacokinetics
List the routes of administration of drugs in each class.
Described the absorption and distribution of each class of drug and how this impacts on the
choice of the route of administration.
Describe the mechanisms for bioactivation of the salicylates and how this impacts on their
use for the treatment of inflammatory bowel disease.
Adverse effects, drug interactions and contraindications
Describe the main adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class.
Describe the principal contraindications or precautions of the drugs of each class.
Therapeutic uses
Know the selective use of each class of drug for the treatment of ulcerative colitis vs. Crohn’s
disease.
13
Clinical Pharmacology
Subsequent to the finding of efficacy of sulfasalazine, it was determined that efficacy was
mediated mostly by the 5-aminosalicylic acid that was released by sulfasalzine
hydrolysis in the lower GI tract. Thus patients intolerant to sulfonamide drugs can be
given 5-aminosalicylate directly to eliminate exposure to the sulfonamide moiety.
From a steroid perspective, prednisone is most cost effective with change to
methylprednisolone in patients with hepatic impairment.
Use of infliximab remains a second line intervention for those patients having failed more
established drug therapies.
Side effects from TNF-alpha inhibitions are significant, especially related to the increased
susceptibility to infection.
Relevance
USMLE topic
Principles of therapeutics
Gastrointestinal System, Normal
Mechanisms of action and use of drugs for
Processes – organ structure and
treatment of disorders of the
function including motility, digestion and
gastrointestinal system; anti-inflammatory,
immunosuppressive drugs
absorption; cell/tissue structure &
function including endocrine and neural
regulatory functions; gastrointestinal
defense mechanisms and normal flora
Abnormal Processes – inflammatory and
immunologic disorders; systemic
disorders affecting the gastrointestinal
system; idiopathic disorders
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1 Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
Notes
Objectives for salicylates and steroids are covered under Analgesic, Antipyretic,
Antiinflammatory Drugs
Objectives for mitotic inhibitors are covered under Chemotherapy Drugs
Drugs used to Treat Nausea and Vomiting
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to Consider
Emetic drugs
Dopamine receptor agonist
Non-selective emetics
Apomorphine
Syrup of Ipecac
14
Anti-Emetic Drugs
Dopamine receptor
antagonists
5-HT3 receptor
antagonists
METOCLOPRAMIDE
DOLASETRON
PROCHLORPERAZINE GRANISETRON
haloperidol
ONDANSETRON
PALONOSETRON
ramosetron
Neurokinin receptor
antagonists
APREPITANT
Corticosteroids
METHYL PREDNISOLONE
PREDNISONE
dexamethasone
Cannabinoid receptor Histamine receptor
antagonists
antagonists
DRONABINOL
DIMENHYDRINATE
nabilone
DIPHENHYDRAMINE
cyclizine
hydroxyzine
meclizine
promethazine
Benzodiazepines
Muscarinic receptor
antagonists
LORAZEPAM
SCOPOLAMINE
ALPRAZOLAM
DIAZEPAM
Learning Objectives
Physiology and Pathophysiology
Describe the central and peripheral nervous system mechanisms responsible for nausea and
vomiting.
Mechanisms of action
Describe the mechanism of action of emetic drugs.
Explain the cellular and molecular mechanisms of action of each drug class.
Describe the use of multi-drug treatment of nausea and vomiting.
Actions on organ systems
Describe the pharmacological effects of each drug in each class.
Pharmacokinetics
Know the absorption, distribution, metabolism and excretion of each drug class.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class
Describe the principal contraindications of the drugs of each class
Therapeutic uses
Know the appropriate uses of anti-emetic drugs for the treatment of specific conditions such
as chemotherapy-induced nausea and vomiting, postoperative nausea and vomiting,
motion sickness, vertigo, and nausea and vomiting during pregnancy.
15
Clinical Pharmacology
Syrup of ipecac is no longer recommended as an antiemetic, because of its lack of efficacy
relative to the time of poison ingestion. It also has a potent sedative effect that could
increase risk of aspiration pneumonia after induction of emesis.
Response to antiemetic drug treatment is highly variable among patients. These drugs are
used most often in conjunction with chemotherapy, and are usually specified by
protocol. Administration of dimenhydrinate or diphenhydramine should be done with
caution because of their risk of abuse, and the narrow therapeutic index between
efficacy and substantial toxicity.
The scopolamine patch is an effective antinauseant intervention and is successfully used
for space travelers.
Relevance
USMLE topic
Principles of therapeutics
Gastrointestinal System, Normal
Mechanisms of action and use of drugs for
Processes – organ structure and
treatment of disorders of the
function including motility; Central and
gastrointestinal system; drugs to alter
Peripheral Nervous Systems – brain
gastrointestinal motility; drugs affecting
stem; blood-brain barrier
the autonomic nervous system
Abnormal Processes – idiopathic
disorders; systemic disorders affecting
the gastrointestinal system; druginduced adverse effects on the
gastrointestinal system
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety-Table 1
Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
Notes
Antigas/Antiflatulent
SIMETHICONE
activated charcoal
Miscellaneous Gastrointestinal Drugs
Digestive Enzyme
Drug for Gallstones
α-GALACTOSIDASE
ursodiol
LACTASE
PANCRELIPASE
Learning Objectives
Explain mechanism of action, effects, side effects, toxicities, pharmacokinetics and
therapeutic uses of each agent.
Clinical Pharmacology
Activated charcoal should be used with caution because of the risk of impaction in the GI
tract.
Relevance
16
USMLE topic
Gastrointestinal System-Principles of
therapeutics
Principles of therapeutics
Mechanisms of action and use of drugs for
treatment of disorders of the
gastrointestinal system Pancreatic
replacement therapy and treatment of
pancreatitis
Other therapeutic modalities
Topic C
Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Notes
17
Use of Drugs in Pharmacotherapy of Common Gastrointestinal Problems
The course of instruction should include the pharmacotherapy of common gastrointestinal
disorders including: “heart burn,” gastroesopogeal reflux disorders, gastritis, bloating,
distension, constipation (functional, acute, chronic, idiopathic, iatrogenic), diarrhea
(functional, pathogenic, iatrogenic), peptic ulcer disease (duodenal, esophageal,
gastric and inflammatory bowel diseases (Crohn’s disease and ulcerative colitis),
cramping and irritable bowel syndrome.
Clinical Pharmacology
Already addressed above in the specific section. When using opioid analgesics to
manage pain associated with IBD, sufficient drug needs to be administered so as to
counter that smooth muscle spasm induced by low doses of this class of drug. Dose
should be mg/kg tailored to each patient.
Relevance
USMLE topic
Principles of therapeutics
Gastrointestinal System, Normal
Mechanisms of action and use of drugs for
Processes – organ structure and
treatment of disorders of the
function including digestion; cell/tissue
gastrointestinal system
structure & function including endocrine
and neural regulatory functions;
gastrointestinal secretory products
Abnormal Processes – idiopathic
disorders
AAMC Medical School Objectives
Project Report X Patient Safety-Table 1
Topic C
Drug treatment of common conditions and
diseases, using frequently prescribed
classes of drugs for the treatment and
prevention of disease
Notes
18
Chemotherapy
Subcommittee:
George Brenner (Chair) [email protected]
Gudas, Lorraine J. [email protected]
Lazo, John S, [email protected]
Matta, Jaime [email protected]
Greg Reed <[email protected]>
Vrana, Kent, [email protected]
Basic Principles Of Antimicrobial Therapy
Recommended Curriculum Equivalent: 1 hr
Learning Objectives
Define the terms: antibiotics, selective toxicity, therapeutic index, bacteriostatic and
bactericidal, chemotherapeutic spectrum.
Understand the MIC and MBC values.
Describe the terms synergism and antagonism.
Discuss the classification of antimicrobial drugs based upon the mechanism of action.
Explain the modes of action of various antimicrobial drugs.
Define bacterial resistance and illustrate the mechanisms involved in acquiring
bacterial resistance.
Describe the basic principles of combination therapy with antimicrobial drugs.
Cell Wall Synthesis Inhibitors
Recommended Curriculum Equivalent: 2 hr
Drug Classes and Drugs to consider
Penicillins
Cephalosporins and vancomycin
AMPICILLIN
CEFTRIAXONE
AZTREONAM
CEPHALEXIN
PENICILLIN G
VANCOMYCIN
PIPERACILLIN
cefaclor
IMIPENEM
cefazolin
amoxicillin
cefepime
clavulanic acid
cefotaxime
cloxacillin
cefoxitin
indanyl carbenicillin
ceftazidime
meropenem
cefuroxime
methicillin
fosfomycin
mezlocillin
nafcillin
oxacillin
penicillin V
sulbactam
tazobactam.
ticarcillin
Learning Objectives
Mechanism of action
Describe the structural relationship of the penicillin molecule with antimicrobial activity.
Explain the mechanism of action of β-lactam antibiotics
Understand the principle of combination of inhibitors of β-lactamase with penicillins
(List such combinations).
Explain the pharmacological basis for combining imipenem with cilastatin.
Describe the structural differences between penicillins and cephalosporins.
Explain the mechanism of action of cephalosporins.
Discuss the mechanism of action of vancomycin and of fosfomycin.
Pharmacokinetics
Describe the pharmacokinetic properties of penicillins.
Describe the repository penicillins.
List the penicillinase-resistant penicillins.
Describe the four generations of cephalosporins with specific examples and the
differences in their antimicrobial spectrum and pharmacokinetic properties.
Describe the pharmacokinetic properties of vancomycin.
Adverse effects and contraindications
Describe the principal adverse effects of penicillins.
Describe the principal contraindication of penicillins.
Describe the adverse effects due to cephalosporins and vancomycin.
Explain the terms superinfection and cross-hypersensitivity.
Therapeutic uses
Discuss primary therapeutic indications for penicillin G.
Describe the indications for broad-spectrum penicillins.
Describe the antimicrobial activity of monobactams and carbapenems.
Describe the main therapeutic indications of cephalosporins and vancomycin.
Clinical Pharmacology
Vancomycin use should be reserved for treatment of MRSA infections. Carbapenems
and 3rd and 4th generation cephalosporin antibiotics should be reserved for patients
with very serious polymicrobial infections. Carbapenems can reduce the serum
concentration of valproate, leading to recurrence of seizures.
