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. 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.

B. 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) The American Medical Association 2) The American Pharmaceutical Association 3) The United States Pharmacopeial Convention

F. 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.

G. 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 non- competitive) 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 dose- response 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. 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) 5. 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 6. 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, co- transmitters 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 Direct Acting Cholinergic Indirect Related Drugs Cholinergic Ester- Cholinergic Alkaloid Acting Agonists Agonists ACETYLCHOLINE PILOCARPINE ECHOTHIOPHATE PRALIDOXIME BETHANECHOL EDROPHONIUM obidoxime NEOSTIGMINE sarin malathion VX series parathion physostimine pyridostigmine 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 Principles of therapeutics Central and Peripheral Nervous System 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 AAMC Medical School Objectives Topic C Project Report X Patient Safety- Table 1 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 Topic C Project Report X Patient Safety-Table 1 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 Indirect and Mixed Acting Antagonists Adrenergic Antagonists Agents phenoxybenzamine PRAZOSIN AMPHETAMINE phentolamine tamsulosin ephedrine terazosin 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 Topic C Project Report X Patient Safety-Table 1 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 NOREPINEPHRINE (NE) brain derived neurotrophic factor (BDNF) 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 System- normal processes-cell/tissue structure and function; synthesis, storage, release, reuptake, and degradation of neurotransmitters and neuromodulators; pre- and post- synaptic receptor interactions, trophic and growth factors; brain homeostasis, blood-brain barrier AAMC Medical School Objectives Topic C Project Report X Patient Safety

General Anesthetics Recommended Curriculum Equivalent: 1.5 hr Drug Classes and Drugs to consider Inhalational Intravenous Primary agents Secondary agents Primary agents Secondary agents DESFLURANE ETOMIDATE methohexital ISOFLURANE KETAMINE thiopental NITROUS OXIDE PROPOFOL (N2O) SEVOFLURANE 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 Topic C Project Report X Patient Safety- Table 1 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 Secondary agents BENZOCAINE articaine BUPIVACAINE cocaine LIDOCAINE prilocaine PROCAINE tetracaine ROPIVACAINE 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 Topic C Project Report X Patient Safety- Table 1 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 Agonist/Antagonists and Antagonists Primary Secondary Primary Secondary CODEINE diphenoxylate BUPRENORPHINE buprenorphine- FENTANYL heroin NALOXONE naloxone HYDROCODONE loperamide NALTREXONE butorphanol HYDROMORPHONE meperidine nalbuphine METHADONE combinations - nalorphine MORPHINE opioids plus nalmefene OXYCODONE acetaminophen pentazocine OXYMORPHONE and ASA TRAMADOL 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 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 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 guaifenesin DEXTROMETHORPHAN HYDROCODONE 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 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 Motor Disorders and Centrally Acting Muscle Relaxants Recommended Curriculum Equivalent: 1 hr Drugs to consider Primary Secondary AMANTADINE apomorphine BACLOFEN cyclobenzaprine BENZTROPINE propranolol CARBIDOPA tizanidine DANTROLENE trihexyphenidyl DIAZEPAM DIPHENHYDRAMINE DOPAMINE ENTACAPONE L-DOPA PRAMIPEXOLE RASAGILINE ROPINEROLE SELEGILINE (deprenyl) TETRABENAZINE 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 L- DOPA/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 L- DOPA 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 Principles of therapeutics Central & Peripheral Nervous System- Antiparkinsonian drugs Normal processes- motor system; basal ganglia; synthesis, storage, release reuptake and degradation of neurotransmitters Abnormal Processes- Parkinson disease, 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

Antiseizure drugs Recommended Curriculum Equivalent: 1 hr Drugs to consider Primary Secondary CARBAMAZEPINE clonazepam DIAZEPAM ezogabine ETHOSUXIMIDE fosphenytoin LAMOTRIGINE lacosamide LORAZEPAM levetiracetam PHENOBARBITAL perampanel PHENYTOIN pregabalin TIAGABINE primidone TOPIRAMATE rufinamide VALPROIC ACID 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 Secondary AMITRIPTYLINE citalopram BUPROPION clomipramine DULOXETINE desipramine ESCITALOPRAM fluvoxamine FLUOXETINE imipramine NORTRIPTYLINE mirtazapine PAROXETINE phenelzine ST. JOHN’S WORT trazodone SELEGILINE SERTRALINE TRANYLCYPROMINE VENLAFAXINE 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 Topic C Project Report X Patient Safety-Table 1 Drug treatment of common conditions

