PHARMACOLOGY: Core Concepts and Learning Objectives I ...

Core Concepts

Pharmacology & Therapeutics

PHARMACOLOGY: Core Concepts and Learning

Objectives

I. MEDICAL KNOWLEDGE

After each of the following specific lecture topics students will be expected to be able to understand, discuss and explain each of the following pharmacological concepts. Where appropriate a list of the relevant drugs is provided for each topic. In these cases, students should be able to identify which specific drugs belong to each major drug class, as well as have an understanding of the indications, clinical effect, mechanism of action and adverse effects of each of the major drug classes.

A. BASIC CONCEPTS IN PHARMACOLOGY

A1. PRINCIPLES OF PHARMACOLOGY

1. The different types of drugs formulations and their respective advantages and disadvantages. 2. The various routes of drug administration and their respective advantages and disadvantages for specific therapeutic indications. 3. The various factors that affect drug absorption, drug distribution and drug excretion. 4. The role of receptors as targets for drug action and their role in the mediation of drug responses. 5. The fundamental difference between an agonist and antagonist. 6. The relationship between generic versions of drugs and their branded product. 7. The differences in the chemical equivalence, biological equivalence and therapeutic equivalence of a drug product as related to generic drug substitution. 8. The concept of drug bioavailability. 9. The essentials of the drug approval process. 10. The concept that in addition to beneficial clinical effects the use of drugs can also lead to toxic side effects

A2. PHARMACODYNAMICS

1. The relationship between drug dose (or concentration), receptor occupation and biological response. 2. The concepts of drug selectivity, potency, efficacy, full and partial agonism and neutral and negative antagonism. 3. The different types of pharmacologic antagonism and the difference between pharmacological and non-pharmacological types of drug antagonism. 4. The concept of spare receptors, how it can be experimentally demonstrated, and how it may be reflected in the shape of the dose-response curve. 5. The difference between graded and quantal dose response relationships and the information that can be provided by each of these relationships. 6. How drugs can produce beneficial versus toxic effects via the same receptor or different receptors, and how toxic effects may be managed in each of these situations. 7. The key aspects of the 5 major types of receptor signaling mechanisms and the similarities and differences between the adenylyl cyclase and the phosphoinositide signal transduction systems.

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Pharmacology & Therapeutics

8. The different types of altered responsiveness to drugs, the concepts of supersensitivity and densensitization and how these will affect the dose response curve. 9. The differences between homologous and heterologous desensitization, the mechanisms that contribute to each of these phenomena and the clinical implications of these phenomena.

A3. PHARMACOKINETICS

1. The definition of pharmacokinetics according to the acronym ADME (Absorption, Distribution, Metabolism and Elimination). 2. The mechanisms by which drugs are absorbed in the body to reach their sites of action (e.g. aqueous & lipid diffusion, active transport, etc.). 3. The chemical characteristics of drugs (e.g. solubility, pKa) and other factors (e.g. regional differences in blood flow, transporters, non-specific binding) that influence drug absorption. 4. The one-compartment and two-compartment model of drug distribution and elimination 5. The concept of Volume of Distribution and the effect of plasma protein binding on drug distribution. 6. How differential drug distribution can create drug reservoirs that affect the time course and magnitude of a drug's effect. 7. The difference between first-order, zero-order and dose-dependent kinetics of drug elimination and examples of commonly prescribed drugs that typically display these kinetic profiles. 8. The concept of steady-state with regard to plasma drug concentrations. 9. The importance of different pharmacokinetic parameters on the time course of drug action. 10. The concept that Volume of Distribution (Vd) and Clearance of Elimination (CL) are the primary pharmacokinetic parameters and that elimination half-life and elimination rate constants are dependent on Vd and CL. 11. The use of pharmacokinetic parameters to determine the loading dose and maintenance dose of specific drug regimens. 12. An understanding of how repetitive drug administration or continuous drug infusion can attain steady-state therapeutic drug concentrations. 13. The roles of the kidney and liver in the elimination of drugs from the body and the factors that affect hepatic clearance (hepatic blood flow, protein binding, intrinsic clearance).