USMLE topic
Cardiovascular System – Abnormal
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Relevance
Principles of therapeutics
Antimicrobials and antiparasitics
Topic C
Drug treatment of common conditions
and diseases
Protein Synthesis Inhibitors
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Aminoglycosides
Macrolides
Streptogramins
GENTAMICIN
AZITHROMYCIN
quinupristin/dalfopristin
amikacin
CLARITHROMYCIN
neomycin
ERYTHROMYCIN
streptomycin
telithromycin
tobramycin
Lincosamides
clindamycin
Oxazolidinones
LINEZOLID
Tetracyclines
DOXYCYCLINE
TIGECYCLINE
minocycline
tetracycline
Others
MUPIROCIN
Chloramphenicol
Learning Objectives
Mechanism of action
Discuss the mechanism of action of each class of protein synthesis inhibitors.
Explain the mechanism of acquired drug resistance to aminoglycosides, tetracyclines,
and macrolides.
Explain the rational basis for combination therapy with an aminoglycoside and a
penicillin, cephalosporin, or vancomycin.
Pharmacokinetics
Describe the pharmacokinetic properties of each class of protein synthesis inhibitors,
including their routes of administration. Explain the importance of peak and trough
levels of aminoglycosides.
Discuss the need of and the method of dose adjustment for aminoglycosides in
patients with compromised renal function.
Adverse effects and drug interactions
Discuss the main toxicities of each class of protein synthesis inhibitors.
Describe the major drug interactions of macrolides due to inhibition of cytochrome
P450 enzymes.
Therapeutic uses
Describe the primary therapeutic indications for each class of protein synthesis
inhibitors.
Discuss the therapeutic options for treating skin and soft tissue infections, and
systemic infections due to methicillin-resistant or vancomycin-resistant bacteria.
Clinical Pharmacology
Use of macrolide antibiotics in patients receiving cacium channel blockers is
associated with an increased risk of hypotension due to inhibition of CYP3A4
activity. Macrolide antibiotics also increase the risk of toxicity to statins
metabolized by CYP3A4. Use of linezolid for more than 10 days is associated with
bone marrow depression.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System – Abnormal
Antimicrobials and antiparasitics
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
Inhibitors of Nucleic Acid metabolism and Drugs interfering with intermediary
metabolism
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Fluoroquinolones
Rifamycins
CIPROFLOXACIN
RIFAMPIN
levofloxacin
rifaximin
Nitroimidazole
Dihydrofolate reductase inhibitors
METRONIDAZOLE
COTRIMOXAZOLE
trimethoprim
Sulfonamides
Other Agents
COTRIMOXAZOLE
DAPTOMYCIN
sulfamethoxazole
FIDAXOMICIN
nitrofurantoin
Learning Objectives
Mechanism of action
Explain the mechanism of action of each class of antibiotics.
Discuss the synergistic inhibition due to sequential blockade with cotrimoxazole.
Learn the adverse effects of ciprofloxacin, including contraindications in children and
pregnant women.
Pharmacokinetics
Describe the pharmacokinetics properties of each class of antibiotics.
Describe the drug interactions of fluoroquinolones, including the effect of ingested
cations on drug absorption.
Adverse effects
Describe the major toxicities of each class of drugs.
Therapeutic uses
Describe the therapeutic indications each class of antimicrobial drugs. List the
advantages of newer fluoroquinolones over ciprofloxacin.
Describe the major therapeutic indications of sulfonamides alone, and in combination
with trimethoprim (cotrimoxazole).
Discuss the emergence of microbial resistance to cotrimoxazole and fluoroquinolone
drugs, and its implications for the treatment of urinary tract infections and
gonorrhea.
Describe the role and use of various drugs in the treatment of methicillin-resistant
Staphylococcus aureus infections.
Describe and compare the role of metronidazole, vancomycin, and fidaxomicin in the
treatment of Clostridium difficile infections.
Discuss the therapeutic options for treating traveler’s diarrhea.
Clinical Pharmacology
When administered concurrently with warfarin, metronidazole is associated with an
increased anticoagulant activity. Caution in using rifampin with other drugs
metabolized by CYP3A4 due to its enzyme induction property.
Relevance
USMLE topic
Cardiovascular System – Abnormal
processes
Principles of therapeutics
Antimicrobials and antiparasitics
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
Antimycobacterial Drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
ETHAMBUTOL
azithromycin
ISONIAZID
clarithromycin
RIFAMPIN
clofazimine
PYRAZINAMIDE
dapsone
RIFAPENTINE
rifabutin
streptomycin
thalidomide
Learning Objectives
Mechanism of action
List the first line antitubercular drugs and explain their mechanisms of action.
Define the various phases of actively and slow growing Mycobacterium tuberculosis
and compare the relative effectiveness of various drugs.
Describe the drugs used in the treatment of Hansen's disease and their mechanism of
action.
Pharmacokinetics
Describe the pharmacokinetic profile of isoniazid and rifampin.
Adverse effects and drug interactions
Describe the adverse effects of isoniazid, rifampin, ethambutol and pyrazinamide.
Explain the drug interactions of rifampin with anticoagulants and other drugs, such as
oral contraceptives.
Therapeutic uses
Describe the regimen recommended for treatment of latent tuberculosis (formerly
prophylaxis) and active tuberculosis.
Explain the rationale for newer short-course regimens for latent and active
tuberculosis, including the use of isoniazid and rifapentine.
Describe the emergence of multidrug-resistant tuberculosis and its implications for the
treatment of these infections.
Discuss the use of rifabutin, clarithromycin and azithromycin for treatment of
Mycobacterium avium complex.
Describe the drugs used for reversing the lepra reactions and the erythema nodosum
leprosum reaction.
Explain the WHO regimen for treatment of leprosy.
Clinical Pharmacology
Mostly covered already in other sections of this document. Nothing special to add
here.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System – Abnormal
Antimicrobials and antiparasitics
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
Antiparasitic Drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
ALBENDAZOLE
atovaquone
IVERMECTIN
diethylcarbamazine
METRONIDAZOLE
diloxanide
MILTEFOSINE
iodoquinol
NITAZOXANIDE
mebendazole
PERMETHRIN
nifurtimox
PRAZIQUENTAL
paromomycin
SPINOSAD
pentamidine
TINIDAZOLE
pyrantel pamoate
pyrimethamine/sulfonamide
sodium stibogluconate
sulfadiazine
suramin
tinidazole
trimetrexate
Learning Objectives
Mechanism of action
Describe the mechanism of action of mebendazole, praziquantel, pentamidine, and
atovaquone.
Therapeutic uses
Learn the drugs of choice and alternate drugs available for treatment of diseases due
to various helminthes.
Learn the broad spectrum anthelminthic drugs and their spectrum of activity.
Learn the opportunistic infections commonly known to occur in AIDS patients and the
drugs used for their treatment.
Learn the drugs of choice for treatment of asymptomatic, mild to moderate and severe
intestinal disease and hepatic abscess due to E. histolytica.
Learn the drugs used for the treatment of protozoal diseases (giardiasis,
trypanosomiasis, and leishmaniasis).
Learn the drugs used for toxoplasmosis, an opportunistic infection in AIDS patients.
Clinical Pharmacology
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System – Abnormal
Antimicrobials and antiparasitics
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
Antimalarial drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
ARTESUNATE
atovaquone/proguanil
ARTEMETHER/LUMEFANTRINE
pyrimethamine
CHLOROQUINE
Sulfadoxine
DOXYCYCLINE
MEFLOQUINE
PRIMAQUINE
QUININE
Learning Objectives
Mechanism of action
Describe the various locations in the life cycle of malarial parasites where the
antimalarial drugs are effective.
Describe the mechanisms of action of chloroquine, primaquine and pyrimethamine.
Discuss the mechanism of resistance to chloroquine.
Learn the mechanism of action of artemisinin derivatives.
Pharmacokinetics
Describe the pharmacokinetic properties of chloroquine.
Describe the pharmacokinetic properties and metabolism of artesunate and
artemether.
Adverse effects
Explain the mechanism of hemolytic anemia induced by primaquine in AfricanAmerican males.
Describe cinchonism.
Describe the toxic effects of chloroquine.
Therapeutic uses
List the drugs of choice for treatment of uncomplicated illness and severe illness due to
P. vivax, P. ovale, P. malariae and P. falciparum.
Describe the regimen for prophylaxis for chloroquine-sensitive and chloroquineresistant areas.
Discuss the drug combination in Fansidar, Coartem, and Malarone and their
therapeutic use.
Describe the therapeutic indications for artemisinin derivatives.
Clinical Pharmacology
Drug interactions likely in patients with malaria and concurrent HIV infection due to
polypharmacy and effects especially on CYP3A4 activity.
Relevance
USMLE topic
Cardiovascular System – Abnormal
processes
Principles of therapeutics
Antimicrobials and antiparasitics
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
Antifungal Drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
AMPHOTERICIN B
flucytosine
CASPOFUNGIN (echinocandins)
ketoconazole
FLUCONAZOLE
micafungin
ITRACONAZOL
posaconazole
TERBINAFINE
griseofulvin
VORICONAZOLE
nystatin
sulfamethoxazole-trimethoprim
(cotrimoxazole)
Learning Objectives
Mechanism of action
Discuss the mechanism of action of each class of antifungal drugs.
Discuss the advantages of liposomal preparations of amphotericin B.
Pharmacokinetics
Describe the pharmacokinetic properties of the various antifungal drugs.
Adverse effects
Describe the important adverse effects of the various antifungal drugs.
Discuss the drug interactions of griseofulvin and warfarin; ketoconazole and warfarin.
Therapeutic uses
Describe the major therapeutic indications of the antifungal drugs, including current
recommendations for treating aspergillosis, blastomycosis, superficial and systemic
candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis,
and sporotrichosis.
Describe the use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis
jiroveci infections.
Discuss the appropriate duration of treatment of various fungal infections and the role
of surgical debridement in treating subcutaneous mycoses.
Describe host factors that predispose patients to fungal infections.
Clinical Pharmacology
Many antifungals are strong inhibitors of CYP3A4 and caution is indicated for patients
receiving concurrent drug therapy where CYP3A4 is a prominent drug metabolism
pathway.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System – Abnormal
Antimicrobials and antiparasitics
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
ACYCLOVIR
BOCEPREVIR
FOSCARNET
GANCICLOVIR
OSELTAMIVIR
RIBAVARIN
TELAPREVIR
TRIFLURIDINE
ZANAMIVIR
Antiviral Drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
amantadine
idoxuridine
peginterferon alfa
rimantadine
valacyclovir
valganciclovir
Learning Objectives
Mechanism of action
Classify antiviral drugs based upon their site of inhibition in the viral replication cycle.
Explain the mechanism of action of each antiviral drug.