Drugs for treatment bipolar disorder Drugs to consider Primary Secondary CARBAMAZEPINE clonazepam LAMOTRIGENE clozapine LITHIUM CARBONATE levetiracetam VALPROIC ACID paliperidone ATYPICAL ANTIPSYCHOTICS: primidone ARIPIPRAZOLE zonisamide OLANZAPINE QUETIAPINE RISPERIDONE ZIPRASIDONE 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 Topic C Project Report X Patient Safety-Table 1 Drug treatment of common conditions

Drugs for treatment of psychoses Recommended Curriculum Equivalent: 1.5 hr Drugs to consider Primary Secondary CHLORPROMAZINE paliperidone ARIPIPRAZOLE perphenazine CLOZAPINE quetiapine FLUPHENAZINE thiothixene HALOPERIDOL ziprasidone OLANZAPINE RISPERIDONE 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 Secondary ALPRAZOLAM buspirone DIAZEPAM chloral hydrate DULOXETINE dexmedetomidine ESCITALOPRAM diphenhydramine ESZOPICLONE gamma-hydroxybutyrate FLUMAZENIL (ANTAGONIST) hydroxyzine FLUOXETINE lorazepam LORAZEPAM oxazepam MIDAZOLAM temazepam RAMELTEON zaleplon SERTRALINE VENLAFAXINE ZOLPIDEM 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 non- benzodiazepine 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 half- life 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 Topic A Project Report X Patient Safety-Table 1 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 Secondary agents AMPHETAMINES ephedrine ATOMOXETINE theophylline CAFFEINE METHYLPHENIDATE MODAFINIL PHENTERMINE 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 Topic C Project Report X Patient Safety-Table 1 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, sedative- hypnotics and anxiolytics. Drugs to consider - Psychostimulants Primary Secondary AMPHETAMINES cathinone and analogs BUPROPION ephedrine COCAINE phentermine METHAMPHETAMINE METHYLPHENIDATE NICOTINE VARENICLINE 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 Principles of therapeutics Central and Peripheral Nervous System Treatment for substance abuse disorders, amphetamines, psychopharmacological agents AAMC Medical School Objectives Topic C Project Report X Patient Safety-Table 1 Drug treatment of common conditions Topic G Diagnosis and management of patients with substance abuse problems Drugs to Consider - Ethanol and alcoholism Primary Secondary ETHANOL acamprosate FOMEPIZOLE ethylene glycol METHANOL topiramate NALTREXONE 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 Topic C Project Report X Patient Safety-Table 1 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 Topic C Project Report X Patient Safety-Table 1 Drug treatment of common conditions Topic G Diagnosis and management of patients with substance abuse problems

Drugs to Consider - Marijuana Primary Secondary DELTA-9-TETRAHYDROCANNABINOL designer cannabinoids (THC) hashish DRONABINOL K-2 MARIJUANA 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 Topic C Project Report X Patient Safety-Table 1 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 Topic C Project Report X Patient Safety-Table 1 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 secobarbital DIAZEPAM zolpidem ALPRAZOLAM FLUNITRAZEPAM 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 Topic G Project Report X Patient Safety-Table 1 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 Topic E Project Report X Patient Safety-Table 1 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 Second Generation DIMENHYDRINATE FEXOFENADINE DIPHENHYDRAMINE LORATADINE PROMETHAZINE cetirizine chlorpheniramine hydroxyzine Histamine Release Endogenous Substances H Receptor Antagonists 2 Modifiers HISTAMINE CIMETIDINE CROMOLYN FAMOTIDINE omalizumab RANITIDINE nizatidine 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 Topic C Project Report X Patient Safety-Table 1 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 Principles of therapeutics Central and Peripheral Nervous System- Normal processes: cell/tissue structure Mechanisms of action and use of drugs and function-synthesis, storage, for treatment of disorders of the release, reuptake, and degradation of nervous system-antimigraine agents neurotransmitters and neuromodulators AAMC Medical School Objectives Topic C Project Report X Patient Safety-Table 1 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 PDE inhibitor NO Donors PGE1 Analog NITRIC SILDENAFIL SODIUM alprostadil OXIDE NITROPRUSSIDE nitroglycerin Learning Objectives 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 Leukotrienes Endogenous Analogs Endogenous Leukotriene Modifiers