A4. DRUG METABOLISM AND DRUG INTERACTIONS

1. The different types of metabolic transformations that drugs undergo and their physiological consequences. 2. The potential changes in the chemical properties of a drug metabolite versus the properties of the parent drug. 3. The concept that the effects of one drug can be modified by the prior, or simultaneous, administration of a second drug. 4. The major mechanisms that can lead to drug-drug interactions 5. The role that drug metabolism plays in mediating drug-drug interactions. 6. The role that enzyme induction and inhibition of metabolic enzymes play in drug metabolism.

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A6. DRUG DISCOVERY AND CLINICAL TRIALS

1. An understanding of the different phases of clinical trials. 2. The differences between single and double blind designs for clinical trials. 3. The definition of an IND and a NDA. 4. The ways in which a clinical drug study is evaluated.

A7. PHARMACOGENOMICS

1. The concept of variability in drug responses among the general population. 2. The major phase I and II isozymes associated with adverse drug reactions. 3. The role of polymorphisms in CYP2D6, N-Acetyltransferase 2, CYP2C9, CYP3A4 and VKORC1 in drug actions and the patient response to drugs. 4. The application of pharmacogenomic techniques to clinical trials and clinical practice and how pharmacogenomic DNA-based diagnosis can be coupled to the use of innovative personalized patient-specific therapy. 5. The use of recombinant proteins and antibody-based therapy in the treatment of disease- their advantages and disadvantages. 6. The molecular basis of gene silencing and how this technology can potentially be applied to treat disease.

A8. TOXICOLOGY

1. The dose-response relationships that define toxicological effects. 2. The major toxic endpoints. 3. The most common types of toxic agents, routes of exposure and types of exposure. 4. The categories of teratogens and their classification. 5. The common toxic syndromes including:

a) cholinergic and anticholinergic syndrome, b) hemoglobinopathies c) sympathomimetic excess

d) narcotic overdose and narcotic withdrawal syndromes.

B. AUTONOMIC PHARMACOLOGY

B1. DRUG ACTION AT THE SYNAPSE: AN INTRODUCTION

1. The five essential steps involved in neurotransmission 2. The major pre-synaptic and post-synaptic mechanisms by which drugs act enhance or decrease synaptic transmission. 3. The five major classes of neurotransmitters and specific examples of each (e.g. biogenic amino acids, amino acids, peptides, nucleotides and gases) 4. The unique features of classic and peptidergic neurotransmission. 5. The major differences between indirect and direct acting agonists 6. The major mechanisms by which synaptic transmission of adrenergic neurons can be altered pharmacologically. 7. The major side effects that can occur by combining indirect acting agonists of the sympathetic nervous system with other drugs that influence sympathetic neurotransmission.

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Pharmacology & Therapeutics

B2. ADRENERGIC AGONISTS AND ANTAGONISTS

1. The distinctive anatomical and chemical characteristics of the sympathetic and parasympathetic nervous systems. 2. The visceral organs that are innervated by the sympathetic and parasympathetic systems and the functional responses of the organs to activation of either system. 3. The main subtypes of adrenergic receptors and the most common second messenger systems to which they are coupled, and how these second messenger mediate their biological effect. 4. The distribution of the adrenergic receptor subtypes in the visceral organs. 5. Understand how the activation of adrenergic receptors normally expressed on the presynaptic membrane is able to influence neurotransmitter release.