Pharmacokinetics
Compare pharmacokinetic properties of acyclovir, valacyclovir, and ganciclovir, and
valganciclovir.
Adverse effects
List their adverse side effect and therapeutic complications. Describe potential drug
interactions.
Therapeutic uses
Describe major therapeutic indications for each antiviral drugs.
Compare the drugs and regimens used for prevention and treatment of
cytomegalovirus infections.
Describe the role and use of oseltamivir and zanamivir in the prophylaxis and treatment
of influenza.
Describe the emergence and mechanism of influenza virus resistance to amantadine
and rimantadine.
Describe the use of combination drug therapy in the treatment of hepatitis B and
hepatitis C.
Clinical Pharmacology
In drug therapy of hepatitis, polypharmacy is the standard of care. Use of telaprevir,
peginterferon and ribavirin as a treatment strategy increases risk for anemia.
Telaprevir is both a substrate and inhibitor of CYP3A4 and P-glycoprotein. Thus,
drug interactions are predictable, especially with concurrent therapies that have high
presystemic elimination by these two mechanisms.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System – Abnormal
Antimicrobials and antiparasitics
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions and
diseases
Antiretroviral Drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
Nucleoside Reverse Transcriptase
Non-Nucleoside Reverse Transcriptase
Inhibitors (NRTI)
Inhibitors (NNRTIs)
ABACAVIR
EFAVIRENZ
LAMIVUDINE (3-TC)
NEVIRAPINE
TENOFOVIR DISOPROXIL
ZIDOVUDINE (AZT)
EMTRICITABINE
didanosine (ddI)
stavudine (D4T)
HIV-1 protease inhibitors
Fusion Inhibitors
ATAZANAVIR
ENFUVIRTIDE
RITONAVIR
MARAVAROC
amprenavir
indinavir
lopinavir
nelfinavir
saquinavir
DNA Strand Transfer Inhibitor
RALTEGRAVIR
Learning Objectives
Mechanism of action
Classify anti-HIV drugs based upon their site of inhibition in the viral replication cycle.
Learn the mechanism of action of individual nucleoside reverse transcriptase inhibitors.
Explain the mechanisms of action of each class of anti-HIV drugs.
Explain the use of combinations of drugs derived from different drug classes
Pharmacokinetics
Compare pharmacokinetic properties of each class of anti-HIV drugs.
Adverse effects
Learn major side effects of each class of anti-HIV drugs, with emphasis on the
metabolic and cardiovascular adverse effects.
Describe the major drug interactions of anti-HIV drugs, with emphasis on interactions
involving inhibition or induction of cytochrome P450 enzymes.
Therapeutic uses
Describe the various currently preferred drug combinations used for the treatment of
HIV infections.
Describe the rationale and components of once-a-day formulations for treating HIV
infections.
Describe the CD4 cell and viral load criteria for the initiation of drug therapy for HIV
infection, and the criteria for changing drug therapy due to viral resistance.
Describe the use of drugs for treating maternal infections and prevention of maternalfetal transmission during pregnancy.
Describe the use of drugs for the prevention of HIV infection in adults.
Clinical Pharmacology
Present standard of care involves polypharmacy and almost invariably is associated
with drug interactions when co-morbidities are also treated with drugs. Extreme
caution is advised in choosing drugs for co-morbidities that may affect the elimination
mechanisms of the ART drugs prescribed.
Relevance
USMLE topic
Principles of therapeutics
Cardiovascular System – Abnormal
Antimicrobials and antiparasitics
processes
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic C
Drug treatment of common conditions
and diseases
Basic Principles of Cancer Chemotherapy
Recommended Curriculum Equivalent: 1 hr
Learning Objectives
Explain the role of chemotherapy in the management of patients with cancer.
Describe the prospects for “cure”, or long term survival in cases of advanced cancer.
Compare and contrast the strategies and outcomes from standard cytotoxic
chemotherapy and targeted therapies.
Describe the various limitations to effective drug treatment.
Define and explain the terms: selective toxicity, mass doubling time and growth fraction.
Explain the concepts of “total cell kill” and tumor stem cells in cancer treatment.
Explain the term cell cycle specificity and be able to classify the various anticancer
drugs based on the cell cycle specificity.
Describe the principles of combination chemotherapy in the treatment of cancer.
Explain the mechanisms of resistance to anticancer drugs.
Describe adverse effects of anticancer drugs, and approaches to minimizing adverse
effects.
Anticancer Drugs
Recommended Curriculum Equivalent: 3 hr
Drugs to consider
Alkylating agents
Antimetabolites
CYCLOPHOSPHAMIDE
CAPECITABINE
MECHLORETHAMINE
CYTARABINE
MELPHALAN
5-FLUOROURACIL
NITROSOUREAS (carmustine and
GEMCITABINE
lomustine)
METHOTREXATE
busulfan
fludarabine
dacarbazine
6-mercaptopurine
ifosfamide
thioguanine
Natural products
Tyrosine kinase inhibitors
BLEOMYCIN
IMATINIB
CAMPTOTHECIN analogs (irinotecan,
dasatinib
topotecan)
erlotinib
DAUNORUBICIN
gefitinib
DOXORUBICIN
lapatinib
DOCETAXEL
sunitinib
ETOPOSIDE (VP-16)
PACLITAXEL
VINBLASTINE
VINCRISTINE
idarubicin
Monoclonal Antibodies
Hormones
Miscellaneous Agents
TRASTUZUMAB
TAMOXIFEN
BORTEZOMIB
cetuximab
aromatase inhibitors
CISPLATIN
rituximab
(anastrozole, letrozole)
all-trans-retinoic acid (ATRA)
flutamide
asparaginase
glucocorticoids
carboplatin
(prednisone)
hydroxyurea
goserelin
interferon alpha 2a
leuprolide
lenalidomide
procarbazine
sorafenib
vorinostat
Learning Objectives
Mechanism of action
Describe the mechanism of action of various individual anticancer drugs under each
class.
Explain the bioactivation pathways required for the action of cyclophosphamide.
Describe the intracellular activation pathways of different antimetabolites.
Explain the use of antidote in high dose methotrexate therapy.
Adverse effects
Describe the common toxicities for each class of anticancer drugs.
Describe the specific major toxicity of individual anticancer drugs.
Describe the cumulative dose-dependent toxicity of anthracyclines.
Therapeutic uses
List the major therapeutic indications of various anticancer drugs.
Describe the drug combinations that have shown activity against specific types of
cancer.
Explain the concept of adjuvant chemotherapy and describe various regimens used in
the treatment of cancer of different organ systems.
Discuss the impact of both patient and tumor genotypes on drug choices and efficacy in
cancer chemotherapy.
Clinical Pharmacology
Since these treatments are cytotoxic, drug interactions are to be expected, and
pretreatment evaluation for possible interactions resulting in toxicity and/or loss of
efficacy of drug therapy for co-morbidities is mandatory.
Relevance
USMLE topic
Principles of therapeutics
Antineoplastics
All organ systems
AAMC Medical School Objectives
Project Report X Patient Safety
Table 1
Topic E
How to find and use the most up-to-date
info on drugs
Immunomodulatory Drugs
Recommended Curriculum Equivalent: 1 hr
Drugs to consider
AZATHIOPRINE
antithymocyte globulin
CYCLOSPORINE
cyclophosphamide
MYCOPHENOLATE MOFETIL
daclizumab
PREDNISONE
etanercept
infliximab
interferons (alpha, beta & gamma)
lenalidomide
methotrexate
muromonab-cd3
rho(d) immune globulin
sirolimus (rapamycin)
tacrolimus
thalidomide
Learning Objectives
Mechanism of action
Define the general principles of immunosuppression and immunostimulation.
Describe the mechanism of action of immunosuppressants and immunostimulants.
Adverse effects
Describe the toxicities of antibodies and other agents used as immunosuppressants
Describe the different types of allergic reactions to drugs
Therapeutic uses
Describe the clinical uses of immunosuppressants.
Clinical Pharmacology Due to the high first pass elimination of cyclosporine, any
additional drug therapy must be evaluated for potential interactions with CYP3A4 and Pglycoprotein that might place the patient’s transplanted organ at risk.
USMLE topic
Relevance
Principles of therapeutics
Musculoskeletal System
Mechanisms of action and use of drugs
for treatment of disorders of the
musculoskeletal system
AAMC Medical School Objectives
Project Report X Patient Safety
Topic C
Drug treatment of common conditions
and diseases, using frequently
prescribed classes of drugs for the
treatment and prevention of disease
Table 1
Hemostasis and Blood Forming Organs
Subcommittee:
Williams, Patricia B. (Chair) [email protected]
McMillan, David [email protected]
Dobrydneva, Yuliya [email protected]
Hemostasis and Blood Forming Organs
Recommended Curriculum Equivalent: 1.5 hr
Drugs for Treating Anemia
Minerals
Vitamins
DEFEROXAMINE
CYANOCOBALAMIN
FERROUS SULFATE
FOLIC ACID
ferrous gluconate
VITAMIN B12
iron dextran
Hematopoietic growth factors
ERYTHROPOIETINS
Myeloid Growth Factors
EPOETIN ALFA
Filgrastim
Darbepoetin
Sargramostim
Thrombopoietic Growth Factors
Interleukin-11
Thrombopoietin
Learning Objectives
Physiology and pathophysiology
Diagram the normal physiological control of hematopoietic growth factors and the
effect of kidney failure on erythropoiesis.
Relate factors that can lead to abnormal iron balance including genetic
hemochromatosis to the iron absorption and transport pathways.
Describe the biochemical systems, which are impaired in B-12 and folic acid
deficiency, and the role of cyanocobalamin and folic acid in correcting the metabolic
defect in DNA thymine and methionine synthesis.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the pharmacological effects of each class of drugs on the hematopoietic
system.
Pharmacokinetics
Describe the possible etiologies, which should be considered if a delayed or
diminished response to doses of recombinant erythropoietin within the
recommended dose range occurs.
Analyze how the pharmacokinetics and therapeutic effects of epoetin alpha and
darbepoetin alpha differs between normal and anemic dialysis patients.
Describe the sources, transport, metabolism, storage, and excretion of vitamin B-12
and folic acid. State the factors, which influence the bioavailability of vitamin B-12
and folic acid.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects and contraindications of the drugs in each
class.
Describe the clinically important drug interactions of the drugs in each class.
Identify adverse events associated with erythropoietin use in cancer patients, and black box
warning on erythropoietin preparations.
Therapeutic uses
Apply the criteria for oral therapy versus parenteral iron therapy to a patient with iron
deficiency anemia. Consider the associated side effects and the predicted rates of
response to the two therapies.