PGE2 ALPROSTADIL LTB4 ZAFIRLUKAST PGF2Α MISOPROSTOL LTC4,D4,E4 Montelukast PROSTACYCLIN Latanoprost Zileuton THROMBOXANE A2 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 anti- inflammatory 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 Topic D 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 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 Principles of therapeutics Pharmacodynamic and Pharmacokinetic Signal transduction Processes-general principles Mechanisms of action and use of drugs Gastrointestinal System for treatment of disorders of the gastrointestinal system

AAMC Medical School Objectives Topic C Project Report X Patient Safety-Table 1 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. Relevance USMLE topic Principles of therapeutics Respiratory System Mechanisms of action and use of drugs for treatment of disorders of the respiratory system-bronchodilator drugs

AAMC Medical School Objectives Project Topic C Report X Patient Safety-Table 1 Drug treatment of common conditions and disease

Notes Objectives for steroids are covered under Adrenal Cortex

Hypersensitivity and Immunopharmacology Recommended Curriculum Equivalent: 1 hr Drug Classes and Drugs to consider Immunosuppressants Drugs acting on Drugs acting on cytokines or on Cytotoxic drugs Lymphotoxic drugs Immunocompetent Other cytokine cells receptors

AZATHIOPRINE 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 Principles of therapeutics Immune System Mechanisms of action and use of drugs that specifically affect immune function- immunomodulating drugs AAMC Medical School Objectives Project Topic C Report X Patient Safety-Table 1 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.

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Antirheumatic Drugs Recommended Curriculum Equivalent: 0.5 hr Drug Classes and Drugs to consider DMARDS (Disease Modifying Antirheumatic Drugs) COX Inhibitors Biologics Traditional ASPIRIN ANAKINRA METHOTREXATE IBUPROFEN ETANERCEPT hydroxychloroquine NAPROXEN INFLIXIMAB leflunomide celecoxib 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 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

Notes Objectives for COX inhibitors are covered under Analgesic, Antipyretic, Antiinflammatory Drugs. Rasburicase is used in pediatric patients receiving cancer chemotherapy.

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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

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Notes

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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 HPV & Molluscum, Actinic Psoriasis 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 Immuno- Steroids Biologicals balance of enteric therapy suppressives bacteria

19 balsalazide budesonide azathioprine infliximab ciprofloxacin mesalamine hydrocortisone mercaptopurine natalizumab metronidazole olsalazine prednisone methotrexate lactobacillus spp. sulfasalazine 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/NK 5-HT Antagonists 1 Corticosteroids Others 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 eradicating H. Antacids 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 Prostaglandin Testosterone PDE5 Inhibitors Others Analog Replacement sildenafil alprostadil methyltestosterone papaverine tadalafil testosterone topical phentolamine vardenafil testosterone enanthate

Therapeutic uses Outline the use of these drugs in treating erectile dysfunction. Drugs for Allergic Reactions

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Drug Classes and Drugs to consider Autacoid Glucocorticoids Decongestants Anticholinergics Anaphylaxis Antagonists fluticasone phenylephrine ipratropium epinephrine antihistamines prednisone pseudoephedrine 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 Ca++ Blockers β-Agonists COX inhibitors Therapy 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.