6. The relative affinities of epinephrine, norepinephrine and the prototypical -adrenergic receptor agonist isoproternol for the different adrenergic receptors. 7. How a drug's affinity for a particular receptor influences its potency in mediating arterial contraction, bronchial smooth muscle relaxation and cardiac contractility. 8. How the different catecholamines influence cardiovascular and bronchial function and what receptors mediate these responses. 9. How the prototypical synthetic adrenergic agonists influence cardiovascular and bronchial function and what receptors mediate these responses. 10. The most common toxic side effects of the endogenous and synthetic adrenergic agonists and an understanding of why they occur. 11. The most important therapeutic uses for the endogenous and synthetic adrenergic agonists. 12. The most common indirect acting sympathomimetics and their most prominent effects. 13. The most important toxic side effects and therapeutic uses of adrenergic agonists. 14. Identify which adrenergic agonists have the most important therapeutic value in the treatment of the following disorders: a) Shock

b) Hypotension c) Nasal congestion d) Asthma e) Anaphylaxis f) Attention-deficit disorder

15. The major -adrenergic receptor antagonists currently used in clinical practice and their principal indications

16. The most serious side effects caused by -adrenergic receptor antagonists

17. Why selective 1-adrenergic receptor antagonists are preferable for the treatment of

hypertension as compared to non-selective -adrenergic receptor antagonists

18. The major -adrenergic receptor antagonists that are most commonly used in clinical practice and their principal indications

19. Understand the differences between the different -adrenergic receptor antagonists with regard to their selectivity and duration of action.

20. Understand the relationship between the selectivity of the different -adrenergic receptor antagonists and their toxic side effects.

21. Understand how differences in the selectivity of the -adrenergic receptor antagonists helps determine which agent is most suitable for a particular condition in a specific patient population.

22. Identify the major indications for -adrenergic receptor antagonists and the mechanisms by which they mediate their clinical effects.

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Relevant Drugs A. Adrenergic Agonists

I. Direct acting Sympathomimectics Epinephrine Norepinephrine Dopamine

II. Non-selective-adrenergic agonists Isoproternol

III. Selective 1-adrenergic receptor agonist Dobutamine

IV. Selective-adrenerigic receptor agonists Terbutaline Albuterol

V. Selective 1-adrenergic agonist Phenylephrine

VI. Selective 2-adrenegic agonist Clonidine

VII. Indirectly acting Sympathomimectics Amphetamine Metamphetamine Methylphenidate Ephedrine Pseudoephedrine Tyramine

B-adrenergic antagonists I. Non-selective -blockers Propranolol Timolol Nadolol

II. Cardioselective 1-blockers Metoprolol Atenolol Esmolol

III. Partial -adrenerigc receptor agonist Pindolol

C-adrenergic receptor antagonists I. Non-selective -receptor antagonists Phenoxybenzaine (irreversible) Phentolamine (reversible)

II. Selective 1 receptor antagonists Prazosin Doxazosin Terazosin

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B3. CHOLINERIC AGONISTS AND ANTAGONISTS

1. The distinctive anatomical and chemical characteristics of the parasympathetic system. 2. The visceral organs that are innervated by the parasympathetic system and the functional responses of the organs to parasympathetic activation. 3. The main structural and functional differences between nicotinic and muscarinic receptors, their mechanisms of action, and their location in the body. 4. The differences between parasympathetic and nicotinic effects in the body. 5. The mechanisms behind directly and indirectly acting cholinergic agonists. 6. The differences in the pharmacological activity of key quaternary nitrogen analogs of choline. 7.The mechanism by which pilocarpine exerts it therapeutic effect in the treatment of glaucoma 8. The two different types of cholinesterase in the body, their location, and their mechanism of action. 9. The key representative reversible cholinesterase inhibitors, their clinical applications, and pharmacological effects. 10. The mechanism of action of the irreversible cholinesterase inhibitors, and the reason behind the success of 2-PAM as an antidote to irreversible cholinesterase inhibition. 11. The toxic pharmacologic effects caused by exposure to organophosphates and its pharmacological treatment 12. The major clinical applications for atropinic agents 13. The dose-dependent pharmacological effects of atropine. 14. The symptoms of acute atropine poisoning, and its treatment.