Summarize the risks of acute iron poisoning in children and its treatment.
Evaluate the pharmacologic management of chronic iron overload disease (e.g.
secondary to chronic blood transfusion, iron absorption disturbances, etc.).
Explain the appropriate management of the patient with a megaloblastic anemia in
regards to both acute and chronic management, vitamin dosage and expected
response.
Compare the possible metabolic reasons why folic acid will correct the erythropoietic
lesion but not the neurologic lesion in Addisonian pernicious anemia.
What is the rationale for the use of folic acid in patients with elevated serum levels of
homocysteine or spina bifida?
Compare the therapeutic applications for myeloid growth factors with those for
thrombopoietic growth factors.
Differentiate approaches to treatment of folic-dependent vs B12- dependent
megaloblastic anemia; describe how laboratory tests guide choice of treatment.
Describe cancer vs non-cancer indications for myeloid growth factors. Delineate
specific types of cancer where these growth factors are contradicted.
Notes
Clinical Pharmacology
In chronic kidney disease, iron absorption from the gastrointestinal tract is often
impaired. Intravenous iron may be considered and may decrease the dose of more
expensive erythropoiesis-stimulating therapies. Caution in that i.v. high molecular
weight iron preparations are associated with increased risk of anaphylaxis.
Relevance
USMLE topic
Principles of therapeutics
Hematopoietic and Lymphoreticular
Treatment of anemia, drugs stimulating
Systems-Abnormal Processes-Anemia
erythrocyte production
of Chronic Disease
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table 1
conditions,
Topic D: Management of less common but
severe medical conditions and emergencies.
Anticoagulant Drugs
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to Consider
Indirect Thrombin
Inhibitors
HEPARIN
PROTAMINE
SULFATE (antidote)
Direct Thrombin
Inhibitors
Factor Xa
Inhibitors
Inhibitors of Clotting
Factor Synthesis
DABIGATRAN
ENOXAPARIN
VITAMIN K
bivalirudin
RIVAROXABAN
(antidote)
lepirudin
fondaparinux
WARFARIN
Learning Objectives
Physiology and Pathophysiology
Explain the role of the coagulation cascade in the regulation of hemostasis.
Describe the synthesis of the vitamin K-dependent clotting factors, and explain the
role of antithrombin in the regulation of hemostasis.
Examine the pathogenesis of venous thrombosis.
Mechanism of Action
Explain the molecular mechanism of action of the drugs in each drug class.
Compare the structural features of unfractionated heparin, direct thrombin inhibitors
and factor Xa inhibitors that determine their target specificity.
Relate the structural similarity of warfarin to vitamin K to explain the mechanism of
action of inhibitors of clotting factor synthesis.
Actions On Organ Systems
Analyze the effect of heparin on platelet aggregation and plasma lipids.
Explain how the anticoagulant responses to heparin and warfarin are monitored
clinically using aPTT and INR, respectively.
Pharmacokinetics
Identify the anticoagulants that are orally effective vs. those that must be given
parenterally.
Compare the rates of onset of action of heparin with warfarin in regard to their routes
of administration and mechanisms of action.
Apply the effects of warfarin on vitamin K-dependent clotting factor turnover to its
anticoagulant activity.
Explain how genetic polymorphisms in CYP2C9 and VKORC1 can affect the patient
response to warfarin.
Adverse Effects, Drug Interactions and Contraindications
State the principal complication of anticoagulant therapy (bleeding) and describe the
adverse effects and contraindications of the drugs in each class.
Describe the incidence and time to onset of heparin-induced thrombocytopenia.
Explain how protamine and vitamin K are used as antidotes to excessive bleeding
caused by heparin and warfarin, respectively.
Describe the effects of warfarin therapy during pregnancy on the developing fetus.
Discuss the disease, drug, food and herbal interactions with warfarin; explain how
dietary vitamin K can affect warfarin therapy.
Therapeutic Uses
Evaluate parenteral and oral anticoagulant therapy for initial and long-term
management of patients with venous thrombosis and pulmonary embolism.
Formulate a plan for the pharmacological management of thromboembolic
complications from heparin-induced thrombocytopenia.
Apply the goals of warfarin therapy to its use in patients with:
atrial fibrillation
prosthetic heart valves
myocardial infarction
stroke
Defend the advantages/disadvantages of treatment with dabigatran or rivoraxaban,
instead of warfarin for oral anticoagulant therapy.
Notes
Clinical Pharmacology
Patients receiving heparin for more than 4 days have an up to 5% risk of
developing heparin-induced thrombocytopenia. Non-heparin anticoagulant
alternatives are used to treat this condition, including fondaparinux, a factor
X inhibitor, that is used off label. Its advantages include once daily,
subcutaneous administration and the lack of effect on INR. It is important to
remember that fondaparinux has no antidote for its infrequent causation of a
major bleeding episode. The drug may also accumulate in patients with
renal insufficiency and is contraindicated in patients with a creatinine
clearance of < 30 ml/min.
Dabigatran and rivaroxaban were designed as alternatives to warfarin, but both
also predispose patients to high risk for stroke, serious bleeding and blood
clots. Like fondaparinux, both have no known antidote, accumulate in
patients with renal insufficiency, and interact with many of the same drugs
that interact with warfarin. As a P-glycoprotein substrate, dabigatran’s use
must be reconsidered during concurrent administration of drugs that induce
or inhibit P-glycoprotein.
Relevance
USMLE topic
Principles of therapeutics
Hematopoietic and Lymphoreticular
anticoagulants
Systems-Abnormal ProcessesHemorrhagic and Hemostatic Disorders
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table 1
conditions,
Topic D: Management of less common
but severe medical conditions and
emergencies.
Antiplatelet Drugs
Recommended Curriculum Equivalent: 0.75 hr
Drug Classes and Drugs to consider
PhosphoCyclooxygenase
ADP P2Y12
GPIIb/IIIa
INHIBITORS
diesterase
Inhibitors
Inhibitors
inhibitors
OF PAR-1
Inhibitors
ASPIRIN
CLOPIDOGREL dipyridamole ABCIXIMAB
vorapaxar
(acetylsalicylic
TICLOPIDINE
EPTIFIBATIDE
acid)
parasugrel
tirofiban
ibuprofen
Learning Objectives
Physiology and pathophysiology
Explain the role of platelet aggregation in the regulation of hemostasis.
Describe the pathogenesis of thrombosis with respect to the platelet activation.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Describe how inhibition of prostaglandin synthesis affects platelet aggregation,
specifically the role of COX-1 and COX-2.
Compare differences and similarities in mechanism of action for antiplatelet drugs:
e.g. aspirin, dipyridamole, clopidogrel, abciximab, vorapaxar.
Actions on organ systems
Identify the site of action of each drug in the platelet aggregation process.
Pharmacokinetics
Contrast the effects and time course of aspirin with nonsteroidal anti-inflammatory
agents (NSAIDs) and cyclooxygenase 2 (COX2) inhibitors on platelet function.
Demonstrate how manipulation of the dosing regimen for aspirin can reduce adverse
effects, particularly on the GI tract.
Describe difference in routes of administration for different classes of antiplatelet
drugs.
Adverse effects, drug interactions and contraindications
Describe the principal adverse effects and contraindications of the drugs in each
class.
Discuss drug-drug, drug-food, and drug-disease interactions of each drug.
Explain how concomitant use of NSAIDS, e.g. ibuprofen, can interfere with the
antiplatelet actions of aspirin.
Contrast the effects of reversible with irreversible inhibitors on duration of action.
Therapeutic uses
Discuss the approach to the management of the patient on short term and long term
antiplatelet therapy.
Explain the role of the platelet glycoprotein IIb/IIIa inhibitors in the diagnosis and
management of coronary artery disease.
Contrast the effects of aspirin, dipyridamole, clopidogrel, and propranolol for primary
post MI prophylaxis.
Compare differences and similarities in appropriate clinical indications for antiplatelet
agents.
Notes
The antiinflammatory, analgesic and antipyretic effects of aspirin and NSAIDS,
including COX-2 inhibitors, are discussed in Analgesics Knowledge Objectives.
Clinical Pharmacology
Low-dose enteric-coated aspirin is now considered standard of care to prevent
recurrence of a mycocardial infarction. In patients with atrial fibrillation and
one or more additional risk factors, warfarin was found superior to
clopidogrel plus aspirin for stroke risk reduction (ACTIVE W Trial).
In selected patients with CHF in normal sinus rhythm warfarin has no
advantage over aspirin for stroke risk reduction (WARCEF trial). It is
important to emphasize to patients receiving low-dose enteric-coated aspirin
either prophylactically or post-myocardial infarction that concurrent NSAIDs
for pain management are contraindicated, and that acetaminophen becomes
the first choice non-opioid analgesic for initial pain management.
Relevance
USMLE topic
Principles of therapeutics
Hematopoietic and Lymphoreticular
Anti-platelet drugs
Systems-Abnormal ProcessesHemorrhagic and Hemostatic Disorders
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table 1
conditions,
Topic D: Management of less common
but severe medical conditions and
emergencies.
Thrombolytic Drugs
Recommended Curriculum Equivalent: 0.25 hr
Drug Classes and Drugs to Consider
Plasminogen Activators
Inhibitors of Fibrinolysis
t-PA
aminocaproic acid
ALTEPLASE
reteplase
tenectaplase
Learning Objectives
Physiology and pathophysiology
Explain the role of plasminogen in thrombolysis
Describe the role of thrombolysis in the physiology of hemostasis
Mechanism of action
Contrast the molecular mechanism and site of action of alteplase with
aminocaproic acid.
Describe the pharmacologic effects of alteplase on thrombi.
Pharmacokinetics
Differentiate between the pharmacokinetic properties of t-PA, alteplase and
tenectaplase.
Adverse effects, drug interactions and contraindications
Relate the major adverse effect of thrombolytic drugs to their mechanism of action.
Describe the primary contraindications for thrombolytic drugs.
Therapeutic uses
Identify the major indications for thrombolytic drug therapy:
Myocardial infarction
Ischemic stroke
Deep venous thrombosis
Pulmonary embolism
Discuss aminocaproic acid (EACA), a fibrinolytic inhibitor, which is used
routinely along with desmopressin and factor replacement in dental
procedures in patients with hemophilia and von Willebrand’s disease and for
non-dental bleeding episodes in both diseases.