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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 Topic C: Drug treatment of common Project Report X Patient Safety-Table 1 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 Principles of therapeutics Cardiovascular System; Renal/Urinary Mechanisms of action, use, adverse effects of System- Abnormal Processes- Metabolic drugs for treatment of disorder of and Regulatory Disorders (Systolic and cardiovascular system-Inotropic agents diastolic dysfunction, low-and high output and treatment of heart failure heart failure, systemic hypertension) AAMC Medical School Objectives Project Topic C: Drug treatment of common Report X Patient Safety-Table 1 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 Angiotensin Angiotensin Aldosterone Renin Antagonists 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 β1 Selective phenoxybenzamine PRAZOSIN PROPRANOLOL METOPROLOL CARVEDILOL phentolamine doxazosin nadolol atenolol LABETALOL pindolol nebivolol timolol

Diuretics Vasodilators amiloride Venous Arterial Both CHLORTHALIDONE ISOSORBIDE DINITRATE CALCIUM BLOCKERS NITROPRUSSIDE eplerenone nitroglycerin (DIHYDROPYRIDINES, ANGIOTENSIN furosemide DILTIAZEM, VERAPAMIL) CONVERTING HYDROCHLOROTHIAZIDE HYDRALAZINE ENZYME spironolactone diazoxide INHIBITORS triamterene minoxidil ANGIOTENSIN RECEPTOR BLOCKERS alpha blockers Combination of hydralazine and isosorbide dinitrate (BiDil) Centrally Acting Pulmonary Hypertension Hypertensive Emergency Agents and Urgency CLONIDINE Endothelin PDE 5 Prostaglandins NITROPRUSSIDE methyldopa Antagonists Inhibitors (Prostacyclin) clevidipine ambrisentan sildenafil epoprostenol esmolol bosentan tadalafil iloprost fenoldopam treprostinil 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. African- Americans, 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 Processes- Mechanisms 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 vasospasm- induced 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 Processes- Drug 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 WARFARIN DABIGATRAN (oral) fondaparinux ENOXAPARIN argatroban rivaroxaban (oral) dalteparin bivalirudin tinzaparin lepirudin desirudin 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 heparin- induced 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 Systems- Drug affecting blood coagulation, thrombolytic Abnormal Processes-Hemorrhagic and agents, and antiplatelet agents Hemostatic Disorders Cardiovascular System-Abnormal Processes- Traumatic and Mechanical Disorders & Vascular Disorders AAMC Medical School Objectives Topic C: Drug treatment of common conditions Project Report X Patient Safety-Table 1 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 Mast Cell Stabilizer Anti-IgE Antagonists 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 ALBUTEROL SALMETEROL aminophylline TIOTROPIUM 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 exercise- induced 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 physico- chemical 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. Relevance USMLE topic Principles of therapeutics Respiratory system Bronchodilator drugs AAMC Medical School Objectives Topic C Project Report X Patient Safety – Table 1 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

10. Anticholesterolemic Agents Bile Acid Sequestrants HMG CoA Fibric Acid Miscellaneous Reductase Derivatives Mechanisms Inhibitors CHOLESTYRAMINE ATORVASTATIN GEMFIBROZIL EZETIMIBE colestipol FLUVASTATIN fenofibrate niacin colesevelam LOVASTATIN nicotinic acid PRAVASTATIN omega-3 ethyl esters ROSUVASTATIN SIMVASTATIN

11. Anticholinergic Agents Nicotinic Receptor Antagonists Muscarinic Receptor Antagonists (Ganglionic Blockers) trimethaphan (historical) ATROPINE hexamethonium (historical) IPRATROPIUM tiotropium

12. Anticoagulant Agents Oral Anticoagulants Heparins Thrombin Inhibitors Factor Xa Inhibitor WARFARIN ENOXAPARIN argatroban fondaparinux HEPARIN bivalirudin rivaroxaban (oral) dalteparin DABIGATRAN (oral) tinzaparin LEPIRUDIN

13. Antiplatelet Agents Miscellaneous Phosphodiesterase Glycoprotein IIb/IIIA ADP Receptor Mechanisms Inhibitors Inhibitors Antagonists ASPIRIN cilostazol ABCIXIMAB CLOPIDOGREL dipyridamole eptifibatide PRASUGREL tirofiban ticlopidine ticagrelor