Relevant Drugs A. Nicotinic agonists Nicotine Succinylcholine

B. Muscarinic Agonists Quaternary Nitrogen analogs of Choline Acteylcholine Methacholine Carbachol Bethanechol

C. Naturally occurring Tertiary Amines Muscarine Pilocarpine

D. Cholinesterase inhibitors Reversible

Neostigmine Edrophonium Physostigmine Donepezil

Irriversible Pralidoximine (2-PAM) Echothiophate

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E. Muscarinic Antagonists Atropine Scopolamine Glycopyrrolate

B4. NEUROMUSCULAR RELAXANTS

1. The mechanisms by which skeletal muscle nicotinic receptor activation stimulates skeletal muscle contraction including the agonists, receptors, and post-synaptic signaling mechanisms that initiate contraction. 2. The difference in mechanism of action between depolarizing and non-depolarizing neuromuscular blockers 3. The major pharmacokinetic features of the two classes of neuromuscular blockers. 4. How cholinesterase inhibition affects the paralysis produced by depolarizing and nondepolarizing neuromuscular blockers. 5. The mechanisms by which the action of neuromuscular blockers are terminated and how these mechanisms are exploited clinically. 6. The major characteristics of non-depolarizing or depolarizing neuromuscular blockers that make them suitable for specific clinical uses 7. The prominent side effects of each class of skeletal muscle relaxant. 8. The antidote for either class of neuromuscular blockers. 9. The characteristics of phase I and phase II block with depolarizing neuromuscular blockers and why phase II should be avoided. 10. The characteristics of the non-depolarizing neuromuscular blockers pancuronium, rocuronium, mivacuronium and vecuronium and why these characteristics make a given agent preferable over another for use in the long-term ventilation/intubation of either a healthy patient or patient with renal failure. 11. The mechanisms by which baclofen and benzodiazepines alter somatic motor neuron excitation. 12. The mode of administration and major side effects of baclofen and benzodiazepines when used as neuromuscular relaxants. 13. The mechanisms by which tizanidine and dantrolene reduce muscle spasticity and recognize the major side effects of both drugs. 14. The important alternative use of dantrolene in clinical practice.

Relevant Drugs A. Non-depolarizing blocking drugs-competitive antagonists Pancuronium D-tubocurarine Vecuronium Rocuronium Mivacuronium

B. Deploarizing blocking durgs-Agonists Succinylcholine

C. Spasmolytic drugs Baclofen Benzodiazepines (e.g. Diazepam, Clonazepam) Tizanidine Dantrolene

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C. ANESTHETICS AND ANALGESICS

C1. LOCAL ANESTHETICS

1. The mechanisms by which local anesthetics block nerve conduction. 2. An understanding of how the physiochemical properties of local anesthetics influence the pharmacodynamics and pharmacokinetics of these drugs. 3. What undesirable side effects may occur with the use of local anesthetics and why these side effects happen. 4. The unique characteristics and the common clinical use for each prototypical local anesthetic. 5. The common uses of the local anesthetics with particular emphasis on spinal and epidural anesthesia. 6. The most commonly caused severe complications of local anesthetics when they are systemically absorbed or injected intravenously.

Relevant Drugs A. Esters: Procaine Cocaine Tetracaine Benzocaine

B. Amides: Lidocaine Mepivacaine Bupivacaine L-Bupivacaine Ropivacaine

C2. GENERAL ANESTHETICS

1. The definition of general anesthesia and how it can be achieved. 2. A working understanding of the pharmacokinetics for inhalational anesthetics. 3. The various stages of anesthesia. 4. How the blood:gas coefficient influences the onset of action (and termination of anesthesia) for inhaled anesthetics. 5. How the ventilation rate and pulmonary blood flow influence the onset of action for inhalation anesthetics. 6. How blood flow to a tissue influences the tension of an anesthetics gas in that tissue. 7. The definition of minimum alveolar concentration (MAC) and what information it provides about a volatile anesthetic. 8. The pharmacokinetic properties of the ultrashort-acting hypnotics and how these properties make this class of drugs popular general anesthetic agents. 9. The advantages and disadvantages for clinically used inhaled and intravenously administered general anesthetics. When they should be used and when they are contraindicated. 10. The concept that inhalational and intravenous anesthetics cause varying degrees of respiratory depression with an exception being ketamine.

Relevant Drugs A. Halogenated Hydrocarbons:

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