Notes
Clinical Pharmacology
The plasminogen activator thrombolysis drugs have been studied almost exclusively
in acute myocardial infarction patients. These fibrin-specific agents are perceived
to be associated with a lower all-cause mortality than the nonspecific thrombolytic
drug streptokinase. These drugs are still considered too new to determine their
ultimate utility for other thrombotic disorders, and whether or not adverse events
are drug class-specific or a reflection of differences among competing marketed
products.
Relevance
USMLE topic
Hematopoietic and Lymphoreticular
Systems-Abnormal ProcessesHemorrhagic and Hemostatic Disorders
Principles of therapeutics
thrombolytic drugs
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table 1
conditions
Topic D: Management of less common
but severe medical conditions and
emergencies.
Endocrine Pharmacology
Subcommittee
Shelley Tischkau, Chair, [email protected]
Brunton, Laurence, [email protected]
Mary L. Thomas, [email protected]
Introduction to Endocrine Pharmacology
Recommended Curriculum Equivalent: 0.5 hr
Learning Objectives
Physiology and pathophysiology
General functions of hormones and their target organs; principal type of hormones
(structure-activity relationships, location and type of receptors). Types of feedback
regulation involved in maintaining necessary blood level of hormone.
Etiology of endocrine syndromes including those due to: hormone deficiency/excess,
receptor defect, hormone resistance, abnormal hormone dynamics, binding proteins
Mechanism of action
Mechanisms of hormone action including: receptors and signal transduction pathways
for hormones (the location of receptors, molecular events activated by hormones
that interact with intracellular receptors and second messenger systems that are
commonly linked to membrane-associated extracellular receptors)
Pharmacokinetics
Regulation of hormone synthesis/release/disposition: the role of day-night rhythms,
patterns of release, binding proteins, modulating factors (neurotransmitters,
releasing hormones, nutrients), and measurement in biological fluids
Growth
Hormone
OCTREOTIDE
PEGVISOMAN
T
SERMORELIN
SOMATROPIN
bromocriptine
lanreotide
mecasermin
Hypothalamus, Anterior Pituitary 1
Recommended Curriculum Equivalent: 2.0 hr
Drug Classes and Drugs to consider
Prolactin
Gonadotropins
ACTH
TSH
BROMOCRIPTIN CHORIONIC -hCG
thyrotropin
E
GANIRELIX
cosyntropin
CABERGOLINE GONADOTROPIN
HUMAN
LEUPROLIDE
UROFOLLITROPIN
abarelix
cetrorelix
follitropin
goserelin
histrelin
lutropin alpha
menotropins
nafarelin
triptorelin
Learning Objectives
Physiology and pathophysiology
Know releasing factors (GHRH, GnRH, DA) and trophic hormones (ACTH, TSH, GH,
LH, FSH, prolactin) of the anterior pituitary.
Understand the regulation of growth hormone (GH) biosynthesis and secretion
including the roles of growth hormone releasing hormone (GHRH) and GH-releasing
peptides, glucose levels, somatostatin, and dopamine – age; body composition.
Know role of insulin-like growth factor 1 in secondary effects of GH and in feedback
regulation of GH secretion
Know the physiological conditions that elicit growth hormone secretion; outline how
specific diagnostic maneuvers can elicit GH secretion.
Understand the regulation of prolactin biosynthesis secretion and release by suckling;
effect of dopaminergic and serotonergic agonists and antagonists
List pharmacological actions that can induce hyperprolactinemia.
Understand the medical problems related to hypersecretion of prolactin in the female
(galactorrhea, amenorrhea, infertility) and in the male (hypogonadism, infertility).
Know the hypothalamic-anterior pituitary-gonadal axis, target tissue products (inhibin
and sex steroids), and feedback pathways. Describe the kinetics of secretion for
GnRH and the relationship to the therapeutic uses of synthetic analogs, the mode of
administration and therapeutic considerations.
Understand the physiological importance of ACTH suppression by pharmacological
glucocorticoids
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the biological actions of growth hormone on peripheral tissues (e.g., protein
synthesis, intermediary metabolism).
Outline the role(s) of IGF-1.
Describe the biological actions of prolactin on breast development and lactation; learn
the interrelationship of the hormones that are involved in breast development and
lactation: growth hormone, estrogen, progesterone, glucocorticoids, TRH, prolactin,
oxytocin, and insulin.
Know clinical uses of GnRH and its agonist and antagonist analogs.
Adverse effects, drug interactions and contraindications
List the adverse effects of GH therapy in children and adults.
Describe the adverse effects of GnRH and analogs as therapeutic agents when used
to treat infertility, prostatic carcinoma, endometriosis, central precocious puberty.
Therapeutic uses
Understand the medical problems related to hypo- or hyper- secretion of GH and the
role of releasing/replacement therapy and release inhibiting drugs in the
management of these states, respectively.
Understand the mode of administration and therapeutic considerations: intermittent
(infertility) versus continuous administration (endometriosis, uterine fibroids,
prostate cancer), precocious puberty.
Describe the utility of the rapid ACTH stimulation test in diagnosing pituitary-adrenal
disorders and what endpoint is measured.
Notes
Clinical Pharmacology
Low bioavailability of bromocriptine makes it very susceptible to drug interactions,
because it is metabolized by CYP3A4, a P450 isoform that is readily induced or
inhibited by concurrently administered medications. It has recently been approved
for management of type 2 diabetes, but it is only marginally effective for this
indication.
Relevance
USMLE topic
1) Endocrine system-Normal Processeshypothalamus and anterior pituitary
gland
2) Endocrine system-Abnormal
Processes-neoplastic disorder,
metabolic and regulatory processes,
systemic disorders, congenital and
genetic disorders affecting the
endocrine system
3) Reproductive System-Normal
processes, hypothalamic-pituitarygonadal axis
4) Reproductive System-Abnormal
processes-congenital and genetic
disorders-disorders relating to
pregnancy
AAMC Medical School Objectives
Project Report X Patient Safety – Table
1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
endocrine system
Hormones and hormone analogs
Stimulators of hormone production
Inhibitors of hormone production
Hormone antagonists
Potentiators of hormone action
Gonadotropin-releasing hormone and
gonadotropin replacement, incudin all
gonadotropin-releasing antagonists
Stimulators and inhibitors of lactation
Topic C: Drug treatment of common
conditions
Hypothalamus and Posterior Pituitary
Recommended Curriculum Equivalent: 1.0 hr
Drug Classes and Drugs to consider
Vasopressin
Oxytocin
DESMOPRESSIN
OXYTOCIN
VASOPRESSIN
chlorpropamide
conivaptan
demeclocycline
tolvaptan
Learning Objectives
Physiology and pathophysiology
Discuss the effects of vasopressin on receptor subtypes and signal transduction
systems in vascular smooth muscle and the kidney. Describe the mechanisms by
which vasopressin increases renal water conservation.
Consider drugs that affect vasopressin release/action and their relationship to the
therapy of diabetes insipidus (DI) and SIADH
List drugs that can cause diabetes insipidus (nephrogenic and neurogenic) and
SIADH.
Describe the pharmacokinetics and actions of oxytocin and roles in parturition and
lactation.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the pharmacokinetics and actions of vasopressin and analogs.
Adverse effects, drug interactions and contraindications
Understand the toxicity and contraindications for oxytocin.
Therapeutic uses
Preparations and routes administration of vasopressin analogs available for treating
neurogenic and partial diabetes insipidus, bleeding of esophageal varices and
deficient blood clotting factors in hemophilia.
Understand the diagnostic and therapeutic uses of oxytocin.
Notes
Clinical Pharmacology
Relevance
USMLE topic
1) Endocrine system-Normal Processeshypothalamus and posterior pituitary
pituitary gland
2) Endocrine system-Abnormal
Processes-neoplastic disorder,
metabolic and regulatory processes,
systemic disorders
3) Renal/Urinary System-Abnormal
Processes-metabolic and regulatory
disorders, systemic diseases affecting
the renal system
4) Reproductive system-Normal
processes-pregnancy, labor and
delivery
AAMC Medical School Objectives
Project Report X Patient Safety – Table
1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
endocrine system
Hormones and hormone analogs
Inhibitors of hormone production
Hormone antagonists
Drugs used to treat volume, electrolyte
and acid-base disorders
Female reproductive tract-Stimulants and
inhibitors of labor
Topic C: Drug treatment of common
conditions
ADRENAL CORTEX
Recommended Curriculum Equivalent: 1.5 hr
Drug Classes and Drugs to consider
Glucocorticoid-related
Mineralocorticoid-related
CORTISOL (hydrocortisone)
ALDOSTERONE
DEXAMETHASONE
FLUDROCORTISONE
KETOCONAZOLE
SPIRONOLACTONE
METYRAPONE
eplerenone
PREDNISONE
aminoglutethimide
beclomethasone
betamethasone
etomidate
fluticasone
mifepristone
mitotane
prednisolone
triamcinolone
Learning Objectives
Physiology and pathophysiology
Describe the regulation of corticosteroid synthesis by ACTH and angiotensin.
Review the regulation of aldosterone secretion by angiotensin (I, II, and III).
Mechanism of action
Explain the molecular mechanism of action of agonists and antagonists in each drug
class. Be aware of receptor-independent effects via 11-beta-steroid hydroxylase on
corticosteroid specificity.
Actions on organ systems
Describe the actions of corticosteroids on intermediary metabolism, growth and
development, electrolyte homeostasis, immune and inflammatory responses.
Understand the cellular/molecular mechanisms of action of corticosteroids.
Know the importance of synthetic glucocorticoids, especially those modifications that
enhance pharmacodynamic activity and/or determine activity based on route of
administration.
Pharmacokinetics
Describe the significance of corticosteroid disposition (protein binding,
biotransformation, enzyme induction) that may necessitate changes in dosage
regimens.
Adverse effects, drug interactions and contraindications
List the adverse effects/contraindications related to corticosteroid use.
List the adverse effects of excessive mineralocorticoid activity.
Therapeutic uses
Explain the rationale for corticosteroid use in replacement therapy, as antiinflammatory and immunosuppressive agents, and as diagnostic agents in
hypothalamo-pituitary adrenocortical disease/dysfunction.
Explain the use of fludrocortisone in replacement therapy.
Explain the rationale for alternate day therapy and the necessity for slow withdrawal
following chronic therapy with glucocorticoids.
Explain the rationale for spironolactone in treating primary hyperaldosteronism.
Notes
Clinical Pharmacology
Prednisone is a prodrug and may be poorly activated in patients with severe liver
disease.
Ketoconazole is a potent inhibitor of both CYP3A4 and P-glycoprotein. It is to be used
with caution in patients receiving other drug therapies that are modulated by this
transporter (P-gp) and drug metabolizing enzyme (3A4).