14. Atrial Natriuretic Peptide Agonists nesiritide

15. Calcium Channel Blockers (Calcium Entry Blockers) Dihydropyridines Phenylalkylamine Benzothiazepines Others AMLODIPINE VERAPAMIL DILTIAZEM bepridil FELODIPINE flunarizine NIFEDIPINE clevidipine isradipine nicardipine nimodipine nisoldipine

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

19. Diuretics Loop Diuretics Thiazide Diuretics Potassium-Sparing Diuretics ETHACRYNIC ACID HYDROCHLOROTHIAZIDE EPLERENONE FUROSEMIDE INDAPAMIDE SPIRONOLACTONE bumetanide chlorothiazide amiloride torsemide chlorthalidone triamterene metolazone

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)

27. Phosphodiesterase Inhibitors PDE 3 Inhibitors PDE 4 Inhibitors PDE 5 Inhibitors cilostazol roflumilast sildenafil inamrinone tadalafil milrinone

28. Vasodilators Organic Nitrates Others (Miscellaneous Mechanisms) ISOSORBIDE MONONITRATE HYDRALAZINE NITROGLYCERIN NITROPRUSSIDE amyl nitrite diazoxide isosorbide dinitrate 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 Drug Classes and Drugs to Consider Carbonic Osmotic Loop Anhydrase Diuretic Diuretics Inhibitor acetazolamide mannitol FUROSEMIDE bumetanide Distal tubule K-sparing Diuretics Diuretics CHLORTHALIDONE AMILORIDE HYDROCHLOROTHIAZIDE SPIRONOLACTONE metolazone 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 Disorders- Principles of Therapeutics: Antihypertensive Drugs. Renal/Urinary System-Abnormal Processes AAMC Medical School Objectives Project Topic C: Report X Patient Safety - Table 1 Drug treatment of common conditions

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 Principles of therapeutics Renal/Urinary System Drugs and fluids used to treat volume, electrolyte, and acid-base disorders

AAMC Medical School Objectives Project Topic D Report X Patient Safety - Table 1 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 Second generation OMEPRAZOLE 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

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Acid Reducers and Drugs for the Treatment of Peptic Ulcer Disease

H2 Receptor Antagonists Endogenous Substance First Generation Second Generation histamine 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

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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

Notes

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Acid Reducers and Drugs for the Treatment of Peptic Ulcer Disease Acid Neutralizers (Classic Antacid preparations) Endogenous Single agent Mixed preparations substance H+ ALUMINUM HYDROXIDE ALUMINUM HYDROXIDE CALCIUM CARBONATE MAGNESIUM HYDROXIDE/ 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

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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 gastrointestinal secretory products reflux Abnormal Processes – idiopathic disorders AAMC Medical School Objectives Topic C Project Report X Patient Safety-Table 1 Drug treatment of less common but severe conditions Notes

Drugs for the Treatment of Peptic Ulcer Disease Cytoprotectant agents Endogenous Analog Surface protectant substance

PGE2 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 dose- related 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

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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 of structure & function including endocrine peptic ulcer disease and neural regulatory functions; gastrointestinal secretory products; gastrointestinal defense mechanisms Abnormal Processes – drug-induced adverse effects on the gastrointestinal system AAMC Medical School Objectives Topic C Project Report X Patient Safety-Table 1 Drug treatment of less common but severe conditions Notes

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Drugs for the Treatment of Peptic Ulcer Disease Helicobacter pylori eradication Triple therapy Quadruple therapy Antibiotics Acid Antibiotics Acid other suppression suppression AMOXICILLIN PPI CLARITHROMYCIN H2- BISMUTH CLARITHROMYCIN TETRACYLCINES BLOCKERS SUBSALICYLATE METRONIDAZOLE PPI TETRACYLCINES 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 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; treatment and structure & function including endocrine prophylaxis of peptic ulcer disease and neural regulatory functions; gastrointestinal secretory products Abnormal Processes – infectious 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

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Prokinetic Drugs and Laxatives Recommended Curriculum Equivalent: 1 hr Drug Classes and Drugs to consider Drugs used to treat upper GI Drugs used to treat lower GI motility disorders motility disorders (Gastroparesis, (Constipation) dyspepsia, GERD) METOCLOPRAMIDE Receptor mediated Laxatives cisapride ALVIMOPAN DOCUSATE domperidone LUBIPROSTONE LACTULOSE erythromycin METHYLNALTREXONE METHYLCELLULOSE tegaserod bethanechol POLYETHYLENE GLYCOL

neostigmine SODIUM PHOSPATE renzapride SODIUM CITRATE tegaserod 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.