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – adrenal cortex,
Mechanisms of action and use of drugs
adrenal medulla
for treatment of disorders of the
2) Normal process – cell tissue structure
endocrine system
function, hormone synthesis secretion
Hormones and hormone analogs
action and metabolism
Inhibitors of hormone production
3) Abnormal process – adrenal disorders, Hormone antagonists
neoplastic disorders
Drugs used to treat volume, electrolyte
4) Abnormal processes – drug-induced
and acid-base disorders
adverse effects on the endocrine
system
5) Abnormal processes – systemic
disorder affecting the endocrine system
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table
conditions
1
Topic D: Management of less common
but severe medical conditions and
emergencies
THYROID
Recommended Curriculum Equivalent: 1.0
Drug Classes and Drugs to consider
LEVOTHYROXINE
METHIMAZOLE
POTASSIUM
IODIDE
PROPRANOLOL
PROPYLTHIOURACIL
RADIOIODINE (131I)
carbimazole iodide salts
ipodate
triiodothyronine (liothyronine)
Learning Objectives
Physiology and pathophysiology
Outline the regulation and the key steps in thyroid hormone synthesis and peripheral
conversion.
Explain the mechanisms by which thyroid hormones regulate cellular function.
Describe the signs/symptoms of hypothyroidism (myxedema) and the consequences
of the disease that can alter drug therapy for other concurrent diseases.
Mechanism of action
Explain the molecular mechanism of action of each of the drugs listed above.
Actions on organ systems
Delineate the relationship between thyroid hormones and the actions of
catecholamines and provide the rationale for the use of propranolol in the treatment
of hyperthyroidism.
Pharmacokinetics
Provide the pharmacokinetic rationale for selecting the most appropriate form of
thyroid hormone as replacement therapy.
Identify the best index of adequate replacement therapy with thyroid hormone.
Provide the pharmacokinetic rationale for selecting the most appropriate anti-thyroid
drug for treating hyperthyroidism (diffuse toxic goiter) in a non-pregnant versus a
pregnant female.
Adverse effects, drug interactions and contraindications
Describe the adverse effects of anti-thyroid medications and identify those that are
potentially life threatening.
Therapeutic uses
Describe the caution necessary when replacing thyroid hormone in a patient with a
history of coronary artery disease.
Describe the rationale and order of administration of drugs given to treat thyroid
storm.
Provide the rationale for the uses of drugs/radioiodine in treating hyperthyroidism;
explain their mechanism(s) of action; consequences of radioiodine use.
Notes
Clinical Pharmacology
Only thyroxine is indicated for the treatment of hypothyroidism. Use of triiodothyronine is dangerous because of its increased potency and rapid and
potential adverse effects on cardiac function.
Propylthiouracil is the antithyroid drug of choice in pregnancy because of its shorter
half-life and its lesser tendency to cross the placenta.
Although propranolol is active in decreasing conversion of T4 to T3, this has no place
in the therapeutic approach to management of hyperthyroidism to reduce T3
production. Propranolol is only indicated in thyroid storm to decrease the
enhancement of catecholamine stimulation of cardiac contractility in the
hyperthyroid state.
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – thyroid gland
Mechanisms of action and use of drugs
2) Normal processes – thyroid hormone
for treatment of disorders of the
synthesis, secretion action and
endocrine system
metabolism
Hormones and hormone analogs
3) Abnormal process – thyroid disorders, Inhibitors of hormone production
neoplastic disorders
Hormone antagonists
4) Abnormal processes, metabolic and
regulatory processes
5) Abnormal processes – infectious,
inflammatory and immunological
disorders
6) abnormal processes – drug-induced
adverse effects on the endocrine
system
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table
conditions
1
Topic D: Management of less common
but severe medical conditions and
emergencies
PARATHYROID and Ca++ and PO4- Homeostasis
Recommended Curriculum Equivalent: 0.5 hr
Drug Classes and Drugs to consider
ALENDRONATE
CALCITRIOL
CALCIUM GLUCONATE
PARATHYROID HORMONE
calcitonin
cinacalcet
denosumab
furosemide
ibandronate
pamidronate
paracalcitol
plicamycin
prednisone
sevelamer
sodium fluoride
teriparatide
vitamin D (cholecalciferol/ergocalciferol)
zoledronate
Learning Objectives
Physiology and pathophysiology
Understand the regulation of calcium homeostasis and the physiological actions of
parathyroid hormone (PTH), calcitonin (CT) and 1,25-dihydroxyvitaminD3 [1,25(OH)2D3]; understand the role(s) of 1alpha-hydroxylation of 25-OH vitamin D, and of
kidney, liver and GI tract in vitamin D homeostasis.
Describe the mechanisms regulating synthesis, secretion of PTH and actions and CT
their mechanism(s) of action on bone, kidney and intestine.
Be aware of the extra-renal 1alpha-hydroxylation of 25-OH vitamin D and potential
importance in the innate immune system and in cancer prevention and therapy
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Adverse effects, drug interactions and contraindications
Review the possible adverse effects of CT, 1,25-(OH)2D3 and calcium supplements.
Describe the chronic toxicity associated with long-term use of sodium fluoride.
Therapeutic uses
Know the available preparations of CT, 1,25-(OH)2D3, and calcium supplements and
their clinical uses; compare and contrast the treatment of hypo- and hyperparathyroidism.
Understand the clinical value of bisphosphonates and CT in the treatment of:
hypercalcemia, Paget’s disease, osteoporosis (postmenopausal and
glucocorticoid-induced).
Know current guideline for vitamin D supplementation and goals for blood level of
vitamin D.
Know current recommendations for treating osteoporosis, especially with respect to
use of bisphosphonates, estrogens (esp. raloxifene), teriparatide, and
denosumab.
Notes
Clinical Pharmacology
Calcium carbonate preparations remain the most cost effective form for patients
requiring calcium supplementation. Calcium supplements should always be taken
with vitamin D to enhance their bioavailability.
Chronic use of bisphosphonates is being questioned, since there is lack of evidence
for efficacy for fracture prevention beyond 3-5 years of ingestion.
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – parathyroid gland Mechanisms of action and use of drugs
2) Normal processes – vitamin D
for treatment of disorders of the
synthesis, secretion, action and
endocrine system
metabolism
Hormones and hormone analogs
3) Abnormal process – parathyroid
Inhibitors of hormone production
disorders, neoplastic disorders
Hormone antagonists
4) Abnormal processes, metabolic and
regulatory processes
5) Abnormal processes – idiopathic
disorders
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table
conditions
1
THE ENDOCRINE PANCREAS
Recommended Curriculum Equivalent: 1.5 Hr
Drug Classes and Drugs to consider
ACARBOSE
INSULINS (aspart, glulisine, lispro, regular, NPH, detemir, glargine)
METFORMIN
GLIPIZIDE
PIOGLITAZONE
REPAGLINIDE
chlorpropamide
exenatide
liraglutide
glucagon
glimepiride
glyburide
nateglinide
pramlintide
rosiglitazone
saxagliptin
sitagliptin
Learning Objectives
Physiology and pathophysiology
Describe the normal daily patterns insulin secretion and changes that occur in
different types of diabetes mellitus.
Describe the effects of insulin and glucagon on intermediary metabolism and ion
transport.
Describe the effects of incretin hormones, esp. GLP-1, on insulin and glucagon
secretion.
Describe the effects of amylin on glucagon secretion.
Describe the pathophysiology of the primary types of diabetes mellitus (bihormonal
disease – insulin and glucagon), and their sequelae: diabetic ketoacidosis and nonketotic hyperosmolar coma.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Pharmacokinetics
Describe the pharmacokinetic (onset and duration of action) rationale for the use of
insulin preparations in ‘split-mixed’ or continuous s.c. infusion.
List commonly used drugs with which sulfonylurea compounds are known to interact
and the postulated mechanisms for these interactions (first vs. second generation).
Adverse effects, drug interactions and contraindications
Describe the clinical manifestations and management of overdose with insulin and
oral hypoglycemic agents, respectively.
Therapeutic uses
Explain the mechanisms by which oral anti-diabetic agents act and the influence these
mechanisms have on selection for therapy in individual patients (e.g., obese).
Describe the relative roles of insulin and oral hypoglycemics in the treatment of type I
and type II diabetes mellitus.
Discuss the use of recombinant DNA insulin preparations and the insulin pumps that
are employed in certain patients.
Know the utility of assessing HbA1c.
Notes
Clinical Pharmacology
Metformin has become the defacto first line agent for drug therapy of type 2 diabetes.
The next step is usually to add a sulfonylurea. Combination drug products are
being heavily marketed and are consistently more expensive than ingestion of the
generic durgs separately.
If a DPP-4 inhibitor is considered as add-on therapy, linagliptin may be preferable in
patients with renal impairment, since there is no need to adjust drug dose for this
pathology. However safety of DDP-4 inhibitor with long-term use remains to be
established. Use of glitaxones as add-on therapy is associated with weight gain
and the potential increased risk of heart failure.
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – pancreatic islets
Mechanisms of action and use of drugs
2) Normal processes – insulin synthesis,
for treatment of disorders of the
secretion action and metabolism
endocrine system
3) Abnormal process – neoplastic
Hormones and hormone analogs
disorders, pancreatic islets
Inhibitors of hormone production
4) Abnormal processes, metabolic and
Hormone antagonists
regulatory processes, diabetes mellitus Potentiators of hormone action
5) Abnormal processes – infectious,
Other treatment for diabetes
inflammatory and immunologic
disorders
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table
conditions
1
GONADAL HORMONES
Recommended Curriculum Equivalent: 1.5 HR
Drug Classes and Drugs to consider
Estrogen/progestins
Androgens
ANASTROZOLE
FINASTERIDE
CLOMIPHENE
FLUTAMIDE
ETHINYL
OXANDROLONE
ESTRADIOL
TESTOSTERONE
EXEMESTANE
cicalutamide
MEDROXYPROGESTERONE
cyproterone
NORETHINDRONE
danazol
PROGESTERONE
leuprolide
RALOXIFENE
TAMOXIFEN
conjugated/esterified estrogens
diethylstilbestrol
drosperinone
estradiol 17ß
estrone
levonogestrel
mestranol
mifepristone
norgestrel
phytoestrogens
ulipristal
Learning Objectives
Physiology and pathophysiology
Describe the gametogenic and steroidogenic functions of the ovary and their
regulation by gonadotropins.
Know the sources of androgens (ovary, testes, adrenal) and understand their
regulation of secretion; define the roles of LH and FSH on gonadal function.
Define the importance of androgens for sexual differentiation and puberty.
Understand medical problems associated with hypo- (hypogonadism) and
hyperfunction (precocious puberty, hyperandrogenism) and rationale for therapy.
Describe the rationale for the clinical uses of androgens in: replacement therapy,
anemia, and catabolic states.
Mechanism of action
Describe, in general terms, the cellular/molecular mechanism of action of sex steroids.
Distinguish between direct effects of testosterone and those mediated by
dihydrotestosterone and estradiol. Know the mechanisms of action of all agents
listed above.
Actions on organ systems
Elucidate the effects of estrogen on: cardiovascular function, intermediary
metabolism, electrolyte and water balance, cognition, reproductive function, skin,
plasma proteins and blood lipids hepatic function
Describe the effects of estrogens on laboratory tests, including liver function, clotting
factors, thyroid hormone disposition and adrenocortical function.
Describe the effects of androgens on growth and development (anabolic actions vs.
androgenic actions).
Pharmacokinetics
Describe differences in absorption, distribution, and elimination between synthetic and
natural estrogens, including those in the environment (e.g., phytoestrogens).
Compare the routes of administration, absorption and relative duration of action of
synthetic androgens and testosterone.
Adverse effects, drug interactions and contraindications
List major adverse effects/contraindications for estrogens and progestins alone and in
combination.
List the most common drug and nutriceutical interactions with estrogens and
progestins.
Describe the adverse effects of androgens/anabolic steroids when used in male and
female.
Correlate the hepatoxicity of certain androgens/anabolic steroids with their chemical
structure.
Therapeutic uses
Describe the use of drugs such as clomiphene and gonadotropic drugs for the
treatment of infertility.
State the rationale for the various dosage schedule (e.g., biphasics, triphasics), for
oral contraception when combination (estrogen-progestin) therapy is used.
List agents used for postcoital contraception.
List types of hormonal contraceptive agents, other than combination agents, and their
routes of administration.
Describe some of the therapeutic and diagnostic uses of estrogens and progestins
other than their utility as oral contraceptives.
Describe the rationale for use of long-acting progestins for long-term suppression of
ovulation.
Describe the rationale for the replacement use of estrogens and estrogen/progestin in
postmenopausal osteoporosis, cognitive disorders, and cardiovascular disease.
Describe the use of estrogen receptor antagonists and aromatase inhibitors in breast
cancer.
Define the term “selective estrogen receptor modifier” (SERM); provide examples and
outline their therapeutic utility.
Explain the mechanism of action mifepristone (RU 486) and other abortifacients.
Notes
Clinical Pharmacology
If androgens are used concurrently in patients receiving anticoagulant therapy,
increased monitoring of INR (clotting time) is indicated.
Use of SSRI’s concurrently with tamoxifen must be limited to those antidepressants
that are not potent CYP2D6 substrates, since tamoxifen in pharmacologically
activated by metabolism via CYP2D6.
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – female structure
Mechanisms of action and use of drugs
and function, including breast
for treatment of disorders of the
2) Normal processes – male structure and
reproductive system
function
Female reproductive tract
3) Abnormal process – infectious,
- Fertility drugs
inflammatory and immunologic
- Contraceptives
disorders
- Estrogen, progesterone
4) Abnormal processes – traumatic and
replacement, treatment of
mechanical disorders
menopause
5) Abnormal processes, neoplastic
- Estrogen and progesterone
disorders
antagonists
6) Abnormal processes – metabolic and
Male reproductive tract
regulatory processes
- Fertility drugs
7) Abnormal processes – systemic
- Androgen replacement and
disorders affecting reproductive
antagonists
function
8) Abnormal processes – drug-induced
abnormal effects on the reproductive
system
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table
conditions
1
FEMALE UROGENITAL SYSTEM
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
Oxytocics
Tocolytics
DINOPROST
INDOMETHACIN
OXYTOCIN
atosiban
MIFEPRISTONE
magnesium sulfate
ERGONOVINE
nifedipine
dinoprostone
terbutaline
misoprostol
Learning Objectives
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Actions on organ systems
Describe the receptors targeted by the oxytocics and the sensitivity of the uterus to
the various oxytocics during the three trimesters of pregnancy.
Pharmacokinetics
State the usual route(s) of administration, onset and duration of action of the various
oxytocic agents.
State the usual route(s) of administration as well as onset and duration of action of the
various tocolytic agents.
Adverse effects, drug interactions and contraindications
Describe the potential adverse effects of the oxytocic agents in the mother (uterine,
extrauterine) and in the infant.
Therapeutic uses
Describe the clinical use of the individual oxytocics.
Discuss the utilization of RU486 (mifepristone) versus prostaglandins and oxtocics in
therapeutic abortion.
Identify the potential benefits and risks of administering tocolytic (anti-contraction)
agents to the mother and baby.
Notes
Clinical Pharmacology
There is some concern that there are good data to support efficacy of any of the
toclytic agents (anti-contraction medications or labor repressants) in humans.
Relevance
USMLE topic
1) Normal Processes – female structure
and function
2) Normal processes – pregnancy, labor
and delivery, gestational uterus,
placenta
3) Abnormal process – infectious,
inflammatory and immunologic
disorders
4) Abnormal processes – disorders of
pregnancy
AAMC Medical School Objectives
Project Report X Patient Safety – Table
1
Principles of therapeutics
Mechanisms of action and use of drugs
for treatment of disorders of the
reproductive system
Female reproductive tract
- Stimulants and inhibitors of labor
- abortifacients
Topic C: Drug treatment of common
conditions
MALE UROGENITAL SYSTEM
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
SILDENAFIL
TAMSULOSIN
TERAZOSIN
alprostadil
doxazosin
tadalafil
vardenafil
Learning Objectives
Physiology and pathophysiology
Describe the neuroendocrine factors that regulate functions of the male urogenital
tract.
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Adverse effects, drug interactions and contraindications
List the adverse effects and contraindications of the prototype agents in the drug list.
Therapeutic uses
Know the drugs that can be used to treat benign prostatic hyperplasia and impotence.
State the usual routes of administration of alprostadil and sildenafil.
Describe the proposed mechanism of action of the drug listed above and relate the
resulting pharmacological effects to their clinical use.
Notes
Clinical Pharmacology
Alpha-1 adrenergic receptor blockers remain the standard of care for symptomatic
management of BPH.
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – Male structure
Mechanisms of action and use of drugs
and function
for treatment of disorders of the
2) Abnormal processes – neoplastic
reproductive system
disorders
Male reproductive tract
3) Abnormal process – infectious,
- fertility drugs
inflammatory and immunologic
- gonadotropin replacement
disorders
- antineoplastics
4) Abnormal processes – metabolic and
- restoration of potency
regulatory processes
5) Abnormal processes – drug-induced
effects on the reproductive system
6) Abnormal Processes – traumatic and
mechanical disorders
AAMC Medical School Objectives
Project Report X Patient Safety – Table
1
Topic C: Drug treatment of common
conditions
OBESITY
Recommended Curriculum Equivalent: 1 hr
Drug Classes and Drugs to consider
orlistat
lorcaserin
phentermine/topiramate extended-release
Learning Objectives
Physiology and pathophysiology
Describe the neuroendocrine factors that regulate feeding and satiation
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Adverse effects, drug interactions and contraindications
List the adverse effects and contraindications of the agents in the drug list.
Therapeutic uses
Know the drugs that can be used to treat obesity.
State the usual routes of administration of the drugs.
Describe the proposed mechanism of action of the drug listed above and relate the
resulting pharmacological effects to their clinical use.
Notes
Clinical Pharmacology
Diet and exercise remain the most effective interventions to treat obesity. Drug
therapy for this health condition has been disappointing for the most part. Rebound
weight gain on discontinuation of drug therapy occurs universally.
Surgical management of severely obese patients, although risky, is likely to be the
only intervention with the potential for lasting benefit.
Relevance
USMLE topic
Principles of therapeutics
1) Normal Processes – Adipose tissue
Mechanisms of action and use of drugs
2) Abnormal processes – systemic
for treatment of disorders of the
disorders affecting the endocrine
endocrine system
system
Antiobesity agents
3) Abnormal processes – metabolic and
regulatory processes
AAMC Medical School Objectives
Topic C: Drug treatment of common
Project Report X Patient Safety – Table
conditions
1
TOXICOLOGY AND THERAPY OF INTOXICATION
Subcommittee
Rankin, Gary O. (Chair) [email protected]
Dickerson, Richard, [email protected]
Matta, Jaimé, [email protected]
Alan Parrish, [email protected]
Introduction to Toxicology and Therapy of Intoxication
A medical pharmacology course should be primarily concerned with three aspects of
toxicology: adverse effects of therapeutic agents, acute intoxications, and chronic
poisoning/environmental toxicology. The adverse effects of drugs should be taught
along with the pharmacology of individual drugs or groups of drugs.
The discussion of acute intoxications should constitute a short, but important, part of
the pharmacology course and should deal with the techniques and procedures used
in dealing with the effects of exposure to acutely toxic materials. Lectures dealing
with chronic intoxications should emphasize environmental toxicology and risk
assessment.
Principles of Toxicology
Recommended Curriculum Equivalent: 1 hr
Learning Objectives
Describe how toxicants are influenced by the basic pharmacokinetic and
pharmacodynamic processes such as absorption, distribution, biotransformation,
excretion and cellular targets.
Explain the principles of bioactivation of chemicals to toxic species.
Describe the concept of dose-response curves and how it can be helpful in the
management of acute and chronic poisonings.
Explain the concepts of threshold levels for toxicity.
Describe measures for determining the safety of a drug or non-therapeutic chemical
(e.g. therapeutic ratio).
Explain how toxicogenetics can alter responses to chemicals
Priority Toxic Chemicals
Recommended Curriculum Equivalent: 2 hr
Drugs and Chemical Toxicants
Antidotes
ACETAMINOPHEN
N-ACETYL-L-CYSTEINE
AIR POLLUTANTS
ACTIVATED CHARCOAL
ALCOHOLS (ETHANOL, METHANOL, ATROPINE/2-PAM
ETHYLENE GLYCOL)
ETHANOL
BENZODIAZEPINES
FLUMAZENIL
CARBON MONOXIDE
METHYLENE BLUE
HEROIN, MORPHINE
METAL CHELATORS (EDETATE, 2,3IRON
DIMERCAPTOSUCCINIC ACID,
LEAD
DIMERCAPROL, DEFEROXAMINE)
MERCURY
NALOXONE
PESTICIDES
(ORGANOPHOSPHATES SODIUM BICARBONATE
AND CARBAMATES)
fomepizole
SALICYLATES
glucagon
beta-blockers
oxygen
cyanide
sodium or amyl nitrite/sodium thiosulfate
Learning Objectives
Explain how exposure to the primary and secondary toxicants can occur.