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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; drug- induced 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.

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Anti-diarrheal drugs Recommended Curriculum Equivalent: 0.5 hr Drug Classes and Drugs to consider Serotonergic- Adrenergic Opioid- compounds Probiotics compounds compounds LOPERAMIDE alosetron clonidine bifidobacterium diphenoxylate cilansetron infantis somatostatin analog muscarinic antagonists other octreotide ATROPINE BISMUTH SUBSALICYLATE DICYCLOMINE bismuth citrate hyoscyamine scopolamine 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.

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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; drug- induced 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:

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Drugs used for the Treatment of Inflammatory Bowel Disease Recommended Curriculum Equivalent: 0.5 hr Drug Classes and Drugs to consider Monoclonal Salicylates Steroids Anti-mitotic agents antibodies 5-AMINO SALICYLIC HYDROCORTISONE 6-mercaptopurine INFLIXIMAB ACID METHYLPREDNISOLONE azathioprine SULFAPYRIDINE PREDNISONE cyclosporine SULFASALAZINE budesonide methotrexate balsalazide Antibiotics Probiotics ciprofloxacin VSL #2 clarithromycin lactobacillus metronidazole 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.

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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, absorption; cell/tissue structure & immunosuppressive drugs 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

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Anti-Emetic Drugs

Dopamine receptor 5-HT3 receptor Cannabinoid receptor Histamine receptor antagonists antagonists antagonists antagonists METOCLOPRAMIDE DOLASETRON DRONABINOL DIMENHYDRINATE PROCHLORPERAZINE GRANISETRON nabilone DIPHENHYDRAMINE haloperidol ONDANSETRON cyclizine PALONOSETRON hydroxyzine ramosetron meclizine promethazine Neurokinin receptor Corticosteroids Benzodiazepines Muscarinic receptor antagonists antagonists APREPITANT METHYL - LORAZEPAM SCOPOLAMINE PREDNISOLONE ALPRAZOLAM PREDNISONE DIAZEPAM dexamethasone 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.

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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; drug- induced 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

Miscellaneous Gastrointestinal Drugs Antigas/Antiflatulent Digestive Enzyme Drug for Gallstones SIMETHICONE α-GALACTOSIDASE ursodiol activated charcoal 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

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USMLE topic Principles of therapeutics Gastrointestinal System-Principles of Mechanisms of action and use of drugs for therapeutics treatment of disorders of the gastrointestinal system Pancreatic replacement therapy and treatment of pancreatitis Other therapeutic modalities 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

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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 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

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Chemotherapy

Subcommittee:

George Brenner (Chair) [email protected] Gudas, Lorraine J. [email protected] Lazo, John S, [email protected] Matta, Jaime [email protected] Greg Reed 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. Relevance USMLE topic Principles of therapeutics Cardiovascular System – Abnormal Antimicrobials and antiparasitics processes AAMC Medical School Objectives Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 Oxazolidinones Tetracyclines clindamycin LINEZOLID 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 Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 Principles of therapeutics Cardiovascular System – Abnormal Antimicrobials and antiparasitics processes AAMC Medical School Objectives Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 African- American 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 chloroquine- resistant 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 Principles of therapeutics Cardiovascular System – Abnormal Antimicrobials and antiparasitics processes AAMC Medical School Objectives Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 and diseases

Antiviral Drugs Recommended Curriculum Equivalent: 1 hr Drugs to consider ACYCLOVIR amantadine BOCEPREVIR idoxuridine FOSCARNET peginterferon alfa GANCICLOVIR rimantadine OSELTAMIVIR valacyclovir RIBAVARIN valganciclovir TELAPREVIR TRIFLURIDINE ZANAMIVIR 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 Topic C Project Report X Patient Safety Drug treatment of common conditions and Table 1 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 maternal- fetal 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 Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 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 Topic E Project Report X Patient Safety How to find and use the most up-to-date Table 1 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 P- glycoprotein that might place the patient’s transplanted organ at risk.

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 Topic C Project Report X Patient Safety Drug treatment of common conditions and diseases, using frequently Table 1 prescribed classes of drugs for the treatment and prevention of disease

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 Direct Thrombin Factor Xa Inhibitors of Clotting Inhibitors Inhibitors Inhibitors Factor Synthesis HEPARIN DABIGATRAN ENOXAPARIN VITAMIN K PROTAMINE bivalirudin RIVAROXABAN (antidote) SULFATE (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 Processes- Hemorrhagic 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 Phospho- Cyclooxygenase ADP P2Y GPIIb/IIIa INHIBITORS 12 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 Processes- Hemorrhagic 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 Principles of therapeutics Hematopoietic and Lymphoreticular thrombolytic drugs Systems-Abnormal Processes- Hemorrhagic 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.

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

Hypothalamus, Anterior Pituitary 1 Recommended Curriculum Equivalent: 2.0 hr Drug Classes and Drugs to consider Growth Prolactin Gonadotropins ACTH TSH Hormone OCTREOTIDE BROMOCRIPTIN CHORIONIC -hCG thyrotropin PEGVISOMAN E GANIRELIX cosyntropin T CABERGOLINE GONADOTROPIN SERMORELIN HUMAN SOMATROPIN LEUPROLIDE bromocriptine UROFOLLITROPIN lanreotide abarelix mecasermin 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 Principles of therapeutics 1) Endocrine system-Normal Processes- Mechanisms of action and use of drugs hypothalamus and anterior pituitary for treatment of disorders of the gland endocrine system 2) Endocrine system-Abnormal Hormones and hormone analogs Processes-neoplastic disorder, Stimulators of hormone production metabolic and regulatory processes, Inhibitors of hormone production systemic disorders, congenital and Hormone antagonists genetic disorders affecting the Potentiators of hormone action endocrine system Gonadotropin-releasing hormone and 3) Reproductive System-Normal gonadotropin replacement, incudin all processes, hypothalamic-pituitary- gonadotropin-releasing antagonists gonadal axis Stimulators and inhibitors of lactation 4) Reproductive System-Abnormal processes-congenital and genetic disorders-disorders relating to pregnancy AAMC Medical School Objectives Topic C: Drug treatment of common Project Report X Patient Safety – Table conditions 1

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 Principles of therapeutics 1) Endocrine system-Normal Processes- Mechanisms of action and use of drugs hypothalamus and posterior pituitary for treatment of disorders of the pituitary gland endocrine system 2) Endocrine system-Abnormal Hormones and hormone analogs Processes-neoplastic disorder, Inhibitors of hormone production metabolic and regulatory processes, Hormone antagonists systemic disorders Drugs used to treat volume, electrolyte 3) Renal/Urinary System-Abnormal and acid-base disorders Processes-metabolic and regulatory Female reproductive tract-Stimulants and disorders, systemic diseases affecting inhibitors of labor the renal system 4) Reproductive system-Normal processes-pregnancy, labor and delivery AAMC Medical School Objectives Topic C: Drug treatment of common Project Report X Patient Safety – Table conditions 1

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 anti- inflammatory 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 tri- iodothyronine 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 hyper- parathyroidism. 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 non- ketotic 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 Principles of therapeutics 1) Normal Processes – female structure Mechanisms of action and use of drugs and function for treatment of disorders of the 2) Normal processes – pregnancy, labor reproductive system and delivery, gestational uterus, Female reproductive tract placenta - Stimulants and inhibitors of labor 3) Abnormal process – infectious, - abortifacients inflammatory and immunologic disorders 4) Abnormal processes – disorders of pregnancy AAMC Medical School Objectives Topic C: Drug treatment of common Project Report X Patient Safety – Table conditions 1

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 Topic C: Drug treatment of common Project Report X Patient Safety – Table conditions 1

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, 2,3- IRON 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 Topic B: Principles of clinically important Project Report X Patient Safety – pharmacokinetics Table 1 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