Describe the signs and symptoms of a toxic exposure induced by each of the toxicants.
Describe the mechanism of toxicity of the primary and secondary toxicants.
Compare and contrast the toxicity induced by various metals.
Compare and contrast the toxicity induced by the neurotoxic pesticides.
Describe the antidote and/or treatment for each toxicant.
Management of Acute Intoxications
Recommended Curriculum Equivalent: 1 hr
Learning Objectives
This section can be case-based to follow up on the identification of priority toxicant
poisoning and the therapeutic aspects of treating intoxications. Alternatively, lectures
can be provided to teach the “decision-tree” approach to the treatment of acute
intoxications using examples such as acetaminophen overdose.
Explain the basic principles of managing an acute intoxication from a drug or non-drug.
Describe how decisions are made to determine how an acute intoxication should be
handled.
Define what is a toxidrome and know the main signs and drugs/toxins that are
associated with the anticholinergic, sympathomimetic and cholinergic toxidromes.
Describe common intoxications and their management.
Define a Poison Control Center and services and information it can provide to
physicians.
Clinical Pharmacology
Polyelectrolyte lavage solution has become the standard of care for poisoning by
modified release dosage forms. Administration must be titrated to prevent induction
of nausea and vomiting and is continued until the presence of a clear rectal effluent.
This intervention is only to be used in conscious patients.
For salicylate overdose, acetazolamide is only to be considered as an intervention with
failure to alkalinize the urine after intravenous doses of bicarbonate. CAUTION:
Serum potassium must be carefully monitored to limit the potential for cardiac
arrhythmias. Glucose is also to be administered to counter the uncoupling of
mitochondrial oxidative phosphorylation by circulating salicylic acid.
Syrup of ipecac is no longer recommended as a home remedy for pediatric
intoxications, since its emetic action is not effective to remove clinically relevant
amounts of dosage forms in the time period after the ingestion when it is likely to be
administered. Its acute sedative effect may increase the risk of aspiration
pneumonia.
Activated charcoal is not effective as an antidote for drug overdose in patients
appearing at Emergency Departments, since its efficacy has only been demonstrated
within 2 hours of the toxic ingestion. Almost no overdose patients ever appear for
treatment within this time interval.
Environmental Toxicology/Risk Assessment
Recommended Curriculum Equivalent: 1 hr
Learning Objectives
Explain the concept of risk versus dose and methods for risk assessment.
Describe the concept of pre-carcinogens, proximate carcinogens and ultimate
carcinogens.
Describe bioactivation pathways for carcinogens.
Describe mechanisms of chemical carcinogenesis.
Differentiate between mutagenicity and carcinogenicity.
Describe chemical preventive mechanisms from carcinogenicity.
Describe how toxicogenomic studies may be used to identify potential modes of action
and/or bioactivation for a chemical and determine across species for use in risk
assessment.
Relevance
USMLE topic
Principles of therapeutics
General Principles – Pharmacodynamic
Mechanisms of action and use of drugs for
and pharmacokinetic processes
treatment of toxic overdose
AAMC Medical School Objectives
Project Report X Patient Safety –
Table 1
Topic B: Principles of clinically important
pharmacokinetics
Topic C: Drug treatment of common
conditions
Topic D: Management of less common
but severe medical conditions and
emergencies
Vitamins
Subcommittee
Matta, Jaimé (Chair) [email protected]
James O'Donnell, [email protected]
Lawrence I. Rothblum, [email protected]
Recommended Curriculum Equivalent: 2.0 hr
Vitamin Classes and Vitamins to consider
Lipid soluble vitamins
Water soluble vitamins
Vitamins A, D, E, K
cyanocobalamin
folic acid
nicotinamide
nicotinic acid
pyridoxine
thiamine
vitamin C
Learning Objectives
Physiology and pathophysiology
Distinguish between vitamins and antioxidants.(definitions and sources).
Define what antioxidants are and provide examples of at least five types of
endogenous antioxidant compounds present in the human body. Be familiar with
regularly updated scientific information on antioxidants (e.g.
http://www.nlm.nih.gov/medlineplus/antioxidants.html).
Identify what are some of the populations (e.g. elderly, alcoholics, pregnant women INH.
treated TB patients) that have the highest risk of having some form of vitamin
deficiency.
Understand the vitamin deficiency related problems that are commonly associated with:
ethanol abuse, genetic polymorphisms, drug use, dietary deficiencies.
Mechanism of action
Summarize the mechanism of action of the water-soluble and lipid-soluble vitamins in a
healthy human body (fairly extensively covered in biochemistry).
Actions on organ systems
Describe the pharmacological and non-pharmacological effects of the deficiency of each
of these water and lipid-soluble vitamin types as they relate to disease processes.
Describe the role of Vitamin K as an antidote in warfarin overdose; effects of diets
deficient in vitamin K in patients on warfarin.
Adverse effects and toxicities
Describe the principal adverse effects and toxicities for overdose and toxic levels of
both water-soluble and lipid-soluble vitamins (hypervitaminosis).
Therapeutic uses
Know how vitamins are regulated (The Dietary Supplement Health and Education Act of
1994). Recognize that vitamins packaged and marketed and administered in certain
dosage forms are regulated as prescription drugs (DSHEA only covers oral
medications that are swallowed)
Know key concepts of the 2005 Dietary guidelines recommended by the FDA for using
vitamin supplements. Very broad
Know what are the recommended 2005 Dietary guidelines for achieving optimal vitamin
supplementation strategies in sensitive populations.
Define what is mean by Recommended Dietary Allowances (RDA) in relation to vitamin
use. Is the RDA a currently used term? *
Describe the use of thiamine in the emergency treatment of alcoholism.
Notes
Identify at least three reliable sources sources (internet databases, CD-ROM) that
provide information on vitamins and antioxidants. These include
www.health.gov/dietaryguidelines/dga2005/,
http://www.fda.gov/consumer/updates/vitamins111907.html#regulated
Serious adverse events associated with vitamins and any dietary supplement
manufacturer although very rare must be reported to FDA within 15 days of the
manufacturer receiving the adverse event report. These can be reported directly to
FDA through its MedWatch program at 1-800-FDA-1088 or online at
www.fda.gov/medwatch.
*The Reference Daily Intake or Recommended Daily Intake (RDI) is the daily intake
level of a nutrient that is considered to be sufficient to meet the requirements of 97–
98% of healthy individuals in every demographic in the United States (where it was
developed, but has since been used in other places).
The RDI is used to determine the Daily Value (DV) of foods, which is printed on nutrition
facts labels in the United States and Canada, which is regulated by the Food and
Drug Administration (FDA), and Health Canada.
The RDI is based on the older Recommended Dietary Allowance (RDA) from 1968;[1]
newer RDAs have since been introduced in the Dietary Reference Intake system,
but the RDI is still used for nutrition labeling.
Clinical Pharmacology
Relevance
USMLE topic
Principles of therapeutics
Multisystem processes: nutrition—vitamin
Other therapeutic modalities
deficiencies and/or toxicities, mineral
deficiencies and/or toxicities
AAMC Medical School Objectives Project Topic C
Report X Patient Safety – Table 1
Drug treatment of common conditions
and diseases
Herbals
Subcommittee
Pamela Potter, Ph.D. (Chair)
[email protected]
Herbals
Recommended Curriculum Equivalent: 0.75 hr
PRIMARY DRUGS
SECONDARY DRUGS
BITTER ORANGE/ EPHEDRA
aloe vera
ECHINACEA
black cohosh
FLAXSEED
chamomile
GINGER
evening primrose oil
GINKGO
feverfew
GLUCOSAMINE CHONDROITIN
guarana
GREEN TEA
hoodia
SAW PALMETTO
kava
ST JOHN’S WORT
milk thistle
TURMERIC/CURCUMIN
valerian
yohimbe
Learning Objectives
Actions on Organ Systems
Know mechanisms of herbal action and similarity to prescription medication, eg bitter
orange contains synephrine, Saw Palmetto block testosterone, St John’s Wort
inhibits 5-HT, MAO.
Know that some herbal products have demonstrated effectiveness in some areas, but
most have not
Adverse Effects, drug interactions and contraindications
Know that serious drug interactions may occur, including:
• Bitter orange with MAOIs
• Ginkgo with anticoagulants
• St John’s Wort with protease inhibitors, calcineurin inhibitors, oral contraceptives,
antidepressants, general anesthetics, digoxin, warfarin, phenytoin
• Yohimbe with clonidine, MAOIs, tricyclic antidepressants and phenothiazines
Know that adverse effects include allergy (chamomile, echinacea, milk thistle, feverfew,
gingko), increased blood pressure and possible stroke (bitter orange, ephedra), liver
damage (concentrated green tea extracts, kava).
Know that use of many herbal products is contraindicated in pregnancy.
Notes
Be aware that there is little regulation of herbal products, and although FDA does try to
remove fraudulent and unsafe products, there is no guarantee that the labeling is
accurate.
Know that some products are monitored by independent laboratories such as
www.consumerlab.com.
Clinical Pharmacology
There is no acceptable high quality evidence for efficacy of Ginkgo biloba, and its use
should be discouraged. Saw palmetto is marginally effective as a treatment
strategy for benign prostatic hypertrophy.
Although demonstrated clinically effective for the treatment of mild to moderate
depression, St. Johns Wort has considerable potential for drug interactions, due
mainly to its induction of CYP 3A4 and P-glycoprotein. This herbal preparation is
not to be used concurrently with SSRI’s due to increased risk of inducing the
serotonin syndrome.
Ginger has demonstrated clinical efficacy in reduction of nausea and vomiting.
However, its use concurrently with prescribed drug therapy for this problem has not
been adequately evaluated.
Use of Echinacea to stimulate immunity is of concern in patients who already have
pathology related to autoimmunity. Use by patients receiving concurrent
immunosuppressive drug therapy is a concern but remains to be rigorously
evaluated in clinical studies. Such clinical studies are unlikely due to ethical issues
that would arise from their proposal.
Relevance
USMLE topic
Principles of therapeutics
Complementary and alternative therapies
Multisystem processes
AAMC Medical School Objectives
Topic C
Project Report X Patient Safety – Table 1 Drug treatment of common conditions
and diseases